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No survival benefit with adjuvant girentuximab in high-risk RCC
The monoclonal antibody girentuximab does not appear to have a clinical benefit in patients with high-risk clear cell renal cell carcinoma (ccRCC).
Adjuvant therapy with girentuximab failed to improve either disease-free or overall survival, compared with placebo, in a cohort of patients who had undergone full surgical resection, according to phase 3 results of the ARISER trial.
In a subset of patients with CAIX scores of 200 or greater, however, there was disease-free survival benefit although it did not reach significance, reported lead author Karim Chamie, MD, of the David Geffen School of Medicine at UCLA, and his colleagues (JAMA Oncol. 2017;3[7]:913-20).
The drug was well tolerated, with an excellent safety profile, and there were no reported drug-related serious adverse events.
“Our finding that girentuximab was more effective in the subgroup of patients younger than 65 years is consistent with these observations and, while requiring prospective confirmation, suggests that an insufficient activation of [antibody-dependent cellular cytotoxicity] could explain the failure of its efficacy,” wrote Dr. Chamie and his colleagues.
The authors also point out that “virtually all trials of adjuvant therapy in high-risk RCC have failed to show a treatment benefit,” and thus illustrates the difficulty in identifying successful adjuvant therapies.
“The success of future adjuvant trials will require use of inclusion criteria sufficiently broad to meet accrual goals while limiting inclusion to patients who are most likely to benefit from therapy,” they write.
Girentuximab is a chimeric monoclonal antibody that binds carbonic anhydrase IX, a cell surface glycoprotein that is ubiquitously expressed in ccRCC. Phase 2 studies showed the agent to be safe and active in this setting, and served as the basis for conducting the current phase 3 ARISER trial (Adjuvant Rencarex Immunotherapy Phase 3 Trial to Study Efficacy in Nonmetastatic RCC).
The randomized, double-blind, placebo-controlled trial was conducted at 142 academic medical centers in 15 countries in North and South America and Europe and included a cohort of 864 patients who had undergone partial or radical nephrectomy for ccRCC and fell into one of the following high-risk groups: pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater.
The cohort was randomly assigned to either a single loading dose of girentuximab, 50 mg (week 1), followed by weekly intravenous infusions of girentuximab, 20 mg (weeks 2-24), or placebo, stratified by risk group and region.
The overall disease-free survival was comparable for the two groups: at 5 years it was 53.9% and 51.6% for the girentuximab and placebo groups, respectively, while the median disease-free survival was 71.4 months (interquartile range, 3 months to not reached) for patients who received girentuximab and was not reached for those receiving placebo (P = .74).
Median overall survival was not reached for either of the two groups, and there was no difference in overall survival between arms (hazard ratio, 0.99; 95% confidence interval, 0.74-1.32).
Adverse events were reported in 185 patients (21.6%), and were comparable between groups, and serious events occurred in 72 patients (8.4%), and were also comparable between the two arms.
The study was funded by Wilex, AG. Dr. Chamie receives research support from and serves as a consultant for UroGen Pharma, receives grant support from Phase One Foundation and Stop Cancer, and is a consultant for Cold Genesys and a scientific advisory board member of Altor. Several coauthors reported relationships with industry.
The monoclonal antibody girentuximab does not appear to have a clinical benefit in patients with high-risk clear cell renal cell carcinoma (ccRCC).
Adjuvant therapy with girentuximab failed to improve either disease-free or overall survival, compared with placebo, in a cohort of patients who had undergone full surgical resection, according to phase 3 results of the ARISER trial.
In a subset of patients with CAIX scores of 200 or greater, however, there was disease-free survival benefit although it did not reach significance, reported lead author Karim Chamie, MD, of the David Geffen School of Medicine at UCLA, and his colleagues (JAMA Oncol. 2017;3[7]:913-20).
The drug was well tolerated, with an excellent safety profile, and there were no reported drug-related serious adverse events.
“Our finding that girentuximab was more effective in the subgroup of patients younger than 65 years is consistent with these observations and, while requiring prospective confirmation, suggests that an insufficient activation of [antibody-dependent cellular cytotoxicity] could explain the failure of its efficacy,” wrote Dr. Chamie and his colleagues.
The authors also point out that “virtually all trials of adjuvant therapy in high-risk RCC have failed to show a treatment benefit,” and thus illustrates the difficulty in identifying successful adjuvant therapies.
“The success of future adjuvant trials will require use of inclusion criteria sufficiently broad to meet accrual goals while limiting inclusion to patients who are most likely to benefit from therapy,” they write.
Girentuximab is a chimeric monoclonal antibody that binds carbonic anhydrase IX, a cell surface glycoprotein that is ubiquitously expressed in ccRCC. Phase 2 studies showed the agent to be safe and active in this setting, and served as the basis for conducting the current phase 3 ARISER trial (Adjuvant Rencarex Immunotherapy Phase 3 Trial to Study Efficacy in Nonmetastatic RCC).
The randomized, double-blind, placebo-controlled trial was conducted at 142 academic medical centers in 15 countries in North and South America and Europe and included a cohort of 864 patients who had undergone partial or radical nephrectomy for ccRCC and fell into one of the following high-risk groups: pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater.
The cohort was randomly assigned to either a single loading dose of girentuximab, 50 mg (week 1), followed by weekly intravenous infusions of girentuximab, 20 mg (weeks 2-24), or placebo, stratified by risk group and region.
The overall disease-free survival was comparable for the two groups: at 5 years it was 53.9% and 51.6% for the girentuximab and placebo groups, respectively, while the median disease-free survival was 71.4 months (interquartile range, 3 months to not reached) for patients who received girentuximab and was not reached for those receiving placebo (P = .74).
Median overall survival was not reached for either of the two groups, and there was no difference in overall survival between arms (hazard ratio, 0.99; 95% confidence interval, 0.74-1.32).
Adverse events were reported in 185 patients (21.6%), and were comparable between groups, and serious events occurred in 72 patients (8.4%), and were also comparable between the two arms.
The study was funded by Wilex, AG. Dr. Chamie receives research support from and serves as a consultant for UroGen Pharma, receives grant support from Phase One Foundation and Stop Cancer, and is a consultant for Cold Genesys and a scientific advisory board member of Altor. Several coauthors reported relationships with industry.
The monoclonal antibody girentuximab does not appear to have a clinical benefit in patients with high-risk clear cell renal cell carcinoma (ccRCC).
Adjuvant therapy with girentuximab failed to improve either disease-free or overall survival, compared with placebo, in a cohort of patients who had undergone full surgical resection, according to phase 3 results of the ARISER trial.
In a subset of patients with CAIX scores of 200 or greater, however, there was disease-free survival benefit although it did not reach significance, reported lead author Karim Chamie, MD, of the David Geffen School of Medicine at UCLA, and his colleagues (JAMA Oncol. 2017;3[7]:913-20).
The drug was well tolerated, with an excellent safety profile, and there were no reported drug-related serious adverse events.
“Our finding that girentuximab was more effective in the subgroup of patients younger than 65 years is consistent with these observations and, while requiring prospective confirmation, suggests that an insufficient activation of [antibody-dependent cellular cytotoxicity] could explain the failure of its efficacy,” wrote Dr. Chamie and his colleagues.
The authors also point out that “virtually all trials of adjuvant therapy in high-risk RCC have failed to show a treatment benefit,” and thus illustrates the difficulty in identifying successful adjuvant therapies.
“The success of future adjuvant trials will require use of inclusion criteria sufficiently broad to meet accrual goals while limiting inclusion to patients who are most likely to benefit from therapy,” they write.
Girentuximab is a chimeric monoclonal antibody that binds carbonic anhydrase IX, a cell surface glycoprotein that is ubiquitously expressed in ccRCC. Phase 2 studies showed the agent to be safe and active in this setting, and served as the basis for conducting the current phase 3 ARISER trial (Adjuvant Rencarex Immunotherapy Phase 3 Trial to Study Efficacy in Nonmetastatic RCC).
The randomized, double-blind, placebo-controlled trial was conducted at 142 academic medical centers in 15 countries in North and South America and Europe and included a cohort of 864 patients who had undergone partial or radical nephrectomy for ccRCC and fell into one of the following high-risk groups: pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater.
The cohort was randomly assigned to either a single loading dose of girentuximab, 50 mg (week 1), followed by weekly intravenous infusions of girentuximab, 20 mg (weeks 2-24), or placebo, stratified by risk group and region.
