Suresh S. Ramalingam, MD
Amid rapid-fire developments in non–small cell lung cancer (NSCLC) research, the role of checkpoint immunotherapy continues to mature. Experts from the United States, France, and Italy discussed the evolution of therapy for patients with advanced nonsquamous disease during a recent OncLive®
panel. Moderator Suresh S.
Ramalingam, MD, opened the discussion by noting that there has been a “sea change in the way advanced lung cancer is treated.” Along with the many molecularly targeted therapies now available for patients with mutations, immunotherapy agents have been approved in several countries. In all, the FDA has approved has approved 3 checkpoint blockade immunotherapies for patients with NSCLC: pembrolizumab (Keytruda) and nivolumab (Opdivo), both monoclonal antibodies that inhibit PD-1, and atezolizumab (Tecentriq), which inhibits PD-L1. Another PD-L1 inhibitor, durvalumab (Imfinzi), is under review for patients with stage III unresectable NSCLC.
The approvals issued thus far differ in disease settings, patient populations, and use of PD-L1 expression levels to select candidates for treatment.
Pembrolizumab Establishes First-Line Niche
Pembrolizumab was originally approved by the FDA for the second-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 at any level, regardless of histology. Indications for pembrolizumab monotherapy were subsequently expanded to include treatment-naïve patients whose tumors express PD-L1 with a tumor proportion score (TPS) ≥50%.1
This was based on the results of the randomized phase III KEYNOTE-024 trial in which pembrolizumab was compared with investigator’s choice of chemotherapy for advanced NSCLC tumors with PD-L1 expression with TPS ≥50%.2
Patients in the chemotherapy arm were permitted to cross over to pembrolizumab after disease progression. Approximately 30% of the more than 1600 patients screened had the enrollment biomarker and 305 were enrolled.2 The primary endpoint was median progression-free survival (PFS), which reached 10.3 months in the pembrolizumab arm versus 6 months in the chemotherapy arm (HR for disease progression or death, 0.50; 95% CI, 0.37-0.68; P <.001).2 Investigators presented updated findings at the 2017 American Society of Clinical Oncology Annual Meeting, which showed significantly better median PFS in the pembrolizumab arm than in the chemotherapy arm (HR, 0.50; P <.0001) and significantly better overall survival (OS; HR, 0.60; P
“The primary endpoint was, at least for me, shocking because there was a significant clinical improvement, not only significant improvement in PFS,” said Giorgio V. Scagliotti, MD, PhD. “More importantly...there was also an improvement in the overall survival despite the study allowing the crossover.”
The OS benefit was more pronounced in updated results presented during the 18th World Conference on Lung Cancer (WCLC) in October, which was after the Peer Exchange® program took place. In the WCLC findings, the median OS for patients treated with pembrolizumab was 30.2 months versus 14.2 months with chemotherapy, representing a 37% reduction in the risk of death (HR, 0.63; 95% CI, 0.47-0.86; P
In May 2017, the FDA granted accelerated approval to pembrolizumab in combination with the chemotherapy agents pemetrexed (Alimta) and carboplatin for the first-line treatment of advanced nonsquamous NSCLC.5
Approval was based on results from the KEYNOTE-021 trial, which did not stratify patients according to PD-L1 expression.6
Patients were chemotherapy-naïve and had no targetable EGFR or ALK genomic aberrations. Participants were randomly assigned to pembrolizumab plus chemotherapy with carboplatin and pemetrexed for 24 months or to 3 to 4 cycles of chemotherapy only.6
After completing initial treatment assignments, all patients in the study were switched to pembrolizumab maintenance therapy for an indefinite amount of time. Interim results showed a significantly higher objective response rate (ORR) in the combination arm than the chemotherapy-only arm, which was the primary objective of KEYNOTE-021 (55% vs 29%, respectively; P
Borghaei and colleagues presented updated data at the European Society for Medical Oncology (ESMO) 2017 Congress.7
The ORR was 57% in the pembrolizumab arm versus 32% in the chemotherapy-only arm (P
= .0029), and the median PFS was significantly longer in the pembrolizumab arm than in the chemotherapy arm (19 vs 8.9 months, respectively; P
OS was not reached in either arm, but the authors said the HR for OS increasingly favored the pembrolizumab arm (HR, 0.90-0.69 to 0.59, respectively) over time.