Renal Cell Carcinoma

Some patients with advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs) can safely undergo nephrectomy and experience favorable surgical outcomes and pathologic responses, a cohort study suggests.

“The introduction of several novel classes of systemic therapies, including targeted therapies and most recently ICI, has revolutionized the management of metastatic RCC over the last decade,” noted the investigators, who were led by Nirmish Singla, MD, from the department of urology at the University of Texas Southwestern Medical Center, Dallas. “With these new therapies, the role of nephrectomy in the treatment paradigm for advanced RCC has continued to evolve.”

The investigators undertook a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced RCC who had received ICIs. Half had received nivolumab (Opdivo) alone, while the other half had received nivolumab in combination with ipilimumab (Yervoy); in six patients, these therapies were given first line.

Study results reported in Urologic Oncology showed that, at the time of nephrectomy, the patients had a median age of 64 years, with a range from 41 years to 83 years. Surgery was performed laparoscopically in five cases, and four patients had a concomitant thrombectomy.

The median operative time was 180 minutes, and the median estimated blood loss was 100 mL. None of the patients experienced major intraoperative complications. Four experienced postoperative complications; in three, they were addressed with interventional radiology procedures. The median length of stay was 4 days.

Pathology findings showed that one patient achieved a response to immunotherapy in the primary tumor (pT0), and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer (pM0). All surgical margins were negative.

During a median postoperative follow-up of 180 days, one patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism complicated by sepsis. Six patients did not have any complications or readmissions.

“In our experience, nephrectomy following ICI for RCC is both safe and technically feasible. Surgical and postoperative outcomes are encouraging, and pathologic response to ICI is strikingly favorable in both the primary tumor and metastatic sites,” Dr. Singla and coinvestigators wrote. “Biopsies of lesions responding radiographically to ICIs should be considered prior to surgical excision.”

“As multimodal management in the immunotherapy era continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants further study,” they conclude.

Dr. Singla disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Singla N et al. Urol Oncol. 2019 Sep 12. doi: 10.1016/j.urolonc.2019.08.012.

Some patients with advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs) can safely undergo nephrectomy and experience favorable surgical outcomes and pathologic responses, a cohort study suggests.

“The introduction of several novel classes of systemic therapies, including targeted therapies and most recently ICI, has revolutionized the management of metastatic RCC over the last decade,” noted the investigators, who were led by Nirmish Singla, MD, from the department of urology at the University of Texas Southwestern Medical Center, Dallas. “With these new therapies, the role of nephrectomy in the treatment paradigm for advanced RCC has continued to evolve.”

The investigators undertook a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced RCC who had received ICIs. Half had received nivolumab (Opdivo) alone, while the other half had received nivolumab in combination with ipilimumab (Yervoy); in six patients, these therapies were given first line.

Study results reported in Urologic Oncology showed that, at the time of nephrectomy, the patients had a median age of 64 years, with a range from 41 years to 83 years. Surgery was performed laparoscopically in five cases, and four patients had a concomitant thrombectomy.

The median operative time was 180 minutes, and the median estimated blood loss was 100 mL. None of the patients experienced major intraoperative complications. Four experienced postoperative complications; in three, they were addressed with interventional radiology procedures. The median length of stay was 4 days.

Pathology findings showed that one patient achieved a response to immunotherapy in the primary tumor (pT0), and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer (pM0). All surgical margins were negative.

During a median postoperative follow-up of 180 days, one patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism complicated by sepsis. Six patients did not have any complications or readmissions.

“In our experience, nephrectomy following ICI for RCC is both safe and technically feasible. Surgical and postoperative outcomes are encouraging, and pathologic response to ICI is strikingly favorable in both the primary tumor and metastatic sites,” Dr. Singla and coinvestigators wrote. “Biopsies of lesions responding radiographically to ICIs should be considered prior to surgical excision.”

“As multimodal management in the immunotherapy era continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants further study,” they conclude.

Dr. Singla disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Singla N et al. Urol Oncol. 2019 Sep 12. doi: 10.1016/j.urolonc.2019.08.012.

Some patients with advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs) can safely undergo nephrectomy and experience favorable surgical outcomes and pathologic responses, a cohort study suggests.

“The introduction of several novel classes of systemic therapies, including targeted therapies and most recently ICI, has revolutionized the management of metastatic RCC over the last decade,” noted the investigators, who were led by Nirmish Singla, MD, from the department of urology at the University of Texas Southwestern Medical Center, Dallas. “With these new therapies, the role of nephrectomy in the treatment paradigm for advanced RCC has continued to evolve.”

The investigators undertook a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced RCC who had received ICIs. Half had received nivolumab (Opdivo) alone, while the other half had received nivolumab in combination with ipilimumab (Yervoy); in six patients, these therapies were given first line.

Study results reported in Urologic Oncology showed that, at the time of nephrectomy, the patients had a median age of 64 years, with a range from 41 years to 83 years. Surgery was performed laparoscopically in five cases, and four patients had a concomitant thrombectomy.

The median operative time was 180 minutes, and the median estimated blood loss was 100 mL. None of the patients experienced major intraoperative complications. Four experienced postoperative complications; in three, they were addressed with interventional radiology procedures. The median length of stay was 4 days.

