Checkpoint inhibitors have revolutionized the treatment of advanced non–small cell lung cancer (NSCLC), but evidence of their benefit was restricted to the second-line setting. However, early-phase trials with both pembrolizumab (Keytruda) and nivolumab (Opdivo) demonstrated favorable results in chemotherapy-naive NSCLC patients; these encouraging data led to the first randomized comparisons between antibodies that target programmed cell death protein 1 (PD-1) vs platinum-based chemotherapy.
These data were presented at the 2016 ESMO (European Society for Medical Oncology) Congress. The excitement among lung cancer experts was universal. Pivotal trials of pembrolizumab and nivolumab in the first-line setting took center stage at ESMO’s Presidential Session—but only one met its trial’s primary endpoint.
Based on an impressive survival benefit over platinum-based chemotherapy, pembrolizumab was approved by the U.S. Food and Drug Administration in programmed cell death ligand 1 (PD-L1)–positive NSCLC as first-line therapy on October 24, 2016 (see page 35). This checkpoint inhibitor will become “the ultimate game-changer in our therapeutic landscape so far,” predicted Corey Langer, MD, Director of the Thoracic Oncology Program, Abramson Cancer Center, University of Pennsylvania Health System. Dr. Langer said the results usher in a “complicated but also very exciting” change in the treatment paradigm for advanced NSCLC. “After almost 30 years of laboring in the trenches,” he said, “I am excited to see that, all of a sudden, we have so many therapeutic options.”
“It’s the most hopeful time for patients with lung cancer I have seen in my career,” agreed Roy Herbst, MD, PhD, Ensign Professor of Medicine (Medical Oncology), Professor of Pharmacology, and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital. “Now the challenge for all of us is to figure out how to help the other 70% of patients in the same way using even more sophisticated predictive markers and drug combinations.”
Pembrolizumab Superior to Platinum Agents
These data suggest that pembrolizumab may be the new standard of care for first-line therapy in PD-L1–expressing advanced NSCLC without treatable oncogenic aberrations.— Martin Reck, MD, PhD
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The phase III KEYNOTE-024 trial, conducted in 16 countries, compared pembrolizumab (200 mg every 3 weeks) to the investigator’s choice of a platinum-doublet (4–6 cycles) in 305 previously untreated patients with advanced NSCLC who had PD-L1 expression ≥ 50% (wild-type for EGFR and ALK).1 After a median follow-up of 11.2 months, pembrolizumab significantly prolonged progression-free survival over chemotherapy, from 6.0 months to 10.3 months (hazard ratio [HR] = 0.50; P < .001); the strongest signal (HR = 0.35) was observed in the squamous histology subset, reported Martin Reck, MD, PhD, of the German Center of Lung Research in Grosshansdorf, Germany. The results were simultaneously published in The New England Journal of Medicine.2
“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,” Dr. Reck commented.
In addition, overall survival was also significantly improved, with 70% of pembrolizumab-treated patients alive at 1 year, compared with 54% of the chemotherapy arm (HR = 0.60; P = .005). The median overall survival was not reached in either arm. Pembrolizumab was also associated with higher response rates (45% vs 28%) and longer response duration (median not reached vs 6.3 months).
Anti–PD-1 Agents in First-Line Treatment of Lung Cancer
- Two phase III trials evaluated anti–PD-1 agents as first-line treatment of patients with advanced NSCLC who had PD-L1 expression and lacked a targetable oncogenic mutation.
- KEYNOTE-024 met its primary endpoint for pembrolizumab, showing a 50% reduction in disease progression. Median progression-free survival was 10.3 vs 6.0 months for chemotherapy (P < .001).
- CheckMate-026 did not meet its primary endpoint. Median progression-free survival was 4.2 months in the nivolumab arm and 5.9 months in the chemotherapy arm among patients with PD-L1 ≥ 5% (P = .2511).
“These benefits have been consistent, and they improved over time,” Dr. Reck commented, referring to both progression-free and overall survival. “We observed an improvement in overall survival, despite the fact that about 50% of the control arm crossed over to receive an anti–PD-1 agent.” The superior efficacy of pembrolizumab triggered an early stopping of the trial by the Data Monitoring Committee.
Adverse events were also lower with pembrolizumab. Toxicities of any grade occurred in 73% of patients receiving pembrolizumab and 90% of patients receiving chemotherapy; grades 3–5 treatment-related events occurred in 27% and 53%, respectively.
“These data suggest that pembrolizumab may be the new standard of care for first-line therapy in PD-L1–expressing advanced NSCLC without treatable oncogenic aberrations,” Dr. Reck said.
Very encouraging results were also presented from a phase II study evaluating pembrolizumab in combination with carboplatin and pemetrexed (Alimta) in previously untreated patients with advanced nonsquamous NSCLC and any degree of PD-L1 expression. Median progression-free survival was 13.0 months for the immunotherapy/chemotherapy combination vs 8.9 months for chemotherapy alone, according to Dr. Langer.3 A phase III trial of this approach is currently underway. (see here).
Nivolumab Not Superior to Chemotherapy
Nivolumab did not meet the primary endpoint of superior progression-free survival in patients with PD-L1 ≥ 5%, compared with chemotherapy.— Mark A. Socinski, MD
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In contrast, the results were disappointing for nivolumab in the first-line setting in a less highly selected population.4 The phase III CheckMate-026 trial enrolled 541 previously untreated patients with NSCLC who had ≥ 1% PD-L1 expression, randomizing them to nivolumab (3 mg/kg) or a platinum-based doublet selected by the investigator. Patients’ tumors were wild-type for EGFR and ALK.
“Nivolumab did not meet the primary endpoint of superior progression-free survival in patients with PD-L1 ≥ 5%, compared with chemotherapy,” said Mark A. Socinski, MD, Executive Medical Director of the Florida Hospital Cancer Institute. Dr. Socinski led CheckMate-026 while he was at the University of Pittsburgh Cancer Center.
Median progression-free survival was 4.2 months in the nivolumab arm and 5.9 months in thre platinum-based doublet arm (HR = 1.15; P = .2511). One-year progression-free survival was approximately 23% in each arm. Median overall survival was also similar: 14.4 months with nivolumab and 13.2 months with chemotherapy (HR = 1.02; 95% confidence interval: 0.80–1.30); more than 50% of the chemotherapy arm crossed over to receive immunotherapy upon disease progression. Objective responses were observed in 26.1% and 33.5%, respectively, with a median duration of response of 12.1 months and 5.7 months.
There were fewer treatment-related events, however, with nivolumab than with chemotherapy. Among all treated patients, toxicities of any grade were observed in 71% of patients receiving nivolumab and 92.4% of patients receiving platinum doublets; grade 3/4 events occurred in 17.6% and 50.6%, respectively.
“Outcomes in subgroups mirrored those of the overall study population,” Dr. Socinski reported.
The phase III CheckMate-227 trial is currently evaluating three first-line options for nivolumab: nivolumab monotherapy, ipilimumab (Yervoy)/nivolumab (Opdivo), and chemotherapy, in patients with PD-L1 ≥ 1% and in those with PD-L1 < 1%. ■
Disclosure: Dr. Herbst reported no potential conflicts of interest. Dr. Reck has received honoraria for lectures and consultancy from Roche, Lilly, MSD, Bristol-Myers Squibb, AstraZeneca, Merck, Pfizer, Boehringer-Ingelheim, Novartis, and Celgene.
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