Genitourinary Cancer

ORLANDO – Active surveillance prior to initiating targeted therapy could be an option for some patients with metastatic renal cell carcinoma (mRCC), according to new findings.

“Active surveillance does not affect the efficacy of subsequent therapies,” said lead study author Davide Bimbatti, MD, of the Azienda Ospedaliera Universitaria Integrata, University of Verona (Italy). “In selected patients, active surveillance allows us to delay the start of systemic treatment, and patients in active surveillance rarely have a worsening of prognostic class,” he said in a press briefing held at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Targeted therapies can improve survival in mRCC but treatment is not curative and associated toxicities can interfere with quality of life and force patients to discontinue treatment. Active surveillance delays the use of systemic therapy and associated toxicities, and is a feasible strategy for patients with indolent disease.

However, the effect of active surveillance on tumor burden and prognosis have not been investigated.

To address this issue, Dr. Bimbatti and his colleagues conducted a retrospective study and evaluated the effect of active surveillance on overall survival and postsurveillance overall survival, progression-free survival, and tumor burden (a measure of the number of sites and tumor size).

The study cohort included 48 patients with mRCC who underwent active surveillance during 2007-2016 and changes in the International mRCC Database Consortium (IMDC) prognostic class and tumor burden were analyzed for associations with these endpoints.

At baseline, 69% of patients had a favorable prognostic IMDC class, 25% were at an intermediate class, and 6% had a poor class designation. The main sites of metastases were lung (56%), lymph nodes (25%), pancreas (14%), adrenal gland (8%), CNS (8%), and bone (6%).

At a median follow-up of 37.3 months, 79.2% of patients were still alive and, at a median surveillance duration of 16.7 months, 71% of patients had begun a targeted therapy. There were a total of 17 deaths (33%).

Median progression-free survival was 16.6 months and median postsurveillance overall survival was 39.1 months.

During active surveillance, only four patients transitioned from good to intermediate IMDC prognostic class. IMDC classes overall maintained their prognostic value during active surveillance, Dr. Bimbatti said. IMDC class was also the only factor that was associated with time on surveillance.

At baseline, tumor burden was in one site for 65% of patients, two sites in 31%, and three or more sites for 4%, but during active surveillance, changes occurred in one site in 35% of patients, two in 48%, and more than two in 17%.

A change in tumor burden (greater than or equal to 2.2 times the original burden), however, was related to poorer postsurveillance survival (hazard ratio,1.23; P less than .01), but not with overall survival (HR, 1.0; P less than .05).

Conversely, any increase in metastatic sites was associated with both significantly worse postsurveillance and overall survival (HR = 2.6, P = 0.04; and HR = 3.3, P less than 0.01).

Commenting on the study, Primo N. Lara Jr., MD, of the University of California, Davis, Comprehensive Cancer Center explained that active surveillance “remains a reasonable option for highly selected patients.”

“[The investigators] provide reassuring data that active surveillance does not alter the IMDC risk grouping,” he said, and that the results of this study overall, were similar to those of prior research.

There were some limitations to the study, in that it was retrospective and conducted at a single institution. “It also failed to account for psychosocial issues such as anxiety during the active surveillance phase,” he said.

Critical questions also remain, Dr. Lara added, such as what are the validated selection criteria for patients entering active surveillance or what is the threshold of tumor burden to warrant active surveillance discontinuation.

The funding source was not disclosed. Dr. Bimbatti and his coauthors have no disclosures. Dr. Lara reports financial ties to multiple pharmaceutical companies.

ORLANDO – Active surveillance prior to initiating targeted therapy could be an option for some patients with metastatic renal cell carcinoma (mRCC), according to new findings.

“Active surveillance does not affect the efficacy of subsequent therapies,” said lead study author Davide Bimbatti, MD, of the Azienda Ospedaliera Universitaria Integrata, University of Verona (Italy). “In selected patients, active surveillance allows us to delay the start of systemic treatment, and patients in active surveillance rarely have a worsening of prognostic class,” he said in a press briefing held at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Targeted therapies can improve survival in mRCC but treatment is not curative and associated toxicities can interfere with quality of life and force patients to discontinue treatment. Active surveillance delays the use of systemic therapy and associated toxicities, and is a feasible strategy for patients with indolent disease.

However, the effect of active surveillance on tumor burden and prognosis have not been investigated.

To address this issue, Dr. Bimbatti and his colleagues conducted a retrospective study and evaluated the effect of active surveillance on overall survival and postsurveillance overall survival, progression-free survival, and tumor burden (a measure of the number of sites and tumor size).

The study cohort included 48 patients with mRCC who underwent active surveillance during 2007-2016 and changes in the International mRCC Database Consortium (IMDC) prognostic class and tumor burden were analyzed for associations with these endpoints.

At baseline, 69% of patients had a favorable prognostic IMDC class, 25% were at an intermediate class, and 6% had a poor class designation. The main sites of metastases were lung (56%), lymph nodes (25%), pancreas (14%), adrenal gland (8%), CNS (8%), and bone (6%).

At a median follow-up of 37.3 months, 79.2% of patients were still alive and, at a median surveillance duration of 16.7 months, 71% of patients had begun a targeted therapy. There were a total of 17 deaths (33%).

Median progression-free survival was 16.6 months and median postsurveillance overall survival was 39.1 months.

During active surveillance, only four patients transitioned from good to intermediate IMDC prognostic class. IMDC classes overall maintained their prognostic value during active surveillance, Dr. Bimbatti said. IMDC class was also the only factor that was associated with time on surveillance.

At baseline, tumor burden was in one site for 65% of patients, two sites in 31%, and three or more sites for 4%, but during active surveillance, changes occurred in one site in 35% of patients, two in 48%, and more than two in 17%.

A change in tumor burden (greater than or equal to 2.2 times the original burden), however, was related to poorer postsurveillance survival (hazard ratio,1.23; P less than .01), but not with overall survival (HR, 1.0; P less than .05).

Conversely, any increase in metastatic sites was associated with both significantly worse postsurveillance and overall survival (HR = 2.6, P = 0.04; and HR = 3.3, P less than 0.01).

Commenting on the study, Primo N. Lara Jr., MD, of the University of California, Davis, Comprehensive Cancer Center explained that active surveillance “remains a reasonable option for highly selected patients.”

“[The investigators] provide reassuring data that active surveillance does not alter the IMDC risk grouping,” he said, and that the results of this study overall, were similar to those of prior research.

There were some limitations to the study, in that it was retrospective and conducted at a single institution. “It also failed to account for psychosocial issues such as anxiety during the active surveillance phase,” he said.

Critical questions also remain, Dr. Lara added, such as what are the validated selection criteria for patients entering active surveillance or what is the threshold of tumor burden to warrant active surveillance discontinuation.

The funding source was not disclosed. Dr. Bimbatti and his coauthors have no disclosures. Dr. Lara reports financial ties to multiple pharmaceutical companies.

ORLANDO – Active surveillance prior to initiating targeted therapy could be an option for some patients with metastatic renal cell carcinoma (mRCC), according to new findings.

“Active surveillance does not affect the efficacy of subsequent therapies,” said lead study author Davide Bimbatti, MD, of the Azienda Ospedaliera Universitaria Integrata, University of Verona (Italy). “In selected patients, active surveillance allows us to delay the start of systemic treatment, and patients in active surveillance rarely have a worsening of prognostic class,” he said in a press briefing held at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Targeted therapies can improve survival in mRCC but treatment is not curative and associated toxicities can interfere with quality of life and force patients to discontinue treatment. Active surveillance delays the use of systemic therapy and associated toxicities, and is a feasible strategy for patients with indolent disease.

However, the effect of active surveillance on tumor burden and prognosis have not been investigated.

To address this issue, Dr. Bimbatti and his colleagues conducted a retrospective study and evaluated the effect of active surveillance on overall survival and postsurveillance overall survival, progression-free survival, and tumor burden (a measure of the number of sites and tumor size).

The study cohort included 48 patients with mRCC who underwent active surveillance during 2007-2016 and changes in the International mRCC Database Consortium (IMDC) prognostic class and tumor burden were analyzed for associations with these endpoints.

At baseline, 69% of patients had a favorable prognostic IMDC class, 25% were at an intermediate class, and 6% had a poor class designation. The main sites of metastases were lung (56%), lymph nodes (25%), pancreas (14%), adrenal gland (8%), CNS (8%), and bone (6%).

At a median follow-up of 37.3 months, 79.2% of patients were still alive and, at a median surveillance duration of 16.7 months, 71% of patients had begun a targeted therapy. There were a total of 17 deaths (33%).

Median progression-free survival was 16.6 months and median postsurveillance overall survival was 39.1 months.

During active surveillance, only four patients transitioned from good to intermediate IMDC prognostic class. IMDC classes overall maintained their prognostic value during active surveillance, Dr. Bimbatti said. IMDC class was also the only factor that was associated with time on surveillance.

At baseline, tumor burden was in one site for 65% of patients, two sites in 31%, and three or more sites for 4%, but during active surveillance, changes occurred in one site in 35% of patients, two in 48%, and more than two in 17%.

A change in tumor burden (greater than or equal to 2.2 times the original burden), however, was related to poorer postsurveillance survival (hazard ratio,1.23; P less than .01), but not with overall survival (HR, 1.0; P less than .05).

Conversely, any increase in metastatic sites was associated with both significantly worse postsurveillance and overall survival (HR = 2.6, P = 0.04; and HR = 3.3, P less than 0.01).

Commenting on the study, Primo N. Lara Jr., MD, of the University of California, Davis, Comprehensive Cancer Center explained that active surveillance “remains a reasonable option for highly selected patients.”

“[The investigators] provide reassuring data that active surveillance does not alter the IMDC risk grouping,” he said, and that the results of this study overall, were similar to those of prior research.

There were some limitations to the study, in that it was retrospective and conducted at a single institution. “It also failed to account for psychosocial issues such as anxiety during the active surveillance phase,” he said.

Critical questions also remain, Dr. Lara added, such as what are the validated selection criteria for patients entering active surveillance or what is the threshold of tumor burden to warrant active surveillance discontinuation.

The funding source was not disclosed. Dr. Bimbatti and his coauthors have no disclosures. Dr. Lara reports financial ties to multiple pharmaceutical companies.

