Gilead's Arcus TIGIT Combo Shows Survival Benefit in Canceled Lung Cancer Study

Arcus Biosciences has reported promising results from a now-discontinued study examining domvanalimab, an Fc-silent anti-TIGIT monoclonal antibody partnered with Gilead Sciences, alongside the PD-1 inhibitor zimberelimab. These results were shared at the Society for Immunotherapy of Cancer (SITC) annual meeting, amidst a challenging period for the TIGIT inhibitor class, which has faced multiple high-profile setbacks. Enthusiasm for TIGIT inhibitors has waned following clinical failures such as Roche's tiragolumab and the discontinuation of Merck & Co.'s studies on vibostolimab in lung cancer and melanoma.

However, some recent developments have rekindled hopes for the TIGIT inhibitor class. New data from iTEOS Therapeutics and GSK in September showed promising response rates for their combination of TIGIT inhibitor belrestotug and PD-1 inhibitor Jemperli (dostarlimab) in lung cancer, suggesting transformative potential still exists for these treatments in non-small cell lung cancer (NSCLC).

The ARC-10 study initially started as a randomized Phase III trial and was later adjusted to compare the combination of domvanalimab and zimberelimab against Merck's Keytruda (pembrolizumab). The first part of the trial, now reported, evaluated domvanalimab plus zimberelimab, zimberelimab alone, and platinum doublet chemotherapy in regions where anti-PD-(L)1 monotherapy was not yet the standard of care.

Earlier this year, Arcus and Gilead decided to halt enrollment in ARC-10, choosing to focus on advancing two other late-stage trials, STAR-121 and STAR-221, which target lung and gastrointestinal cancers, respectively. The SITC conference presentation centered on patients with advanced or metastatic NSCLC who had high levels of the PD-L1 marker (TPS ≥50%) and no genetic mutations treatable with targeted therapies, with data cutoff as of May 17.

The combination of domvanalimab with zimberelimab demonstrated substantial benefits. It resulted in a 36% reduction in the risk of death compared to zimberelimab alone. The median overall survival (OS) for the combination treatment had not been reached, whereas it was 24.4 months for zimberelimab and 11.9 months for chemotherapy. Progression-free survival (PFS) also improved significantly, standing at 11.5 months for the combination therapy, compared to 6.2 months for zimberelimab and 9.6 months for chemotherapy.

Dimitry Nuyten, Arcus's chief medical officer, highlighted the significance of these findings, noting that this was the first instance of improved overall survival reported for domvanalimab and zimberelimab. He emphasized that the results contribute to the evidence that domvanalimab could offer differentiated efficacy, safety, and tolerability compared to other Fc-enabled anti-TIGIT antibodies.

In terms of safety, the combination of domvanalimab and zimberelimab was generally well-tolerated, with fewer treatment-related adverse events (TRAEs) leading to discontinuation than chemotherapy. The discontinuation rate due to side effects was 23.5% for chemotherapy, compared to 10.5% for the combination therapy and 7.5% for zimberelimab alone. Grade ≥3 TRAEs were also more frequent with chemotherapy (47.1%) than with the combination therapy (21.1%) or zimberelimab monotherapy (15%). Treatment-related deaths were lower in the combination arm (2.6%, one case of sudden death) compared to zimberelimab (10%, various causes) and chemotherapy (11.8%, various causes).

In summary, while the TIGIT inhibitor class faces significant challenges, Arcus Biosciences' recent data on domvanalimab and zimberelimab presents a hopeful outlook. These findings suggest that the combination therapy could potentially offer a differentiated and effective treatment option for patients with advanced or metastatic NSCLC.