Pathology findings showed that one patient achieved a response to immunotherapy in the primary tumor (pT0), and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer (pM0). All surgical margins were negative.

During a median postoperative follow-up of 180 days, one patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism complicated by sepsis. Six patients did not have any complications or readmissions.

“In our experience, nephrectomy following ICI for RCC is both safe and technically feasible. Surgical and postoperative outcomes are encouraging, and pathologic response to ICI is strikingly favorable in both the primary tumor and metastatic sites,” Dr. Singla and coinvestigators wrote. “Biopsies of lesions responding radiographically to ICIs should be considered prior to surgical excision.”

“As multimodal management in the immunotherapy era continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants further study,” they conclude.

Dr. Singla disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Singla N et al. Urol Oncol. 2019 Sep 12. doi: 10.1016/j.urolonc.2019.08.012.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

There is no significant difference in response or survival rates between the combination of ipilimumab/nivolumab (ipi-nivo) and immuno-oncology plus vascular endothelial growth factor inhibition (IOVE) for patients with metastatic renal cell carcinoma.

Therefore, the treatment should probably be directed by patient preferences, among other things, Shaan Dudani, MD, and colleagues wrote in European Oncology.

“Given the current lack of evidence to suggest a difference in efficacy between treatment strategies, patients, clinicians and policy makers are likely to take into account other considerations, such as toxicity, cost, logistics, prognostic categories, and patient preferences in deciding between the various front-line [immuno-oncology] combination regimens,” wrote Dr. Dudani, of the University of Calgary, and coauthors.

The team examined response rates among 263 patients with metastatic renal cell carcinoma from the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) dataset. Patients treated with any first-line IOVE combination (n = 113) were compared with those treated with ipi-nivo (n = 75). Patients were about 62 years old. The most common sites of metastasis were liver (about 20%) and bone (about 33%), and about 20% had sarcomatoid features (about 20%). Most (about 75%) had multiple metastatic sites.

Thirty percent of those in the IOVE group and 40% in the ipi-nivo group had received second-line treatments. These included axitinib, levantinib plus severolimus, nivolumab alone, pazopanib, and sunitinib, as well as other treatments.

At a mean follow-up of 11.7 months, the response rates were 33% for IOVE and 40% for ipi-nivo. This difference was not statistically significant (between group difference, 7%; 95% confidence interval, –8% to 22%; P = .4). Complete response occurred in 2% in IOVE and 5% of the ipi-nivo group.

The time to treatment failure was 14.3 months for IOVE and 10.2 months for ipi-nivo – again not a significant difference (P = .2). Time to next treatment also was not significantly different (19.7 vs. 17.9 months; P = .4). Neither group met the study’s overall survival goal.

After adjustment for IMDC risk score, hazard ratios for death were 0.71 for IOVE and 1.74 for ipi-nivo. There were no significant between-group differences when comparing intermediate- and poor-risk patients or when the analysis was restricted only to favorable-risk patients. Among 55 who received second-line therapy, there was also no significant difference in time to treatment failure.

“It was interesting, though not surprising, to observe that the majority [88%] of second-line therapies in this cohort were VEGF-based following ipi-nivo vs. IOVE combinations,” the authors noted. “The higher response rates observed in patients receiving second-line VEGF combinations is noteworthy and thought provoking. Biologically, it is plausible that VEGF-based second-line therapy would be more likely to be effective in the VEGF-naive ipi-nivo cohort. It remains to be seen whether the numerical difference in time to treatment failure becomes significant with increased sample size and further follow-up, and whether this contributes to differences in overall survival, which ultimately impacts treatment selections in the first-line setting.”

Dr. Dudani had no financial disclosures.

SOURCE: Dudani S et al. Euro Onc. 2019 Aug 22. doi: 10.1016/j.eururo.2019.07.048.
 

There is no significant difference in response or survival rates between the combination of ipilimumab/nivolumab (ipi-nivo) and immuno-oncology plus vascular endothelial growth factor inhibition (IOVE) for patients with metastatic renal cell carcinoma.

Therefore, the treatment should probably be directed by patient preferences, among other things, Shaan Dudani, MD, and colleagues wrote in European Oncology.

“Given the current lack of evidence to suggest a difference in efficacy between treatment strategies, patients, clinicians and policy makers are likely to take into account other considerations, such as toxicity, cost, logistics, prognostic categories, and patient preferences in deciding between the various front-line [immuno-oncology] combination regimens,” wrote Dr. Dudani, of the University of Calgary, and coauthors.

The team examined response rates among 263 patients with metastatic renal cell carcinoma from the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) dataset. Patients treated with any first-line IOVE combination (n = 113) were compared with those treated with ipi-nivo (n = 75). Patients were about 62 years old. The most common sites of metastasis were liver (about 20%) and bone (about 33%), and about 20% had sarcomatoid features (about 20%). Most (about 75%) had multiple metastatic sites.

Thirty percent of those in the IOVE group and 40% in the ipi-nivo group had received second-line treatments. These included axitinib, levantinib plus severolimus, nivolumab alone, pazopanib, and sunitinib, as well as other treatments.

At a mean follow-up of 11.7 months, the response rates were 33% for IOVE and 40% for ipi-nivo. This difference was not statistically significant (between group difference, 7%; 95% confidence interval, –8% to 22%; P = .4). Complete response occurred in 2% in IOVE and 5% of the ipi-nivo group.

