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Adding an immune checkpoint inhibitor to trastuzumab (Herceptin) and chemotherapy increased the response rate by almost 50% in HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer, according to preliminary data from an ongoing trial.

The objective response rate (ORR) increased from 51.9% with chemotherapy and trastuzumab to 74.4% with the addition of pembrolizumab (Keytruda). Twice as many patients in the pembrolizumab arm had tumor shrinkage of at least 80%.

The safety profile was similar between the regimens, with the exception of immune-mediated adverse events (AEs), which occurred more often with pembrolizumab, reported Yelena Y. Janjigian MD, of Memorial Sloan Kettering Cancer Center in New York City, during the virtual World Congress on Gastrointestinal Cancer (WCGC).

"Pembrolizumab plus trastuzumab and chemotherapy resulted in a statistically significant and clinically meaningful 22.7% improvement in overall response rate compared with placebo plus trastuzumab and chemotherapy," she said. "These responses were deeper and more durable. Adverse events were similar between arms. Observed adverse events were as expected, and no new safety concerns were identified.

Janjigian noted that the study will continue as planned and that an analysis of overall survival (OS) and progression-free survival (PFS) will be performed in the future in accordance with the analysis plan for the protocol. "I am excited to note that pembrolizumab and trastuzumab-chemotherapy is a potential new first-line treatment for locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma, at least in the United States, as the FDA for the indication on May 5, 2021," she said.

The findings are consistent with showing that trastuzumab has , and combining the drug with an anti-PD-1 antibody is a promising strategy for unresectable/metastatic HER2-positive gastric/GEJ cancer, said WCGC invited discussant Kei Muro, MD, PhD, of Aichi Cancer Center Hospital in Nagoya, Japan.

"Excitingly higher efficacy on the pembrolizumab arm was observed, and no new safety concerns were observed," he added. "Although accelerated FDA approval has been obtained, OS and PFS results are still awaited."

Results of the trial with pembrolizumab, combined with previously reported findings for with nivolumab in non-HER2 gastric-GEJ cancer, mean that "immuno-oncology will now be administered to all first-line gastric cancer patients regardless of HER2 status," Muro continued.

He said the results also raised new questions that require evaluation in future studies: Is there potential for the regimen in the perioperative setting for HER2-positive patients? Can immune checkpoint inhibitors be combined with other anti-HER2 agents? Which biomarkers may have utility for the combination of pembrolizumab, trastuzumab, and chemotherapy?

Janjigian reported findings from a planned interim efficacy analysis of KEYNOTE-811 after enrollment of 264 patients. The intention-to-treat population comprised 434 patients enrolled as of June 2020 (of a planned accrual target of 692).

Eligible patients had untreated advanced HER2-positive gastric-GEJ cancer. All patients received trastuzumab and fluorouracil-cisplatin or capecitabine-oxaliplatin chemotherapy and were randomized to pembrolizumab or placebo.

The trial has dual primary endpoints of OS and PFS by independent review. ORR and duration of response are key secondary endpoints.

Janjigian reported that 97% of patients in the pembrolizumab arm of the efficacy population had some degree of tumor shrinkage, as did 90% of those in the placebo arm. A third of patients in the pembrolizumab arm had tumor shrinkage of at least 80% as compared with 15% of patients in the placebo group.

The 22.7% absolute difference in ORR proved to be highly significant (P=0.0006), she said. Complete responses occurred in 11% of the pembrolizumab arm versus 3% of the placebo group. The disease control rate was 96.2% with pembrolizumab and 89.3% with placebo, a nonsignificant difference. A consistent difference favoring the addition of pembrolizumab was seen across all prespecified subgroups.

Immune-mediated AEs occurred in 34% of the pembrolizumab arm and 21% of the placebo arm. Grade 3-5 AEs (10% vs 3%), serious AEs (9% vs 3%), and AEs leading to discontinuation (6% vs 2%) all occurred more often with pembrolizumab.

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