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Tivozanib gets EU approval for advanced RCC
The European Commission has approved tivozanib for the treatment of advanced renal cell carcinoma (RCC) in adult patients in the European Union, Norway, and Iceland.
Tivozanib (Fotivda) is a vascular endothelial growth factor receptor tyrosine kinase inhibitor, taken orally once daily. It is indicated for first-line treatment of patients, naive to both vascular endothelial growth factor receptors and mTOR pathway inhibitors, experiencing disease progression following one cytokine therapy treatment, according to the press release.
Its approval is based on superior progression-free survival (PFS) in TIVO-1, a phase 3 trial comparing the efficacy and tolerability of tivozanib (1.5 mg once daily) with that of sorafenib (400 mg twice daily). In the overall trial population of 517 patients with advanced RCC, PFS was 11.9 months for patients treated with tivozanib, compared with 9.1 months for those treated with sorafenib (hazard ratio, 0.797; 95% confidence interval, 0.639-0.993; P = .042).
Patients in the tivozanib arm also experienced fewer cases of diarrhea and hand-foot syndrome, and required fewer dose reductions because of adverse effects than did those taking sorafenib.
The approval follows a recommendation from the Committee for Medical Products for Human Use.
The Food and Drug Administration rejected the New Drug Application for tivozanib in 2013, based on TIVO-1 data. Aveo Oncology plans to reapply in the United States with data from TIVO-3, expected in early 2018, they said in the press release.
The European Commission has approved tivozanib for the treatment of advanced renal cell carcinoma (RCC) in adult patients in the European Union, Norway, and Iceland.
Tivozanib (Fotivda) is a vascular endothelial growth factor receptor tyrosine kinase inhibitor, taken orally once daily. It is indicated for first-line treatment of patients, naive to both vascular endothelial growth factor receptors and mTOR pathway inhibitors, experiencing disease progression following one cytokine therapy treatment, according to the press release.
Its approval is based on superior progression-free survival (PFS) in TIVO-1, a phase 3 trial comparing the efficacy and tolerability of tivozanib (1.5 mg once daily) with that of sorafenib (400 mg twice daily). In the overall trial population of 517 patients with advanced RCC, PFS was 11.9 months for patients treated with tivozanib, compared with 9.1 months for those treated with sorafenib (hazard ratio, 0.797; 95% confidence interval, 0.639-0.993; P = .042).
Patients in the tivozanib arm also experienced fewer cases of diarrhea and hand-foot syndrome, and required fewer dose reductions because of adverse effects than did those taking sorafenib.
The approval follows a recommendation from the Committee for Medical Products for Human Use.
The Food and Drug Administration rejected the New Drug Application for tivozanib in 2013, based on TIVO-1 data. Aveo Oncology plans to reapply in the United States with data from TIVO-3, expected in early 2018, they said in the press release.
The European Commission has approved tivozanib for the treatment of advanced renal cell carcinoma (RCC) in adult patients in the European Union, Norway, and Iceland.
Tivozanib (Fotivda) is a vascular endothelial growth factor receptor tyrosine kinase inhibitor, taken orally once daily. It is indicated for first-line treatment of patients, naive to both vascular endothelial growth factor receptors and mTOR pathway inhibitors, experiencing disease progression following one cytokine therapy treatment, according to the press release.
Its approval is based on superior progression-free survival (PFS) in TIVO-1, a phase 3 trial comparing the efficacy and tolerability of tivozanib (1.5 mg once daily) with that of sorafenib (400 mg twice daily). In the overall trial population of 517 patients with advanced RCC, PFS was 11.9 months for patients treated with tivozanib, compared with 9.1 months for those treated with sorafenib (hazard ratio, 0.797; 95% confidence interval, 0.639-0.993; P = .042).
Patients in the tivozanib arm also experienced fewer cases of diarrhea and hand-foot syndrome, and required fewer dose reductions because of adverse effects than did those taking sorafenib.
