Ali Tafreshi

Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial

BACKGROUND In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). METHODS In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients. FINDINGS Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and -0·9 (-4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44-0·97; two-sided nominal p=0·029). INTERPRETATION Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC. FUNDING Merck & Co.

Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer

Background Standard first‐line therapy for metastatic, squamous non–small‐cell lung cancer (NSCLC) is platinum‐based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD‐L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. Methods In this double‐blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin‐bound [nab]–paclitaxel for the first 4 cycles. Primary end points were overall survival and progression‐free survival. Results After a median follow‐up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab‐combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo‐combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD‐L1 expression. The median progression‐free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab‐combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo‐combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab‐combination group and in 68.2% of the patients in the placebo‐combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab‐combination group than in the placebo‐combination group (13.3% vs. 6.4%). Conclusions In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab‐paclitaxel resulted in significantly longer overall survival and progression‐free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE‐407 ClinicalTrials.gov number, NCT02775435.)

PS3 KEYNOTE-024 Update: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced NSCLC with PD-L1 Tumor Proportion Score ≥50%

nivolumab + ipilimumab and chemotherapy, respectively. Grade 3e4 select TRAEs by category with nivolumab + ipilimumab included hepatic (8%), endocrine (4%), and skin (4%), and were consistent with previous reports. Median time to onset of select TRAEs ranged from 2 to 15 weeks, and the majority resolved (median time: 10 weeks). PRO results will be reported in the final presentation. Conclusion: First-line nivolumab + ipilimumab significantly prolonged PFS vs chemotherapy in patients with NSCLC and high TMB 10 mut/Mb regardless of PD-L1 expression. These results validate the role of TMB as a biomarker for the use of nivolumab + ipilimumab in first-line NSCLC. Safety of nivolumab + low-dose ipilimumab was manageable.