Editor's Note: At a recent international oncology academic conference, Professor Avivit Peer presented the latest findings from the KEYMAKER-U04 Substudy 04B. This study investigated the efficacy and safety of adding an anti-LAG-3 or anti-TIGIT antibody to the standard-of-care enfortumab vedotin (EV) plus pembrolizumab backbone as a first-line treatment for advanced urothelial carcinoma (UC). Our editorial team has summarized the core academic content for our readers.01 Background and Study Design: Exploring “Triplet” Immune Strategies Built on EV + Pembrolizumab
Currently, EV plus pembrolizumab is the first-line standard of care (SOC) for locally advanced or metastatic urothelial carcinoma (UC). KEYMAKER-U04 Substudy 04B is a Phase 1/2 substudy designed to evaluate whether the addition of another immune checkpoint inhibitor to the EV + pembrolizumab combination could further enhance efficacy.
The study introduced two novel immune checkpoint inhibitors: favezelimab (a humanized IgG4 anti-LAG-3 monoclonal antibody that prevents LAG-3 from binding to its ligand, MHC-II) and vibostolimab (a humanized IgG1 anti-TIGIT monoclonal antibody that blocks interaction with its ligands, CD155 and CD112).
The study enrolled a total of 124 patients with previously untreated advanced UC, who were randomized 1:1:1 into three treatment arms:
- Arm A: EV + favezelimab (anti-LAG-3) + pembrolizumab
- Arm B: EV + vibostolimab (anti-TIGIT) + pembrolizumab
- Arm C (Control): EV + pembrolizumab
The primary endpoints were investigator-assessed objective response rate (ORR) and safety. Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). Baseline characteristics were well-balanced across the groups, with approximately 20% of patients presenting with liver metastases, consistent with real-world disease distribution. The median follow-up time was approximately 1 year.
02 Efficacy Data: Triplet Therapies Failed to Significantly Improve ORR with No Survival Benefit Observed
Regarding efficacy assessment, Professor Peer noted that the ORR was similar across the three treatment arms, with overlapping confidence intervals (CIs). Notably, the ORR for the anti-TIGIT triplet arm (Arm B) was numerically lower.
Concerning the complete response (CR) rate, although the CR rates across all treatment arms in this study appeared numerically lower compared to the previously published EV-302 study data (which was approximately 30%), at the time of data cutoff, over 30% of responding patients achieved tumor shrinkage greater than 80%. Given that this is an exploratory, signal-finding study with a small sample size, Professor Peer emphasized that the CR data should be interpreted with caution.
In terms of survival and response maintenance, between 51% and 68% of patients across the three arms were still in an ongoing response at the time of data cutoff. However, the PFS rates at 6 months were similar across all groups. Overall, the addition of anti-LAG-3 or anti-TIGIT inhibitors to the EV + pembrolizumab regimen failed to provide additional efficacy benefits for patients with first-line advanced UC.
03 Safety Analysis: Dual Immune Blockade Significantly Increases Toxicity and Discontinuation Risks
The overall safety profile was generally consistent with the known safety profiles of the individual agents. However, specific data comparisons revealed obvious overlapping toxicities in the triplet regimens:
- Grade 3–5 Treatment-Related Adverse Events (TRAEs): The incidence in the anti-TIGIT triplet arm (Arm B) was numerically higher than in the other arms.
- Treatment Discontinuation Rate: The rates of treatment discontinuation due to adverse events in the two triplet arms (Arm A and Arm B) were significantly higher than in the doublet control arm (Arm C) receiving EV + pembrolizumab alone.
- Immune-Mediated Adverse Events (imAEs): The incidence was higher in the triplet arms, mainly manifesting as thyroid dysfunction, severe skin reactions, and infusion reactions (mostly low-grade).
Considering the small sample size and data cutoff, the triplet regimens overall demonstrated additive toxicity without commensurate clinical reward.
04 Expert Commentary and Future Outlook: The Doublet Regimen Cornerstone Remains Solid
In conclusion, Professor Peer emphasized that for patients with advanced UC, the addition of LAG-3- or TIGIT-targeted immune checkpoint inhibitors to EV + pembrolizumab showed no indication of improved efficacy. Instead, the triplet strategies led to additive toxicity and higher rates of treatment discontinuation.
Based on these results, the exploration of this specific triplet strategy (EV combined with dual immune checkpoint blockade) has been discontinued. These findings conversely validate and solidify the foundational role of EV + pembrolizumab as the standard of care for first-line advanced UC. Professor Peer finally noted that while anti-TIGIT and anti-LAG-3 strategies continue to be evaluated in other tumor types and alternative combinations, their additive application in the first-line treatment of advanced UC did not achieve the anticipated breakthrough.
