TIGIT Therapies Face Setbacks, but Key Players Persist in Development

In recent months, the pharmaceutical industry has witnessed a series of disappointments in the development of TIGIT-targeting therapies. Despite these setbacks, several companies remain committed to advancing candidates in this once-promising immuno-oncology space. This article examines the current landscape of TIGIT-focused drug development, highlighting both the challenges and the ongoing efforts to bring these therapies to market.

TIGIT: A Complex Target with Persistent Challenges

TIGIT (T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain) is a receptor found in certain immune cells that plays a role in regulating cytokine release and suppressing T cell activity. Overexpressed in many cancers, TIGIT has been identified as a potential target for enhancing the body's antitumor response. However, the complexity of the TIGIT pathway has proven to be a significant hurdle in drug development.

Several high-profile failures have marked the TIGIT landscape in recent years. Roche's tiragolumab failed to improve survival in non-small cell lung cancer (NSCLC) patients in two separate trials, SKYSCRAPER-06 and SKYSCRAPER-01. Merck encountered similar difficulties, terminating late-stage studies of its anti-TIGIT antibody vibostolimab due to treatment toxicity and safety concerns. Most recently, GSK's partnership with iTeos Therapeutics ended after their candidate, belrestotug, failed to demonstrate improved progression-free survival in NSCLC and head and neck cancer trials.

Dr. Padmanee Sharma, a professor at MD Anderson Cancer Center, notes that the exact mechanism of TIGIT is not fully understood, suggesting that other proteins may be involved or that TIGIT itself may have additional cellular functions. This lack of complete understanding has contributed to the difficulties in developing effective therapies.

Persisting Players in TIGIT Development

Despite these setbacks, several pharmaceutical companies are continuing their efforts to develop TIGIT-targeting therapies, each with a unique approach:

AstraZeneca's Broad Development Program

AstraZeneca is pursuing an extensive late-stage development program for its TIGIT therapy, rilvegostomig. The company has 10 Phase III studies underway, exploring applications in NSCLC, gastric cancer, biliary tract cancer, and other solid tumors. Rilvegostomig's bispecific structure allows it to target both TIGIT and PD-1, potentially leading to enhanced immune activation and improved anti-tumor responses.

Early results have been promising, with Phase Ib data showing a 57.5% confirmed overall response rate (ORR) and a 95% disease control rate in advanced or metastatic NSCLC when combined with the antibody-drug conjugate Datroway.

Gilead and Arcus Biosciences' 'Silent' Approach

Gilead and Arcus Biosciences are co-developing domvanalimab, a monoclonal antibody targeting TIGIT. Unlike some competitors, domvanalimab features Fc-silent properties, which may minimize unintended effects on non-target cells. The partners are testing domvanalimab in combination with Arcus' PD-1 inhibitor zimberelimab and chemotherapy for NSCLC, upper gastrointestinal cancer, and head and neck carcinoma.

Recent data from the Phase II EDGE-Gastric trial showed a 58.5% ORR and 57.6% 12-month progression-free survival in gastric cancer patients. The partners have now advanced to late-stage development with the STAR-221 study in gastric and esophageal cancers.

As the TIGIT landscape continues to evolve, these persistent players are hoping that their differentiated approaches will yield success where others have faltered. The coming years will be crucial in determining whether TIGIT-targeting therapies can overcome the challenges that have hindered their development thus far and deliver on their initial promise in cancer treatment.