FDA Lowers Pembrolizumab PD-L1 Cutoff in NSCLC, Expands Approval to Stage III

The FDA has expanded the approval for pembrolizumab monotherapy for the frontline treatment of patients with stage III non–small cell lung cancer, who are ineligible for surgery or definitive chemoradiation, or metastatic NSCLC, with a PD-L1 expression (tumor proportion score) level of ≥1% and do not harbor EGFR or ALK aberrations.

The FDA has expanded the approval for pembrolizumab (Keytruda) monotherapy for 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 harbor EGFR or ALK aberrations.1

The approval is based on findings from the phase III KEYNOTE-042 trial, which showed that frontline pembrolizumab led to 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).2 In 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 KEYNOTE-042 trial demonstrated a survival benefit with Keytruda monotherapy across histologies in certain patients with stage III or metastatic non—small cell lung cancer whose tumors expressed PD-L1 in at least 1% of tumor cells," said Gilberto Lopes, MD, associate director for global oncology at the Sylvester Comprehensive Cancer Center at the University of Miami, in a press release. "As a practicing oncologist, having additional options available for patients is important in the rapidly evolving treatment landscape for lung cancer, which remains the leading cause of cancer death in the United States."

The agency granted the priority review designation in September 2018, making the original action date January 11, 2019; however, in December 2018, the FDA extended the review period for the sBLA, making the new 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.

Single-agent pembrolizumab was previously indicated in the first-line setting for patients with metastatic NSCLC and TPS ≥50% whose tumors do not harbor EGFR or ALK abnormalities.

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).

While median progression-free survival with pembrolizumab was higher in patients with TPS >50% at 7.1 months compared with 6.4 months with chemotherapy (HR, 0.81; 95% CI, 0.67-0.99), it was lower in the TPS >1% group, at 5.4 with pembrolizumab and 6.5 months with chemotherapy (HR, 1.07; 95% CI, 0.94-1.21).

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.

"This expanded first-line indication now makes Keytruda monotherapy an option for more patients with non—small cell lung cancer, including those for whom combination therapy may not be appropriate," said Jonathan Cheng, MD, vice president, oncology clinical research, Merck Research Laboratories.


  1. FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥1%). FDA. Published April 11, 2019. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm635857.htm. 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) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. Presented at: 2018 ASCO Annual Meeting; June 1-5; Chicago. Abstract LBA4.