FDA Expands Pemetrexed Label With Combination of Pembrolizumab and Platinum Chemotherapy for the First-Line Treatment of Metastatic Nonsquamous NSCLC
Today, the U.S. Food and Drug Administration (FDA) granted approval for a new indication for pemetrexed (Alimta) for injection in combination with pembrolizumab (Keytruda) and platinum chemotherapy for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations. This indication is approved based on data from the phase III KEYNOTE-189 trial, which enrolled patients regardless of programmed death-ligand 1 (PD-L1) expression and had dual primary endpoints of overall survival (OS) and progression-free survival (PFS).
Pemetrexed in combination with pembrolizumab and carboplatin was first approved in June 2018 under the FDA’s accelerated approval process for the first-line treatment of patients with metastatic nonsquamous NSCLC, based on tumor response rates and PFS data from the phase II KEYNOTE-021 trial (Cohort G1). In accordance with the accelerated approval process, continued approval was contingent upon verification and description of clinical benefit, which has now been demonstrated in the KEYNOTE-189 trial and has resulted in the FDA converting the accelerated approval to full approval.
KEYNOTE-189 Results
KEYNOTE-189 was a randomized, double-blind, placebo-controlled, phase III study that evaluated pemetrexed in combination with pembrolizumab and cisplatin or carboplatin compared with pemetrexed in combination with placebo and cisplatin or carboplatin, in 616 untreated patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Patients had no sensitizing EGFR or ALK genomic tumor aberrations, and had not previously received systemic therapy for advanced disease.
Median OS in the pemtrexed/pembrolizumab/platinum chemotherapy arm was not reached vs 11.3 months in the pemetrexed/placebo/platinum chemotherapy arm; median PFS in the pemtrexed/pembrolizumab/platinum chemotherapy arm was 8.8 months vs 4.9 months in the pemetrexed/placebo/platinum chemotherapy arm; and overall response rate was 48% in the pemtrexed/pembrolizumab/platinum chemotherapy arm vs 19% in the pemtrexed/placebo/platinum chemotherapy arm.
Safety was evaluated in 405 patients who received pemetrexed in combination with pembrolizumab and platinum chemotherapy and 202 patients who received placebo, pemetrexed, and platinum chemotherapy. Pemetrexed was discontinued for adverse reactions in 23% of patients in the pemtrexed/pembrolizumab/platinum chemotherapy arm. The most common adverse reactions resulting in discontinuation of pemetrexed in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to the interruption of pemetrexed occurred in 49% of patients in the pemtrexed/pembrolizumab/platinum chemotherapy arm; the most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed in this arm (≥ 2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%). Adverse reactions of any grade occurring in ≥ 20% of patients receiving pemetrexed in combination with pembrolizumab and platinum chemotherapy were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).
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