Lung Cancer

Working night shifts has been associated with an increased risk for certain cancers, as well as other health disorders. Indeed, the World Health Organization’s International Agency for Research on Cancer (IARC) has classified night shift work as “probably carcinogenic to humans.”

But why night shift should elevate the risk for cancer has been unclear.

A new study shows that a simulated night shift schedule significantly altered the normal circadian rhythmicity of genes that are involved in cancer hallmark pathways. It also found that this circadian misalignment caused circadian dysregulation of genes involved in key DNA repair pathways.

“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s biological sciences division in Richland, Wash.

The study was published online in the Journal of Pineal Research.
 

Study conducted among volunteers 

The study was carried out among healthy volunteers who were subjected to simulated night shift or day shift schedules.

The cohort comprised 14 adults between the ages of 22 and 34 years who had normal nighttime sleep schedules. They were randomly assigned (seven in each group) to a simulated day shift schedule that involved 3 days of daytime wakefulness (6 a.m.-10 p.m.), or a simulated night shift schedule involving 3 days of nighttime wakefulness (6 p.m.-10 a.m.).

After the 3 days of simulated shift work, all participants were then kept in a constant routine protocol (used to study humans’ internally generated biological rhythms independent of any external influences). As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under laboratory conditions with constant light exposure and room temperature and evenly distributed food intake (hourly isocaloric snacks).

Blood samples were collected at 3-hour intervals and used for leukocyte transcriptome analysis and DNA damage assessment.

The authors found that the circadian expression of canonical clock genes was substantially altered by the simulated night shift schedule vs. the day shift schedule. Four genes (CRY1, CRY2, PER2, and NR1D2) lost their normal day-shift rhythmicity following the night shift schedule, and NPAS2 gene expression was not rhythmic during the day shift but exhibited circadian rhythmicity in the simulated night shift condition. Three other genes (NR1D1, PER3, and DBP) were significantly rhythmic during both shifts.

The team also looked at the effect of night shift on circadian rhythmicity in cancer hallmark genes, using a panel of 726 genes. The analysis showed that:

• 257 (35.4%) were rhythmic after at least one of the two simulated shift work conditions.
• 113 (15.6%) were rhythmic in day shift only.
• 96 (13.2%) were rhythmic during night shift only.
• 48 (6.6%) were rhythmic during both shifts.

A subset of 10 (1.4%) genes exhibited a significant phase advance (3.7 to 8.3 hours) or phase delay (2.8 to 7.0 hours) during the night shift vs. the day shift.

Thus, the authors concluded, shift work caused significant disturbances in the rhythmicity of gene expression in cancer hallmark pathways.

Findings also showed that night shift work increases endogenous and exogenous DNA damage. Endogenous DNA damage was generally higher after the night shift compared to the day shift, and across the 24-hour constant routine the percentage of cells with BRCA1 and g H2AX foci was significantly higher for night shift.
 

Next steps

The team said that the next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk for cancer.

If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes, they suggested.  

“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” co-senior author Hans Van Dongen, PhD, a professor at Washington State University in Pullman and director of the WSU Sleep and Performance Research Center, Spokane, said in a statement. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”

The study was supported by start-up funds from Washington State University and a Center for Human Health and the Environment grant from North Carolina State University, and in part by the United States Army Medical Research and Development Command, the National Institutes of Health, CDMRP (Congressionally Directed Medical Research Programs) Peer Reviewed Cancer Research Program award, and the BRAVE investment.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Working night shifts has been associated with an increased risk for certain cancers, as well as other health disorders. Indeed, the World Health Organization’s International Agency for Research on Cancer (IARC) has classified night shift work as “probably carcinogenic to humans.”

But why night shift should elevate the risk for cancer has been unclear.

A new study shows that a simulated night shift schedule significantly altered the normal circadian rhythmicity of genes that are involved in cancer hallmark pathways. It also found that this circadian misalignment caused circadian dysregulation of genes involved in key DNA repair pathways.

“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s biological sciences division in Richland, Wash.

The study was published online in the Journal of Pineal Research.
 

Study conducted among volunteers 

The study was carried out among healthy volunteers who were subjected to simulated night shift or day shift schedules.

The cohort comprised 14 adults between the ages of 22 and 34 years who had normal nighttime sleep schedules. They were randomly assigned (seven in each group) to a simulated day shift schedule that involved 3 days of daytime wakefulness (6 a.m.-10 p.m.), or a simulated night shift schedule involving 3 days of nighttime wakefulness (6 p.m.-10 a.m.).

After the 3 days of simulated shift work, all participants were then kept in a constant routine protocol (used to study humans’ internally generated biological rhythms independent of any external influences). As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under laboratory conditions with constant light exposure and room temperature and evenly distributed food intake (hourly isocaloric snacks).

Blood samples were collected at 3-hour intervals and used for leukocyte transcriptome analysis and DNA damage assessment.

The authors found that the circadian expression of canonical clock genes was substantially altered by the simulated night shift schedule vs. the day shift schedule. Four genes (CRY1, CRY2, PER2, and NR1D2) lost their normal day-shift rhythmicity following the night shift schedule, and NPAS2 gene expression was not rhythmic during the day shift but exhibited circadian rhythmicity in the simulated night shift condition. Three other genes (NR1D1, PER3, and DBP) were significantly rhythmic during both shifts.

The team also looked at the effect of night shift on circadian rhythmicity in cancer hallmark genes, using a panel of 726 genes. The analysis showed that:

• 257 (35.4%) were rhythmic after at least one of the two simulated shift work conditions.
• 113 (15.6%) were rhythmic in day shift only.
• 96 (13.2%) were rhythmic during night shift only.
• 48 (6.6%) were rhythmic during both shifts.

A subset of 10 (1.4%) genes exhibited a significant phase advance (3.7 to 8.3 hours) or phase delay (2.8 to 7.0 hours) during the night shift vs. the day shift.

Thus, the authors concluded, shift work caused significant disturbances in the rhythmicity of gene expression in cancer hallmark pathways.

Findings also showed that night shift work increases endogenous and exogenous DNA damage. Endogenous DNA damage was generally higher after the night shift compared to the day shift, and across the 24-hour constant routine the percentage of cells with BRCA1 and g H2AX foci was significantly higher for night shift.
 

Next steps

The team said that the next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk for cancer.

If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes, they suggested.  

“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” co-senior author Hans Van Dongen, PhD, a professor at Washington State University in Pullman and director of the WSU Sleep and Performance Research Center, Spokane, said in a statement. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”

The study was supported by start-up funds from Washington State University and a Center for Human Health and the Environment grant from North Carolina State University, and in part by the United States Army Medical Research and Development Command, the National Institutes of Health, CDMRP (Congressionally Directed Medical Research Programs) Peer Reviewed Cancer Research Program award, and the BRAVE investment.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Working night shifts has been associated with an increased risk for certain cancers, as well as other health disorders. Indeed, the World Health Organization’s International Agency for Research on Cancer (IARC) has classified night shift work as “probably carcinogenic to humans.”

But why night shift should elevate the risk for cancer has been unclear.

A new study shows that a simulated night shift schedule significantly altered the normal circadian rhythmicity of genes that are involved in cancer hallmark pathways. It also found that this circadian misalignment caused circadian dysregulation of genes involved in key DNA repair pathways.

“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s biological sciences division in Richland, Wash.

The study was published online in the Journal of Pineal Research.
 

Study conducted among volunteers 

The study was carried out among healthy volunteers who were subjected to simulated night shift or day shift schedules.

The cohort comprised 14 adults between the ages of 22 and 34 years who had normal nighttime sleep schedules. They were randomly assigned (seven in each group) to a simulated day shift schedule that involved 3 days of daytime wakefulness (6 a.m.-10 p.m.), or a simulated night shift schedule involving 3 days of nighttime wakefulness (6 p.m.-10 a.m.).

After the 3 days of simulated shift work, all participants were then kept in a constant routine protocol (used to study humans’ internally generated biological rhythms independent of any external influences). As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under laboratory conditions with constant light exposure and room temperature and evenly distributed food intake (hourly isocaloric snacks).

Blood samples were collected at 3-hour intervals and used for leukocyte transcriptome analysis and DNA damage assessment.

The authors found that the circadian expression of canonical clock genes was substantially altered by the simulated night shift schedule vs. the day shift schedule. Four genes (CRY1, CRY2, PER2, and NR1D2) lost their normal day-shift rhythmicity following the night shift schedule, and NPAS2 gene expression was not rhythmic during the day shift but exhibited circadian rhythmicity in the simulated night shift condition. Three other genes (NR1D1, PER3, and DBP) were significantly rhythmic during both shifts.

The team also looked at the effect of night shift on circadian rhythmicity in cancer hallmark genes, using a panel of 726 genes. The analysis showed that:

• 257 (35.4%) were rhythmic after at least one of the two simulated shift work conditions.
• 113 (15.6%) were rhythmic in day shift only.
• 96 (13.2%) were rhythmic during night shift only.
• 48 (6.6%) were rhythmic during both shifts.

A subset of 10 (1.4%) genes exhibited a significant phase advance (3.7 to 8.3 hours) or phase delay (2.8 to 7.0 hours) during the night shift vs. the day shift.

Thus, the authors concluded, shift work caused significant disturbances in the rhythmicity of gene expression in cancer hallmark pathways.

Findings also showed that night shift work increases endogenous and exogenous DNA damage. Endogenous DNA damage was generally higher after the night shift compared to the day shift, and across the 24-hour constant routine the percentage of cells with BRCA1 and g H2AX foci was significantly higher for night shift.
 

Next steps

The team said that the next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk for cancer.

If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes, they suggested.  

“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” co-senior author Hans Van Dongen, PhD, a professor at Washington State University in Pullman and director of the WSU Sleep and Performance Research Center, Spokane, said in a statement. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”

The study was supported by start-up funds from Washington State University and a Center for Human Health and the Environment grant from North Carolina State University, and in part by the United States Army Medical Research and Development Command, the National Institutes of Health, CDMRP (Congressionally Directed Medical Research Programs) Peer Reviewed Cancer Research Program award, and the BRAVE investment.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

A version of this article first appeared on Medscape.com.

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

A version of this article first appeared on Medscape.com.

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

A version of this article first appeared on Medscape.com.

An increase in the use of hypofractionated radiotherapy for lung cancer has been one of the many consequences of the COVID-19 pandemic, according to initial data from the COVID-RT Lung study.

The U.K.-based study showed that patients with stage I-III lung cancer who were set to undergo radiotherapy with curative intent were more likely to receive fewer fractions at higher doses when treated between April and October 2020. During that period, 19% of patients had their radiotherapy dose or fractionation schedule changed to deviate from standard care.

In addition, 8% of patients who were set to undergo surgery ultimately received radiotherapy instead, presumably to ease pressures on already struggling intensive care services, said Kathryn Banfill, MBChB, of Christie NHS Foundation Trust in Manchester, England.

Dr. Banfill presented results from the COVID-RT Lung study at the European Lung Cancer Virtual Congress 2021 (Abstract 203MO).


 

New guidelines prompt study

When the COVID-19 pandemic began, European and joint European and North American guidelines were issued to try to ensure that lung cancer patients would continue to receive the best possible treatment under the circumstances. This included guidance on how and when to use treatments such as radiotherapy.

One U.K. guideline included recommendations on the use of hypofractionation in the COVID-19 era. The recommendations focused on altering the dosage or length of radiotherapy treatments to try to reduce the number of hospital visits, thereby reducing the risk of exposing patients to SARS-CoV-2.

“The aim of these guidelines is very much to reduce the risk to patients,” Dr. Banfill said. “These patients are often at higher risk of serious COVID-19, both as a result of their cancer and also as a result of many of the coexisting medical conditions that they have, such as COPD [chronic obstructive pulmonary disease],” she explained.

The COVID-RT Lung study was essentially born out of these guidelines. The goals of the study were to see what changes to radiotherapy practice occurred as a result of the guidelines and to assess how the changes have affected patient outcomes.
 

Changes to diagnosis and treatment

COVID-RT Lung is an ongoing, prospective study of patients with biopsy- or imaging-proven stage I–III lung cancer who were referred for, or treated with, radical radiotherapy at one of 26 oncology centers in the United Kingdom between April and October 2020.

Records on 1,117 patients were available for the initial analysis. The patients’ median age was 72 years (range, 38-93 years), and half were women.

The records showed changes to diagnostic investigations in 14% of patients (n = 160). Changes included not obtaining histology (4.6%, n = 51), not conducting nodal sampling (3.1%, n = 35), not performing pulmonary function tests (1.8%, n = 20), not conducting brain imaging (2.9%, n = 32), not performing PET/CT scans or having out-of-date scans (4.2%, n = 47), and delays in diagnosis (0.6%, n = 7).

Changes to treatment – deviations from standard care – occurred in 37% of patients (n = 415). This included 19% of patients (n = 210) having changes to radiotherapy dose or fractionation schedule, 8% (n = 86) undergoing radiotherapy instead of surgery, and 13% (n = 143) having their chemotherapy omitted or reduced.

The median number of radiotherapy fractions was 15 for patients who had their radiotherapy adjusted and 20 for those who had no treatment amendments.

“Those who had their treatment changed were more likely to have hypofractionated or ultra-hypofractionated radiotherapy,” Dr. Banfill said.

This was particularly true for patients with early-stage disease, she noted, where there was an increase in the percentage of patients getting more than 15 Gy per fraction. Even in stage III disease, there was an increased use of 3–5 Gy per fraction, although “virtually nobody” who had a change in treatment received less than 2 Gy per fraction, Dr. Banfill said.

“The changes are in line with what was reported in international recommendations,” observed Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium, who discussed the findings at the meeting.
 

Few patients had COVID-19

“It was striking to me to see that so few patients developed COVID-19 prior to radiotherapy or during radiotherapy,” Dr. Lievens noted. “This is actually something that we’ve also experienced in our setting.”

Indeed, just 15 patients (1%) were diagnosed with COVID-19, 10 of whom were diagnosed before receiving radiotherapy.

Dr. Banfill observed that the COVID-19 diagnosis had been “a reasonable time” before the patients started radiotherapy, and some had been diagnosed with lung cancer as a result of having a chest x-ray for suspected COVID-19.

Of the four patients who were diagnosed during treatment, two had their radiotherapy interrupted as a result.

The low COVID-19 rate is perhaps a result of the protective measures recommended in the United Kingdom, such as advising patients to shield from others, Dr. Banfill said.
 

Are changes to practice likely to hold?

“Part of the reason we actually stopped the data collection in October was that people were starting to go, ‘Well, is this actually a change?’ because they’d been doing it for 6 months,” Dr. Banfill observed during the discussion session.

“It was becoming almost normal for some of these hypofractionated changes. I think there is potential for these to become more embedded going forward,” she said. Data on how these changes might affect patients in the long term is going to be the focus of a future analysis.

“There is ongoing data collection on recurrence and survival and toxicity, which will hopefully provide more information on the outcomes of this patient group,” Dr. Banfill said.

The COVID-RT Lung project is supported by the NIHR Manchester Biomedical Research Centre. Dr. Banfill and Dr. Lievens reported no relevant conflicts of interest.

An increase in the use of hypofractionated radiotherapy for lung cancer has been one of the many consequences of the COVID-19 pandemic, according to initial data from the COVID-RT Lung study.

The U.K.-based study showed that patients with stage I-III lung cancer who were set to undergo radiotherapy with curative intent were more likely to receive fewer fractions at higher doses when treated between April and October 2020. During that period, 19% of patients had their radiotherapy dose or fractionation schedule changed to deviate from standard care.

In addition, 8% of patients who were set to undergo surgery ultimately received radiotherapy instead, presumably to ease pressures on already struggling intensive care services, said Kathryn Banfill, MBChB, of Christie NHS Foundation Trust in Manchester, England.

