Genitourinary Cancer

For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Susan London/MDedge News

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Susan London/MDedge News

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Susan London/MDedge News

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

The Food and Drug Administration has approved enzalutamide (Xtandi) for patients with metastatic castration-sensitive prostate cancer (mCSPC).

The drug was previously approved for patients with castration-resistant prostate cancer.

Approval was based on radiographic progression-free survival (rPFS) improvement in ARCHES, a trial of 1,150 patients with mCSPC randomized to receive either enzalutamide or placebo daily. All patients received a gonadotropin-releasing hormone analogue or had a prior bilateral orchiectomy.

Median rPFS was not reached in the enzalutamide, arm compared with 19.4 months (95% confidence interval, 16.6 to not reached) in the placebo arm (HR 0.39; 95% CI, 0.30-0.50; P less than .0001), the FDA said in a statement.

The most common adverse reactions in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.

The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily with or without food, the FDA said.

[email protected]





 

The Food and Drug Administration has approved enzalutamide (Xtandi) for patients with metastatic castration-sensitive prostate cancer (mCSPC).

The drug was previously approved for patients with castration-resistant prostate cancer.

Approval was based on radiographic progression-free survival (rPFS) improvement in ARCHES, a trial of 1,150 patients with mCSPC randomized to receive either enzalutamide or placebo daily. All patients received a gonadotropin-releasing hormone analogue or had a prior bilateral orchiectomy.

Median rPFS was not reached in the enzalutamide, arm compared with 19.4 months (95% confidence interval, 16.6 to not reached) in the placebo arm (HR 0.39; 95% CI, 0.30-0.50; P less than .0001), the FDA said in a statement.

The most common adverse reactions in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.

The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily with or without food, the FDA said.

[email protected]





 

The Food and Drug Administration has approved enzalutamide (Xtandi) for patients with metastatic castration-sensitive prostate cancer (mCSPC).

The drug was previously approved for patients with castration-resistant prostate cancer.

Approval was based on radiographic progression-free survival (rPFS) improvement in ARCHES, a trial of 1,150 patients with mCSPC randomized to receive either enzalutamide or placebo daily. All patients received a gonadotropin-releasing hormone analogue or had a prior bilateral orchiectomy.

Median rPFS was not reached in the enzalutamide, arm compared with 19.4 months (95% confidence interval, 16.6 to not reached) in the placebo arm (HR 0.39; 95% CI, 0.30-0.50; P less than .0001), the FDA said in a statement.

The most common adverse reactions in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.

The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily with or without food, the FDA said.

[email protected]





 

Single-fraction radiation could not be shown to be noninferior to multi-fraction radiation at improving walking function in patients with spinal compression from metastatic cancer, but the small differences seen in a noninferiority trial may not matter to patients, investigators suggest.

Among 686 patients with spinal compression from metastatic cancer randomly assigned in a clinical trial to receive either 8 Gy of radiation in a single fraction or 20 Gy delivered in 5 fractions over 5 consecutive days, 69.3% of patients in the single-fraction arm had good ambulatory status at 8 weeks, compared with 72.7% of patients in the multi-fraction arm (P for noninferiority = .06), reported Peter J Hoskin, BSc, MBBS, MD, of Mount Vernon Cancer Centre in Northwood, England, and colleagues.

The trial did not meet the endpoint of noninferiority of single-fraction radiation for improving ambulation at 8 weeks because the lower limit of the 95% confidence interval (CI) was –11.5%, overlapping the noninferiority margin of –11%.

“However, for all other time points, the CI limits were within the noninferiority margin, and the observed risk differences between single-fraction and multi-fraction radiotherapy groups in ambulatory status were small and unlikely to be of clinical importance,” the investigators wrote in JAMA.

The authors note that although radiotherapy is widely used as a palliative measure for patients with spinal canal compression caused my metastatic disease, there is no agreement on the optimum schedule, with some guidelines recommending higher doses in multiple fractions, and others recommending a single 8 Gy does for patients with painful spinal sites.

To see whether single-fraction radiation could be noninferior to multi-fraction, the investigators enrolled patients in 42 sites in the United Kingdom and 5 in Australia into the SCORAD trial, and randomly assigned them to either single-fraction (345 patients) or multi-fraction (341 patients) radiation. The median age of those enrolled was 70 years, and 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer.

As noted, the primary endpoint of noninferiority of single-fraction radiation at improving ambulatory status at week 8 was not met. Ambulatory status was based on a 4-point scale and was classified as either grade 1: ambulatory without the use of aids and grade 5 of 5 of muscle power, or grade 2: ambulatory with aids or grade 4 of 5 of muscle power.

An analysis of secondary endpoints showed that the difference in ambulatory status grade 1 or 2 in the single- vs. multi-fraction group at week 1 was −0.4% (P value for noninferiority = .004), at week 4 it was −0.7% (P value for noninferiority = .01), and at week 12 it was 4.1% (P value for noninferiority = .002).

Overall survival rates at 12 weeks were 50% in the single-fraction group vs. 55% in the multi-fraction group; this difference was not statistically significant.

Of 11 other secondary endpoints analyzed, including ambulatory and safety endpoints, the between-group differences were not statistically significant or did not meet noninferiority criteria, the authors noted.

They concluded that although the trial did not meet the primary endpoint, ”the extent to which the lower bound of the CI overlapped with the noninferiority margin should be taken into account when interpreting the clinical importance of these findings.”

Cancer Research UK and Cancer Council Queensland funded the trial. Dr. Hoskin reported being supported by the National Institute for Health Research Manchester Biomedical Research Centre.

SOURCE: Hoskin PJ et al. JAMA 2019 Dec 3. doi: 10.1001/jama.2019.17913.

Single-fraction radiation could not be shown to be noninferior to multi-fraction radiation at improving walking function in patients with spinal compression from metastatic cancer, but the small differences seen in a noninferiority trial may not matter to patients, investigators suggest.

Among 686 patients with spinal compression from metastatic cancer randomly assigned in a clinical trial to receive either 8 Gy of radiation in a single fraction or 20 Gy delivered in 5 fractions over 5 consecutive days, 69.3% of patients in the single-fraction arm had good ambulatory status at 8 weeks, compared with 72.7% of patients in the multi-fraction arm (P for noninferiority = .06), reported Peter J Hoskin, BSc, MBBS, MD, of Mount Vernon Cancer Centre in Northwood, England, and colleagues.

The trial did not meet the endpoint of noninferiority of single-fraction radiation for improving ambulation at 8 weeks because the lower limit of the 95% confidence interval (CI) was –11.5%, overlapping the noninferiority margin of –11%.

“However, for all other time points, the CI limits were within the noninferiority margin, and the observed risk differences between single-fraction and multi-fraction radiotherapy groups in ambulatory status were small and unlikely to be of clinical importance,” the investigators wrote in JAMA.

The authors note that although radiotherapy is widely used as a palliative measure for patients with spinal canal compression caused my metastatic disease, there is no agreement on the optimum schedule, with some guidelines recommending higher doses in multiple fractions, and others recommending a single 8 Gy does for patients with painful spinal sites.

To see whether single-fraction radiation could be noninferior to multi-fraction, the investigators enrolled patients in 42 sites in the United Kingdom and 5 in Australia into the SCORAD trial, and randomly assigned them to either single-fraction (345 patients) or multi-fraction (341 patients) radiation. The median age of those enrolled was 70 years, and 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer.

As noted, the primary endpoint of noninferiority of single-fraction radiation at improving ambulatory status at week 8 was not met. Ambulatory status was based on a 4-point scale and was classified as either grade 1: ambulatory without the use of aids and grade 5 of 5 of muscle power, or grade 2: ambulatory with aids or grade 4 of 5 of muscle power.