The overall disease-free survival was comparable for the two groups: at 5 years it was 53.9% and 51.6% for the girentuximab and placebo groups, respectively, while the median disease-free survival was 71.4 months (interquartile range, 3 months to not reached) for patients who received girentuximab and was not reached for those receiving placebo (P = .74).
Median overall survival was not reached for either of the two groups, and there was no difference in overall survival between arms (hazard ratio, 0.99; 95% confidence interval, 0.74-1.32).
Adverse events were reported in 185 patients (21.6%), and were comparable between groups, and serious events occurred in 72 patients (8.4%), and were also comparable between the two arms.
The study was funded by Wilex, AG. Dr. Chamie receives research support from and serves as a consultant for UroGen Pharma, receives grant support from Phase One Foundation and Stop Cancer, and is a consultant for Cold Genesys and a scientific advisory board member of Altor. Several coauthors reported relationships with industry.
FROM JAMA ONCOLOGY
Key clinical point: Adjuvant girentuximab did not confer a survival benefit in patients with high-risk clear cell renal cell carcinoma.
Major finding: Five-year disease-free survival was 53.9% and 51.6% for the girentuximab and placebo groups, respectively.
Data source: A phase 3 placebo controlled multicenter clinical trial that included 864 patients with high-risk clear cell renal cell carcinoma.
Disclosures: The study was funded by Wilex, AG. Dr. Chamie receives research support from and serves as a consultant for UroGen Pharma, receives grant support from Phase One Foundation and Stop Cancer, and is a consultant for Cold Genesys and a scientific advisory board member of Altor. Several coauthors reported relationships with industry.
Savolitinib improves PFS in some with MET-driven papillary renal cell carcinoma
Savolitinib, a highly selective inhibitor of c-Met receptor tyrosine kinase, improved progression-free survival in a small portion of patients with MET-driven advanced renal papillary cell cancer.
The molecule, being developed by Hutchison China MediTech Limited and AstraZeneca, extended progression-free survival by about 5 months in these patients, compared with those whose tumors were not MET driven (6.2 vs. 1.4 months, respectively), reported Toni Choueiri, MD, and his colleagues (J Clin Oncol 2017. doi: 10.1200/JCO.2017.72.2967).
Of 109 patients in the phase II study, 44 (40%) had MET-driven disease. The cancer was MET independent in 46 (42%); MET status was unknown in the remainder.
Half of those with MET-driven tumors experienced stable disease, and 61% experienced tumor shrinkage ranging from 0.7% to 66%. Tumor shrinkage occurred in 20% of those with MET-independent tumors. These also responded less vigorously (shrinkage 0.5%-20%).
Of the eight patients exhibiting a partial response, six were still responding to treatment at the study’s end, with response ranging from 2 to 16 months. Two patients experienced progressive disease after 1.8 and 2.8 months. By the end of the study, disease progression had occurred in 75% of the MET-driven cases, 96% of the MET-independent cases, and 74% of cases whose MET status was unknown.
“These results confirm that savolitinib … holds promise as a personalized treatment for patients with metastatic MET-driven papillary renal cell carcinoma,” the investigators wrote. The data also support the June launch of the phase III SAVOIR trial, they noted.
SAVOIR will enroll about 180 patients with MET-driven renal papillary cancer confirmed by a next-generation molecular sequencing developed by the companies for savolitinib response. Patients will be randomized to continuous treatment with savolitinib 600 mg orally, once daily, or intermittent treatment with sunitinib 50 mg orally once daily (4 weeks on/2 weeks off), on a 6-week cycle.
Dr. Choueiri has been a consultant for and received research funding from numerous pharmaceutical companies, including AstraZeneca.
[email protected]
On Twitter @Alz_gal
Savolitinib, a highly selective inhibitor of c-Met receptor tyrosine kinase, improved progression-free survival in a small portion of patients with MET-driven advanced renal papillary cell cancer.
The molecule, being developed by Hutchison China MediTech Limited and AstraZeneca, extended progression-free survival by about 5 months in these patients, compared with those whose tumors were not MET driven (6.2 vs. 1.4 months, respectively), reported Toni Choueiri, MD, and his colleagues (J Clin Oncol 2017. doi: 10.1200/JCO.2017.72.2967).
Of 109 patients in the phase II study, 44 (40%) had MET-driven disease. The cancer was MET independent in 46 (42%); MET status was unknown in the remainder.
Half of those with MET-driven tumors experienced stable disease, and 61% experienced tumor shrinkage ranging from 0.7% to 66%. Tumor shrinkage occurred in 20% of those with MET-independent tumors. These also responded less vigorously (shrinkage 0.5%-20%).
Of the eight patients exhibiting a partial response, six were still responding to treatment at the study’s end, with response ranging from 2 to 16 months. Two patients experienced progressive disease after 1.8 and 2.8 months. By the end of the study, disease progression had occurred in 75% of the MET-driven cases, 96% of the MET-independent cases, and 74% of cases whose MET status was unknown.
“These results confirm that savolitinib … holds promise as a personalized treatment for patients with metastatic MET-driven papillary renal cell carcinoma,” the investigators wrote. The data also support the June launch of the phase III SAVOIR trial, they noted.
SAVOIR will enroll about 180 patients with MET-driven renal papillary cancer confirmed by a next-generation molecular sequencing developed by the companies for savolitinib response. Patients will be randomized to continuous treatment with savolitinib 600 mg orally, once daily, or intermittent treatment with sunitinib 50 mg orally once daily (4 weeks on/2 weeks off), on a 6-week cycle.
Dr. Choueiri has been a consultant for and received research funding from numerous pharmaceutical companies, including AstraZeneca.
[email protected]
On Twitter @Alz_gal
Savolitinib, a highly selective inhibitor of c-Met receptor tyrosine kinase, improved progression-free survival in a small portion of patients with MET-driven advanced renal papillary cell cancer.
The molecule, being developed by Hutchison China MediTech Limited and AstraZeneca, extended progression-free survival by about 5 months in these patients, compared with those whose tumors were not MET driven (6.2 vs. 1.4 months, respectively), reported Toni Choueiri, MD, and his colleagues (J Clin Oncol 2017. doi: 10.1200/JCO.2017.72.2967).
Of 109 patients in the phase II study, 44 (40%) had MET-driven disease. The cancer was MET independent in 46 (42%); MET status was unknown in the remainder.
Half of those with MET-driven tumors experienced stable disease, and 61% experienced tumor shrinkage ranging from 0.7% to 66%. Tumor shrinkage occurred in 20% of those with MET-independent tumors. These also responded less vigorously (shrinkage 0.5%-20%).
Of the eight patients exhibiting a partial response, six were still responding to treatment at the study’s end, with response ranging from 2 to 16 months. Two patients experienced progressive disease after 1.8 and 2.8 months. By the end of the study, disease progression had occurred in 75% of the MET-driven cases, 96% of the MET-independent cases, and 74% of cases whose MET status was unknown.
“These results confirm that savolitinib … holds promise as a personalized treatment for patients with metastatic MET-driven papillary renal cell carcinoma,” the investigators wrote. The data also support the June launch of the phase III SAVOIR trial, they noted.
SAVOIR will enroll about 180 patients with MET-driven renal papillary cancer confirmed by a next-generation molecular sequencing developed by the companies for savolitinib response. Patients will be randomized to continuous treatment with savolitinib 600 mg orally, once daily, or intermittent treatment with sunitinib 50 mg orally once daily (4 weeks on/2 weeks off), on a 6-week cycle.
Dr. Choueiri has been a consultant for and received research funding from numerous pharmaceutical companies, including AstraZeneca.
[email protected]
On Twitter @Alz_gal
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: A partial response occurred in 18% of these patients, who gained about 5 months of progression-free disease compared with those with MET-independent tumors.
Data source: A phase II trial comprising 109 patients.
Disclosures: Dr. Choueiri has been a consultant for and received research funds from AstraZeneca, which is developing the drug.
PROTECT: Pazopanib falls short as adjuvant therapy for high-risk RCC
CHICAGO – The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, the PROTECT investigators reported at the annual meeting of the American Society of Clinical Oncology.
Pazopanib (Votrient) is an oral multitargeted tyrosine kinase inhibitor active against the vascular endothelial growth factor receptor (VEGFR). Adjuvant use of other agents in this class has yielded mixed results, noted lead investigator Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York.
