GSK and iTeos presented interim data from their Phase II GALAXIES Lung-201 trial at the European Society for Medical Oncology (ESMO) Congress 2024, showcasing the potential of belrestotug, a TIGIT inhibitor, in combination with Jemperli (dostarlimab) for first-line treatment of non-small cell lung cancer (NSCLC) patients with high PD-L1 expression. The open-label trial's analysis, with a median follow-up of 7.3 months, suggests a promising avenue for enhancing anti-tumor immunity, although further data on survival and durability are needed.
Enhanced Response Rates with Belrestotug Combination
The GALAXIES Lung-201 trial evaluated three dose levels of belrestotug (100, 400, and 1000mg) in combination with dostarlimab. The results indicated that the combination therapy nearly doubled the confirmed overall response rate (ORR) compared to dostarlimab monotherapy. Notably, higher dose levels of belrestotug led to over a 90% decrease in circulating tumor DNA (ctDNA), suggesting a more profound response. In the 400mg dose arm, the confirmed ORR was 59.4% compared to 28.1% with Jemperli monotherapy, although neither arm experienced a complete response. For context, Keytruda monotherapy achieved a 45% ORR in first-line PD-L1 high patients in its KEYNOTE-024 trial.
Safety Profile and Adverse Events
While the belrestotug and Jemperli combination demonstrated enhanced efficacy, it also presented a higher incidence of treatment-related adverse events (TRAEs). The combination arm experienced an 84% overall TRAE rate compared to 59% with Jemperli alone. Treatment-related immune-related adverse events (TR-irAEs) were also more frequent in the combination arm (56% versus 19%), leading to a higher discontinuation rate (16% versus 6%). Although Grade 3 or above TR-irAE rates were similar between the two arms (16% versus 13%), unique Grade 3+ events such as pruritus, rash, and immune-mediated lung disease were observed in the belrestotug combination group. A single Grade 5 event was also reported in the combination arm.
Path to Phase III and Market Potential
Based on the Phase II results, belrestotug 400mg was selected as the recommended Phase III dose (RP3D) for the registrational GALAXIES Lung-301 trial. This Phase III trial aims to compare belrestotug plus Jemperli against Keytruda monotherapy in approximately 1,000 patients globally. The market anticipates the belrestotug combination to reach $871 million by the end of the decade. However, to gain widespread adoption, the combination will need to demonstrate a convincing overall survival (OS) benefit to shift prescribing habits from existing PD-1 regimens and compete with emerging therapies like antibody-drug conjugates and bispecific antibodies.
Competitive Landscape
The TIGIT inhibitor landscape is competitive, with multiple players including Roche, MSD, Arcus/Gilead, iTeos/GSK, Beigene, and AstraZeneca vying for a share of the NSCLC market. Roche's tiragolumab + Tecentriq combination has faced challenges, while Arcus/Gilead's domvanalimab + zimberelimab has shown some promise. The failure of MSD’s vibostolimab + pembrolizumab in the second-line setting underscores the challenges in developing effective TIGIT-based therapies.