An analysis of secondary endpoints showed that the difference in ambulatory status grade 1 or 2 in the single- vs. multi-fraction group at week 1 was −0.4% (P value for noninferiority = .004), at week 4 it was −0.7% (P value for noninferiority = .01), and at week 12 it was 4.1% (P value for noninferiority = .002).

Overall survival rates at 12 weeks were 50% in the single-fraction group vs. 55% in the multi-fraction group; this difference was not statistically significant.

Of 11 other secondary endpoints analyzed, including ambulatory and safety endpoints, the between-group differences were not statistically significant or did not meet noninferiority criteria, the authors noted.

They concluded that although the trial did not meet the primary endpoint, ”the extent to which the lower bound of the CI overlapped with the noninferiority margin should be taken into account when interpreting the clinical importance of these findings.”

Cancer Research UK and Cancer Council Queensland funded the trial. Dr. Hoskin reported being supported by the National Institute for Health Research Manchester Biomedical Research Centre.

SOURCE: Hoskin PJ et al. JAMA 2019 Dec 3. doi: 10.1001/jama.2019.17913.

Single-fraction radiation could not be shown to be noninferior to multi-fraction radiation at improving walking function in patients with spinal compression from metastatic cancer, but the small differences seen in a noninferiority trial may not matter to patients, investigators suggest.

Among 686 patients with spinal compression from metastatic cancer randomly assigned in a clinical trial to receive either 8 Gy of radiation in a single fraction or 20 Gy delivered in 5 fractions over 5 consecutive days, 69.3% of patients in the single-fraction arm had good ambulatory status at 8 weeks, compared with 72.7% of patients in the multi-fraction arm (P for noninferiority = .06), reported Peter J Hoskin, BSc, MBBS, MD, of Mount Vernon Cancer Centre in Northwood, England, and colleagues.

The trial did not meet the endpoint of noninferiority of single-fraction radiation for improving ambulation at 8 weeks because the lower limit of the 95% confidence interval (CI) was –11.5%, overlapping the noninferiority margin of –11%.

“However, for all other time points, the CI limits were within the noninferiority margin, and the observed risk differences between single-fraction and multi-fraction radiotherapy groups in ambulatory status were small and unlikely to be of clinical importance,” the investigators wrote in JAMA.

The authors note that although radiotherapy is widely used as a palliative measure for patients with spinal canal compression caused my metastatic disease, there is no agreement on the optimum schedule, with some guidelines recommending higher doses in multiple fractions, and others recommending a single 8 Gy does for patients with painful spinal sites.

To see whether single-fraction radiation could be noninferior to multi-fraction, the investigators enrolled patients in 42 sites in the United Kingdom and 5 in Australia into the SCORAD trial, and randomly assigned them to either single-fraction (345 patients) or multi-fraction (341 patients) radiation. The median age of those enrolled was 70 years, and 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer.

As noted, the primary endpoint of noninferiority of single-fraction radiation at improving ambulatory status at week 8 was not met. Ambulatory status was based on a 4-point scale and was classified as either grade 1: ambulatory without the use of aids and grade 5 of 5 of muscle power, or grade 2: ambulatory with aids or grade 4 of 5 of muscle power.

An analysis of secondary endpoints showed that the difference in ambulatory status grade 1 or 2 in the single- vs. multi-fraction group at week 1 was −0.4% (P value for noninferiority = .004), at week 4 it was −0.7% (P value for noninferiority = .01), and at week 12 it was 4.1% (P value for noninferiority = .002).

Overall survival rates at 12 weeks were 50% in the single-fraction group vs. 55% in the multi-fraction group; this difference was not statistically significant.

Of 11 other secondary endpoints analyzed, including ambulatory and safety endpoints, the between-group differences were not statistically significant or did not meet noninferiority criteria, the authors noted.

They concluded that although the trial did not meet the primary endpoint, ”the extent to which the lower bound of the CI overlapped with the noninferiority margin should be taken into account when interpreting the clinical importance of these findings.”

Cancer Research UK and Cancer Council Queensland funded the trial. Dr. Hoskin reported being supported by the National Institute for Health Research Manchester Biomedical Research Centre.

SOURCE: Hoskin PJ et al. JAMA 2019 Dec 3. doi: 10.1001/jama.2019.17913.

The combination of atezolizumab plus bevacizumab may offer some benefit to patients with advanced renal cell carcinoma, especially those who are positive for programmed death-ligand 1 (PD-L1), investigators report.

The overall response rate (ORR) among such patients was 60%, compared with 19% in PD-L1–negative patients, Bradley A. McGregor, MD, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of Clinical Oncology.

The data were presented last summer at the American Society of Clinical Oncology Annual Meeting in Chicago.

The phase 2 study comprised 60 patients, 42 of whom had variant histology RCC, and 18 of whom had clear cell RCC (ccRCC ) with at least 20% sarcomatoid differentiation. All patients had advanced renal cell carcinoma of various histologies, including papillary (12), chromophobe (10), unclassified (9), TFE3 translocation (5), collecting duct (5), and medullary (1). Most (65%) had not received prior systemic therapy.

They all received infusions of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks. No dose modifications were allowed. Dose delays were allowed, and patients could also drop one agent and continue with the other. Treatment continued until disease progression, toxicity, or intolerable side effects.

The median number of cycles was 9.5, although the range was wide (1-42). At analysis, 15 were still on the treatment, but 45 had dropped out. Reasons were disease progression (34), death (1), toxicity (5), or unspecified (8). Six patients delayed bevacizumab doses, half because of adverse events.

After a median follow-up of 13 months, the ORR was 33%. Those with ccRCC with sarcomatoid differentiation responded best to the combination (ORR, 50%). Those with variant-histology RCC responded less robustly (ORR, 26%).

ORR varied by baseline risk category, being 33% in favorable-, 45% in intermediate-, and 11% in poor-risk patients. Median time to response was 2.7 months, median response duration was 8.9 months, and median progression-free survival was 8.3 months.

PD-L1 status was determined in 36 patients; 15 were positive. Among the positive patents, ORR was 60%, compared with 19% in PD-L1 negative patients. Response rates varied with tumor characteristics. Among patients with ccRCC with sarcomatoid differentiation, the ORR was 50% in PD-L1–positive patients and 29% in negative patients. In patients with variant histology RCC, the ORR was also better in PD-L1 positive patients (67% vs. 14%).

The most common treatment-related side effects were fatigue (35%), proteinuria (35%), musculoskeletal pain (33%), diarrhea (22%), rash (20%), hypertension (18%), pruritus (18%), thyroid dysfunction (17%), hepatitis (15%), fever (13%), and mucositis (12%). Thirty-four patients developed at least one grade 3 adverse event; there were no grade 4 or 5 toxicities. One patient died, presumably because of disease progression.

Quality of life scores were largely stable during treatment.

“The combination demonstrated responses across several subtypes of RCC, including collecting duct and medullary carcinoma, histologies that are often treated with cytotoxic chemotherapy,” the authors said. “This is notable given the generally poor prognosis and low response rate associated with variant histology RCC in trials to date.”

The study also suggests the PD-L1 status might be “intriguing as a biomarker for response to atezolizumab and bevacizumab in variant histology RCC. We plan to conduct additional correlative work, including genomic profiling and assessment of the immune microenvironment, to better elucidate markers of response and resistance,” the authors wrote.

SOURCE: McGregor BA et al. J Clin Oncol. 2019 Nov 13. doi: 10.1200/JCO.19.01882.

The combination of atezolizumab plus bevacizumab may offer some benefit to patients with advanced renal cell carcinoma, especially those who are positive for programmed death-ligand 1 (PD-L1), investigators report.

