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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Sunday, April 14, 2019

FDA Expands Pembrolizumab Indication for First-Line Treatment of NSCLC

The FDA has approved an expanded label for pembrolizumab, an anti-PD-1 therapy, as monotherapy for the first-line treatment of patients with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 (tumor proportion score [TPS] ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

The approval is based on results from the phase III KEYNOTE-042 trial, in which overall survival (OS) was sequentially tested as part of a pre-specified analysis plan. In the trial, pembrolizumab monotherapy demonstrated a statistically significant improvement in OS compared with chemotherapy alone in patients whose tumors expressed PD-L1 with a TPS ≥50 percent, with a TPS ≥20 percent, and then in the entire study population (TPS ≥1%). 

KEYNOTE-042 was a randomized, multi-center, open-label, active-controlled trial in patients with stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors expressed PD-L1 (TPS ≥1%) and who had not received prior systemic treatment for metastatic NSCLC.

Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within 26 weeks prior to initiation of study treatment were ineligible.

The study enrolled 1,274 patients who were randomized (1:1) to receive pembrolizumab 200 mg intravenously every 3 weeks (n=637) or investigator's choice of either of the following chemotherapy regimens (n=637):

  • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of six cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; or
  • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies

Treatment with pembrolizumab continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ)-defined progression of disease, unacceptable toxicity, or a maximum of 24 months.

The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50 percent NSCLC, the subgroup of patients with TPS ≥20 percent NSCLC, and the overall population with TPS ≥1 percent NSCLC. Additional efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) in the subgroup of patients with TPS ≥50 percent NSCLC, the subgroup of patients with TPS ≥20 percent NSCLC, and the overall population with TPS ≥1 percent NSCLC as assessed by a blinded independent central radiologists' (BICR) review according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS ≥20 percent NSCLC were intermediate between the results of those with PD-L1 TPS ≥1 percent and those with PD-L1 TPS ≥50 percent. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49 percent NSCLC, the median OS was 13.4 months (95% CI, 10.7-18.2) for the KEYTRUDA group and 12.1 months (95% CI, 11.0-14.0) in the chemotherapy group, with an HR of 0.92 (95% CI, 0.77-1.11).

In KEYNOTE-042, the safety of pembrolizumab was investigated in patients with PD-L1 expressing, previously untreated stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC. Pembrolizumab was discontinued for adverse reactions in 19 percent of 636 patients. The most common adverse reactions resulting in permanent discontinuation of pembrolizumab were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%).

Adverse reactions leading to interruption of pembrolizumab occurred in 33 percent of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of pembrolizumab (≥2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (≥2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) with pembrolizumab A was fatigue (25%).

"The KEYNOTE-042 trial demonstrated a survival benefit with [pembrolizumab] monotherapy across histologies in certain patients with stage III or metastatic non-small cell lung cancer whose tumors expressed PD-L1 in at least 1 percent of tumor cells," said Dr. Gilberto Lopes, Associate Director for Global Oncology at the Sylvester Comprehensive Cancer Center at the University of Miami. "As a practicing oncologist, having additional options available for patients is important in the rapidly evolving treatment landscape for lung cancer, which remains the leading cause of cancer death in the U.S."

Pembrolizumab was the first anti-PD-1 therapy in metastatic NSCLC approved in the first-line setting as combination therapy or monotherapy.