Triple Therapy for HER2-Positive Gastric Cancer Shrinks Tumors

In HER2-positive gastric cancer, the addition of pembrolizumab (Keytruda, Merck) to trastuzumab (Herceptin, Roche) and platinum-based chemotherapy led to a significant improvement in overall response rate, according to results from the first interim analysis of the KEYNOTE-811 phase 3, randomized clinical trial.

The results of the trial, initially presented at the 2021 annual meeting of the American Society of Clinical Oncology and now published in Nature, were instrumental in the May 2021 FDA approval of pembrolizumab plus trastuzumab along with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma.

Pembrolizumab is an anti–programmed death–ligand 1 (PD-L1) antibody, which blocks a key immune escape mechanism employed by cancer cells. Trastuzumab causes an immune response that leads to HER2 internalization and cellular recycling, as well as stimulating HER2-specific T cells. Death of cancer cells from platinum-containing chemotherapy stimulates dendritic cells, which in turn promote tumor-specific T cells.

In her studies of immunotherapy and gastric cancer, lead author Yelena Janjigian, MD, chief of the gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center, New York, noticed a trend in HER2-positive patients. “PD-L1 overexpression actually can occur and continue to increase while the patient is on trastuzumab as a mode of resistance,” Janjigian said in an interview.

That observation prompted the idea to combine a PD-L1 inhibitor in a phase 3 clinical trial. The results were striking. “I’ve never seen such depth of response. You could see responses as early as week 3 – after just one dose – and no one’s ever shown that before,” Janjigian said.

The new study randomized 264 patients to receive pembrolizumab or placebo in combination with trastuzumab plus fluoropyrimidine- and platinum-containing chemotherapy. In the intention-to-treat population, 81.3% of the population was male, and the primary tumor site was the stomach in 68.4%. The pembrolizumab group had a significantly higher objective response rate than the placebo group (74.4% vs. 51.9%; P = .00006).

The median decrease in lesion size was 65% in the pembrolizumab group and 49% in the placebo group. 32.3% of the pembrolizumab group had at least an 80% decrease in lesion size, versus 14.8% in the placebo group. The pembrolizumab group had more complete responses (11.3% vs. 3.1%).

The message from this is that biomarkers are critical, even if actionable ones are rare, Janjigian said. “Even though it feels like it’s only 10% or 5% of population, you start chipping away at it. How do we cure cancer? We cure it one percentage at a time through biomarker testing.”

Writing in a commentary published with the study, Myriam Chalabi, MD, a physician specializing in gastrointestinal oncology with the Netherlands Cancer Institute, Amsterdam, described the findings as “impressive in terms of the tumor responses.” But she was cautious saying data on progression-free survival and overall survival are needed to understand how well the proposed treatment would work long term.

“Given that PD-1 blockade seems to complement trastuzumab and chemotherapy for the treatment of HER2-positive gastric cancers, Janjigian and colleagues’ study has moved the field forward, and their findings could be the next, long-awaited development in the treatment of these cancers,” she wrote.

A key limitation is that the study looked at overall response rate, rather than the overall survival. The latter results should come within a year, Janjigian said.

The study was funded by Merck. Janjigian has received research funding from Merck, Rgenix, Bayer, Genentech/Roche, Bristol-Myers Squibb, and Eli Lilly, and has served on advisory boards for Rgenix, Merck Serono, Bristol-Myers Squibb, Eli Lilly, Pfizer, Bayer, Imugene, Merck Sharp & Dohme, Daiichi-Sankyo, Zymeworks, SeaGen, Basilea Pharmaceutical, and AstraZeneca. She has equity in Rgenix.

This article originally appeared on, part of the Medscape Professional Network.

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