The overall response rate (ORR) among such patients was 60%, compared with 19% in PD-L1–negative patients, Bradley A. McGregor, MD, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of Clinical Oncology.

The data were presented last summer at the American Society of Clinical Oncology Annual Meeting in Chicago.

The phase 2 study comprised 60 patients, 42 of whom had variant histology RCC, and 18 of whom had clear cell RCC (ccRCC ) with at least 20% sarcomatoid differentiation. All patients had advanced renal cell carcinoma of various histologies, including papillary (12), chromophobe (10), unclassified (9), TFE3 translocation (5), collecting duct (5), and medullary (1). Most (65%) had not received prior systemic therapy.

They all received infusions of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks. No dose modifications were allowed. Dose delays were allowed, and patients could also drop one agent and continue with the other. Treatment continued until disease progression, toxicity, or intolerable side effects.

The median number of cycles was 9.5, although the range was wide (1-42). At analysis, 15 were still on the treatment, but 45 had dropped out. Reasons were disease progression (34), death (1), toxicity (5), or unspecified (8). Six patients delayed bevacizumab doses, half because of adverse events.

After a median follow-up of 13 months, the ORR was 33%. Those with ccRCC with sarcomatoid differentiation responded best to the combination (ORR, 50%). Those with variant-histology RCC responded less robustly (ORR, 26%).

ORR varied by baseline risk category, being 33% in favorable-, 45% in intermediate-, and 11% in poor-risk patients. Median time to response was 2.7 months, median response duration was 8.9 months, and median progression-free survival was 8.3 months.

PD-L1 status was determined in 36 patients; 15 were positive. Among the positive patents, ORR was 60%, compared with 19% in PD-L1 negative patients. Response rates varied with tumor characteristics. Among patients with ccRCC with sarcomatoid differentiation, the ORR was 50% in PD-L1–positive patients and 29% in negative patients. In patients with variant histology RCC, the ORR was also better in PD-L1 positive patients (67% vs. 14%).

The most common treatment-related side effects were fatigue (35%), proteinuria (35%), musculoskeletal pain (33%), diarrhea (22%), rash (20%), hypertension (18%), pruritus (18%), thyroid dysfunction (17%), hepatitis (15%), fever (13%), and mucositis (12%). Thirty-four patients developed at least one grade 3 adverse event; there were no grade 4 or 5 toxicities. One patient died, presumably because of disease progression.

Quality of life scores were largely stable during treatment.

“The combination demonstrated responses across several subtypes of RCC, including collecting duct and medullary carcinoma, histologies that are often treated with cytotoxic chemotherapy,” the authors said. “This is notable given the generally poor prognosis and low response rate associated with variant histology RCC in trials to date.”

The study also suggests the PD-L1 status might be “intriguing as a biomarker for response to atezolizumab and bevacizumab in variant histology RCC. We plan to conduct additional correlative work, including genomic profiling and assessment of the immune microenvironment, to better elucidate markers of response and resistance,” the authors wrote.

SOURCE: McGregor BA et al. J Clin Oncol. 2019 Nov 13. doi: 10.1200/JCO.19.01882.

The combination of atezolizumab plus bevacizumab may offer some benefit to patients with advanced renal cell carcinoma, especially those who are positive for programmed death-ligand 1 (PD-L1), investigators report.

The overall response rate (ORR) among such patients was 60%, compared with 19% in PD-L1–negative patients, Bradley A. McGregor, MD, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of Clinical Oncology.

The data were presented last summer at the American Society of Clinical Oncology Annual Meeting in Chicago.

The phase 2 study comprised 60 patients, 42 of whom had variant histology RCC, and 18 of whom had clear cell RCC (ccRCC ) with at least 20% sarcomatoid differentiation. All patients had advanced renal cell carcinoma of various histologies, including papillary (12), chromophobe (10), unclassified (9), TFE3 translocation (5), collecting duct (5), and medullary (1). Most (65%) had not received prior systemic therapy.

They all received infusions of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks. No dose modifications were allowed. Dose delays were allowed, and patients could also drop one agent and continue with the other. Treatment continued until disease progression, toxicity, or intolerable side effects.

The median number of cycles was 9.5, although the range was wide (1-42). At analysis, 15 were still on the treatment, but 45 had dropped out. Reasons were disease progression (34), death (1), toxicity (5), or unspecified (8). Six patients delayed bevacizumab doses, half because of adverse events.

After a median follow-up of 13 months, the ORR was 33%. Those with ccRCC with sarcomatoid differentiation responded best to the combination (ORR, 50%). Those with variant-histology RCC responded less robustly (ORR, 26%).

ORR varied by baseline risk category, being 33% in favorable-, 45% in intermediate-, and 11% in poor-risk patients. Median time to response was 2.7 months, median response duration was 8.9 months, and median progression-free survival was 8.3 months.

PD-L1 status was determined in 36 patients; 15 were positive. Among the positive patents, ORR was 60%, compared with 19% in PD-L1 negative patients. Response rates varied with tumor characteristics. Among patients with ccRCC with sarcomatoid differentiation, the ORR was 50% in PD-L1–positive patients and 29% in negative patients. In patients with variant histology RCC, the ORR was also better in PD-L1 positive patients (67% vs. 14%).

The most common treatment-related side effects were fatigue (35%), proteinuria (35%), musculoskeletal pain (33%), diarrhea (22%), rash (20%), hypertension (18%), pruritus (18%), thyroid dysfunction (17%), hepatitis (15%), fever (13%), and mucositis (12%). Thirty-four patients developed at least one grade 3 adverse event; there were no grade 4 or 5 toxicities. One patient died, presumably because of disease progression.

Quality of life scores were largely stable during treatment.

“The combination demonstrated responses across several subtypes of RCC, including collecting duct and medullary carcinoma, histologies that are often treated with cytotoxic chemotherapy,” the authors said. “This is notable given the generally poor prognosis and low response rate associated with variant histology RCC in trials to date.”

The study also suggests the PD-L1 status might be “intriguing as a biomarker for response to atezolizumab and bevacizumab in variant histology RCC. We plan to conduct additional correlative work, including genomic profiling and assessment of the immune microenvironment, to better elucidate markers of response and resistance,” the authors wrote.

SOURCE: McGregor BA et al. J Clin Oncol. 2019 Nov 13. doi: 10.1200/JCO.19.01882.

NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

Jennifer Smith/MDedge News

Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.

“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”

Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.

At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.

For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.

Results

Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.

Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.

“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.

He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”

Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).

Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.

Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.

SOURCE: Msaouel P et al. SITC 2019. Abstract O23.

NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

Jennifer Smith/MDedge News

Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.

“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”

Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.

At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.

For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.

Results

Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.

Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.

“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.

He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”

Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).

Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.

Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.

SOURCE: Msaouel P et al. SITC 2019. Abstract O23.

NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

Jennifer Smith/MDedge News

Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.

“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”

Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.

At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.

For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.

Results

Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.

Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.

“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.

He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”

Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).

Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.

Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.

SOURCE: Msaouel P et al. SITC 2019. Abstract O23.

First-line sunitinib therapy for metastatic renal cell carcinoma (mRCC) has somewhat differing effectiveness and safety when used in real-world practice, compared with clinical trials, suggests the OSSMAR multicenter retrospective cohort study.

Investigators led by Marwan Ghosn, MD, Hotel-Dieu de France University Hospital and Saint Joseph University, Beirut, Lebanon, analyzed outcomes among 289 patients with mRCC started on sunitinib (Sutent), an oral multitargeted tyrosine kinase inhibitor, between 2006 and 2016 at 10 centers in Africa and the Middle East region.