The time to treatment failure was 14.3 months for IOVE and 10.2 months for ipi-nivo – again not a significant difference (P = .2). Time to next treatment also was not significantly different (19.7 vs. 17.9 months; P = .4). Neither group met the study’s overall survival goal.

After adjustment for IMDC risk score, hazard ratios for death were 0.71 for IOVE and 1.74 for ipi-nivo. There were no significant between-group differences when comparing intermediate- and poor-risk patients or when the analysis was restricted only to favorable-risk patients. Among 55 who received second-line therapy, there was also no significant difference in time to treatment failure.

“It was interesting, though not surprising, to observe that the majority [88%] of second-line therapies in this cohort were VEGF-based following ipi-nivo vs. IOVE combinations,” the authors noted. “The higher response rates observed in patients receiving second-line VEGF combinations is noteworthy and thought provoking. Biologically, it is plausible that VEGF-based second-line therapy would be more likely to be effective in the VEGF-naive ipi-nivo cohort. It remains to be seen whether the numerical difference in time to treatment failure becomes significant with increased sample size and further follow-up, and whether this contributes to differences in overall survival, which ultimately impacts treatment selections in the first-line setting.”

Dr. Dudani had no financial disclosures.

SOURCE: Dudani S et al. Euro Onc. 2019 Aug 22. doi: 10.1016/j.eururo.2019.07.048.
 

There is no significant difference in response or survival rates between the combination of ipilimumab/nivolumab (ipi-nivo) and immuno-oncology plus vascular endothelial growth factor inhibition (IOVE) for patients with metastatic renal cell carcinoma.

Therefore, the treatment should probably be directed by patient preferences, among other things, Shaan Dudani, MD, and colleagues wrote in European Oncology.

“Given the current lack of evidence to suggest a difference in efficacy between treatment strategies, patients, clinicians and policy makers are likely to take into account other considerations, such as toxicity, cost, logistics, prognostic categories, and patient preferences in deciding between the various front-line [immuno-oncology] combination regimens,” wrote Dr. Dudani, of the University of Calgary, and coauthors.

The team examined response rates among 263 patients with metastatic renal cell carcinoma from the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) dataset. Patients treated with any first-line IOVE combination (n = 113) were compared with those treated with ipi-nivo (n = 75). Patients were about 62 years old. The most common sites of metastasis were liver (about 20%) and bone (about 33%), and about 20% had sarcomatoid features (about 20%). Most (about 75%) had multiple metastatic sites.

Thirty percent of those in the IOVE group and 40% in the ipi-nivo group had received second-line treatments. These included axitinib, levantinib plus severolimus, nivolumab alone, pazopanib, and sunitinib, as well as other treatments.

At a mean follow-up of 11.7 months, the response rates were 33% for IOVE and 40% for ipi-nivo. This difference was not statistically significant (between group difference, 7%; 95% confidence interval, –8% to 22%; P = .4). Complete response occurred in 2% in IOVE and 5% of the ipi-nivo group.

The time to treatment failure was 14.3 months for IOVE and 10.2 months for ipi-nivo – again not a significant difference (P = .2). Time to next treatment also was not significantly different (19.7 vs. 17.9 months; P = .4). Neither group met the study’s overall survival goal.

After adjustment for IMDC risk score, hazard ratios for death were 0.71 for IOVE and 1.74 for ipi-nivo. There were no significant between-group differences when comparing intermediate- and poor-risk patients or when the analysis was restricted only to favorable-risk patients. Among 55 who received second-line therapy, there was also no significant difference in time to treatment failure.

“It was interesting, though not surprising, to observe that the majority [88%] of second-line therapies in this cohort were VEGF-based following ipi-nivo vs. IOVE combinations,” the authors noted. “The higher response rates observed in patients receiving second-line VEGF combinations is noteworthy and thought provoking. Biologically, it is plausible that VEGF-based second-line therapy would be more likely to be effective in the VEGF-naive ipi-nivo cohort. It remains to be seen whether the numerical difference in time to treatment failure becomes significant with increased sample size and further follow-up, and whether this contributes to differences in overall survival, which ultimately impacts treatment selections in the first-line setting.”

Dr. Dudani had no financial disclosures.

SOURCE: Dudani S et al. Euro Onc. 2019 Aug 22. doi: 10.1016/j.eururo.2019.07.048.
 

Loss-of-function mutations in the PBRM1 gene are more common among patients with metastatic clear cell renal cell carcinoma (ccRCC) who have clinical responses to immune checkpoint inhibitors (ICIs), but the mutations fall a little short of serving as clinical biomarkers, investigators say.

Among patients with metastatic ccRCC enrolled in a randomized, phase 3 clinical trial comparing nivolumab (Opdivo) with everolimus (Afinitor) in patients who had previously received antiangiogenic therapy, patients with responses to nivolumab were more than twice as likely as nonresponders to have a truncating loss-of-function mutation in PBRM1, reported Toni K. Choueiri, MD, and colleagues from the Dana-Farber Cancer Institute in Boston.

Patients with PBRM1 mutations were also more likely to have a clinical benefit (complete/partial response, or stable disease with tumor shrinkage and progression-free survival [PFS] of at least 6 months) as well as better PFS and overall survival than patients without mutations.

