Pembrolizumab Approved for Advanced NSCLC

FDA

The PD-1 inhibitor pembrolizumab (Keytruda) was approved by the FDA today for patients with pretreated advanced non—small cell lung cancer (NSCLC) across all histologies whose tumors express PD-L1.

FDA’s accelerated approval was based on data from the phase I KEYNOTE-001 trial, in which the overall response rate with the drug was 41% among a subgroup of 61 patients with PD-L1—positive tumors as determined by the PD-L1 IHC 22C3 pharmDx diagnostic test which also received FDA approval. The patients received 10 mg/kg of Keytruda every 2 or 3 weeks. Response duration ranged from 2.1 to 9.1 months. Patients in the subgroup had progressed after receiving platinum-based chemotherapy or targeted agents for ALK- or EGFR-mutation positive patients.

“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.

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 toxicty. 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 three 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.

“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.”

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.