ORLANDO – Although two cycles of bleomycin-etoposide-cisplatin (BEP) chemotherapy typically comprise adjuvant treatment for nonseminomatous or combined germ cell testicular cancer, investigators suggest one cycle may be sufficient.

“Over recent years, evidence has begun to accumulate that one single cycle of BEP may be sufficient to reduce the recurrence rate to below 5%,” said Robert Anthony Huddart, MBBS, MRCP, FRCR, PhD, of the Institute of Cancer Research in Sutton, England. “If this is confirmed, it means we could have a similar cure rate to two cycles of lower-dose BEP and that would reduce the overall burden of chemotherapy and health care resource usage.”

Dr. Huddart and his coauthors assessed 246 people from 33 centers in the United Kingdom. The patients had stage I nonseminomatous or combined germ cell testicular cancer. Instead of the standard two cycles of lower-dose etoposide regimen, BE360P post orchidectomy, the investigators administered one dose of BE500P and then followed patients for a mean 39 months.

The primary endpoint of the single-arm study was malignant recurrence at 2 years. Some patients will recur with acute, undifferentiated disease at multiple sites, often with rising markers; the treatment for these patients is further chemotherapy, Dr. Huddart explained. In contrast, other patients present with differentiated teratomas, usually in the peritoneum; they tend to be marker negative and candidates for surgical resection.

Malignant recurrence rate

“The headline result for the study is … we had three malignant recurrences, for a 1.3% rate, with an upper confidence limit of 4% – below our 5% target,” Dr. Huddart said at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. “We also had three patients – or 1.3% – who presented with differential teratoma[s], so the overall event rate was 2.6% at 2 years.”

“This adjuvant chemotherapy is highly successful in reducing recurrence, with a 2-year recurrence-free rate of 98%. And it does avoid the need for intensive surveillance,” Dr. Huddart said.

“This paper demonstrates that single-cycle treatment is safe and effective and two cycles are unnecessary,” said study discussant Noel W. Clarke, MBBS, FRCS, of the Christie Hospital NHS Foundation Trust in Manchester, England. “So why don’t we give all patients this kind of treatment? It doesn’t come without toxicity,” he said.

Adverse events

Myelosuppression comprised the majority of grade 3 and 4 acute toxicities in the study, which “is what you would expect with BEP chemotherapy,” Dr. Huddart said. The most common adverse events were neutropenia, leukopenia, and febrile neutropenia. He pointed out that the febrile neutropenia rate “was a low 6.4%.” A total of 104 patients experienced any toxicity.

A meeting attendee asked why the investigators did not consider a lower dose of etoposide in the study. Dr. Huddart replied, “We used a standard dose BEP because etoposide reduction might reduce the toxicity, but it might also reduce the efficacy.”

In terms of overall survival, three participants died during the study. One presented 6 months after adjuvant chemotherapy with a large, intra-abdominal recurrence; another patient died from a secondary primary lung cancer; and the third from a drug overdose.

In addition to the 2-year primary outcomes, by 4 years, another malignancy recurrence occurred, for a cumulative rate of 1.8%; including teratomas, the all-recurrence rate increased to 3.1%. “Therefore, we can successfully demonstrate the rate of malignancy after one cycle of BEP is less than 5%,” Dr. Huddart said.

Participants were aged 16 years and older with clinical stage I disease, including both mixed or pure nonseminomatous germ cell tumors. Patients also received two prophylactic agents. “We were keen to reduce the incidence of neutropenic sepsis and gave propped up G-CSF [granulocyte-colony stimulating factor] and propped up antibiotics,” Dr. Huddart said.

“This is a new treatment approach for an uncommon cancer,” Dr. Huddart said. Adoption of the protocol would reduce the overall exposure to chemotherapy in a young patient population, he added. “Just 20% of patients were [older than] age 40.”

ORLANDO – Although two cycles of bleomycin-etoposide-cisplatin (BEP) chemotherapy typically comprise adjuvant treatment for nonseminomatous or combined germ cell testicular cancer, investigators suggest one cycle may be sufficient.

“Over recent years, evidence has begun to accumulate that one single cycle of BEP may be sufficient to reduce the recurrence rate to below 5%,” said Robert Anthony Huddart, MBBS, MRCP, FRCR, PhD, of the Institute of Cancer Research in Sutton, England. “If this is confirmed, it means we could have a similar cure rate to two cycles of lower-dose BEP and that would reduce the overall burden of chemotherapy and health care resource usage.”

Dr. Huddart and his coauthors assessed 246 people from 33 centers in the United Kingdom. The patients had stage I nonseminomatous or combined germ cell testicular cancer. Instead of the standard two cycles of lower-dose etoposide regimen, BE360P post orchidectomy, the investigators administered one dose of BE500P and then followed patients for a mean 39 months.

The primary endpoint of the single-arm study was malignant recurrence at 2 years. Some patients will recur with acute, undifferentiated disease at multiple sites, often with rising markers; the treatment for these patients is further chemotherapy, Dr. Huddart explained. In contrast, other patients present with differentiated teratomas, usually in the peritoneum; they tend to be marker negative and candidates for surgical resection.

Malignant recurrence rate

“The headline result for the study is … we had three malignant recurrences, for a 1.3% rate, with an upper confidence limit of 4% – below our 5% target,” Dr. Huddart said at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. “We also had three patients – or 1.3% – who presented with differential teratoma[s], so the overall event rate was 2.6% at 2 years.”

“This adjuvant chemotherapy is highly successful in reducing recurrence, with a 2-year recurrence-free rate of 98%. And it does avoid the need for intensive surveillance,” Dr. Huddart said.

“This paper demonstrates that single-cycle treatment is safe and effective and two cycles are unnecessary,” said study discussant Noel W. Clarke, MBBS, FRCS, of the Christie Hospital NHS Foundation Trust in Manchester, England. “So why don’t we give all patients this kind of treatment? It doesn’t come without toxicity,” he said.

Adverse events

Myelosuppression comprised the majority of grade 3 and 4 acute toxicities in the study, which “is what you would expect with BEP chemotherapy,” Dr. Huddart said. The most common adverse events were neutropenia, leukopenia, and febrile neutropenia. He pointed out that the febrile neutropenia rate “was a low 6.4%.” A total of 104 patients experienced any toxicity.

A meeting attendee asked why the investigators did not consider a lower dose of etoposide in the study. Dr. Huddart replied, “We used a standard dose BEP because etoposide reduction might reduce the toxicity, but it might also reduce the efficacy.”

In terms of overall survival, three participants died during the study. One presented 6 months after adjuvant chemotherapy with a large, intra-abdominal recurrence; another patient died from a secondary primary lung cancer; and the third from a drug overdose.

In addition to the 2-year primary outcomes, by 4 years, another malignancy recurrence occurred, for a cumulative rate of 1.8%; including teratomas, the all-recurrence rate increased to 3.1%. “Therefore, we can successfully demonstrate the rate of malignancy after one cycle of BEP is less than 5%,” Dr. Huddart said.

Participants were aged 16 years and older with clinical stage I disease, including both mixed or pure nonseminomatous germ cell tumors. Patients also received two prophylactic agents. “We were keen to reduce the incidence of neutropenic sepsis and gave propped up G-CSF [granulocyte-colony stimulating factor] and propped up antibiotics,” Dr. Huddart said.

“This is a new treatment approach for an uncommon cancer,” Dr. Huddart said. Adoption of the protocol would reduce the overall exposure to chemotherapy in a young patient population, he added. “Just 20% of patients were [older than] age 40.”

ORLANDO – Although two cycles of bleomycin-etoposide-cisplatin (BEP) chemotherapy typically comprise adjuvant treatment for nonseminomatous or combined germ cell testicular cancer, investigators suggest one cycle may be sufficient.

“Over recent years, evidence has begun to accumulate that one single cycle of BEP may be sufficient to reduce the recurrence rate to below 5%,” said Robert Anthony Huddart, MBBS, MRCP, FRCR, PhD, of the Institute of Cancer Research in Sutton, England. “If this is confirmed, it means we could have a similar cure rate to two cycles of lower-dose BEP and that would reduce the overall burden of chemotherapy and health care resource usage.”

Dr. Huddart and his coauthors assessed 246 people from 33 centers in the United Kingdom. The patients had stage I nonseminomatous or combined germ cell testicular cancer. Instead of the standard two cycles of lower-dose etoposide regimen, BE360P post orchidectomy, the investigators administered one dose of BE500P and then followed patients for a mean 39 months.

The primary endpoint of the single-arm study was malignant recurrence at 2 years. Some patients will recur with acute, undifferentiated disease at multiple sites, often with rising markers; the treatment for these patients is further chemotherapy, Dr. Huddart explained. In contrast, other patients present with differentiated teratomas, usually in the peritoneum; they tend to be marker negative and candidates for surgical resection.

Malignant recurrence rate

“The headline result for the study is … we had three malignant recurrences, for a 1.3% rate, with an upper confidence limit of 4% – below our 5% target,” Dr. Huddart said at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. “We also had three patients – or 1.3% – who presented with differential teratoma[s], so the overall event rate was 2.6% at 2 years.”

“This adjuvant chemotherapy is highly successful in reducing recurrence, with a 2-year recurrence-free rate of 98%. And it does avoid the need for intensive surveillance,” Dr. Huddart said.

“This paper demonstrates that single-cycle treatment is safe and effective and two cycles are unnecessary,” said study discussant Noel W. Clarke, MBBS, FRCS, of the Christie Hospital NHS Foundation Trust in Manchester, England. “So why don’t we give all patients this kind of treatment? It doesn’t come without toxicity,” he said.

Adverse events

Myelosuppression comprised the majority of grade 3 and 4 acute toxicities in the study, which “is what you would expect with BEP chemotherapy,” Dr. Huddart said. The most common adverse events were neutropenia, leukopenia, and febrile neutropenia. He pointed out that the febrile neutropenia rate “was a low 6.4%.” A total of 104 patients experienced any toxicity.

A meeting attendee asked why the investigators did not consider a lower dose of etoposide in the study. Dr. Huddart replied, “We used a standard dose BEP because etoposide reduction might reduce the toxicity, but it might also reduce the efficacy.”

In terms of overall survival, three participants died during the study. One presented 6 months after adjuvant chemotherapy with a large, intra-abdominal recurrence; another patient died from a secondary primary lung cancer; and the third from a drug overdose.