The patients had a median age at diagnosis of 58.7 years, and 85.8% had clear cell histology. Two-thirds had metastases at diagnosis, and 15.2% and 31.4% had favorable- and poor-risk disease, respectively, according to expanded Memorial Sloan Kettering Cancer Center criteria. Overall, 52.2% had undergone partial or radical nephrectomy, and nearly all were receiving sunitinib as first-line therapy.

Study results, reported in the Journal of Global Oncology, showed that the mean total sunitinib starting dose was 48.1 mg, with most patients (87.6%) started on a dose of 50 mg. On average, the drug was given for 9.6 months.

The overall response rate was 20.8%, and responses lasted for a median of of 8.2 months. With a median follow-up of 7.8 months, patients had a median time to progression of 5.7 months and a median overall survival of 7.8 months. The 12- and 24-month rates of overall survival were 34.3% and 11.4%, respectively.

Although 60.9% of patients experienced adverse events, only 8.0% experienced serious adverse events. The main adverse events were gastrointestinal and hematologic, mirroring those seen previously in trials. About a third of the whole study cohort (28.7%) discontinued sunitinib therapy.

“OSSMAR is the first study in the Middle East involving several Arab countries and evaluating the use of real-time sunitinib in the treatment of mRCC. As a result, this study is of primary importance because it allows for a better assessment of the actual effectiveness and practical adverse events of sunitinib in the population in our region,” Dr. Ghosn and coinvestigators maintained.

Compared with patients in clinical trials, OSSMAR patients had poorer overall survival, possibly due to factors such as a relatively lower nephrectomy rate, real-world influences such as comorbidities, and losses to follow-up, the investigators proposed.

At the same time, the OSSMAR cohort also had a lower rate of adverse events, although this difference likely reflects less rigorous assessment of toxicity in real-world practice, they noted.

Dr. Ghosn disclosed that he has relationships with numerous pharmaceutical companies. The study did not receive any specific funding.

SOURCE: Ghosn M et al. J Glob Oncol. 2019 Oct 5. doi: 10.1200/JGO.18.00238.

First-line sunitinib therapy for metastatic renal cell carcinoma (mRCC) has somewhat differing effectiveness and safety when used in real-world practice, compared with clinical trials, suggests the OSSMAR multicenter retrospective cohort study.

Investigators led by Marwan Ghosn, MD, Hotel-Dieu de France University Hospital and Saint Joseph University, Beirut, Lebanon, analyzed outcomes among 289 patients with mRCC started on sunitinib (Sutent), an oral multitargeted tyrosine kinase inhibitor, between 2006 and 2016 at 10 centers in Africa and the Middle East region.

The patients had a median age at diagnosis of 58.7 years, and 85.8% had clear cell histology. Two-thirds had metastases at diagnosis, and 15.2% and 31.4% had favorable- and poor-risk disease, respectively, according to expanded Memorial Sloan Kettering Cancer Center criteria. Overall, 52.2% had undergone partial or radical nephrectomy, and nearly all were receiving sunitinib as first-line therapy.

Study results, reported in the Journal of Global Oncology, showed that the mean total sunitinib starting dose was 48.1 mg, with most patients (87.6%) started on a dose of 50 mg. On average, the drug was given for 9.6 months.

The overall response rate was 20.8%, and responses lasted for a median of of 8.2 months. With a median follow-up of 7.8 months, patients had a median time to progression of 5.7 months and a median overall survival of 7.8 months. The 12- and 24-month rates of overall survival were 34.3% and 11.4%, respectively.

Although 60.9% of patients experienced adverse events, only 8.0% experienced serious adverse events. The main adverse events were gastrointestinal and hematologic, mirroring those seen previously in trials. About a third of the whole study cohort (28.7%) discontinued sunitinib therapy.

“OSSMAR is the first study in the Middle East involving several Arab countries and evaluating the use of real-time sunitinib in the treatment of mRCC. As a result, this study is of primary importance because it allows for a better assessment of the actual effectiveness and practical adverse events of sunitinib in the population in our region,” Dr. Ghosn and coinvestigators maintained.

Compared with patients in clinical trials, OSSMAR patients had poorer overall survival, possibly due to factors such as a relatively lower nephrectomy rate, real-world influences such as comorbidities, and losses to follow-up, the investigators proposed.

At the same time, the OSSMAR cohort also had a lower rate of adverse events, although this difference likely reflects less rigorous assessment of toxicity in real-world practice, they noted.

Dr. Ghosn disclosed that he has relationships with numerous pharmaceutical companies. The study did not receive any specific funding.

SOURCE: Ghosn M et al. J Glob Oncol. 2019 Oct 5. doi: 10.1200/JGO.18.00238.

First-line sunitinib therapy for metastatic renal cell carcinoma (mRCC) has somewhat differing effectiveness and safety when used in real-world practice, compared with clinical trials, suggests the OSSMAR multicenter retrospective cohort study.

Investigators led by Marwan Ghosn, MD, Hotel-Dieu de France University Hospital and Saint Joseph University, Beirut, Lebanon, analyzed outcomes among 289 patients with mRCC started on sunitinib (Sutent), an oral multitargeted tyrosine kinase inhibitor, between 2006 and 2016 at 10 centers in Africa and the Middle East region.

The patients had a median age at diagnosis of 58.7 years, and 85.8% had clear cell histology. Two-thirds had metastases at diagnosis, and 15.2% and 31.4% had favorable- and poor-risk disease, respectively, according to expanded Memorial Sloan Kettering Cancer Center criteria. Overall, 52.2% had undergone partial or radical nephrectomy, and nearly all were receiving sunitinib as first-line therapy.

Study results, reported in the Journal of Global Oncology, showed that the mean total sunitinib starting dose was 48.1 mg, with most patients (87.6%) started on a dose of 50 mg. On average, the drug was given for 9.6 months.

The overall response rate was 20.8%, and responses lasted for a median of of 8.2 months. With a median follow-up of 7.8 months, patients had a median time to progression of 5.7 months and a median overall survival of 7.8 months. The 12- and 24-month rates of overall survival were 34.3% and 11.4%, respectively.

Although 60.9% of patients experienced adverse events, only 8.0% experienced serious adverse events. The main adverse events were gastrointestinal and hematologic, mirroring those seen previously in trials. About a third of the whole study cohort (28.7%) discontinued sunitinib therapy.

“OSSMAR is the first study in the Middle East involving several Arab countries and evaluating the use of real-time sunitinib in the treatment of mRCC. As a result, this study is of primary importance because it allows for a better assessment of the actual effectiveness and practical adverse events of sunitinib in the population in our region,” Dr. Ghosn and coinvestigators maintained.

Compared with patients in clinical trials, OSSMAR patients had poorer overall survival, possibly due to factors such as a relatively lower nephrectomy rate, real-world influences such as comorbidities, and losses to follow-up, the investigators proposed.

At the same time, the OSSMAR cohort also had a lower rate of adverse events, although this difference likely reflects less rigorous assessment of toxicity in real-world practice, they noted.

Dr. Ghosn disclosed that he has relationships with numerous pharmaceutical companies. The study did not receive any specific funding.

SOURCE: Ghosn M et al. J Glob Oncol. 2019 Oct 5. doi: 10.1200/JGO.18.00238.

Patients whose clear cell renal cell carcinoma (RCC) tumors lack the cytoskeleton linker protein ezrin have a poorer prognosis, finds a single-center retrospective cohort study.

The number of small renal masses discovered incidentally is rising, and some of these tumors can or must be treated less aggressively, according to lead investigator Marcos Vinicius O. Ferrari, MD, urology division, A.C. Camargo Cancer Center, São Paulo, and coinvestigators. “Thus, it is important to identify molecular markers that have prognostic value that can assist physicians in therapeutic strategies.”

