Pembrolizumab May Enhance Current Treatments for Esophagogastric Cancers

Advanced cancers of the stomach, esophagus, and gastroesophageal junction (collectively called esophagogastric cancers) have poor prognoses. A recent phase III trial showed that even in patients with esophagogastric cancers with ERBB2 (encoding HER2) amplification or HER2 protein overexpression, treatment with the anti-HER2 therapy trastuzumab plus standard-of-care cytotoxic chemotherapy resulted in a median overall survival of only 13.8 months. Based on evidence that anti–PD-1 could augment this treatment regimen, perhaps partially because preclinical data suggest that trastuzumab may upregulate PD-1 and/or PD-L1, Janjigian and colleagues conducted a phase II trial of the anti–PD-1 therapy pembrolizumab with trastuzumab plus chemotherapy (fluoropyrimidine plus a platinum-based drug) as a first-line treatment regimen in 37 patients with metastatic HER2-positive esophagogastric cancers. This open-label, nonrandomized, single-arm, single-center study met its primary endpoint of 70% of patients experiencing no progression after six months on the study treatment. Further, all patients with measurable disease exhibited tumor regression following treatment initiation, 17% of patients experienced a complete response, the median duration of response was 9.4 months, and the median overall survival was 27.3 months. Treatment-related adverse events (TRAE) occurred in 97% of patients, two of which (grade 3 nephritis) were serious and necessitated treatment discontinuation; however, no treatment-related deaths occurred. Immune-related TRAEs—including interstitial nephritis (8% of patients), transaminitis (5% of patients), and colitis (3% of patients)—resulted in discontinuation of pembrolizumab but continuation of trastuzumab plus chemotherapy in 11% of patients. Overall, the most common TRAEs were grade 1 to 2 paresthesia or peripheral sensory neuropathy, hyperglycemia, fatigue, anemia, and gastrointestinal side effects. In summary, the addition of pembrolizumab to trastuzumab plus chemotherapy appears safe and may have benefits in this patient population. As a result of these findings, a randomized, double-blinded, international phase III study of trastuzumab plus chemotherapy with pembrolizumab or placebo is now under way.

Janjigian YY, Maron SB, Chatila WK, Millang B, Chavan SS, Alterman C, et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol 2020;21:82–31.

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