Breast Cancer

The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.

Dr. Cecil Fox/National Cancer Institute

“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.

“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.

In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.

Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.

“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”

Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”

In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”

The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.

The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
 

dbrunk@mdedge.com

SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.

The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.

Dr. Cecil Fox/National Cancer Institute

“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.

“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.

In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.

Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.

“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”

Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”

In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”

The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.

The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
 

dbrunk@mdedge.com

SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.

The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.

Dr. Cecil Fox/National Cancer Institute

“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.

“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.

In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.

Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.

“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”

Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”

In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”

The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.

The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
 

dbrunk@mdedge.com

SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.

Breast cancer survivors may have a lower prevalence of cardiac risk factors at the time of first myocardial infarction and better outcomes compared with those having a first MI from the general population, according to findings from a retrospective study.

In addition, women without breast cancer were younger at the time of first MI compared with survivors, wrote Srikanth Yandrapalli, MD, of New York Medical College, Valhalla, and colleagues. Their report is in the American Journal of Medicine.

The researchers identified 1,644,032 women with a first MI, 56,842 of whom were breast cancer survivors. The team evaluated differences in the prevalence of cardiac risk factors and related outcomes in breast cancer survivors in comparison to the general population.

At baseline, the mean age of subjects with a history of breast cancer was 77 years (range, 11 years), while the mean age of women without breast cancer was 71 years (range, 15 years).

Clinical data were collected from the United States National Inpatient Sample for January 2005 to September 2015. Other outcomes assessed were differences in baseline characteristics and the rate of in-hospital mortality in both groups.

After analysis, the researchers found that breast cancer survivors had a lower prevalence of diabetes mellitus (30.1% vs. 33.1%), obesity (9.4% vs. 13.0%), and smoking (24.1% vs. 27.0%), but higher rates of dyslipidemia (52.7% vs. 48.4%) and hypertension (73.6% vs. 68.1%), compared with women without breast cancer (All P less than .001).

With respect to age, women without breast cancer were 6 years younger than breast cancer survivors at the time of first acute MI (mean age, 71 vs. 77 years; P less than .001).

In addition, the rate of in-hospital mortality was higher in women without breast cancer (7.9%) compared with survivors (7.1%) (P less than .001). After risk adjustment, these results remained unchanged (odds ratio, 0.89; 95% confidence interval, 0.82-0.94).

“Breast cancer survivors in the U.S. are at least 6 years older than the general population of women without breast cancer, and they had a favorable cardiac risk factor profile at the time of first myocardial infarction,” Dr. Yandrapalli and colleagues explained. “The reason for these findings are unclear and hypothesis generating,” they added.

The researchers acknowledged that a key limitation of the study was the retrospective design. As a result, the potential effects of residual confounding should be considered when interpreting the results.

“The favorable impact of health education and participation in cancer survivorship programs on these observed differences in breast cancer survivors should be further explored,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Yandrapalli S et al. Am J Med. 2019 Nov 9. doi: 10.1016/j.amjmed.2019.10.018.

Breast cancer survivors may have a lower prevalence of cardiac risk factors at the time of first myocardial infarction and better outcomes compared with those having a first MI from the general population, according to findings from a retrospective study.

In addition, women without breast cancer were younger at the time of first MI compared with survivors, wrote Srikanth Yandrapalli, MD, of New York Medical College, Valhalla, and colleagues. Their report is in the American Journal of Medicine.

The researchers identified 1,644,032 women with a first MI, 56,842 of whom were breast cancer survivors. The team evaluated differences in the prevalence of cardiac risk factors and related outcomes in breast cancer survivors in comparison to the general population.

At baseline, the mean age of subjects with a history of breast cancer was 77 years (range, 11 years), while the mean age of women without breast cancer was 71 years (range, 15 years).

Clinical data were collected from the United States National Inpatient Sample for January 2005 to September 2015. Other outcomes assessed were differences in baseline characteristics and the rate of in-hospital mortality in both groups.

After analysis, the researchers found that breast cancer survivors had a lower prevalence of diabetes mellitus (30.1% vs. 33.1%), obesity (9.4% vs. 13.0%), and smoking (24.1% vs. 27.0%), but higher rates of dyslipidemia (52.7% vs. 48.4%) and hypertension (73.6% vs. 68.1%), compared with women without breast cancer (All P less than .001).

With respect to age, women without breast cancer were 6 years younger than breast cancer survivors at the time of first acute MI (mean age, 71 vs. 77 years; P less than .001).

In addition, the rate of in-hospital mortality was higher in women without breast cancer (7.9%) compared with survivors (7.1%) (P less than .001). After risk adjustment, these results remained unchanged (odds ratio, 0.89; 95% confidence interval, 0.82-0.94).

“Breast cancer survivors in the U.S. are at least 6 years older than the general population of women without breast cancer, and they had a favorable cardiac risk factor profile at the time of first myocardial infarction,” Dr. Yandrapalli and colleagues explained. “The reason for these findings are unclear and hypothesis generating,” they added.

The researchers acknowledged that a key limitation of the study was the retrospective design. As a result, the potential effects of residual confounding should be considered when interpreting the results.

“The favorable impact of health education and participation in cancer survivorship programs on these observed differences in breast cancer survivors should be further explored,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Yandrapalli S et al. Am J Med. 2019 Nov 9. doi: 10.1016/j.amjmed.2019.10.018.

Breast cancer survivors may have a lower prevalence of cardiac risk factors at the time of first myocardial infarction and better outcomes compared with those having a first MI from the general population, according to findings from a retrospective study.

In addition, women without breast cancer were younger at the time of first MI compared with survivors, wrote Srikanth Yandrapalli, MD, of New York Medical College, Valhalla, and colleagues. Their report is in the American Journal of Medicine.

The researchers identified 1,644,032 women with a first MI, 56,842 of whom were breast cancer survivors. The team evaluated differences in the prevalence of cardiac risk factors and related outcomes in breast cancer survivors in comparison to the general population.

At baseline, the mean age of subjects with a history of breast cancer was 77 years (range, 11 years), while the mean age of women without breast cancer was 71 years (range, 15 years).

Clinical data were collected from the United States National Inpatient Sample for January 2005 to September 2015. Other outcomes assessed were differences in baseline characteristics and the rate of in-hospital mortality in both groups.

After analysis, the researchers found that breast cancer survivors had a lower prevalence of diabetes mellitus (30.1% vs. 33.1%), obesity (9.4% vs. 13.0%), and smoking (24.1% vs. 27.0%), but higher rates of dyslipidemia (52.7% vs. 48.4%) and hypertension (73.6% vs. 68.1%), compared with women without breast cancer (All P less than .001).

With respect to age, women without breast cancer were 6 years younger than breast cancer survivors at the time of first acute MI (mean age, 71 vs. 77 years; P less than .001).

In addition, the rate of in-hospital mortality was higher in women without breast cancer (7.9%) compared with survivors (7.1%) (P less than .001). After risk adjustment, these results remained unchanged (odds ratio, 0.89; 95% confidence interval, 0.82-0.94).

“Breast cancer survivors in the U.S. are at least 6 years older than the general population of women without breast cancer, and they had a favorable cardiac risk factor profile at the time of first myocardial infarction,” Dr. Yandrapalli and colleagues explained. “The reason for these findings are unclear and hypothesis generating,” they added.

The researchers acknowledged that a key limitation of the study was the retrospective design. As a result, the potential effects of residual confounding should be considered when interpreting the results.

“The favorable impact of health education and participation in cancer survivorship programs on these observed differences in breast cancer survivors should be further explored,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Yandrapalli S et al. Am J Med. 2019 Nov 9. doi: 10.1016/j.amjmed.2019.10.018.