The investigators studied 575 consecutive patients who underwent radical or partial nephrectomy for clear cell RCC during 1985-2016. A single pathologist reclassified all cases and determined the most representative tumor areas for tissue immunohistochemistry for ezrin and moesin, proteins that link the actin cytoskeleton to the cell membrane and that play roles in cell adhesion, migration, and growth.

Results reported in Urologic Oncology showed that 18.3% of tumors were negative for ezrin and 2.8% were negative for moesin.

Compared with counterparts who had ezrin-positive tumors, patients with ezrin-negative tumors had higher pathologic T stage (P less than .001); were less likely to have incidentally discovered tumors (P = .007); and were more likely to have clinical stage III or IV disease (P = .012), synchronous metastasis (P less than .001), and an International Society of Urological Pathology histologic grade of 3 or 4 (P = .025).

Similarly, compared with counterparts who had moesin-positive tumors, patients with moesin-negative tumors had higher pathologic T stage (P = .025) and pathologic N stage (P = .007), and were more likely to have clinical stage III or IV disease (P = .027).

The 10-year rate of disease-specific survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (70% vs. 88%; P less than .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 86%; P = .065). Similarly, the 10-year rate of overall survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (68% vs. 86%; P = .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 84%; P = .142).

In multivariate analyses, ezrin negativity was associated with a near doubling of the risk of disease-specific survival events (hazard ratio, 1.89; 95% confidence interval, 1.11-3.20) and with a trend toward poorer overall survival. Moesin negativity was not independently associated with either outcome.

“Negative expression of ezrin was associated with major prognostic factors in renal cancer and significantly influenced tumor-related death,” Dr. Ferrari and coinvestigators summarize, noting that this aligns with the pattern seen in bladder and ovarian cancers, but contrasts with the pattern seen in head and neck, colorectal, cervical, and breast cancers.

“The exact mechanism by which negative ezrin expression influences tumor progression and survival rates is unknown,” they conclude. “We encourage further prospective studies to analyze ezrin to determine its value in the prognosis of clear cell RCC.”

Dr. Ferrari disclosed that he had no relevant conflicts of interest. The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

SOURCE: Ferrari MVO et al. Urol Oncol. 2019 Oct 22. doi: 10.1016/j.urolonc.2019.09.011.
 

Patients whose clear cell renal cell carcinoma (RCC) tumors lack the cytoskeleton linker protein ezrin have a poorer prognosis, finds a single-center retrospective cohort study.

The number of small renal masses discovered incidentally is rising, and some of these tumors can or must be treated less aggressively, according to lead investigator Marcos Vinicius O. Ferrari, MD, urology division, A.C. Camargo Cancer Center, São Paulo, and coinvestigators. “Thus, it is important to identify molecular markers that have prognostic value that can assist physicians in therapeutic strategies.”

The investigators studied 575 consecutive patients who underwent radical or partial nephrectomy for clear cell RCC during 1985-2016. A single pathologist reclassified all cases and determined the most representative tumor areas for tissue immunohistochemistry for ezrin and moesin, proteins that link the actin cytoskeleton to the cell membrane and that play roles in cell adhesion, migration, and growth.

Results reported in Urologic Oncology showed that 18.3% of tumors were negative for ezrin and 2.8% were negative for moesin.

Compared with counterparts who had ezrin-positive tumors, patients with ezrin-negative tumors had higher pathologic T stage (P less than .001); were less likely to have incidentally discovered tumors (P = .007); and were more likely to have clinical stage III or IV disease (P = .012), synchronous metastasis (P less than .001), and an International Society of Urological Pathology histologic grade of 3 or 4 (P = .025).

Similarly, compared with counterparts who had moesin-positive tumors, patients with moesin-negative tumors had higher pathologic T stage (P = .025) and pathologic N stage (P = .007), and were more likely to have clinical stage III or IV disease (P = .027).

The 10-year rate of disease-specific survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (70% vs. 88%; P less than .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 86%; P = .065). Similarly, the 10-year rate of overall survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (68% vs. 86%; P = .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 84%; P = .142).

In multivariate analyses, ezrin negativity was associated with a near doubling of the risk of disease-specific survival events (hazard ratio, 1.89; 95% confidence interval, 1.11-3.20) and with a trend toward poorer overall survival. Moesin negativity was not independently associated with either outcome.

“Negative expression of ezrin was associated with major prognostic factors in renal cancer and significantly influenced tumor-related death,” Dr. Ferrari and coinvestigators summarize, noting that this aligns with the pattern seen in bladder and ovarian cancers, but contrasts with the pattern seen in head and neck, colorectal, cervical, and breast cancers.

“The exact mechanism by which negative ezrin expression influences tumor progression and survival rates is unknown,” they conclude. “We encourage further prospective studies to analyze ezrin to determine its value in the prognosis of clear cell RCC.”

Dr. Ferrari disclosed that he had no relevant conflicts of interest. The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

SOURCE: Ferrari MVO et al. Urol Oncol. 2019 Oct 22. doi: 10.1016/j.urolonc.2019.09.011.
 

Patients whose clear cell renal cell carcinoma (RCC) tumors lack the cytoskeleton linker protein ezrin have a poorer prognosis, finds a single-center retrospective cohort study.

The number of small renal masses discovered incidentally is rising, and some of these tumors can or must be treated less aggressively, according to lead investigator Marcos Vinicius O. Ferrari, MD, urology division, A.C. Camargo Cancer Center, São Paulo, and coinvestigators. “Thus, it is important to identify molecular markers that have prognostic value that can assist physicians in therapeutic strategies.”

The investigators studied 575 consecutive patients who underwent radical or partial nephrectomy for clear cell RCC during 1985-2016. A single pathologist reclassified all cases and determined the most representative tumor areas for tissue immunohistochemistry for ezrin and moesin, proteins that link the actin cytoskeleton to the cell membrane and that play roles in cell adhesion, migration, and growth.

Results reported in Urologic Oncology showed that 18.3% of tumors were negative for ezrin and 2.8% were negative for moesin.

Compared with counterparts who had ezrin-positive tumors, patients with ezrin-negative tumors had higher pathologic T stage (P less than .001); were less likely to have incidentally discovered tumors (P = .007); and were more likely to have clinical stage III or IV disease (P = .012), synchronous metastasis (P less than .001), and an International Society of Urological Pathology histologic grade of 3 or 4 (P = .025).

Similarly, compared with counterparts who had moesin-positive tumors, patients with moesin-negative tumors had higher pathologic T stage (P = .025) and pathologic N stage (P = .007), and were more likely to have clinical stage III or IV disease (P = .027).

The 10-year rate of disease-specific survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (70% vs. 88%; P less than .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 86%; P = .065). Similarly, the 10-year rate of overall survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (68% vs. 86%; P = .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 84%; P = .142).

In multivariate analyses, ezrin negativity was associated with a near doubling of the risk of disease-specific survival events (hazard ratio, 1.89; 95% confidence interval, 1.11-3.20) and with a trend toward poorer overall survival. Moesin negativity was not independently associated with either outcome.

“Negative expression of ezrin was associated with major prognostic factors in renal cancer and significantly influenced tumor-related death,” Dr. Ferrari and coinvestigators summarize, noting that this aligns with the pattern seen in bladder and ovarian cancers, but contrasts with the pattern seen in head and neck, colorectal, cervical, and breast cancers.

“The exact mechanism by which negative ezrin expression influences tumor progression and survival rates is unknown,” they conclude. “We encourage further prospective studies to analyze ezrin to determine its value in the prognosis of clear cell RCC.”

Dr. Ferrari disclosed that he had no relevant conflicts of interest. The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

SOURCE: Ferrari MVO et al. Urol Oncol. 2019 Oct 22. doi: 10.1016/j.urolonc.2019.09.011.
 