“The association of PBRM1 truncating mutations with response to anti–[programmed death-1] therapy was confirmed in an independent ccRCC cohort. However, key limitations restrict use of PBRM1 mutations as a clinical biomarker,” they wrote in a research letter to JAMA Oncology.

Those limitations include an only modest effect of mutations on response and survival, a lack of evidence for a PBRM1 mutation effect in the first-line setting, and a possible association between mutations and benefit from prior antiangiogenic therapies, they acknowledged.

Dr. Choueiri was a coauthor of a previous study of genomic correlates of response to ICIs in ccRCC, which found that PBRM1 loss may influence response to checkpoint inhibitors by altering global tumor-cell expression.

In the current study, he and his colleagues looked at archival tumor tissue from an independent cohort of 382 patients who were part of a larger phase 3 trial. Of this group, 189 were treated with nivolumab, and 193 were treated with everolimus. PBRM1 mutations were identified in 55 of the nivolumab-treated patients (29%) and in 45 of the everolimus-treated patients (23%).

When they looked at clinical responses, they found that 15 of 38 patients with response to nivolumab (39%) had truncating PBRM1 mutations, compared with 16 of 74 nonresponding patients (22%), which translated into an odds ratio for response of 2.34 (P = .04).

Similarly, PBRM1 mutations among nivolumab-treated patients were significantly associated with clinical benefit (OR, 2.14; P = .0497), PFS (hazard ratio for progression, 0.67; P = .03), and overall survival (HR, 0.65; P = .03).

In contrast, there were no significant associations in everolimus-treated patients between PBRM1 mutations and either response, PFS, or overall survival.

“The concomitant presence of other cellular or molecular features may further influence the findings described herein. Nonetheless, this validated association between PBRM1 alterations and ICI response in a large randomized study represents a further step toward the development of genomic predictors for immunotherapies in advanced RCC,” the investigators concluded.

The study was supported by Department of Defense Congressionally Directed Medical Research Programs and Bristol-Myers Squibb. Dr. Choueiri disclosed personal fees from Bristol-Myers Squibb and fees and grants from other companies. One coauthor is a Bristol-Myers Squibb employee and shareholder.

SOURCE: Choueiri TK et al. JAMA Oncol. 2019 Sep 5. doi: 10.1001/jamaoncol.2019.3158.

Loss-of-function mutations in the PBRM1 gene are more common among patients with metastatic clear cell renal cell carcinoma (ccRCC) who have clinical responses to immune checkpoint inhibitors (ICIs), but the mutations fall a little short of serving as clinical biomarkers, investigators say.

Among patients with metastatic ccRCC enrolled in a randomized, phase 3 clinical trial comparing nivolumab (Opdivo) with everolimus (Afinitor) in patients who had previously received antiangiogenic therapy, patients with responses to nivolumab were more than twice as likely as nonresponders to have a truncating loss-of-function mutation in PBRM1, reported Toni K. Choueiri, MD, and colleagues from the Dana-Farber Cancer Institute in Boston.

Patients with PBRM1 mutations were also more likely to have a clinical benefit (complete/partial response, or stable disease with tumor shrinkage and progression-free survival [PFS] of at least 6 months) as well as better PFS and overall survival than patients without mutations.

“The association of PBRM1 truncating mutations with response to anti–[programmed death-1] therapy was confirmed in an independent ccRCC cohort. However, key limitations restrict use of PBRM1 mutations as a clinical biomarker,” they wrote in a research letter to JAMA Oncology.

Those limitations include an only modest effect of mutations on response and survival, a lack of evidence for a PBRM1 mutation effect in the first-line setting, and a possible association between mutations and benefit from prior antiangiogenic therapies, they acknowledged.

Dr. Choueiri was a coauthor of a previous study of genomic correlates of response to ICIs in ccRCC, which found that PBRM1 loss may influence response to checkpoint inhibitors by altering global tumor-cell expression.

In the current study, he and his colleagues looked at archival tumor tissue from an independent cohort of 382 patients who were part of a larger phase 3 trial. Of this group, 189 were treated with nivolumab, and 193 were treated with everolimus. PBRM1 mutations were identified in 55 of the nivolumab-treated patients (29%) and in 45 of the everolimus-treated patients (23%).

When they looked at clinical responses, they found that 15 of 38 patients with response to nivolumab (39%) had truncating PBRM1 mutations, compared with 16 of 74 nonresponding patients (22%), which translated into an odds ratio for response of 2.34 (P = .04).

Similarly, PBRM1 mutations among nivolumab-treated patients were significantly associated with clinical benefit (OR, 2.14; P = .0497), PFS (hazard ratio for progression, 0.67; P = .03), and overall survival (HR, 0.65; P = .03).

In contrast, there were no significant associations in everolimus-treated patients between PBRM1 mutations and either response, PFS, or overall survival.

“The concomitant presence of other cellular or molecular features may further influence the findings described herein. Nonetheless, this validated association between PBRM1 alterations and ICI response in a large randomized study represents a further step toward the development of genomic predictors for immunotherapies in advanced RCC,” the investigators concluded.