NATIONAL HARBOR, MD – PRS-343, a 4-1BB/HER2 bispecific molecule, has demonstrated safety and antitumor activity in patients with heavily pretreated, HER2-positive solid tumors, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

In a phase 1 trial of 18 evaluable patients, PRS-343 produced partial responses in 2 patients and enabled 8 patients to maintain stable disease. PRS-343 was considered well tolerated at all doses and schedules tested.

“PRS-343 is a bispecific construct targeting HER2 as well as 4-1BB,” said Geoffrey Y. Ku, MD, of Memorial Sloan Kettering Cancer Center in New York. “The HER2 component of the molecule localizes it into the tumor microenvironment of any HER2-positive cells. If the density of the HER2 protein is high enough, that facilitates cross-linkage of 4-1BB.

“4-1BB is an immune agonist that’s present in activated T cells, and cross-linkage helps to improve T-cell exhaustion and is also critical for T-cell expansion. The idea is that, by localizing 4-1BB activation to the tumor microenvironment, we can avoid some of the systemic toxicities associated with naked 4-1BB antibodies,” Dr. Ku added.

The ongoing, phase 1 trial of PRS-343 (NCT03330561) has enrolled 53 patients with a range of HER2-positive malignancies. To be eligible, patients must have progressed on standard therapy or have a tumor for which no standard therapy is available.

The most common diagnosis among enrolled patients is gastroesophageal cancer (n = 19), followed by breast cancer (n = 14), gynecologic cancers (n = 6), colorectal cancer (n = 5), and other malignancies.

The patients’ median age at baseline was 61 years (range, 29-92 years), and a majority were female (62%). Most patients (79%) had received three or more prior lines of therapy, including anti-HER2 treatments. Breast cancer patients had received a median of four anti-HER2 treatments, and gastric cancer patients had received a median of two.

The patients have been treated with PRS-343 at 11 dose levels, ranging from 0.0005 mg/kg to 8 mg/kg, given every 3 weeks. The highest dose, 8 mg/kg, was also given every 2 weeks.

Treatment-related adverse events (TRAEs) included infusion-related reactions (9%), fatigue (9%), chills (6%), flushing (6%), nausea (6%), diarrhea (6%), vomiting (5%), and noncardiac chest pain (4%).

“This was an extremely well-tolerated drug,” Dr. Ku said. “Out of 111 TRAEs, only a tiny proportion were grade 3, and toxicities mostly clustered around infusion-related reactions, constitutional symptoms, as well as gastrointestinal symptoms.”

Grade 3 TRAEs included infusion-related reactions (2%), fatigue (1%), flushing (3%), and noncardiac chest pain (1%). There were no grade 4-5 TRAEs.

At the data cutoff (Oct. 23, 2019), 18 patients were evaluable for a response at active dose levels (2.5 mg/kg, 5 mg/kg, and 8 mg/kg).

Two patients achieved a partial response, and eight had stable disease. “This translates to a response rate of 11% and a disease control rate of 55%,” Dr. Ku noted.

Both responders received PRS-343 at 8 mg/kg every 2 weeks. One of these patients had stage 4 gastric adenocarcinoma, and one had stage 4 gynecologic carcinoma.

Of the eight patients with stable disease, three received PRS-343 at 8 mg/kg every 2 weeks, two received 8 mg/kg every 3 weeks, one received the 5 mg/kg dose, and two received the 2.5 mg/kg dose.

Dr. Ku noted that the average time on treatment significantly increased in patients who received PRS-343 at 8 mg/kg every 2 weeks. Additionally, both responders and patients with stable disease had a “clear increase” in CD8+ T cells.

“[PRS-343] has demonstrated antitumor activity in heavily pretreated patients across multiple tumor types, and the treatment history, specifically the receipt of prior anti-HER2 therapy, indicates this is a 4-1BB-driven mechanism of action,” Dr. Ku said. “Based on these results, future studies are planned for continued development in defined HER2-positive indications.”

The current study is sponsored by Pieris Pharmaceuticals. Dr. Ku disclosed relationships with Arog Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck, Zymeworks, and Pieris Pharmaceuticals.

SOURCE: Ku GY et al. SITC 2019, Abstract O82.
 

NATIONAL HARBOR, MD – PRS-343, a 4-1BB/HER2 bispecific molecule, has demonstrated safety and antitumor activity in patients with heavily pretreated, HER2-positive solid tumors, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

In a phase 1 trial of 18 evaluable patients, PRS-343 produced partial responses in 2 patients and enabled 8 patients to maintain stable disease. PRS-343 was considered well tolerated at all doses and schedules tested.

“PRS-343 is a bispecific construct targeting HER2 as well as 4-1BB,” said Geoffrey Y. Ku, MD, of Memorial Sloan Kettering Cancer Center in New York. “The HER2 component of the molecule localizes it into the tumor microenvironment of any HER2-positive cells. If the density of the HER2 protein is high enough, that facilitates cross-linkage of 4-1BB.

“4-1BB is an immune agonist that’s present in activated T cells, and cross-linkage helps to improve T-cell exhaustion and is also critical for T-cell expansion. The idea is that, by localizing 4-1BB activation to the tumor microenvironment, we can avoid some of the systemic toxicities associated with naked 4-1BB antibodies,” Dr. Ku added.

The ongoing, phase 1 trial of PRS-343 (NCT03330561) has enrolled 53 patients with a range of HER2-positive malignancies. To be eligible, patients must have progressed on standard therapy or have a tumor for which no standard therapy is available.

The most common diagnosis among enrolled patients is gastroesophageal cancer (n = 19), followed by breast cancer (n = 14), gynecologic cancers (n = 6), colorectal cancer (n = 5), and other malignancies.

The patients’ median age at baseline was 61 years (range, 29-92 years), and a majority were female (62%). Most patients (79%) had received three or more prior lines of therapy, including anti-HER2 treatments. Breast cancer patients had received a median of four anti-HER2 treatments, and gastric cancer patients had received a median of two.

The patients have been treated with PRS-343 at 11 dose levels, ranging from 0.0005 mg/kg to 8 mg/kg, given every 3 weeks. The highest dose, 8 mg/kg, was also given every 2 weeks.

Treatment-related adverse events (TRAEs) included infusion-related reactions (9%), fatigue (9%), chills (6%), flushing (6%), nausea (6%), diarrhea (6%), vomiting (5%), and noncardiac chest pain (4%).

“This was an extremely well-tolerated drug,” Dr. Ku said. “Out of 111 TRAEs, only a tiny proportion were grade 3, and toxicities mostly clustered around infusion-related reactions, constitutional symptoms, as well as gastrointestinal symptoms.”

Grade 3 TRAEs included infusion-related reactions (2%), fatigue (1%), flushing (3%), and noncardiac chest pain (1%). There were no grade 4-5 TRAEs.

At the data cutoff (Oct. 23, 2019), 18 patients were evaluable for a response at active dose levels (2.5 mg/kg, 5 mg/kg, and 8 mg/kg).

Two patients achieved a partial response, and eight had stable disease. “This translates to a response rate of 11% and a disease control rate of 55%,” Dr. Ku noted.

Both responders received PRS-343 at 8 mg/kg every 2 weeks. One of these patients had stage 4 gastric adenocarcinoma, and one had stage 4 gynecologic carcinoma.

Of the eight patients with stable disease, three received PRS-343 at 8 mg/kg every 2 weeks, two received 8 mg/kg every 3 weeks, one received the 5 mg/kg dose, and two received the 2.5 mg/kg dose.

Dr. Ku noted that the average time on treatment significantly increased in patients who received PRS-343 at 8 mg/kg every 2 weeks. Additionally, both responders and patients with stable disease had a “clear increase” in CD8+ T cells.

“[PRS-343] has demonstrated antitumor activity in heavily pretreated patients across multiple tumor types, and the treatment history, specifically the receipt of prior anti-HER2 therapy, indicates this is a 4-1BB-driven mechanism of action,” Dr. Ku said. “Based on these results, future studies are planned for continued development in defined HER2-positive indications.”

