Application to Expand Pembrolizumab NSCLC Indication Submitted to the FDA

A supplemental new drug application for pembrolizumab for advanced non-small cell lung cancer (NSCLC) with PD-L1 expression on ≥1% of tumors cells has been submitted to the FDA.

According to Merck, developer of the PD-1 inhibitor, the application is based on an overall survival (OS) improvement with pembrolizumab versus chemotherapy in NSCLC in the open-label phase II/III KEYNOTE-010 trial. The aim of the sNDA is to provide supporting evidence to convert the accelerated approval granted to the medication in October 2015 to a full indication. Additionally, the new data could lessen the PD-L1 expression threshold to ≥1% of cells. A standard FDA review is scheduled to last 10 months.

“The data from KEYNOTE-010 demonstrated an overall survival benefit in patients with PD-L1 expression on 1% or more of the cancer cells,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said in a statement. “We look forward to working with the FDA over the course of the application review process and remain committed to advancing our broad clinical program for cancers where patients are in need of new options, including lung cancer.”

In the KEYNOTE-010 study, 1034 patients with PD-L1 expression on at least 1% of tumor cells were randomized in a 1:1:1 ratio to receive docetaxel at 75 mg/m2 (n = 343) or pembrolizumab at 2 mg/kg (n = 345) or a larger experimental dose of 10 mg/kg (n = 346). All treatments were administered every 3 weeks.

All patients enrolled in the study had progression on at least 2 cycles of a prior platinum-containing chemotherapy, and had an ECOG performance status between 0 and 1. The primary endpoints of the study were OS and progression-free survival (PFS) in the full population and those with PD-L1 expression on greater than 50% of tumor cells. PD-L1 was confirmed by immunohistochemistry using the companion diagnostic test PD-L1 IHC 22C3 PharmDx.

The median OS was 10.4 months with the FDA-approved dose of 2 mg/kg of pembrolizumab compared with 8.5 months with docetaxel in those with >1% PD-L1 expressing NSCLC (HR, 0.71; 95% CI, 0.58-0.88; P = .0008). With the larger dose of pembrolizumab (10 mg/kg), median OS was 12.7 months, representing a 39% reduction in the risk of death versus docetaxel (HR, 0.61; 95% CI, 0.49-0.75; P <.0001).

After a median follow-up of 13.1 months, the estimated 1-year OS rates were 43.2% and 52.3% for the 2 mg/kg and 10 mg/kg doses, respectively. The 1-year OS rate with docetaxel was 34.6%.

In those with ≥50% PD-L1 expression, the median OS with the 2 mg/kg dose of pembrolizumab was 14.9 months versus 8.2 months with docetaxel (HR, 0.54; 95% CI, 0.38-0.77; P = .0002). In the 10 mg/kg arm, the median OS was 17.3 months, representing a 50% improvement over docetaxel (HR, 0.50; 95% CI, 0.36-0.70; P <.0001).

Median PFS was not significantly improved with pembrolizumab in those with >1% PD-L1 expression, possibly due to pseudoprogression. In this group, median PFS was 3.9 months with the 2 mg/kg dose of pembrolizumab versus 4.0 months with docetaxel (HR, 0.88; 95% CI, 0.74-1.05; P = .07). For the 10 mg/kg dose of pembrolizumab, median PFS was 4.0 months (HR vs docetaxel, 0.79; 95% CI, 0.66-0.94; P = .004). The P value for significance was set as <.001.

In those with ≥50% PD-L1 expression, media PFS was 5.0 and 5.2 months, with the 2 mg/kg and 10 mg/kg doses of pembrolizumab, respectively. With docetaxel, median PFS was 4.1 months. Overall, there was a statistically significant 41% reduction in the risk of progression or death for both doses of pembrolizumab over chemotherapy (P <.0001).

Grade 3 to 5 treatment-related adverse events (AEs) were less frequently observed with pembrolizumab compared with docetaxel. In the 2-mg/kg arm, 13% of patients experienced a grade 3 to 5 AE versus 35% in the docetaxel arm. In the 10-mg/kg arm, 16% of patients had a grade 3/5 AE.

The most frequently observed grade 3 to 5 AEs with pembrolizumab were decreased appetite, fatigue, nausea, rash, diarrhea, asthenia, stomatitis, and anemia. Three treatment-related deaths occurred within each pembrolizumab arm. The most common immune-mediate AEs with pembrolizumab in the 2 mg/kg and 10 mg/kg arms, respectively, were hypothyroidism (8% and 8%), hyperthyroidism (4% and 6%), and pneumonitis (5% and 4%).

“This is an exciting time, and studies such as KEYNOTE-010 with Keytruda are paving the way to a better understanding of how to identify the right medicine for each patient,” senior author Roy S. Herbst, MD, the Ensign Professor of Medicine and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, said in a statement when the findings were released. “These study findings show Keytruda provided superior overall survival in patients with advanced lung cancer who had positive PD-L1 expression, and support its potential in the treatment of this disease.”

The accelerated approval for pembrolizumab in NSCLC was based on the phase I KEYNOTE-001 trial, in which the objective response rate with the drug was 41% among a subgroup of 61 patients with pretreated ≥50% PD-L1—expressing advanced NSCLC as determined by the 22C3 pharmDx diagnostic test. Response duration ranged from 2.1 to 9.1 months.

In addition to the NSCLC approval, pembrolizumab is also approved at a recommended dose of 2 mg/kg every 3 weeks for patients with unresectable or metastatic melanoma. The agent continues to be assessed across a variety of settings and various tumor types.


  1. Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial [Published Online December 19, 2015]. Lancet. doi:10.1016/S0140-6736(15)01281-7.