In PROTECT, a phase III randomized controlled trial of more than 1,500 patients who had undergone nephrectomy for high-risk locally advanced RCC, pazopanib started at 600 mg daily did not yield significantly better disease-free survival than placebo, the trial’s primary endpoint. The drug did have a significant benefit when started at 800 mg daily, but that dose had to be lowered partway through because of a high rate of discontinuation due to adverse events.
“The trial did not meet its primary endpoint,” Dr. Motzer concluded. “Pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”
Expert perspective
“The current landscape of RCC adjuvant therapy is really controversial,” commented invited discussant Daniel Y. C. Heng, MD, MPH, of the University of Calgary (Alta.) Tom Baker Cancer Centre.
“Are these [factors] important or not? I think a lot of this is being overshadowed by things that are going on right now,” Dr. Heng maintained. “There are newer medications, such as PD-1 and PD-L1 inhibitors that are now being studied. And there are now perioperative studies as well – should we be using these drugs before nephrectomy and after nephrectomy to prime the immune system to get better outcomes?”
At the end of the day, identification of a reliable predictive biomarker will be key to using the VEGFR tyrosine kinase inhibitors, he concluded. “I look forward to the future where we can actually use these tests to determine who will benefit most from adjuvant therapy so that we can maximize patient outcomes.”
Study details
The PROTECT trial was funded by Novartis Oncology and randomized 1,538 patients with resected pT2 (high grade), pT3, or greater nonmetastatic clear cell RCC, a highly vascular tumor typically reliant on aberrant signaling in the VEGF pathway.
The patients were assigned evenly to receive pazopanib or placebo for 1 year. The starting dose was lowered from 800 mg daily to 600 mg daily (with escalation permitted) after 403 patients had been treated.
In intention-to-treat analysis among patients started on the 600-mg dose and having a median follow-up of about 31 months, disease-free survival was better with pazopanib but not significantly so (hazard ratio, 0.86; P = .16), Dr. Motzer reported.
In secondary analyses, pazopanib did have a significant disease-free survival benefit among patients started on the 800-mg dose (hazard ratio, 0.69; P = .02) and among the entire trial population started on either dose (hazard ratio, 0.80; P = .01).
One possible explanation for the differing results seen with the two doses was the difference in follow-up, as the 800-mg group was treated earlier in the trial, he proposed. But with an additional year of blinded follow-up, the benefit in the 600-mg group actually diminished, whereas that in the 800-mg group did not.
Another possibility was the somewhat better performance of the placebo group used for comparison with the lower dose: the 3-year disease-free survival rate with placebo was 64% for the 600-mg comparison but 56% for the 800-mg comparison. “One factor that could explain differences in the outcomes of the placebo groups includes unidentified patient demographic characteristics,” Dr. Motzer noted.
Overall survival was statistically indistinguishable between the pazopanib and placebo groups, regardless of dose. However, “the results are inconclusive as the data are not yet mature,” he said, with a definitive analysis planned for 2019.
Compared with counterparts given placebo, patients started on the 600-mg dose of pazopanib had a higher rate of grade 3 or 4 adverse events overall (60% vs. 21%), driven in large part by higher rates of hypertension and increased alanine aminotransferase levels.
“Although the intent of modifying the protocol dose of pazopanib from 800 mg to 600 mg was to reduce the rate of discontinuation and improve the safety profile ... both cohorts had similar discontinuation rates and safety profiles,” Dr. Motzer noted.
A quality of life analysis for the 600-mg group using the 19-item Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) showed values were consistently lower with the drug than with placebo during treatment, with a crossing of the threshold for a minimally important difference at week 8.
Pharmacokinetic analyses from the trial, reported in a poster at the meeting (Abstract 4564), showed that in the group starting pazopanib at 600 mg, disease-free survival was longer in patients who achieved higher drug trough concentrations at week 3 or 5.
CHICAGO – The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, the PROTECT investigators reported at the annual meeting of the American Society of Clinical Oncology.
Pazopanib (Votrient) is an oral multitargeted tyrosine kinase inhibitor active against the vascular endothelial growth factor receptor (VEGFR). Adjuvant use of other agents in this class has yielded mixed results, noted lead investigator Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York.
In PROTECT, a phase III randomized controlled trial of more than 1,500 patients who had undergone nephrectomy for high-risk locally advanced RCC, pazopanib started at 600 mg daily did not yield significantly better disease-free survival than placebo, the trial’s primary endpoint. The drug did have a significant benefit when started at 800 mg daily, but that dose had to be lowered partway through because of a high rate of discontinuation due to adverse events.
“The trial did not meet its primary endpoint,” Dr. Motzer concluded. “Pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”
Expert perspective
“The current landscape of RCC adjuvant therapy is really controversial,” commented invited discussant Daniel Y. C. Heng, MD, MPH, of the University of Calgary (Alta.) Tom Baker Cancer Centre.
“Are these [factors] important or not? I think a lot of this is being overshadowed by things that are going on right now,” Dr. Heng maintained. “There are newer medications, such as PD-1 and PD-L1 inhibitors that are now being studied. And there are now perioperative studies as well – should we be using these drugs before nephrectomy and after nephrectomy to prime the immune system to get better outcomes?”
At the end of the day, identification of a reliable predictive biomarker will be key to using the VEGFR tyrosine kinase inhibitors, he concluded. “I look forward to the future where we can actually use these tests to determine who will benefit most from adjuvant therapy so that we can maximize patient outcomes.”
Study details
The PROTECT trial was funded by Novartis Oncology and randomized 1,538 patients with resected pT2 (high grade), pT3, or greater nonmetastatic clear cell RCC, a highly vascular tumor typically reliant on aberrant signaling in the VEGF pathway.
The patients were assigned evenly to receive pazopanib or placebo for 1 year. The starting dose was lowered from 800 mg daily to 600 mg daily (with escalation permitted) after 403 patients had been treated.
In intention-to-treat analysis among patients started on the 600-mg dose and having a median follow-up of about 31 months, disease-free survival was better with pazopanib but not significantly so (hazard ratio, 0.86; P = .16), Dr. Motzer reported.
In secondary analyses, pazopanib did have a significant disease-free survival benefit among patients started on the 800-mg dose (hazard ratio, 0.69; P = .02) and among the entire trial population started on either dose (hazard ratio, 0.80; P = .01).
One possible explanation for the differing results seen with the two doses was the difference in follow-up, as the 800-mg group was treated earlier in the trial, he proposed. But with an additional year of blinded follow-up, the benefit in the 600-mg group actually diminished, whereas that in the 800-mg group did not.
Another possibility was the somewhat better performance of the placebo group used for comparison with the lower dose: the 3-year disease-free survival rate with placebo was 64% for the 600-mg comparison but 56% for the 800-mg comparison. “One factor that could explain differences in the outcomes of the placebo groups includes unidentified patient demographic characteristics,” Dr. Motzer noted.
Overall survival was statistically indistinguishable between the pazopanib and placebo groups, regardless of dose. However, “the results are inconclusive as the data are not yet mature,” he said, with a definitive analysis planned for 2019.
Compared with counterparts given placebo, patients started on the 600-mg dose of pazopanib had a higher rate of grade 3 or 4 adverse events overall (60% vs. 21%), driven in large part by higher rates of hypertension and increased alanine aminotransferase levels.
“Although the intent of modifying the protocol dose of pazopanib from 800 mg to 600 mg was to reduce the rate of discontinuation and improve the safety profile ... both cohorts had similar discontinuation rates and safety profiles,” Dr. Motzer noted.
A quality of life analysis for the 600-mg group using the 19-item Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) showed values were consistently lower with the drug than with placebo during treatment, with a crossing of the threshold for a minimally important difference at week 8.
Pharmacokinetic analyses from the trial, reported in a poster at the meeting (Abstract 4564), showed that in the group starting pazopanib at 600 mg, disease-free survival was longer in patients who achieved higher drug trough concentrations at week 3 or 5.
CHICAGO – The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, the PROTECT investigators reported at the annual meeting of the American Society of Clinical Oncology.
Pazopanib (Votrient) is an oral multitargeted tyrosine kinase inhibitor active against the vascular endothelial growth factor receptor (VEGFR). Adjuvant use of other agents in this class has yielded mixed results, noted lead investigator Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York.