The current study is sponsored by Pieris Pharmaceuticals. Dr. Ku disclosed relationships with Arog Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck, Zymeworks, and Pieris Pharmaceuticals.

SOURCE: Ku GY et al. SITC 2019, Abstract O82.
 

NATIONAL HARBOR, MD – PRS-343, a 4-1BB/HER2 bispecific molecule, has demonstrated safety and antitumor activity in patients with heavily pretreated, HER2-positive solid tumors, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

In a phase 1 trial of 18 evaluable patients, PRS-343 produced partial responses in 2 patients and enabled 8 patients to maintain stable disease. PRS-343 was considered well tolerated at all doses and schedules tested.

“PRS-343 is a bispecific construct targeting HER2 as well as 4-1BB,” said Geoffrey Y. Ku, MD, of Memorial Sloan Kettering Cancer Center in New York. “The HER2 component of the molecule localizes it into the tumor microenvironment of any HER2-positive cells. If the density of the HER2 protein is high enough, that facilitates cross-linkage of 4-1BB.

“4-1BB is an immune agonist that’s present in activated T cells, and cross-linkage helps to improve T-cell exhaustion and is also critical for T-cell expansion. The idea is that, by localizing 4-1BB activation to the tumor microenvironment, we can avoid some of the systemic toxicities associated with naked 4-1BB antibodies,” Dr. Ku added.

The ongoing, phase 1 trial of PRS-343 (NCT03330561) has enrolled 53 patients with a range of HER2-positive malignancies. To be eligible, patients must have progressed on standard therapy or have a tumor for which no standard therapy is available.

The most common diagnosis among enrolled patients is gastroesophageal cancer (n = 19), followed by breast cancer (n = 14), gynecologic cancers (n = 6), colorectal cancer (n = 5), and other malignancies.

The patients’ median age at baseline was 61 years (range, 29-92 years), and a majority were female (62%). Most patients (79%) had received three or more prior lines of therapy, including anti-HER2 treatments. Breast cancer patients had received a median of four anti-HER2 treatments, and gastric cancer patients had received a median of two.

The patients have been treated with PRS-343 at 11 dose levels, ranging from 0.0005 mg/kg to 8 mg/kg, given every 3 weeks. The highest dose, 8 mg/kg, was also given every 2 weeks.

Treatment-related adverse events (TRAEs) included infusion-related reactions (9%), fatigue (9%), chills (6%), flushing (6%), nausea (6%), diarrhea (6%), vomiting (5%), and noncardiac chest pain (4%).

“This was an extremely well-tolerated drug,” Dr. Ku said. “Out of 111 TRAEs, only a tiny proportion were grade 3, and toxicities mostly clustered around infusion-related reactions, constitutional symptoms, as well as gastrointestinal symptoms.”

Grade 3 TRAEs included infusion-related reactions (2%), fatigue (1%), flushing (3%), and noncardiac chest pain (1%). There were no grade 4-5 TRAEs.

At the data cutoff (Oct. 23, 2019), 18 patients were evaluable for a response at active dose levels (2.5 mg/kg, 5 mg/kg, and 8 mg/kg).

Two patients achieved a partial response, and eight had stable disease. “This translates to a response rate of 11% and a disease control rate of 55%,” Dr. Ku noted.

Both responders received PRS-343 at 8 mg/kg every 2 weeks. One of these patients had stage 4 gastric adenocarcinoma, and one had stage 4 gynecologic carcinoma.

Of the eight patients with stable disease, three received PRS-343 at 8 mg/kg every 2 weeks, two received 8 mg/kg every 3 weeks, one received the 5 mg/kg dose, and two received the 2.5 mg/kg dose.

Dr. Ku noted that the average time on treatment significantly increased in patients who received PRS-343 at 8 mg/kg every 2 weeks. Additionally, both responders and patients with stable disease had a “clear increase” in CD8+ T cells.

“[PRS-343] has demonstrated antitumor activity in heavily pretreated patients across multiple tumor types, and the treatment history, specifically the receipt of prior anti-HER2 therapy, indicates this is a 4-1BB-driven mechanism of action,” Dr. Ku said. “Based on these results, future studies are planned for continued development in defined HER2-positive indications.”

The current study is sponsored by Pieris Pharmaceuticals. Dr. Ku disclosed relationships with Arog Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck, Zymeworks, and Pieris Pharmaceuticals.

SOURCE: Ku GY et al. SITC 2019, Abstract O82.
 

In this edition of “How I will treat my next patient,” I highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).

Osimertinib in advanced NSCLC

In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.

At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).

More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.

The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.

What this means in clinical practice

The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”

For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.

In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.

MONARCH 2: Abemaciclib plus fulvestrant

In the MONARCH 2, randomized, placebo-controlled, phase 3 trial, abemaciclib plus fulvestrant (abema-F) significantly improved PFS, in comparison with placebo plus fulvestrant (placebo-F; 16.9 months vs. 9.3 months; HR, 0.563) in 669 premenopausal (with concurrent ovarian function suppression) and postmenopausal women with metastatic breast cancer (mBC) who had disease progression on one to two lines of prior hormonal therapy (J Clin Oncol. 2017;35[25]:2875-84).

At ESMO 2019, George W. Sledge Jr., MD, of Stanford (Calif.) Medical Center, and colleagues reported the OS results, a secondary endpoint for the trial (JAMA Oncol. 2019 Sep 29. doi. 10.1001/jamaoncol.2019.4782). At the prespecified interim analysis point, median OS for abema-F was 46.7 months vs. 37.3 months for placebo-F (HR, 0.757; 95% CI 0.505-0.945; P = .0137). Patients with greatest benefit from abema-F were exactly the patients who needed the most help – those with visceral metastases (HR 0.675) and with primary resistance to prior hormonal therapy (HR, 0.686).

At 3 years, at least three times as many patients remained progression free with abema-F, compared with placebo-F, and the abema-F patients experienced prolongation in time to eventual chemotherapy (50.2 months vs. 22.1 months; HR, 0.625).

What this means in clinical practice

Many times I find myself sitting at the annual meeting of the American Society of Clinical Oncology and thinking, “Only a medical oncologist like me would find this result exciting.” Prior to ESMO 2019, MONARCH 2 (and a similar study presented at ESMO 2019, MONALEESA-3, which employed an alternative CDK 4/6 inhibitor, ribociclib, with similar OS results) added to the body of literature that caused NCCN guidelines to list all of the approved CDK 4/6 inhibitors plus endocrine therapy for first- or second-line use in patients with hormone-receptor positive, HER2/neu-negative mBC. NCCN guidelines have the caveat that, among patients with disease progression on CDK 4/6 inhibitors in the first-line setting, there are no data to support continuing the CDK 4/6 inhibitor or switching to an alternative CDK 4/6 inhibitor thereafter.

For that shrinking group of patients and doctors who choose to avoid CDK 4/6 inhibitors for first-line treatment, as we describe risks and benefits of using a CDK 4/6 inhibitor for second- or third-line therapy, we have high-quality OS information from ESMO 2019 to answer the “Is it worth it?” question.

Are the results of MONARCH 2 and MONALEESA-3 practice changing? No. We were already convinced. Should we be excited that we have this new information for discussions with our patients? Absolutely.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).

Osimertinib in advanced NSCLC

In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.

At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).

More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.

The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.

What this means in clinical practice

The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”

For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.

In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.

MONARCH 2: Abemaciclib plus fulvestrant

In the MONARCH 2, randomized, placebo-controlled, phase 3 trial, abemaciclib plus fulvestrant (abema-F) significantly improved PFS, in comparison with placebo plus fulvestrant (placebo-F; 16.9 months vs. 9.3 months; HR, 0.563) in 669 premenopausal (with concurrent ovarian function suppression) and postmenopausal women with metastatic breast cancer (mBC) who had disease progression on one to two lines of prior hormonal therapy (J Clin Oncol. 2017;35[25]:2875-84).

