Pembrolizumab Approved by FDA as First-Line Therapy for PD-L1-Expressing NSCLC


Pembrolizumab gains an FDA approval for frontline therapy of non-small cell lung cancer (NSCLC).

Edward B. Garon, MD

Edward B. Garon, MD

Edward B. Garon, MD

The PD-L1 inhibitor immunotherapy pembrolizumab (Keytruda) has received FDA approval to treat patients with metastatic non­—small cell lung cancer (NSCLC) in the frontline setting. The approval applies to patients whose tumors have ≥50% PD-L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations.

“It is exciting to have an expanded group of patients who are now eligible for this drug," Edward B. Garon, MD, director, Thoracic Oncology, Jonsson Comprehensive Cancer Center, UCLA, said in a statement. "What is particularly encouraging is that we are now able to select, based on features in the tumor, approximately a quarter of advanced lung cancer patients who can receive immunotherapy as their initial treatment. This will allow them to live longer while delaying, and in some cases potentially avoiding, the side effects of traditional chemotherapy.”

The FDA’s approval October 24 is based on data from the phase III KEYNOTE-024 trial, in which single-agent pembrolizumab reduced the risk of death by 40% and improved progression-free survival (PFS) by 4.3 months compared with doublet chemotherapy for untreated patients with advanced NSCLC with PD-L1 expression on ≥50% of cells.1,2

Along with the frontline approval, the FDA also authorized an update to pembrolizumab’s label to include data from the KEYNOTE-010 trial,3 which examined the PD-1 inhibitor in the second-line setting and beyond for patients with NSCLC and PD-L1 expression levels of ≥1% who have progressed on platinum-based chemotherapy and EGFR- or ALK-targeted therapy for individuals harboring those aberrations. The action converts the accelerated approval pembrolizumab previously received in this setting to a full approval.

KEYNOTE-024 screened 1934 patients with NSCLC for eligibility, of which 1653 yielded appropriate tissue for testing. Overall, 30.2% of samples expressed PD-L1 on ≥50% of cells by immunohistochemistry. Patients with EGFR- or ALK-positive tumors were excluded. Of those who met the PD-L1 expression requirements, 305 were randomized to receive pembrolizumab (n = 154) or chemotherapy (n = 151), which most commonly included carboplatin plus pemetrexed (n = 67). In the chemotherapy arm, 46 patients went on to receive maintenance therapy with pemetrexed and an additional 66 patients (43.7%) crossed over to the pembrolizumab arm following progression.

Patient characteristics were well balanced between arms, except for smoking status and the incidence of brain metastases. Overall, there were more patients in the chemotherapy arm who had never smoked (12.6%) versus the pembrolizumab arm (3.2%). Additionally, more patients in the pembrolizumab arm had brain metastases (11.7%) compared with the chemotherapy group (6.6%). However, these differences were not deemed statistically significant.

The median age of patients in the pembrolizumab arm was 64.5 years, and 59.7% were male. Twenty-two percent were current smokers, and 64.3% had an ECOG performance status of 1. The most common histology was nonsquamous (81.2%).

Pembrolizumab was administered at a fixed 200 mg IV infusion every 3 weeks. In the chemotherapy arm, patients could receive 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 estimated 6-month overall survival (OS) rate was 80.2% with pembrolizumab versus 72.4% with chemotherapy (HR, 0.60; 95% CI, 0.41-0.89; P = .005). The median PFS was 10.3 months with pembrolizumab versus 6.0 months with chemotherapy (HR, 0.50; 95% CI, 0.37-0.68; P <.001).

The 6-month PFS rate was 62.1% in the pembrolizumab arm versus 50.3% with chemotherapy. This benefit remained consistent across subgroups. At the time of the analysis, median OS had not yet been reached. The objective response rate with pembrolizumab was 44.8% compared with 27.8% with chemotherapy. The duration of response was not reached in the immunotherapy arm versus 6.3 months with chemotherapy.

In those with squamous histology (n = 56), there was a 65% reduction in the risk of progression or death with pembrolizumab versus chemotherapy (HR, 0.35; 95% CI, 0.17-0.71). In the nonsquamous group (n = 249), the risk of disease progression or death was reduced by 45% with the immunotherapy (HR, 0.55; 95% CI; 0.39-0.76).

The pembrolizumab benefit was less pronounced when compared with platinum-based chemotherapy regimens that contained pemetrexed (HR, 0.63; 95% CI, 0.44-0.91). When pemetrexed was omitted, there was a 71% reduction in the risk of progression or death with pembrolizumab (HR, 0.29; 95% CI, 0.17-0.50).

“Keytruda improved survival, compared to traditional chemotherapy, in patients with non—small cell lung cancer whose tumors express high levels of PD-L1,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, the manufacturer of pembrolizumab, said in a statement. “The approval of Keytruda for the first-line treatment of metastatic non-small cell lung cancer has the potential to change the treatment landscape for these patients.”

Immune-Related Adverse Events

Fewer treatment-related adverse events (AEs) were seen with the PD-1 inhibitor versus chemotherapy (73.4% vs 90%). Grade 3 to 5 AEs were significantly less common with pembrolizumab (26.6%) compared with chemotherapy (53.3%). Serious AEs were similar between the 2 arms for pembrolizumab and chemotherapy, respectively (21.4% vs 20.7%). AEs led to treatment discontinuation for 7.1% of patients in the pembrolizumab arm versus 10.7% of those receiving chemotherapy.

The most common treatment-related AEs of any severity for pembrolizumab were diarrhea (14.3%), fatigue (10.4%), and pyrexia (10.4%). With chemotherapy, the most common AEs of any-grade were anemia (44%), nausea (43.3%), and fatigue (28.7%). Immune-mediated AEs occurred in 29.2% of those treated with pembrolizumab versus 4.7% of those in the chemotherapy arm.

“With this new indication, Keytruda can now be a first treatment option instead of chemotherapy for patients with metastatic non&shy;—small cell lung cancer whose tumors express high levels of PD-L1,” Roy S. Herbst, MD, PhD, professor of medicine and chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven, said in a statement. “These data reaffirm the importance of testing for PD-L1 expression in non&shy;–small cell lung cancer in order to identify those patients who are most likely to benefit from treatment with Keytruda.”


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 either 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 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 2-mg/kg dose 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 = .001). 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 <.001).

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 = .001). 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 <.001).

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, 0.73-1.04; 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 5.2 months with both the 2-mg/kg and 10-mg/kg doses of pembrolizumab, and 4.1 months with docetaxel. Overall, there was a statistically significant 42% reduction in the risk of progression or death for both doses of pembrolizumab over chemotherapy (HR, 0.58; 95% CI, 0.43-0.77; P = .001).

Grade 3 to 5 treatment-related 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%).


  • Reck M, Rodriguez-Abreu D, Robinson AG, et al. KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA8.
  • Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1—Positive Non–Small-Cell Lung Cancer [published online October 9, 2016]. N Engl J Med. DOI: 10.1056/NEJMoa1606774.
  • 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. Lancet. 2016;387(10027):1540-1550.

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