Shelley Coleman

Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC

BACKGROUND The cancer‐cell–killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor–mediated immunosuppression with bevacizumab. This open‐label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non–small‐cell lung cancer (NSCLC) who had not previously received chemotherapy. METHODS We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator‐assessed progression‐free survival both among patients in the intention‐to‐treat population who had a wild‐type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T‐cell (Teff) gene signature in the tumor (Teff‐high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. RESULTS In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression‐free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff‐high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression‐free survival was also longer in the ABCP group than in the BCP group in the entire intention‐to‐treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD‐L1) expression, those with low Teff gene‐signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. CONCLUSIONS The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression‐free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD‐L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann–La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143.)

Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study.

Abstract Background The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation–positive metastatic melanoma. We present final OS data from BRIM-3. Patients and methods Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib. Results Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0–15.4] versus 9.7 months [95% CI 7.9–12.8; hazard ratio (HR) 0.81 [95% CI 0.67–0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0–15.4) versus 10.3 months (95% CI 9.1–12.8); HR 0.81 (95% CI 0.68–0.96); P = 0.01]. Kaplan–Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis. Conclusions Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies. ClinicalTrials.gov NCT01006980.

ORAL01.04: Phase II Trial of Atezolizumab for Patients with PD-L1–Selected Advanced NSCLC (BIRCH): Updated Efficacy and Exploratory Biomarker Results: Topic: Medical Oncology

47% and 39% in the two cohorts in unselected patients (Table) and median duration of response was not reached after a median follow-up of 12.8 months and 11.8 months. Responses were seen across all PD-L1 subgroups, and were enriched among those with greater PD-L1, up to 100% and 86% among those with 50% PD-L1 expression (Table). Responses were achieved in patients with EGFR mutations and in never smokers. Conclusion: First-line therapy with nivolumab plus ipilimumab demonstrates pronounced and durable clinical activity and a manageable safety profile. The nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W schedule is being evaluated in a phase III clinical trial in first-line advanced NSCLC.