The approval follows a recommendation from the Committee for Medical Products for Human Use.
The Food and Drug Administration rejected the New Drug Application for tivozanib in 2013, based on TIVO-1 data. Aveo Oncology plans to reapply in the United States with data from TIVO-3, expected in early 2018, they said in the press release.
Adverse effects of PD-1/PD-L1 inhibitors varied by tumor type in systematic review
The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.
Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.
“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).
The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.
Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).
The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.
“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.
The reviewers reported having no funding sources and no relevant conflicts of interest.
The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.
Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.
“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).
The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.
Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).
The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.
“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.
The reviewers reported having no funding sources and no relevant conflicts of interest.
The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.
Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.
“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).
The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.
Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).
The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.
“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.
The reviewers reported having no funding sources and no relevant conflicts of interest.
FROM ANNALS OF ONCOLOGY
Key clinical point: Immune-related adverse effects varied by tumor type in patients receiving programmed cell death protein 1 (PD-1) and PD-L1 inhibitors.
Major finding: Patients with melanoma who received PD-1/PD-L1 inhibitors were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8), compared with patients with non-small cell lung cancer, who were significantly more likely to develop pneumonitis.
Data source: A systematic review and meta-analysis of 48 prospective trials of immune checkpoint inhibitors in of 6,938 adults with solid tumors.
Disclosures: The reviewers reported having no funding sources and no relevant conflicts of interest.
Exelixis seeks expanded indication for cabozantinib in RCC
Exelixis has submitted a supplemental New Drug Application to the Food and Drug Administration for cabozantinib (Cabometyx) for the treatment of previously untreated advanced renal cell carcinoma (RCC).
The application, announced on Aug. 16, seeks to allow the manufacturer to modify the label. Cabozantinib was approved in April 2016 for treatment of patients with advanced RCC who had previously received antiangiogenic therapy.
The results of the trial were published in the Journal of Clinical Oncology (2017 Feb 20;35[6]:591-7). An independent review committee confirmed the primary efficacy endpoint results in June 2017.
Exelixis has submitted a supplemental New Drug Application to the Food and Drug Administration for cabozantinib (Cabometyx) for the treatment of previously untreated advanced renal cell carcinoma (RCC).
The application, announced on Aug. 16, seeks to allow the manufacturer to modify the label. Cabozantinib was approved in April 2016 for treatment of patients with advanced RCC who had previously received antiangiogenic therapy.
The results of the trial were published in the Journal of Clinical Oncology (2017 Feb 20;35[6]:591-7). An independent review committee confirmed the primary efficacy endpoint results in June 2017.
Exelixis has submitted a supplemental New Drug Application to the Food and Drug Administration for cabozantinib (Cabometyx) for the treatment of previously untreated advanced renal cell carcinoma (RCC).
The application, announced on Aug. 16, seeks to allow the manufacturer to modify the label. Cabozantinib was approved in April 2016 for treatment of patients with advanced RCC who had previously received antiangiogenic therapy.
The results of the trial were published in the Journal of Clinical Oncology (2017 Feb 20;35[6]:591-7). An independent review committee confirmed the primary efficacy endpoint results in June 2017.
FDA advisory committee to consider adjuvant sunitinib for RCC
The Oncologic Drugs Advisory Committee to the Food and Drug Administration will meet on Sept. 19 to discuss a supplemental new drug application for sunitinib (Sutent), for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy.
Sunitinib is an oral antiangiogenic agent that has been approved for the treatment of advanced RCC since 2006.
The FDA accepted the new drug application in May and is expected to issue a decision by January 2018.
Results for sunitinib as adjuvant treatment have been mixed. No significant differences in disease-free survival or overall survival were found in the phase 3 ASSURE between patients receiving adjuvant sunitinib and those receiving placebo, according to results published in The Lancet. However, adjuvant sunitinib prolonged disease-free survival by 1.2 years, compared with placebo, in the phase 3 S-TRAC trial, presented at the 2016 ESMO Congress and published in the New England Journal of Medicine. S-TRAC results are the basis for the new drug application submitted by Pfizer, Inc., according to a press release.
