Richard Pazdur, MD
The FDA granted an accelerated approval to pembrolizumab (Keytruda) as a treatment for patients with pretreated advanced non–small cell lung cancer (NSCLC) across all histologies whose tumors express PD-L1. The PD-1 inhibitor was approved along with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, and is indicated for patients who progressed on or after platinum-containing chemotherapy or EGFR-
targeted agents in patients harboring those mutations.
The approval was based on data from 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. 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.
“Our growing understanding of underlying molecular pathways and how our immune system interacts with cancer is leading to important advances in medicine,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Keytruda gives physicians the ability to target specific patients who may be most likely to benefit from this drug.”
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.
“This important news means that we now have a new immunotherapy option to help patients with squamous and nonsquamous metastatic non–small cell lung cancer with disease progression on or after platinum-containing chemotherapy and whose tumors express PD-L1. The durability of response with immune checkpoint inhibitors is exciting and has given new options for our patients,” Naiyer Rizvi, MD, director of Thoracic Oncology and director of Immunotherapeutics, New York Presbyterian Hospital, Columbia University Medical Center, and a principal investigator for the Keytruda lung cancer clinical program said in a statement. “And, with the approval of the first PD-L1 companion diagnostic, we can identify patients who are more likely to experience benefit from Keytruda.”
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 is now the second FDA-approved PD-1 inhibitor in lung cancer, and first across all NSCLC histologies. The PD-1 agent nivolumab (Opdivo) was approved in March 2015 for patients with NSCLC who have progressed on or after platinum-based chemotherapy; however, the indication is limited to individuals with squamous histology.
Nivolumab recently received an FDA priority review designation in the nonsquamous NSCLC setting. Under the expedited process, the FDA’s decision deadline is January 2, 2016.
Beyond lung cancer, pembrolizumab is also approved for patients with advanced melanoma.