Dr. Banfill presented results from the COVID-RT Lung study at the European Lung Cancer Virtual Congress 2021 (Abstract 203MO).


 

New guidelines prompt study

When the COVID-19 pandemic began, European and joint European and North American guidelines were issued to try to ensure that lung cancer patients would continue to receive the best possible treatment under the circumstances. This included guidance on how and when to use treatments such as radiotherapy.

One U.K. guideline included recommendations on the use of hypofractionation in the COVID-19 era. The recommendations focused on altering the dosage or length of radiotherapy treatments to try to reduce the number of hospital visits, thereby reducing the risk of exposing patients to SARS-CoV-2.

“The aim of these guidelines is very much to reduce the risk to patients,” Dr. Banfill said. “These patients are often at higher risk of serious COVID-19, both as a result of their cancer and also as a result of many of the coexisting medical conditions that they have, such as COPD [chronic obstructive pulmonary disease],” she explained.

The COVID-RT Lung study was essentially born out of these guidelines. The goals of the study were to see what changes to radiotherapy practice occurred as a result of the guidelines and to assess how the changes have affected patient outcomes.
 

Changes to diagnosis and treatment

COVID-RT Lung is an ongoing, prospective study of patients with biopsy- or imaging-proven stage I–III lung cancer who were referred for, or treated with, radical radiotherapy at one of 26 oncology centers in the United Kingdom between April and October 2020.

Records on 1,117 patients were available for the initial analysis. The patients’ median age was 72 years (range, 38-93 years), and half were women.

The records showed changes to diagnostic investigations in 14% of patients (n = 160). Changes included not obtaining histology (4.6%, n = 51), not conducting nodal sampling (3.1%, n = 35), not performing pulmonary function tests (1.8%, n = 20), not conducting brain imaging (2.9%, n = 32), not performing PET/CT scans or having out-of-date scans (4.2%, n = 47), and delays in diagnosis (0.6%, n = 7).

Changes to treatment – deviations from standard care – occurred in 37% of patients (n = 415). This included 19% of patients (n = 210) having changes to radiotherapy dose or fractionation schedule, 8% (n = 86) undergoing radiotherapy instead of surgery, and 13% (n = 143) having their chemotherapy omitted or reduced.

The median number of radiotherapy fractions was 15 for patients who had their radiotherapy adjusted and 20 for those who had no treatment amendments.

“Those who had their treatment changed were more likely to have hypofractionated or ultra-hypofractionated radiotherapy,” Dr. Banfill said.

This was particularly true for patients with early-stage disease, she noted, where there was an increase in the percentage of patients getting more than 15 Gy per fraction. Even in stage III disease, there was an increased use of 3–5 Gy per fraction, although “virtually nobody” who had a change in treatment received less than 2 Gy per fraction, Dr. Banfill said.

“The changes are in line with what was reported in international recommendations,” observed Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium, who discussed the findings at the meeting.
 

Few patients had COVID-19

“It was striking to me to see that so few patients developed COVID-19 prior to radiotherapy or during radiotherapy,” Dr. Lievens noted. “This is actually something that we’ve also experienced in our setting.”

Indeed, just 15 patients (1%) were diagnosed with COVID-19, 10 of whom were diagnosed before receiving radiotherapy.

Dr. Banfill observed that the COVID-19 diagnosis had been “a reasonable time” before the patients started radiotherapy, and some had been diagnosed with lung cancer as a result of having a chest x-ray for suspected COVID-19.

Of the four patients who were diagnosed during treatment, two had their radiotherapy interrupted as a result.

The low COVID-19 rate is perhaps a result of the protective measures recommended in the United Kingdom, such as advising patients to shield from others, Dr. Banfill said.
 

Are changes to practice likely to hold?

“Part of the reason we actually stopped the data collection in October was that people were starting to go, ‘Well, is this actually a change?’ because they’d been doing it for 6 months,” Dr. Banfill observed during the discussion session.

“It was becoming almost normal for some of these hypofractionated changes. I think there is potential for these to become more embedded going forward,” she said. Data on how these changes might affect patients in the long term is going to be the focus of a future analysis.

“There is ongoing data collection on recurrence and survival and toxicity, which will hopefully provide more information on the outcomes of this patient group,” Dr. Banfill said.

The COVID-RT Lung project is supported by the NIHR Manchester Biomedical Research Centre. Dr. Banfill and Dr. Lievens reported no relevant conflicts of interest.

An increase in the use of hypofractionated radiotherapy for lung cancer has been one of the many consequences of the COVID-19 pandemic, according to initial data from the COVID-RT Lung study.

The U.K.-based study showed that patients with stage I-III lung cancer who were set to undergo radiotherapy with curative intent were more likely to receive fewer fractions at higher doses when treated between April and October 2020. During that period, 19% of patients had their radiotherapy dose or fractionation schedule changed to deviate from standard care.

In addition, 8% of patients who were set to undergo surgery ultimately received radiotherapy instead, presumably to ease pressures on already struggling intensive care services, said Kathryn Banfill, MBChB, of Christie NHS Foundation Trust in Manchester, England.

Dr. Banfill presented results from the COVID-RT Lung study at the European Lung Cancer Virtual Congress 2021 (Abstract 203MO).


 

New guidelines prompt study

When the COVID-19 pandemic began, European and joint European and North American guidelines were issued to try to ensure that lung cancer patients would continue to receive the best possible treatment under the circumstances. This included guidance on how and when to use treatments such as radiotherapy.

One U.K. guideline included recommendations on the use of hypofractionation in the COVID-19 era. The recommendations focused on altering the dosage or length of radiotherapy treatments to try to reduce the number of hospital visits, thereby reducing the risk of exposing patients to SARS-CoV-2.

“The aim of these guidelines is very much to reduce the risk to patients,” Dr. Banfill said. “These patients are often at higher risk of serious COVID-19, both as a result of their cancer and also as a result of many of the coexisting medical conditions that they have, such as COPD [chronic obstructive pulmonary disease],” she explained.

The COVID-RT Lung study was essentially born out of these guidelines. The goals of the study were to see what changes to radiotherapy practice occurred as a result of the guidelines and to assess how the changes have affected patient outcomes.
 

Changes to diagnosis and treatment

COVID-RT Lung is an ongoing, prospective study of patients with biopsy- or imaging-proven stage I–III lung cancer who were referred for, or treated with, radical radiotherapy at one of 26 oncology centers in the United Kingdom between April and October 2020.

Records on 1,117 patients were available for the initial analysis. The patients’ median age was 72 years (range, 38-93 years), and half were women.

The records showed changes to diagnostic investigations in 14% of patients (n = 160). Changes included not obtaining histology (4.6%, n = 51), not conducting nodal sampling (3.1%, n = 35), not performing pulmonary function tests (1.8%, n = 20), not conducting brain imaging (2.9%, n = 32), not performing PET/CT scans or having out-of-date scans (4.2%, n = 47), and delays in diagnosis (0.6%, n = 7).

Changes to treatment – deviations from standard care – occurred in 37% of patients (n = 415). This included 19% of patients (n = 210) having changes to radiotherapy dose or fractionation schedule, 8% (n = 86) undergoing radiotherapy instead of surgery, and 13% (n = 143) having their chemotherapy omitted or reduced.

The median number of radiotherapy fractions was 15 for patients who had their radiotherapy adjusted and 20 for those who had no treatment amendments.

“Those who had their treatment changed were more likely to have hypofractionated or ultra-hypofractionated radiotherapy,” Dr. Banfill said.

This was particularly true for patients with early-stage disease, she noted, where there was an increase in the percentage of patients getting more than 15 Gy per fraction. Even in stage III disease, there was an increased use of 3–5 Gy per fraction, although “virtually nobody” who had a change in treatment received less than 2 Gy per fraction, Dr. Banfill said.

“The changes are in line with what was reported in international recommendations,” observed Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium, who discussed the findings at the meeting.
 

Few patients had COVID-19

“It was striking to me to see that so few patients developed COVID-19 prior to radiotherapy or during radiotherapy,” Dr. Lievens noted. “This is actually something that we’ve also experienced in our setting.”

Indeed, just 15 patients (1%) were diagnosed with COVID-19, 10 of whom were diagnosed before receiving radiotherapy.

Dr. Banfill observed that the COVID-19 diagnosis had been “a reasonable time” before the patients started radiotherapy, and some had been diagnosed with lung cancer as a result of having a chest x-ray for suspected COVID-19.

Of the four patients who were diagnosed during treatment, two had their radiotherapy interrupted as a result.

The low COVID-19 rate is perhaps a result of the protective measures recommended in the United Kingdom, such as advising patients to shield from others, Dr. Banfill said.
 

Are changes to practice likely to hold?

“Part of the reason we actually stopped the data collection in October was that people were starting to go, ‘Well, is this actually a change?’ because they’d been doing it for 6 months,” Dr. Banfill observed during the discussion session.

“It was becoming almost normal for some of these hypofractionated changes. I think there is potential for these to become more embedded going forward,” she said. Data on how these changes might affect patients in the long term is going to be the focus of a future analysis.

“There is ongoing data collection on recurrence and survival and toxicity, which will hopefully provide more information on the outcomes of this patient group,” Dr. Banfill said.

The COVID-RT Lung project is supported by the NIHR Manchester Biomedical Research Centre. Dr. Banfill and Dr. Lievens reported no relevant conflicts of interest.

The list of medical comorbidities associated with high risk for severe COVID-19 now includes moderate to severe asthma, diabetes, and substance use disorders, according to the Centers for Disease Control and Prevention.

The CDC’s latest list consists of 17 conditions or groups of related conditions that may increase patients’ risk of developing severe outcomes of COVID-19, the CDC said on a web page intended for the general public.

On a separate page, the CDC defines severe outcomes “as hospitalization, admission to the intensive care unit, intubation or mechanical ventilation, or death.”

Asthma is included in the newly expanded list with other chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis; the list’s heart disease entry covers coronary artery disease, heart failure, cardiomyopathies, and hypertension, the CDC said.

rfranki@mdedge.com

The list of medical comorbidities associated with high risk for severe COVID-19 now includes moderate to severe asthma, diabetes, and substance use disorders, according to the Centers for Disease Control and Prevention.

The CDC’s latest list consists of 17 conditions or groups of related conditions that may increase patients’ risk of developing severe outcomes of COVID-19, the CDC said on a web page intended for the general public.

On a separate page, the CDC defines severe outcomes “as hospitalization, admission to the intensive care unit, intubation or mechanical ventilation, or death.”

Asthma is included in the newly expanded list with other chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis; the list’s heart disease entry covers coronary artery disease, heart failure, cardiomyopathies, and hypertension, the CDC said.

rfranki@mdedge.com

The list of medical comorbidities associated with high risk for severe COVID-19 now includes moderate to severe asthma, diabetes, and substance use disorders, according to the Centers for Disease Control and Prevention.

The CDC’s latest list consists of 17 conditions or groups of related conditions that may increase patients’ risk of developing severe outcomes of COVID-19, the CDC said on a web page intended for the general public.

On a separate page, the CDC defines severe outcomes “as hospitalization, admission to the intensive care unit, intubation or mechanical ventilation, or death.”

Asthma is included in the newly expanded list with other chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis; the list’s heart disease entry covers coronary artery disease, heart failure, cardiomyopathies, and hypertension, the CDC said.

rfranki@mdedge.com

A novel technique for pulmonary nodule ablation is feasible and safe for the treatment of early-stage lung cancers, lung metastases, and highly suspicious lung nodules, according to investigators.

The technique – bronchoscopic transbronchial microwave ablation – had a 100% technical success rate and produced low rates of complications in a single-center study.

“We combined the best of both worlds [for this] technique,” said investigator Joyce Chan, MBBS, of Prince of Wales Hospital in Hong Kong, when describing the method at the European Lung Cancer Virtual Congress 2021 (Abstract 64MO).

Dr. Chan explained that microwave ablation of lung nodules is faster and produces larger ablation zones, compared with radiofrequency ablation, and bronchoscopic ablation is thought to produce fewer pleural-based complications than percutaneous ablation.

Bronchoscopic transbronchial microwave ablation is performed in a hybrid operating room. First, the patient is intubated and anesthetized. Then, electromagnetic navigation bronchoscopy is used to zero in on the lung nodule, which is punctured by a microwave catheter. Cone-beam CT is used to confirm the location of the catheter.

“Next, we connect the system externally to a console, and then we just press the button to microwave it, just like what you do to food,” Dr. Chan explained.

Ablation takes about 10 minutes, and another CT is done to assess success. Ground-glass opacities are seen in the ablated area.
 

Study results

Dr. Chan and colleagues performed a retrospective analysis of 36 patients who underwent bronchoscopic transbronchial microwave ablation between March 2019 and December 2020.

The patients were unfit for or unwilling to undergo surgical resection. They had to have stage 1a lung cancers, isolated lung oligometastases, or radiologically suspicious lesions. The nodules had to be less than 3 cm in size, preferably with a bronchus leading directly to the lesion.

The patients had a mean age of 68 years. Their lesions had a mean maximal diameter of 15.2 mm, and 68% were in the peripheral one-third of the lung.

In all, 44 nodules were treated with bronchoscopic transbronchial microwave ablation. The technical success rate was 100%, although eight nodules required double ablation.

The majority of patients (95%) were discharged within 3 days, with 77% discharged on day 1. Complications included mild pain (15.9%), pneumothorax (9.1%), fever/ablation reaction (4.5%), self-limiting hemoptysis (2.3%), and bronchopleural fistula (2.3%).

The ablation zone volume decreased “rapidly” in the first 6-9 months, then leveled off, Dr. Chan noted.

In the 16 nodules with 1 year of follow-up, there were 2 complete responses, 13 partial responses, and no progressions.

It’s too soon to know if the recurrence rate will be lower than the up to 30% recurrence rate with percutaneous microwave ablation, and it’s too soon to know if, without transpleural puncture, the risk of tumor seeding is lower, Dr. Chan said.

“This presentation ... is extremely important,” said invited discussant John Edwards, MBChB, PhD, of Sheffield (England) Teaching Hospitals National Health Service Foundation Trust. “There is a great novelty value in the combination. The complications and the radiologic response rates were quite acceptable.”

The research was funded by the University Grants Committee in Hong Kong. Dr. Chan reported having no disclosures. Her colleagues disclosed relationships with Medtronic, Siemens Healthineers, and Johnson & Johnson. Dr. Edwards disclosed relationships with AstraZeneca, Zimmer Biomet, Stryker Leibinger, Pacific Biosciences, BioNano Genomics, Argenx, and Moderna.

aotto@mdedge.com

A novel technique for pulmonary nodule ablation is feasible and safe for the treatment of early-stage lung cancers, lung metastases, and highly suspicious lung nodules, according to investigators.

The technique – bronchoscopic transbronchial microwave ablation – had a 100% technical success rate and produced low rates of complications in a single-center study.

“We combined the best of both worlds [for this] technique,” said investigator Joyce Chan, MBBS, of Prince of Wales Hospital in Hong Kong, when describing the method at the European Lung Cancer Virtual Congress 2021 (Abstract 64MO).

Dr. Chan explained that microwave ablation of lung nodules is faster and produces larger ablation zones, compared with radiofrequency ablation, and bronchoscopic ablation is thought to produce fewer pleural-based complications than percutaneous ablation.

Bronchoscopic transbronchial microwave ablation is performed in a hybrid operating room. First, the patient is intubated and anesthetized. Then, electromagnetic navigation bronchoscopy is used to zero in on the lung nodule, which is punctured by a microwave catheter. Cone-beam CT is used to confirm the location of the catheter.

“Next, we connect the system externally to a console, and then we just press the button to microwave it, just like what you do to food,” Dr. Chan explained.

