Immunotherapy-Based Triplet Highly Active in Frontline HER2+ Esophagogastric Cancer

Yelena Y. Janjigian, MD

Pembrolizumab (Keytruda) combined with trastuzumab (Herceptin) and chemotherapy demonstrated promising clinical activity in patients with HER2-positive metastatic esophagogastric cancer, according to findings from a phase 2 trial published in the Lancet Oncology.

Among 37 evaluable patients with gastric, esophageal, or gastroesophageal junction (GEJ) cancer, 26 (70%) remained progression-free at 6 months, achieving the primary end point of the trial. The overall response rate (ORR) was 91% (n = 32), comprising a 17% (n = 6) complete response rate and a 74% (n = 26) partial response rate. The disease control rate was 100%.

"The results of this study suggest that the addition of pembrolizumab to trastuzumab and chemotherapy is safe and active in treating metastatic esophagogastric cancer. The efficacy of this combination is being evaluated in the randomized double-blind phase 3 KEYNOTE-811 trial," first author Yelena Y. Janjigian, MD, of Memorial Sloan Kettering Cancer Center, and coinvestigators wrote.

The study enrolled 37 patients with untreated stage IV HER2-positive esophagogastric cancer, unselected for PD-L1 expression status, between November 11, 2016, and January 23, 2019. The data cutoff was August 6, 2019. The median age was 60 years (range, 21-84), 78% of patients were men, and 86% of patients were white. Fifty-nine percent of patients had an ECOG performance status of 1 and 41% of patients had an ECOG performance status of 0. Chemotherapy regimens received included capecitabine (65%), 5-fluorouracil (35%), oxaliplatin (97%), and cisplatin (3%). The primary tumor sites were esophageal (38%), GEJ (32%), and gastric (30%).

Patients could receive an initial induction cycle comprising a 200-mg flat dose of IV pembrolizumab and an 8-mg/kg loading dose of IV trastuzumab. In subsequent cycles, patients were treated with 130 mg/m² of IV oxaliplatin or 80 mg/m² of cisplatin on day 1; 850 mg/m² of oral capecitabine 2 times daily for 2 weeks, followed by 1 week off (or IV 5-fluorouracil at 800 mg/m² per day on days 1-5); and a 200-mg flat dose of IV pembrolizumab, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle.

The trial had a primary end point of 6-month progression-free survival (PFS), assuming enrollment of 37 patients and 26 or more progression-free at 6 months. Secondary end points included overall survival (OS), ORR, and disease control rate.

The median PFS was 13.0 months (95% CI, 8.6—not reached [NR]). The median OS was 27.3 months (95% CI, 18.8–NR), and the 12-months OS rate was 80% (95% CI, 68-95).

"The activity of the combination investigated in this study might relate to trastuzumab’s induction of antibody-dependent cell-mediated cytotoxicity, which has been suggested to prime antitumor immune responses by enhancing presentation of tumor antigens, Janjigian et al wrote.

The most frequently reported treatment-related adverse event (AE) across all grades was neuropathy, which occurred in 97% of patients. The most common grade 3/4 AEs were lymphocytopenia (19% grade 3; 5% grade 4), decreased electrolytes (16%, all grade 3), and anemia (11%, all grade 3). There were 2 incidents of serious AEs, both grade 3 nephritis that led to the patient discontinuing treatment. Immune-related AEs led to discontinuation of pembrolizumab in four patients. No treatment-related deaths occurred during the trial.

The phase 3 KEYNOTE-811 trial (NCT03615326), which is actively recruiting, is comparing pembrolizumab plus trastuzumab in combination with standard of care chemotherapy versus trastuzumab in combination with standard chemotherapy in patients with HER2-positive gastric cancer.

Janjigian Y, Maron S, Chatila WK, 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 [published online May 18, 2020]. Lancet Oncol. https://doi.org/10.1016/S1470-2045(20)30169-8