Gilead, Arcus tumble again in TIGIT, triggering 2 trial culls

Gilead and Arcus Discontinue TIGIT Trials Due to Futility

Gilead Sciences and Arcus Biosciences are discontinuing their Phase 3 STAR-121 study of the investigational TIGIT drug domvanalimab in combination with a PD-1 blocker and chemotherapy for metastatic non-small cell lung cancer (NSCLC) due to futility. An independent data panel found the comparison against Merck’s Keytruda plus chemotherapy to be futile, though no new safety issues were identified. This failure has prompted Gilead to decline an option continuation payment, signaling a significant rollback of its cancer collaboration with Arcus, which will end Gilead's access to several early-stage TIGIT therapies and its participation in new Arcus early-stage programs by July 14. The partners also terminated the Phase 2 EDGE-Lung study for domvanalimab in NSCLC.

• The Phase 3 STAR-121 study, evaluating domvanalimab combined with a PD-1 blocker and chemotherapy for metastatic NSCLC, was terminated due to futility. An independent data panel determined the regimen was futile compared to Merck’s Keytruda plus chemotherapy, without identifying any new safety concerns during regular check-ins.
• Following the STAR-121 failure, Gilead decided not to make an option continuation payment, leading to a significant reduction in its cancer collaboration with Arcus. This decision will cut off Gilead’s access to a portfolio of early-stage TIGIT therapies and end its opportunity to participate in new Arcus early-stage programs by July 14, though Gilead retains time-limited options for other programs like AB801, AB598, and AB102.
• The discontinuation of STAR-121 adds to a series of disappointments in the TIGIT-targeting therapy space, which has seen numerous failed studies, terminated partnerships, and significant financial investments. A BioSpace analysis indicates that companies have collectively spent at least $1.4 billion upfront on TIGIT partnership contracts, with potential milestones of $5 billion largely remaining unpaid due to widespread clinical setbacks.
• In addition to STAR-121, the partners have also decided to terminate the Phase 2 EDGE-Lung study, which was also investigating domvanalimab in non-small cell lung cancer. This further consolidates the impact of the Phase 3 futility finding on their joint development efforts for the TIGIT asset.

Domvanalimab's Futility in Metastatic NSCLC: STAR-121 Trial Outcomes

The STAR-121 trial evaluated domvanalimab, an anti-TIGIT antibody, in metastatic NSCLC but demonstrated futility in achieving meaningful clinical outcomes. While specific details of this trial are limited in the available literature, the broader landscape of recent metastatic NSCLC studies provides important context for understanding the challenges in this therapeutic area. Multiple phase III trials have shown varying degrees of success with different therapeutic approaches, highlighting the complex nature of treatment selection in advanced disease.

Recent immunotherapy studies have demonstrated mixed but generally positive results in metastatic NSCLC. A comprehensive analysis of dual immunotherapy plus chemotherapy across nine studies involving 7,271 participants showed median overall survival increased to approximately 15.8 months versus 11.0 months with standard chemotherapy, with hazard ratios ranging from 0.66 to 0.77. The CJLSG1901 phase 2 study in older patients with metastatic non-squamous NSCLC treated with pembrolizumab plus pemetrexed achieved an overall response rate of 36.7%, median progression-free survival of 7.6 months, and median overall survival of 19.4 months. Safety profiles showed manageable toxicity with immune-related pneumonitis occurring in 2-5% of patients in dual immunotherapy studies, mostly low-grade and responsive to corticosteroids.

Targeted therapy approaches continue to show substantial efficacy in biomarker-selected populations. The ALEX trial final analysis of alectinib versus crizotinib in ALK-positive NSCLC demonstrated median overall survival of 81.1 months versus 54.2 months respectively, with a hazard ratio of 0.78. The KRYSTAL-12 phase 3 trial of adagrasib versus docetaxel in KRAS-mutated NSCLC showed median progression-free survival of 5.5 months versus 3.8 months with a hazard ratio of 0.58, though grade 3 or higher treatment-related adverse events occurred in 47% of adagrasib patients compared to 46% with docetaxel. The PAPILLON study of amivantamab-chemotherapy in EGFR exon 20 insertion-mutated NSCLC achieved median time to treatment discontinuation of 13.2 months versus 7.5 months for chemotherapy alone, with crossover-adjusted overall survival showing favorable hazard ratios of 0.52-0.60.

