Where next for TIGIT?

As the markets reopen after the Independence Day holiday investors will rightly be wondering where Thursday's failure of Roche’s tiragolumab leaves other companies that have also placed bets on the TIGIT mechanism.

Given the many setbacks of this approach, and the fact that its few successes have been qualified, it might come as a shock just how many large TIGIT studies are ongoing: OncologyPipeline reveals 25 pivotal trials, of which the ones that haven’t failed are seeking to enrol over 15,000 patients. The spotlight now falls on Gilead/Arcus and Merck & Co, which are in phase 3 with near-identical settings to the one in which Roche’s Skyscraper-06 just bombed.

That setting is first-line NSCLC, in which an anti-TIGIT MAb is tested as part of a triplet that includes an anti-PD-(L)1 and chemo. Skyscraper-06 has failed comprehensively, even showing survival advantages for the control cohort of Keytruda plus chemo, versus tiragolumab plus Tecentriq and chemo.

Perhaps most exposed to a similar failure now is Arcus’s Gilead-partnered domvanalimab. Notably, in January Gilead doubled down on this approach, investing a further $320m in its partner and announcing a focus on the Star-121 study while discontinuing Arc-10, a first-line PD-(L)1 combo test analogous to Skyscraper-01, on which Roche is to report final OS data this year.

Star-121 already looked risky: domvanalimab is being combined with zimberelimab, evidently an underwhelming anti-PD-1 MAb, and is being compared against a Keytruda/chemo combo. Now Skyscraper-06’s control arm has shown clinically the perils of such an approach.

Merck itself is also at risk in the chemo triplet setting, in the recently delayed Keyvibe-007 study. Though the group has the luxury of combining its vibostolimab with Keytruda, the lack of scientific support for the addition of TIGIT on top of PD-(L)1 blockade plus chemo weighs heavy.

It’s also notable that Skyscraper-06 wasn’t the first TIGIT/PD-(L)1/chemo triplet trial to fall on stony ground. In mid-2023 BeiGene scrapped its Advantig-306 study of ociperlimab plus Tevimbra and chemo, though that move was a deprioritisation in the wake of Novartis declining to opt in to ociperlimab’s development – Advantig-306 was withdrawn before starting.

Selected phase 3 NSCLC trials involving anti-TIGIT MAbs

Notes: FDC=fixed-dose combination; CRT=chemoradiotherapy; *delayed from Nov 2025, after primary endpoint was changed from OS in all-comers to OS in PD-L1 ≥1% expressers; **AstraZeneca-sponsored trial. Source: OncologyPipeline.

It seems that whatever hope remains for TIGIT in first-line NSCLC lies in a straight PD-(L)1 combo. However, while Skyscraper-01 might yet show a technical success on final OS analysis this year, the result could be negated by its Tecentriq control arm underperforming Keytruda on a cross-trial basis.

While Gilead scrapped the Arc-10 trial in this setting, still in play as part of TIGIT/PD-(L)1 doublets are ociperlimab (Advantig-302), vibostolimab (Keyvibe-003) and of course iTeos’s belrestotug, whose partner GSK recently moved to begin the Galaxies Lung-301 study at last.

Qualified successes

NSCLC isn’t the only cancer in which taking TIGIT blockade into pivotal studies now looks questionable. For instance, Merck’s Keyvibe-003 trial of a vibostolimab/Keytruda/chemo triplet in first-line SCLC was started just as Roche’s analogous Skyscraper-02 study failed in mid-2022. 

The few successes TIGIT has scored have hardly been resounding: Skyscraper-01 faces the prospect of an underwhelming comparator arm; Skyscraper-08, in oesophageal squamous cell carcinoma, was a Chinese study in which control patients received chemo rather than the western IO standard; and the Morpheus-liver trial, on the back of which Roche started Imbrave-152, was criticised for the underperformance of its control cohort.

Still, however qualified the successes have been, they’ve been enough for pharma to keep pouring millions into the TIGIT mechanism. There won’t be long to wait for its next test: Skyscraper-03, testing tiragolumab in stage III NSCLC, is also due to read out by the end of this year.

Crunching the TIGIT numbers

Source: OncologyPipeline.

This is an updated version of a story published earlier.