In addition to the 2-year primary outcomes, by 4 years, another malignancy recurrence occurred, for a cumulative rate of 1.8%; including teratomas, the all-recurrence rate increased to 3.1%. “Therefore, we can successfully demonstrate the rate of malignancy after one cycle of BEP is less than 5%,” Dr. Huddart said.

Participants were aged 16 years and older with clinical stage I disease, including both mixed or pure nonseminomatous germ cell tumors. Patients also received two prophylactic agents. “We were keen to reduce the incidence of neutropenic sepsis and gave propped up G-CSF [granulocyte-colony stimulating factor] and propped up antibiotics,” Dr. Huddart said.

“This is a new treatment approach for an uncommon cancer,” Dr. Huddart said. Adoption of the protocol would reduce the overall exposure to chemotherapy in a young patient population, he added. “Just 20% of patients were [older than] age 40.”

Orlando – The updated results of a large phase III trial support the use of chemoradiation with 5-fluorouracil (5-FU) and mitomycin C (MMC) and confirm that this treatment regimen should be a standard of care for muscle-invasive bladder cancer (MIBC).

When comparing patients who received radiation therapy with those who received chemoradiation, there was a robust improvement in bladder cancer specific survival for the latter when adjusted for known prognostic factors (hazard ratio, 0.73; P = .043).

There was also a borderline significant improvement in metastasis-free survival (HR, 0.78) and a significant reduction in the need for salvage cystectomy in the patients treated with chemoradiation (2-year rate, chemoradiotherapy11% vs. radiation therapy:17%, HR, 0.54; P = .03).

There were no statistically significant differences between groups when it came to overall survival, but, even though overall survival did not reach significance, at 2 years, there was a hint of separation of the curves, explained study author Emma Hall, MD, from the Institute of Cancer Research, London at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and the Society of Urologic Oncology.

One of the treatment arms received a reduced rate of radiation therapy to see if that would decrease toxicity. “The radiation therapy volume modification that we used did not reduce toxicity, but there is no evidence of an increase in local failure rate, suggesting it is safe to pursue clinical trials of volume sparing radiation therapy using newer technology adaptive delivery techniques,” said Dr. Hall.

The initial findings of the BC2001 study showed that adding chemotherapy (5-FU + MMC) to radiotherapy significantly improved rates of MIBC locoregional control but that reduced high-dose volume versus standard radiotherapy did not significantly reduce late side effects.

This study was a clinical trial set up to test two different questions in the treatment of MIBC, as an alternative to cystectomy. “We wanted to see if adding synchronous chemotherapy to radiotherapy would improve locoregional recurrence control and if reducing the radiation dose to uninvolved bladder would reduce toxicity and not impact local regional recurrence control,” according to Dr. Hall.

Under the 2 x 2 partial factorial design, 458 patients were randomized to radiation therapy (n = 178) or chemoradiation (n = 182) and/or to standard radiation therapy (n = 108) or reduced high-dose volume radiation therapy (n = 111).

The primary endpoint was locoregional control, and secondary endpoints included overall survival, bladder-cancer specific survival, metastasis-free survival, and salvage cystectomy rates.

The initial patients received radiation therapy instead of chemoradiation, and there was a robust improvement in bladder cancer–specific survival when adjusted for known prognostic factors (HR, 0.73; P = .043).

The analysis, presented in 2012, showed a reduction of about one-third of locoregional recurrence. The local control rates were 54% in the radiotherapy-alone arm and 67% in the chemoradiotherapy arm.

There was no significant difference in overall survival at that time.

For the radiotherapy comparison, the rate of late toxicity was low, and much lower than was anticipated, at the outset of the trial, and there was no difference in treatment groups, said Dr. Hall.

In an updated analysis, with a median of 10 years of follow-up, 70% of the patients were now deceased. “These represent robust data, and it is unlikely we will see any changes to the data,” she noted.

The findings presented now had an additional 4 years of follow-up, and while there were additional late events, the results were basically the same.

The rate of local control now showed a 40% reduction in the risk of recurrence and 5-year local control rates of 49% in the radiotherapy arm and 63% in the chemoradiotherapy arm.

“With 10 years follow up, an improvement in locoregional control and a reduced salvage cystectomy rate is confirmed with chemoradiotherapy,” Dr. Hall concluded, “and, taken together with the good quality of life data we have, this is important for this group.”

In a discussion of the paper, Dr. Jonathan Rosenberg, MD, from Memorial Sloan Kettering Cancer Center in New York, agrees with the conclusion that the data continue to support the use of chemoradiotherapy and that 5-FU + MMC is a good option.

He noted that 5-FU + MMC is a standard of care regardless of cisplatin eligibility, but he cannot draw conclusions on dose volume. “There are also other options for chemosensitization,” he said, but it is also import to determine the best way to select patients who will derive the most benefit from chemoradiation.

“There is a high need for robust predictive biomarkers, and we need novel approaches to move beyond chemotherapy,” he said.

The study was supported by Cancer Research UK. Dr Hall has received research funding from Accuray, AstraZeneca, Aventis, and Bayer. Several co-authors also have disclosed relationships with industry. Dr. Rosenberg has disclosed multiple relationships with industry.

Orlando – The updated results of a large phase III trial support the use of chemoradiation with 5-fluorouracil (5-FU) and mitomycin C (MMC) and confirm that this treatment regimen should be a standard of care for muscle-invasive bladder cancer (MIBC).

When comparing patients who received radiation therapy with those who received chemoradiation, there was a robust improvement in bladder cancer specific survival for the latter when adjusted for known prognostic factors (hazard ratio, 0.73; P = .043).

There was also a borderline significant improvement in metastasis-free survival (HR, 0.78) and a significant reduction in the need for salvage cystectomy in the patients treated with chemoradiation (2-year rate, chemoradiotherapy11% vs. radiation therapy:17%, HR, 0.54; P = .03).

There were no statistically significant differences between groups when it came to overall survival, but, even though overall survival did not reach significance, at 2 years, there was a hint of separation of the curves, explained study author Emma Hall, MD, from the Institute of Cancer Research, London at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and the Society of Urologic Oncology.

One of the treatment arms received a reduced rate of radiation therapy to see if that would decrease toxicity. “The radiation therapy volume modification that we used did not reduce toxicity, but there is no evidence of an increase in local failure rate, suggesting it is safe to pursue clinical trials of volume sparing radiation therapy using newer technology adaptive delivery techniques,” said Dr. Hall.

The initial findings of the BC2001 study showed that adding chemotherapy (5-FU + MMC) to radiotherapy significantly improved rates of MIBC locoregional control but that reduced high-dose volume versus standard radiotherapy did not significantly reduce late side effects.

This study was a clinical trial set up to test two different questions in the treatment of MIBC, as an alternative to cystectomy. “We wanted to see if adding synchronous chemotherapy to radiotherapy would improve locoregional recurrence control and if reducing the radiation dose to uninvolved bladder would reduce toxicity and not impact local regional recurrence control,” according to Dr. Hall.

Under the 2 x 2 partial factorial design, 458 patients were randomized to radiation therapy (n = 178) or chemoradiation (n = 182) and/or to standard radiation therapy (n = 108) or reduced high-dose volume radiation therapy (n = 111).

The primary endpoint was locoregional control, and secondary endpoints included overall survival, bladder-cancer specific survival, metastasis-free survival, and salvage cystectomy rates.

The initial patients received radiation therapy instead of chemoradiation, and there was a robust improvement in bladder cancer–specific survival when adjusted for known prognostic factors (HR, 0.73; P = .043).

The analysis, presented in 2012, showed a reduction of about one-third of locoregional recurrence. The local control rates were 54% in the radiotherapy-alone arm and 67% in the chemoradiotherapy arm.

There was no significant difference in overall survival at that time.

For the radiotherapy comparison, the rate of late toxicity was low, and much lower than was anticipated, at the outset of the trial, and there was no difference in treatment groups, said Dr. Hall.

In an updated analysis, with a median of 10 years of follow-up, 70% of the patients were now deceased. “These represent robust data, and it is unlikely we will see any changes to the data,” she noted.

The findings presented now had an additional 4 years of follow-up, and while there were additional late events, the results were basically the same.

The rate of local control now showed a 40% reduction in the risk of recurrence and 5-year local control rates of 49% in the radiotherapy arm and 63% in the chemoradiotherapy arm.

“With 10 years follow up, an improvement in locoregional control and a reduced salvage cystectomy rate is confirmed with chemoradiotherapy,” Dr. Hall concluded, “and, taken together with the good quality of life data we have, this is important for this group.”

In a discussion of the paper, Dr. Jonathan Rosenberg, MD, from Memorial Sloan Kettering Cancer Center in New York, agrees with the conclusion that the data continue to support the use of chemoradiotherapy and that 5-FU + MMC is a good option.

He noted that 5-FU + MMC is a standard of care regardless of cisplatin eligibility, but he cannot draw conclusions on dose volume. “There are also other options for chemosensitization,” he said, but it is also import to determine the best way to select patients who will derive the most benefit from chemoradiation.

“There is a high need for robust predictive biomarkers, and we need novel approaches to move beyond chemotherapy,” he said.

The study was supported by Cancer Research UK. Dr Hall has received research funding from Accuray, AstraZeneca, Aventis, and Bayer. Several co-authors also have disclosed relationships with industry. Dr. Rosenberg has disclosed multiple relationships with industry.

Orlando – The updated results of a large phase III trial support the use of chemoradiation with 5-fluorouracil (5-FU) and mitomycin C (MMC) and confirm that this treatment regimen should be a standard of care for muscle-invasive bladder cancer (MIBC).

When comparing patients who received radiation therapy with those who received chemoradiation, there was a robust improvement in bladder cancer specific survival for the latter when adjusted for known prognostic factors (hazard ratio, 0.73; P = .043).

There was also a borderline significant improvement in metastasis-free survival (HR, 0.78) and a significant reduction in the need for salvage cystectomy in the patients treated with chemoradiation (2-year rate, chemoradiotherapy11% vs. radiation therapy:17%, HR, 0.54; P = .03).

There were no statistically significant differences between groups when it came to overall survival, but, even though overall survival did not reach significance, at 2 years, there was a hint of separation of the curves, explained study author Emma Hall, MD, from the Institute of Cancer Research, London at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and the Society of Urologic Oncology.

One of the treatment arms received a reduced rate of radiation therapy to see if that would decrease toxicity. “The radiation therapy volume modification that we used did not reduce toxicity, but there is no evidence of an increase in local failure rate, suggesting it is safe to pursue clinical trials of volume sparing radiation therapy using newer technology adaptive delivery techniques,” said Dr. Hall.