In PROTECT, a phase III randomized controlled trial of more than 1,500 patients who had undergone nephrectomy for high-risk locally advanced RCC, pazopanib started at 600 mg daily did not yield significantly better disease-free survival than placebo, the trial’s primary endpoint. The drug did have a significant benefit when started at 800 mg daily, but that dose had to be lowered partway through because of a high rate of discontinuation due to adverse events.
“The trial did not meet its primary endpoint,” Dr. Motzer concluded. “Pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”
Expert perspective
“The current landscape of RCC adjuvant therapy is really controversial,” commented invited discussant Daniel Y. C. Heng, MD, MPH, of the University of Calgary (Alta.) Tom Baker Cancer Centre.
“Are these [factors] important or not? I think a lot of this is being overshadowed by things that are going on right now,” Dr. Heng maintained. “There are newer medications, such as PD-1 and PD-L1 inhibitors that are now being studied. And there are now perioperative studies as well – should we be using these drugs before nephrectomy and after nephrectomy to prime the immune system to get better outcomes?”
At the end of the day, identification of a reliable predictive biomarker will be key to using the VEGFR tyrosine kinase inhibitors, he concluded. “I look forward to the future where we can actually use these tests to determine who will benefit most from adjuvant therapy so that we can maximize patient outcomes.”
Study details
The PROTECT trial was funded by Novartis Oncology and randomized 1,538 patients with resected pT2 (high grade), pT3, or greater nonmetastatic clear cell RCC, a highly vascular tumor typically reliant on aberrant signaling in the VEGF pathway.
The patients were assigned evenly to receive pazopanib or placebo for 1 year. The starting dose was lowered from 800 mg daily to 600 mg daily (with escalation permitted) after 403 patients had been treated.
In intention-to-treat analysis among patients started on the 600-mg dose and having a median follow-up of about 31 months, disease-free survival was better with pazopanib but not significantly so (hazard ratio, 0.86; P = .16), Dr. Motzer reported.
In secondary analyses, pazopanib did have a significant disease-free survival benefit among patients started on the 800-mg dose (hazard ratio, 0.69; P = .02) and among the entire trial population started on either dose (hazard ratio, 0.80; P = .01).
One possible explanation for the differing results seen with the two doses was the difference in follow-up, as the 800-mg group was treated earlier in the trial, he proposed. But with an additional year of blinded follow-up, the benefit in the 600-mg group actually diminished, whereas that in the 800-mg group did not.
Another possibility was the somewhat better performance of the placebo group used for comparison with the lower dose: the 3-year disease-free survival rate with placebo was 64% for the 600-mg comparison but 56% for the 800-mg comparison. “One factor that could explain differences in the outcomes of the placebo groups includes unidentified patient demographic characteristics,” Dr. Motzer noted.
Overall survival was statistically indistinguishable between the pazopanib and placebo groups, regardless of dose. However, “the results are inconclusive as the data are not yet mature,” he said, with a definitive analysis planned for 2019.
Compared with counterparts given placebo, patients started on the 600-mg dose of pazopanib had a higher rate of grade 3 or 4 adverse events overall (60% vs. 21%), driven in large part by higher rates of hypertension and increased alanine aminotransferase levels.
“Although the intent of modifying the protocol dose of pazopanib from 800 mg to 600 mg was to reduce the rate of discontinuation and improve the safety profile ... both cohorts had similar discontinuation rates and safety profiles,” Dr. Motzer noted.
A quality of life analysis for the 600-mg group using the 19-item Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) showed values were consistently lower with the drug than with placebo during treatment, with a crossing of the threshold for a minimally important difference at week 8.
Pharmacokinetic analyses from the trial, reported in a poster at the meeting (Abstract 4564), showed that in the group starting pazopanib at 600 mg, disease-free survival was longer in patients who achieved higher drug trough concentrations at week 3 or 5.
AT ASCO 2017
Key clinical point:
Major finding: Compared with placebo, pazopanib started at 600 mg daily did not significantly reduce the risk of disease-free survival events (hazard ratio, 0.86; P = .16).
Data source: A phase III randomized controlled trial among 1,538 patients who had undergone nephrectomy for high-risk locally advanced RCC (PROTECT trial).
Disclosures: Dr. Motzer disclosed that he is a consultant to Eisai, Exelixis, Merck, Novartis, and Pfizer, and that he receives research funding from Bristol-Myers Squibb (institutional), Eisai (institutional), Genentech/Roche (institutional), GlaxoSmithKline (institutional), Novartis (institutional), and Pfizer (institutional). The trial was funded by Novartis Oncology.
Immune-agonist combo has activity against several tumor types
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
AT ASCO 2017
Key clinical point: A combination of a GITR-agonist and anti-PD-1 agent was safe and produced partial responses in patients with heavily pretreated advanced cancers.
Major finding: Two patients with cancers that had progression on a PD-1 inhibitor had durable partial responses.
Data source: A phase I/IIa dose-finding and safety study of BMS986156 alone or in combination with nivolumab (Opdivo).
Disclosures: The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising for several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
Alternating therapy in renal cell carcinoma fails to show an advantage
There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.
The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.
Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.
Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).
Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).
There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.
Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.
Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.
Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.
The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.
There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.
The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.
Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.
Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).
Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).
There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.
Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.
Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.
Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.
The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.
There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.
The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.
Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.
Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).
Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).
There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.
Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.
Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.
Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.
The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.
FROM JAMA ONCOLOGY
Key clinical point:
Major finding: The median time to progression or death was 7.4 months for the combination versus 9.4 months for pazopanib alone (P = .37).
Data source: Randomized, multicenter controlled trial.
Disclosures: The principal investigator Dr. Cirkel reports travel expenses from Novartis, which, along with GlaxoSmithKline, provided funding for this study.
Novel agent varlilumab shows activity in RCC
A novel, first-in-class, agonist anti-CD27 monoclonal antibody was found to be clinically and biologically active, according to early findings published in the Journal of Clinical Oncology.
In this phase I first-in-human study of varlilumab, doses at 0.1 to 10 mg/kg were well tolerated by patients with advanced solid tumors. In addition, antitumor activity was also observed. One heavily pretreated patient with stage IV disease renal cell carcinoma (RCC) experienced durable and significant tumor regression, with 78% tumor shrinkage and a partial response that persisted for 2.3 years without additional anticancer therapy, reported Howard A. Burris, MD, of the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, and his colleagues (J Clin Oncol. 2017 May 2. doi: 10.1200/JCO.2016.70.1508).
In addition, eight patients achieved stable disease for more than 3 months while on the study.
“This phase I study of varlilumab provides proof of concept and a rationale for further study in combination with immunotherapies and traditional therapies,” wrote Dr. Burris and his colleagues. “Therapy that targets multiple nonredundant pathways that regulate immune responses may be synergistic and enhance antitumor immune responses.”
The study was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and activity of varlilumab when used as a single agent in patients with advanced solid tumors.
The entire cohort included 56 patients enrolled at nine centers, and the dose escalation component included 25 patients. The expansion part of the trial included 16 patients with melanoma and 15 patients with RCC.
The most common cancer type in the dose-escalation phase was colorectal cancer (40%) followed by melanoma (28%). All patients had stage IV disease and, in general, were heavily pretreated.
A median of 4 doses was administered to the cohort (1-21), and, in the dose escalation phase, the 10 mg/kg was reached without identifying a maximum tolerated dose. Only one patient experienced a dose limiting toxicity, which was grade 3 asymptomatic hyponatremia (129 mmol/L) that occurred at the 1.0-mg/kg dose level.
A total of eight patients achieved stable disease, including four with RCC (duration of stable disease: 5.3, 5.6, 9.3, and 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one patient with colorectal adenocarcinoma (5.7 months).
A novel, first-in-class, agonist anti-CD27 monoclonal antibody was found to be clinically and biologically active, according to early findings published in the Journal of Clinical Oncology.
In this phase I first-in-human study of varlilumab, doses at 0.1 to 10 mg/kg were well tolerated by patients with advanced solid tumors. In addition, antitumor activity was also observed. One heavily pretreated patient with stage IV disease renal cell carcinoma (RCC) experienced durable and significant tumor regression, with 78% tumor shrinkage and a partial response that persisted for 2.3 years without additional anticancer therapy, reported Howard A. Burris, MD, of the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, and his colleagues (J Clin Oncol. 2017 May 2. doi: 10.1200/JCO.2016.70.1508).
In addition, eight patients achieved stable disease for more than 3 months while on the study.