The advisory committee will consider comments from the public if submitted by Sept. 5, as electronic comments through the electronic filing system or by mail/hand delivery/courier at Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
The docket number is FDA-2017-N-1063.
The Oncologic Drugs Advisory Committee to the Food and Drug Administration will meet on Sept. 19 to discuss a supplemental new drug application for sunitinib (Sutent), for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy.
Sunitinib is an oral antiangiogenic agent that has been approved for the treatment of advanced RCC since 2006.
The FDA accepted the new drug application in May and is expected to issue a decision by January 2018.
Results for sunitinib as adjuvant treatment have been mixed. No significant differences in disease-free survival or overall survival were found in the phase 3 ASSURE between patients receiving adjuvant sunitinib and those receiving placebo, according to results published in The Lancet. However, adjuvant sunitinib prolonged disease-free survival by 1.2 years, compared with placebo, in the phase 3 S-TRAC trial, presented at the 2016 ESMO Congress and published in the New England Journal of Medicine. S-TRAC results are the basis for the new drug application submitted by Pfizer, Inc., according to a press release.
The advisory committee will consider comments from the public if submitted by Sept. 5, as electronic comments through the electronic filing system or by mail/hand delivery/courier at Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
The docket number is FDA-2017-N-1063.
The Oncologic Drugs Advisory Committee to the Food and Drug Administration will meet on Sept. 19 to discuss a supplemental new drug application for sunitinib (Sutent), for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy.
Sunitinib is an oral antiangiogenic agent that has been approved for the treatment of advanced RCC since 2006.
The FDA accepted the new drug application in May and is expected to issue a decision by January 2018.
Results for sunitinib as adjuvant treatment have been mixed. No significant differences in disease-free survival or overall survival were found in the phase 3 ASSURE between patients receiving adjuvant sunitinib and those receiving placebo, according to results published in The Lancet. However, adjuvant sunitinib prolonged disease-free survival by 1.2 years, compared with placebo, in the phase 3 S-TRAC trial, presented at the 2016 ESMO Congress and published in the New England Journal of Medicine. S-TRAC results are the basis for the new drug application submitted by Pfizer, Inc., according to a press release.
The advisory committee will consider comments from the public if submitted by Sept. 5, as electronic comments through the electronic filing system or by mail/hand delivery/courier at Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
The docket number is FDA-2017-N-1063.
Sequential pazopanib and everolimus nets good survival in metastatic RCC
Sequential treatment with pazopanib and everolimus yields a median overall survival exceeding 2 years in predominantly older and sicker patients with metastatic renal cell carcinoma (RCC) treated in real-world settings, according to results of an Italian multicenter cohort study.
“These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance,” wrote Sabrina Rossetti, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale, Naples, and associates (Front Pharmacol. 2017 Jul 20;8:484).
“Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile and may be feasible even for elderly patients or with multiple comorbidities,” they said.
The investigators prospectively enrolled 31 consecutive patients with newly diagnosed metastatic RCC. They had a median age of 68 years. Fully 73.3% underwent nephrectomy before treatment; 87.1% had at least one comorbidity, and 25.8% had at least three of them.
All patients were treated with the antiangiogenic tyrosine kinase inhibitor pazopanib (Votrient) as first-line therapy and, after disease progression on that agent or discontinuation for toxicity, with the mTOR inhibitor everolimus (Afinitor) as second-line therapy.
The median overall survival with the two-drug sequence was 26.5 months. Median progression-free survival was 10.6 months with pazopanib and 5.3 months with everolimus.
Patients were able to continue on pazopanib for a median time of 8.1 months, with 31% requiring dose reduction. They were able to continue on everolimus for a median time of 4.4 months, with 16% requiring dose reduction.
