The EMA's Committee for Medicinal Products for Human Use has granted a positive opinion for use of pembrolizumab (Keytruda) as a treatment for patients with locally advanced or metastatic PD-L1-positive non–small cell lung cancer.
Roger Dansey, MD
The EMA's Committee for Medicinal Products for Human Use (CHMP) has granted a positive opinion for use of pembrolizumab (Keytruda) as a treatment for patients with locally advanced or metastatic PD-L1-positive non—small cell lung cancer (NSCLC) following at least 1 chemotherapy regimen.
The recommendation is based on data from the KEYNOTE-010 and KEYNOTE-001 trials. Receiving the positive opinion suggests pembrolizumab is likely to be approved for this indication in the EU when the European Commission issues its final decision, which is expected by the third quarter of 2016.
“This news marks an important step in making Keytruda available for appropriate patients suffering from locally advanced or metastatic non—small cell lung cancer,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said in a statement. “We are grateful to patients and investigators around the world who participated in these studies and who are helping to advance this important new treatment.”
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 overall survival (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 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 = .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%).
In the KEYNOTE-001 trial the overall response rate (ORR) with pembrolizumab was 41% among a subgroup of 61 patients with pretreated PD-L1—positive advanced NSCLC as determined by the 22C3 pharmDx diagnostic test. Response duration ranged from 2.1 to 9.1 months. A survival improvement has yet to be demonstrated in a clinical trial, and the accelerated approval is contingent upon the eventual outcomes of confirmatory studies.
Overall, the KEYNOTE-001 trial included 495 previously treated and treatment-naïve patients with advanced or metastatic NSCLC. The total population comprised a training set of 182 patients and a validation set of 313 patients. Pembrolizumab was administered at three dosages: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. The researchers assessed patient responses every 9 weeks. The ORR for the entire study population was nearly 20%.
Patients in the 61-patient subgroup on which the approval was based expressed PD-L1 on ≥50% of their tumor cells, and had progressed after receiving platinum-based chemotherapy or targeted agents for ALK- or EGFR-mutation positive patients. Patients received single-agent pembrolizumab at 10 mg/kg every 2 (n = 27) or 3 (n = 34) weeks until progression or unacceptable toxicity. The primary endpoints of the trial were overall response and duration of response.
Twenty-one of the 25 (84%) responses in this group had ongoing responses, including 11 patients with ongoing responses of ≥6 months. The dosing schedule of 2 weeks versus 3 weeks did not impact ORR and duration of response.
Activity with pembrolizumab was also observed in limited follow-up from a separate subgroup of PD-L1­—positive patients (n = 25), who received a dose of 2 mg/kg every 3 weeks. The FDA approval in NSCLC is for this lower 2 mg/kg dose.
Fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%) were the most common adverse events (AEs) with pembrolizumab. Severe immune-mediated side effects included pneumonitis, colitis, hepatitis, hypophysitis, hyperthyroidism, hypothyroidism, type 1 diabetes mellitus, and nephritis. AE-related discontinuations and serious adverse reactions occurred in 14% and 38% of patients, respectively.
In the United States, the FDA granted an accelerated approval to pembrolizumab in October 2015 as a treatment for patients with pretreated advanced NSCLC across all histologies whose tumors express PD-L1. The indication, which was based on the KEYNOTE-001 data, is specifically for patients who progressed on or after platinum-containing chemotherapy or EGFR-or ALK-targeted agents in patients harboring those mutations. The FDA is currently reviewing a supplemental new drug application from BMS based on KEYNOTE-010 that is intended to convert the accelerated pembrolizumab NSCLC approval into a full approval.