“This phase I study of varlilumab provides proof of concept and a rationale for further study in combination with immunotherapies and traditional therapies,” wrote Dr. Burris and his colleagues. “Therapy that targets multiple nonredundant pathways that regulate immune responses may be synergistic and enhance antitumor immune responses.”
The study was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and activity of varlilumab when used as a single agent in patients with advanced solid tumors.
The entire cohort included 56 patients enrolled at nine centers, and the dose escalation component included 25 patients. The expansion part of the trial included 16 patients with melanoma and 15 patients with RCC.
The most common cancer type in the dose-escalation phase was colorectal cancer (40%) followed by melanoma (28%). All patients had stage IV disease and, in general, were heavily pretreated.
A median of 4 doses was administered to the cohort (1-21), and, in the dose escalation phase, the 10 mg/kg was reached without identifying a maximum tolerated dose. Only one patient experienced a dose limiting toxicity, which was grade 3 asymptomatic hyponatremia (129 mmol/L) that occurred at the 1.0-mg/kg dose level.
A total of eight patients achieved stable disease, including four with RCC (duration of stable disease: 5.3, 5.6, 9.3, and 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one patient with colorectal adenocarcinoma (5.7 months).
A novel, first-in-class, agonist anti-CD27 monoclonal antibody was found to be clinically and biologically active, according to early findings published in the Journal of Clinical Oncology.
In this phase I first-in-human study of varlilumab, doses at 0.1 to 10 mg/kg were well tolerated by patients with advanced solid tumors. In addition, antitumor activity was also observed. One heavily pretreated patient with stage IV disease renal cell carcinoma (RCC) experienced durable and significant tumor regression, with 78% tumor shrinkage and a partial response that persisted for 2.3 years without additional anticancer therapy, reported Howard A. Burris, MD, of the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, and his colleagues (J Clin Oncol. 2017 May 2. doi: 10.1200/JCO.2016.70.1508).
In addition, eight patients achieved stable disease for more than 3 months while on the study.
“This phase I study of varlilumab provides proof of concept and a rationale for further study in combination with immunotherapies and traditional therapies,” wrote Dr. Burris and his colleagues. “Therapy that targets multiple nonredundant pathways that regulate immune responses may be synergistic and enhance antitumor immune responses.”
The study was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and activity of varlilumab when used as a single agent in patients with advanced solid tumors.
The entire cohort included 56 patients enrolled at nine centers, and the dose escalation component included 25 patients. The expansion part of the trial included 16 patients with melanoma and 15 patients with RCC.
The most common cancer type in the dose-escalation phase was colorectal cancer (40%) followed by melanoma (28%). All patients had stage IV disease and, in general, were heavily pretreated.
A median of 4 doses was administered to the cohort (1-21), and, in the dose escalation phase, the 10 mg/kg was reached without identifying a maximum tolerated dose. Only one patient experienced a dose limiting toxicity, which was grade 3 asymptomatic hyponatremia (129 mmol/L) that occurred at the 1.0-mg/kg dose level.
A total of eight patients achieved stable disease, including four with RCC (duration of stable disease: 5.3, 5.6, 9.3, and 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one patient with colorectal adenocarcinoma (5.7 months).
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: A novel, first-in-class, agonist anti-CD27 monoclonal antibody showed activity in solid tumors when used as monotherapy.
Major finding: Two patients with advanced renal cell carcinoma experienced tumor shrinkage and durable responses while eight achieved stable disease.
Data source: Phase I first-in-human study comprising 56 patients with advanced colorectal cancer, renal cell carcinoma, and melanoma.
Disclosures: The study was supported by Celldex Therapeutics. Dr. Burris has no disclosures, and several coauthors have declared relationships with the industry.
Debulking called reasonable for unresectable liver cancer
MIAMI BEACH – Cytoreductive debulking surgery for neuroendocrine liver metastases provides a lower but “reasonable” long-term survival, compared with curative intent surgery, according to results of a study presented at the annual meeting of the Americas Hepatico-Pancreato-Biliary Association.
Liver debulking for patients with grossly unresectable disease is therefore an option that may extend survival, the study researchers said.
“Surgical resection offers the best chance for long-term survival but may not be technically feasible for all our patients,” said Fabio Bagante, MD, a resident at the University of Verona (Italy). “Debulking neuroendocrine liver metastases has been proposed as an alternative.”
Dr. Bagante and coinvestigators compared outcomes between 180 patients who had debulking surgery (defined as an R2 outcome) and 449 who underwent curative intent resection (R0 or R1). Patients had surgery between 1990 and 2015 at eight institutions, and the primary outcome was overall survival. The mean follow-up was 51 months; during that time, 174 patients died.
The 5-year overall survival was 72% in the debulking group and 89% in the curative intent group. The 10-year overall survival was 41% in the debulking group and 77% among the curative intent surgery patients.
“Debulking operations for neuroendocrine liver metastases provide lower but reasonable long-term survival, compared with patients who underwent curative intent,” Dr. Bagante said.
“Nearly 3 in 10 patients underwent debulking surgery,” Dr. Bagante said. “It was more common among the elderly, males with symptomatic disease, and patients with greater liver involvement.”
Patients in the liver-debulking groups were also significantly more likely to have high–tumor grade disease, 35%, versus 13% of the curative intent resection group (P less than .001). They were also more likely to have metastatic disease, with an N1 rate of 73% versus 52% (P less than .001).
“Great work. Thanks for presenting this topic. It’s quite a debated topic,” said study discussant Aaron Lee, DO, of the department of general surgery at Cleveland Clinic Florida in Weston. “I looked at your data on asymptomatic patients who had a 5-year survival of 60%; U.K. data show [the] same survival without any intervention.” He asked Dr. Bagante to comment on operating on patients without any symptoms.
“Regarding the role of symptoms as a predictor of survival, there are many papers in the literature debating what are the true predictors of survival,” Dr. Bagante noted. “We don’t think [symptoms have an] impact; our data do not demonstrate that. We think the biologic behavior of the disease, the impact of the progression of the disease, and the grade of the tumor, [indicated by] Ki-67, could have more of a role.”
MIAMI BEACH – Cytoreductive debulking surgery for neuroendocrine liver metastases provides a lower but “reasonable” long-term survival, compared with curative intent surgery, according to results of a study presented at the annual meeting of the Americas Hepatico-Pancreato-Biliary Association.
Liver debulking for patients with grossly unresectable disease is therefore an option that may extend survival, the study researchers said.
“Surgical resection offers the best chance for long-term survival but may not be technically feasible for all our patients,” said Fabio Bagante, MD, a resident at the University of Verona (Italy). “Debulking neuroendocrine liver metastases has been proposed as an alternative.”
Dr. Bagante and coinvestigators compared outcomes between 180 patients who had debulking surgery (defined as an R2 outcome) and 449 who underwent curative intent resection (R0 or R1). Patients had surgery between 1990 and 2015 at eight institutions, and the primary outcome was overall survival. The mean follow-up was 51 months; during that time, 174 patients died.
The 5-year overall survival was 72% in the debulking group and 89% in the curative intent group. The 10-year overall survival was 41% in the debulking group and 77% among the curative intent surgery patients.
“Debulking operations for neuroendocrine liver metastases provide lower but reasonable long-term survival, compared with patients who underwent curative intent,” Dr. Bagante said.
“Nearly 3 in 10 patients underwent debulking surgery,” Dr. Bagante said. “It was more common among the elderly, males with symptomatic disease, and patients with greater liver involvement.”
Patients in the liver-debulking groups were also significantly more likely to have high–tumor grade disease, 35%, versus 13% of the curative intent resection group (P less than .001). They were also more likely to have metastatic disease, with an N1 rate of 73% versus 52% (P less than .001).
“Great work. Thanks for presenting this topic. It’s quite a debated topic,” said study discussant Aaron Lee, DO, of the department of general surgery at Cleveland Clinic Florida in Weston. “I looked at your data on asymptomatic patients who had a 5-year survival of 60%; U.K. data show [the] same survival without any intervention.” He asked Dr. Bagante to comment on operating on patients without any symptoms.
“Regarding the role of symptoms as a predictor of survival, there are many papers in the literature debating what are the true predictors of survival,” Dr. Bagante noted. “We don’t think [symptoms have an] impact; our data do not demonstrate that. We think the biologic behavior of the disease, the impact of the progression of the disease, and the grade of the tumor, [indicated by] Ki-67, could have more of a role.”
