GSK’s $625m TIGIT bet approaches crunch time

Around the time of peak TIGIT mania in 2021 GSK placed a significant bet on this mechanism, licensing iTeos’s anti-TIGIT MAb belrestotug for $625m up front. Subsequent work has proceeded somewhat cautiously, but belrestotug’s key trial, the phase 2 Galaxies Lung-201 study, is now expected to yield data at last.

This tests the all-important use of first-line, PD-L1-high lung cancer, a TIGIT setting that’s already tripped up Gilead and Arcus, though Roche’s tiragolumab just about remains in play. iTeos investors are bearish, however, showing how the TIGIT bubble has deflated in the past two years: iTeos had $633m in cash at the end of 2023, but its market cap stands at only $422m.

Reasons for caution include the fact that the Galaxies Lung-201 readout has been delayed, having initially been due last year, and iTeos announcements have recently focused on other pipeline assets. Moreover, GSK was to have begun a phase 3 NSCLC belrestotug study in 2023, but still there’s no sign of any such pivotal trial, and its initiation looks to be dependent on the Galaxies Lung-201 readout.

On the plus side, iTeos has long argued that belrestotug differs from other anti-TIGIT MAbs, binding a unique epitope on the target protein and showing depletion of immunosuppressive T regulatory cells. Moreover, data at AACR 2021 suggested that the molecule might have some monotherapy activity – a novel finding that might have helped trigger the GSK deal.

On top of PD-1

Galaxies Lung-201 uses a now familiar design, combining belrestotug with an anti-PD-1 drug, and testing this against PD-1 blockade alone in first-line NSCLC expressing PD-L1 at 50% or higher – a setting Roche suggested was the most likely to show additive efficacy.

There’s a key difference, however: in iTeos’s case the PD-1 combo drug is GSK’s Jemperli, which the Perla study has suggested is at least as good as Merck & Co’s market-leading Keytruda. The comparator is Keytruda, so on the basis of Perla GSK/iTeos seem to have maximised their chances of a positive result even before any additive belrestotug benefit is considered.

This contrasts with Roche and Gilead/Arcus, neither of whose anti-TIGIT MAbs, tiragolumab and domvanalimab respectively, have so far been compared against Keytruda. The latter’s predicament is especially acute, given that its chosen comparator, zimberelimab, appears to be a sub-standard anti-PD-1 drug, a fact that will undermine any efficacy that domvanalimab might add.

However, any positive data GSK/iTeos are able to demonstrate will have to be weighed against Galaxies Lung-201’s 300-patient size. Anything less than a solid win would be expected to melt away in a larger subsequent pivotal study.

What to look for

So what can investors expect to see when Galaxies Lung-201 finally reads out? The trial’s primary endpoint is response rate, and given that enrolment began in October 2022 data on PFS, and perhaps an idea of how OS is shaping up, should also be expected.

Still, the trial readout having been delayed when its primary endpoint is ORR – a measure that doesn’t need time to “mature” – suggests that the ORR analysis might have underwhelmed, and that the companies are waiting to see if survival shows something better. 

It’s interesting that Galaxies Lung-201 includes a Jemperli monotherapy cohort, in addition to the Keytruda comparator arm. It’s possible for belrestotug plus Jemperli to win against one but not the other – something that could undermine the impact of the data generated.

It’s also important to set Galaxies Lung-201 in the context of other trials, such as GSK/iTeos’s own phase 2 TIG-006 study, testing belrestotug plus Jemperli in first-line head and neck cancer; already iTeos has been talking up this use as a first-to-market opportunity, hinting further at a possible de-emphasising of NSCLC. TIG-006 also reads out this year.

The key comparators in 1st-line, PD-L1≥50% NSCLC

Note: *approved use. Source: OncologyPipeline.