Ablation takes about 10 minutes, and another CT is done to assess success. Ground-glass opacities are seen in the ablated area.
 

Study results

Dr. Chan and colleagues performed a retrospective analysis of 36 patients who underwent bronchoscopic transbronchial microwave ablation between March 2019 and December 2020.

The patients were unfit for or unwilling to undergo surgical resection. They had to have stage 1a lung cancers, isolated lung oligometastases, or radiologically suspicious lesions. The nodules had to be less than 3 cm in size, preferably with a bronchus leading directly to the lesion.

The patients had a mean age of 68 years. Their lesions had a mean maximal diameter of 15.2 mm, and 68% were in the peripheral one-third of the lung.

In all, 44 nodules were treated with bronchoscopic transbronchial microwave ablation. The technical success rate was 100%, although eight nodules required double ablation.

The majority of patients (95%) were discharged within 3 days, with 77% discharged on day 1. Complications included mild pain (15.9%), pneumothorax (9.1%), fever/ablation reaction (4.5%), self-limiting hemoptysis (2.3%), and bronchopleural fistula (2.3%).

The ablation zone volume decreased “rapidly” in the first 6-9 months, then leveled off, Dr. Chan noted.

In the 16 nodules with 1 year of follow-up, there were 2 complete responses, 13 partial responses, and no progressions.

It’s too soon to know if the recurrence rate will be lower than the up to 30% recurrence rate with percutaneous microwave ablation, and it’s too soon to know if, without transpleural puncture, the risk of tumor seeding is lower, Dr. Chan said.

“This presentation ... is extremely important,” said invited discussant John Edwards, MBChB, PhD, of Sheffield (England) Teaching Hospitals National Health Service Foundation Trust. “There is a great novelty value in the combination. The complications and the radiologic response rates were quite acceptable.”

The research was funded by the University Grants Committee in Hong Kong. Dr. Chan reported having no disclosures. Her colleagues disclosed relationships with Medtronic, Siemens Healthineers, and Johnson & Johnson. Dr. Edwards disclosed relationships with AstraZeneca, Zimmer Biomet, Stryker Leibinger, Pacific Biosciences, BioNano Genomics, Argenx, and Moderna.

aotto@mdedge.com

A novel technique for pulmonary nodule ablation is feasible and safe for the treatment of early-stage lung cancers, lung metastases, and highly suspicious lung nodules, according to investigators.

The technique – bronchoscopic transbronchial microwave ablation – had a 100% technical success rate and produced low rates of complications in a single-center study.

“We combined the best of both worlds [for this] technique,” said investigator Joyce Chan, MBBS, of Prince of Wales Hospital in Hong Kong, when describing the method at the European Lung Cancer Virtual Congress 2021 (Abstract 64MO).

Dr. Chan explained that microwave ablation of lung nodules is faster and produces larger ablation zones, compared with radiofrequency ablation, and bronchoscopic ablation is thought to produce fewer pleural-based complications than percutaneous ablation.

Bronchoscopic transbronchial microwave ablation is performed in a hybrid operating room. First, the patient is intubated and anesthetized. Then, electromagnetic navigation bronchoscopy is used to zero in on the lung nodule, which is punctured by a microwave catheter. Cone-beam CT is used to confirm the location of the catheter.

“Next, we connect the system externally to a console, and then we just press the button to microwave it, just like what you do to food,” Dr. Chan explained.

Ablation takes about 10 minutes, and another CT is done to assess success. Ground-glass opacities are seen in the ablated area.
 

Study results

Dr. Chan and colleagues performed a retrospective analysis of 36 patients who underwent bronchoscopic transbronchial microwave ablation between March 2019 and December 2020.

The patients were unfit for or unwilling to undergo surgical resection. They had to have stage 1a lung cancers, isolated lung oligometastases, or radiologically suspicious lesions. The nodules had to be less than 3 cm in size, preferably with a bronchus leading directly to the lesion.

The patients had a mean age of 68 years. Their lesions had a mean maximal diameter of 15.2 mm, and 68% were in the peripheral one-third of the lung.

In all, 44 nodules were treated with bronchoscopic transbronchial microwave ablation. The technical success rate was 100%, although eight nodules required double ablation.

The majority of patients (95%) were discharged within 3 days, with 77% discharged on day 1. Complications included mild pain (15.9%), pneumothorax (9.1%), fever/ablation reaction (4.5%), self-limiting hemoptysis (2.3%), and bronchopleural fistula (2.3%).

The ablation zone volume decreased “rapidly” in the first 6-9 months, then leveled off, Dr. Chan noted.

In the 16 nodules with 1 year of follow-up, there were 2 complete responses, 13 partial responses, and no progressions.

It’s too soon to know if the recurrence rate will be lower than the up to 30% recurrence rate with percutaneous microwave ablation, and it’s too soon to know if, without transpleural puncture, the risk of tumor seeding is lower, Dr. Chan said.

“This presentation ... is extremely important,” said invited discussant John Edwards, MBChB, PhD, of Sheffield (England) Teaching Hospitals National Health Service Foundation Trust. “There is a great novelty value in the combination. The complications and the radiologic response rates were quite acceptable.”

The research was funded by the University Grants Committee in Hong Kong. Dr. Chan reported having no disclosures. Her colleagues disclosed relationships with Medtronic, Siemens Healthineers, and Johnson & Johnson. Dr. Edwards disclosed relationships with AstraZeneca, Zimmer Biomet, Stryker Leibinger, Pacific Biosciences, BioNano Genomics, Argenx, and Moderna.

aotto@mdedge.com

Significant survival gains were seen when the immune checkpoint inhibitor camrelizumab was added to standard chemotherapy for the first-line treatment of advanced squamous non–small cell lung cancer (NSCLC) in a phase 3 trial conducted in China.

Results of the CAMEL-sq trial showed a progression-free survival (PFS) advantage of 3.6 months with camrelizumab plus chemotherapy, compared with chemotherapy plus placebo (P < .0001). The median overall survival (OS) was not reached in the camrelizumab arm, but it was significantly better than in the placebo arm (P < .0001).

Camrelizumab plus chemotherapy is already a standard of care in China for patients with advanced nonsquamous NSCLC who are negative for EGFR and ALK mutations, study investigator Caicun Zhou, MD, PhD, said when presenting the CAMEL-sq results at the European Lung Cancer Virtual Congress 2021 (Abstract 96O).

The CAMEL-sq findings now support the combination as a “standard first-line treatment for advanced squamous NSCLC,” said Dr. Zhou of Shanghai Pulmonary Hospital and Tongji University.

“The study has kind of changed our daily practice,” he said. “I do think we will have the label, camrelizumab plus chemo as first-line treatment for squamous [NSCLC] in China, maybe in a couple of months.”

“Camrelizumab will most likely be another brick in the wall for our Chinese patients and colleagues to use for patients with squamous histology, non–small cell lung cancer in addition to pembrolizumab,” said Julie Renee Brahmer, MD, of Johns Hopkins Medicine in Baltimore, who was the invited discussant for the trial.

Dr. Brahmer noted that the PFS hazard ratio in this trial – 0.37 – was “impressive.”
 

Patients and treatment

CAMEL-sq is a phase 3, double-blind, multicenter trial. The 390 patients enrolled had pathologically-confirmed stage IIIB or IV squamous NSCLC, and they had not received any prior treatment.

Patients received four to six cycles of chemotherapy, consisting of carboplatin and paclitaxel given every 3 weeks. Camrelizumab was added to one arm at a dose of 200 mg, and placebo was added to the other.

This was followed by a maintenance phase in which patients remained on active treatment with camrelizumab or placebo for up to 2 years. Patients in the placebo arm could cross over to camrelizumab at progression.

The median age of patients was similar in the camrelizumab and placebo arms (64 years and 62 years, respectively). The majority of study subjects in both arms were men (more than 90%), had a history of smoking (more than 80%), and had stage IV disease (more than 70%).
 

Efficacy and safety

The median PFS was 8.5 months in the camrelizumab arm and 4.9 months in the placebo arm (HR, 0.37; P < .0001). The median OS was not reached in the camrelizumab arm and was 14.5 months in the placebo arm (HR, 0.55, P < .0001).

The survival benefits were observed in spite of a crossover rate of 46.9%, Dr. Zhou noted.

Furthermore, survival benefits were consistent across all the subgroups tested. Regardless of age, sex, performance status, smoking history, disease stage, presence of liver or brain metastases, or PD-L1 expression, there was an apparent advantage of camrelizumab over placebo.

The objective response rate was higher in the camrelizumab arm than in the placebo arm, at 64.8% and 36.7%, respectively (P < .0001).

The clinical response seen with camrelizumab was “robust and durable,” Dr. Zhou said. Indeed, the duration of response was 13.1 months in the camrelizumab arm and 4.4 months in the placebo arm.

Grade 3/4 treatment-related adverse events (AEs) were reported in a similar percentage of camrelizumab- or placebo-treated patients (73.6% and 71.4%, respectively). However, “the majority of treatment-related adverse effects were chemotherapy related,” Dr. Zhou pointed out. This included decreased total white blood cell, neutrophil, red blood cell, and platelet counts as well as alopecia and increased liver enzymes.

Immune-related AEs occurred in 76.7% of patients in the camrelizumab arm and 20.4% of those in the placebo arm.

“The majority of immune-related adverse events were grade 1 or grade 2; easily manageable in our daily practice,” Dr. Zhou noted.
 

Putting CAMEL-sq into perspective

Data from other trials of immunotherapy-chemotherapy combinations in squamous NSCLC have been presented recently but with less impressive results, Dr. Brahmer said.

In one trial – ORIENT-12 – sintilimab was combined with gemcitabine and cisplatin (ESMO 2020, Abstract LBA56). The median PFS, per investigators, was 5.5 months with sintilimab and 4.9 months without it, both of which are lower than the 8.5 months seen with camrelizumab plus chemotherapy in the CAMEL-sq trial.

Another trial is KEYNOTE-407, in which patients received pembrolizumab or placebo plus a carboplatin-paclitaxel (or nab-paclitaxel) regimen. Three-year follow-up data from the trial were presented at ELCC 2021 (Abstract 97O). Continued improvements in second PFS (HR, 0.59) and OS (HR, 0.71) were observed with pembrolizumab-chemotherapy versus placebo-chemotherapy.

“We have to remember the high PD-L1-negative disease rate in the CAMEL-sq study, compared to the KEYNOTE-407 rate,” before stacking the two studies against each other, Dr. Brahmer noted. In KEYNOTE-407, almost 35% of patients had PD-L1 expression of less than 1%, compared with nearly 50% in the CAMEL-sq study.

That aside, “very similar impressive 1-year progression-free survival rates are seen on both studies,” Dr. Brahmer said. “I hope that camrelizumab has continued follow-up so we can see how these patients will do long-term.

“My eyebrows were raised a little bit at the camrelizumab immune-related AE rate of almost 76%, compared to the immune-related AE rate of about 36% in the KEYNOTE-407 study,” Dr. Brahmer said.

She noted, however, that almost two-thirds of the immune-related AEs in CAMEL-sq were due to reactive cutaneous capillary endothelial proliferation, which doesn’t appear to have been previously reported with PD-1 or PD-L1 inhibitors. This is a side effect seen in studies of liver cancer and may be linked to PFS, Dr. Brahmer said.

CAMEL-sq is funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Zhou disclosed honoraria from multiple pharmaceutical companies, including the study sponsor. Two of Dr. Zhou’s coauthors are employees of the company. Dr. Brahmer disclosed relationships with Amgen, Bristol Myers Squibb, Eli Lily, GlaxoSmithKline, Merck, Sanofi, Easi, AstraZeneca, Genentech, Regeneron, and RAPT Therapeutics Inc.

Significant survival gains were seen when the immune checkpoint inhibitor camrelizumab was added to standard chemotherapy for the first-line treatment of advanced squamous non–small cell lung cancer (NSCLC) in a phase 3 trial conducted in China.

Results of the CAMEL-sq trial showed a progression-free survival (PFS) advantage of 3.6 months with camrelizumab plus chemotherapy, compared with chemotherapy plus placebo (P < .0001). The median overall survival (OS) was not reached in the camrelizumab arm, but it was significantly better than in the placebo arm (P < .0001).

Camrelizumab plus chemotherapy is already a standard of care in China for patients with advanced nonsquamous NSCLC who are negative for EGFR and ALK mutations, study investigator Caicun Zhou, MD, PhD, said when presenting the CAMEL-sq results at the European Lung Cancer Virtual Congress 2021 (Abstract 96O).

The CAMEL-sq findings now support the combination as a “standard first-line treatment for advanced squamous NSCLC,” said Dr. Zhou of Shanghai Pulmonary Hospital and Tongji University.

“The study has kind of changed our daily practice,” he said. “I do think we will have the label, camrelizumab plus chemo as first-line treatment for squamous [NSCLC] in China, maybe in a couple of months.”

“Camrelizumab will most likely be another brick in the wall for our Chinese patients and colleagues to use for patients with squamous histology, non–small cell lung cancer in addition to pembrolizumab,” said Julie Renee Brahmer, MD, of Johns Hopkins Medicine in Baltimore, who was the invited discussant for the trial.

Dr. Brahmer noted that the PFS hazard ratio in this trial – 0.37 – was “impressive.”
 

Patients and treatment

CAMEL-sq is a phase 3, double-blind, multicenter trial. The 390 patients enrolled had pathologically-confirmed stage IIIB or IV squamous NSCLC, and they had not received any prior treatment.

Patients received four to six cycles of chemotherapy, consisting of carboplatin and paclitaxel given every 3 weeks. Camrelizumab was added to one arm at a dose of 200 mg, and placebo was added to the other.

This was followed by a maintenance phase in which patients remained on active treatment with camrelizumab or placebo for up to 2 years. Patients in the placebo arm could cross over to camrelizumab at progression.

The median age of patients was similar in the camrelizumab and placebo arms (64 years and 62 years, respectively). The majority of study subjects in both arms were men (more than 90%), had a history of smoking (more than 80%), and had stage IV disease (more than 70%).
 

Efficacy and safety

The median PFS was 8.5 months in the camrelizumab arm and 4.9 months in the placebo arm (HR, 0.37; P < .0001). The median OS was not reached in the camrelizumab arm and was 14.5 months in the placebo arm (HR, 0.55, P < .0001).

The survival benefits were observed in spite of a crossover rate of 46.9%, Dr. Zhou noted.

Furthermore, survival benefits were consistent across all the subgroups tested. Regardless of age, sex, performance status, smoking history, disease stage, presence of liver or brain metastases, or PD-L1 expression, there was an apparent advantage of camrelizumab over placebo.

The objective response rate was higher in the camrelizumab arm than in the placebo arm, at 64.8% and 36.7%, respectively (P < .0001).

The clinical response seen with camrelizumab was “robust and durable,” Dr. Zhou said. Indeed, the duration of response was 13.1 months in the camrelizumab arm and 4.4 months in the placebo arm.

Grade 3/4 treatment-related adverse events (AEs) were reported in a similar percentage of camrelizumab- or placebo-treated patients (73.6% and 71.4%, respectively). However, “the majority of treatment-related adverse effects were chemotherapy related,” Dr. Zhou pointed out. This included decreased total white blood cell, neutrophil, red blood cell, and platelet counts as well as alopecia and increased liver enzymes.

Immune-related AEs occurred in 76.7% of patients in the camrelizumab arm and 20.4% of those in the placebo arm.

“The majority of immune-related adverse events were grade 1 or grade 2; easily manageable in our daily practice,” Dr. Zhou noted.
 

Putting CAMEL-sq into perspective

Data from other trials of immunotherapy-chemotherapy combinations in squamous NSCLC have been presented recently but with less impressive results, Dr. Brahmer said.