MIAMI BEACH – Cytoreductive debulking surgery for neuroendocrine liver metastases provides a lower but “reasonable” long-term survival, compared with curative intent surgery, according to results of a study presented at the annual meeting of the Americas Hepatico-Pancreato-Biliary Association.
Liver debulking for patients with grossly unresectable disease is therefore an option that may extend survival, the study researchers said.
“Surgical resection offers the best chance for long-term survival but may not be technically feasible for all our patients,” said Fabio Bagante, MD, a resident at the University of Verona (Italy). “Debulking neuroendocrine liver metastases has been proposed as an alternative.”
Dr. Bagante and coinvestigators compared outcomes between 180 patients who had debulking surgery (defined as an R2 outcome) and 449 who underwent curative intent resection (R0 or R1). Patients had surgery between 1990 and 2015 at eight institutions, and the primary outcome was overall survival. The mean follow-up was 51 months; during that time, 174 patients died.
The 5-year overall survival was 72% in the debulking group and 89% in the curative intent group. The 10-year overall survival was 41% in the debulking group and 77% among the curative intent surgery patients.
“Debulking operations for neuroendocrine liver metastases provide lower but reasonable long-term survival, compared with patients who underwent curative intent,” Dr. Bagante said.
“Nearly 3 in 10 patients underwent debulking surgery,” Dr. Bagante said. “It was more common among the elderly, males with symptomatic disease, and patients with greater liver involvement.”
Patients in the liver-debulking groups were also significantly more likely to have high–tumor grade disease, 35%, versus 13% of the curative intent resection group (P less than .001). They were also more likely to have metastatic disease, with an N1 rate of 73% versus 52% (P less than .001).
“Great work. Thanks for presenting this topic. It’s quite a debated topic,” said study discussant Aaron Lee, DO, of the department of general surgery at Cleveland Clinic Florida in Weston. “I looked at your data on asymptomatic patients who had a 5-year survival of 60%; U.K. data show [the] same survival without any intervention.” He asked Dr. Bagante to comment on operating on patients without any symptoms.
“Regarding the role of symptoms as a predictor of survival, there are many papers in the literature debating what are the true predictors of survival,” Dr. Bagante noted. “We don’t think [symptoms have an] impact; our data do not demonstrate that. We think the biologic behavior of the disease, the impact of the progression of the disease, and the grade of the tumor, [indicated by] Ki-67, could have more of a role.”
AT AHPBA 2017
Key clinical point:
Major finding: The 10-year overall survival was 77% in the curative intent surgery group, compared with 41% among the debulking patients.
Data source: A retrospective database study of 629 people with neuroendocrine liver metastases.
Disclosures: Dr. Bagante and Dr. Lee had no relevant financial disclosures.
Metformin linked with better survival in RCC patients with diabetes
Metformin use was associated with better survival for patients with renal cell carcinoma and diabetes in a meta-analysis, investigators report.
Yang Li, MD, and associates at Chongqing (China) Medical University, performed a pooled analysis of data from 254,329 patients with both localized and metastatic renal cell carcinoma, and found the risk of mortality was reduced in patients exposed to metformin (hazard ratio, 0.41; P less than .001).
However, there was significant heterogeneity among the eight eligible studies included in the meta-analysis, Dr. Li and associates reported (Int Urol Nephrol. 2017 Mar 7. doi: 10.1007/s11255-017-1548-4).
In a subgroup analysis, the association held in patients with localized disease, but was not significant in those with metastatic disease.
The current meta-analysis suggests that the use of metformin could improve the survival of kidney cancer patients, particularly those with localized disease; however, further studies are needed, the investigators conclude.
The authors declared that they had no conflicts of interest.
Metformin use was associated with better survival for patients with renal cell carcinoma and diabetes in a meta-analysis, investigators report.
Yang Li, MD, and associates at Chongqing (China) Medical University, performed a pooled analysis of data from 254,329 patients with both localized and metastatic renal cell carcinoma, and found the risk of mortality was reduced in patients exposed to metformin (hazard ratio, 0.41; P less than .001).
However, there was significant heterogeneity among the eight eligible studies included in the meta-analysis, Dr. Li and associates reported (Int Urol Nephrol. 2017 Mar 7. doi: 10.1007/s11255-017-1548-4).
In a subgroup analysis, the association held in patients with localized disease, but was not significant in those with metastatic disease.
The current meta-analysis suggests that the use of metformin could improve the survival of kidney cancer patients, particularly those with localized disease; however, further studies are needed, the investigators conclude.
The authors declared that they had no conflicts of interest.
Metformin use was associated with better survival for patients with renal cell carcinoma and diabetes in a meta-analysis, investigators report.
Yang Li, MD, and associates at Chongqing (China) Medical University, performed a pooled analysis of data from 254,329 patients with both localized and metastatic renal cell carcinoma, and found the risk of mortality was reduced in patients exposed to metformin (hazard ratio, 0.41; P less than .001).
However, there was significant heterogeneity among the eight eligible studies included in the meta-analysis, Dr. Li and associates reported (Int Urol Nephrol. 2017 Mar 7. doi: 10.1007/s11255-017-1548-4).
In a subgroup analysis, the association held in patients with localized disease, but was not significant in those with metastatic disease.
The current meta-analysis suggests that the use of metformin could improve the survival of kidney cancer patients, particularly those with localized disease; however, further studies are needed, the investigators conclude.
The authors declared that they had no conflicts of interest.
Key clinical point:
Major finding: In a pooled analysis of data from eight studies, the risk of mortality was reduced in patients exposed to metformin (hazard ratio, 0.41; P less than .001).
Data source: A meta-analysis of eight studies including 254,329 patients with renal cell carcinoma.
Disclosures: The authors declared that they had no conflicts of interest.
No benefit from adjuvant sunitinib or sorafenib for clear cell renal cancer
Adjuvant sunitinib or sorafenib show no significant advantages in disease-free or overall survival over placebo in patients with high-risk clear cell renal cancer, according to secondary analysis of data from the ASSURE trial.
The primary analysis of data from the ASSURE trial, which included patients with all types of renal cell carcinoma, had failed to show a benefit in disease-free survival.
“Given recently published results of a 750-patient randomized trial, S-TRAC, (sunitinib 50 mg daily [4/2 schedule] vs placebo in clear cell predominant pT3-4 or node-positive disease) that show improved [disease-free survival], the appropriate adjuvant strategy for high-risk patients is unclear,” Naomi B. Haas, MD, and coauthors wrote (JAMA Oncol. 2017 Mar 9. doi: 10.1001/jamaoncol.2017.0076).
Therefore, the investigators focused on a subset of patients from the ASSURE trial with high-risk clear cell renal cancer to determine if there might be a benefit in this group.
The secondary analysis involved 1,069 participants with pT3 and higher or node-positive renal cancer with clear cell histology who were randomized to receive 54 weeks of sunitinib (50mg, oral daily for 28 of 42 days per cycle), sorafenib (400 mg, oral twice daily continuously), or placebo.
The 5-year disease-free survival rate was 47.7% for patients in the sunitinib arm, 49.9% for those taking sorafenib, and 50% for placebo, with no statistically significant difference between the three groups. The 5-year overall survival rate was 75.2% for the sunitinib arm, 80.2% in the sorafenib arm, and 76.5% for those on placebo, with no statistically significant differences between the groups, reported Dr. Haas of the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, and colleagues.
“This high-risk population had a better 5-year recurrence-free rate (around 50%) than expected (41.9% for high-risk disease and 36.0% for node-positive disease), possibly a result of better surgical technique, more accurate staging, or unknown biologic factors,” the authors wrote.
When the researchers analyzed disease-free survival according to quartiles of total dose per 6-week cycle, they also found no differences between each quartile of average dose per cycle.
There was, however, a significantly higher rate of grade 3 or higher adverse events in the sunitinib arm (66%) and sorafenib group (72%), compared with placebo (22%).
“Based on this analysis, a rationale for adjuvant therapy in this high-risk population is not elucidated,” Dr. Haas and colleagues said.
The study was coordinated by the ECOG-ACRIN Cancer Research Group and supported by Public Health Service grants, the National Cancer Institute, National Institutes of Health, and the Department of Health & Human Services. The drugs and placebos were provided by Bayer and Pfizer through the National Cancer Institute.