The initial findings of the BC2001 study showed that adding chemotherapy (5-FU + MMC) to radiotherapy significantly improved rates of MIBC locoregional control but that reduced high-dose volume versus standard radiotherapy did not significantly reduce late side effects.

This study was a clinical trial set up to test two different questions in the treatment of MIBC, as an alternative to cystectomy. “We wanted to see if adding synchronous chemotherapy to radiotherapy would improve locoregional recurrence control and if reducing the radiation dose to uninvolved bladder would reduce toxicity and not impact local regional recurrence control,” according to Dr. Hall.

Under the 2 x 2 partial factorial design, 458 patients were randomized to radiation therapy (n = 178) or chemoradiation (n = 182) and/or to standard radiation therapy (n = 108) or reduced high-dose volume radiation therapy (n = 111).

The primary endpoint was locoregional control, and secondary endpoints included overall survival, bladder-cancer specific survival, metastasis-free survival, and salvage cystectomy rates.

The initial patients received radiation therapy instead of chemoradiation, and there was a robust improvement in bladder cancer–specific survival when adjusted for known prognostic factors (HR, 0.73; P = .043).

The analysis, presented in 2012, showed a reduction of about one-third of locoregional recurrence. The local control rates were 54% in the radiotherapy-alone arm and 67% in the chemoradiotherapy arm.

There was no significant difference in overall survival at that time.

For the radiotherapy comparison, the rate of late toxicity was low, and much lower than was anticipated, at the outset of the trial, and there was no difference in treatment groups, said Dr. Hall.

In an updated analysis, with a median of 10 years of follow-up, 70% of the patients were now deceased. “These represent robust data, and it is unlikely we will see any changes to the data,” she noted.

The findings presented now had an additional 4 years of follow-up, and while there were additional late events, the results were basically the same.

The rate of local control now showed a 40% reduction in the risk of recurrence and 5-year local control rates of 49% in the radiotherapy arm and 63% in the chemoradiotherapy arm.

“With 10 years follow up, an improvement in locoregional control and a reduced salvage cystectomy rate is confirmed with chemoradiotherapy,” Dr. Hall concluded, “and, taken together with the good quality of life data we have, this is important for this group.”

In a discussion of the paper, Dr. Jonathan Rosenberg, MD, from Memorial Sloan Kettering Cancer Center in New York, agrees with the conclusion that the data continue to support the use of chemoradiotherapy and that 5-FU + MMC is a good option.

He noted that 5-FU + MMC is a standard of care regardless of cisplatin eligibility, but he cannot draw conclusions on dose volume. “There are also other options for chemosensitization,” he said, but it is also import to determine the best way to select patients who will derive the most benefit from chemoradiation.

“There is a high need for robust predictive biomarkers, and we need novel approaches to move beyond chemotherapy,” he said.

The study was supported by Cancer Research UK. Dr Hall has received research funding from Accuray, AstraZeneca, Aventis, and Bayer. Several co-authors also have disclosed relationships with industry. Dr. Rosenberg has disclosed multiple relationships with industry.

A new large study has identified 78 significantly mutated genes (SMGs) and has enlarged the genetic landscape of prostate cancer. In addition, 37 genes that were not previously reported as SMGs in prostate cancer and 23 that were not previously identified as recurrently altered in cancer, were identified.

“Through aggregation and uniform genomic analysis, we refined the map of somatic mutations in prostate cancer and identified cancer genes and pathways not previously associated with this disease,” said lead author Dr. Joshua Armenia, of the Memorial Sloan Kettering Cancer Center, New York.

“Our findings may inform patient stratification and translational investigation,” Dr. Armenia said in a press briefing held in 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

SilverV/thinkstockphotos

op@frontlinemedcom.com

A new large study has identified 78 significantly mutated genes (SMGs) and has enlarged the genetic landscape of prostate cancer. In addition, 37 genes that were not previously reported as SMGs in prostate cancer and 23 that were not previously identified as recurrently altered in cancer, were identified.

“Through aggregation and uniform genomic analysis, we refined the map of somatic mutations in prostate cancer and identified cancer genes and pathways not previously associated with this disease,” said lead author Dr. Joshua Armenia, of the Memorial Sloan Kettering Cancer Center, New York.

“Our findings may inform patient stratification and translational investigation,” Dr. Armenia said in a press briefing held in 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

SilverV/thinkstockphotos

op@frontlinemedcom.com

A new large study has identified 78 significantly mutated genes (SMGs) and has enlarged the genetic landscape of prostate cancer. In addition, 37 genes that were not previously reported as SMGs in prostate cancer and 23 that were not previously identified as recurrently altered in cancer, were identified.

“Through aggregation and uniform genomic analysis, we refined the map of somatic mutations in prostate cancer and identified cancer genes and pathways not previously associated with this disease,” said lead author Dr. Joshua Armenia, of the Memorial Sloan Kettering Cancer Center, New York.

“Our findings may inform patient stratification and translational investigation,” Dr. Armenia said in a press briefing held in 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

SilverV/thinkstockphotos

op@frontlinemedcom.com

The presence and amount of full-length androgen receptor biomarker detected in the circulating tumor cells of people with metastatic castration-resistant prostate cancer can inform prognosis, a prospective study reveals.

Investigators report significant differences in prostate-specific antigen 50 (PSA50) values, PSA progression-free survival, clinical and/or radiologic progression-free survival, as well as overall survival, based on baseline levels of the amplified androgen receptor full-length (AR-FL) marker. The findings suggest quantification of AR-FL could serve as a clinically useful molecular biomarker in addition to AR-V7 status.

Prognosis differed among the 48% of patients with no detectable AR-FL marker, the 26% with amplification values below a median, and the remaining 26% with values above the median. The study included 202 men tested before starting hormonal treatment with either abiraterone or enzalutamide.

“Despite androgen deprivation, the androgen receptor continues to play a crucial role in prostate cancer,” Emmanuel S. Antonarakis, MBBCh, of Johns Hopkins University in Baltimore, said at in a press briefing held at the 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. Dr. Antonarakis presented the findings on behalf of lead author John Silberstein, MD, and their coinvestigators.

Researchers found an inverse association with higher level of AR-FL and PSA50 responses. Also, men who did not achieve a PSA50 response had a mean of 55.4 transcripts, compared with 6.7 transcripts for those who did. Analyzed another way, the AR-FL–negative patients had a 62% PSA response rate, compared with 54% among the AR-FL–positive patients with amplification below the median and 28% for AR-FL–positive patients with values above the median.

In a multivariate analysis, controlling for AR-V7 and clinical variables, AR-FL remained prognostic for inferior PSA progression-free survival (hazard ratio, 1.06, P = .04). “A similar picture was seen with radiographic progression-free survival,” Dr. Antonarakis said. The best prognosis was for patients with undetectable AR-FL and the worst was for patients with detectable values above the median (HR, 1.04). However, AR-FL only trended toward significance (P = .13).

Similarly, for overall survival, AR-FL–negative patients had the best prognosis and patients with AR-FL above median had the worst in the multivariate analysis (HR, 1.07). “AR-FL reached borderline clinical significance,” he said (P = .06).

The presence of AR-V7 was independently prognostic in the multivariate analysis as well. “In conjunction with AR-V7, AR-FL quantification could serve as an additional biomarker to detect abiraterone or enzalutamide sensitivity or resistance,” Dr. Antonarakis said.

The current research builds on previous findings in this patient population. For example, genetic aberrations in circulating tumor DNA were associated with treatment resistance and inferior outcomes, including a worse progression-free survival, Dr. Antonarakis said (Clin. Cancer Res. 2015;21:2315-24). Other researchers demonstrated similar outcomes, both worse progression-free survival and overall survival among patients who had amplification or mutation of AR, compared with wild type, Dr. Antonarakis said.

These investigators used cell-free DNA to quantify AR, and the current study assessed circulating tumor cell–derived AR.

“Our vision is, very shortly in the future, we will have a liquid biopsy in patients to fully characterize their full complement of AR – patients with copy number gains, mutations in their genes, and splicing variance in the clinic,” Dr. Antonarakis said. It’s important to consider all three factors, he added.

Did you see any patients who were AR-V7 positive but AR-FL negative? study discussant Angelo Demarzo, MD, PhD, of Johns Hopkins University in Baltimore asked. “We have yet to find a patient like this. AR full length so far is always present when AR-V7 is positive,” Dr. Antonarakis replied. He added, however, “There is a subset of patients who are AR-V7 negative who have a high burden of AR full length, and they will still have a high risk.”
 

op@frontlinemedcom.com

The presence and amount of full-length androgen receptor biomarker detected in the circulating tumor cells of people with metastatic castration-resistant prostate cancer can inform prognosis, a prospective study reveals.

Investigators report significant differences in prostate-specific antigen 50 (PSA50) values, PSA progression-free survival, clinical and/or radiologic progression-free survival, as well as overall survival, based on baseline levels of the amplified androgen receptor full-length (AR-FL) marker. The findings suggest quantification of AR-FL could serve as a clinically useful molecular biomarker in addition to AR-V7 status.

Prognosis differed among the 48% of patients with no detectable AR-FL marker, the 26% with amplification values below a median, and the remaining 26% with values above the median. The study included 202 men tested before starting hormonal treatment with either abiraterone or enzalutamide.

“Despite androgen deprivation, the androgen receptor continues to play a crucial role in prostate cancer,” Emmanuel S. Antonarakis, MBBCh, of Johns Hopkins University in Baltimore, said at in a press briefing held at the 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. Dr. Antonarakis presented the findings on behalf of lead author John Silberstein, MD, and their coinvestigators.

Researchers found an inverse association with higher level of AR-FL and PSA50 responses. Also, men who did not achieve a PSA50 response had a mean of 55.4 transcripts, compared with 6.7 transcripts for those who did. Analyzed another way, the AR-FL–negative patients had a 62% PSA response rate, compared with 54% among the AR-FL–positive patients with amplification below the median and 28% for AR-FL–positive patients with values above the median.

In a multivariate analysis, controlling for AR-V7 and clinical variables, AR-FL remained prognostic for inferior PSA progression-free survival (hazard ratio, 1.06, P = .04). “A similar picture was seen with radiographic progression-free survival,” Dr. Antonarakis said. The best prognosis was for patients with undetectable AR-FL and the worst was for patients with detectable values above the median (HR, 1.04). However, AR-FL only trended toward significance (P = .13).

