Harry H. Yoon, MD
Harry H. Yoon, MD, Associate Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, the invited discussant of the study presented by Janjigan et al, commented on the strong rationale for combining an anti-HER2 agent, anti–programmed cell death protein 1 (PD-1) agent, and chemotherapy. These data are the first reported for this approach in metastatic HER2-positive esophagogastric cancer, he noted.
“Immune checkpoint inhibition alone has limited efficacy in most patients. We know that some common cytotoxic agents have immune-promoting properties, and investigators have hypothesized that efficacy may be improved by combining PD-1 blockade with certain cytotoxic agents—those that cause immunogenic cell death. There are also now considerable data showing that trastuzumab not only helps direct innate immunity via antibody-dependent cellular cytotoxicity, but also enhances adaptive immunity by helping induce immunogenic cell death,” he explained.
With the caveat that these are cross-trial comparisons, Dr. Yoon referenced two large front-line studies to put the data from the current trial into context. Both ToGA1 and the JACOB trial,2 he said, showed response rates with trastuzumab plus chemotherapy to be less than 50% (vs 87% in the current study); median progression-free survival to be shorter than the 11.4 months achieved here; and median overall survival to be approximately 14 months, whereas it was not reached with trastuzumab/pembrolizumab plus chemotherapy.
“We know median overall survival is likely to be higher, given that the lower boundary of the 95th confidence interval was 13.6 months in this trial, and the 12-month survival was higher than in prior studies,” he predicted.
While acknowledging that this is a small study, Dr. Yoon maintained: “These are encouraging efficacy data for this combination, which will be appropriately tested in a definitive phase III trial. More importantly, the data provide proof of concept for future research with multitargeted immunotherapy for esophagogastric cancer, giving us evidence supporting the combination of PD-1 blockade, an antibody against an oncogenic driver that also enhances adaptive immunity, and chemotherapy agents that cause immunogenic cell death.” ■
DISCLOSURE: Dr. Yoon has received honoraria from and is a consultant/advisor for Astellas, LSK Biopharma, Merck Sharp & Dohme, and BeiGene; has received institutional research funding from Boston Biomedical, Lilly/ImClone, Merck, and Roche/Genentech; and has received travel expenses from Lilly.
1. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2010.
2. Tabernero J, Hoff PM, Shin S, et al: Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol 19:1372-1384, 2018.
When added to first-line chemotherapy in patients with untreated metastatic HER2-positive esophageal, gastroesophageal junction, and gastric adenocarcinoma, the combination of pembrolizumab and trastuzumab produced responses in 87% of patients, with 100% of patients experiencing disease control and ...