Pembrolizumab Approved by FDA for Lower PD-L1 Cutoff in NSCLC

The approval for&nbsp;pembrolizumab (Keytruda) has been expanded to include the&nbsp;frontline treatment of patients with stage III non&ndash;small cell lung cancer, who are ineligible for surgery or definitive chemoradiation, or metastatic NSCLC, with a PD-L1 expression level of &ge;1% and do not harbor <em>EGFR</em> or <em>ALK</em> aberrations.

The indication for pembrolizumab (Keytruda) has been expanded by the FDA to include the frontline treatment of patients with stage III non—small cell lung cancer (NSCLC) who are ineligible for surgery or definitive chemoradiation, or metastatic NSCLC, with a PD-L1 expression (tumor proportion score [TPS]) level of ≥1% and do not harborEGFRorALKaberrations.1

Pembrolizumab monotherapy was previously indicated in the first-line setting for patients with metastatic NSCLC and TPS ≥50% whose tumors do not harborEGFRorALKabnormalities.

In findings from the phase III KEYNOTE-042 trial, on which the approval is based, treatment with frontline pembrolizumab resulted in a median overall survival (OS) of 16.7 months 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= .0036).2In an exploratory analysis that examined all patients with PD-L1 TPS of 1% to 49%, the median OS was 13.4 months and 12.1 months with pembrolizumab and chemotherapy, respectively (HR, 0.92; 95% CI, 0.77-1.11).

The agency granted pembrolizumab a priority review designation in September 2018, which made the original action date January 11, 2019; however, the FDA extended the review period for the sBLA in December 2018, making the new action date April 11, 2019. Merck (MSD), the developer of the PD-1 inhibitor, previously reported in a press release that the extension would allow ample time for the FDA to review additional information the company had submitted for the sBLA.

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

Patients were stratified 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 or 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. The primary endpoint was OS.

Following a median follow-up of 12.8 months, 13.7% of patients were still receiving treatment with pembrolizumab and 4.9% were receiving the PD-1 inhibitor as maintenance therapy.

Results showed that OS did correlate with greater levels of PD-L1 expression: TPS ≥50% (20 vs 12.2 months; HR, 0.69; 95% CI, 0.56-0.85;P= .0006), TPS ≥20% (17.7 vs 13.0 months; HR, 0.77; 95% CI, 0.64-0.92;P= .004).

Additionally, 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 superiority with duration of response in all 3 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).

Regarding safety, 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%) versus pembrolizumab, which led to discontinuation rates of 9.4% and 9% of patients, respectively.


  1. FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS &ge;1%). FDA. Published April 11, 2019. Accessed April 11, 2019.
  2. 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) &ge; 1%: Open-label, phase 3 KEYNOTE-042 study. Presented at: 2018 ASCO Annual Meeting; June 1-5; Chicago. Abstract LBA4.