In this edition of “How I will treat my next patient,” I review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.

Metastatic CRPC

Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).

Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.

Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).

Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).

PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.

 

What this means in practice

During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.

Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.

For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.
 

Advanced ovarian cancer

The randomized, double-blind, placebo-controlled, phase 3 PAOLA-1/ENGOT-ov25 trial studied patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer who had surgery, platinum-taxane chemotherapy, and at least 3 months of bevacizumab. Patients were randomized to maintenance treatment with an additional 12 months of bevacizumab plus 24 months of PARPi with olaparib or placebo. Germline BRCA mutations were not required (Ray-Coquard I et al. ESMO 2019, Abstract LBA2).

As reported at ESMO, adding PARPi to bevacizumab maintenance provided a clinically meaningful PFS benefit of 22.1 months, in comparison with 16.6 months for bevacizumab alone. The difference was statistically significant.

For patients with tumor BRCA mutations (tBRCAm), PFS was 37.2 months with olaparib vs. 21.7 months for placebo (HR, 0.31). The PFS benefit was even more impressive for homologous recombination deficient (HRD)–positive patients, inclusive of those with tBRCAm (PFS 37.2 months for PARPi vs. 17.7 months for placebo; and in the 152 HRD-positive patients without tBRCAm, (median PFS 28.1 months vs. 16.6 months; HR, 0.43).

The improved PFS in patients with tBRCAm is similar to that reported in the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer (N Engl J Med. 2018; 379:2495-2505), but the PFS in the control arm was longer in PAOLA-1 than in SOLO1, perhaps because of the use of bevacizumab in PAOLA-1. PARPi did not affect tolerance to bevacizumab.

In PAOLA-1, the HRD-positive patients who lacked tBRCAm and, by extension, lacked germline BRCA mutations – a new population of patients – was identified who benefited substantially from maintenance PARPi in the first-line setting.
 

What this means in practice

PAOLA-1 demonstrates that PARPi can improve outcomes in first-line treatment – and in patients beyond those with germline BRCA mutations. As a result, PAOLA-1 potentially changes the standard of care for initial treatment of the respectable fraction of patients with previously untreated, advanced müllerian cancers who have either tBRCAm or HRD positive tumors.

Importantly, PAOLA-1 is one of many published trials that stimulates the discussion of cost vs. value for combinations of biologics. The incremental benefit from the second biologic (in this case PARPi) is almost never completely additive or supra-additive to the benefit associated with the first biologic (in this case, bevacizumab). In that regard, despite the fact that PARPi showed a PFS benefit in the intent-to-treat population overall, precisely defining the patient population that has the greatest benefit will facilitate the goal of getting the treatments of greatest “value for cost” to our patients in the most responsible way.

Additional research will hopefully define the relative contribution of bevacizumab to PARPi in patients who benefited so dramatically from PARPi in PAOLA-1.
 

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

In this edition of “How I will treat my next patient,” I review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.

Metastatic CRPC

Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).

Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.

Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).

Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).

PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.

 

What this means in practice

During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.

Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.

For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.
 

Advanced ovarian cancer

The randomized, double-blind, placebo-controlled, phase 3 PAOLA-1/ENGOT-ov25 trial studied patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer who had surgery, platinum-taxane chemotherapy, and at least 3 months of bevacizumab. Patients were randomized to maintenance treatment with an additional 12 months of bevacizumab plus 24 months of PARPi with olaparib or placebo. Germline BRCA mutations were not required (Ray-Coquard I et al. ESMO 2019, Abstract LBA2).

As reported at ESMO, adding PARPi to bevacizumab maintenance provided a clinically meaningful PFS benefit of 22.1 months, in comparison with 16.6 months for bevacizumab alone. The difference was statistically significant.

For patients with tumor BRCA mutations (tBRCAm), PFS was 37.2 months with olaparib vs. 21.7 months for placebo (HR, 0.31). The PFS benefit was even more impressive for homologous recombination deficient (HRD)–positive patients, inclusive of those with tBRCAm (PFS 37.2 months for PARPi vs. 17.7 months for placebo; and in the 152 HRD-positive patients without tBRCAm, (median PFS 28.1 months vs. 16.6 months; HR, 0.43).

The improved PFS in patients with tBRCAm is similar to that reported in the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer (N Engl J Med. 2018; 379:2495-2505), but the PFS in the control arm was longer in PAOLA-1 than in SOLO1, perhaps because of the use of bevacizumab in PAOLA-1. PARPi did not affect tolerance to bevacizumab.

In PAOLA-1, the HRD-positive patients who lacked tBRCAm and, by extension, lacked germline BRCA mutations – a new population of patients – was identified who benefited substantially from maintenance PARPi in the first-line setting.
 

What this means in practice

PAOLA-1 demonstrates that PARPi can improve outcomes in first-line treatment – and in patients beyond those with germline BRCA mutations. As a result, PAOLA-1 potentially changes the standard of care for initial treatment of the respectable fraction of patients with previously untreated, advanced müllerian cancers who have either tBRCAm or HRD positive tumors.

Importantly, PAOLA-1 is one of many published trials that stimulates the discussion of cost vs. value for combinations of biologics. The incremental benefit from the second biologic (in this case PARPi) is almost never completely additive or supra-additive to the benefit associated with the first biologic (in this case, bevacizumab). In that regard, despite the fact that PARPi showed a PFS benefit in the intent-to-treat population overall, precisely defining the patient population that has the greatest benefit will facilitate the goal of getting the treatments of greatest “value for cost” to our patients in the most responsible way.

Additional research will hopefully define the relative contribution of bevacizumab to PARPi in patients who benefited so dramatically from PARPi in PAOLA-1.
 

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

In this edition of “How I will treat my next patient,” I review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.

Metastatic CRPC

Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).

Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.

Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).

Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).

PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.

 

What this means in practice

During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.

Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.

For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.
 

Advanced ovarian cancer

The randomized, double-blind, placebo-controlled, phase 3 PAOLA-1/ENGOT-ov25 trial studied patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer who had surgery, platinum-taxane chemotherapy, and at least 3 months of bevacizumab. Patients were randomized to maintenance treatment with an additional 12 months of bevacizumab plus 24 months of PARPi with olaparib or placebo. Germline BRCA mutations were not required (Ray-Coquard I et al. ESMO 2019, Abstract LBA2).

As reported at ESMO, adding PARPi to bevacizumab maintenance provided a clinically meaningful PFS benefit of 22.1 months, in comparison with 16.6 months for bevacizumab alone. The difference was statistically significant.

For patients with tumor BRCA mutations (tBRCAm), PFS was 37.2 months with olaparib vs. 21.7 months for placebo (HR, 0.31). The PFS benefit was even more impressive for homologous recombination deficient (HRD)–positive patients, inclusive of those with tBRCAm (PFS 37.2 months for PARPi vs. 17.7 months for placebo; and in the 152 HRD-positive patients without tBRCAm, (median PFS 28.1 months vs. 16.6 months; HR, 0.43).

The improved PFS in patients with tBRCAm is similar to that reported in the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer (N Engl J Med. 2018; 379:2495-2505), but the PFS in the control arm was longer in PAOLA-1 than in SOLO1, perhaps because of the use of bevacizumab in PAOLA-1. PARPi did not affect tolerance to bevacizumab.

In PAOLA-1, the HRD-positive patients who lacked tBRCAm and, by extension, lacked germline BRCA mutations – a new population of patients – was identified who benefited substantially from maintenance PARPi in the first-line setting.
 

What this means in practice

PAOLA-1 demonstrates that PARPi can improve outcomes in first-line treatment – and in patients beyond those with germline BRCA mutations. As a result, PAOLA-1 potentially changes the standard of care for initial treatment of the respectable fraction of patients with previously untreated, advanced müllerian cancers who have either tBRCAm or HRD positive tumors.

