Pembrolizumab regimen extends survival in advanced gastric, gastroesophageal cancer
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The addition of pembrolizumab to chemotherapy significantly extended survival among patients with advanced HER2-negative gastric or gastroesophageal junction cancer, according to results of the phase 3 KEYNOTE-859 study.
The findings, presented during an ESMO Virtual Plenary session Thursday, also showed statistically significant and clinically meaningful improvements in PFS and overall response rate with the first-line pembrolizumab (Keytruda, Merck) regimen. Moreover, researchers observed no new safety signals.
Rationale
Five-year survival rates for advanced or metastatic gastric cancer remain below 10% despite available therapies, according to Sung Young Rha, MD, professor of medical oncology in the department of internal medicine and director of Songdang Institute for Cancer Research at Yonsei University College of Medicine in Seoul, Republic of Korea.
“Although regulatory approvals and guideline recommendations are different globally, immunotherapy plus chemotherapy is becoming the standard of care for the first-line treatment of metastatic gastric cancer,” she said during a presentation.
Regimens that contain PD-1 inhibitors include chemotherapy plus nivolumab (Opdivo, Bristol Myers Squibb) for patients with HER2-negative tumors and chemotherapy plus trastuzumab (Herceptin, Genentech) and pembrolizumab for HER2-positive tumors.
Methodology
The randomized, double-blind KEYNOTE-859 trial evaluated pembrolizumab plus chemotherapy vs. placebo plus chemotherapy among 1,579 patents with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma and a known PD-L1 status.
Researchers randomly assigned patients to 200 mg pembrolizumab (n = 790) or placebo (n = 789) via IV every 3 weeks for up to 2 years with investigator’s choice of 5-FU and cisplatin or capecitabine and oxaliplatin chemotherapy. They stratified randomization according to region (Europe, Israel, North America and Australia vs. Asia vs. all other regions), PD-L1 CPS (<1 vs. 1) and chemotherapy regimen.
The pembrolizumab and placebo groups had similar baseline characteristics, including median age (61 years vs. 62 years) and percentages of patients with a PD-L1 combined positive score (CPS) of 1 or greater (78.2% for both) and 10 or greater (35.3% vs. 34.5%).
OS served as the primary endpoint. Secondary endpoints included PFS, ORR and duration of response according to RECIST version 1.1 by blinded independent central review, as well as safety in the as-treated population.
Median follow-up was 31 months (range, 15.3-46.3).
Results
Sixty patients in the pembrolizumab group and 24 patients in the placebo group completed treatment.
Compared with the placebo group, the pembrolizumab group had longer median OS (12.9 months vs. 11.5 months; HR = 0.78; 95% CI, 0.7-0.87) and longer median PFS (6.9 months vs. 5.6 months; HR = 0.76; 95% CI, 0.67-0.85), as well as higher 24-month rates of OS (28.2% vs. 18.9%) and PFS (17.8% vs. 9.4%).
Researchers found generally consistent benefit with pembrolizumab vs. placebo across subgroups, including by PD-L1 CPS. Detailed data from subgroup analyses will be shared at a future medical meeting, Rha said.
Results also showed the pembrolizumab group had a higher ORR (51.3% vs. 42%; P = .00009) and longer median duration of response (8 months vs. 5.7 months) than the placebo group.
More than half of patients in each group experienced grade 3 to grade 5 treatment-related adverse events, including 59.4% in the pembrolizumab group and 51.1% in the placebo group. The placebo group had a higher rate of deaths due to treatment-related adverse events (1% vs. 2%).
Immune-mediated adverse events occurred at a higher rate in the pembrolizumab group (any grade, 27.1% vs. 9.3%; grade 3-5, 7.9% vs. 1.7%).
“The observed safety profile was as expected for a regimen containing pembrolizumab and chemotherapy,” Rha said. “Overall, our data support the combination of pembrolizumab and chemotherapy as a new treatment option for this patient population.”
Implications
In her analysis of the findings, Elizabeth Smythe, MD, of Cambridge University Hospitals NHS Foundation Trust, said the results suggest the pembrolizumab regimen can provide variably meaningful improvements in survival that often are dependent on PD-L1 expression.
“Treatment decisions will vary according to regional regulatory approvals,” she said, as well as funder appraisals and discussions between clinicians and patients of the benefit according to PD-L1 status.
“Finally, PD-L1 as a predictive biomarker needs more work,” she said.
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Rha SY, et al. Abstract VP1-2023. Presented at: ESMO Virtual Plenary: February 2023 Session; Feb. 16, 2023.
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