The FDA has approved pembrolizumab, an anti-PD-1 therapy, for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) >=1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy.
This indication is approved under the FDA's accelerated approval regulations based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
The accelerated approval for pembrolizumab was based on data from a global, multicenter, non-randomized, open-label, multi-cohort trial, KEYNOTE-059, that enrolled 259 patients with gastric or GEJ adenocarcinoma who progressed on at least two prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet; HER2/neu-positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients with active autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible.
Patients received pembrolizumab at a dose of 200 mg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6-9 weeks. The major efficacy outcome measures were objective response rate (ORR) according to RECIST 1.1, as assessed by independent central review, and duration of response.
Among the 259 patients, 55 percent (n=143) had tumors that expressed PD-L1 with a CPS >=1 and microsatellite stable tumor status or undetermined microsatellite instability (MSI) or mismatch repair status. The baseline characteristics of these 143 patients were: median age 64 years (47% age 65 or older); 77 percent male; 82 percent white, 11 percent Asian; and ECOG performance status of 0 (43%) and 1 (57%). Eighty-five percent had M1 disease and 7 percent had M0 disease. Fifty-one percent had two and 49 percent had three or more prior lines of therapy in the recurrent or metastatic setting.
For the 143 patients, the ORR was 13.3 percent (95% CI: 8.2, 20.0)-with a complete response rate of 1.4 percent and a partial response rate of 11.9 percent. Among the 19 responding patients, the duration of response ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of 6 months or longer and five patients (26%) having responses of 12 months or longer.
Among the 259 patients, seven (3%) had tumors that were determined to be MSI-High. An objective response was observed in four patients, including one complete response. The duration of response ranged from 5.3+ to 14.1+ months.
Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or non-small cell lung cancer. The most common adverse reactions for pembrolizumab (reported in >=20% of patients) were fatigue, musculoskeletal pain, decreased appetite, pruritis, diarrhea, nausea, rash, pyrexia, cough, dyspnea, and constipation.