In a single-center phase II trial reported in The Lancet Oncology, Janjigian et al found that the addition of pembrolizumab to trastuzumab and chemotherapy showed activity in the first-line treatment of HER2-positive metastatic esophagogastric cancer.
The investigator-initiated trial enrolled 37 evaluable patients with gastric, esophageal, or gastroesophageal junction cancer at Memorial Sloan Kettering Cancer Center between November 2016 and January 2019. Patients were eligible to receive an initial induction cycle of pembrolizumab at 200 mg and an 8-mg/kg trastuzumab loading dose. In subsequent cycles, patients received oxaliplatin at 130 mg/m² or cisplatin at 80 mg/m² on day 1, capecitabine at 850 mg/m² twice a day for 2 weeks followed by 1 week off (or fluorouracil at 800 mg/m² per day on days 1–5), and pembrolizumab at 200 mg plus trastuzumab at 6 mg/kg on day 1 of each 3-week cycle.
The primary endpoint was 6-month progression-free survival. If 26 or more of the total 37 patients were free of progression at 6 months, the regimen was to be considered acceptable for further investigation.
Overall, 38% of patients had programmed cell death ligand 1 (PD-L1) expression of ≥ 1%, with all other patients having PD-L1–negative tumors or unknown status. Most patients received a chemotherapy regimen that included capecitabine (65%) and oxaliplatin (97%).
At data cutoff (August 2019), median follow-up among survivors was 13.0 months. The primary endpoint was achieved, with 26 (70%, 95% confidence interval [CI] = 54%–83%) of 37 patients remaining progression-free at 6 months. Median progression-free survival was 13.0 months (95% CI = 8.6 months–not reached).
Kaplan-Meier estimated median overall survival was 27.3 months (95% CI = 18.8 months–not reached), with a 12-month rate of 80%. Among 35 patients with measurable disease, objective response was observed in 32 (91%) (including complete response in 6 [17%]) and stable disease was observed in 3 (9%), yielding a disease control rate of 100%.
The most common treatment-related adverse event of any grade was neuropathy (97%). The most common treatment-related grade 3 or 4 adverse events were lymphocytopenia (24%), decreased electrolytes (16%), and anemia (11%). Treatment-related grade 3 or 4 serious adverse events occurred in two patients (grade 3 nephritis, leading to treatment discontinuation in both). Overall, 10% of patients had treatment-related adverse events leading to treatment discontinuation. Immune-related adverse events included interstitial nephritis (8%), elevated transaminases (5%), and colitis (3%), and required discontinuation of pembrolizumab in four patients (11%). No treatment-related deaths were observed.
The investigators concluded, “Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomized phase III clinical trial assessing the efficacy and safety of pembrolizumab vs placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic esophagogastric cancer is underway (KEYNOTE-811).”
Yelena Y. Janjigian, MD, of the Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Merck & Co. For full disclosures of the study authors, visit thelancet.com.