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Pembrolizumab (Keytruda) Shines in Lung Cancer Studies

FDA approval decision scheduled for December

Positive results from two major studies of pembrolizumab (Keytruda, Merck), an anti-programmed death-1 (PD-1) therapy, in the first-line treatment of patients with metastatic non–small-cell lung cancer (NSCLC) have been announced at the European Society for Medical Oncology (ESMO) 2016 Congress.

The phase 3, randomized KEYNOTE-024 study evaluated pembrolizumab as monotherapy compared with standard-of-care platinum-based chemotherapy in the treatment of 305 patients with squamous and nonsquamous metastatic NSCLC. The patients had received no prior systemic chemotherapy treatment for their advanced disease; their tumors did not harbor an epidermal growth factor receptor (EGFR)-sensitizing mutation or ALK translocation, and their tumors expressed high levels of programmed death ligand-1 (PD-L1).

The patients were randomly assigned to receive a 200-mg fixed dose of pembrolizumab every three weeks (n = 154) or four to six cycles of the investigator’s choice of one of five platinum-based chemotherapy regimens (n = 151): carboplatin or cisplatin plus pemetrexed; carboplatin or cisplatin plus gemcitabine; or carboplatin plus paclitaxel. Pemetrexed maintenance therapy was permitted for patients with nonsquamous histologies. Patients assigned to the control arm had the option of crossing over to pembrolizumab upon disease progression. The median follow-up period was 11.2 months. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), the objective response rate (ORR), and safety.

The findings, published in the New England Journal of Medicine, demonstrated that pembrolizumab reduced the risk of disease progression or death by 50% compared with chemotherapy (hazard ratio [HR], 0.50; P < 0.001). The median PFS for pembrolizumab was 10.3 months compared with 6.0 months for chemotherapy. At six months, 62% of patients treated with pembrolizumab were alive and had no disease progression compared with 50% of those receiving chemotherapy.

In addition, treatment with pembrolizumab resulted in a 40% reduction in the risk of death compared with chemotherapy (HR, 0.60; P = 0.005); this finding included 66 patients (44%) in the chemotherapy arm who crossed over to receive pembrolizumab once their cancer had progressed. Further, the ORR was 45% for patients receiving pembrolizumab, including six complete responses, compared with 28% with chemotherapy, including one complete response.

Based on these results, pembrolizumab is the only anti–PD-1 therapy to demonstrate PFS and OS compared with chemotherapy for the first-line treatment of both squamous and nonsquamous NSCLC in patients whose tumors expressed high levels of PD-L1 and did not express EGFR or ALK genetic aberrations, according to Merck. Data from the KEYNOTE-24 study was submitted to the FDA, which granted a breakthrough therapy designation and priority review for pembrolizumab, with a target action date of December 24, 2016.

The multicenter, open-label, phase 1/2 KEYNOTE-021 trial evaluated the efficacy and safety of pembrolizumab in combination with pemetrexed and carboplatin compared with pemetrexed and carboplatin in a group of patients (cohort G) with metastatic, nonsquamous, EGFR- and ALK-negative NSCLC in the first-line treatment setting. The patients were randomly assigned to four cycles of pembrolizumab (200 mg plus carboplatin AUC 5 [5 mg/mL/min] plus pemetrexed 500 mg/m2 every three weeks) or carboplatin plus pemetrexed alone, followed by maintenance pemetrexed with or without pembrolizumab. Randomization was stratified by PD-L1 expression (positive or negative). Patients assigned to the chemotherapy arm were allowed to cross over to pembrolizumab monotherapy if they experienced disease progression. Treatment response was assessed every six weeks for the first 18 weeks; every nine weeks through the first year; and every 12 weeks in the second year. The primary endpoint was ORR; secondary endpoints included PFS, OS, and the duration of response.

In cohort G, pembrolizumab plus chemotherapy (carboplatin plus pemetrexed) achieved a 55% ORR compared with 29% for chemotherapy alone––the standard of care––and reduced the risk of disease progression or death by 47%. To date, pembrolizumab is the only anti–PD-1 therapy to demonstrate superior efficacy in combination with chemotherapy compared with chemotherapy alone in this cohort of NSCLC patients receiving first-line treatment, according to Merck. The data were published in Lancet Oncology.

Source: Merck; October 9, 2016.

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