At ESMO 2019, George W. Sledge Jr., MD, of Stanford (Calif.) Medical Center, and colleagues reported the OS results, a secondary endpoint for the trial (JAMA Oncol. 2019 Sep 29. doi. 10.1001/jamaoncol.2019.4782). At the prespecified interim analysis point, median OS for abema-F was 46.7 months vs. 37.3 months for placebo-F (HR, 0.757; 95% CI 0.505-0.945; P = .0137). Patients with greatest benefit from abema-F were exactly the patients who needed the most help – those with visceral metastases (HR 0.675) and with primary resistance to prior hormonal therapy (HR, 0.686).

At 3 years, at least three times as many patients remained progression free with abema-F, compared with placebo-F, and the abema-F patients experienced prolongation in time to eventual chemotherapy (50.2 months vs. 22.1 months; HR, 0.625).

What this means in clinical practice

Many times I find myself sitting at the annual meeting of the American Society of Clinical Oncology and thinking, “Only a medical oncologist like me would find this result exciting.” Prior to ESMO 2019, MONARCH 2 (and a similar study presented at ESMO 2019, MONALEESA-3, which employed an alternative CDK 4/6 inhibitor, ribociclib, with similar OS results) added to the body of literature that caused NCCN guidelines to list all of the approved CDK 4/6 inhibitors plus endocrine therapy for first- or second-line use in patients with hormone-receptor positive, HER2/neu-negative mBC. NCCN guidelines have the caveat that, among patients with disease progression on CDK 4/6 inhibitors in the first-line setting, there are no data to support continuing the CDK 4/6 inhibitor or switching to an alternative CDK 4/6 inhibitor thereafter.

For that shrinking group of patients and doctors who choose to avoid CDK 4/6 inhibitors for first-line treatment, as we describe risks and benefits of using a CDK 4/6 inhibitor for second- or third-line therapy, we have high-quality OS information from ESMO 2019 to answer the “Is it worth it?” question.

Are the results of MONARCH 2 and MONALEESA-3 practice changing? No. We were already convinced. Should we be excited that we have this new information for discussions with our patients? Absolutely.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).

Osimertinib in advanced NSCLC

In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.

At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).

More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.

The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.

What this means in clinical practice

The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”

For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.

In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.

MONARCH 2: Abemaciclib plus fulvestrant

In the MONARCH 2, randomized, placebo-controlled, phase 3 trial, abemaciclib plus fulvestrant (abema-F) significantly improved PFS, in comparison with placebo plus fulvestrant (placebo-F; 16.9 months vs. 9.3 months; HR, 0.563) in 669 premenopausal (with concurrent ovarian function suppression) and postmenopausal women with metastatic breast cancer (mBC) who had disease progression on one to two lines of prior hormonal therapy (J Clin Oncol. 2017;35[25]:2875-84).

At ESMO 2019, George W. Sledge Jr., MD, of Stanford (Calif.) Medical Center, and colleagues reported the OS results, a secondary endpoint for the trial (JAMA Oncol. 2019 Sep 29. doi. 10.1001/jamaoncol.2019.4782). At the prespecified interim analysis point, median OS for abema-F was 46.7 months vs. 37.3 months for placebo-F (HR, 0.757; 95% CI 0.505-0.945; P = .0137). Patients with greatest benefit from abema-F were exactly the patients who needed the most help – those with visceral metastases (HR 0.675) and with primary resistance to prior hormonal therapy (HR, 0.686).

At 3 years, at least three times as many patients remained progression free with abema-F, compared with placebo-F, and the abema-F patients experienced prolongation in time to eventual chemotherapy (50.2 months vs. 22.1 months; HR, 0.625).

What this means in clinical practice

Many times I find myself sitting at the annual meeting of the American Society of Clinical Oncology and thinking, “Only a medical oncologist like me would find this result exciting.” Prior to ESMO 2019, MONARCH 2 (and a similar study presented at ESMO 2019, MONALEESA-3, which employed an alternative CDK 4/6 inhibitor, ribociclib, with similar OS results) added to the body of literature that caused NCCN guidelines to list all of the approved CDK 4/6 inhibitors plus endocrine therapy for first- or second-line use in patients with hormone-receptor positive, HER2/neu-negative mBC. NCCN guidelines have the caveat that, among patients with disease progression on CDK 4/6 inhibitors in the first-line setting, there are no data to support continuing the CDK 4/6 inhibitor or switching to an alternative CDK 4/6 inhibitor thereafter.

For that shrinking group of patients and doctors who choose to avoid CDK 4/6 inhibitors for first-line treatment, as we describe risks and benefits of using a CDK 4/6 inhibitor for second- or third-line therapy, we have high-quality OS information from ESMO 2019 to answer the “Is it worth it?” question.

Are the results of MONARCH 2 and MONALEESA-3 practice changing? No. We were already convinced. Should we be excited that we have this new information for discussions with our patients? Absolutely.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

BARCELONA – A progressive aerobic and resistance exercise intervention improved the android:gynoid fat ratio (AGFR) in breast cancer survivors, which could provide important health benefits.

AGFR is associated with increased risk for cardiovascular disease and type 2 diabetes in breast cancer survivors, therefore exercise-induced AGFR improvement may reduce the risk for such comorbid conditions, Christina Dieli-Conwright, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

A significant decrease in AGFR from baseline was noted in 50 survivors of stage I-III breast cancer who participated in the exercise intervention, compared with 50 such survivors randomized to a usual care group (P less than .001), and strong correlations were found between AGFR and homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.95; P less than .01), the investigators found.

Study participants had a mean age of 53 years, 54% were overweight (body mass index greater than 25 kg/m²), 63% were Hispanic, 90% had undergone a mastectomy, and 76% received chemotherapy and radiation therapy. Adherence to the intervention, which involved three weekly sessions of supervised, progressive, moderate-to-vigorous aerobic and resistance exercise for 16 weeks, was 95%.

AGFR was calculated using whole-body dual-energy x-ray absorptiometry and HOMA-IR was calculated using fasting insulin and glucose levels.

“Exercise reduces fat mass in breast cancer survivors, however, few studies have focused on AGFR,” the investigators wrote.

The findings of the current study suggest that a progressive aerobic and resistance exercise intervention is an effective strategy for decreasing AGFR in breast cancer survivors, they concluded.

The National Cancer Institute funded the study. The authors reported having no disclosures.

SOURCE: Dieli-Conwright C et al. ESMO 2019, Abstract 228P.

BARCELONA – A progressive aerobic and resistance exercise intervention improved the android:gynoid fat ratio (AGFR) in breast cancer survivors, which could provide important health benefits.

AGFR is associated with increased risk for cardiovascular disease and type 2 diabetes in breast cancer survivors, therefore exercise-induced AGFR improvement may reduce the risk for such comorbid conditions, Christina Dieli-Conwright, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

A significant decrease in AGFR from baseline was noted in 50 survivors of stage I-III breast cancer who participated in the exercise intervention, compared with 50 such survivors randomized to a usual care group (P less than .001), and strong correlations were found between AGFR and homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.95; P less than .01), the investigators found.

Study participants had a mean age of 53 years, 54% were overweight (body mass index greater than 25 kg/m²), 63% were Hispanic, 90% had undergone a mastectomy, and 76% received chemotherapy and radiation therapy. Adherence to the intervention, which involved three weekly sessions of supervised, progressive, moderate-to-vigorous aerobic and resistance exercise for 16 weeks, was 95%.

AGFR was calculated using whole-body dual-energy x-ray absorptiometry and HOMA-IR was calculated using fasting insulin and glucose levels.

“Exercise reduces fat mass in breast cancer survivors, however, few studies have focused on AGFR,” the investigators wrote.