The study was supported by Department of Defense Congressionally Directed Medical Research Programs and Bristol-Myers Squibb. Dr. Choueiri disclosed personal fees from Bristol-Myers Squibb and fees and grants from other companies. One coauthor is a Bristol-Myers Squibb employee and shareholder.

SOURCE: Choueiri TK et al. JAMA Oncol. 2019 Sep 5. doi: 10.1001/jamaoncol.2019.3158.

Loss-of-function mutations in the PBRM1 gene are more common among patients with metastatic clear cell renal cell carcinoma (ccRCC) who have clinical responses to immune checkpoint inhibitors (ICIs), but the mutations fall a little short of serving as clinical biomarkers, investigators say.

Among patients with metastatic ccRCC enrolled in a randomized, phase 3 clinical trial comparing nivolumab (Opdivo) with everolimus (Afinitor) in patients who had previously received antiangiogenic therapy, patients with responses to nivolumab were more than twice as likely as nonresponders to have a truncating loss-of-function mutation in PBRM1, reported Toni K. Choueiri, MD, and colleagues from the Dana-Farber Cancer Institute in Boston.

Patients with PBRM1 mutations were also more likely to have a clinical benefit (complete/partial response, or stable disease with tumor shrinkage and progression-free survival [PFS] of at least 6 months) as well as better PFS and overall survival than patients without mutations.

“The association of PBRM1 truncating mutations with response to anti–[programmed death-1] therapy was confirmed in an independent ccRCC cohort. However, key limitations restrict use of PBRM1 mutations as a clinical biomarker,” they wrote in a research letter to JAMA Oncology.

Those limitations include an only modest effect of mutations on response and survival, a lack of evidence for a PBRM1 mutation effect in the first-line setting, and a possible association between mutations and benefit from prior antiangiogenic therapies, they acknowledged.

Dr. Choueiri was a coauthor of a previous study of genomic correlates of response to ICIs in ccRCC, which found that PBRM1 loss may influence response to checkpoint inhibitors by altering global tumor-cell expression.

In the current study, he and his colleagues looked at archival tumor tissue from an independent cohort of 382 patients who were part of a larger phase 3 trial. Of this group, 189 were treated with nivolumab, and 193 were treated with everolimus. PBRM1 mutations were identified in 55 of the nivolumab-treated patients (29%) and in 45 of the everolimus-treated patients (23%).

When they looked at clinical responses, they found that 15 of 38 patients with response to nivolumab (39%) had truncating PBRM1 mutations, compared with 16 of 74 nonresponding patients (22%), which translated into an odds ratio for response of 2.34 (P = .04).

Similarly, PBRM1 mutations among nivolumab-treated patients were significantly associated with clinical benefit (OR, 2.14; P = .0497), PFS (hazard ratio for progression, 0.67; P = .03), and overall survival (HR, 0.65; P = .03).

In contrast, there were no significant associations in everolimus-treated patients between PBRM1 mutations and either response, PFS, or overall survival.

“The concomitant presence of other cellular or molecular features may further influence the findings described herein. Nonetheless, this validated association between PBRM1 alterations and ICI response in a large randomized study represents a further step toward the development of genomic predictors for immunotherapies in advanced RCC,” the investigators concluded.

The study was supported by Department of Defense Congressionally Directed Medical Research Programs and Bristol-Myers Squibb. Dr. Choueiri disclosed personal fees from Bristol-Myers Squibb and fees and grants from other companies. One coauthor is a Bristol-Myers Squibb employee and shareholder.

SOURCE: Choueiri TK et al. JAMA Oncol. 2019 Sep 5. doi: 10.1001/jamaoncol.2019.3158.

For patients with localized renal cell carcinoma (RCC), stereotactic ablative body radiotherapy (SABR) may be an effective alternative to surgery, according to findings from a retrospective study.

Patients with smaller tumors and nonmetastatic disease achieved the best outcomes with SABR, reported lead author Rodney E. Wegner, MD, of Allegheny Health Network Cancer Institute, Pittsburgh, and colleagues.

“Radiation therapy is often overlooked in [RCC] as historic preclinical data reported RCC as being relatively radioresistant to external beam radiation at conventional doses,” the investigators wrote in Advances in Radiation Oncology. However, SABR may be able to overcome this resistance by delivering “highly conformal dose escalated radiation,” the investigators noted, citing two recent reports from the International Radiosurgery Oncology Consortium for Kidney (IROCK) that showed promising results (J Urol. 2019 Jun;201[6]:1097-104 and Cancer. 2018 Mar 1;124[5]:934-42).

The present study included 347 patients with RCC from the National Cancer Database who were treated with SABR and not surgery. Most patients (94%) did not have systemic therapy. Similar proportions lacked lymph node involvement (97%) or distant metastasis (93%). About three-quarters of patients (76%) had T1 disease. The median SABR dose was 45 Gy, ranging from 35 to 54 Gy, most frequently given in three fractions.

After a median follow-up of 36 months, ranging from 1 to 156 months, median overall survival across all patients was 58 months. SABR was most effective for patients with nonmetastatic disease who had smaller tumors.

An inverse correlation between tumor size and overall survival was apparent given that patients with tumors 2.5 cm or smaller had the longest median overall survival, at 92 months, with decrements in survival as tumors got larger. Survival dropped to 88 months for tumors 2.6-3.5 cm, 44 months for tumors 3.5-5.0 cm, and finally to 26 months for tumors larger than 5.0 cm. In addition to tumor size and metastatic disease, age was a risk factor for shorter survival.