Importantly, PAOLA-1 is one of many published trials that stimulates the discussion of cost vs. value for combinations of biologics. The incremental benefit from the second biologic (in this case PARPi) is almost never completely additive or supra-additive to the benefit associated with the first biologic (in this case, bevacizumab). In that regard, despite the fact that PARPi showed a PFS benefit in the intent-to-treat population overall, precisely defining the patient population that has the greatest benefit will facilitate the goal of getting the treatments of greatest “value for cost” to our patients in the most responsible way.

Additional research will hopefully define the relative contribution of bevacizumab to PARPi in patients who benefited so dramatically from PARPi in PAOLA-1.
 

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

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.

BARCELONA – The androgen receptor inhibitor apalutamide was associated with a 45% improvement in time to second progression in patients with nonmetastatic, castration-resistant prostate cancer as well as an overall survival edge, although the latter fell just short of statistical significance in an interim analysis of results from the SPARTAN trial.

Among 1,207 men with nonmetastatic castration-resistant prostate cancer (CRPC), those randomly assigned to apalutamide had significantly longer second progression-free survival (PFS2), an exploratory endpoint defined as the time of study entry to progression on subsequent treatment.

In all, 69% of patients on placebo and 40% of those on apalutamide went on to another life-prolonging therapy, usually abiraterone acetate (Zytiga) plus prednisone. The respective median PFS2s were 43.8 and 55.6 months, translating into a hazard ratio for second progression in the apalutamide group of 0.55 (P less than .0001).

Overall survival (OS) also trended toward a benefit for apalutamide, but the difference did not reach the prespecified boundary for significance in this planned interim analysis, reported Matthew R. Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston.

Among men randomly assigned in the phase 3 trial to receive apalutamide (Erleada), the 4-year OS rate was 72.1%, compared with 64.7% for patients assigned to placebo.

“This OS benefit for apalutamide was observed despite crossover of placebo patients to apalutamide, and higher rates of subsequent life-prolonging therapy in the placebo group,” he said at the European Society for Medical Oncology Congress.

Apalutamide was approved by the Food and Drug Administration in 2018 for treatment of patients with nonmetastatic CRPC who were on androgen deprivation therapy with a rapidly rising prostate-specific antigen level and no detectable distant metastases on conventional imaging.

That approval was based on the primary results from SPARTAN, which showed a median metastasis-free survival for patients taking apalutamide of 40.5 months, compared with 16.2 months for patients taking placebo.

The drug also recently received FDA approval for treatment of men with metastatic CRPC, based on results of the TITAN trial.

Overall survival

At the time of the primary analysis of SPARTAN for metastasis-free survival, the OS data were immature, with only 104 of 427 events required for the prespecified analysis.

At ESMO 2019, Dr. Smith presented results of the second interim survival analysis looking at the effects of apalutamide on OS, as well as time to chemotherapy, PFS2, and safety.

In the trial, men with nonmetastatic CRPC were randomized on a 2:1 basis to receive either apalutamide 240 mg daily (806 patients) or placebo (401) plus androgen deprivation therapy, either with gonadotropin-releasing hormone analogue therapy or with surgical castration.

At a median follow-up of 41 months, median OS was not reached in either arm. As noted before, the 4-year OS rate was higher in the apalutamide group, translating into a HR for death of 0.75. However, the P value of .0197 was higher than the prespecified O’Brien-Fleming boundary of 0.0121, which means that the study follow-up will continue per protocol, with the final analysis for overall survival planned after 427 deaths have occurred, Dr. Smith said.

The survival benefit with apalutamide either trended toward significance across all subgroups, with notable benefits in patients aged younger than 65 years, those with good performance status, prostate-specific antigen doubling time longer than 6 months, and those with locoregional disease status of N1 versus N0.

The secondary endpoint of time to chemotherapy initiation was not formally tested because OS did not reach statistical significance, but proportionally fewer patients on apalutamide had started cytotoxic chemotherapy at the time of the interim analysis (14% vs. 20% of patients on placebo). The median time to initiation of chemotherapy has not been reached in either trial arm, however.

The safety profile of the androgen receptor inhibitor was consistent with that seen in the primary PFS analysis, with any adverse event seen in 97.3% of patients versus 93.7% of patients on placebo, grade 3-4 adverse events in 53.1% versus 36.7%, any serious adverse event in 33.5% versus 24.9%, events leading to treatment discontinuation in 13.8% versus 7.3%, and fatal adverse events in 2.1 versus .5%.

“Of some note, discontinuation due to disease progression was 34% in the apalutamide group, compared to 74% in the placebo group,” Dr. Smith said.

“These results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic CRPC,” he concluded.

PFS2 data ‘important’

Invited discussant Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, acknowledged it’s too early to draw conclusions about OS, but added that the PFS2 data are important.

Neil Osterweil/MDedge News

The 45% reduction in risk of progression “is particularly important in this trial because abiraterone was provided as a potential salvage treatment in both arms. So in other words, in that trial they were almost truly comparing early AR [androgen receptor] targeting versus deferred AR targeting, at least in some patients, and it seems that [apalutamide] is making a difference in terms of second progression,” he said.

An unanswered question about the trial, however, is how active abiraterone was post apalutamide in the experimental, because there are data suggesting minimal efficacy in sequential therapy of AR-targeted agents, he added.

The SPARTAN trial was funded by Janssen. Dr. Smith disclosed an advisory role, research funding, and travel reimbursement for Janssen and others. Dr. Fizazi disclosed consulting for Janssen and others.

SOURCE: Smith MR et al. ESMO 2019, Abstract 843O

BARCELONA – The androgen receptor inhibitor apalutamide was associated with a 45% improvement in time to second progression in patients with nonmetastatic, castration-resistant prostate cancer as well as an overall survival edge, although the latter fell just short of statistical significance in an interim analysis of results from the SPARTAN trial.

Among 1,207 men with nonmetastatic castration-resistant prostate cancer (CRPC), those randomly assigned to apalutamide had significantly longer second progression-free survival (PFS2), an exploratory endpoint defined as the time of study entry to progression on subsequent treatment.

In all, 69% of patients on placebo and 40% of those on apalutamide went on to another life-prolonging therapy, usually abiraterone acetate (Zytiga) plus prednisone. The respective median PFS2s were 43.8 and 55.6 months, translating into a hazard ratio for second progression in the apalutamide group of 0.55 (P less than .0001).

Overall survival (OS) also trended toward a benefit for apalutamide, but the difference did not reach the prespecified boundary for significance in this planned interim analysis, reported Matthew R. Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston.

Among men randomly assigned in the phase 3 trial to receive apalutamide (Erleada), the 4-year OS rate was 72.1%, compared with 64.7% for patients assigned to placebo.

“This OS benefit for apalutamide was observed despite crossover of placebo patients to apalutamide, and higher rates of subsequent life-prolonging therapy in the placebo group,” he said at the European Society for Medical Oncology Congress.

Apalutamide was approved by the Food and Drug Administration in 2018 for treatment of patients with nonmetastatic CRPC who were on androgen deprivation therapy with a rapidly rising prostate-specific antigen level and no detectable distant metastases on conventional imaging.

That approval was based on the primary results from SPARTAN, which showed a median metastasis-free survival for patients taking apalutamide of 40.5 months, compared with 16.2 months for patients taking placebo.

The drug also recently received FDA approval for treatment of men with metastatic CRPC, based on results of the TITAN trial.

Overall survival

At the time of the primary analysis of SPARTAN for metastasis-free survival, the OS data were immature, with only 104 of 427 events required for the prespecified analysis.