In one trial – ORIENT-12 – sintilimab was combined with gemcitabine and cisplatin (ESMO 2020, Abstract LBA56). The median PFS, per investigators, was 5.5 months with sintilimab and 4.9 months without it, both of which are lower than the 8.5 months seen with camrelizumab plus chemotherapy in the CAMEL-sq trial.

Another trial is KEYNOTE-407, in which patients received pembrolizumab or placebo plus a carboplatin-paclitaxel (or nab-paclitaxel) regimen. Three-year follow-up data from the trial were presented at ELCC 2021 (Abstract 97O). Continued improvements in second PFS (HR, 0.59) and OS (HR, 0.71) were observed with pembrolizumab-chemotherapy versus placebo-chemotherapy.

“We have to remember the high PD-L1-negative disease rate in the CAMEL-sq study, compared to the KEYNOTE-407 rate,” before stacking the two studies against each other, Dr. Brahmer noted. In KEYNOTE-407, almost 35% of patients had PD-L1 expression of less than 1%, compared with nearly 50% in the CAMEL-sq study.

That aside, “very similar impressive 1-year progression-free survival rates are seen on both studies,” Dr. Brahmer said. “I hope that camrelizumab has continued follow-up so we can see how these patients will do long-term.

“My eyebrows were raised a little bit at the camrelizumab immune-related AE rate of almost 76%, compared to the immune-related AE rate of about 36% in the KEYNOTE-407 study,” Dr. Brahmer said.

She noted, however, that almost two-thirds of the immune-related AEs in CAMEL-sq were due to reactive cutaneous capillary endothelial proliferation, which doesn’t appear to have been previously reported with PD-1 or PD-L1 inhibitors. This is a side effect seen in studies of liver cancer and may be linked to PFS, Dr. Brahmer said.

CAMEL-sq is funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Zhou disclosed honoraria from multiple pharmaceutical companies, including the study sponsor. Two of Dr. Zhou’s coauthors are employees of the company. Dr. Brahmer disclosed relationships with Amgen, Bristol Myers Squibb, Eli Lily, GlaxoSmithKline, Merck, Sanofi, Easi, AstraZeneca, Genentech, Regeneron, and RAPT Therapeutics Inc.

Significant survival gains were seen when the immune checkpoint inhibitor camrelizumab was added to standard chemotherapy for the first-line treatment of advanced squamous non–small cell lung cancer (NSCLC) in a phase 3 trial conducted in China.

Results of the CAMEL-sq trial showed a progression-free survival (PFS) advantage of 3.6 months with camrelizumab plus chemotherapy, compared with chemotherapy plus placebo (P < .0001). The median overall survival (OS) was not reached in the camrelizumab arm, but it was significantly better than in the placebo arm (P < .0001).

Camrelizumab plus chemotherapy is already a standard of care in China for patients with advanced nonsquamous NSCLC who are negative for EGFR and ALK mutations, study investigator Caicun Zhou, MD, PhD, said when presenting the CAMEL-sq results at the European Lung Cancer Virtual Congress 2021 (Abstract 96O).

The CAMEL-sq findings now support the combination as a “standard first-line treatment for advanced squamous NSCLC,” said Dr. Zhou of Shanghai Pulmonary Hospital and Tongji University.

“The study has kind of changed our daily practice,” he said. “I do think we will have the label, camrelizumab plus chemo as first-line treatment for squamous [NSCLC] in China, maybe in a couple of months.”

“Camrelizumab will most likely be another brick in the wall for our Chinese patients and colleagues to use for patients with squamous histology, non–small cell lung cancer in addition to pembrolizumab,” said Julie Renee Brahmer, MD, of Johns Hopkins Medicine in Baltimore, who was the invited discussant for the trial.

Dr. Brahmer noted that the PFS hazard ratio in this trial – 0.37 – was “impressive.”
 

Patients and treatment

CAMEL-sq is a phase 3, double-blind, multicenter trial. The 390 patients enrolled had pathologically-confirmed stage IIIB or IV squamous NSCLC, and they had not received any prior treatment.

Patients received four to six cycles of chemotherapy, consisting of carboplatin and paclitaxel given every 3 weeks. Camrelizumab was added to one arm at a dose of 200 mg, and placebo was added to the other.

This was followed by a maintenance phase in which patients remained on active treatment with camrelizumab or placebo for up to 2 years. Patients in the placebo arm could cross over to camrelizumab at progression.

The median age of patients was similar in the camrelizumab and placebo arms (64 years and 62 years, respectively). The majority of study subjects in both arms were men (more than 90%), had a history of smoking (more than 80%), and had stage IV disease (more than 70%).
 

Efficacy and safety

The median PFS was 8.5 months in the camrelizumab arm and 4.9 months in the placebo arm (HR, 0.37; P < .0001). The median OS was not reached in the camrelizumab arm and was 14.5 months in the placebo arm (HR, 0.55, P < .0001).

The survival benefits were observed in spite of a crossover rate of 46.9%, Dr. Zhou noted.

Furthermore, survival benefits were consistent across all the subgroups tested. Regardless of age, sex, performance status, smoking history, disease stage, presence of liver or brain metastases, or PD-L1 expression, there was an apparent advantage of camrelizumab over placebo.

The objective response rate was higher in the camrelizumab arm than in the placebo arm, at 64.8% and 36.7%, respectively (P < .0001).

The clinical response seen with camrelizumab was “robust and durable,” Dr. Zhou said. Indeed, the duration of response was 13.1 months in the camrelizumab arm and 4.4 months in the placebo arm.

Grade 3/4 treatment-related adverse events (AEs) were reported in a similar percentage of camrelizumab- or placebo-treated patients (73.6% and 71.4%, respectively). However, “the majority of treatment-related adverse effects were chemotherapy related,” Dr. Zhou pointed out. This included decreased total white blood cell, neutrophil, red blood cell, and platelet counts as well as alopecia and increased liver enzymes.

Immune-related AEs occurred in 76.7% of patients in the camrelizumab arm and 20.4% of those in the placebo arm.

“The majority of immune-related adverse events were grade 1 or grade 2; easily manageable in our daily practice,” Dr. Zhou noted.
 

Putting CAMEL-sq into perspective

Data from other trials of immunotherapy-chemotherapy combinations in squamous NSCLC have been presented recently but with less impressive results, Dr. Brahmer said.

In one trial – ORIENT-12 – sintilimab was combined with gemcitabine and cisplatin (ESMO 2020, Abstract LBA56). The median PFS, per investigators, was 5.5 months with sintilimab and 4.9 months without it, both of which are lower than the 8.5 months seen with camrelizumab plus chemotherapy in the CAMEL-sq trial.

Another trial is KEYNOTE-407, in which patients received pembrolizumab or placebo plus a carboplatin-paclitaxel (or nab-paclitaxel) regimen. Three-year follow-up data from the trial were presented at ELCC 2021 (Abstract 97O). Continued improvements in second PFS (HR, 0.59) and OS (HR, 0.71) were observed with pembrolizumab-chemotherapy versus placebo-chemotherapy.

“We have to remember the high PD-L1-negative disease rate in the CAMEL-sq study, compared to the KEYNOTE-407 rate,” before stacking the two studies against each other, Dr. Brahmer noted. In KEYNOTE-407, almost 35% of patients had PD-L1 expression of less than 1%, compared with nearly 50% in the CAMEL-sq study.

That aside, “very similar impressive 1-year progression-free survival rates are seen on both studies,” Dr. Brahmer said. “I hope that camrelizumab has continued follow-up so we can see how these patients will do long-term.

“My eyebrows were raised a little bit at the camrelizumab immune-related AE rate of almost 76%, compared to the immune-related AE rate of about 36% in the KEYNOTE-407 study,” Dr. Brahmer said.

She noted, however, that almost two-thirds of the immune-related AEs in CAMEL-sq were due to reactive cutaneous capillary endothelial proliferation, which doesn’t appear to have been previously reported with PD-1 or PD-L1 inhibitors. This is a side effect seen in studies of liver cancer and may be linked to PFS, Dr. Brahmer said.

CAMEL-sq is funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Zhou disclosed honoraria from multiple pharmaceutical companies, including the study sponsor. Two of Dr. Zhou’s coauthors are employees of the company. Dr. Brahmer disclosed relationships with Amgen, Bristol Myers Squibb, Eli Lily, GlaxoSmithKline, Merck, Sanofi, Easi, AstraZeneca, Genentech, Regeneron, and RAPT Therapeutics Inc.

Stereotactic body radiotherapy (SBRT) produced high disease control rates but serious toxicity in a retrospective study of patients with ultra-central lung tumors.

Of the 72 patients studied, 15 (21%) experienced grade 3 or higher toxicity and 10 (14%) died of bronchopulmonary hemorrhage.

This doesn’t completely write off the use of SBRT for ultra-central lung tumors, according to Joyce Lodeweges, MD, of University Medical Center (UMC) Utrecht in the Netherlands.

“We have to inform the patient very well that there are some high risks to this treatment,” she said at the European Lung Cancer Virtual Congress 2021 (Abstract 61M0).

Dr. Lodeweges noted that keeping the biologically effective dose of radiation to the main bronchus below a certain threshold (< 90 Gy) could reduce the risk of toxicity significantly, making SBRT a viable option for some patients. In addition, MRI-guided daily adaptation of the radiation treatment to organs at risk may make the treatment safer.
 

Varying definitions, regimens spur debate

SBRT is standard care in peripherally located, stage I non–small cell lung cancer that is inoperable or if the patient refuses surgery, noted study discussant Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium.

“[SBRT] has good local control rates with low toxicity even in patients with COPD or being elderly,” Dr. Lievens said.

“In more moderately central tumors, there is quite some evidence that risk-adapted fractionation schemes can be delivered in a safe way and lead to high local control rates,” she added. “For ultra-central legions, there’s still not a recommendation to treat with SBRT because we see a lot of increased toxicity.”

“For ultra-central tumors, SBRT is still under debate,” agreed Dr. Lodeweges. “This is because of the varying definitions in the literature and the varying fractionation schemes used.”

How the location of tumors is defined is important. Central tumors are those that are at least 2 cm away from the main bronchial tree, whereas ultra-central tumors are those that butt onto it or overlap it.

In Dr. Lodeweges’s study, ultra-central tumors were defined as those with a planning target volume (PTV) abutting or overlapping the main bronchi, trachea, and/or esophagus.
 

Study details

Between 2012 and 2020, there were 72 patients with ultra-central lung tumors treated at UMC Utrecht. Most patients (78%) had a PTV covering the main bronchus, with 21% each having PTVs overlapping the trachea or esophagus.

Patients received a protracted SBRT regimen of 60 Gy given in 12 fractions. The median follow-up was 19 months.

The local failure-free survival rate was 98% at 1 year and 85% at 2 years. Overall survival rates were 77% and 52%, respectively.

Receiving a biologically effective dose of more than 90 Gy to the main bronchus increased the risk of grade 3 or higher toxicity. On the other hand, patient age and tumor histology did not affect the risk of adverse events.

The use of antithrombotic therapy didn’t have any bearing on toxicity either, but it’s a possible risk factor to consider, Dr. Lodeweges said. Peri- or endobronchial tumor location is another consideration.
 

Findings in context

How do the results of the current study sit with other studies of SBRT in non–small cell lung cancer? Dr. Lievens pointed out that overall survival at 2 years was lower in the current trial (52%) than in patients with central tumors treated in the RTOG 0813 trial (68%-73%) or those with peripheral tumors in the CHISEL trial (77%).

There were, of course, different fractions and doses of radiotherapy used in these trials, with lower doses and more fractions in the UMC Utrecht study, and there was higher toxicity when ultra-central lesions were treated.

“Optimized radiotherapy dose fractionation regimens are investigated quite intensively to improve the clinical benefit. This is an important area of research,” Dr. Lievens said.

The high local control rates but serious risk of bronchopulmonary hemorrhage seen in the current study “calls for further investigation of dose/volume parameters in the context of the location of the tumor but also in the context of other treatment modalities,” she added. “Advanced technologies in radiotherapy, which allow better imaging and daily adaptation, such as the MR-Linac, can optimize clinical benefits.”

The study was supported by UMC Utrecht and received no commercial funding. Dr. Lodeweges and Dr. Lievens had no relevant conflicts of interest.

Stereotactic body radiotherapy (SBRT) produced high disease control rates but serious toxicity in a retrospective study of patients with ultra-central lung tumors.

Of the 72 patients studied, 15 (21%) experienced grade 3 or higher toxicity and 10 (14%) died of bronchopulmonary hemorrhage.

This doesn’t completely write off the use of SBRT for ultra-central lung tumors, according to Joyce Lodeweges, MD, of University Medical Center (UMC) Utrecht in the Netherlands.

“We have to inform the patient very well that there are some high risks to this treatment,” she said at the European Lung Cancer Virtual Congress 2021 (Abstract 61M0).

Dr. Lodeweges noted that keeping the biologically effective dose of radiation to the main bronchus below a certain threshold (< 90 Gy) could reduce the risk of toxicity significantly, making SBRT a viable option for some patients. In addition, MRI-guided daily adaptation of the radiation treatment to organs at risk may make the treatment safer.
 

Varying definitions, regimens spur debate

SBRT is standard care in peripherally located, stage I non–small cell lung cancer that is inoperable or if the patient refuses surgery, noted study discussant Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium.

“[SBRT] has good local control rates with low toxicity even in patients with COPD or being elderly,” Dr. Lievens said.

“In more moderately central tumors, there is quite some evidence that risk-adapted fractionation schemes can be delivered in a safe way and lead to high local control rates,” she added. “For ultra-central legions, there’s still not a recommendation to treat with SBRT because we see a lot of increased toxicity.”

“For ultra-central tumors, SBRT is still under debate,” agreed Dr. Lodeweges. “This is because of the varying definitions in the literature and the varying fractionation schemes used.”

How the location of tumors is defined is important. Central tumors are those that are at least 2 cm away from the main bronchial tree, whereas ultra-central tumors are those that butt onto it or overlap it.

In Dr. Lodeweges’s study, ultra-central tumors were defined as those with a planning target volume (PTV) abutting or overlapping the main bronchi, trachea, and/or esophagus.
 

Study details

Between 2012 and 2020, there were 72 patients with ultra-central lung tumors treated at UMC Utrecht. Most patients (78%) had a PTV covering the main bronchus, with 21% each having PTVs overlapping the trachea or esophagus.

Patients received a protracted SBRT regimen of 60 Gy given in 12 fractions. The median follow-up was 19 months.

The local failure-free survival rate was 98% at 1 year and 85% at 2 years. Overall survival rates were 77% and 52%, respectively.

Receiving a biologically effective dose of more than 90 Gy to the main bronchus increased the risk of grade 3 or higher toxicity. On the other hand, patient age and tumor histology did not affect the risk of adverse events.

The use of antithrombotic therapy didn’t have any bearing on toxicity either, but it’s a possible risk factor to consider, Dr. Lodeweges said. Peri- or endobronchial tumor location is another consideration.
 

Findings in context

How do the results of the current study sit with other studies of SBRT in non–small cell lung cancer? Dr. Lievens pointed out that overall survival at 2 years was lower in the current trial (52%) than in patients with central tumors treated in the RTOG 0813 trial (68%-73%) or those with peripheral tumors in the CHISEL trial (77%).

There were, of course, different fractions and doses of radiotherapy used in these trials, with lower doses and more fractions in the UMC Utrecht study, and there was higher toxicity when ultra-central lesions were treated.

“Optimized radiotherapy dose fractionation regimens are investigated quite intensively to improve the clinical benefit. This is an important area of research,” Dr. Lievens said.

The high local control rates but serious risk of bronchopulmonary hemorrhage seen in the current study “calls for further investigation of dose/volume parameters in the context of the location of the tumor but also in the context of other treatment modalities,” she added. “Advanced technologies in radiotherapy, which allow better imaging and daily adaptation, such as the MR-Linac, can optimize clinical benefits.”