Similarly, for overall survival, AR-FL–negative patients had the best prognosis and patients with AR-FL above median had the worst in the multivariate analysis (HR, 1.07). “AR-FL reached borderline clinical significance,” he said (P = .06).

The presence of AR-V7 was independently prognostic in the multivariate analysis as well. “In conjunction with AR-V7, AR-FL quantification could serve as an additional biomarker to detect abiraterone or enzalutamide sensitivity or resistance,” Dr. Antonarakis said.

The current research builds on previous findings in this patient population. For example, genetic aberrations in circulating tumor DNA were associated with treatment resistance and inferior outcomes, including a worse progression-free survival, Dr. Antonarakis said (Clin. Cancer Res. 2015;21:2315-24). Other researchers demonstrated similar outcomes, both worse progression-free survival and overall survival among patients who had amplification or mutation of AR, compared with wild type, Dr. Antonarakis said.

These investigators used cell-free DNA to quantify AR, and the current study assessed circulating tumor cell–derived AR.

“Our vision is, very shortly in the future, we will have a liquid biopsy in patients to fully characterize their full complement of AR – patients with copy number gains, mutations in their genes, and splicing variance in the clinic,” Dr. Antonarakis said. It’s important to consider all three factors, he added.

Did you see any patients who were AR-V7 positive but AR-FL negative? study discussant Angelo Demarzo, MD, PhD, of Johns Hopkins University in Baltimore asked. “We have yet to find a patient like this. AR full length so far is always present when AR-V7 is positive,” Dr. Antonarakis replied. He added, however, “There is a subset of patients who are AR-V7 negative who have a high burden of AR full length, and they will still have a high risk.”
 

op@frontlinemedcom.com

The presence and amount of full-length androgen receptor biomarker detected in the circulating tumor cells of people with metastatic castration-resistant prostate cancer can inform prognosis, a prospective study reveals.

Investigators report significant differences in prostate-specific antigen 50 (PSA50) values, PSA progression-free survival, clinical and/or radiologic progression-free survival, as well as overall survival, based on baseline levels of the amplified androgen receptor full-length (AR-FL) marker. The findings suggest quantification of AR-FL could serve as a clinically useful molecular biomarker in addition to AR-V7 status.

Prognosis differed among the 48% of patients with no detectable AR-FL marker, the 26% with amplification values below a median, and the remaining 26% with values above the median. The study included 202 men tested before starting hormonal treatment with either abiraterone or enzalutamide.

“Despite androgen deprivation, the androgen receptor continues to play a crucial role in prostate cancer,” Emmanuel S. Antonarakis, MBBCh, of Johns Hopkins University in Baltimore, said at in a press briefing held at the 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. Dr. Antonarakis presented the findings on behalf of lead author John Silberstein, MD, and their coinvestigators.

Researchers found an inverse association with higher level of AR-FL and PSA50 responses. Also, men who did not achieve a PSA50 response had a mean of 55.4 transcripts, compared with 6.7 transcripts for those who did. Analyzed another way, the AR-FL–negative patients had a 62% PSA response rate, compared with 54% among the AR-FL–positive patients with amplification below the median and 28% for AR-FL–positive patients with values above the median.

In a multivariate analysis, controlling for AR-V7 and clinical variables, AR-FL remained prognostic for inferior PSA progression-free survival (hazard ratio, 1.06, P = .04). “A similar picture was seen with radiographic progression-free survival,” Dr. Antonarakis said. The best prognosis was for patients with undetectable AR-FL and the worst was for patients with detectable values above the median (HR, 1.04). However, AR-FL only trended toward significance (P = .13).

Similarly, for overall survival, AR-FL–negative patients had the best prognosis and patients with AR-FL above median had the worst in the multivariate analysis (HR, 1.07). “AR-FL reached borderline clinical significance,” he said (P = .06).

The presence of AR-V7 was independently prognostic in the multivariate analysis as well. “In conjunction with AR-V7, AR-FL quantification could serve as an additional biomarker to detect abiraterone or enzalutamide sensitivity or resistance,” Dr. Antonarakis said.

The current research builds on previous findings in this patient population. For example, genetic aberrations in circulating tumor DNA were associated with treatment resistance and inferior outcomes, including a worse progression-free survival, Dr. Antonarakis said (Clin. Cancer Res. 2015;21:2315-24). Other researchers demonstrated similar outcomes, both worse progression-free survival and overall survival among patients who had amplification or mutation of AR, compared with wild type, Dr. Antonarakis said.

These investigators used cell-free DNA to quantify AR, and the current study assessed circulating tumor cell–derived AR.

“Our vision is, very shortly in the future, we will have a liquid biopsy in patients to fully characterize their full complement of AR – patients with copy number gains, mutations in their genes, and splicing variance in the clinic,” Dr. Antonarakis said. It’s important to consider all three factors, he added.

Did you see any patients who were AR-V7 positive but AR-FL negative? study discussant Angelo Demarzo, MD, PhD, of Johns Hopkins University in Baltimore asked. “We have yet to find a patient like this. AR full length so far is always present when AR-V7 is positive,” Dr. Antonarakis replied. He added, however, “There is a subset of patients who are AR-V7 negative who have a high burden of AR full length, and they will still have a high risk.”
 

op@frontlinemedcom.com

Treatment with checkpoint inhibitor pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma, according to new research.

Data from the KEYNOTE-045 trial was presented simultaneously at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, and published in the New England Journal of Medicine.

The open-label, international phase III trial involved 542 patients with advanced urothelial carcinoma that had recurred or progressed after platinum-based chemotherapy. Participants were randomized either to 200 mg pembrolizumab every 3 weeks, or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy.

After a median follow-up of 14.1 months, researchers saw a 27% lower hazard ratio for death among the pembrolizumab group, compared with the chemotherapy group (P = .002), with a median overall survival of 10.3 months with pembrolizumab, compared with 7.4 months with chemotherapy (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683).

The estimated overall survival rate at 1 year was 43.9% among those treated with pembrolizumab and 30.7% in the chemotherapy group. The authors also saw no significant differences when each chemotherapy regimen was examined separately.

Patients treated with pembrolizumab also showed a significant higher objective response rate, compared with those treated with chemotherapy (21.1% vs. 11.4%, P = .001). At the time of data cut-off, 72% of patients in the pembrolizumab group showed a continued response, compared with 35% of the chemotherapy group.

“Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment,” wrote Joaquim Bellmunt, MD, PhD, from the Dana-Farber Cancer Institute, Boston and his coauthors. “Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy.”

They also looked at how the level of programmed death 1 ligand (PD-L1) expression in the tumor influenced response by examining outcomes in a subgroup of patients whose tumor PD-L1 combined positive score – the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells – exceeded 10%.

In this group, median overall survival was 8 months with pembrolizumab, compared with 5.2 months with chemotherapy, representing a significant 43% reduction in mortality with immunotherapy.

There was an interaction between smoking status and response, with current smokers showing a significantly greater response that favored pembrolizumab. The authors pointed out that this effect has also been observed in other advanced cancers, and may reflect the impact of a greater mutational load in the cancers of smokers.

The study did not find any difference in the duration of progression-free survival between the two groups, nor among participants with a PD-L1 combined positive score of 10% of more. Median progression-free survival was 2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group.

Researchers also noted a lower rate of adverse events among patients treated with pembrolizumab, compared with chemotherapy. Treatment-related adverse events of grade 3-5 occurred in 49.4% of patients on chemotherapy, compared with 15% of those on pembrolizumab.

There was one death from treatment-related pneumonitis in the pembrolizumab group, and three deaths attributed to the study treatment; one urinary tract obstruction, one malignant neoplasm, and one unspecified cause. In the chemotherapy group, there were two treatment-related deaths from sepsis, one from septic shock, and one unspecified.

The most common adverse events with chemotherapy were alopecia, fatigue, and anemia, while in the pembrolizumab group the most common side effects were pruritis, fatigue, and nausea.

The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.

Treatment with checkpoint inhibitor pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma, according to new research.

Data from the KEYNOTE-045 trial was presented simultaneously at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, and published in the New England Journal of Medicine.

The open-label, international phase III trial involved 542 patients with advanced urothelial carcinoma that had recurred or progressed after platinum-based chemotherapy. Participants were randomized either to 200 mg pembrolizumab every 3 weeks, or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy.

After a median follow-up of 14.1 months, researchers saw a 27% lower hazard ratio for death among the pembrolizumab group, compared with the chemotherapy group (P = .002), with a median overall survival of 10.3 months with pembrolizumab, compared with 7.4 months with chemotherapy (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683).

The estimated overall survival rate at 1 year was 43.9% among those treated with pembrolizumab and 30.7% in the chemotherapy group. The authors also saw no significant differences when each chemotherapy regimen was examined separately.

Patients treated with pembrolizumab also showed a significant higher objective response rate, compared with those treated with chemotherapy (21.1% vs. 11.4%, P = .001). At the time of data cut-off, 72% of patients in the pembrolizumab group showed a continued response, compared with 35% of the chemotherapy group.

“Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment,” wrote Joaquim Bellmunt, MD, PhD, from the Dana-Farber Cancer Institute, Boston and his coauthors. “Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy.”

They also looked at how the level of programmed death 1 ligand (PD-L1) expression in the tumor influenced response by examining outcomes in a subgroup of patients whose tumor PD-L1 combined positive score – the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells – exceeded 10%.

In this group, median overall survival was 8 months with pembrolizumab, compared with 5.2 months with chemotherapy, representing a significant 43% reduction in mortality with immunotherapy.

There was an interaction between smoking status and response, with current smokers showing a significantly greater response that favored pembrolizumab. The authors pointed out that this effect has also been observed in other advanced cancers, and may reflect the impact of a greater mutational load in the cancers of smokers.

The study did not find any difference in the duration of progression-free survival between the two groups, nor among participants with a PD-L1 combined positive score of 10% of more. Median progression-free survival was 2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group.

Researchers also noted a lower rate of adverse events among patients treated with pembrolizumab, compared with chemotherapy. Treatment-related adverse events of grade 3-5 occurred in 49.4% of patients on chemotherapy, compared with 15% of those on pembrolizumab.

