FDA Delays Decision on Frontline Pembrolizumab sBLA in NSCLC

The FDA has extended the review period for a supplemental biologics license application (sBLA) for single-agent pembrolizumab (Keytruda) for the frontline treatment of patients with locally advanced or metastatic nonsquamous or squamous non—small cell lung cancer (NSCLC) with a PD-L1 expression (tumor proportion score [TPS]) level of ≥1% and no EGFR or ALK genomic tumor aberrations.

UPDATE 4/11/2019: FDA Lowers Pembrolizumab PD-L1 Cutoff in NSCLC, Expands Approval to Stage III

Merck (MSD), the manufacturer of pembrolizumab, reported in a press release that the extension will allow ample time for the FDA to review additional information the company submitted for the application. The new action date for the sBLA is April 11, 2019.

In September 2018, Merck reported that the FDA had granted a priority review to the sBLA based on findings from the phase III KEYNOTE-042 trial, in which the median overall survival (OS) was 16.7 months with frontline pembrolizumab monotherapy compared with 12.1 months with standard chemotherapy in patients with advanced or metastatic NSCLC and TPS ≥1% (HR, 0.81; 95% CI, 0.71-0.93; P = .0018). Across all patients with PD-L1 TPS of 1% to 49%, which was an exploratory analysis, the median OS was 13.4 months with pembrolizumab compared with 12.1 months for chemotherapy (HR, 0.92; 95% CI, 0.77-1.11).

The initial action date the FDA set was January 11, 2019. Single-agent pembrolizumab is already approved by the FDA in the frontline setting for patients with metastatic NSCLC and TPS ≥50% whose tumors do not harbor EGFR or ALK genomic aberrations.

In the large, randomized phase III KEYNOTE-042 trial, 1274 patients with locally advanced or metastatic NSCLC were randomized to pembrolizumab or chemotherapy with paclitaxel plus carboplatin or pemetrexed plus carboplatin. Both squamous and nonsquamous cancers were included, but not cancers with genetic changes that could be treated with targeted therapies such as EGFR and ALK inhibitors.

Patients were separated into 3 arms according to TPS: ≥50% (n = 599), ≥20% (n = 818), and ≥1% (n = 1274). An equal number of patients in each PD-L1 expression group received pembrolizumab and chemotherapy. Patients were randomized 1:1 to receive either 200 mg of pembrolizumab every 3 weeks for ≤35 cycles or investigator’s choice of chemotherapy regimens for ≤6 cycles. OS was the primary endpoint.

After a median follow-up of 12.8 months, 13.7% of patients were still on pembrolizumab and 4.9% were receiving the agent as maintenance therapy.

Overall survival correlated with greater levels of PD-L1 expression: TPS ≥50% (20 vs 12.2 months; HR, 0.69; 95% CI, 0.56-0.85; P = .0003), TPS ≥20% (17.7 vs 13.0 months; HR, 0.77; 95% CI, 0.64-0.92; P = .002).

Response rates were higher among patients who received pembrolizumab: TPS ≥50% (39.5% vs. 32%), TPS ≥20% (33.4% vs 28.9%), and TPS ≥1% (27.3% vs 26.5%) compared with chemotherapy. Similarly, pembrolizumab showed superior duration of response in all three groups: TPS ≥50% (20.2 vs 10.8 months), TPS ≥20% (20.2 vs 8.3 months), and TPS ≥1% (20.2 vs 8.3 months).

In addition, these patients experienced fewer severe adverse events (AEs; 17.8% vs. 41%). Treatment-related AEs occurred more often in those who received chemotherapy (89.9% vs 62.7%) compared with pembrolizumab, which led to discontinuation in 9.4% and 9% of patients, respectively.

Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. Presented at: 2018 ASCO Annual Meeting; June 1-5; Chicago. Abstract LBA4.