The findings of the current study suggest that a progressive aerobic and resistance exercise intervention is an effective strategy for decreasing AGFR in breast cancer survivors, they concluded.

The National Cancer Institute funded the study. The authors reported having no disclosures.

SOURCE: Dieli-Conwright C et al. ESMO 2019, Abstract 228P.

BARCELONA – A progressive aerobic and resistance exercise intervention improved the android:gynoid fat ratio (AGFR) in breast cancer survivors, which could provide important health benefits.

AGFR is associated with increased risk for cardiovascular disease and type 2 diabetes in breast cancer survivors, therefore exercise-induced AGFR improvement may reduce the risk for such comorbid conditions, Christina Dieli-Conwright, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

A significant decrease in AGFR from baseline was noted in 50 survivors of stage I-III breast cancer who participated in the exercise intervention, compared with 50 such survivors randomized to a usual care group (P less than .001), and strong correlations were found between AGFR and homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.95; P less than .01), the investigators found.

Study participants had a mean age of 53 years, 54% were overweight (body mass index greater than 25 kg/m²), 63% were Hispanic, 90% had undergone a mastectomy, and 76% received chemotherapy and radiation therapy. Adherence to the intervention, which involved three weekly sessions of supervised, progressive, moderate-to-vigorous aerobic and resistance exercise for 16 weeks, was 95%.

AGFR was calculated using whole-body dual-energy x-ray absorptiometry and HOMA-IR was calculated using fasting insulin and glucose levels.

“Exercise reduces fat mass in breast cancer survivors, however, few studies have focused on AGFR,” the investigators wrote.

The findings of the current study suggest that a progressive aerobic and resistance exercise intervention is an effective strategy for decreasing AGFR in breast cancer survivors, they concluded.

The National Cancer Institute funded the study. The authors reported having no disclosures.

SOURCE: Dieli-Conwright C et al. ESMO 2019, Abstract 228P.

ORLANDO – Cumulative evidence over the years has shown that bisphosphonates reduce distant metastases in postmenopausal women with early-stage breast cancer but that effect does not seem to extend to younger, premenopausal women who may experience adverse effects with bisphosphonates, nor has it been replicated in other types of cancer, such as lung or prostate, Robert Coleman MBBS, MD, said in a presentation marking the 50th anniversary of the publication of the first papers describing the then-new class of drugs.

“We have some science – at least in postmenopausal breast cancer – [showing] that we’re really making a difference, but we don’t understand why it’s not working in the other patients or in the other diseases,” said Dr. Coleman of the University of Sheffield (England) at the annual meeting of the American Society for Bone and Mineral Research.
 

Mixed findings in early studies

Early studies showing the metastases-prevention effects of bisphosphonates were with clodronate. In one study, Dr. Coleman said, researchers found that oral clodronate at a dose of 1,600 mg/day as a supplementary treatment to standard treatment for primary, operable breast cancer reduced the risk of bone metastases in a cohort of 1,069 patients with stage 1-3 breast cancer (hazard ratio, 0.692; P = .043) over 5 years (Breast Cancer Res. 2006 Mar 15. doi: 10.1186/bcr1384). Another trial, of 302 patients with breast cancer who received oral clodronate at 1,600 mg/day for 2 years, found that 20.4% of patients who received oral clodronate had died by 8.5 years of follow-up, compared with 40.7% of those who did not receive the intervention (Ann Oncol. 2008;19[12]:2007-11).

However, those results were in conflict with findings from an earlier study in which researchers followed patients with breast cancer who received 1,600 mg/day of oral clodronate or placebo for 3 years. They found a similar number of bone metastases in the clodronate and placebo groups (32% and 29%, respectively), as well as a lower overall disease-free survival rate at 10 years for the clodronate group, compared with the placebo group (45% vs. 58%; Acta Oncol. 2004;43[7]:650-6).“For various other reasons, clodronate did not gain traction as a therapeutic strategy in early-stage breast cancer,” said Dr. Coleman, although emerging evidence showed that other bisphosphonate agents were effective in some patients with breast cancer.

In a 2009 article, Gnant et al. reported that premenopausal patients, who underwent primary surgery for stage 1 or stage 2 breast cancer and received standard goserelin therapy for induced menopause and endocrine therapy (either tamoxifen or anastrozole) in addition to treatment with zoledronic acid, had a disease-free survival rate of 94.0% at a median 47.8 months of follow-up (N Eng J Med. 2009;360:679-91). After a median 94.4 months of follow-up, the investigators reported a lower risk of disease progression (HR, 0.77; 95% confidence interval, 0.60-0.99; P = .042) and death (HR, 0.66; 95% CI, 0.43-1.02; P = .064; Ann Oncol. 2015;26[2]:313-20).

In his own group, Dr. Coleman and colleagues recruited patients with early-stage breast cancer in the AZURE trial, a phase 3 study of 3,360 patients who received standard therapy with or without zoledronic acid 4 mg every 3-4 weeks for 6 doses, followed by 8 doses every 3 months then 5 doses every 6 months (N Eng J Med. 2011;365:1396-405). “We saw no effect,” said Dr. Coleman. “[That was] very different from what was shown by [Dr.] Gnant.”

For a subgroup of postmenopausal patients, Dr. Coleman and colleagues found that the adjusted HR for disease-free survival was 0.82 for women who were more than 5 years postmenopausal (95% CI, 0.67-1.00) at the time of breast cancer and bisphosphonate treatment, but women younger than 40 years had worse survival outcomes at 10 years (HR, 1.56; 95% CI, 1.09-2.22) and had a significantly higher risk of death from breast cancer (HR, 1.67; 95% CI, 1.16-2.40; J Bone Oncol. 2018 Sep 27. doi: 10.1016/j.jbo.2018.09.008).
 

Trying to reconcile disparate findings

Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.

In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.

“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.

However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.

In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.

“From the cancer perspective, bisphosphonates have transformed the experience for many of our patients with advanced disease, and now we’re working to see great improvements, at least in common diseases such as postmenopausal breast cancer,” he concluded.

Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.

ORLANDO – Cumulative evidence over the years has shown that bisphosphonates reduce distant metastases in postmenopausal women with early-stage breast cancer but that effect does not seem to extend to younger, premenopausal women who may experience adverse effects with bisphosphonates, nor has it been replicated in other types of cancer, such as lung or prostate, Robert Coleman MBBS, MD, said in a presentation marking the 50th anniversary of the publication of the first papers describing the then-new class of drugs.

“We have some science – at least in postmenopausal breast cancer – [showing] that we’re really making a difference, but we don’t understand why it’s not working in the other patients or in the other diseases,” said Dr. Coleman of the University of Sheffield (England) at the annual meeting of the American Society for Bone and Mineral Research.
 

Mixed findings in early studies

Early studies showing the metastases-prevention effects of bisphosphonates were with clodronate. In one study, Dr. Coleman said, researchers found that oral clodronate at a dose of 1,600 mg/day as a supplementary treatment to standard treatment for primary, operable breast cancer reduced the risk of bone metastases in a cohort of 1,069 patients with stage 1-3 breast cancer (hazard ratio, 0.692; P = .043) over 5 years (Breast Cancer Res. 2006 Mar 15. doi: 10.1186/bcr1384). Another trial, of 302 patients with breast cancer who received oral clodronate at 1,600 mg/day for 2 years, found that 20.4% of patients who received oral clodronate had died by 8.5 years of follow-up, compared with 40.7% of those who did not receive the intervention (Ann Oncol. 2008;19[12]:2007-11).

However, those results were in conflict with findings from an earlier study in which researchers followed patients with breast cancer who received 1,600 mg/day of oral clodronate or placebo for 3 years. They found a similar number of bone metastases in the clodronate and placebo groups (32% and 29%, respectively), as well as a lower overall disease-free survival rate at 10 years for the clodronate group, compared with the placebo group (45% vs. 58%; Acta Oncol. 2004;43[7]:650-6).“For various other reasons, clodronate did not gain traction as a therapeutic strategy in early-stage breast cancer,” said Dr. Coleman, although emerging evidence showed that other bisphosphonate agents were effective in some patients with breast cancer.

