At ESMO: One Anti-PD1 Agent Moves to the Head of the Line in Advanced NSCLC
By Adrian Barfield
For patients with advanced NSCLC lacking a targetable mutation, platinum-based doublets have been the standard of care for 30 years. The anti-PD1 antibodies nivolumab (Opdivo; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck) and atezolizumab (Tecentriq; Genentech) each demonstrated improved survival over docetaxel in patients progressing on platinum-based doublets.
Having already revolutionized the treatment of advanced NSCLC, these compounds are being tested in previously untreated patients. This where the compounds may be parting ways.
Phase 3 studies in NSCLC were the highlights of the European Society for Medical Oncology (ESMO) 2016 Congress. Most importantly, in the front-line setting, the KEYNOTE 024 trial of single-agent pembrolizumab met its primary endpoint, achieving not only a progression-free survival (PFS) but an overall survival (OS) benefit versus chemotherapy.1
Nivolumab, on the other hand, essentially tanked as a first-line agent in CheckMate 026.2
A preliminary analysis of the phase 3 OAK study of second-line atezolizumab also stoked the checkpoint inhibitor fire.3
OBR was there to capture the data and obtain insights from lung cancer experts.
Invited discussant of KEYNOTE 024, Jean-Charles Soria, MD, of the Institute Gustave Roussy and Paris University XI, noted that since PFS was improved with pembrolizumab by 50% and OS by 40%, platinum doublets are “no longer dominant.” “There’s a new player, and probably a new standard of care,” he said.
Assuming its likely FDA approval in the front line, pembrolizumab has become “the ultimate game changer in our therapeutic landscape,” agreed Corey Langer, MD, Director of the Thoracic Oncology Program, Abramson Cancer Center, University of Pennsylvania Health System, who said the results of the study usher in a “complicated but also very exciting” change in the treatment paradigm for advanced NSCLC.
Pembrolizumab Trial Meets Primary Endpoint
KEYNOTE 024 was an open-label, randomized phase 3 trial of pembrolizumab versus platinum-doublet chemotherapy as first-line treatment in 305 advanced NSCLC patients with PD-L1 expression ≥50% and no targetable mutation (which would warrant targeted treatment).
After a median follow-up of 11.2 months, median PFS was 10.3 months with pembrolizumab versus 6.0 months with chemotherapy (HR=0.50; P<0.001), reported Martin Reck, MD, PhD, of the German Center of Lung Research in Grosshansdorf.
One-year survival was 70% versus 54%, respectively (HR=0.60; P=0.005). Pembrolizumab was also associated with higher objective response rates (ORR) (45% vs 28%), longer response duration (median not reached, vs 6.3 months), and a lower incidence of adverse events.
“In untreated patients without targetable mutations and with high expression of PD-L1, pembrolizumab has been shown to be a very attractive first-line treatment option,” commented Dr. Reck.
Also at ESMO, Dr. Langer reported positive results of a phase 2 study of pembrolizumab plus chemotherapy (carboplatin/pemetrexed) versus chemotherapy alone as first-line treatment in patients with non-squamous histology.4
The study enrolled 123 patients from KEYNOTE 021 (cohort G) with any PD-L1 status. The primary endpoint, ORR, was 55% with pembrolizumab/chemotherapy versus 29% for chemotherapy alone (P=0.0016).
PFS was significantly improved, from 8.9 months with chemotherapy to 13.0 months with the combination (HR=0.53; P=0.0102).
“This makes KEYNOTE-021 one of the first randomized, controlled trials of first-line therapy for advanced NSCLC in which median PFS exceeded 1 year,” noted Dr. Langer.
Response rates appeared to be similar in patients with PD-L1 expression <1% and those with higher levels of PD-L1 expression. With early follow-up, and with nearly three quarters of control subjects crossing over to immunotherapy upon progression, there was no difference in overall survival.