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- or ALK-targeted agents in patients harboring those mutations.
The FDA granted an accelerated approval to Keytruda (pembrolizumab) 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- or ALK-targeted agents in patients harboring those mutations.
The approval was based on data from the phase 1 KEYNOTE-001 trial, in which the overall response rate with the drug was 41 percent (25 patients) 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 clincial trial, and the acclerated approval is contingent upon the eventual outcomes of confirmatory studies.
“We are pleased that today’s approval of Keytruda provides physicians and patients with a new anti-PD-1 immunotherapy option to help fight this deadly disease,” Andrea Ferris, president and chairman, LUNGevity Foundation, said in a statement. “It is an exciting time as more treatment options are becoming available that help to combat cancer by harnessing the power of the body’s own immune system.”
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. Keytruda was administered at three dosages: 2 mg/kg every three weeks, 10 mg/kg every three weeks or 10 mg/kg every two weeks. The researchers assessed patient responses every nine weeks.
Patients in the 61-patient subgroup on which the approval was based expressed PD-L1 on at least 50 percent 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 two (27 patients) or three (34 patients) weeks until progression or unacceptable toxicty. The primary endpoints of the trial were overall response and duration of response.
Twenty-one of the 25 (84 percent) responses in this group had ongoing responses, including 11 patients with ongoing responses of at least six months. The dosing schedule of two weeks versus three weeks did not impact overall response rate and duration of response.
Activity with pembrolizumab was also observed in limited follow-up from a separate subgroup of PD-L1 positive patients (25 patients), who received a dose of 2 mg/kg every three 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 non-squamous 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, 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. “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 percent), decreased appetite (25 percent), dyspnea (23 percent) and cough (29 percent) were the most common side effects with Keytruda. Severe immune-mediated side effects included pneumonitis, colitis, hepatitis, hypophysitis, hyperthyroidism, hypothyroidism, type 1 diabetes mellitus and nephritis. Adverse event-related discontinuations and serious adverse reactions occurred in 14 percent and 38 percent 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.
Keytruda is now the second FDA-approved PD-1 inhibitor in lung cancer, and first across all NSCLC histologies. The PD-1 agent Opdivo (nivolumab) 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.
“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, 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.”
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.
Beyond lung cancer, Keytruda is also approved for the treatment of patients with advanced melanoma.