Adjuvant sunitinib or sorafenib show no significant advantages in disease-free or overall survival over placebo in patients with high-risk clear cell renal cancer, according to secondary analysis of data from the ASSURE trial.
The primary analysis of data from the ASSURE trial, which included patients with all types of renal cell carcinoma, had failed to show a benefit in disease-free survival.
“Given recently published results of a 750-patient randomized trial, S-TRAC, (sunitinib 50 mg daily [4/2 schedule] vs placebo in clear cell predominant pT3-4 or node-positive disease) that show improved [disease-free survival], the appropriate adjuvant strategy for high-risk patients is unclear,” Naomi B. Haas, MD, and coauthors wrote (JAMA Oncol. 2017 Mar 9. doi: 10.1001/jamaoncol.2017.0076).
Therefore, the investigators focused on a subset of patients from the ASSURE trial with high-risk clear cell renal cancer to determine if there might be a benefit in this group.
The secondary analysis involved 1,069 participants with pT3 and higher or node-positive renal cancer with clear cell histology who were randomized to receive 54 weeks of sunitinib (50mg, oral daily for 28 of 42 days per cycle), sorafenib (400 mg, oral twice daily continuously), or placebo.
The 5-year disease-free survival rate was 47.7% for patients in the sunitinib arm, 49.9% for those taking sorafenib, and 50% for placebo, with no statistically significant difference between the three groups. The 5-year overall survival rate was 75.2% for the sunitinib arm, 80.2% in the sorafenib arm, and 76.5% for those on placebo, with no statistically significant differences between the groups, reported Dr. Haas of the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, and colleagues.
“This high-risk population had a better 5-year recurrence-free rate (around 50%) than expected (41.9% for high-risk disease and 36.0% for node-positive disease), possibly a result of better surgical technique, more accurate staging, or unknown biologic factors,” the authors wrote.
When the researchers analyzed disease-free survival according to quartiles of total dose per 6-week cycle, they also found no differences between each quartile of average dose per cycle.
There was, however, a significantly higher rate of grade 3 or higher adverse events in the sunitinib arm (66%) and sorafenib group (72%), compared with placebo (22%).
“Based on this analysis, a rationale for adjuvant therapy in this high-risk population is not elucidated,” Dr. Haas and colleagues said.
The study was coordinated by the ECOG-ACRIN Cancer Research Group and supported by Public Health Service grants, the National Cancer Institute, National Institutes of Health, and the Department of Health & Human Services. The drugs and placebos were provided by Bayer and Pfizer through the National Cancer Institute.
Adjuvant sunitinib or sorafenib show no significant advantages in disease-free or overall survival over placebo in patients with high-risk clear cell renal cancer, according to secondary analysis of data from the ASSURE trial.
The primary analysis of data from the ASSURE trial, which included patients with all types of renal cell carcinoma, had failed to show a benefit in disease-free survival.
“Given recently published results of a 750-patient randomized trial, S-TRAC, (sunitinib 50 mg daily [4/2 schedule] vs placebo in clear cell predominant pT3-4 or node-positive disease) that show improved [disease-free survival], the appropriate adjuvant strategy for high-risk patients is unclear,” Naomi B. Haas, MD, and coauthors wrote (JAMA Oncol. 2017 Mar 9. doi: 10.1001/jamaoncol.2017.0076).
Therefore, the investigators focused on a subset of patients from the ASSURE trial with high-risk clear cell renal cancer to determine if there might be a benefit in this group.
The secondary analysis involved 1,069 participants with pT3 and higher or node-positive renal cancer with clear cell histology who were randomized to receive 54 weeks of sunitinib (50mg, oral daily for 28 of 42 days per cycle), sorafenib (400 mg, oral twice daily continuously), or placebo.
The 5-year disease-free survival rate was 47.7% for patients in the sunitinib arm, 49.9% for those taking sorafenib, and 50% for placebo, with no statistically significant difference between the three groups. The 5-year overall survival rate was 75.2% for the sunitinib arm, 80.2% in the sorafenib arm, and 76.5% for those on placebo, with no statistically significant differences between the groups, reported Dr. Haas of the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, and colleagues.
“This high-risk population had a better 5-year recurrence-free rate (around 50%) than expected (41.9% for high-risk disease and 36.0% for node-positive disease), possibly a result of better surgical technique, more accurate staging, or unknown biologic factors,” the authors wrote.
When the researchers analyzed disease-free survival according to quartiles of total dose per 6-week cycle, they also found no differences between each quartile of average dose per cycle.
There was, however, a significantly higher rate of grade 3 or higher adverse events in the sunitinib arm (66%) and sorafenib group (72%), compared with placebo (22%).
“Based on this analysis, a rationale for adjuvant therapy in this high-risk population is not elucidated,” Dr. Haas and colleagues said.
The study was coordinated by the ECOG-ACRIN Cancer Research Group and supported by Public Health Service grants, the National Cancer Institute, National Institutes of Health, and the Department of Health & Human Services. The drugs and placebos were provided by Bayer and Pfizer through the National Cancer Institute.
FROM JAMA ONCOLOGY
Key clinical point: Adjuvant sunitinib or sorafenib show no significant benefit in disease-free or overall survival in patients with high-risk clear cell renal cancer.
Major finding: The 5-year disease-free survival rate was 47.7% for patients treated with sunitinib, 49.9% for those treated with sorafenib, and 50% for those given placebo.
Data source: Secondary analysis of data from the ASSURE trial in 1,943 patients with pT3 and higher or node-positive renal cancer with clear cell histology.
Disclosures: The study was coordinated by the ECOG-ACRIN Cancer Research Group and supported by Public Health Service grants, the National Cancer Institute, National Institutes of Health, and the Department of Health & Human Services. The drugs and placebos were provided by Bayer and Pfizer through the National Cancer Institute.
Genomic differences seen in mRCC during first- and second-line therapy
ORLANDO – In the largest assessment to date of circulating tumor DNA (ctDNA) in patients with metastatic renal cell carcinoma (mRCC), the majority of patients were found to have clinically relevant genomic alterations.
The most frequently occurring alterations for the entire cohort were TP53, VHL, NF1, EGFR, and ARID1A, but, importantly, the genetic profiles differed between patients receiving first-line therapy and those receiving second-line treatments.
“Compared to patients receiving first-line therapy, patients receiving post–first-line agents had increased genomic alterations in TP53, NF1, EGFR, and PIK3CA,” said lead study author Sumanta K. Pal, MD, a urologic oncologist at City of Hope, Duarte, Calif.
“These alterations underscore potential mechanisms of resistance,” said Dr. Pal, who presented the findings of his study in a press briefing held at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology..
Several targeted therapies have been approved for mRCC, including vascular endothelial growth factor–targeted therapies, mammalian target of rapamycin inhibitors, and checkpoint inhibitors. However, treatment of mRCC is generally distinctly different for the first- and second-line settings.
Dr. Pal noted that, while “efforts such as the TCGA [The Cancer Genome Atlas] have shed some light on the tumor biology, it is important to keep in mind that these datasets reflect earlier stages of disease. Certainly, there may be an evolution of tumor biology as patients progress toward metastasis.”
Circulating tumor markers represent a practical means of serially assessing tumor biology, and ctDNA can account for tumor heterogeneity. In this study, the authors sought to determine the mutational landscape of mRCC as well as to assess changes across patients receiving first-line and subsequent therapies by using ctDNA.
Data were obtained from 224 patients who received ctDNA profiling at progression as part of routine clinical care using Guardant360, a CLIA-certified comprehensive plasma assay that evaluated 70 genes. Of this group, 64 and 56 patients were coded as receiving frontline and post–first-line agents, respectively.
Genomic alterations were pooled for the entire group, and first and second (subsequent) therapies were compared, based on conventional practice patterns (first-line regimens included sunitinib, pazopanib and bevacizumab, and second line included everolimus, axitinib, cabozantinib, and nivolumab).
Genomic alterations were found in 78.6% of patients, with an average of 3.3 genomic alterations per patient. For patients receiving first-line therapy, the average number of ctDNA alterations was 2.9, compared with 3.7 for those in the cohort who were receiving second-line therapy. The median (range) ctDNA variant allele fractions were 0.23 (0.05-9.92) in the first-line group and 0.24 (0.04-47.14) in second line.
The authors observed that there were disparities in genomic alterations between both patient cohorts, with the highest disparity seen in (second vs. first line) TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%).
