FDA Approves Merck & Co.’s KEYTRUDA (Pembrolizumab) As First-Line Combination Therapy With Pemetrexed And Carboplatin For Patients With Metastatic Nonsquamous Non-Small Cell Lung Cancer (NSCLC), Irrespective Of PD-L1 Expression

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, in combination with pemetrexed (brand name Alimta®) and carboplatin (pem/carbo), a commonly used chemotherapy regimen, for the first-line treatment of metastatic nonsquamous NSCLC, irrespective of PD-L1 expression. Under the FDA’s accelerated approval regulations, this indication is approved based on tumor response rate and progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

The approval was based on data from KEYNOTE-021, Cohort G1, in 123 previously untreated patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations and irrespective of PD-L1 expression. In this trial, KEYTRUDA + pem/carbo demonstrated an objective response rate (ORR) that was nearly double the ORR of pem/carbo alone (55 percent [95% CI: 42, 68] compared to 29 percent [95% CI: 18, 41], respectively; all responses were partial responses). Among patients who received KEYTRUDA + pem/carbo, 93 percent had a duration of response of six months or more (range 1.4+ to 13.0+ months) compared to 81 percent who received pem/carbo alone (range 1.4+ to 15.2+ months). In addition, findings demonstrated an improvement in PFS (HR 0.53 [95% CI, 0.31-0.91; p=0.0205]), with a median PFS of 13.0 months (95% CI, 8.3-not estimable) for patients treated with KEYTRUDA + pem/carbo compared to 8.9 months (95% CI, 4.4-10.3) with pem/carbo alone.

Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered when appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions; for Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA (pembrolizumab). Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated and infusion-related adverse reactions and use in pregnancy, see “Selected Important Safety Information” below.

The improved responses seen with the KEYTRUDA plus pemetrexed/carboplatin regimen are significant, and highlight the importance of finding new approaches that address the unmet needs of patients with metastatic nonsquamous non-small cell lung cancer,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “Today’s approval further supports our commitment to improve the lives of people with cancer.”

This approval marks an important milestone in the treatment of lung cancer. Now, pembrolizumab in combination with pemetrexed and carboplatin can be prescribed in the first-line setting for patients with metastatic nonsquamous non-small cell lung cancer, irrespective of PD-L1 expression,” said Dr. Corey Langer, director of thoracic oncology and professor of medicine at the Hospital of the University of Pennsylvania. “Physicians should continue to use each patient’s individual characteristics – including biomarker status, histology, and other clinical factors – to determine the best treatment plan for each person.”

The combination therapy indication makes KEYTRUDA an option for more patients. KEYTRUDA is the only anti-PD-1 approved in the first-line setting as both monotherapy and combination therapy for appropriate patients with metastatic NSCLC. KEYTRUDA is approved as monotherapy in the first-line setting for patients with metastatic NSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] =50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. KEYTRUDA as monotherapy is also indicated for the second-line or greater treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS =1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

The combination of this immunotherapy with pemetrexed and carboplatin is more good news for patients,” said Bonnie J. Addario, a lung cancer survivor and founder of the Bonnie J. Addario Lung Cancer Foundation. “Congratulations to Merck and the FDA for moving so swiftly on this important addition to our patients’ options for treatment. With this approval, hope for lung cancer patients continues to improve.”

Data Supporting the Approval

The efficacy of KEYTRUDA (pembrolizumab) was investigated in patients enrolled in the open-label, multicenter, multi-cohort KEYNOTE-021 study; the efficacy data are limited to patients with metastatic nonsquamous NSCLC randomized within the single cohort (Cohort G1). The KEYNOTE-021G1 trial was conducted in collaboration with Eli Lilly and Company, the maker of pemetrexed. The key eligibility criteria for this cohort were locally advanced or metastatic nonsquamous NSCLC, regardless of tumor PD-L1 expression status, and no prior systemic treatment for metastatic disease. Patients with autoimmune disease that required systemic therapy within two years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Patients in KEYNOTE-021G1 were randomized to receive KEYTRUDA + pem/carbo (n=60) or pem/carbo alone (n=63). Patients in the KEYTRUDA combination arm received KEYTRUDA (200 mg), pemetrexed (500 mg/m2), and carboplatin (AUC 5 mg/mL/min) every three weeks for four cycles followed by KEYTRUDA every three weeks. In the control arm, patients received pemetrexed (500 mg/m2) and carboplatin (AUC 5 mg/mL/min) alone for four cycles. At the investigator’s discretion, maintenance pemetrexed (500 mg/m2) every three weeks was permitted in both treatment arms. Treatment with KEYTRUDA continued until Response Evaluation Criteria in Solid Tumors (RECIST) 1.1-defined progression of disease as determined by blinded independent central review (BICR), unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.

The major efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Additional efficacy outcome measures were PFS as assessed by BICR using RECIST 1.1, duration of response, and overall survival (OS).

Findings from this cohort demonstrated an ORR with KEYTRUDA + pem/carbo of 55 percent (95% CI: 42, 68) compared to 29 percent (95% CI: 18, 41) for pem/carbo alone. KEYTRUDA in this combination also reduced the risk of disease progression or death by 47 percent (HR, 0.53 [95% CI, 0.31, 0.91]; p=0.0205).

Exploratory analyses found similar results in patients with or without PD-L1 expression, with an ORR in patients whose tumors did not express PD-L1 (TPS <1%) of 57 percent with KEYTRUDA + pem/carbo compared to 13.0 percent with pem/carbo alone; in patients with PD-L1 TPS =1%, the ORR was 54 percent with KEYTRUDA + pem/carbo compared to 38 percent with pem/carbo alone.

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