“The results presented demonstrate excellent post-SABR outcomes, with median overall survival in the range of 7-8 years for smaller lesions,” the investigators wrote. “This is particularly impressive considering that many of these patients were likely medically inoperable.”

The researchers noted that most of kidney SABR is done at academic centers, which highlights the importance of appropriate technology and training for delivering this treatment.

“Further prospective research is needed to verify its safety and efficacy,” the investigators concluded.

No external funding was provided for the project and the investigators reported no conflicts of interest.

SOURCE: Wegner RE et al. Adv Rad Onc. 2019 Aug 8. doi: 10.1016/j.adro.2019.07.018.
 

For patients with localized renal cell carcinoma (RCC), stereotactic ablative body radiotherapy (SABR) may be an effective alternative to surgery, according to findings from a retrospective study.

Patients with smaller tumors and nonmetastatic disease achieved the best outcomes with SABR, reported lead author Rodney E. Wegner, MD, of Allegheny Health Network Cancer Institute, Pittsburgh, and colleagues.

“Radiation therapy is often overlooked in [RCC] as historic preclinical data reported RCC as being relatively radioresistant to external beam radiation at conventional doses,” the investigators wrote in Advances in Radiation Oncology. However, SABR may be able to overcome this resistance by delivering “highly conformal dose escalated radiation,” the investigators noted, citing two recent reports from the International Radiosurgery Oncology Consortium for Kidney (IROCK) that showed promising results (J Urol. 2019 Jun;201[6]:1097-104 and Cancer. 2018 Mar 1;124[5]:934-42).

The present study included 347 patients with RCC from the National Cancer Database who were treated with SABR and not surgery. Most patients (94%) did not have systemic therapy. Similar proportions lacked lymph node involvement (97%) or distant metastasis (93%). About three-quarters of patients (76%) had T1 disease. The median SABR dose was 45 Gy, ranging from 35 to 54 Gy, most frequently given in three fractions.

After a median follow-up of 36 months, ranging from 1 to 156 months, median overall survival across all patients was 58 months. SABR was most effective for patients with nonmetastatic disease who had smaller tumors.

An inverse correlation between tumor size and overall survival was apparent given that patients with tumors 2.5 cm or smaller had the longest median overall survival, at 92 months, with decrements in survival as tumors got larger. Survival dropped to 88 months for tumors 2.6-3.5 cm, 44 months for tumors 3.5-5.0 cm, and finally to 26 months for tumors larger than 5.0 cm. In addition to tumor size and metastatic disease, age was a risk factor for shorter survival.

“The results presented demonstrate excellent post-SABR outcomes, with median overall survival in the range of 7-8 years for smaller lesions,” the investigators wrote. “This is particularly impressive considering that many of these patients were likely medically inoperable.”

The researchers noted that most of kidney SABR is done at academic centers, which highlights the importance of appropriate technology and training for delivering this treatment.

“Further prospective research is needed to verify its safety and efficacy,” the investigators concluded.

No external funding was provided for the project and the investigators reported no conflicts of interest.

SOURCE: Wegner RE et al. Adv Rad Onc. 2019 Aug 8. doi: 10.1016/j.adro.2019.07.018.
 

For patients with localized renal cell carcinoma (RCC), stereotactic ablative body radiotherapy (SABR) may be an effective alternative to surgery, according to findings from a retrospective study.

Patients with smaller tumors and nonmetastatic disease achieved the best outcomes with SABR, reported lead author Rodney E. Wegner, MD, of Allegheny Health Network Cancer Institute, Pittsburgh, and colleagues.

“Radiation therapy is often overlooked in [RCC] as historic preclinical data reported RCC as being relatively radioresistant to external beam radiation at conventional doses,” the investigators wrote in Advances in Radiation Oncology. However, SABR may be able to overcome this resistance by delivering “highly conformal dose escalated radiation,” the investigators noted, citing two recent reports from the International Radiosurgery Oncology Consortium for Kidney (IROCK) that showed promising results (J Urol. 2019 Jun;201[6]:1097-104 and Cancer. 2018 Mar 1;124[5]:934-42).

The present study included 347 patients with RCC from the National Cancer Database who were treated with SABR and not surgery. Most patients (94%) did not have systemic therapy. Similar proportions lacked lymph node involvement (97%) or distant metastasis (93%). About three-quarters of patients (76%) had T1 disease. The median SABR dose was 45 Gy, ranging from 35 to 54 Gy, most frequently given in three fractions.

After a median follow-up of 36 months, ranging from 1 to 156 months, median overall survival across all patients was 58 months. SABR was most effective for patients with nonmetastatic disease who had smaller tumors.

An inverse correlation between tumor size and overall survival was apparent given that patients with tumors 2.5 cm or smaller had the longest median overall survival, at 92 months, with decrements in survival as tumors got larger. Survival dropped to 88 months for tumors 2.6-3.5 cm, 44 months for tumors 3.5-5.0 cm, and finally to 26 months for tumors larger than 5.0 cm. In addition to tumor size and metastatic disease, age was a risk factor for shorter survival.

