iTeos Therapeutics and GlaxoSmithKline (GSK) have announced the discontinuation of their investigational anti-TIGIT monoclonal antibody belrestotug (EOS-448/GSK4428859) after the therapy failed to demonstrate sufficient efficacy in two Phase II clinical trials. The studies evaluated belrestotug in patients with non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC).
The decision marks another significant setback for the TIGIT (T cell immunoreceptor with Ig and ITIM domains) inhibitor class, which has been viewed as a promising but increasingly challenging pathway in immuno-oncology.
Trial Results and Decision
The Phase II trials evaluated belrestotug in combination with GSK's PD-1 inhibitor dostarlimab in both treatment-naïve and previously treated patients. According to the companies, the studies failed to meet their primary efficacy endpoints, with the drug showing insufficient clinical benefit to warrant continued development.
"While we are disappointed by these results, they provide important insights into the complex biology of the TIGIT pathway," said Michel Detheux, Ph.D., President and CEO of iTeos Therapeutics. "Our rigorous approach to clinical development means making data-driven decisions, even difficult ones, to ensure we focus resources on programs with the highest probability of benefiting patients."
The companies did not release detailed efficacy data but indicated that the safety profile remained consistent with previous observations from earlier-stage trials.
Impact on the TIGIT Landscape
Belrestotug's failure adds to mounting challenges for the TIGIT inhibitor class. Several pharmaceutical companies have invested heavily in this pathway, which theoretically offers a complementary mechanism to PD-1/PD-L1 inhibition by targeting a different immune checkpoint.
"The TIGIT story has become increasingly complex," said Axel Hoos, M.D., Ph.D., Chief Medical Officer at GSK. "While we've seen promising biomarker modulation and preclinical synergy with PD-1 inhibition, translating these findings into meaningful clinical outcomes has proven more difficult than anticipated."
The setback follows other disappointments in the TIGIT field, including Roche's tiragolumab, which has shown mixed results across multiple trials. However, some TIGIT programs remain in active development, with companies exploring biomarker-driven approaches to identify patient populations most likely to benefit.
Scientific Context and Mechanism
TIGIT functions as an immune checkpoint that suppresses T cell and natural killer (NK) cell activity. By blocking TIGIT, researchers hoped to enhance anti-tumor immune responses, particularly when combined with PD-1/PD-L1 inhibitors.
The scientific rationale for targeting TIGIT remains sound, according to immunology experts. "The challenge isn't necessarily with the biology of TIGIT itself, but rather with our understanding of which patients might benefit most from its inhibition," explained Jennifer Wargo, M.D., a professor of surgical oncology and genomic medicine at MD Anderson Cancer Center, who was not involved in the trials.
Business Implications
For iTeos, a clinical-stage biopharmaceutical company focused on developing novel immuno-oncology therapeutics, the discontinuation represents a significant pipeline setback. The company's stock declined following the announcement.
GSK, which had partnered with iTeos in June 2021 in a deal worth up to $2.1 billion, will likely redirect resources to other oncology programs in its portfolio. The collaboration had been viewed as a strategic move by GSK to strengthen its position in immuno-oncology.
"Both companies will continue to analyze the data to extract valuable scientific insights that may inform future immuno-oncology approaches," said Hesham Abdullah, Senior Vice President of Oncology R&D at GSK. "We remain committed to advancing innovative cancer therapies through our diverse pipeline."
Future Directions
Despite this setback, both companies emphasized their commitment to oncology research. iTeos continues to advance its adenosine pathway inhibitor program, including EOS-850, an A2A receptor antagonist currently in clinical development.
The broader scientific community remains interested in understanding why TIGIT inhibitors have underperformed in clinical trials despite promising preclinical data. Ongoing research is focusing on potential biomarkers that might identify responsive patient subgroups and exploring novel combination approaches.
"The field is still learning how to optimally target immune checkpoints beyond PD-1," noted Roy Baynes, M.D., Ph.D., a prominent oncology researcher. "Each disappointment provides valuable lessons that ultimately advance our understanding of cancer immunology."
Industry analysts suggest that while the TIGIT pathway has faced challenges, interest in novel immune checkpoint inhibitors remains strong, with several other targets being explored in early-stage clinical trials.
