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Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.

ABSTRACT: We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab?+?bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-? response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.

SUBMITTER: McDermott DF

PROVIDER: S-EPMC6721896 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.

McDermott David F DF Huseni Mahrukh A MA Atkins Michael B MB Motzer Robert J RJ Rini Brian I BI Escudier Bernard B Fong Lawrence L Joseph Richard W RW Pal Sumanta K SK Reeves James A JA Sznol Mario M Hainsworth John J Rathmell W Kimryn WK Stadler Walter M WM Hutson Thomas T Gore Martin E ME Ravaud Alain A Bracarda Sergio S Suárez Cristina C Danielli Riccardo R Gruenwald Viktor V Choueiri Toni K TK Nickles Dorothee D Jhunjhunwala Suchit S Piault-Louis Elisabeth E Thobhani Alpa A Qiu Jiaheng J Chen Daniel S DS Hegde Priti S PS Schiff Christina C Fine Gregg D GD Powles Thomas T

Nature medicine 20180604 6

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 ( ...[more]

PMID: 29867230

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Project description:ObjectiveTo evaluate patient-reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression-free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death-ligand 1 (PD-L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC).Patients and methodsPatients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks (n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks (n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6-week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2-point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib.ResultsCompletion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue-related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22-0.71); RCC symptoms, 0.22 (0.12-0.41); and symptom interference, 0.36 (0.22-0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions.ConclusionPROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).

Project description:BACKGROUND:Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS:We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS:A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS:Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).

Project description:BackgroundThe efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.MethodsIn this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.ResultsOverall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.ConclusionsNivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).

Project description:BackgroundIn a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib.MethodsWe randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety.ResultsA total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.ConclusionsProgression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.).

Dataset Information

Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.

Publications

Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.

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