There was one death from treatment-related pneumonitis in the pembrolizumab group, and three deaths attributed to the study treatment; one urinary tract obstruction, one malignant neoplasm, and one unspecified cause. In the chemotherapy group, there were two treatment-related deaths from sepsis, one from septic shock, and one unspecified.

The most common adverse events with chemotherapy were alopecia, fatigue, and anemia, while in the pembrolizumab group the most common side effects were pruritis, fatigue, and nausea.

The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.

Treatment with checkpoint inhibitor pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma, according to new research.

Data from the KEYNOTE-045 trial was presented simultaneously at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, and published in the New England Journal of Medicine.

The open-label, international phase III trial involved 542 patients with advanced urothelial carcinoma that had recurred or progressed after platinum-based chemotherapy. Participants were randomized either to 200 mg pembrolizumab every 3 weeks, or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy.

After a median follow-up of 14.1 months, researchers saw a 27% lower hazard ratio for death among the pembrolizumab group, compared with the chemotherapy group (P = .002), with a median overall survival of 10.3 months with pembrolizumab, compared with 7.4 months with chemotherapy (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683).

The estimated overall survival rate at 1 year was 43.9% among those treated with pembrolizumab and 30.7% in the chemotherapy group. The authors also saw no significant differences when each chemotherapy regimen was examined separately.

Patients treated with pembrolizumab also showed a significant higher objective response rate, compared with those treated with chemotherapy (21.1% vs. 11.4%, P = .001). At the time of data cut-off, 72% of patients in the pembrolizumab group showed a continued response, compared with 35% of the chemotherapy group.

“Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment,” wrote Joaquim Bellmunt, MD, PhD, from the Dana-Farber Cancer Institute, Boston and his coauthors. “Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy.”

They also looked at how the level of programmed death 1 ligand (PD-L1) expression in the tumor influenced response by examining outcomes in a subgroup of patients whose tumor PD-L1 combined positive score – the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells – exceeded 10%.

In this group, median overall survival was 8 months with pembrolizumab, compared with 5.2 months with chemotherapy, representing a significant 43% reduction in mortality with immunotherapy.

There was an interaction between smoking status and response, with current smokers showing a significantly greater response that favored pembrolizumab. The authors pointed out that this effect has also been observed in other advanced cancers, and may reflect the impact of a greater mutational load in the cancers of smokers.

The study did not find any difference in the duration of progression-free survival between the two groups, nor among participants with a PD-L1 combined positive score of 10% of more. Median progression-free survival was 2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group.

Researchers also noted a lower rate of adverse events among patients treated with pembrolizumab, compared with chemotherapy. Treatment-related adverse events of grade 3-5 occurred in 49.4% of patients on chemotherapy, compared with 15% of those on pembrolizumab.

There was one death from treatment-related pneumonitis in the pembrolizumab group, and three deaths attributed to the study treatment; one urinary tract obstruction, one malignant neoplasm, and one unspecified cause. In the chemotherapy group, there were two treatment-related deaths from sepsis, one from septic shock, and one unspecified.

The most common adverse events with chemotherapy were alopecia, fatigue, and anemia, while in the pembrolizumab group the most common side effects were pruritis, fatigue, and nausea.

The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.

ORLANDO – A genetic assay for prostate cancer typically used after radical prostatectomy could be used earlier, at the time of diagnostic biopsy testing, to classify patients as low, intermediate, and high risk for metastasis and disease-specific mortality, new research reveals.

Based on an approximately 1-mm biopsy sample, the Decipher Prostate Cancer Classifier assesses the activity of 22 genes relevant to prostate cancer. In a multicenter study of 175 patients, investigators found the 5-year risk for metastatic disease was 5.0% among patients classified as low risk by Decipher, 9.3% in the intermediate-risk group, and 23.4% in the high-risk patients.

Local Therapy for High-Risk Patients?

A meeting attendee asked if a patient is “known to be high risk on biopsy, and has a 23% chance of metastasis after treatment, why treat with local treatment in the first place?”

“For these patients, we’re meeting them up front and they have a high risk of disease, a 23% chance of metastasis, I think we’re going to throw everything we can at them,” Dr. Nguyen said. Multiple randomized controlled trials indicate intensifying therapy can improve outcomes and that local therapy contributes to overall survival in these patients, he added. “For these patients who have very high risk disease, we have enough randomized data to show local therapy is still important. The next thing we need to do is work on personalizing their systemic therapy, and figuring out how to integrate these novel systemic therapies based on their genomic scores.”

Disease-Specific Survival

Eleven participants in the study died from prostate cancer. The only variable associated with prostate-specific disease mortality was the Decipher classification, with a hazard ratio of 1.57 for every 10% increase in the score on a univariate model (P = .02).

Dr. Nguyen and his coinvestigators also assessed 5-year prostate cancer specific mortality. They found a 9.4% rate in the Decipher high-risk group, compared with 0% in both the intermediate- and low-risk groups.

“Okay, we have this data. How do we incorporate this test into our practices?” Dr. Nguyen asked. Because the low-risk patients only comprised 13% of the study population, he was unable to state that this group could be directed to active surveillance based on the findings.

What about NCCN intermediate risk? Should these people treated with dose-escalated radiation therapy also be given short-course hormone therapy? “So far we have not seen a survival improvement, and we’re awaiting a definitive trial,” Dr. Nguyen said.

Prognostic, Not Predictive

Could the high-risk classification help physicians decide among prostatectomy, radiation, and long-course hormone therapy versus enrolling patients in a clinical trial to test a novel agent? “Perhaps, and there is some rationale for thinking in that direction,” Dr. Nguyen said. “But it is important to understand the difference between a prognostic and predictive biomarker. We’ve shown Decipher has prognostic value for identifying patients at risk for distant metastases and death.” In contrast, randomized controlled trials would be required to identify a predictive marker that ultimately could guide choice of treatment in an individual, he said.

“Robust markers are needed to see who needs treatment, and which treatment is best for primary and metastatic prostate cancer,” said study discussant Angelo DeMarzo, MD, PhD, of Johns Hopkins University. He asked Dr. Nguyen about the next best step in his research.

“Our paper was mostly intermediate- and high-risk patients; I would personally love to learn more about which patients need long-course, short-course, or no hormone treatment,” Dr. Nguyen said. He would also like to conduct randomized trials to assess any role of Decipher classification for active surveillance, and for guiding treatment intensification versus de-escalation for those patients who receive therapy.

ORLANDO – A genetic assay for prostate cancer typically used after radical prostatectomy could be used earlier, at the time of diagnostic biopsy testing, to classify patients as low, intermediate, and high risk for metastasis and disease-specific mortality, new research reveals.

Based on an approximately 1-mm biopsy sample, the Decipher Prostate Cancer Classifier assesses the activity of 22 genes relevant to prostate cancer. In a multicenter study of 175 patients, investigators found the 5-year risk for metastatic disease was 5.0% among patients classified as low risk by Decipher, 9.3% in the intermediate-risk group, and 23.4% in the high-risk patients.

Local Therapy for High-Risk Patients?

A meeting attendee asked if a patient is “known to be high risk on biopsy, and has a 23% chance of metastasis after treatment, why treat with local treatment in the first place?”

“For these patients, we’re meeting them up front and they have a high risk of disease, a 23% chance of metastasis, I think we’re going to throw everything we can at them,” Dr. Nguyen said. Multiple randomized controlled trials indicate intensifying therapy can improve outcomes and that local therapy contributes to overall survival in these patients, he added. “For these patients who have very high risk disease, we have enough randomized data to show local therapy is still important. The next thing we need to do is work on personalizing their systemic therapy, and figuring out how to integrate these novel systemic therapies based on their genomic scores.”

Disease-Specific Survival

Eleven participants in the study died from prostate cancer. The only variable associated with prostate-specific disease mortality was the Decipher classification, with a hazard ratio of 1.57 for every 10% increase in the score on a univariate model (P = .02).

Dr. Nguyen and his coinvestigators also assessed 5-year prostate cancer specific mortality. They found a 9.4% rate in the Decipher high-risk group, compared with 0% in both the intermediate- and low-risk groups.

“Okay, we have this data. How do we incorporate this test into our practices?” Dr. Nguyen asked. Because the low-risk patients only comprised 13% of the study population, he was unable to state that this group could be directed to active surveillance based on the findings.

What about NCCN intermediate risk? Should these people treated with dose-escalated radiation therapy also be given short-course hormone therapy? “So far we have not seen a survival improvement, and we’re awaiting a definitive trial,” Dr. Nguyen said.

Prognostic, Not Predictive

Could the high-risk classification help physicians decide among prostatectomy, radiation, and long-course hormone therapy versus enrolling patients in a clinical trial to test a novel agent? “Perhaps, and there is some rationale for thinking in that direction,” Dr. Nguyen said. “But it is important to understand the difference between a prognostic and predictive biomarker. We’ve shown Decipher has prognostic value for identifying patients at risk for distant metastases and death.” In contrast, randomized controlled trials would be required to identify a predictive marker that ultimately could guide choice of treatment in an individual, he said.

“Robust markers are needed to see who needs treatment, and which treatment is best for primary and metastatic prostate cancer,” said study discussant Angelo DeMarzo, MD, PhD, of Johns Hopkins University. He asked Dr. Nguyen about the next best step in his research.

“Our paper was mostly intermediate- and high-risk patients; I would personally love to learn more about which patients need long-course, short-course, or no hormone treatment,” Dr. Nguyen said. He would also like to conduct randomized trials to assess any role of Decipher classification for active surveillance, and for guiding treatment intensification versus de-escalation for those patients who receive therapy.

ORLANDO – A genetic assay for prostate cancer typically used after radical prostatectomy could be used earlier, at the time of diagnostic biopsy testing, to classify patients as low, intermediate, and high risk for metastasis and disease-specific mortality, new research reveals.

Based on an approximately 1-mm biopsy sample, the Decipher Prostate Cancer Classifier assesses the activity of 22 genes relevant to prostate cancer. In a multicenter study of 175 patients, investigators found the 5-year risk for metastatic disease was 5.0% among patients classified as low risk by Decipher, 9.3% in the intermediate-risk group, and 23.4% in the high-risk patients.

Local Therapy for High-Risk Patients?

A meeting attendee asked if a patient is “known to be high risk on biopsy, and has a 23% chance of metastasis after treatment, why treat with local treatment in the first place?”

