Roger M. Perlmutter, MD, PhD
Frontline pembrolizumab (Keytruda) improved overall survival (OS) versus chemotherapy in non–small cell lung cancer (NSCLC) patients with high levels of PD-L1 expression, according to results from the phase III KEYNOTE-024 trial reported by Merck, the company developing the PD-1 inhibitor.
Pembrolizumab was also shown to extend progression-free survival (PFS) in the first-line NSCLC setting. Based on the findings, an independent panel recommended that the trial be halted and that patients in the chemotherapy arm be allowed to cross over and receive pembrolizumab.
“We believe that the KEYNOTE-024 results have the potential to change the therapeutic paradigm in first-line treatment of non–small cell lung cancer,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement. “We look forward to sharing these data with the medical community and with regulatory authorities around the world.”
The open-label phase III KEYNOTE-024 trial randomized 305 treatment-naive patients with advanced NSCLC to receive pembrolizumab or standard platinum-based chemotherapy. The trial only included patients with high levels of PD-L1 expression on their tumors, defined as ≥50% as measured by a central laboratory with an immunohistochemistry assay.
Pembrolizumab was administered as a 200 mg IV infusion on the first day of each 21-day cycle until a maximum of 35 cycles or progressive disease. Patients randomized to chemotherapy received paclitaxel plus carboplatin, pemetrexed plus carboplatin, pemetrexed plus cisplatin, gemcitabine plus carboplatin, or gemcitabine plus cisplatin. Maintenance pemetrexed was allowed for patients with nonsquamous NSCLC. The primary endpoint was PFS, with secondary outcome measures including OS and overall response rate (ORR).
The safety data for pembrolizumab in KEYNOTE-024 were similar to previously reported outcomes with the PD-1 inhibitor in advanced NSCLC. Merck intends to submit the complete results from the study at an upcoming medical conference.
Data for frontline pembrolizumab in NSCLC from the phase I KEYNOTE-001 trial were previously published in The New England Journal of Medicine
The KEYNOTE-001 data reported in NEJM
included 495 patients with advanced NSCLC, 101 of whom were treatment-naive. All 495 patients received at least 1 dose of pembrolizumab and had an ECOG performance status ≤1. Pembrolizumab was administered at 2 mg/kg or 10 mg/kg IV every 3 weeks or 10 mg/kg IV every 2 weeks. The median follow-up was 10.9 months.
The ORR was 24.8% (95% CI, 16.7-34.3) in the 101 treatment-naive patients. The median OS was 16.2 months (95% CI, 16.2 to not reached) in these patients, and the median PFS was 6.0 months (95% CI, 4.1-8.6). The median duration of response was 23.3 months (range, 1.0-23.3).
Efficacy outcomes were also determined by PD-L1 status. Among treatment-naive patients with PD-L1 expression ≥50%, the ORR was 50% (95% CI, 24.7-75.3), the PFS was 12.5 months (95% CI, 2.4 to 12.5), and the median OS was not yet reached.
In the overall 495-patients NSCLC population, the most common all-grade adverse events (AEs) were fatigue (19.4%), pruritus (10.7%), decreased appetite (10.5%), rash (9.7%), arthralgia (9.1%), diarrhea (8.1%), and nausea (7.5%). The most frequently reported grade 3/4 AEs were dyspnea (3.8%), pneumonitis (1.8%), asthenia (1%), and decreased appetite (1%).
The FDA granted an accelerated approval to pembrolizumab in October 2015 as a treatment for patients with pretreated advanced non–small cell lung cancer across all histologies whose tumors express PD-L1. The PD-1 inhibitor was approved along with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, and is indicated for patients who progress on or after platinum-containing chemotherapy or EGFR-or ALK-targeted agents in patients harboring those mutations.
Garon EB, Rizvi N, Hu R, et al. Pembrolizumab for the treatment of non–small cell lung cancer. N Engl J Med. 2015;372:2018-2028.