In a 2009 article, Gnant et al. reported that premenopausal patients, who underwent primary surgery for stage 1 or stage 2 breast cancer and received standard goserelin therapy for induced menopause and endocrine therapy (either tamoxifen or anastrozole) in addition to treatment with zoledronic acid, had a disease-free survival rate of 94.0% at a median 47.8 months of follow-up (N Eng J Med. 2009;360:679-91). After a median 94.4 months of follow-up, the investigators reported a lower risk of disease progression (HR, 0.77; 95% confidence interval, 0.60-0.99; P = .042) and death (HR, 0.66; 95% CI, 0.43-1.02; P = .064; Ann Oncol. 2015;26[2]:313-20).

In his own group, Dr. Coleman and colleagues recruited patients with early-stage breast cancer in the AZURE trial, a phase 3 study of 3,360 patients who received standard therapy with or without zoledronic acid 4 mg every 3-4 weeks for 6 doses, followed by 8 doses every 3 months then 5 doses every 6 months (N Eng J Med. 2011;365:1396-405). “We saw no effect,” said Dr. Coleman. “[That was] very different from what was shown by [Dr.] Gnant.”

For a subgroup of postmenopausal patients, Dr. Coleman and colleagues found that the adjusted HR for disease-free survival was 0.82 for women who were more than 5 years postmenopausal (95% CI, 0.67-1.00) at the time of breast cancer and bisphosphonate treatment, but women younger than 40 years had worse survival outcomes at 10 years (HR, 1.56; 95% CI, 1.09-2.22) and had a significantly higher risk of death from breast cancer (HR, 1.67; 95% CI, 1.16-2.40; J Bone Oncol. 2018 Sep 27. doi: 10.1016/j.jbo.2018.09.008).
 

Trying to reconcile disparate findings

Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.

In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.

“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.

However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.

In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.

“From the cancer perspective, bisphosphonates have transformed the experience for many of our patients with advanced disease, and now we’re working to see great improvements, at least in common diseases such as postmenopausal breast cancer,” he concluded.

Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.

ORLANDO – Cumulative evidence over the years has shown that bisphosphonates reduce distant metastases in postmenopausal women with early-stage breast cancer but that effect does not seem to extend to younger, premenopausal women who may experience adverse effects with bisphosphonates, nor has it been replicated in other types of cancer, such as lung or prostate, Robert Coleman MBBS, MD, said in a presentation marking the 50th anniversary of the publication of the first papers describing the then-new class of drugs.

“We have some science – at least in postmenopausal breast cancer – [showing] that we’re really making a difference, but we don’t understand why it’s not working in the other patients or in the other diseases,” said Dr. Coleman of the University of Sheffield (England) at the annual meeting of the American Society for Bone and Mineral Research.
 

Mixed findings in early studies

Early studies showing the metastases-prevention effects of bisphosphonates were with clodronate. In one study, Dr. Coleman said, researchers found that oral clodronate at a dose of 1,600 mg/day as a supplementary treatment to standard treatment for primary, operable breast cancer reduced the risk of bone metastases in a cohort of 1,069 patients with stage 1-3 breast cancer (hazard ratio, 0.692; P = .043) over 5 years (Breast Cancer Res. 2006 Mar 15. doi: 10.1186/bcr1384). Another trial, of 302 patients with breast cancer who received oral clodronate at 1,600 mg/day for 2 years, found that 20.4% of patients who received oral clodronate had died by 8.5 years of follow-up, compared with 40.7% of those who did not receive the intervention (Ann Oncol. 2008;19[12]:2007-11).

However, those results were in conflict with findings from an earlier study in which researchers followed patients with breast cancer who received 1,600 mg/day of oral clodronate or placebo for 3 years. They found a similar number of bone metastases in the clodronate and placebo groups (32% and 29%, respectively), as well as a lower overall disease-free survival rate at 10 years for the clodronate group, compared with the placebo group (45% vs. 58%; Acta Oncol. 2004;43[7]:650-6).“For various other reasons, clodronate did not gain traction as a therapeutic strategy in early-stage breast cancer,” said Dr. Coleman, although emerging evidence showed that other bisphosphonate agents were effective in some patients with breast cancer.

In a 2009 article, Gnant et al. reported that premenopausal patients, who underwent primary surgery for stage 1 or stage 2 breast cancer and received standard goserelin therapy for induced menopause and endocrine therapy (either tamoxifen or anastrozole) in addition to treatment with zoledronic acid, had a disease-free survival rate of 94.0% at a median 47.8 months of follow-up (N Eng J Med. 2009;360:679-91). After a median 94.4 months of follow-up, the investigators reported a lower risk of disease progression (HR, 0.77; 95% confidence interval, 0.60-0.99; P = .042) and death (HR, 0.66; 95% CI, 0.43-1.02; P = .064; Ann Oncol. 2015;26[2]:313-20).

In his own group, Dr. Coleman and colleagues recruited patients with early-stage breast cancer in the AZURE trial, a phase 3 study of 3,360 patients who received standard therapy with or without zoledronic acid 4 mg every 3-4 weeks for 6 doses, followed by 8 doses every 3 months then 5 doses every 6 months (N Eng J Med. 2011;365:1396-405). “We saw no effect,” said Dr. Coleman. “[That was] very different from what was shown by [Dr.] Gnant.”

For a subgroup of postmenopausal patients, Dr. Coleman and colleagues found that the adjusted HR for disease-free survival was 0.82 for women who were more than 5 years postmenopausal (95% CI, 0.67-1.00) at the time of breast cancer and bisphosphonate treatment, but women younger than 40 years had worse survival outcomes at 10 years (HR, 1.56; 95% CI, 1.09-2.22) and had a significantly higher risk of death from breast cancer (HR, 1.67; 95% CI, 1.16-2.40; J Bone Oncol. 2018 Sep 27. doi: 10.1016/j.jbo.2018.09.008).
 

Trying to reconcile disparate findings

Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.

In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.

“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.

However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.

In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.

“From the cancer perspective, bisphosphonates have transformed the experience for many of our patients with advanced disease, and now we’re working to see great improvements, at least in common diseases such as postmenopausal breast cancer,” he concluded.

Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.

BARCELONA – A supervised and adapted exercise program improved quality of life, physical functioning, and strength in breast cancer survivors participating in the MAMA MOVE Gaia study.

Of 19 women who initiated participation in the program, which included a 16-week control phase followed by a 16-week exercise training intervention phase, 15 completed the program, and, after the training intervention, they experienced a significant increase in handgrip strength and sit-to-stand repetitions, Ana Joaquim, MD, of Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

During the control phase of the prospective nonrandomized study, participants experienced no significant changes over time in any domain of quality of life as measured by the EORTC QLQ-C30 questionnaire, although a trend toward improved physical functioning was noted at an evaluation performed 8 weeks after the control phase, compared with one performed just prior to the intervention phase (77.3 to 85.3 points, P = .051), the investigators said.

After the intervention phase, however, handgrip strength improved significantly at both the limb where surgery was performed and at the nonoperated limb (from 22.2 to 25.6 kg.f and from 22.6 to 26.9 kg.f). Similar results were observed for a sit-to-stand test (improvement from 12 to 17 repetitions).

Participants in the single-arm clinical trial were assessed after 8 weeks of the control phase, immediately prior to the intervention period, 8 weeks after the control phase, and 16 weeks into the invention phase.

The intervention phase consisted of 3 60-minute sessions per week of combined moderate to vigorous aerobic and strength exercise, defined as exercise at 65%-85% of maximum heart rate or at 6-8 points on the OMNI scale. Mean compliance among the participants was 63.6%.