“For these patients, we’re meeting them up front and they have a high risk of disease, a 23% chance of metastasis, I think we’re going to throw everything we can at them,” Dr. Nguyen said. Multiple randomized controlled trials indicate intensifying therapy can improve outcomes and that local therapy contributes to overall survival in these patients, he added. “For these patients who have very high risk disease, we have enough randomized data to show local therapy is still important. The next thing we need to do is work on personalizing their systemic therapy, and figuring out how to integrate these novel systemic therapies based on their genomic scores.”

Disease-Specific Survival

Eleven participants in the study died from prostate cancer. The only variable associated with prostate-specific disease mortality was the Decipher classification, with a hazard ratio of 1.57 for every 10% increase in the score on a univariate model (P = .02).

Dr. Nguyen and his coinvestigators also assessed 5-year prostate cancer specific mortality. They found a 9.4% rate in the Decipher high-risk group, compared with 0% in both the intermediate- and low-risk groups.

“Okay, we have this data. How do we incorporate this test into our practices?” Dr. Nguyen asked. Because the low-risk patients only comprised 13% of the study population, he was unable to state that this group could be directed to active surveillance based on the findings.

What about NCCN intermediate risk? Should these people treated with dose-escalated radiation therapy also be given short-course hormone therapy? “So far we have not seen a survival improvement, and we’re awaiting a definitive trial,” Dr. Nguyen said.

Prognostic, Not Predictive

Could the high-risk classification help physicians decide among prostatectomy, radiation, and long-course hormone therapy versus enrolling patients in a clinical trial to test a novel agent? “Perhaps, and there is some rationale for thinking in that direction,” Dr. Nguyen said. “But it is important to understand the difference between a prognostic and predictive biomarker. We’ve shown Decipher has prognostic value for identifying patients at risk for distant metastases and death.” In contrast, randomized controlled trials would be required to identify a predictive marker that ultimately could guide choice of treatment in an individual, he said.

“Robust markers are needed to see who needs treatment, and which treatment is best for primary and metastatic prostate cancer,” said study discussant Angelo DeMarzo, MD, PhD, of Johns Hopkins University. He asked Dr. Nguyen about the next best step in his research.

“Our paper was mostly intermediate- and high-risk patients; I would personally love to learn more about which patients need long-course, short-course, or no hormone treatment,” Dr. Nguyen said. He would also like to conduct randomized trials to assess any role of Decipher classification for active surveillance, and for guiding treatment intensification versus de-escalation for those patients who receive therapy.

ORLANDO – A large analysis has identified 65 novel prostate cancer susceptibility loci, including an early-onset locus, and captured an additional 6% of the familial relevant risk for prostate cancer.

In the Oncoarray stratified analysis, the researchers detected two single nucleotide polymorphisms (SNPs) that were associated with early-onset prostate cancer, defined as disease occurring in men younger than 55 years, and four that were associated with both aggressive and indolent disease.

roobcio/Thinkstock

ORLANDO – A large analysis has identified 65 novel prostate cancer susceptibility loci, including an early-onset locus, and captured an additional 6% of the familial relevant risk for prostate cancer.

In the Oncoarray stratified analysis, the researchers detected two single nucleotide polymorphisms (SNPs) that were associated with early-onset prostate cancer, defined as disease occurring in men younger than 55 years, and four that were associated with both aggressive and indolent disease.

roobcio/Thinkstock

ORLANDO – A large analysis has identified 65 novel prostate cancer susceptibility loci, including an early-onset locus, and captured an additional 6% of the familial relevant risk for prostate cancer.

In the Oncoarray stratified analysis, the researchers detected two single nucleotide polymorphisms (SNPs) that were associated with early-onset prostate cancer, defined as disease occurring in men younger than 55 years, and four that were associated with both aggressive and indolent disease.

roobcio/Thinkstock

ORLANDO – Some people with advanced kidney cancer who respond to immune checkpoint inhibitor therapy and subsequently stop because of immune-related adverse events may continue to see a clinical benefit for 6 months or longer, a retrospective, multicenter study reveals.

In fact, investigators labeled 42% of 19 patients with metastatic renal cell carcinoma (mRCC) “durable responders” to checkpoint inhibitor blockade. “What we’ve demonstrated is that, despite patients stopping their treatment, there is a subset who continue to have disease in check and controlled despite [their] not being on any therapy,” Rana R. McKay, MD, of the University of California, San Diego, said.

“Our subset was small, only 19 patients, so the next step is to validate our findings in larger study, and actually conduct a prospective trial to assess if discontinuation of therapy is worthwhile to investigate in this population,” Dr. McKay said during a press briefing prior to the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

PD-1/PDL-1 inhibitors demonstrate efficacy against an expanding list of malignancies, Dr. McKay said. The current standard is to administer these agents on a continuous basis until cancer progression or toxicity occurs. However, the study raises the possibility of intentionally discontinuing their use in some patients in the future, primarily because PD-1/PD-L1 inhibitors are associated with a wide range of side effects. Most concerning are immune-related adverse events “which are thought to be due to immune system activation,” she said.

“These drugs work to reinvigorate the immune response, and one of the unintended consequences is … they may also elicit an autoimmune response against one or more organs in the body,” said Sumanta Pal, MD, of City of Hope Medical Center in Duarte, Calif. and moderator of the press briefing.

“There was a wide spectrum of adverse events affecting different organ systems,” Dr. McKay said, “including pneumonitis, myositis, nephritis, hepatitis, pericarditis, and myocarditis, just to name a few.” A total of 84% of patients required steroids to treat immune-related adverse events, 11% needed additional immunosuppressant agents to treat their symptoms, and 53% have ongoing toxicity.

“If a patient has immune-related side effects, the impact can be serious,” Dr. Pal said. “This [study] certainly supports the premise that those individuals who experience immune related side effects could have a tangible benefit from the drug nonetheless.”

Median patient age was 68 years, 74% were male and 26% had aggressive disease. In the durable responders group, the median time on treatment was 11 months and median time off treatment was 20 months. In contrast, the patients whose cancer worsened immediately after therapy cessation were treated a median 4 months and were off treatment a median of only 2 months. A total of 63% received either PD-1 or PD-L1 monotherapy and the remainder received one of these inhibitors in combination with other systemic therapies.

Prospective studies are warranted to determine approaches to customize immunotherapy based on response, Dr. McKay said. A phase II study is planned to assess optimized management of nivolumab therapy based on response in patients with mRCC, she added

op@frontlinemedcom.com

ORLANDO – Some people with advanced kidney cancer who respond to immune checkpoint inhibitor therapy and subsequently stop because of immune-related adverse events may continue to see a clinical benefit for 6 months or longer, a retrospective, multicenter study reveals.

In fact, investigators labeled 42% of 19 patients with metastatic renal cell carcinoma (mRCC) “durable responders” to checkpoint inhibitor blockade. “What we’ve demonstrated is that, despite patients stopping their treatment, there is a subset who continue to have disease in check and controlled despite [their] not being on any therapy,” Rana R. McKay, MD, of the University of California, San Diego, said.

“Our subset was small, only 19 patients, so the next step is to validate our findings in larger study, and actually conduct a prospective trial to assess if discontinuation of therapy is worthwhile to investigate in this population,” Dr. McKay said during a press briefing prior to the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

PD-1/PDL-1 inhibitors demonstrate efficacy against an expanding list of malignancies, Dr. McKay said. The current standard is to administer these agents on a continuous basis until cancer progression or toxicity occurs. However, the study raises the possibility of intentionally discontinuing their use in some patients in the future, primarily because PD-1/PD-L1 inhibitors are associated with a wide range of side effects. Most concerning are immune-related adverse events “which are thought to be due to immune system activation,” she said.

“These drugs work to reinvigorate the immune response, and one of the unintended consequences is … they may also elicit an autoimmune response against one or more organs in the body,” said Sumanta Pal, MD, of City of Hope Medical Center in Duarte, Calif. and moderator of the press briefing.

“There was a wide spectrum of adverse events affecting different organ systems,” Dr. McKay said, “including pneumonitis, myositis, nephritis, hepatitis, pericarditis, and myocarditis, just to name a few.” A total of 84% of patients required steroids to treat immune-related adverse events, 11% needed additional immunosuppressant agents to treat their symptoms, and 53% have ongoing toxicity.

“If a patient has immune-related side effects, the impact can be serious,” Dr. Pal said. “This [study] certainly supports the premise that those individuals who experience immune related side effects could have a tangible benefit from the drug nonetheless.”

Median patient age was 68 years, 74% were male and 26% had aggressive disease. In the durable responders group, the median time on treatment was 11 months and median time off treatment was 20 months. In contrast, the patients whose cancer worsened immediately after therapy cessation were treated a median 4 months and were off treatment a median of only 2 months. A total of 63% received either PD-1 or PD-L1 monotherapy and the remainder received one of these inhibitors in combination with other systemic therapies.

Prospective studies are warranted to determine approaches to customize immunotherapy based on response, Dr. McKay said. A phase II study is planned to assess optimized management of nivolumab therapy based on response in patients with mRCC, she added

op@frontlinemedcom.com

ORLANDO – Some people with advanced kidney cancer who respond to immune checkpoint inhibitor therapy and subsequently stop because of immune-related adverse events may continue to see a clinical benefit for 6 months or longer, a retrospective, multicenter study reveals.

In fact, investigators labeled 42% of 19 patients with metastatic renal cell carcinoma (mRCC) “durable responders” to checkpoint inhibitor blockade. “What we’ve demonstrated is that, despite patients stopping their treatment, there is a subset who continue to have disease in check and controlled despite [their] not being on any therapy,” Rana R. McKay, MD, of the University of California, San Diego, said.

“Our subset was small, only 19 patients, so the next step is to validate our findings in larger study, and actually conduct a prospective trial to assess if discontinuation of therapy is worthwhile to investigate in this population,” Dr. McKay said during a press briefing prior to the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

PD-1/PDL-1 inhibitors demonstrate efficacy against an expanding list of malignancies, Dr. McKay said. The current standard is to administer these agents on a continuous basis until cancer progression or toxicity occurs. However, the study raises the possibility of intentionally discontinuing their use in some patients in the future, primarily because PD-1/PD-L1 inhibitors are associated with a wide range of side effects. Most concerning are immune-related adverse events “which are thought to be due to immune system activation,” she said.