The study was supported by UMC Utrecht and received no commercial funding. Dr. Lodeweges and Dr. Lievens had no relevant conflicts of interest.

Stereotactic body radiotherapy (SBRT) produced high disease control rates but serious toxicity in a retrospective study of patients with ultra-central lung tumors.

Of the 72 patients studied, 15 (21%) experienced grade 3 or higher toxicity and 10 (14%) died of bronchopulmonary hemorrhage.

This doesn’t completely write off the use of SBRT for ultra-central lung tumors, according to Joyce Lodeweges, MD, of University Medical Center (UMC) Utrecht in the Netherlands.

“We have to inform the patient very well that there are some high risks to this treatment,” she said at the European Lung Cancer Virtual Congress 2021 (Abstract 61M0).

Dr. Lodeweges noted that keeping the biologically effective dose of radiation to the main bronchus below a certain threshold (< 90 Gy) could reduce the risk of toxicity significantly, making SBRT a viable option for some patients. In addition, MRI-guided daily adaptation of the radiation treatment to organs at risk may make the treatment safer.
 

Varying definitions, regimens spur debate

SBRT is standard care in peripherally located, stage I non–small cell lung cancer that is inoperable or if the patient refuses surgery, noted study discussant Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium.

“[SBRT] has good local control rates with low toxicity even in patients with COPD or being elderly,” Dr. Lievens said.

“In more moderately central tumors, there is quite some evidence that risk-adapted fractionation schemes can be delivered in a safe way and lead to high local control rates,” she added. “For ultra-central legions, there’s still not a recommendation to treat with SBRT because we see a lot of increased toxicity.”

“For ultra-central tumors, SBRT is still under debate,” agreed Dr. Lodeweges. “This is because of the varying definitions in the literature and the varying fractionation schemes used.”

How the location of tumors is defined is important. Central tumors are those that are at least 2 cm away from the main bronchial tree, whereas ultra-central tumors are those that butt onto it or overlap it.

In Dr. Lodeweges’s study, ultra-central tumors were defined as those with a planning target volume (PTV) abutting or overlapping the main bronchi, trachea, and/or esophagus.
 

Study details

Between 2012 and 2020, there were 72 patients with ultra-central lung tumors treated at UMC Utrecht. Most patients (78%) had a PTV covering the main bronchus, with 21% each having PTVs overlapping the trachea or esophagus.

Patients received a protracted SBRT regimen of 60 Gy given in 12 fractions. The median follow-up was 19 months.

The local failure-free survival rate was 98% at 1 year and 85% at 2 years. Overall survival rates were 77% and 52%, respectively.

Receiving a biologically effective dose of more than 90 Gy to the main bronchus increased the risk of grade 3 or higher toxicity. On the other hand, patient age and tumor histology did not affect the risk of adverse events.

The use of antithrombotic therapy didn’t have any bearing on toxicity either, but it’s a possible risk factor to consider, Dr. Lodeweges said. Peri- or endobronchial tumor location is another consideration.
 

Findings in context

How do the results of the current study sit with other studies of SBRT in non–small cell lung cancer? Dr. Lievens pointed out that overall survival at 2 years was lower in the current trial (52%) than in patients with central tumors treated in the RTOG 0813 trial (68%-73%) or those with peripheral tumors in the CHISEL trial (77%).

There were, of course, different fractions and doses of radiotherapy used in these trials, with lower doses and more fractions in the UMC Utrecht study, and there was higher toxicity when ultra-central lesions were treated.

“Optimized radiotherapy dose fractionation regimens are investigated quite intensively to improve the clinical benefit. This is an important area of research,” Dr. Lievens said.

The high local control rates but serious risk of bronchopulmonary hemorrhage seen in the current study “calls for further investigation of dose/volume parameters in the context of the location of the tumor but also in the context of other treatment modalities,” she added. “Advanced technologies in radiotherapy, which allow better imaging and daily adaptation, such as the MR-Linac, can optimize clinical benefits.”

The study was supported by UMC Utrecht and received no commercial funding. Dr. Lodeweges and Dr. Lievens had no relevant conflicts of interest.

The KRAS inhibitor adagrasib produced a high disease control rate in patients with advanced or metastatic non–small cell lung cancer (NSCLC), according to data from the KRYSTAL-1 study.

An objective response rate was seen in 45% of patients, with a further 51% achieving stable disease, for a disease control rate of 96%.

“The vast majority of patients had significant tumor shrinkage,” said study investigator Gregory J. Riely, MD, PhD, when presenting the results at the European Lung Cancer Virtual Congress 2021 (Abstract 990_PR).

Dr. Riely, vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center in New York, noted that just 6 of the 70 patients in this phase 1/2 trial showed evidence of measurable tumor growth.

“This new way of targeting an oncogene may very well represent an evolutionary step forward in the management of lung cancer patients, akin to when we first had EGFR inhibitors,” Alastair Greystoke, MBChB, PhD, said in his discussion of the trial.

Dr. Greystoke, a clinical senior lecturer and honorary consultant in medical oncology at Newcastle (England) University, observed that the availability of KRAS-targeting agents could have a large potential impact on clinical practice. They could add another 14% of patients with NSCLC to the list of those who are eligible for molecularly-targeted therapy.

“It may be that soon, almost half our patients with lung adenocarcinoma will have a potential targetable abnormality,” Dr. Greystoke said.
 

Data confirm KRAS as a therapeutic target

Adagrasib is now the second drug to show promise as an inhibitor of KRAS G12C. In a phase 2 trial, the KRAS inhibitor sotorasib produced a response rate of 37%, a median response duration of 10 months, and a median progression-free survival of 6.8 months in patients with NSCLC.

Data on response duration and progression-free survival are not yet available for adagrasib. However, the duration of response extended past 11 months in four of the six patients who achieved a partial response to adagrasib in the phase 1/1b portion of the KRYSTAL-1 trial.

“What we’ve seen from this data, and data with other agents, is that responses are very heterogeneous,” Dr. Greystoke observed. “A small number of patients do not respond at all. In some patients, responses are short-lived, whilst in other patients, responses are long and still ongoing.”
 

KRYSTAL-1 study design and safety

KRYSTAL-1 is an ongoing phase 1/2 study designed to assess the safety and clinical activity of adagrasib in patients with advanced solid tumors that have a KRAS G12C mutation, including NSCLC.

Dr. Riely reported data on 79 patients with advanced or metastatic NSCLC who had progressed despite being treated with chemotherapy and immunotherapy. Of these, 18 patients had participated in the phase 1/1b dose-escalation and dose-expansion phase of the study, and 61 had participated in the phase 2 portion. Adagrasib was given at a twice-daily dose of 600 mg.

The patients’ median age was 65 years, 85% were White, and 57% were women. Almost all (95%) were current or former smokers, which is unsurprising since the KRAS G12C mutation is rarely seen in never-smokers. Almost all patients had nonsquamous histology (96%) and had received PD-1 or PD-L1 inhibitors (92%).

Treatment-related adverse events of any grade occurred in 85% of patients, and 30% of patients had grade 3-4 events. The most frequent treatment-related grade 3-4 adverse events were fatigue (6%), increased ALT or AST (each 5%), QT prolongation (3%), anemia (2%), nausea (2%), and vomiting (2%).

Two grade 5 adverse events were recorded – a case of pneumonitis in a patient with recurrent pneumonitis and one case of cardiac failure. Adverse events led to discontinuation in 4.5% of patients.
 

Greater effect seen with co-mutation

KRAS is commonly co-mutated, so the investigators performed an exploratory analysis to see if the presence of other mutations – STK11, KEAP1, and TP53 – might affect the results of adagrasib.

A greater objective response rate was seen in patients with the STK11 mutation than in those without it (64% and 33%, respectively). STK11 is associated with poorer responses to immune checkpoint inhibitors.

“We hypothesized that adagrasib treatment recruits T cells into the tumor and that T-cell infiltration may reverse STK11-mediated immune suppression,” Dr. Riely said. This theory seemed to be borne out with further analyses, though Dr. Greystoke raised doubts. There was no sign of STK11 mutations having any effect on response rates with adagrasib in preclinical studies.

Patients with KEAP1 as a co-mutation had a lower response rate than that of those without it (36% and 48%, respectively), which is in keeping with what might be expected. KEAP1 is known to be associated to a poor response to chemotherapy and immunotherapy.

“I think this data is very provocative but needs to be confirmed in larger cohorts,” Dr. Greystoke said. It could mean that adagrasib has the potential to turn a “cold tumor, hot,” enabling the use of immunotherapies.

A new cohort has been included in the KRYSTAL-1 study to further evaluate how having both the KRAS G12C and STK11 mutations may affect treatment with adagrasib.

Data could support drug combination

The adagrasib data lend support to the combination of KRAS G12C inhibitors with other molecularly-targeted treatments for NSCLC, Dr. Greystoke said, such as with tyrosine kinase inhibitors or immunotherapies. He noted that high steady-state levels of adagrasib were detected in the blood, and these levels were well above those needed for potential efficacy.

“This gives us confidence that if we do need to drop the dose below the recommended phase 2 dose to allow potential combinations with a small-molecule inhibitor due to overlapping toxicity or overlapping pharmacokinetics, that it is safe to do and shouldn’t [have an] impact on efficacy,” Dr. Greystoke said. “Overall, all this information will help us drive forward the next round of clinical trials of probably a combination of treatments.”

The KRYSTAL-1 study is supported by Mirati Therapeutics, Inc. Dr. Riely disclosed relationships with Mirati Therapeutics, Merck, Novartis, Pfizer, Takeda, and Roche. Dr. Greystoke was not involved in the study but disclosed relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Lilly, Takeda, and Roche.

The KRAS inhibitor adagrasib produced a high disease control rate in patients with advanced or metastatic non–small cell lung cancer (NSCLC), according to data from the KRYSTAL-1 study.

An objective response rate was seen in 45% of patients, with a further 51% achieving stable disease, for a disease control rate of 96%.

“The vast majority of patients had significant tumor shrinkage,” said study investigator Gregory J. Riely, MD, PhD, when presenting the results at the European Lung Cancer Virtual Congress 2021 (Abstract 990_PR).

Dr. Riely, vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center in New York, noted that just 6 of the 70 patients in this phase 1/2 trial showed evidence of measurable tumor growth.

“This new way of targeting an oncogene may very well represent an evolutionary step forward in the management of lung cancer patients, akin to when we first had EGFR inhibitors,” Alastair Greystoke, MBChB, PhD, said in his discussion of the trial.

Dr. Greystoke, a clinical senior lecturer and honorary consultant in medical oncology at Newcastle (England) University, observed that the availability of KRAS-targeting agents could have a large potential impact on clinical practice. They could add another 14% of patients with NSCLC to the list of those who are eligible for molecularly-targeted therapy.

“It may be that soon, almost half our patients with lung adenocarcinoma will have a potential targetable abnormality,” Dr. Greystoke said.
 

Data confirm KRAS as a therapeutic target

Adagrasib is now the second drug to show promise as an inhibitor of KRAS G12C. In a phase 2 trial, the KRAS inhibitor sotorasib produced a response rate of 37%, a median response duration of 10 months, and a median progression-free survival of 6.8 months in patients with NSCLC.

Data on response duration and progression-free survival are not yet available for adagrasib. However, the duration of response extended past 11 months in four of the six patients who achieved a partial response to adagrasib in the phase 1/1b portion of the KRYSTAL-1 trial.

“What we’ve seen from this data, and data with other agents, is that responses are very heterogeneous,” Dr. Greystoke observed. “A small number of patients do not respond at all. In some patients, responses are short-lived, whilst in other patients, responses are long and still ongoing.”
 

KRYSTAL-1 study design and safety

KRYSTAL-1 is an ongoing phase 1/2 study designed to assess the safety and clinical activity of adagrasib in patients with advanced solid tumors that have a KRAS G12C mutation, including NSCLC.

Dr. Riely reported data on 79 patients with advanced or metastatic NSCLC who had progressed despite being treated with chemotherapy and immunotherapy. Of these, 18 patients had participated in the phase 1/1b dose-escalation and dose-expansion phase of the study, and 61 had participated in the phase 2 portion. Adagrasib was given at a twice-daily dose of 600 mg.

The patients’ median age was 65 years, 85% were White, and 57% were women. Almost all (95%) were current or former smokers, which is unsurprising since the KRAS G12C mutation is rarely seen in never-smokers. Almost all patients had nonsquamous histology (96%) and had received PD-1 or PD-L1 inhibitors (92%).

Treatment-related adverse events of any grade occurred in 85% of patients, and 30% of patients had grade 3-4 events. The most frequent treatment-related grade 3-4 adverse events were fatigue (6%), increased ALT or AST (each 5%), QT prolongation (3%), anemia (2%), nausea (2%), and vomiting (2%).

Two grade 5 adverse events were recorded – a case of pneumonitis in a patient with recurrent pneumonitis and one case of cardiac failure. Adverse events led to discontinuation in 4.5% of patients.
 

Greater effect seen with co-mutation

KRAS is commonly co-mutated, so the investigators performed an exploratory analysis to see if the presence of other mutations – STK11, KEAP1, and TP53 – might affect the results of adagrasib.

A greater objective response rate was seen in patients with the STK11 mutation than in those without it (64% and 33%, respectively). STK11 is associated with poorer responses to immune checkpoint inhibitors.

“We hypothesized that adagrasib treatment recruits T cells into the tumor and that T-cell infiltration may reverse STK11-mediated immune suppression,” Dr. Riely said. This theory seemed to be borne out with further analyses, though Dr. Greystoke raised doubts. There was no sign of STK11 mutations having any effect on response rates with adagrasib in preclinical studies.

Patients with KEAP1 as a co-mutation had a lower response rate than that of those without it (36% and 48%, respectively), which is in keeping with what might be expected. KEAP1 is known to be associated to a poor response to chemotherapy and immunotherapy.

“I think this data is very provocative but needs to be confirmed in larger cohorts,” Dr. Greystoke said. It could mean that adagrasib has the potential to turn a “cold tumor, hot,” enabling the use of immunotherapies.

A new cohort has been included in the KRYSTAL-1 study to further evaluate how having both the KRAS G12C and STK11 mutations may affect treatment with adagrasib.

Data could support drug combination

The adagrasib data lend support to the combination of KRAS G12C inhibitors with other molecularly-targeted treatments for NSCLC, Dr. Greystoke said, such as with tyrosine kinase inhibitors or immunotherapies. He noted that high steady-state levels of adagrasib were detected in the blood, and these levels were well above those needed for potential efficacy.

“This gives us confidence that if we do need to drop the dose below the recommended phase 2 dose to allow potential combinations with a small-molecule inhibitor due to overlapping toxicity or overlapping pharmacokinetics, that it is safe to do and shouldn’t [have an] impact on efficacy,” Dr. Greystoke said. “Overall, all this information will help us drive forward the next round of clinical trials of probably a combination of treatments.”

The KRYSTAL-1 study is supported by Mirati Therapeutics, Inc. Dr. Riely disclosed relationships with Mirati Therapeutics, Merck, Novartis, Pfizer, Takeda, and Roche. Dr. Greystoke was not involved in the study but disclosed relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Lilly, Takeda, and Roche.

The KRAS inhibitor adagrasib produced a high disease control rate in patients with advanced or metastatic non–small cell lung cancer (NSCLC), according to data from the KRYSTAL-1 study.

An objective response rate was seen in 45% of patients, with a further 51% achieving stable disease, for a disease control rate of 96%.

“The vast majority of patients had significant tumor shrinkage,” said study investigator Gregory J. Riely, MD, PhD, when presenting the results at the European Lung Cancer Virtual Congress 2021 (Abstract 990_PR).