At ESMO 2019, Dr. Smith presented results of the second interim survival analysis looking at the effects of apalutamide on OS, as well as time to chemotherapy, PFS2, and safety.

In the trial, men with nonmetastatic CRPC were randomized on a 2:1 basis to receive either apalutamide 240 mg daily (806 patients) or placebo (401) plus androgen deprivation therapy, either with gonadotropin-releasing hormone analogue therapy or with surgical castration.

At a median follow-up of 41 months, median OS was not reached in either arm. As noted before, the 4-year OS rate was higher in the apalutamide group, translating into a HR for death of 0.75. However, the P value of .0197 was higher than the prespecified O’Brien-Fleming boundary of 0.0121, which means that the study follow-up will continue per protocol, with the final analysis for overall survival planned after 427 deaths have occurred, Dr. Smith said.

The survival benefit with apalutamide either trended toward significance across all subgroups, with notable benefits in patients aged younger than 65 years, those with good performance status, prostate-specific antigen doubling time longer than 6 months, and those with locoregional disease status of N1 versus N0.

The secondary endpoint of time to chemotherapy initiation was not formally tested because OS did not reach statistical significance, but proportionally fewer patients on apalutamide had started cytotoxic chemotherapy at the time of the interim analysis (14% vs. 20% of patients on placebo). The median time to initiation of chemotherapy has not been reached in either trial arm, however.

The safety profile of the androgen receptor inhibitor was consistent with that seen in the primary PFS analysis, with any adverse event seen in 97.3% of patients versus 93.7% of patients on placebo, grade 3-4 adverse events in 53.1% versus 36.7%, any serious adverse event in 33.5% versus 24.9%, events leading to treatment discontinuation in 13.8% versus 7.3%, and fatal adverse events in 2.1 versus .5%.

“Of some note, discontinuation due to disease progression was 34% in the apalutamide group, compared to 74% in the placebo group,” Dr. Smith said.

“These results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic CRPC,” he concluded.

PFS2 data ‘important’

Invited discussant Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, acknowledged it’s too early to draw conclusions about OS, but added that the PFS2 data are important.

Neil Osterweil/MDedge News

The 45% reduction in risk of progression “is particularly important in this trial because abiraterone was provided as a potential salvage treatment in both arms. So in other words, in that trial they were almost truly comparing early AR [androgen receptor] targeting versus deferred AR targeting, at least in some patients, and it seems that [apalutamide] is making a difference in terms of second progression,” he said.

An unanswered question about the trial, however, is how active abiraterone was post apalutamide in the experimental, because there are data suggesting minimal efficacy in sequential therapy of AR-targeted agents, he added.

The SPARTAN trial was funded by Janssen. Dr. Smith disclosed an advisory role, research funding, and travel reimbursement for Janssen and others. Dr. Fizazi disclosed consulting for Janssen and others.

SOURCE: Smith MR et al. ESMO 2019, Abstract 843O

BARCELONA – The androgen receptor inhibitor apalutamide was associated with a 45% improvement in time to second progression in patients with nonmetastatic, castration-resistant prostate cancer as well as an overall survival edge, although the latter fell just short of statistical significance in an interim analysis of results from the SPARTAN trial.

Among 1,207 men with nonmetastatic castration-resistant prostate cancer (CRPC), those randomly assigned to apalutamide had significantly longer second progression-free survival (PFS2), an exploratory endpoint defined as the time of study entry to progression on subsequent treatment.

In all, 69% of patients on placebo and 40% of those on apalutamide went on to another life-prolonging therapy, usually abiraterone acetate (Zytiga) plus prednisone. The respective median PFS2s were 43.8 and 55.6 months, translating into a hazard ratio for second progression in the apalutamide group of 0.55 (P less than .0001).

Overall survival (OS) also trended toward a benefit for apalutamide, but the difference did not reach the prespecified boundary for significance in this planned interim analysis, reported Matthew R. Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston.

Among men randomly assigned in the phase 3 trial to receive apalutamide (Erleada), the 4-year OS rate was 72.1%, compared with 64.7% for patients assigned to placebo.

“This OS benefit for apalutamide was observed despite crossover of placebo patients to apalutamide, and higher rates of subsequent life-prolonging therapy in the placebo group,” he said at the European Society for Medical Oncology Congress.

Apalutamide was approved by the Food and Drug Administration in 2018 for treatment of patients with nonmetastatic CRPC who were on androgen deprivation therapy with a rapidly rising prostate-specific antigen level and no detectable distant metastases on conventional imaging.

That approval was based on the primary results from SPARTAN, which showed a median metastasis-free survival for patients taking apalutamide of 40.5 months, compared with 16.2 months for patients taking placebo.

The drug also recently received FDA approval for treatment of men with metastatic CRPC, based on results of the TITAN trial.

Overall survival

At the time of the primary analysis of SPARTAN for metastasis-free survival, the OS data were immature, with only 104 of 427 events required for the prespecified analysis.

At ESMO 2019, Dr. Smith presented results of the second interim survival analysis looking at the effects of apalutamide on OS, as well as time to chemotherapy, PFS2, and safety.

In the trial, men with nonmetastatic CRPC were randomized on a 2:1 basis to receive either apalutamide 240 mg daily (806 patients) or placebo (401) plus androgen deprivation therapy, either with gonadotropin-releasing hormone analogue therapy or with surgical castration.

At a median follow-up of 41 months, median OS was not reached in either arm. As noted before, the 4-year OS rate was higher in the apalutamide group, translating into a HR for death of 0.75. However, the P value of .0197 was higher than the prespecified O’Brien-Fleming boundary of 0.0121, which means that the study follow-up will continue per protocol, with the final analysis for overall survival planned after 427 deaths have occurred, Dr. Smith said.

The survival benefit with apalutamide either trended toward significance across all subgroups, with notable benefits in patients aged younger than 65 years, those with good performance status, prostate-specific antigen doubling time longer than 6 months, and those with locoregional disease status of N1 versus N0.

The secondary endpoint of time to chemotherapy initiation was not formally tested because OS did not reach statistical significance, but proportionally fewer patients on apalutamide had started cytotoxic chemotherapy at the time of the interim analysis (14% vs. 20% of patients on placebo). The median time to initiation of chemotherapy has not been reached in either trial arm, however.

The safety profile of the androgen receptor inhibitor was consistent with that seen in the primary PFS analysis, with any adverse event seen in 97.3% of patients versus 93.7% of patients on placebo, grade 3-4 adverse events in 53.1% versus 36.7%, any serious adverse event in 33.5% versus 24.9%, events leading to treatment discontinuation in 13.8% versus 7.3%, and fatal adverse events in 2.1 versus .5%.

“Of some note, discontinuation due to disease progression was 34% in the apalutamide group, compared to 74% in the placebo group,” Dr. Smith said.

“These results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic CRPC,” he concluded.

PFS2 data ‘important’

Invited discussant Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, acknowledged it’s too early to draw conclusions about OS, but added that the PFS2 data are important.

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The 45% reduction in risk of progression “is particularly important in this trial because abiraterone was provided as a potential salvage treatment in both arms. So in other words, in that trial they were almost truly comparing early AR [androgen receptor] targeting versus deferred AR targeting, at least in some patients, and it seems that [apalutamide] is making a difference in terms of second progression,” he said.

An unanswered question about the trial, however, is how active abiraterone was post apalutamide in the experimental, because there are data suggesting minimal efficacy in sequential therapy of AR-targeted agents, he added.

The SPARTAN trial was funded by Janssen. Dr. Smith disclosed an advisory role, research funding, and travel reimbursement for Janssen and others. Dr. Fizazi disclosed consulting for Janssen and others.

SOURCE: Smith MR et al. ESMO 2019, Abstract 843O