Pembrolizumab appears promising for certain patients with gastric, gastroesophageal cancer
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First-line pembrolizumab appeared noninferior to chemotherapy and led to fewer adverse events among certain patients with advanced gastric or gastroesophageal junction cancer, according to results of the phase 3 KEYNOTE-062 study.
However, researchers observed no clinically meaningful benefit with pembrolizumab (Keytruda, Merck) plus chemotherapy compared with chemotherapy alone among patients with a PD-L1 combined positive score (CPS) of 1 or greater.
“An unmet need remains for safe and effective therapies for untreated, advanced gastric or gastroesophageal junction cancer,” Josep Tabernero, MD, PhD, MSc, head of the medical oncology department at Vall d’Hebron Institute of Oncology at Vall d’Hebron Hospital Campus in Spain, and colleagues wrote in the study, published in JAMA Oncology. “Pembrolizumab has been shown to provide antitumor activity with a manageable safety profile in [these] patients.”
The multicenter KEYNOTE-062 study included 763 patients (median age, 62 years; range, 20-87; 72.6% men) with untreated, locally advanced unresectable or metastatic gastric or gastroesophageal cancer and a PD-L1 CPS of 1 or greater.
Tabernero and colleagues randomly assigned patients 1:1:1 to pembrolizumab dosed at 200 mg every 3 weeks for up to 2 years (n = 256), pembrolizumab plus chemotherapy (n = 257) or placebo plus chemotherapy (n = 250). Chemotherapy consisted of cisplatin dosed at 80 mg/m² on day 1 plus either 5-FU dosed at 800 mg/m2 per day on days 1 through 5 or capecitabine dosed at 1,000 mg/m2 twice daily on days 1 through 4 every 3 weeks.
OS among patients with a PD-L1 CPS of 1 or greater and PFS among patients with a PD-L1 CPS of 10 or greater served as primary endpoints.
Median follow-up was 29.4 months (range, 22-41.3).
Results showed pembrolizumab conferred noninferior OS compared with chemotherapy among patients with a CPS of 1 or higher (median, 10.6 months vs. 11.1 months; HR = 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab improved OS vs. chemotherapy among patients with a CPS of 10 or greater (median, 17.4 months vs. 10.8 months; HR = 0.69; 95% CI, 0.49-0.97), although researchers did not statistically test this difference.
The combination of pembrolizumab and chemotherapy did not demonstrate superiority to chemotherapy alone for OS among patients with a CPS of 1 or higher (12.5 months vs. 11.1 months; HR = 0.85; 95% CI, 0.7-1.03) or a CPS of 10 or higher (12.3 months vs. 10.8 months; HR = 0.85; 95% CI, 0.62-1.17), nor for PFS among patients with a CPS of 1 or higher (6.9 months vs. 6.4 months; HR = 0.84; 95% CI, 0.7-1.02).
Among a subset of patients with microsatellite instability-high (MSI-H) tumors (n = 50), pembrolizumab improved OS compared with chemotherapy (median, not reached vs. 8.5 months; HR = 0.29; 95% CI, 0.11-0.81).
“Although limited numbers preclude testing for superiority of pembrolizumab vs. chemotherapy, to our knowledge, this study is the first to show survival benefit of an anti-PD-1 therapy vs. chemotherapy for MSI-H tumors in the first-line setting,” Tabernero and colleagues wrote. “Moreover, the predictive value of a PD-L1 CPS of 10 or greater was maintained after exclusion of MSI-H tumors, suggesting the independent value of these biomarkers.”
Grade 3 or higher treatment-related adverse events occurred among 16.9% of those assigned pembrolizumab alone, 73.2% among those assigned pembrolizumab plus chemotherapy and 69.3% among those assigned chemotherapy alone. Drug-related adverse events associated with treatment discontinuation occurred among 3.9% of the pembrolizumab-alone group, 27.6% of the combination group and 18% of the chemotherapy-alone group, and events associated with death occurred in 2% of the combination group and 1.2% of the other groups.
The negative result of the second readout of KEYNOTE-062 — the lack of superiority of chemotherapy plus pembrolizumab vs. chemotherapy alone — is disappointing for many clinical researchers, according to an editorial accompanying the study by Elizabeth C. Smyth, MD, researcher in the department of oncology at Cambridge University Hospitals NHS Foundation Trust in the U.K., and Markus Moehler, MD, PhD, professor of gastrointestinal oncology at Johannes-Gutenberg University in Germany.
“Is it possible that, in the long run, the effects of cytotoxic agents might interfere with T-cell activity? It has been suggested that sustained exposure to antimetabolites can impede T-cell clonal expansion. However, this effect was not observed in trials of pembrolizumab plus cisplatin and pemetrexed in non-small cell lung cancer, nor in the MSI cohort in KEYNOTE-062,” they wrote. “It is also unclear whether the platinum choice in KEYNOTE-062 may have influenced the outcome: Based on in vitro data, oxaliplatin was a better pembrolizumab partner owing to its putative effect on induced immunogenic cell death.”
References:
- Shitara K, et al. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2020.3370.
- Smyth EC and Moehler M. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2020.2436.
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