Phase II, open-label study of encorafenib plus binimetinib in patients with BRAFV600-mutant metastatic non-small-cell lung cancer

PURPOSE The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with BRAF(V600E/K)-mutant metastatic melanoma. We evaluated the efficacy and safety of encorafenib plus binimetinib in patients with BRAF(V600E)-mutant metastatic non-small-cell lung cancer (NSCLC).METHODS In this ongoing, open-label, single-arm, phase II study, patients with BRAF(V600E)-mutant metastatic NSCLC received oral encorafenib 450 mg once daily plus binimetinib 45 mg twice daily in 28-day cycles. The primary end point was confirmed objective response rate (ORR) by independent radiology review (IRR). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival, time to response, and safety.RESULTS At data cutoff, 98 patients (59 treatment-naive and 39 previously treated) with BRAF(V600E)-mutant metastatic NSCLC received encorafenib plus binimetinib. Median duration of treatment was 9.2 months with encorafenib and 8.4 months with binimetinib. ORR by IRR was 75% (95% CI, 62 to 85) in treatment-naive and 46% (95% CI, 30 to 63) in previously treated patients; median DOR was not estimable (NE; 95% CI, 23.1 to NE) and 16.7 months (95% CI, 7.4 to NE), respectively. DCR after 24 weeks was 64% in treatment-naive and 41% in previously treated patients. Median PFS was NE (95% CI, 15.7 to NE) in treatment-naive and 9.3 months (95% CI, 6.2 to NE) in previously treated patients. The most frequent treatment-related adverse events (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). TRAEs led to dose reductions in 24 (24%) and permanent discontinuation of encorafenib plus binimetinib in 15 (15%) patients. One grade 5 TRAE of intracranial hemorrhage was reported. Interactive visualization of the data presented in this article is available at the PHAROS dashboard ().CONCLUSION For patients with treatment-naive and previously treated BRAF(V600E)-mutant metastatic NSCLC, encorafenib plus binimetinib showed a meaningful clinical benefit with a safety profile consistent with that observed in the approved indication in melanoma.Pathogenesis and treatment of chronic pulmonary disease

First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy in Advanced NSCLC With 1% or Greater Tumor PD-L1 Expression: Patient-Reported Outcomes From CheckMate 227 Part 1

Introduction: In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy. We present the patient-reported outcomes (PROs). Methods: Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. PROs were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted. Results: PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy. Conclusions: Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression. © 2021 International Association for the Study of Lung Cance

Safety of First-line Nivolumab Plus Ipilimumab in Patients With Metastatic Non-Small Cell Lung Cancer: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817.

We characterized first-line nivolumab plus ipilimumab (NIVO+IPI) safety in a large patient population with metastatic non-small cell lung cancer (NSCLC) and efficacy outcomes after NIVO+IPI discontinuation due to treatment-related adverse events (TRAEs). We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 weeks; IPI, 1 mg/kg every 6 weeks) in metastatic NSCLC (CheckMate 227 Part 1, CheckMate 817 cohort A, CheckMate 568 Part 1). Safety endpoints included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged ≥75 years. In the pooled population (N=1255), any-grade TRAEs occurred in 78% of patients, grade 3/4 TRAEs in 34%, and discontinuations of any regimen component due to TRAEs in 21%. The most frequent TRAE and IMAE were diarrhea (20%; grade 3/4, 2%) and rash (17%; grade 3/4, 3%), respectively. The most common grade 3/4 IMAEs were hepatitis (5%) and diarrhea/colitis and pneumonitis (4% each). Pneumonitis was the most common cause of treatment-related death (5/16). Safety in patients aged ≥75 years (n=174) was generally similar to the overall population, but discontinuations of any regimen component due to TRAEs were more common (29%). In patients discontinuing NIVO+IPI due to TRAEs (n=225), 3-year overall survival was 50% (95% CI: 42.6-56.0), and 42% (31.2-52.4) of 130 responders remained in response 2 years after discontinuation. First-line NIVO+IPI was well tolerated in this large population with metastatic NSCLC and in patients aged ≥75 years. Discontinuations due to TRAEs did not reduce long-term survival