ESMO 2024 – iTeos TIGIT meets its efficacy criteria

With some pretty big caveats – chief perhaps being toxicity – iTeos/GSK’s anti-TIGIT MAb belrestotug lived up to its promise in Galaxies Lung-201, a key phase 2 trial in first-line ≥50% PD-L1 expressing non-small cell lung cancer, an ESMO late-breaking presentation revealed on Saturday.

It might come as a disappointment that nothing was revealed about either how survival curves were shaping up, or how an all-important Keytruda comparator cohort performed; in a trial that’s been delayed as extensively as Galaxies Lung-201 these were puzzling omissions. But, at least in terms of response rates, GSK has justified starting the phase 3 Galaxies Lung-301 trial.

That study was announced at last in June, comparing the belrestotug/Jemperli combo in the same PD-L1-high first-line NSCLC setting against Keytruda. Until today the result of Galaxies Lung-201 was under wraps, and all that had been revealed about this phase 2 trial was that it had met “predefined efficacy criteria”, suggested to have been an ORR of 55-60%.

Criteria met

ESMO presentation showed this to be the case, with hints of a dose-response relationship.

The study tested three belrestotug doses, 100mg, 400mg and 1g, and at a 7 June cutoff these yielded respective confirmed ORRs of 60%, 59% and 63%. The comparator cohort for this, termed “substudy 1”, was Jemperli monotherapy, and yielded a 28% confirmed response rate.

Separate cohorts including Keytruda monotherapy – the real-world comparator, and the control in phase 3 – were not revealed, presumably because they formed part of a separate “substudy 2”.

As such, to test the robustness of the readout a cross-trial comparison is necessary. Two trials, Merck’s Keynote-024 and Roche’s Impower-110, yielded ORRs of 45% and 40% respectively for Keytruda and Tecentriq in a similar PD-L1 ≥50% expressers, so on this basis in Galaxies Lung-201 the belrestotug cohorts look numerically better.

The ESMO discussant, National Cancer Institute of Milan’s Dr Marina Garassino, agreed that the cross-trial comparison was broadly positive, and provided a theoretical statistical analysis comparing a 66% ORR in Galaxies Lung-301 against Keynote-024’s 45%, which she said yielded a hypothetical p value of 0.06.

Toxicity

So far so good, but belrestotug’s toxicity has now come to the fore, with grade 3 treatment-related AEs seen in 22-43% of patients, and serious treatment-related AEs in 25-37%.

Three deaths were deemed related to belrestotug (two at 100mg and one at 400mg), caused by immune-mediated lung disease, hepatitis and myocarditis. Treatment discontinuations seemed high, peaking at 40% of the 30 patients in belrestotug’s highest, 1g cohort. Nevertheless, the increase in immune-related AEs was termed “generally manageable”, a sentiment with which Garassino agreed.

With immune-mediated lung disease and myocarditis most frequent in the 1g belrestotug cohort, the data’s presenter, Dr David Spigel of the Sarah Cannon Research Institute, revealed that 400mg was the belrestotug dose chosen for Galaxies Lung-301.

While the ESMO data broadly support GSK’s phase 3 plan, Garassino cautioned about the lesson of the phase 2 Cityscape study of Roche’s anti-TIGIT MAb tiragolumab. This showed a highly promising 69% response rate, which so far hasn’t translated into a phase 3 win on survival.

"We hope to find new galaxies and not black holes," she told ESMO. 

Cross-trial comparison in 1st-line ≥50% PD-L1 NSCLC

Source: ESMO & NEJM.