AstraZeneca becomes TIGIT's last man standing

Arcus hasn’t formally discontinued its Gilead-partnered anti-TIGIT MAb domvanalimab, but the company’s revelation that it was pivoting to the HIF2α inhibitor casdatifan as its new lead project brings an end to its TIGIT adventure in all but name.

The move has been prompted by the failure of domvanalimab’s phase 3 Star-221 study, in gastric cancer; there is some similarity here with Roche, which shut down its tiragolumab programme when that anti-TIGIT MAb flunked its pivotal liver cancer trial, Skyscraper-14, in July. It leaves AstraZeneca as the last company with a significant presence in TIGIT, and its approach shares an uncomfortable similarity with domvanalimab.

Astra is betting on a bispecific MAb, rilvegostomig, which additionally hits PD-1, and which has a reduced Fc effector function. The company reckons this Fc feature will allow it to succeed where tiragolumab, an Fc-active MAb, failed; however, this claim is now on shaky ground, given that domvanalimab is an Fc-silent molecule.

Interim futility

After all the late-stage TIGIT failures, including GSK/iTeos’s belrestotug and Merck & Co’s vibostolimab, Arcus positioned gastric cancer as one setting that could redeem domvanalimab, citing the mid-stage Gastric-Edge study as evidence. However, the Gastric-Edge result, prevented two years ago, was hardly emphatic, and evidently Star-221 was no better.

The parallel with Roche is that the Swiss company had used a mid-stage trial of its own, Morpheus-liver, to back starting a phase 3 liver cancer study of tiragolumab, and when this pivotal effort, Skyscraper-14, failed it led to the termination of all remaining tiragolumab work.

Arcus said on Friday that Star-221 was being discontinued on the recommendation of its data-monitoring committee, which reviewed results from an event-driven, prespecified interim analysis of overall survival.

The study tested a domvanalimab/zimberelimab/chemo triplet against Opdivo plus chemo in first-line upper GI cancers, and had OS as its primary endpoint, sequentially in PD-L1≥5% expressers, PD-L1≥1% expressers, and all-comers. It hasn’t been disclosed how badly domvanalimab performed; to its credit Roche published several failed tiragolumab trials, including Skyscraper-14, at ESMO.

What does this leave in play for domvanalimab? The project is in two other phase 3 trials, both in first-line lung cancer: Star-121 tests a zimberelimab plus chemo triplet versus Keytruda plus chemo in first-line metastatic disease, while Pacific-8 gives domvanalimab on top of Imfinzi in stage III NSCLC. There are good reasons for supposing that both will fail.

Phase 3 trials of domvanalimab

Note: *AstraZeneca-sponsored trial. Source: OncologyPipeline.

For now Star-121 and Pacific-8 continue, but their outcomes will take a back seat to casdatifan. Also to be considered is Gilead, which has doubled down on domvanalimab, upping its financial stake in Arcus; that deal remains in play, at least for the time being.

Arcus is fortunate in having casdatifan in the pipeline, and this HIF2α inhibitor has for some time seemed like an asset to which Arcus could pivot as the failure of domvanalimab looked increasingly likely. That project appears somewhat better than Merck’s Welireg on a cross-trial basis, and has several data readouts coming next year.

Meanwhile, AstraZeneca remains very much active in TIGIT, and rilvegostomig is now in 11 pivotal studies.