Updated Analysis KEYTRUDA® Doubles Overall Survival Compared with Chemotherapy in Advanced NSCLC

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019, about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced Non Small Cell Lung Cancer (NSCLC) have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is an open-label, randomized phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for up to 2 years or the investigator’s choice of platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. Patients in the chemotherapy group who experienced disease progression were allowed to cross over to the KEYTRUDA® group. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Objective Response Rate (ORR) and Safety.

It was previously reported that at a median follow up of 11.2 months, the median PFS was 10.3 months in the KEYTRUDA® group versus 6 months in the chemotherapy group (HR=0.50; P<0.001). However, median OS had not been reached in the KEYTRUDA® group at the time of that analysis. The Independent Data and Safety Monitoring Committee (IDMC) based on these results recommended stopping the trial early, to allow for use of KEYTRUDA® in patients randomly assigned to chemotherapy. Eighty two patients (N=82) assigned to chemotherapy, met criteria to cross over to the KEYTRUDA® group, upon progression.

This publication is an updated analysis of the KEYNOTE-024 study, after a median follow-up of 25.2 months. The median OS was 30 months in the KEYTRUDA® group and 14.2 months in the chemotherapy group (HR=0.63; P=0.002). When adjusted for crossover, the OS benefit was maintained and the Hazard Ratio for OS among KEYTRUDA® group versus chemotherapy group was 0.49. Further, more patients in the KEYTRUDA® group achieved 12-month OS (70.3% versus 54.8%), and an ORR response (45.5% versus 29.8%), compared to the chemotherapy group respectively. The ORR among those who crossed over to KEYTRUDA®, was 20.7%. The median Duration of Response has not yet been reached for patients assigned to KEYTRUDA® and also for those who crossed over to KEYTRUDA®. For those assigned chemotherapy, the median Duration of Response was 7.1 months. Patients in the KEYTRUDA® group had lower rates of Grade 3-5 adverse events, compared to those in the chemotherapy group (31.2% versus 53.3%), as well as a lower rate of any-grade adverse events (76.6% versus 90%).

It was concluded that in this updated analysis of KEYNOTE-024, KEYTRUDA® continued to provide improved Overall Survival benefit, inspite of the high rate of crossover, with lower rates of Adverse Events, when compared to chemotherapy, among patients with metastatic NSCLC and high PD-L1 expression. The authors added that these updated long term results support KEYTRUDA® monotherapy as a standard-of-care regimen for first line treatment of advanced NSCLC with PD-L1 expression of 50% or greater and without EGFR/ALK alterations. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Reck M , Rodríguez–Abreu D, Robinson AG, et al. J Clin Oncol 2019;37:537-546