A key late-stage trial of Arcus Biosciences and Gilead Sciences' anti-TIGIT antibody domvanalimab has flopped, leading Arcus to refocus its R&D priorities and abandon several studies of the drug.
The phase 3 Star-221 study was testing domvanalimab with Arcus’ experimental anti-PD-1 drug zimberelimab, plus chemotherapy, versus Bristol Myers Squibb’s Opdivo, also with chemotherapy, as a first-line treatment for advanced gastric and esophageal cancers.
The survival numbers, however, did not stack up for Arcus and its TIGIT partner Gilead. While omitting a detailed breakdown, Arcus noted that the independent data monitoring committee overseeing the trial recommended stopping the study after an interim analysis found the experimental combo “did not improve [overall survival]” compared to the Opdivo-chemo regimen.
The phase 3 study will now be discontinued “due to futility,” according to a statement released Friday morning. Arcus and Gilead said they are “communicating with investigators to determine appropriate next steps for patients in the study in addition to conducting a detailed analysis to better understand these results.”
Back in October, domvanalimab showed a glimmer of hope in certain gastric and esophageal cancers in the midstage Edge-Gastric study. That trial is also being stopped in light of the phase 3 failure, Arcus said Friday. Testing for its TIGIT will continue in other, non upper GI cancers, Arcus noted in its release.
But Arcus will now refocus its efforts more outside of TIGIT, specifically on its asset casdatifan, an HIF-2a inhibitor once backed by Gilead, as well as its earlier stage small-molecule inflammatory and autoimmune programs.
Arcus will also keep working on quemliclustat, a small-molecule CD73 inhibitor that completed enrollment of a phase 3 study in pancreatic cancer earlier this year. Results from that trial are expected in 2027.
“The results from STAR-221 are not what we had hoped for, and we have important work ahead to meet the needs of patients on our domvanalimab studies and also accelerate the casdatifan and I&I programs,” said Terry Rosen, Ph.D., CEO of Arcus, in a statement.
“We are fortunate to be well capitalized and plan to focus our resources on casdatifan, including studying new early-line combinations in kidney cancer, broadening its development into new tumor types, and extending our capabilities beyond oncology," he continued.
Domvanalimab was one of the last TIGIT candidates still standing after high-profile clinical failures saw the likes of Roche, GSK and BeOne Medicines retreat from a modality that was once hailed as the future of immuno-oncology.
Most of those discarded candidates were Fc-enabled, meaning the antibodies retain a fully functional Fc region to bind to Fc receptors found on the cell surface and contribute to the protective antitumor functions of the immune system. In contrast, domvanalimab is known as Fc-silent, meaning the Fc function has been mutated out.
The only other TIGIT candidate still in the running—AstraZeneca’s TIGIT/PD-1 bispecific antibody rilvegostomig—uses an Fc-silent anti-TIGIT antibody from Compugen.
Arcus and Gilead have endured a rocky R&D road. Gilead penned a potential $2 billion deal with Arcus back in 2020 that included AB154, later known as domvanalimab, as well as several other immuno-oncology targets.
Gilead then doubled down in 2021 when it opted in for etrumadenant, Arcus’ adenosine A2a/A2b receptor antagonist. But the biotech hit pause on development when it decided against moving into a phase 3 for colorectal cancer, after which Gilead walked away.
That wasn't the first time Gilead pivoted from an Arcus project, having also done so for casdatifan back in February. This came after Arcus unveiled phase 1 data in metastatic clear cell renal cell carcinoma in 2024 showing casdatifan achieved a general overall response rate (ORR) of 34% and a confirmed ORR of 25%.
As of August, Gilead still had licenses to another TIGIT molecule and quemliclustat. Gilead also retains a license to zimberelimab that was covered by the original Arcus agreement in 2020.
For its part, Arcus was down 16% in premarket trading Friday.