Roger M. Perlmutter, MD, PhD
Pembrolizumab (Keytruda) extended overall survival (OS) versus docetaxel in previously treated patients with advanced non–small cell lung cancer (NSCLC) in the phase II/III KEYNOTE-010 trial, according to Merck, the manufacturer of the PD-1 inhibitor.
Earlier this month, pembrolizumab received an accelerated approval from the FDA for pretreated patients with advanced PD-L1+ NSCLC across all histologies. The drug was approved along with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, and is indicated for patients who progress on or after platinum-containing chemotherapy or EGFR
-targeted agents in patients harboring those mutations.
Based on the KEYNOTE-010 data, Merck plans to file for full regulatory approval from the FDA by the end of the year.
“The results from this trial provide part of a growing body of evidence supporting the potential of Keytruda in the treatment of non–small cell lung cancer,” said Roger M. Perlmutter, MD, president, Merck Research Laboratories. “Advancing the standard of care in cancer requires a collaborative effort, and we are grateful to the patients, institutions and caregivers who participated in this study. We look forward to sharing our complete data with the scientific community and with regulatory agencies in the near future.”
The international, open-label KEYNOTE-010 trial randomized 1034 patients with PD-L1+ NSCLC to the FDA-approved dose of 2 mg/kg of pembrolizumab, an elevated dose of 10 mg/kg of the PD-1 inhibitor, or 75 mg/m2
of docetaxel. All three regimens were administered at 3-week intervals.
All patients had progressed following platinum-based chemotherapy. All patients expressed PD-L1 on >1% of their tumor cells, and the researchers also assessed a subgroup of “strongly PD-L1–positive” patients, defined as those expressing PD-L1 on ≥50% of their tumor cells.
The primary endpoint was OS, with progression-free survival (PFS) as a secondary outcome measure. Tumor response was measured by RECIST 1.1 at week 12, and then every 6 weeks thereafter.
Pembrolizumab improved overall survival versus docetaxel in both the standard and higher-dose arms, as well as both in the overall study population and in the strongly PD-L1–positive subgroup. PFS was also improved with both doses of pembrolizumab versus chemotherapy in the high PD-L1 expressers. Among patients with PD-L1 expression <50%, PFS was improved with pembrolizumab, but the difference was not statistically significant.
Adverse events with pembrolizumab in KEYNOTE-010 were consistent with the safety profile reported in other studies of the drug in advanced NSCLC, according to Merck.
The accelerated approval for pembrolizumab in lung cancer was based on the phase I KEYNOTE-001 trial, in which the overall response rate (ORR) with the drug 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.
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.
Incidents of Guillain-Barre Syndrome have been reported across clinical studies involving pembrolizumab, and the drug is contraindicated in pregnant or breastfeeding women.
Pembrolizumab was the second FDA-approved PD-1 inhibitor in lung cancer. The anti–PD-1 agent nivolumab (Opdivo) was approved in March 2015 for patients with squamous NSCLC who progress on or after platinum-based chemotherapy. Earlier this month, the FDA expanded nivolumab’s approval in NSCLC to include patients with nonsquamous disease who progress on or following platinum-based chemotherapy, or EGFR- or ALK-targeted agents in patients harboring those mutations.
Nivolumab’s approval is not limited to PD-L1–positive NSCLC patients. A diagnostic for PD-L1, the IHC 28-8 pharmDx test, was approved along with nivolumab, to help guide treatment decisions for patients with both histologies of NSCLC. The test is a "complementary," not a "companion," diagnostic, however, meaning its use is not mandated prior to administering nivolumab.