“The results presented demonstrate excellent post-SABR outcomes, with median overall survival in the range of 7-8 years for smaller lesions,” the investigators wrote. “This is particularly impressive considering that many of these patients were likely medically inoperable.”

The researchers noted that most of kidney SABR is done at academic centers, which highlights the importance of appropriate technology and training for delivering this treatment.

“Further prospective research is needed to verify its safety and efficacy,” the investigators concluded.

No external funding was provided for the project and the investigators reported no conflicts of interest.

SOURCE: Wegner RE et al. Adv Rad Onc. 2019 Aug 8. doi: 10.1016/j.adro.2019.07.018.
 

Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.

In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.

The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.

These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.

Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.

Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).

Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.

All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.

The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.

Response

The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.

Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.

The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.

All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
 

Survival

The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).

The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.

The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.

Safety

The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).

Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).

The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.

This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.

SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.

Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.

In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.

The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.

These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.

Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.

Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).

Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.

All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.

The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.

Response

The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.

Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.

The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.

All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
 

Survival

The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).

The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.

The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.

Safety

The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).

Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).

The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.

This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.

SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.

Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.

In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.

The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.

These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.

Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.

Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).

Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.

All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.

The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.

Response

The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.

Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.

The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.

All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
 

Survival

The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).

The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.

The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.

Safety

The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).

Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).

The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.

This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.

SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.

Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.

Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.

Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.

The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Specific indications for the biosimilar are as follows:

Metastatic colorectal cancer

Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.

Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.

Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.

First-line nonsquamous non–small cell lung cancer

Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.

Recurrent glioblastoma

Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.

Metastatic renal cell carcinoma

Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.

Persistent, recurrent, or metastatic cervical cancer

Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Complete prescribing information can be found on the FDA website.

The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.

Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.

Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.

Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.

The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Specific indications for the biosimilar are as follows:

Metastatic colorectal cancer

Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.

Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.

Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.

First-line nonsquamous non–small cell lung cancer

Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.

Recurrent glioblastoma

Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.

Metastatic renal cell carcinoma

Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.

Persistent, recurrent, or metastatic cervical cancer

Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Complete prescribing information can be found on the FDA website.

The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.

Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.

Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.

Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.

The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Specific indications for the biosimilar are as follows:

Metastatic colorectal cancer

Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.

Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.

Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.

First-line nonsquamous non–small cell lung cancer

Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.

Recurrent glioblastoma

Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.

Metastatic renal cell carcinoma

Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.

Persistent, recurrent, or metastatic cervical cancer

Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Complete prescribing information can be found on the FDA website.

CHICAGO – While cytoreductive nephrectomy is generally still inadvisable in metastatic renal cell carcinoma patients who require medical therapy, an update of the CARMENA trial suggests the procedure may provide benefit for certain patients.

Patients with only one International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor may benefit from cytoreductive nephrectomy, said CARMENA investigator Arnaud Méjean, MD, PhD, in a presentation at the annual meeting of the American Society of Clinical Oncology.

Among patients in CARMENA treated with nephrectomy plus sunitinib, median overall survival was 31.4 months for those with just one risk factor, and 17.6 months for those with two or more (hazard ratio, 1.68; 95% confidence interval, 1.10-2.57; P = .01), suggesting the procedure was “detrimental” to perform in the presence of multiple risk factors, the investigator said.

By contrast, among patients treated with sunitinib alone, there was no significant difference in median overall survival for patients with one risk factor versus those with two or more risk factors, said Dr. Méjean, who is with the Hôpital Européen Georges-Pompidou and Paris Descartes University.

In another analysis of the data, delayed nephrectomy after initial systemic therapy was associated with long overall survival in good responders, supporting that approach as a “good therapeutic strategy,” he said.

Based on these results, Dr. Méjean told ASCO attendees he would “go back to the operating theater to operate just very selected patients.”

In a podium discussion, Alexander Kutikov, MD, FACS, said CARMENA makes it “undeniable” that up-front cytoreductive therapy should be applied to a “very select group” of patients.

While that select group may be defined as the one IMDC risk factor group, Dr. Kutkov said it is also appropriate to offer cytoreductive nephrectomy to carefully selected patients who do not need immediate systemic therapy.

“If the plan is to observe without systemic therapy, proceed with cytoreductive nephrectomy, and for everybody else, I think we take great caution in offering cytoreductive nephrectomy, because it absolutely can harm,” said Dr. Kutikov, professor and chief of urologic oncology at Fox Chase Cancer Center, Philadelphia.

The CARMENA update confirmed that, in general, cytoreductive nephrectomy should not be the standard of care, according to Dr. Méjean.

With follow-up of 61.5 months, or longer than what was previously reported for the 450-patient trial, cytoreductive nephrectomy followed by sunitinib was again found to be not superior to sunitinib alone, he said. Median overall survival was 15.6 months for the nephrectomy plus sunitinib arm versus 19.8 months for the sunitinib arm, showing that sunitinib alone was noninferior based on the statistical design of the trial (hazard ratio, 0.97; 95% CI, 0.79-1.19, with a fixed upper limit for noninferiority of 1.20).

Dr. Méjean reported disclosures related to Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Janssen, Sanofi and Roche.

SOURCE: Méjean A et al. ASCO 2019, Abstract 4508.

CHICAGO – While cytoreductive nephrectomy is generally still inadvisable in metastatic renal cell carcinoma patients who require medical therapy, an update of the CARMENA trial suggests the procedure may provide benefit for certain patients.