Beyond NSCLC: Domvanalimab's Remaining Clinical Development

Beyond NSCLC, domvanalimab is being investigated across multiple oncology indications as part of combination immunotherapy strategies. The clinical development program primarily focuses on dual TIGIT and PD-1 blockade through combination with zimberelimab, an anti-PD-1 antibody.

• Advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma - The EDGE-Gastric study is an ongoing multicenter, international phase 2 trial with three cohorts (one first-line, two second-line or greater settings), where arm A1 evaluates domvanalimab plus zimberelimab combined with FOLFOX chemotherapy in previously untreated HER2-negative patients

• Immunotherapy-refractory hepatocellular carcinoma (HCC) - The LIVERTI trial is a phase 2 study testing domvanalimab plus zimberelimab combination therapy, demonstrating a confirmed overall response rate of 17.2% and median progression-free survival of 4.4 months among 29 enrolled patients

• First-line metastatic NSCLC expansion - The STAR-121 trial (NCT05502237) is a phase 3 randomized, open-label study comparing domvanalimab plus zimberelimab with chemotherapy versus pembrolizumab plus chemotherapy in approximately 720 patients with no actionable gene alterations

• Promising efficacy signals in gastric cancer - In the EDGE-Gastric arm A1 cohort of 41 patients, the combination achieved a 59% confirmed objective response rate, 12.9-month median PFS, and 26.7-month median overall survival, leading to advancement into the phase 3 STAR-221 trial

• Well-tolerated safety profile across indications - Treatment-related adverse events occurred in 55.2% of HCC patients and immune-related adverse events in 27% of gastric cancer patients, with safety profiles consistent with anti-PD-1 plus chemotherapy combinations

TIGIT's NSCLC Setback: Reshaping Immuno-Oncology Strategies

The recent announcement regarding the discontinuation of the Phase 3 STAR-121 study for domvanalimab in metastatic non-small cell lung cancer (mNSCLC) marks a pivotal moment for the TIGIT inhibitor class and the broader immuno-oncology landscape. This investigational TIGIT drug, in combination with a PD-1 blocker and chemotherapy, failed to demonstrate sufficient efficacy against Merck’s Keytruda (pembrolizumab) plus chemotherapy, a well-established standard of care in first-line mNSCLC. While no new safety issues were identified, the independent data panel's finding of futility has prompted Gilead Sciences to decline an option continuation payment and significantly scale back its cancer collaboration with Arcus Biosciences.

This outcome is a significant blow, particularly given the high expectations surrounding TIGIT inhibitors as a potential next-generation immune checkpoint therapy. The STAR-121 study was designed to directly challenge the current benchmark, and its failure underscores the immense difficulty of improving upon existing highly effective regimens in mNSCLC. It raises critical questions about the precise role and additive benefit of TIGIT inhibition in this specific disease setting and combination.

For Gilead, this represents a strategic re-evaluation of its substantial investment in the TIGIT space. The rollback of the collaboration, which includes ending access to several early-stage TIGIT therapies and participation in new Arcus early-stage programs, signals a clear shift in pipeline priorities. Arcus Biosciences, in turn, faces the challenge of navigating forward without a major partner for these assets, potentially impacting its development timelines and funding.

However, the narrative for domvanalimab is not entirely uniform. Prior research has shown encouraging efficacy signals in other indications. For instance, in a Phase 2 study (EDGE-Gastric), domvanalimab combined with a PD-1 inhibitor and FOLFOX demonstrated promising objective response rates and survival data in advanced gastric, gastroesophageal junction, or esophageal cancer, leading to an ongoing Phase 3 trial (STAR-221). Similarly, a Phase 2 study (ARC-10) in PD-L1-high NSCLC showed encouraging efficacy for domvanalimab plus zimberelimab compared to zimberelimab monotherapy or chemotherapy, though this was not a direct comparison to pembrolizumab plus chemotherapy. These findings suggest that while the broad first-line mNSCLC setting may be challenging, there could still be specific patient populations or tumor types where TIGIT inhibition offers a meaningful clinical benefit. The challenge now lies in precisely identifying these niches through robust biomarker strategies and targeted development efforts. The broader TIGIT class will likely face increased scrutiny, demanding stronger evidence of differentiation and efficacy in future trials.