The addition of retlirafusp alfa to capecitabine and oxaliplatin (CAPOX) significantly prolonged overall survival compared with chemotherapy alone as first-line treatment for patients with unresectable, locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction adenocarcinoma, according to results from the phase III RELIGHT trial reported by Peng et al in the Journal of Clinical Oncology.
The investigators evaluated retlirafusp alfa, a bifunctional agent targeting PD-L1 and transforming growth factor beta (TGF-β), based on the rationale that simultaneous blockade of these nonredundant immunosuppressive pathways may enhance antitumor activity.
Study Details
RELIGHT was a two-part phase III study conducted at 64 centers in China. After a safety run-in established 30 mg/kg every 3 weeks as the retlirafusp alfa dose, 731 patients with previously untreated, unresectable, locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction adenocarcinoma were randomly assigned 1:1 to receive retlirafusp alfa plus CAPOX (n = 365) or placebo plus CAPOX (n = 366). Approximately two-thirds of patients in each treatment group had tumors with a PD-L1 combined positive score of ≥ 5.
Treatment consisted of retlirafusp alfa or placebo every 3 weeks plus CAPOX for up to six cycles. The primary endpoint was overall survival in patients with a PD-L1 combined positive score of ≥ 5 and in the intention-to-treat population. Median follow-up was 13.6 months at the May 2024 data cutoff.
Key Results
Among patients with a PD-L1 combined positive score of ≥ 5, median overall survival was 16.8 months with retlirafusp alfa plus CAPOX vs 10.4 months with placebo plus CAPOX (hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.40–0.68; one-sided P < .0001). In the intention-to-treat population, median overall survival was 15.8 vs 11.2 months, respectively (HR = 0.66, 95% CI = 0.53–0.81; one-sided P < .0001).
Median progression-free survival was 7.6 vs 5.5 months among patients with a PD-L1 combined positive score of ≥ 5 (HR = 0.52, 95% CI = 0.42–0.66) and 7.0 vs 5.5 months in the intention-to-treat population (HR = 0.57, 95% CI = 0.48–0.69). Confirmed objective response rates were 56.5% vs 32.7% among patients with a PD-L1 combined positive score of ≥ 5 and 53.4% vs 32.8% in the overall population. Median duration of response was 10.2 vs 5.1 months and 8.5 vs 5.3 months, respectively.
Grade 3 or higher treatment-related adverse events occurred in 62.6% of patients receiving retlirafusp alfa plus CAPOX and 59.0% receiving placebo plus CAPOX. Serious treatment-related adverse events occurred in 34.9% and 24.0% of patients, respectively, and treatment-related deaths occurred in 1.9% and 1.1%. No new safety signals were reported.
The investigators concluded: “Retlirafusp alfa plus CAPOX represents a first-line treatment option for unresectable, locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction adenocarcinoma. A key limitation is that chemotherapy alone served as the comparator, given that the study protocol was finalized before PD-1 inhibitor plus chemotherapy became the approved standard-of-care regimen in China.”
Lin Shen, MD, of the State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by Jiangsu Hengrui Pharmaceuticals Co, Ltd. For full disclosures of the study authors, visit ascopubs.org.