Main adverse events of any grade on pazopanib were hypertension (48.4%), fatigue (32.2%), and thyroid disorders (19.3%). Those on everolimus were anemia (32.2%), hypercholesterolemia (22.6%), and hyperglycemia (22.6%).
“The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib,” noted Dr. Rossetti and colleagues. “The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.”
[email protected]
Sequential treatment with pazopanib and everolimus yields a median overall survival exceeding 2 years in predominantly older and sicker patients with metastatic renal cell carcinoma (RCC) treated in real-world settings, according to results of an Italian multicenter cohort study.
“These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance,” wrote Sabrina Rossetti, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale, Naples, and associates (Front Pharmacol. 2017 Jul 20;8:484).
“Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile and may be feasible even for elderly patients or with multiple comorbidities,” they said.
The investigators prospectively enrolled 31 consecutive patients with newly diagnosed metastatic RCC. They had a median age of 68 years. Fully 73.3% underwent nephrectomy before treatment; 87.1% had at least one comorbidity, and 25.8% had at least three of them.
All patients were treated with the antiangiogenic tyrosine kinase inhibitor pazopanib (Votrient) as first-line therapy and, after disease progression on that agent or discontinuation for toxicity, with the mTOR inhibitor everolimus (Afinitor) as second-line therapy.
The median overall survival with the two-drug sequence was 26.5 months. Median progression-free survival was 10.6 months with pazopanib and 5.3 months with everolimus.
Patients were able to continue on pazopanib for a median time of 8.1 months, with 31% requiring dose reduction. They were able to continue on everolimus for a median time of 4.4 months, with 16% requiring dose reduction.
Main adverse events of any grade on pazopanib were hypertension (48.4%), fatigue (32.2%), and thyroid disorders (19.3%). Those on everolimus were anemia (32.2%), hypercholesterolemia (22.6%), and hyperglycemia (22.6%).
“The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib,” noted Dr. Rossetti and colleagues. “The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.”
[email protected]
Sequential treatment with pazopanib and everolimus yields a median overall survival exceeding 2 years in predominantly older and sicker patients with metastatic renal cell carcinoma (RCC) treated in real-world settings, according to results of an Italian multicenter cohort study.
“These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance,” wrote Sabrina Rossetti, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale, Naples, and associates (Front Pharmacol. 2017 Jul 20;8:484).
“Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile and may be feasible even for elderly patients or with multiple comorbidities,” they said.
The investigators prospectively enrolled 31 consecutive patients with newly diagnosed metastatic RCC. They had a median age of 68 years. Fully 73.3% underwent nephrectomy before treatment; 87.1% had at least one comorbidity, and 25.8% had at least three of them.
All patients were treated with the antiangiogenic tyrosine kinase inhibitor pazopanib (Votrient) as first-line therapy and, after disease progression on that agent or discontinuation for toxicity, with the mTOR inhibitor everolimus (Afinitor) as second-line therapy.
The median overall survival with the two-drug sequence was 26.5 months. Median progression-free survival was 10.6 months with pazopanib and 5.3 months with everolimus.
Patients were able to continue on pazopanib for a median time of 8.1 months, with 31% requiring dose reduction. They were able to continue on everolimus for a median time of 4.4 months, with 16% requiring dose reduction.
Main adverse events of any grade on pazopanib were hypertension (48.4%), fatigue (32.2%), and thyroid disorders (19.3%). Those on everolimus were anemia (32.2%), hypercholesterolemia (22.6%), and hyperglycemia (22.6%).
“The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib,” noted Dr. Rossetti and colleagues. “The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.”
[email protected]
FRONTIERS IN PHARMACOLOGY
Key clinical point:
Major finding: Median overall survival with first-line pazopanib followed by second-line everolimus was 26.5 months.
Data source: A real-world prospective multicenter cohort study of 31 patients with untreated metastatic RCC.
Disclosures: Dr. Rossetti and colleagues disclosed no relevant conflicts of interest. The study was supported by Novartis Farma SpA.
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.