“These drugs work to reinvigorate the immune response, and one of the unintended consequences is … they may also elicit an autoimmune response against one or more organs in the body,” said Sumanta Pal, MD, of City of Hope Medical Center in Duarte, Calif. and moderator of the press briefing.

“There was a wide spectrum of adverse events affecting different organ systems,” Dr. McKay said, “including pneumonitis, myositis, nephritis, hepatitis, pericarditis, and myocarditis, just to name a few.” A total of 84% of patients required steroids to treat immune-related adverse events, 11% needed additional immunosuppressant agents to treat their symptoms, and 53% have ongoing toxicity.

“If a patient has immune-related side effects, the impact can be serious,” Dr. Pal said. “This [study] certainly supports the premise that those individuals who experience immune related side effects could have a tangible benefit from the drug nonetheless.”

Median patient age was 68 years, 74% were male and 26% had aggressive disease. In the durable responders group, the median time on treatment was 11 months and median time off treatment was 20 months. In contrast, the patients whose cancer worsened immediately after therapy cessation were treated a median 4 months and were off treatment a median of only 2 months. A total of 63% received either PD-1 or PD-L1 monotherapy and the remainder received one of these inhibitors in combination with other systemic therapies.

Prospective studies are warranted to determine approaches to customize immunotherapy based on response, Dr. McKay said. A phase II study is planned to assess optimized management of nivolumab therapy based on response in patients with mRCC, she added

op@frontlinemedcom.com

Antibiotics may hamper the effectiveness of immune checkpoint inhibitors for patients with metastatic renal cell carcinoma, according to a small, retrospective study. Using antibiotics within 1 month of starting a checkpoint inhibitor was associated with significantly shorter progression-free survival, as well as a trend toward shorter overall survival, in a study of 80 patients with metastatic renal cell carcinoma.

Although the mechanism remains unknown, the prevailing theory is that antibiotics adversely alter the composition of the gut microbiome, and in so doing, slash the ability of beneficial bacteria to boost efficacy of immune checkpoint blockade.

“The data I presented today are just preliminary. But the results are really important because there is a kind of connection between the microbiome, antibiotics, and immune checkpoint blockade,” Lisa Derosa, MD, of Paris-Sud University, Villejuif, France, said during a press briefing prior to the 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Derosa and her colleagues retrospectively assessed 80 people with metastatic renal cell carcinoma enrolled in prospective trials at Gustave Roussy Cancer Institute. The patients were treated with the PD1/PD-L1 inhibitors alone or in combination. The researchers compared survival of 16 patients who also received broad-spectrum antibiotic therapy within 1 month of their first dose of immunotherapy with 64 others who did not receive antibiotics.

Progression-free survival was significantly shorter for patients in the antibiotic group, 2.3 months versus 8.1 months for the nonantibiotic group (P less than .001) on Kaplan-Meier curves. The statistical significance persisted even after the researchers controlled for age, gender, International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) risk classification, tumor burden, and PPI use in a multivariate analysis. Similarly, the objective response rate to checkpoint inhibition therapy was significantly lower among patients in the antibiotic group (P less than .002).

“There was no significant difference, however, between these groups in overall survival,” Dr. Derosa said.

Despite the findings, Dr. Derosa said it’s too soon to say antibiotics are contraindicated in this patient population. “It may be important to pay attention to these antibiotics in patients treated with immune response inhibitors, but the data are still preliminary.”

“I would propose this data is very intriguing, but it was retrospectively generated, so I consider it hypothesis-generating,” said Sumanta Pal, MD, of City of Hope Medical Center in Duarte, Calif., and moderator of the press briefing. “One has to consider the fact that antibiotics are used under circumstances of medical necessity. I wouldn’t forgo treatment of any active infection … I would use as medically necessary.”

Beta-lactamases and fluoroquinolones comprised the majority of antibiotics in the study. The majority, 67 patients, received immune monotherapy with single-agent PD-1 or PD-L1 inhibitors. Another 10 patients received a combination of a PD-1 inhibitor and a CTLA-4 inhibitor, and 3 were treated with a PD-L1 inhibitor and bevacizumab.

“This is the first analysis evaluating impact of antibiotics on outcome of advanced renal carcinoma patients treated in the era of immune checkpoint blockade,” Dr. Derosa said. “We have a lot of work to do.” She and her colleagues plan to continue enrolling patients in the study. They also plan to evaluate whether alteration of the microbiome composition does play a role in diminishing the effectiveness of immunotherapy, and if so, which types of bacteria are the most likely culprits.

Antibiotics may hamper the effectiveness of immune checkpoint inhibitors for patients with metastatic renal cell carcinoma, according to a small, retrospective study. Using antibiotics within 1 month of starting a checkpoint inhibitor was associated with significantly shorter progression-free survival, as well as a trend toward shorter overall survival, in a study of 80 patients with metastatic renal cell carcinoma.

Although the mechanism remains unknown, the prevailing theory is that antibiotics adversely alter the composition of the gut microbiome, and in so doing, slash the ability of beneficial bacteria to boost efficacy of immune checkpoint blockade.

“The data I presented today are just preliminary. But the results are really important because there is a kind of connection between the microbiome, antibiotics, and immune checkpoint blockade,” Lisa Derosa, MD, of Paris-Sud University, Villejuif, France, said during a press briefing prior to the 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Derosa and her colleagues retrospectively assessed 80 people with metastatic renal cell carcinoma enrolled in prospective trials at Gustave Roussy Cancer Institute. The patients were treated with the PD1/PD-L1 inhibitors alone or in combination. The researchers compared survival of 16 patients who also received broad-spectrum antibiotic therapy within 1 month of their first dose of immunotherapy with 64 others who did not receive antibiotics.

Progression-free survival was significantly shorter for patients in the antibiotic group, 2.3 months versus 8.1 months for the nonantibiotic group (P less than .001) on Kaplan-Meier curves. The statistical significance persisted even after the researchers controlled for age, gender, International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) risk classification, tumor burden, and PPI use in a multivariate analysis. Similarly, the objective response rate to checkpoint inhibition therapy was significantly lower among patients in the antibiotic group (P less than .002).

“There was no significant difference, however, between these groups in overall survival,” Dr. Derosa said.

Despite the findings, Dr. Derosa said it’s too soon to say antibiotics are contraindicated in this patient population. “It may be important to pay attention to these antibiotics in patients treated with immune response inhibitors, but the data are still preliminary.”

“I would propose this data is very intriguing, but it was retrospectively generated, so I consider it hypothesis-generating,” said Sumanta Pal, MD, of City of Hope Medical Center in Duarte, Calif., and moderator of the press briefing. “One has to consider the fact that antibiotics are used under circumstances of medical necessity. I wouldn’t forgo treatment of any active infection … I would use as medically necessary.”

Beta-lactamases and fluoroquinolones comprised the majority of antibiotics in the study. The majority, 67 patients, received immune monotherapy with single-agent PD-1 or PD-L1 inhibitors. Another 10 patients received a combination of a PD-1 inhibitor and a CTLA-4 inhibitor, and 3 were treated with a PD-L1 inhibitor and bevacizumab.

“This is the first analysis evaluating impact of antibiotics on outcome of advanced renal carcinoma patients treated in the era of immune checkpoint blockade,” Dr. Derosa said. “We have a lot of work to do.” She and her colleagues plan to continue enrolling patients in the study. They also plan to evaluate whether alteration of the microbiome composition does play a role in diminishing the effectiveness of immunotherapy, and if so, which types of bacteria are the most likely culprits.

Antibiotics may hamper the effectiveness of immune checkpoint inhibitors for patients with metastatic renal cell carcinoma, according to a small, retrospective study. Using antibiotics within 1 month of starting a checkpoint inhibitor was associated with significantly shorter progression-free survival, as well as a trend toward shorter overall survival, in a study of 80 patients with metastatic renal cell carcinoma.

Although the mechanism remains unknown, the prevailing theory is that antibiotics adversely alter the composition of the gut microbiome, and in so doing, slash the ability of beneficial bacteria to boost efficacy of immune checkpoint blockade.

“The data I presented today are just preliminary. But the results are really important because there is a kind of connection between the microbiome, antibiotics, and immune checkpoint blockade,” Lisa Derosa, MD, of Paris-Sud University, Villejuif, France, said during a press briefing prior to the 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Derosa and her colleagues retrospectively assessed 80 people with metastatic renal cell carcinoma enrolled in prospective trials at Gustave Roussy Cancer Institute. The patients were treated with the PD1/PD-L1 inhibitors alone or in combination. The researchers compared survival of 16 patients who also received broad-spectrum antibiotic therapy within 1 month of their first dose of immunotherapy with 64 others who did not receive antibiotics.

Progression-free survival was significantly shorter for patients in the antibiotic group, 2.3 months versus 8.1 months for the nonantibiotic group (P less than .001) on Kaplan-Meier curves. The statistical significance persisted even after the researchers controlled for age, gender, International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) risk classification, tumor burden, and PPI use in a multivariate analysis. Similarly, the objective response rate to checkpoint inhibition therapy was significantly lower among patients in the antibiotic group (P less than .002).

“There was no significant difference, however, between these groups in overall survival,” Dr. Derosa said.

Despite the findings, Dr. Derosa said it’s too soon to say antibiotics are contraindicated in this patient population. “It may be important to pay attention to these antibiotics in patients treated with immune response inhibitors, but the data are still preliminary.”

“I would propose this data is very intriguing, but it was retrospectively generated, so I consider it hypothesis-generating,” said Sumanta Pal, MD, of City of Hope Medical Center in Duarte, Calif., and moderator of the press briefing. “One has to consider the fact that antibiotics are used under circumstances of medical necessity. I wouldn’t forgo treatment of any active infection … I would use as medically necessary.”

Beta-lactamases and fluoroquinolones comprised the majority of antibiotics in the study. The majority, 67 patients, received immune monotherapy with single-agent PD-1 or PD-L1 inhibitors. Another 10 patients received a combination of a PD-1 inhibitor and a CTLA-4 inhibitor, and 3 were treated with a PD-L1 inhibitor and bevacizumab.

“This is the first analysis evaluating impact of antibiotics on outcome of advanced renal carcinoma patients treated in the era of immune checkpoint blockade,” Dr. Derosa said. “We have a lot of work to do.” She and her colleagues plan to continue enrolling patients in the study. They also plan to evaluate whether alteration of the microbiome composition does play a role in diminishing the effectiveness of immunotherapy, and if so, which types of bacteria are the most likely culprits.