The participants had a median age of 59 and 15 of the 19 were diagnosed with invasive carcinoma. Following surgery, 13 underwent radiotherapy, 15 received chemotherapy, and 18 received hormone therapy.

“Treatments for early breast cancer have side effects that affect quality of life and cause deconditioning,” the investigators wrote, adding that “physical exercise might have a supportive and coadjuvant role in the rehabilitation of breast cancer survivors.”

The MAMA MOVE trial aimed to assess the potential benefits of a community-based supervised exercise training program, and the findings suggest such programs could help improve quality of life, particularly with respect to physical functioning, they concluded.

The MAMA MOVE Gaia study was funded by Liga Portuguesa Contra o Cancro. The investigators reported having no disclosures.
 

SOURCE: Joaquim A et al. ESMO 2019, Abstract 234P.

BARCELONA – A supervised and adapted exercise program improved quality of life, physical functioning, and strength in breast cancer survivors participating in the MAMA MOVE Gaia study.

Of 19 women who initiated participation in the program, which included a 16-week control phase followed by a 16-week exercise training intervention phase, 15 completed the program, and, after the training intervention, they experienced a significant increase in handgrip strength and sit-to-stand repetitions, Ana Joaquim, MD, of Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

During the control phase of the prospective nonrandomized study, participants experienced no significant changes over time in any domain of quality of life as measured by the EORTC QLQ-C30 questionnaire, although a trend toward improved physical functioning was noted at an evaluation performed 8 weeks after the control phase, compared with one performed just prior to the intervention phase (77.3 to 85.3 points, P = .051), the investigators said.

After the intervention phase, however, handgrip strength improved significantly at both the limb where surgery was performed and at the nonoperated limb (from 22.2 to 25.6 kg.f and from 22.6 to 26.9 kg.f). Similar results were observed for a sit-to-stand test (improvement from 12 to 17 repetitions).

Participants in the single-arm clinical trial were assessed after 8 weeks of the control phase, immediately prior to the intervention period, 8 weeks after the control phase, and 16 weeks into the invention phase.

The intervention phase consisted of 3 60-minute sessions per week of combined moderate to vigorous aerobic and strength exercise, defined as exercise at 65%-85% of maximum heart rate or at 6-8 points on the OMNI scale. Mean compliance among the participants was 63.6%.

The participants had a median age of 59 and 15 of the 19 were diagnosed with invasive carcinoma. Following surgery, 13 underwent radiotherapy, 15 received chemotherapy, and 18 received hormone therapy.

“Treatments for early breast cancer have side effects that affect quality of life and cause deconditioning,” the investigators wrote, adding that “physical exercise might have a supportive and coadjuvant role in the rehabilitation of breast cancer survivors.”

The MAMA MOVE trial aimed to assess the potential benefits of a community-based supervised exercise training program, and the findings suggest such programs could help improve quality of life, particularly with respect to physical functioning, they concluded.

The MAMA MOVE Gaia study was funded by Liga Portuguesa Contra o Cancro. The investigators reported having no disclosures.
 

SOURCE: Joaquim A et al. ESMO 2019, Abstract 234P.

BARCELONA – A supervised and adapted exercise program improved quality of life, physical functioning, and strength in breast cancer survivors participating in the MAMA MOVE Gaia study.

Of 19 women who initiated participation in the program, which included a 16-week control phase followed by a 16-week exercise training intervention phase, 15 completed the program, and, after the training intervention, they experienced a significant increase in handgrip strength and sit-to-stand repetitions, Ana Joaquim, MD, of Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

During the control phase of the prospective nonrandomized study, participants experienced no significant changes over time in any domain of quality of life as measured by the EORTC QLQ-C30 questionnaire, although a trend toward improved physical functioning was noted at an evaluation performed 8 weeks after the control phase, compared with one performed just prior to the intervention phase (77.3 to 85.3 points, P = .051), the investigators said.

After the intervention phase, however, handgrip strength improved significantly at both the limb where surgery was performed and at the nonoperated limb (from 22.2 to 25.6 kg.f and from 22.6 to 26.9 kg.f). Similar results were observed for a sit-to-stand test (improvement from 12 to 17 repetitions).

Participants in the single-arm clinical trial were assessed after 8 weeks of the control phase, immediately prior to the intervention period, 8 weeks after the control phase, and 16 weeks into the invention phase.

The intervention phase consisted of 3 60-minute sessions per week of combined moderate to vigorous aerobic and strength exercise, defined as exercise at 65%-85% of maximum heart rate or at 6-8 points on the OMNI scale. Mean compliance among the participants was 63.6%.

The participants had a median age of 59 and 15 of the 19 were diagnosed with invasive carcinoma. Following surgery, 13 underwent radiotherapy, 15 received chemotherapy, and 18 received hormone therapy.

“Treatments for early breast cancer have side effects that affect quality of life and cause deconditioning,” the investigators wrote, adding that “physical exercise might have a supportive and coadjuvant role in the rehabilitation of breast cancer survivors.”

The MAMA MOVE trial aimed to assess the potential benefits of a community-based supervised exercise training program, and the findings suggest such programs could help improve quality of life, particularly with respect to physical functioning, they concluded.

The MAMA MOVE Gaia study was funded by Liga Portuguesa Contra o Cancro. The investigators reported having no disclosures.
 

SOURCE: Joaquim A et al. ESMO 2019, Abstract 234P.

Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.
 

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.
 

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.
 

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

Though survival rates of patients with metastatic breast cancer (MBC) have increased over the last 2 decades, a new study has indicated disparities exist across regions and by variables like age and race.

“It appears from these results that we may be at a crossroads for MBC treatment and survival,” wrote Judith A. Malmgren, PhD, of the University of Washington and her coauthors. The study was published in Cancer. “Access to appropriate, timely, and up‐to‐date diagnosis, care, treatment, and surveillance could turn this fatal disease into a chronic and treatable phenomenon, depending on patient factors, molecular subtype, and insurance capacity to pay for treatment,” they said.

To determine how breast cancer outcomes might vary across regions, the researchers compared breast cancer–specific survival rates (BCSS) from Surveillance, Epidemiology, and End Results-9 (SEER-9) registry data minus a regional subset from the Seattle-Puget Sound (S-PS) region (n = 12,121) to patients from that S-PS region (n = 1,931) and to an individual cohort in that area (n = 261). Five-year BCSS rates were calculated for three time periods: 1990‐1998, 1999‐2004, and 2005‐2011.

All analyzed patients were diagnosed with a first primary, de novo, stage IV breast cancer between the ages of 25 and 84 years from 1990 to 2011. Patients in the SEER-9 group and the S-PS region had a mean age of 61 years, compared with the individual cohort’s mean age of 55 years. Patients in the individual cohort were more likely to reside in a major metropolitan area of over 1 million people, compared with the SEER group and the S-PS region (86% versus 61% and 58%, respectively).

Patients in the SEER-9 group had improved BCSS rates over the study period, from 19% in 1990-1998 (95% confidence interval, 18%-21%; P less than .001) to 26% in 2005-2011 (95% CI, 24%-27%; P less than .001). Patients in the S-PS region saw even greater improvements in BCSS rates, from 21% in 1990-1998 (95% CI, 18%-24%; P less than .001) to 35% in 2005-2011 (95% CI, 32%-39%; P less than .001). But the largest improvement in survival rates came from patients in the individual cohort, who went from 29% in 1990-1998 (95% CI, 18%-37%; P less than .001) to 56% in 2005-2011 (95% CI, 45%-65%; P = .004).

In a proportional hazards model for breast cancer–specific death, reduced hazard in the SEER-9 group was associated with surgery (hazard ratio, 0.58; 95% CI, 0.55-0.61; P less than .001), an age less than 70 (HR, 0.77; 95% CI, 0.73-0.82; P less than .001) and white race (HR, 0.84; 95% CI, 0.79-0.89; P less than .001). Similar associations were seen in the S-PS region with surgery (HR, 0.57; 95% CI, 0.50-0.66; P less than .001) and an age less than 70 (HR, 0.72; 95% CI, 0.62-0.84; P less than .001), but not white race.