Patients with only one International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor may benefit from cytoreductive nephrectomy, said CARMENA investigator Arnaud Méjean, MD, PhD, in a presentation at the annual meeting of the American Society of Clinical Oncology.

Among patients in CARMENA treated with nephrectomy plus sunitinib, median overall survival was 31.4 months for those with just one risk factor, and 17.6 months for those with two or more (hazard ratio, 1.68; 95% confidence interval, 1.10-2.57; P = .01), suggesting the procedure was “detrimental” to perform in the presence of multiple risk factors, the investigator said.

By contrast, among patients treated with sunitinib alone, there was no significant difference in median overall survival for patients with one risk factor versus those with two or more risk factors, said Dr. Méjean, who is with the Hôpital Européen Georges-Pompidou and Paris Descartes University.

In another analysis of the data, delayed nephrectomy after initial systemic therapy was associated with long overall survival in good responders, supporting that approach as a “good therapeutic strategy,” he said.

Based on these results, Dr. Méjean told ASCO attendees he would “go back to the operating theater to operate just very selected patients.”

In a podium discussion, Alexander Kutikov, MD, FACS, said CARMENA makes it “undeniable” that up-front cytoreductive therapy should be applied to a “very select group” of patients.

While that select group may be defined as the one IMDC risk factor group, Dr. Kutkov said it is also appropriate to offer cytoreductive nephrectomy to carefully selected patients who do not need immediate systemic therapy.

“If the plan is to observe without systemic therapy, proceed with cytoreductive nephrectomy, and for everybody else, I think we take great caution in offering cytoreductive nephrectomy, because it absolutely can harm,” said Dr. Kutikov, professor and chief of urologic oncology at Fox Chase Cancer Center, Philadelphia.

The CARMENA update confirmed that, in general, cytoreductive nephrectomy should not be the standard of care, according to Dr. Méjean.

With follow-up of 61.5 months, or longer than what was previously reported for the 450-patient trial, cytoreductive nephrectomy followed by sunitinib was again found to be not superior to sunitinib alone, he said. Median overall survival was 15.6 months for the nephrectomy plus sunitinib arm versus 19.8 months for the sunitinib arm, showing that sunitinib alone was noninferior based on the statistical design of the trial (hazard ratio, 0.97; 95% CI, 0.79-1.19, with a fixed upper limit for noninferiority of 1.20).

Dr. Méjean reported disclosures related to Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Janssen, Sanofi and Roche.

SOURCE: Méjean A et al. ASCO 2019, Abstract 4508.

CHICAGO – While cytoreductive nephrectomy is generally still inadvisable in metastatic renal cell carcinoma patients who require medical therapy, an update of the CARMENA trial suggests the procedure may provide benefit for certain patients.

Patients with only one International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor may benefit from cytoreductive nephrectomy, said CARMENA investigator Arnaud Méjean, MD, PhD, in a presentation at the annual meeting of the American Society of Clinical Oncology.

Among patients in CARMENA treated with nephrectomy plus sunitinib, median overall survival was 31.4 months for those with just one risk factor, and 17.6 months for those with two or more (hazard ratio, 1.68; 95% confidence interval, 1.10-2.57; P = .01), suggesting the procedure was “detrimental” to perform in the presence of multiple risk factors, the investigator said.

By contrast, among patients treated with sunitinib alone, there was no significant difference in median overall survival for patients with one risk factor versus those with two or more risk factors, said Dr. Méjean, who is with the Hôpital Européen Georges-Pompidou and Paris Descartes University.

In another analysis of the data, delayed nephrectomy after initial systemic therapy was associated with long overall survival in good responders, supporting that approach as a “good therapeutic strategy,” he said.

Based on these results, Dr. Méjean told ASCO attendees he would “go back to the operating theater to operate just very selected patients.”

In a podium discussion, Alexander Kutikov, MD, FACS, said CARMENA makes it “undeniable” that up-front cytoreductive therapy should be applied to a “very select group” of patients.

While that select group may be defined as the one IMDC risk factor group, Dr. Kutkov said it is also appropriate to offer cytoreductive nephrectomy to carefully selected patients who do not need immediate systemic therapy.

“If the plan is to observe without systemic therapy, proceed with cytoreductive nephrectomy, and for everybody else, I think we take great caution in offering cytoreductive nephrectomy, because it absolutely can harm,” said Dr. Kutikov, professor and chief of urologic oncology at Fox Chase Cancer Center, Philadelphia.

The CARMENA update confirmed that, in general, cytoreductive nephrectomy should not be the standard of care, according to Dr. Méjean.

With follow-up of 61.5 months, or longer than what was previously reported for the 450-patient trial, cytoreductive nephrectomy followed by sunitinib was again found to be not superior to sunitinib alone, he said. Median overall survival was 15.6 months for the nephrectomy plus sunitinib arm versus 19.8 months for the sunitinib arm, showing that sunitinib alone was noninferior based on the statistical design of the trial (hazard ratio, 0.97; 95% CI, 0.79-1.19, with a fixed upper limit for noninferiority of 1.20).

Dr. Méjean reported disclosures related to Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Janssen, Sanofi and Roche.

SOURCE: Méjean A et al. ASCO 2019, Abstract 4508.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.