FDA Grants Pembrolizumab Priority Review in Frontline NSCLC

Roger M. Perlmutter, MD, PhD

The FDA has granted a priority review to a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) as a first-line treatment for patients with PD-L1—positive non–small cell lung cancer (NSCLC), according to Merck, the manufacturer of the PD-1 inhibitor.

The sBLA is based on data from the phase III KEYNOTE-024 trial, in which frontline pembrolizumab improved overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with NSCLC and PD-L1 expression levels ≥50%. The data from the trial have not yet been presented.

Along with the priority review, pembrolizumab also received a breakthrough therapy designation in this setting from the FDA. The FDA is scheduled to make a final decision on the sBLA for the PD-1 inhibitor by December 24, 2016, in accordance with the Prescription Drug User Fee Act.

“Chemotherapy has been the foundation of first-line treatment for non—small cell lung cancer for decades, so the significant improvement in survival in patients with high PD-L1 expression seen with Keytruda compared to chemotherapy is welcome news,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement. “We appreciate the opportunity to work with regulatory authorities to make Keytruda a first-line treatment option in non–small cell lung cancer.”

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.

Data for frontline pembrolizumab in NSCLC from the phase I KEYNOTE-001 trial were previously published in The New England Journal of Medicine (NEJM). 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.