Dr. Riely, vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center in New York, noted that just 6 of the 70 patients in this phase 1/2 trial showed evidence of measurable tumor growth.

“This new way of targeting an oncogene may very well represent an evolutionary step forward in the management of lung cancer patients, akin to when we first had EGFR inhibitors,” Alastair Greystoke, MBChB, PhD, said in his discussion of the trial.

Dr. Greystoke, a clinical senior lecturer and honorary consultant in medical oncology at Newcastle (England) University, observed that the availability of KRAS-targeting agents could have a large potential impact on clinical practice. They could add another 14% of patients with NSCLC to the list of those who are eligible for molecularly-targeted therapy.

“It may be that soon, almost half our patients with lung adenocarcinoma will have a potential targetable abnormality,” Dr. Greystoke said.
 

Data confirm KRAS as a therapeutic target

Adagrasib is now the second drug to show promise as an inhibitor of KRAS G12C. In a phase 2 trial, the KRAS inhibitor sotorasib produced a response rate of 37%, a median response duration of 10 months, and a median progression-free survival of 6.8 months in patients with NSCLC.

Data on response duration and progression-free survival are not yet available for adagrasib. However, the duration of response extended past 11 months in four of the six patients who achieved a partial response to adagrasib in the phase 1/1b portion of the KRYSTAL-1 trial.

“What we’ve seen from this data, and data with other agents, is that responses are very heterogeneous,” Dr. Greystoke observed. “A small number of patients do not respond at all. In some patients, responses are short-lived, whilst in other patients, responses are long and still ongoing.”
 

KRYSTAL-1 study design and safety

KRYSTAL-1 is an ongoing phase 1/2 study designed to assess the safety and clinical activity of adagrasib in patients with advanced solid tumors that have a KRAS G12C mutation, including NSCLC.

Dr. Riely reported data on 79 patients with advanced or metastatic NSCLC who had progressed despite being treated with chemotherapy and immunotherapy. Of these, 18 patients had participated in the phase 1/1b dose-escalation and dose-expansion phase of the study, and 61 had participated in the phase 2 portion. Adagrasib was given at a twice-daily dose of 600 mg.

The patients’ median age was 65 years, 85% were White, and 57% were women. Almost all (95%) were current or former smokers, which is unsurprising since the KRAS G12C mutation is rarely seen in never-smokers. Almost all patients had nonsquamous histology (96%) and had received PD-1 or PD-L1 inhibitors (92%).

Treatment-related adverse events of any grade occurred in 85% of patients, and 30% of patients had grade 3-4 events. The most frequent treatment-related grade 3-4 adverse events were fatigue (6%), increased ALT or AST (each 5%), QT prolongation (3%), anemia (2%), nausea (2%), and vomiting (2%).

Two grade 5 adverse events were recorded – a case of pneumonitis in a patient with recurrent pneumonitis and one case of cardiac failure. Adverse events led to discontinuation in 4.5% of patients.
 

Greater effect seen with co-mutation

KRAS is commonly co-mutated, so the investigators performed an exploratory analysis to see if the presence of other mutations – STK11, KEAP1, and TP53 – might affect the results of adagrasib.

A greater objective response rate was seen in patients with the STK11 mutation than in those without it (64% and 33%, respectively). STK11 is associated with poorer responses to immune checkpoint inhibitors.

“We hypothesized that adagrasib treatment recruits T cells into the tumor and that T-cell infiltration may reverse STK11-mediated immune suppression,” Dr. Riely said. This theory seemed to be borne out with further analyses, though Dr. Greystoke raised doubts. There was no sign of STK11 mutations having any effect on response rates with adagrasib in preclinical studies.

Patients with KEAP1 as a co-mutation had a lower response rate than that of those without it (36% and 48%, respectively), which is in keeping with what might be expected. KEAP1 is known to be associated to a poor response to chemotherapy and immunotherapy.

“I think this data is very provocative but needs to be confirmed in larger cohorts,” Dr. Greystoke said. It could mean that adagrasib has the potential to turn a “cold tumor, hot,” enabling the use of immunotherapies.

A new cohort has been included in the KRYSTAL-1 study to further evaluate how having both the KRAS G12C and STK11 mutations may affect treatment with adagrasib.

Data could support drug combination

The adagrasib data lend support to the combination of KRAS G12C inhibitors with other molecularly-targeted treatments for NSCLC, Dr. Greystoke said, such as with tyrosine kinase inhibitors or immunotherapies. He noted that high steady-state levels of adagrasib were detected in the blood, and these levels were well above those needed for potential efficacy.

“This gives us confidence that if we do need to drop the dose below the recommended phase 2 dose to allow potential combinations with a small-molecule inhibitor due to overlapping toxicity or overlapping pharmacokinetics, that it is safe to do and shouldn’t [have an] impact on efficacy,” Dr. Greystoke said. “Overall, all this information will help us drive forward the next round of clinical trials of probably a combination of treatments.”

The KRYSTAL-1 study is supported by Mirati Therapeutics, Inc. Dr. Riely disclosed relationships with Mirati Therapeutics, Merck, Novartis, Pfizer, Takeda, and Roche. Dr. Greystoke was not involved in the study but disclosed relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Lilly, Takeda, and Roche.

One year of melatonin, given at 20 mg nightly, after complete resection of non–small cell lung cancer (NSCLC) did not improve disease-free survival (DFS) in a phase 3 trial.

There was a hint of benefit with melatonin among patients with stage III/IV NSCLC. These patients had a hazard reduction of 25% in 5-year DFS. However, the median DFS for patients with advanced disease was the same whether they received melatonin or placebo – 18 months.

In the overall study population, melatonin had no beneficial effects on quality of life, sleep, anxiety, depression, pain, or fatigue, and it did not reduce adverse events from chemotherapy or radiation.

These results were reported in EClinicalMedicine.

“In light of the results, we do not recommend the inclusion of adjuvant melatonin for patients with early-stage NSCLC. Evidence suggests there may be a benefit for those with late-stage disease,” the authors wrote. “However, because of the mixed findings observed, we recommend a follow-up randomized, controlled trial involving a larger population focusing on later-stage resected lung cancer to clarify these results.”

“I would very much like to pursue another controlled study of melatonin specifically in a group of late-stage lung cancer and possibly in other more advanced cancer types,” said lead author Dugald Seely, ND, of the Canadian College of Naturopathic Medicine in Toronto.
 

Study rationale and design

Melatonin has shown promise for treating patients with lung cancer, Dr. Seely and colleagues noted. Melatonin is often recommended by naturopathic doctors following lung cancer surgery, but until now there was no high-level evidence regarding the practice.

For their study, Dr. Seely and colleagues evaluated 709 patients who had undergone NSCLC resection. The patients were randomized to receive placebo (n = 353) or melatonin (n = 356) 1 hour before bedtime for 1 year. A 20-mg melatonin dose was used, which is common in clinical practice and research.

The study arms were well matched, with no “clinically meaningful” differences in demographics, surgery type, cancer type, stage of cancer, or preoperative comorbidities, according to the researchers.

The mean age in both treatment arms was 67 years. Overall, 134 participants received adjuvant chemotherapy (66 melatonin, 68 placebo), and 43 had adjuvant radiation (22 melatonin, 21 placebo).
 

Results

For 2-year DFS, melatonin showed an adjusted relative risk of 1.01 (95% confidence interval, 0.83-1.22; P = .94) versus placebo. The adjusted relative risk in the per-protocol analysis was 1.12 (95% CI, 0.96-1.32; P = .14.)

At 5 years, the median DFS was not reached in either treatment arm. Melatonin showed a hazard ratio of 0.97 (95% CI, 0.86-1.09; P = .84) for 5-year DFS.

Among patients with stage I-II NSCLC, the median DFS was not reached at 5 years in either treatment arm. Among patients with stage III-IV NSCLC, the median DFS was 18 months in both arms.

Melatonin showed a hazard ratio of 0.97 (95% CI, 0.85-1.11; P = .66) in patients with early-stage NSCLC and a hazard reduction of 25% (HR, 0.75; 95% CI, 0.61-0.92; P = .005) in patients with late-stage NSCLC.

For the entire cohort, there were no significant differences between treatment arms in the number, severity, or seriousness of adverse events. Likewise, there were no significant differences between the treatment arms with regard to fatigue, quality of life, or sleep at 1 or 2 years.

Dr. Seely said the most surprising thing about this study was that melatonin didn’t help with sleep.

“Since initiation of the trial, my thinking on the right dose of melatonin to support sleep has changed. Clinically, I see extended-release and, indeed, lower doses to be more effective than 20 mg nightly,” he noted.

Dr. Seely and colleagues also assessed proposed mechanisms for melatonin’s possible benefit in NSCLC but found no effect on natural killer cell cytotoxicity or phenotype and no effect on blood levels of inflammatory cytokines in a substudy of 92 patients.

This research was funded by the Lotte and John Hecht Memorial Foundation and the Gateway for Cancer Research Foundation. The researchers had no relevant disclosures.

aotto@mdedge.com

One year of melatonin, given at 20 mg nightly, after complete resection of non–small cell lung cancer (NSCLC) did not improve disease-free survival (DFS) in a phase 3 trial.

There was a hint of benefit with melatonin among patients with stage III/IV NSCLC. These patients had a hazard reduction of 25% in 5-year DFS. However, the median DFS for patients with advanced disease was the same whether they received melatonin or placebo – 18 months.

In the overall study population, melatonin had no beneficial effects on quality of life, sleep, anxiety, depression, pain, or fatigue, and it did not reduce adverse events from chemotherapy or radiation.

These results were reported in EClinicalMedicine.

“In light of the results, we do not recommend the inclusion of adjuvant melatonin for patients with early-stage NSCLC. Evidence suggests there may be a benefit for those with late-stage disease,” the authors wrote. “However, because of the mixed findings observed, we recommend a follow-up randomized, controlled trial involving a larger population focusing on later-stage resected lung cancer to clarify these results.”

“I would very much like to pursue another controlled study of melatonin specifically in a group of late-stage lung cancer and possibly in other more advanced cancer types,” said lead author Dugald Seely, ND, of the Canadian College of Naturopathic Medicine in Toronto.
 

Study rationale and design

Melatonin has shown promise for treating patients with lung cancer, Dr. Seely and colleagues noted. Melatonin is often recommended by naturopathic doctors following lung cancer surgery, but until now there was no high-level evidence regarding the practice.

For their study, Dr. Seely and colleagues evaluated 709 patients who had undergone NSCLC resection. The patients were randomized to receive placebo (n = 353) or melatonin (n = 356) 1 hour before bedtime for 1 year. A 20-mg melatonin dose was used, which is common in clinical practice and research.

The study arms were well matched, with no “clinically meaningful” differences in demographics, surgery type, cancer type, stage of cancer, or preoperative comorbidities, according to the researchers.

The mean age in both treatment arms was 67 years. Overall, 134 participants received adjuvant chemotherapy (66 melatonin, 68 placebo), and 43 had adjuvant radiation (22 melatonin, 21 placebo).
 

Results

For 2-year DFS, melatonin showed an adjusted relative risk of 1.01 (95% confidence interval, 0.83-1.22; P = .94) versus placebo. The adjusted relative risk in the per-protocol analysis was 1.12 (95% CI, 0.96-1.32; P = .14.)

At 5 years, the median DFS was not reached in either treatment arm. Melatonin showed a hazard ratio of 0.97 (95% CI, 0.86-1.09; P = .84) for 5-year DFS.

Among patients with stage I-II NSCLC, the median DFS was not reached at 5 years in either treatment arm. Among patients with stage III-IV NSCLC, the median DFS was 18 months in both arms.

Melatonin showed a hazard ratio of 0.97 (95% CI, 0.85-1.11; P = .66) in patients with early-stage NSCLC and a hazard reduction of 25% (HR, 0.75; 95% CI, 0.61-0.92; P = .005) in patients with late-stage NSCLC.

For the entire cohort, there were no significant differences between treatment arms in the number, severity, or seriousness of adverse events. Likewise, there were no significant differences between the treatment arms with regard to fatigue, quality of life, or sleep at 1 or 2 years.

Dr. Seely said the most surprising thing about this study was that melatonin didn’t help with sleep.

“Since initiation of the trial, my thinking on the right dose of melatonin to support sleep has changed. Clinically, I see extended-release and, indeed, lower doses to be more effective than 20 mg nightly,” he noted.

Dr. Seely and colleagues also assessed proposed mechanisms for melatonin’s possible benefit in NSCLC but found no effect on natural killer cell cytotoxicity or phenotype and no effect on blood levels of inflammatory cytokines in a substudy of 92 patients.

This research was funded by the Lotte and John Hecht Memorial Foundation and the Gateway for Cancer Research Foundation. The researchers had no relevant disclosures.

aotto@mdedge.com

One year of melatonin, given at 20 mg nightly, after complete resection of non–small cell lung cancer (NSCLC) did not improve disease-free survival (DFS) in a phase 3 trial.

There was a hint of benefit with melatonin among patients with stage III/IV NSCLC. These patients had a hazard reduction of 25% in 5-year DFS. However, the median DFS for patients with advanced disease was the same whether they received melatonin or placebo – 18 months.

In the overall study population, melatonin had no beneficial effects on quality of life, sleep, anxiety, depression, pain, or fatigue, and it did not reduce adverse events from chemotherapy or radiation.

These results were reported in EClinicalMedicine.

“In light of the results, we do not recommend the inclusion of adjuvant melatonin for patients with early-stage NSCLC. Evidence suggests there may be a benefit for those with late-stage disease,” the authors wrote. “However, because of the mixed findings observed, we recommend a follow-up randomized, controlled trial involving a larger population focusing on later-stage resected lung cancer to clarify these results.”

“I would very much like to pursue another controlled study of melatonin specifically in a group of late-stage lung cancer and possibly in other more advanced cancer types,” said lead author Dugald Seely, ND, of the Canadian College of Naturopathic Medicine in Toronto.
 

Study rationale and design

Melatonin has shown promise for treating patients with lung cancer, Dr. Seely and colleagues noted. Melatonin is often recommended by naturopathic doctors following lung cancer surgery, but until now there was no high-level evidence regarding the practice.

For their study, Dr. Seely and colleagues evaluated 709 patients who had undergone NSCLC resection. The patients were randomized to receive placebo (n = 353) or melatonin (n = 356) 1 hour before bedtime for 1 year. A 20-mg melatonin dose was used, which is common in clinical practice and research.

The study arms were well matched, with no “clinically meaningful” differences in demographics, surgery type, cancer type, stage of cancer, or preoperative comorbidities, according to the researchers.

The mean age in both treatment arms was 67 years. Overall, 134 participants received adjuvant chemotherapy (66 melatonin, 68 placebo), and 43 had adjuvant radiation (22 melatonin, 21 placebo).
 

Results

For 2-year DFS, melatonin showed an adjusted relative risk of 1.01 (95% confidence interval, 0.83-1.22; P = .94) versus placebo. The adjusted relative risk in the per-protocol analysis was 1.12 (95% CI, 0.96-1.32; P = .14.)

At 5 years, the median DFS was not reached in either treatment arm. Melatonin showed a hazard ratio of 0.97 (95% CI, 0.86-1.09; P = .84) for 5-year DFS.

Among patients with stage I-II NSCLC, the median DFS was not reached at 5 years in either treatment arm. Among patients with stage III-IV NSCLC, the median DFS was 18 months in both arms.

Melatonin showed a hazard ratio of 0.97 (95% CI, 0.85-1.11; P = .66) in patients with early-stage NSCLC and a hazard reduction of 25% (HR, 0.75; 95% CI, 0.61-0.92; P = .005) in patients with late-stage NSCLC.

For the entire cohort, there were no significant differences between treatment arms in the number, severity, or seriousness of adverse events. Likewise, there were no significant differences between the treatment arms with regard to fatigue, quality of life, or sleep at 1 or 2 years.

