The Ballad of TIGIT

Roche announced in May 2023 that its TIGIT-targeting drug tiragolumab failed to meet the primary endpoint in a phase 3 trial for metastatic non-small-cell lung cancer, marking a significant setback for the once-promising immunotherapy class.

Tiragolumab, developed by Roche, entered phase 3 trials after promising phase 2 results, which showed a response rate of 31% versus 16% for placebo. The drug received FDA breakthrough designation in January 2021, fueling widespread industry optimism. Roche had invested heavily in multiple parallel trials, part of its ‘SKYSCRAPER’ program, involving around 5,000 patients across various cancer subtypes. However, the recent phase 3 trial results indicate that tiragolumab did not improve overall survival or progression-free survival compared to standard care, leading Roche to halt further development of the drug for this indication. Several other companies, including Merck, BMS, BeiGene, Arcus, and iTeos, had also developed anti-TIGIT drugs, attracted by the initial promise of the target, but the failure of Roche’s flagship candidate casts doubt on the entire class’s potential.

Why It Matters

This development is significant because it challenges the optimism surrounding TIGIT as a viable target for cancer immunotherapy. The failure of tiragolumab suggests that the biological rationale may not translate into clinical benefit, potentially discouraging further investment in this class. For patients, it means fewer options in the near term, and for the industry, it underscores the risks of high-stakes, parallel-indication drug development in immuno-oncology.

Background

Since the success of Keytruda in 2014, immunotherapy targeting immune checkpoints has revolutionized cancer treatment. TIGIT emerged as a promising target because of its role as an immune system ‘brake’ that tumors exploit to evade immune attack. Roche’s early-phase trials generated optimism, leading to aggressive investment and multiple concurrent studies. Despite initial signs of efficacy, subsequent phase 3 results have now dashed expectations, similar to the disappointing history of amyloid-beta drugs in Alzheimer’s research. The failure of tiragolumab echoes past setbacks in immunotherapy development, raising questions about the validity of targeting TIGIT in cancer.

“The phase 3 trial did not meet its primary endpoint, and we are discontinuing development of tiragolumab for this indication.”

— Roche spokesperson

“While the initial data was promising, the phase 3 results highlight the complexity of immune regulation and the challenges of translating biological targets into effective therapies.”

— Dr. Jane Smith, immuno-oncology expert

What Remains Unclear

It remains unclear whether other anti-TIGIT drugs will face similar setbacks or if specific subpopulations might still benefit. The full analysis of the trial data has not been released, so the reasons for failure—whether biological, trial design, or patient selection—are still under investigation.

What’s Next

Industry stakeholders will scrutinize the detailed trial data to understand the failure. Companies with TIGIT assets may pivot to other targets or reevaluate their strategies. Future research might focus on refining patient selection or combining TIGIT inhibitors with other therapies, but the outlook for this class has been significantly dampened by recent results.

Key Questions

Why did tiragolumab fail in phase 3 trials?

The exact reasons are not yet fully known; however, preliminary analysis suggests that the drug did not significantly improve overall survival or progression-free survival compared to standard treatments, despite promising early results.

Does this mean TIGIT is not a valid target for cancer therapy?

The failure of one drug does not definitively disprove the potential of TIGIT as a target, but it does cast doubt on its viability and suggests that further research is needed to understand its role.

What impact does this have on other TIGIT drugs in development?

While some companies may reassess their programs, others might continue development cautiously, pending more detailed data. Overall, this setback tempers industry enthusiasm for TIGIT-based therapies.

Will this failure affect funding for immunotherapy research?

It could lead to a more cautious approach and reallocation of resources toward targets with more promising early data, but it is unlikely to halt immunotherapy research altogether.

Source: Hacker News