First-Line Retlirafusp Alfa Plus Chemotherapy for Human Epidermal Growth Factor Receptor 2–Negative Gastric or Gastroesophageal Junction Adenocarcinoma: A Randomized, Double-Blind, Phase III Study (RELIGHT)
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The phase III RELIGHT trial demonstrated that adding the novel anti-PD-L1/TGF-β bispecific antibody retlirafusp alfa to first-line CAPOX chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone in patients with advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma.
Key Findings
Study Design
Study Limitations
Clinical Significance
Retlirafusp alfa represents a highly active first-line treatment option for patients with advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma, achieving remarkably low hazard ratios for both OS (HR 0.53 in CPS ≥5) and PFS. While the efficacy magnitude is robust, its direct clinical applicability in regions where immune checkpoint inhibitor plus chemotherapy is already standard of care will depend on cross-trial comparisons or future head-to-head studies to determine if dual PD-L1/TGF-β blockade outperforms isolated PD-1/PD-L1 blockade.
Historical Context
Historically, advanced HER2-negative gastric cancer was treated with platinum and fluoropyrimidine doublet chemotherapy, yielding a median overall survival of roughly one year. More recently, landmark trials like CheckMate 649 and KEYNOTE-859 established the addition of PD-1 inhibitors to chemotherapy as the new frontline standard, notably extending survival particularly in patients with higher PD-L1 expression. However, gastric cancers frequently exhibit intrinsic resistance to immunotherapy, sometimes mediated by transforming growth factor-beta (TGF-β), which drives stromal fibrosis and immunosuppression. Retlirafusp alfa was developed as a bispecific antibody to simultaneously inhibit the PD-L1 and TGF-β pathways, attempting to overcome this resistance mechanism. RELIGHT is a major phase III validation of this dual-inhibition concept.
Guided Discussion
High-yield insights from every perspective
How does the dual mechanism of a bispecific antibody targeting both PD-L1 and TGF-beta address immune evasion in the tumor microenvironment of gastric adenocarcinomas more effectively than PD-L1 inhibition alone?
Key Response
This question teaches foundational pathophysiology regarding the immunosuppressive tumor microenvironment, specifically highlighting how TGF-beta promotes regulatory T cells, cancer-associated fibroblasts, and T-cell exclusion, which are primary drivers of resistance to standard checkpoint inhibitors.
Given that the current standard of care for first-line HER2-negative advanced gastric cancer often includes chemotherapy plus a PD-1 inhibitor based on PD-L1 CPS, how would you clinically integrate retlirafusp alfa if approved, and what unique adverse events should you monitor for due to the TGF-beta blockade?
Key Response
Focuses on clinical application and management, requiring residents to contrast this new agent with standard therapies (like nivolumab or pembrolizumab) while anticipating novel drug-class toxicities such as mucosal bleeding or cutaneous lesions like keratoacanthomas associated with TGF-beta inhibition.
The efficacy of standard PD-1 inhibitors in gastric cancer is heavily dependent on the PD-L1 CPS score (e.g., CPS greater than or equal to 5). Based on the RELIGHT trial data, does the addition of TGF-beta blockade overcome the inherent immunotherapy resistance in PD-L1 low or negative subgroups, or is the benefit still exclusively driven by the CPS-high population?
Key Response
Pushes the fellow to critically analyze subgroup forest plots and biomarker data to see if this novel mechanism actually addresses the critical unmet need of treating PD-L1 low/negative gastric cancers, rather than just marginally improving outcomes for those who already respond to standard IO.
If retlirafusp alfa establishes a new overall survival benchmark in the first-line setting, how does this disrupt our sequencing for subsequent lines of therapy in gastric cancer, and what are the practical, real-world challenges of substituting established PD-1 inhibitors with a novel bispecific antibody?
Key Response
Encourages high-level strategic thinking about the entire continuum of patient care, financial toxicity, treatment sequencing (e.g., use of ramucirumab/paclitaxel in second line), and the operational hurdles of adopting new bispecifics in community oncology practices.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
The RELIGHT trial compares retlirafusp alfa plus chemotherapy against a control arm of chemotherapy plus placebo. Methodologically, how does the omission of an active control arm (chemotherapy plus an anti-PD-1 agent like nivolumab) limit our ability to isolate and quantify the independent therapeutic contribution of the TGF-beta binding domain?
Key Response
Highlights a crucial methodological flaw and study design critique: because chemotherapy plus immunotherapy is the contemporary standard of care, using a chemotherapy-only control arm makes it impossible to statistically determine if the bispecific antibody is actually superior to standard single-agent PD-1 blockade.
As a reviewer evaluating the internal and external validity of the RELIGHT trial, what critical scrutiny must be applied to the geographic distribution of the enrolled cohort and the post-progression therapies received by the control arm?
Key Response
Focuses on threats to validity common in global Phase III gastric cancer trials, specifically checking if the survival benefit is inflated by a lack of access to standard-of-care immunotherapy upon progression in the control arm, and assessing if the results are generalizable given known biological differences between Asian and non-Asian gastric cancers.
Current NCCN and ESMO guidelines recommend the addition of nivolumab or pembrolizumab to first-line chemotherapy for HER2-negative advanced gastric cancer (Category 1 for CPS greater than or equal to 5). Does the RELIGHT trial provide sufficient evidence to supplant these recommendations with retlirafusp alfa, considering the trial utilized a chemotherapy-only control arm rather than a contemporary standard-of-care control?
Key Response
Directly addresses the pragmatic challenge guideline committees face when grading evidence: determining whether a trial with a positive outcome but an arguably outdated control arm warrants a Category 1 recommendation or should simply be listed as an alternative option alongside established regimens.
Clinical Landscape
Noteworthy Related Trials
CheckMate 649
Tested
Nivolumab plus chemotherapy
Population
First-line HER2-negative advanced gastric, GEJ, or esophageal adenocarcinoma
Comparator
Chemotherapy alone
Endpoint
OS and PFS in PD-L1 CPS >= 5
KEYNOTE-859
Tested
Pembrolizumab plus chemotherapy
Population
First-line HER2-negative advanced gastric or GEJ adenocarcinoma
Comparator
Placebo plus chemotherapy
Endpoint
Overall survival
RATIONALE-305
Tested
Tislelizumab plus chemotherapy
Population
First-line HER2-negative advanced gastric or GEJ adenocarcinoma
Comparator
Placebo plus chemotherapy
Endpoint
Overall survival
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