Dr. Seely said the most surprising thing about this study was that melatonin didn’t help with sleep.

“Since initiation of the trial, my thinking on the right dose of melatonin to support sleep has changed. Clinically, I see extended-release and, indeed, lower doses to be more effective than 20 mg nightly,” he noted.

Dr. Seely and colleagues also assessed proposed mechanisms for melatonin’s possible benefit in NSCLC but found no effect on natural killer cell cytotoxicity or phenotype and no effect on blood levels of inflammatory cytokines in a substudy of 92 patients.

This research was funded by the Lotte and John Hecht Memorial Foundation and the Gateway for Cancer Research Foundation. The researchers had no relevant disclosures.

aotto@mdedge.com

U.S. regulators are stepping up scrutiny of therapies that were granted an accelerated approval to treat cancers on the basis of surrogate endpoints but have failed to show clinical or survival benefits upon more extensive testing.

At issue are a number of cancer indications for immunotherapies. Four have already been withdrawn (voluntarily by the manufacturer), and six more will be reviewed at an upcoming meeting.

In recent years, the US Food and Drug Administration has granted accelerated approvals to oncology medicines on the basis of evidence that suggests a benefit for patients. Examples of such evidence relate to response rates and estimates of tumor shrinkage. But these approvals are granted on the condition that the manufacturer conducts larger clinical trials that show clinical benefit, including benefit in overall survival.

Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, has argued that the point of these conditional approvals is to find acceptable surrogate markers to allow people with “desperate illnesses” to have access to potentially helpful drugs while work continues to determine the drug’s actual benefit to patients.

Oncologists are now questioning whether the FDA has become too lenient in its approach, Daniel A. Goldstein, MD, a senior physician in medical oncology and internal medicine at the Rabin Medical Center, Petah Tikva, Israel, told this news organization.

“The main two things you want from a cancer drug is to live longer and live a higher quality of life,” said Goldstein. “But these endpoints that they’ve been using over the past few years are not really giving us confidence that these drugs are actually going to help to live longer or better.”

Dr. Pazdur said the FDA will consider withdrawing its accelerated approvals when results of further studies do not confirm expected benefit for patients.

“This is like the pendulum has swung as far as it was going to swing and now is on the backswing,” said Dr. Goldstein, also of the department of health policy and management at the University of North Carolina at Chapel Hill. “You could call this a watershed moment.”

Although there’s near universal interest in allowing people with advanced cancer access to promising medicines, there’s also rising concern about exposing patients needlessly to costly drugs with potentially tough side effects. That may prompt a shift in the standards U.S. regulators apply to cancer medicines, Dr. Goldstein said.
 

Indications withdrawn and under review

In a meeting scheduled for April 27-29, the FDA’s Oncologic Drugs Advisory Committee will review indications granted through the accelerated approval process for three immunotherapies: pembrolizumab (Keytruda), atezolizumab (Tecentriq), and nivolumab (Opdivo).

It is part of an industry-wide evaluation of accelerated approvals for cancer indications in which confirmatory trials did not confirm clinical benefit, the FDA noted.

The process has already led to voluntary withdrawals of four cancer indications by the manufacturers, including one indication each for pembrolizumab, atezolizumab, and nivolumab, and one for durvalumab (Imfinzi).

All of these immunotherapies are approved for numerous cancer indications, and they all remain on the market. It is only the U.S. approvals for particular cancer indications that have been withdrawn.

In the past, olaratumab (Lartruvo) was withdrawn from the market altogether. The FDA granted accelerated approval of the drug for soft tissue sarcoma, but clinical benefit was not confirmed in a phase 3 trial.
 

Issue highlighted by Dr. Prasad and Dr. Gyawali

In recent years, much of the attention on accelerated approvals was spurred by the work of a few researchers, particularly Vinay Prasad, MD, MPH, associate professor in the department of epidemiology and biostatistics, University of California, San Francisco, and Bishal Gyawali, MD, PhD, from Queen’s University Cancer Research Institute, Kingston, Ont. (Both are regular contributors to the oncology section of this news organization.)

Dr. Goldstein made this point in a tweet about the FDA’s announcement of the April ODAC meetings:

“Well done to @oncology_bg and @VPrasadMDMPH among others for highlighting in their papers that the FDA wasn’t properly evaluating accelerated approval drugs.

FDA have listened.

And I thought that the impact of academia was limited!”

Dr. Prasad has made the case for closer scrutiny of accelerated approvals in a number of journal articles and in his 2020 book, “Malignant: How Bad Policy and Bad Evidence Harm People with Cancer,” published by Johns Hopkins University Press.

The book includes highlights of a 2016 article published in Mayo Clinic Proceedings that focused on surrogate endpoints used for FDA approvals. In the article, Dr. Prasad and his coauthor report that they did not find formal analyses of the strength of the surrogate-survival correlation in 14 of 25 cases of accelerated approvals (56%) and in 11 of 30 traditional approvals (37%).

“Our results were concerning. They imply that many surrogates are based on little more than a gut feeling. You might rationalize that and argue a gut feeling is the same as ‘reasonably likely to predict,’ but no reasonable person could think a gut feeling means established,” Dr. Prasad writes in his book. “Our result suggests the FDA is using surrogate endpoints far beyond what may be fair or reasonable.”

Dr. Gyawali has argued that the process by which the FDA assesses cancer drugs for approvals has undergone a profound shift. He has most recently remarked on this in an October 2020 commentary on Medscape.

“Until the recent floodgate of approvals based on response rates from single-arm trials, the majority of cancer therapy decisions were supported by evidence generated from randomized controlled trials (RCTs),” Dr. Gyawali wrote. “The evidence base to support clinical decisions in managing therapeutic side effects has been comparatively sparse.”
 

Accelerated approval to improve access

The FDA has struggled for about 2 decades with questions of where to set the bar on evidence for promising cancer drugs.

The agency’s accelerated approval program for drugs began in 1992. During the first decade, the focus was largely on medicines related to HIV.

In the early 2000s, oncology drugs began to dominate the program.

Dr. Pazdur has presided over the FDA’s marked changes regarding the use of surrogate markers when weighing whether to allow sales of cancer medicines. Formerly a professor at the University of Texas MD Anderson Cancer Center, Houston, Dr. Pazdur joined the FDA as director of the Division of Oncology Drug Products in 1999.

Soon after his appointment, he had to field inquiries from pharmaceutical companies about how much evidence they needed to receive accelerated approvals.

Early on, he publicly expressed impatience about the drugmakers’ approach. “The purpose of accelerated approval was not accelerated drug company profits,” Dr. Padzur said at a 2004 ODAC meeting.

Rather, the point is to allow access to potentially helpful drugs while work continues to determine their actual benefit to patients, he explained.

“It wasn’t a license to do less, less, less, and less to a point now that we may be getting companies that are coming in” intent on determining the minimum evidence the FDA will take, Dr. Pazdur said. “It shouldn’t be what is the lowest. It is what is a sufficient amount to give patients and physicians a real understanding of what their drug will do.”

In a 2016 interview with The New York Times, Dr. Pazdur said that his views on cancer drug approvals have evolved with time. He described himself as being “on a jihad to streamline the review process and get things out the door faster.”

“I have evolved from regulator to regulator-advocate,” Dr. Pazdur told the newspaper.

His attitude reflected his personal experience in losing his wife to ovarian cancer in 2015, as well as shifts in science and law. In 2012, Congress passed a law that gave the FDA new resources to speed medicines for life-threatening diseases to market. In addition, advances in genetics appeared to be making some medications more effective and easier to test, Dr. Pazdur said in The New York Times interview.
 

Withdrawals seen as sign of success

Since the program’s inception, only 6% of accelerated approvals for oncology indications have been withdrawn, the FDA said.

It would be a sign that the program is working if the April meetings lead to further withdrawals of indications that have been granted accelerated approval, Julie R. Gralow, MD, chief medical officer of the American Society of Clinical Oncology, said in an interview with this news organization.

“It shouldn’t be seen as a failure,” Dr. Gralow said.

In her own practice at the Fred Hutchinson Cancer Research Center, Seattle, she has seen the value of emerging therapies for patients fighting advanced cancers. During her 25 years of clinical practice in an academic setting, she has gained access to drugs through single-patient investigative new drug applications.

However, this path is not an option for many patients who undergo treatment in facilities other than academic centers, she commented. She noted that the accelerated approval process is a way to expand access to emerging medicines, but she sees a need for caution in the use of drugs that have been given only this conditional approval. She emphasizes that such drugs may be suitable only for certain patients.

“I would say that, for metastatic patients, patients with incurable disease, we are willing to take some risk,” Dr. Gralow said. “We don’t have other options. They can’t wait the years that it would take to get a drug approved.”

One such patient is David Mitchell, who serves as the consumer representative on ODAC. He told this news organization that he is taking three drugs for multiple myeloma that received accelerated approvals: pomalidomide, bortezomib, and daratumumab.

“I want the FDA to have the option to approve drugs in an accelerated pathway, because as a patient taking three drugs granted accelerated approval, I’m benefiting – I’ve lived the benefit,” Mr. Mitchell said, “and I want other patients to have the opportunity to have that benefit.”

He believes that the FDA’s approach regarding accelerated approvals serves to get potentially beneficial medicines to patients who have few options and also fulfills the FDA’s mandate to protect the public from treatments that have little benefit but can cause harm.

Accelerated approval also offers needed flexibility to drugmakers as they develop more specifically targeted drugs for diseases that affect relatively few people, such as multiple myeloma, he said. “As the targeting of your therapies gets tighter and for smaller groups of patients, you have a harder time following the traditional model,” such as conducting large, double-blind, placebo-controlled trials that may indicate increased overall survival, he said.

“To me, this is the way the FDA intended it to work,” he added. “It’s going to offer the accelerated approval based on a surrogate endpoint for a safe drug, but it’s going to require the confirmatory trial, and if the confirmatory trial fails, it will pull the drug off the market.”

Some medicines that have received accelerated approvals may ultimately be found not to benefit patients, Mr. Mitchell acknowledged. But people in his situation, whose disease has progressed despite treatments, may want to take that risk, he added.


 

Four cancer indications recently withdrawn voluntarily by the manufacturer

• December 2020: Nivolumab for the treatment of patients with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy (Bristol Myers Squibb).
• February 2021: Durvalumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or following platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy (AstraZeneca).
• March 2021: Pembrolizumab for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy (Merck).
• March 2021: Atezolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing atezolizumab chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (Genentech).

Six cancer indications under review at the April 2021 ODAC meeting

• Atezolizumab indicated in combination with protein-bound  for the treatment of adults with unresectable locally advanced or metastatic triple-negative  whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥1% of the tumor area), as determined by an FDA-approved test.
• Atezolizumab indicated for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
• Pembrolizumab indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
• Pembrolizumab indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (Combined Positive Score ≥1), as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
• Pembrolizumab indicated for the treatment of patients with  who have been previously treated with .
• Nivolumab indicated as a single agent for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.

A version of this article first appeared on Medscape.com.

U.S. regulators are stepping up scrutiny of therapies that were granted an accelerated approval to treat cancers on the basis of surrogate endpoints but have failed to show clinical or survival benefits upon more extensive testing.

At issue are a number of cancer indications for immunotherapies. Four have already been withdrawn (voluntarily by the manufacturer), and six more will be reviewed at an upcoming meeting.

In recent years, the US Food and Drug Administration has granted accelerated approvals to oncology medicines on the basis of evidence that suggests a benefit for patients. Examples of such evidence relate to response rates and estimates of tumor shrinkage. But these approvals are granted on the condition that the manufacturer conducts larger clinical trials that show clinical benefit, including benefit in overall survival.

Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, has argued that the point of these conditional approvals is to find acceptable surrogate markers to allow people with “desperate illnesses” to have access to potentially helpful drugs while work continues to determine the drug’s actual benefit to patients.

Oncologists are now questioning whether the FDA has become too lenient in its approach, Daniel A. Goldstein, MD, a senior physician in medical oncology and internal medicine at the Rabin Medical Center, Petah Tikva, Israel, told this news organization.

“The main two things you want from a cancer drug is to live longer and live a higher quality of life,” said Goldstein. “But these endpoints that they’ve been using over the past few years are not really giving us confidence that these drugs are actually going to help to live longer or better.”

Dr. Pazdur said the FDA will consider withdrawing its accelerated approvals when results of further studies do not confirm expected benefit for patients.

“This is like the pendulum has swung as far as it was going to swing and now is on the backswing,” said Dr. Goldstein, also of the department of health policy and management at the University of North Carolina at Chapel Hill. “You could call this a watershed moment.”

Although there’s near universal interest in allowing people with advanced cancer access to promising medicines, there’s also rising concern about exposing patients needlessly to costly drugs with potentially tough side effects. That may prompt a shift in the standards U.S. regulators apply to cancer medicines, Dr. Goldstein said.
 

Indications withdrawn and under review

In a meeting scheduled for April 27-29, the FDA’s Oncologic Drugs Advisory Committee will review indications granted through the accelerated approval process for three immunotherapies: pembrolizumab (Keytruda), atezolizumab (Tecentriq), and nivolumab (Opdivo).

It is part of an industry-wide evaluation of accelerated approvals for cancer indications in which confirmatory trials did not confirm clinical benefit, the FDA noted.

The process has already led to voluntary withdrawals of four cancer indications by the manufacturers, including one indication each for pembrolizumab, atezolizumab, and nivolumab, and one for durvalumab (Imfinzi).

All of these immunotherapies are approved for numerous cancer indications, and they all remain on the market. It is only the U.S. approvals for particular cancer indications that have been withdrawn.

In the past, olaratumab (Lartruvo) was withdrawn from the market altogether. The FDA granted accelerated approval of the drug for soft tissue sarcoma, but clinical benefit was not confirmed in a phase 3 trial.
 

Issue highlighted by Dr. Prasad and Dr. Gyawali

In recent years, much of the attention on accelerated approvals was spurred by the work of a few researchers, particularly Vinay Prasad, MD, MPH, associate professor in the department of epidemiology and biostatistics, University of California, San Francisco, and Bishal Gyawali, MD, PhD, from Queen’s University Cancer Research Institute, Kingston, Ont. (Both are regular contributors to the oncology section of this news organization.)

Dr. Goldstein made this point in a tweet about the FDA’s announcement of the April ODAC meetings:

“Well done to @oncology_bg and @VPrasadMDMPH among others for highlighting in their papers that the FDA wasn’t properly evaluating accelerated approval drugs.

FDA have listened.

And I thought that the impact of academia was limited!”

Dr. Prasad has made the case for closer scrutiny of accelerated approvals in a number of journal articles and in his 2020 book, “Malignant: How Bad Policy and Bad Evidence Harm People with Cancer,” published by Johns Hopkins University Press.

The book includes highlights of a 2016 article published in Mayo Clinic Proceedings that focused on surrogate endpoints used for FDA approvals. In the article, Dr. Prasad and his coauthor report that they did not find formal analyses of the strength of the surrogate-survival correlation in 14 of 25 cases of accelerated approvals (56%) and in 11 of 30 traditional approvals (37%).

“Our results were concerning. They imply that many surrogates are based on little more than a gut feeling. You might rationalize that and argue a gut feeling is the same as ‘reasonably likely to predict,’ but no reasonable person could think a gut feeling means established,” Dr. Prasad writes in his book. “Our result suggests the FDA is using surrogate endpoints far beyond what may be fair or reasonable.”

Dr. Gyawali has argued that the process by which the FDA assesses cancer drugs for approvals has undergone a profound shift. He has most recently remarked on this in an October 2020 commentary on Medscape.