“These alterations underscore potential mechanisms of resistance,” said Dr. Pal.
He also pointed out that there were significant differences between the current dataset and other published reports, which may reflect the advanced state of the disease of the patients in this study.
Efforts are also ongoing to add detailed data on demographics and clinical outcomes to the current dataset, Dr. Pal added.
Acting as the paper’s discussant, Primo N. Lara Jr., MD, of the University of California, Davis, Comprehensive Cancer Center pointed out that as there are no validated biomarkers of drug resistance or tumor evolution and that liquid biopsy offers a potential platform.
The use of ctDNA is a “convenient technology that offers new means to assess RCC biology,” said Dr. Lara, but the caveat is that it is “still in its infancy and has no immediate clinical application.”
The current study is “hypothesis generating only.” ctDNA changes need to be related to outcome following treatment, and the functional role of genomic alterations in RCC biology must be validated, he said.
ORLANDO – In the largest assessment to date of circulating tumor DNA (ctDNA) in patients with metastatic renal cell carcinoma (mRCC), the majority of patients were found to have clinically relevant genomic alterations.
The most frequently occurring alterations for the entire cohort were TP53, VHL, NF1, EGFR, and ARID1A, but, importantly, the genetic profiles differed between patients receiving first-line therapy and those receiving second-line treatments.
“Compared to patients receiving first-line therapy, patients receiving post–first-line agents had increased genomic alterations in TP53, NF1, EGFR, and PIK3CA,” said lead study author Sumanta K. Pal, MD, a urologic oncologist at City of Hope, Duarte, Calif.
“These alterations underscore potential mechanisms of resistance,” said Dr. Pal, who presented the findings of his study in a press briefing held at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology..
Several targeted therapies have been approved for mRCC, including vascular endothelial growth factor–targeted therapies, mammalian target of rapamycin inhibitors, and checkpoint inhibitors. However, treatment of mRCC is generally distinctly different for the first- and second-line settings.
Dr. Pal noted that, while “efforts such as the TCGA [The Cancer Genome Atlas] have shed some light on the tumor biology, it is important to keep in mind that these datasets reflect earlier stages of disease. Certainly, there may be an evolution of tumor biology as patients progress toward metastasis.”
Circulating tumor markers represent a practical means of serially assessing tumor biology, and ctDNA can account for tumor heterogeneity. In this study, the authors sought to determine the mutational landscape of mRCC as well as to assess changes across patients receiving first-line and subsequent therapies by using ctDNA.
Data were obtained from 224 patients who received ctDNA profiling at progression as part of routine clinical care using Guardant360, a CLIA-certified comprehensive plasma assay that evaluated 70 genes. Of this group, 64 and 56 patients were coded as receiving frontline and post–first-line agents, respectively.
Genomic alterations were pooled for the entire group, and first and second (subsequent) therapies were compared, based on conventional practice patterns (first-line regimens included sunitinib, pazopanib and bevacizumab, and second line included everolimus, axitinib, cabozantinib, and nivolumab).
Genomic alterations were found in 78.6% of patients, with an average of 3.3 genomic alterations per patient. For patients receiving first-line therapy, the average number of ctDNA alterations was 2.9, compared with 3.7 for those in the cohort who were receiving second-line therapy. The median (range) ctDNA variant allele fractions were 0.23 (0.05-9.92) in the first-line group and 0.24 (0.04-47.14) in second line.
The authors observed that there were disparities in genomic alterations between both patient cohorts, with the highest disparity seen in (second vs. first line) TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%).
“These alterations underscore potential mechanisms of resistance,” said Dr. Pal.
He also pointed out that there were significant differences between the current dataset and other published reports, which may reflect the advanced state of the disease of the patients in this study.
Efforts are also ongoing to add detailed data on demographics and clinical outcomes to the current dataset, Dr. Pal added.
Acting as the paper’s discussant, Primo N. Lara Jr., MD, of the University of California, Davis, Comprehensive Cancer Center pointed out that as there are no validated biomarkers of drug resistance or tumor evolution and that liquid biopsy offers a potential platform.
The use of ctDNA is a “convenient technology that offers new means to assess RCC biology,” said Dr. Lara, but the caveat is that it is “still in its infancy and has no immediate clinical application.”
The current study is “hypothesis generating only.” ctDNA changes need to be related to outcome following treatment, and the functional role of genomic alterations in RCC biology must be validated, he said.
ORLANDO – In the largest assessment to date of circulating tumor DNA (ctDNA) in patients with metastatic renal cell carcinoma (mRCC), the majority of patients were found to have clinically relevant genomic alterations.
The most frequently occurring alterations for the entire cohort were TP53, VHL, NF1, EGFR, and ARID1A, but, importantly, the genetic profiles differed between patients receiving first-line therapy and those receiving second-line treatments.
“Compared to patients receiving first-line therapy, patients receiving post–first-line agents had increased genomic alterations in TP53, NF1, EGFR, and PIK3CA,” said lead study author Sumanta K. Pal, MD, a urologic oncologist at City of Hope, Duarte, Calif.
“These alterations underscore potential mechanisms of resistance,” said Dr. Pal, who presented the findings of his study in a press briefing held at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology..
Several targeted therapies have been approved for mRCC, including vascular endothelial growth factor–targeted therapies, mammalian target of rapamycin inhibitors, and checkpoint inhibitors. However, treatment of mRCC is generally distinctly different for the first- and second-line settings.
Dr. Pal noted that, while “efforts such as the TCGA [The Cancer Genome Atlas] have shed some light on the tumor biology, it is important to keep in mind that these datasets reflect earlier stages of disease. Certainly, there may be an evolution of tumor biology as patients progress toward metastasis.”
Circulating tumor markers represent a practical means of serially assessing tumor biology, and ctDNA can account for tumor heterogeneity. In this study, the authors sought to determine the mutational landscape of mRCC as well as to assess changes across patients receiving first-line and subsequent therapies by using ctDNA.
Data were obtained from 224 patients who received ctDNA profiling at progression as part of routine clinical care using Guardant360, a CLIA-certified comprehensive plasma assay that evaluated 70 genes. Of this group, 64 and 56 patients were coded as receiving frontline and post–first-line agents, respectively.
Genomic alterations were pooled for the entire group, and first and second (subsequent) therapies were compared, based on conventional practice patterns (first-line regimens included sunitinib, pazopanib and bevacizumab, and second line included everolimus, axitinib, cabozantinib, and nivolumab).
Genomic alterations were found in 78.6% of patients, with an average of 3.3 genomic alterations per patient. For patients receiving first-line therapy, the average number of ctDNA alterations was 2.9, compared with 3.7 for those in the cohort who were receiving second-line therapy. The median (range) ctDNA variant allele fractions were 0.23 (0.05-9.92) in the first-line group and 0.24 (0.04-47.14) in second line.
The authors observed that there were disparities in genomic alterations between both patient cohorts, with the highest disparity seen in (second vs. first line) TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%).
“These alterations underscore potential mechanisms of resistance,” said Dr. Pal.
He also pointed out that there were significant differences between the current dataset and other published reports, which may reflect the advanced state of the disease of the patients in this study.
Efforts are also ongoing to add detailed data on demographics and clinical outcomes to the current dataset, Dr. Pal added.
Acting as the paper’s discussant, Primo N. Lara Jr., MD, of the University of California, Davis, Comprehensive Cancer Center pointed out that as there are no validated biomarkers of drug resistance or tumor evolution and that liquid biopsy offers a potential platform.
The use of ctDNA is a “convenient technology that offers new means to assess RCC biology,” said Dr. Lara, but the caveat is that it is “still in its infancy and has no immediate clinical application.”
The current study is “hypothesis generating only.” ctDNA changes need to be related to outcome following treatment, and the functional role of genomic alterations in RCC biology must be validated, he said.
AT THE GENITOURINARY CANCERS SYMPOSIUM
Key clinical point: The genetic profile of tumors in mRCC differed in patients receiving first-line and second-line therapies.
Major finding: Genomic alterations were identified in 78.6% of patients, with an average of 3.3 genomic alterations per patient.
Data source: Experimental study that used circulating tumor DNA to assess the mutational landscape of metastatic renal cell carcinoma.
Disclosures: The funding source is not disclosed. Dr. Pal and his coauthors all report relationships with multiple pharmaceutical companies. Dr. Lara reports financial ties to multiple pharmaceutical companies.