The study results “indicate that the stage IV population that is living longer may be benefiting from many of the same therapies used to treat early breast cancer, especially for patients who are able to handle adjuvant chemotherapy treatment and are HR‐positive,” the researchers said. “However, the lag in survival improvement across different population‐based, geographic regions suggests that some groups and regions may benefit unequally from treatment advances as well as timely diagnosis.”

The study was funded by the Kaplan Cancer Research Fund, the Metastatic Breast Cancer Alliance, and the Surveillance, Epidemiology, and End Results Cancer Surveillance System program of the National Cancer Institute. The authors reported no conflicts of interest.

SOURCE: Malmgren JA et al. Cancer. 2019 Oct 22. doi: 10.1002/cncr.32531.

Though survival rates of patients with metastatic breast cancer (MBC) have increased over the last 2 decades, a new study has indicated disparities exist across regions and by variables like age and race.

“It appears from these results that we may be at a crossroads for MBC treatment and survival,” wrote Judith A. Malmgren, PhD, of the University of Washington and her coauthors. The study was published in Cancer. “Access to appropriate, timely, and up‐to‐date diagnosis, care, treatment, and surveillance could turn this fatal disease into a chronic and treatable phenomenon, depending on patient factors, molecular subtype, and insurance capacity to pay for treatment,” they said.

To determine how breast cancer outcomes might vary across regions, the researchers compared breast cancer–specific survival rates (BCSS) from Surveillance, Epidemiology, and End Results-9 (SEER-9) registry data minus a regional subset from the Seattle-Puget Sound (S-PS) region (n = 12,121) to patients from that S-PS region (n = 1,931) and to an individual cohort in that area (n = 261). Five-year BCSS rates were calculated for three time periods: 1990‐1998, 1999‐2004, and 2005‐2011.

All analyzed patients were diagnosed with a first primary, de novo, stage IV breast cancer between the ages of 25 and 84 years from 1990 to 2011. Patients in the SEER-9 group and the S-PS region had a mean age of 61 years, compared with the individual cohort’s mean age of 55 years. Patients in the individual cohort were more likely to reside in a major metropolitan area of over 1 million people, compared with the SEER group and the S-PS region (86% versus 61% and 58%, respectively).

Patients in the SEER-9 group had improved BCSS rates over the study period, from 19% in 1990-1998 (95% confidence interval, 18%-21%; P less than .001) to 26% in 2005-2011 (95% CI, 24%-27%; P less than .001). Patients in the S-PS region saw even greater improvements in BCSS rates, from 21% in 1990-1998 (95% CI, 18%-24%; P less than .001) to 35% in 2005-2011 (95% CI, 32%-39%; P less than .001). But the largest improvement in survival rates came from patients in the individual cohort, who went from 29% in 1990-1998 (95% CI, 18%-37%; P less than .001) to 56% in 2005-2011 (95% CI, 45%-65%; P = .004).

In a proportional hazards model for breast cancer–specific death, reduced hazard in the SEER-9 group was associated with surgery (hazard ratio, 0.58; 95% CI, 0.55-0.61; P less than .001), an age less than 70 (HR, 0.77; 95% CI, 0.73-0.82; P less than .001) and white race (HR, 0.84; 95% CI, 0.79-0.89; P less than .001). Similar associations were seen in the S-PS region with surgery (HR, 0.57; 95% CI, 0.50-0.66; P less than .001) and an age less than 70 (HR, 0.72; 95% CI, 0.62-0.84; P less than .001), but not white race.

The study results “indicate that the stage IV population that is living longer may be benefiting from many of the same therapies used to treat early breast cancer, especially for patients who are able to handle adjuvant chemotherapy treatment and are HR‐positive,” the researchers said. “However, the lag in survival improvement across different population‐based, geographic regions suggests that some groups and regions may benefit unequally from treatment advances as well as timely diagnosis.”

The study was funded by the Kaplan Cancer Research Fund, the Metastatic Breast Cancer Alliance, and the Surveillance, Epidemiology, and End Results Cancer Surveillance System program of the National Cancer Institute. The authors reported no conflicts of interest.

SOURCE: Malmgren JA et al. Cancer. 2019 Oct 22. doi: 10.1002/cncr.32531.

Though survival rates of patients with metastatic breast cancer (MBC) have increased over the last 2 decades, a new study has indicated disparities exist across regions and by variables like age and race.

“It appears from these results that we may be at a crossroads for MBC treatment and survival,” wrote Judith A. Malmgren, PhD, of the University of Washington and her coauthors. The study was published in Cancer. “Access to appropriate, timely, and up‐to‐date diagnosis, care, treatment, and surveillance could turn this fatal disease into a chronic and treatable phenomenon, depending on patient factors, molecular subtype, and insurance capacity to pay for treatment,” they said.

To determine how breast cancer outcomes might vary across regions, the researchers compared breast cancer–specific survival rates (BCSS) from Surveillance, Epidemiology, and End Results-9 (SEER-9) registry data minus a regional subset from the Seattle-Puget Sound (S-PS) region (n = 12,121) to patients from that S-PS region (n = 1,931) and to an individual cohort in that area (n = 261). Five-year BCSS rates were calculated for three time periods: 1990‐1998, 1999‐2004, and 2005‐2011.

All analyzed patients were diagnosed with a first primary, de novo, stage IV breast cancer between the ages of 25 and 84 years from 1990 to 2011. Patients in the SEER-9 group and the S-PS region had a mean age of 61 years, compared with the individual cohort’s mean age of 55 years. Patients in the individual cohort were more likely to reside in a major metropolitan area of over 1 million people, compared with the SEER group and the S-PS region (86% versus 61% and 58%, respectively).

Patients in the SEER-9 group had improved BCSS rates over the study period, from 19% in 1990-1998 (95% confidence interval, 18%-21%; P less than .001) to 26% in 2005-2011 (95% CI, 24%-27%; P less than .001). Patients in the S-PS region saw even greater improvements in BCSS rates, from 21% in 1990-1998 (95% CI, 18%-24%; P less than .001) to 35% in 2005-2011 (95% CI, 32%-39%; P less than .001). But the largest improvement in survival rates came from patients in the individual cohort, who went from 29% in 1990-1998 (95% CI, 18%-37%; P less than .001) to 56% in 2005-2011 (95% CI, 45%-65%; P = .004).

In a proportional hazards model for breast cancer–specific death, reduced hazard in the SEER-9 group was associated with surgery (hazard ratio, 0.58; 95% CI, 0.55-0.61; P less than .001), an age less than 70 (HR, 0.77; 95% CI, 0.73-0.82; P less than .001) and white race (HR, 0.84; 95% CI, 0.79-0.89; P less than .001). Similar associations were seen in the S-PS region with surgery (HR, 0.57; 95% CI, 0.50-0.66; P less than .001) and an age less than 70 (HR, 0.72; 95% CI, 0.62-0.84; P less than .001), but not white race.

The study results “indicate that the stage IV population that is living longer may be benefiting from many of the same therapies used to treat early breast cancer, especially for patients who are able to handle adjuvant chemotherapy treatment and are HR‐positive,” the researchers said. “However, the lag in survival improvement across different population‐based, geographic regions suggests that some groups and regions may benefit unequally from treatment advances as well as timely diagnosis.”

The study was funded by the Kaplan Cancer Research Fund, the Metastatic Breast Cancer Alliance, and the Surveillance, Epidemiology, and End Results Cancer Surveillance System program of the National Cancer Institute. The authors reported no conflicts of interest.

SOURCE: Malmgren JA et al. Cancer. 2019 Oct 22. doi: 10.1002/cncr.32531.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.