“Until the recent floodgate of approvals based on response rates from single-arm trials, the majority of cancer therapy decisions were supported by evidence generated from randomized controlled trials (RCTs),” Dr. Gyawali wrote. “The evidence base to support clinical decisions in managing therapeutic side effects has been comparatively sparse.”
 

Accelerated approval to improve access

The FDA has struggled for about 2 decades with questions of where to set the bar on evidence for promising cancer drugs.

The agency’s accelerated approval program for drugs began in 1992. During the first decade, the focus was largely on medicines related to HIV.

In the early 2000s, oncology drugs began to dominate the program.

Dr. Pazdur has presided over the FDA’s marked changes regarding the use of surrogate markers when weighing whether to allow sales of cancer medicines. Formerly a professor at the University of Texas MD Anderson Cancer Center, Houston, Dr. Pazdur joined the FDA as director of the Division of Oncology Drug Products in 1999.

Soon after his appointment, he had to field inquiries from pharmaceutical companies about how much evidence they needed to receive accelerated approvals.

Early on, he publicly expressed impatience about the drugmakers’ approach. “The purpose of accelerated approval was not accelerated drug company profits,” Dr. Padzur said at a 2004 ODAC meeting.

Rather, the point is to allow access to potentially helpful drugs while work continues to determine their actual benefit to patients, he explained.

“It wasn’t a license to do less, less, less, and less to a point now that we may be getting companies that are coming in” intent on determining the minimum evidence the FDA will take, Dr. Pazdur said. “It shouldn’t be what is the lowest. It is what is a sufficient amount to give patients and physicians a real understanding of what their drug will do.”

In a 2016 interview with The New York Times, Dr. Pazdur said that his views on cancer drug approvals have evolved with time. He described himself as being “on a jihad to streamline the review process and get things out the door faster.”

“I have evolved from regulator to regulator-advocate,” Dr. Pazdur told the newspaper.

His attitude reflected his personal experience in losing his wife to ovarian cancer in 2015, as well as shifts in science and law. In 2012, Congress passed a law that gave the FDA new resources to speed medicines for life-threatening diseases to market. In addition, advances in genetics appeared to be making some medications more effective and easier to test, Dr. Pazdur said in The New York Times interview.
 

Withdrawals seen as sign of success

Since the program’s inception, only 6% of accelerated approvals for oncology indications have been withdrawn, the FDA said.

It would be a sign that the program is working if the April meetings lead to further withdrawals of indications that have been granted accelerated approval, Julie R. Gralow, MD, chief medical officer of the American Society of Clinical Oncology, said in an interview with this news organization.

“It shouldn’t be seen as a failure,” Dr. Gralow said.

In her own practice at the Fred Hutchinson Cancer Research Center, Seattle, she has seen the value of emerging therapies for patients fighting advanced cancers. During her 25 years of clinical practice in an academic setting, she has gained access to drugs through single-patient investigative new drug applications.

However, this path is not an option for many patients who undergo treatment in facilities other than academic centers, she commented. She noted that the accelerated approval process is a way to expand access to emerging medicines, but she sees a need for caution in the use of drugs that have been given only this conditional approval. She emphasizes that such drugs may be suitable only for certain patients.

“I would say that, for metastatic patients, patients with incurable disease, we are willing to take some risk,” Dr. Gralow said. “We don’t have other options. They can’t wait the years that it would take to get a drug approved.”

One such patient is David Mitchell, who serves as the consumer representative on ODAC. He told this news organization that he is taking three drugs for multiple myeloma that received accelerated approvals: pomalidomide, bortezomib, and daratumumab.

“I want the FDA to have the option to approve drugs in an accelerated pathway, because as a patient taking three drugs granted accelerated approval, I’m benefiting – I’ve lived the benefit,” Mr. Mitchell said, “and I want other patients to have the opportunity to have that benefit.”

He believes that the FDA’s approach regarding accelerated approvals serves to get potentially beneficial medicines to patients who have few options and also fulfills the FDA’s mandate to protect the public from treatments that have little benefit but can cause harm.

Accelerated approval also offers needed flexibility to drugmakers as they develop more specifically targeted drugs for diseases that affect relatively few people, such as multiple myeloma, he said. “As the targeting of your therapies gets tighter and for smaller groups of patients, you have a harder time following the traditional model,” such as conducting large, double-blind, placebo-controlled trials that may indicate increased overall survival, he said.

“To me, this is the way the FDA intended it to work,” he added. “It’s going to offer the accelerated approval based on a surrogate endpoint for a safe drug, but it’s going to require the confirmatory trial, and if the confirmatory trial fails, it will pull the drug off the market.”

Some medicines that have received accelerated approvals may ultimately be found not to benefit patients, Mr. Mitchell acknowledged. But people in his situation, whose disease has progressed despite treatments, may want to take that risk, he added.


 

Four cancer indications recently withdrawn voluntarily by the manufacturer

• December 2020: Nivolumab for the treatment of patients with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy (Bristol Myers Squibb).
• February 2021: Durvalumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or following platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy (AstraZeneca).
• March 2021: Pembrolizumab for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy (Merck).
• March 2021: Atezolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing atezolizumab chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (Genentech).

Six cancer indications under review at the April 2021 ODAC meeting

• Atezolizumab indicated in combination with protein-bound  for the treatment of adults with unresectable locally advanced or metastatic triple-negative  whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥1% of the tumor area), as determined by an FDA-approved test.
• Atezolizumab indicated for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
• Pembrolizumab indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
• Pembrolizumab indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (Combined Positive Score ≥1), as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
• Pembrolizumab indicated for the treatment of patients with  who have been previously treated with .
• Nivolumab indicated as a single agent for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.

A version of this article first appeared on Medscape.com.

U.S. regulators are stepping up scrutiny of therapies that were granted an accelerated approval to treat cancers on the basis of surrogate endpoints but have failed to show clinical or survival benefits upon more extensive testing.

At issue are a number of cancer indications for immunotherapies. Four have already been withdrawn (voluntarily by the manufacturer), and six more will be reviewed at an upcoming meeting.

In recent years, the US Food and Drug Administration has granted accelerated approvals to oncology medicines on the basis of evidence that suggests a benefit for patients. Examples of such evidence relate to response rates and estimates of tumor shrinkage. But these approvals are granted on the condition that the manufacturer conducts larger clinical trials that show clinical benefit, including benefit in overall survival.

Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, has argued that the point of these conditional approvals is to find acceptable surrogate markers to allow people with “desperate illnesses” to have access to potentially helpful drugs while work continues to determine the drug’s actual benefit to patients.

Oncologists are now questioning whether the FDA has become too lenient in its approach, Daniel A. Goldstein, MD, a senior physician in medical oncology and internal medicine at the Rabin Medical Center, Petah Tikva, Israel, told this news organization.

“The main two things you want from a cancer drug is to live longer and live a higher quality of life,” said Goldstein. “But these endpoints that they’ve been using over the past few years are not really giving us confidence that these drugs are actually going to help to live longer or better.”

Dr. Pazdur said the FDA will consider withdrawing its accelerated approvals when results of further studies do not confirm expected benefit for patients.

“This is like the pendulum has swung as far as it was going to swing and now is on the backswing,” said Dr. Goldstein, also of the department of health policy and management at the University of North Carolina at Chapel Hill. “You could call this a watershed moment.”

Although there’s near universal interest in allowing people with advanced cancer access to promising medicines, there’s also rising concern about exposing patients needlessly to costly drugs with potentially tough side effects. That may prompt a shift in the standards U.S. regulators apply to cancer medicines, Dr. Goldstein said.
 

Indications withdrawn and under review

In a meeting scheduled for April 27-29, the FDA’s Oncologic Drugs Advisory Committee will review indications granted through the accelerated approval process for three immunotherapies: pembrolizumab (Keytruda), atezolizumab (Tecentriq), and nivolumab (Opdivo).

It is part of an industry-wide evaluation of accelerated approvals for cancer indications in which confirmatory trials did not confirm clinical benefit, the FDA noted.

The process has already led to voluntary withdrawals of four cancer indications by the manufacturers, including one indication each for pembrolizumab, atezolizumab, and nivolumab, and one for durvalumab (Imfinzi).

All of these immunotherapies are approved for numerous cancer indications, and they all remain on the market. It is only the U.S. approvals for particular cancer indications that have been withdrawn.

In the past, olaratumab (Lartruvo) was withdrawn from the market altogether. The FDA granted accelerated approval of the drug for soft tissue sarcoma, but clinical benefit was not confirmed in a phase 3 trial.
 

Issue highlighted by Dr. Prasad and Dr. Gyawali

In recent years, much of the attention on accelerated approvals was spurred by the work of a few researchers, particularly Vinay Prasad, MD, MPH, associate professor in the department of epidemiology and biostatistics, University of California, San Francisco, and Bishal Gyawali, MD, PhD, from Queen’s University Cancer Research Institute, Kingston, Ont. (Both are regular contributors to the oncology section of this news organization.)

Dr. Goldstein made this point in a tweet about the FDA’s announcement of the April ODAC meetings:

“Well done to @oncology_bg and @VPrasadMDMPH among others for highlighting in their papers that the FDA wasn’t properly evaluating accelerated approval drugs.

FDA have listened.

And I thought that the impact of academia was limited!”

Dr. Prasad has made the case for closer scrutiny of accelerated approvals in a number of journal articles and in his 2020 book, “Malignant: How Bad Policy and Bad Evidence Harm People with Cancer,” published by Johns Hopkins University Press.

The book includes highlights of a 2016 article published in Mayo Clinic Proceedings that focused on surrogate endpoints used for FDA approvals. In the article, Dr. Prasad and his coauthor report that they did not find formal analyses of the strength of the surrogate-survival correlation in 14 of 25 cases of accelerated approvals (56%) and in 11 of 30 traditional approvals (37%).

“Our results were concerning. They imply that many surrogates are based on little more than a gut feeling. You might rationalize that and argue a gut feeling is the same as ‘reasonably likely to predict,’ but no reasonable person could think a gut feeling means established,” Dr. Prasad writes in his book. “Our result suggests the FDA is using surrogate endpoints far beyond what may be fair or reasonable.”

Dr. Gyawali has argued that the process by which the FDA assesses cancer drugs for approvals has undergone a profound shift. He has most recently remarked on this in an October 2020 commentary on Medscape.

“Until the recent floodgate of approvals based on response rates from single-arm trials, the majority of cancer therapy decisions were supported by evidence generated from randomized controlled trials (RCTs),” Dr. Gyawali wrote. “The evidence base to support clinical decisions in managing therapeutic side effects has been comparatively sparse.”
 

Accelerated approval to improve access

The FDA has struggled for about 2 decades with questions of where to set the bar on evidence for promising cancer drugs.

The agency’s accelerated approval program for drugs began in 1992. During the first decade, the focus was largely on medicines related to HIV.

In the early 2000s, oncology drugs began to dominate the program.

Dr. Pazdur has presided over the FDA’s marked changes regarding the use of surrogate markers when weighing whether to allow sales of cancer medicines. Formerly a professor at the University of Texas MD Anderson Cancer Center, Houston, Dr. Pazdur joined the FDA as director of the Division of Oncology Drug Products in 1999.

Soon after his appointment, he had to field inquiries from pharmaceutical companies about how much evidence they needed to receive accelerated approvals.

Early on, he publicly expressed impatience about the drugmakers’ approach. “The purpose of accelerated approval was not accelerated drug company profits,” Dr. Padzur said at a 2004 ODAC meeting.

Rather, the point is to allow access to potentially helpful drugs while work continues to determine their actual benefit to patients, he explained.

“It wasn’t a license to do less, less, less, and less to a point now that we may be getting companies that are coming in” intent on determining the minimum evidence the FDA will take, Dr. Pazdur said. “It shouldn’t be what is the lowest. It is what is a sufficient amount to give patients and physicians a real understanding of what their drug will do.”

In a 2016 interview with The New York Times, Dr. Pazdur said that his views on cancer drug approvals have evolved with time. He described himself as being “on a jihad to streamline the review process and get things out the door faster.”

“I have evolved from regulator to regulator-advocate,” Dr. Pazdur told the newspaper.

His attitude reflected his personal experience in losing his wife to ovarian cancer in 2015, as well as shifts in science and law. In 2012, Congress passed a law that gave the FDA new resources to speed medicines for life-threatening diseases to market. In addition, advances in genetics appeared to be making some medications more effective and easier to test, Dr. Pazdur said in The New York Times interview.
 

Withdrawals seen as sign of success

Since the program’s inception, only 6% of accelerated approvals for oncology indications have been withdrawn, the FDA said.

It would be a sign that the program is working if the April meetings lead to further withdrawals of indications that have been granted accelerated approval, Julie R. Gralow, MD, chief medical officer of the American Society of Clinical Oncology, said in an interview with this news organization.

“It shouldn’t be seen as a failure,” Dr. Gralow said.

In her own practice at the Fred Hutchinson Cancer Research Center, Seattle, she has seen the value of emerging therapies for patients fighting advanced cancers. During her 25 years of clinical practice in an academic setting, she has gained access to drugs through single-patient investigative new drug applications.

However, this path is not an option for many patients who undergo treatment in facilities other than academic centers, she commented. She noted that the accelerated approval process is a way to expand access to emerging medicines, but she sees a need for caution in the use of drugs that have been given only this conditional approval. She emphasizes that such drugs may be suitable only for certain patients.

“I would say that, for metastatic patients, patients with incurable disease, we are willing to take some risk,” Dr. Gralow said. “We don’t have other options. They can’t wait the years that it would take to get a drug approved.”

One such patient is David Mitchell, who serves as the consumer representative on ODAC. He told this news organization that he is taking three drugs for multiple myeloma that received accelerated approvals: pomalidomide, bortezomib, and daratumumab.

“I want the FDA to have the option to approve drugs in an accelerated pathway, because as a patient taking three drugs granted accelerated approval, I’m benefiting – I’ve lived the benefit,” Mr. Mitchell said, “and I want other patients to have the opportunity to have that benefit.”

He believes that the FDA’s approach regarding accelerated approvals serves to get potentially beneficial medicines to patients who have few options and also fulfills the FDA’s mandate to protect the public from treatments that have little benefit but can cause harm.

Accelerated approval also offers needed flexibility to drugmakers as they develop more specifically targeted drugs for diseases that affect relatively few people, such as multiple myeloma, he said. “As the targeting of your therapies gets tighter and for smaller groups of patients, you have a harder time following the traditional model,” such as conducting large, double-blind, placebo-controlled trials that may indicate increased overall survival, he said.

“To me, this is the way the FDA intended it to work,” he added. “It’s going to offer the accelerated approval based on a surrogate endpoint for a safe drug, but it’s going to require the confirmatory trial, and if the confirmatory trial fails, it will pull the drug off the market.”

Some medicines that have received accelerated approvals may ultimately be found not to benefit patients, Mr. Mitchell acknowledged. But people in his situation, whose disease has progressed despite treatments, may want to take that risk, he added.


 

Four cancer indications recently withdrawn voluntarily by the manufacturer

• December 2020: Nivolumab for the treatment of patients with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy (Bristol Myers Squibb).
• February 2021: Durvalumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or following platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy (AstraZeneca).
• March 2021: Pembrolizumab for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy (Merck).
• March 2021: Atezolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing atezolizumab chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (Genentech).

Six cancer indications under review at the April 2021 ODAC meeting

• Atezolizumab indicated in combination with protein-bound  for the treatment of adults with unresectable locally advanced or metastatic triple-negative  whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥1% of the tumor area), as determined by an FDA-approved test.
• Atezolizumab indicated for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
• Pembrolizumab indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
• Pembrolizumab indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (Combined Positive Score ≥1), as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
• Pembrolizumab indicated for the treatment of patients with  who have been previously treated with .
• Nivolumab indicated as a single agent for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.

A version of this article first appeared on Medscape.com.