Roche racks up phase 3 TIGIT win, but trial design leaves doubts

Roche has bagged a phase 3 win in TIGIT. But the victory falls short of being a clear-cut endorsement of the mechanism, with the use of a comparator that is no longer the standard of care complicating efforts to tease out the impact of the investigational antibody.

The data come from SKYSCRAPER-08, the phase 3 trial that caused headlines last year amid speculation that it was set to join the list of TIGIT failures. That chatter was proven wrong on Tuesday evening, when Roche shared the final data in an abstract ahead of its presentation at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium this week.

In the study, which enrolled 461 esophageal cancer patients in five Asian countries, the participants who received Roche’s TIGIT candidate tiragolumab, PD-L1 drug Tecentriq and chemotherapy lived longer than their counterparts on placebo and chemotherapy. 

Median overall survival in the treatment arm was 15.7 months, compared to 11.1 months in the control group, causing the study to hit one of its primary endpoints. The trial met its second primary endpoint by linking the TIGIT regimen to progression-free survival of 6.2 months, versus 5.4 months for the control.

While the results were statistically significant, the choice of comparator arm leaves scope to question the clinical significance of the findings. The current first-line standard of care in patients with advanced esophageal squamous cell carcinoma is checkpoint inhibitor plus platinum-based doublet chemotherapy. 

In SKYSCRAPER-08, a checkpoint inhibitor was used in the TIGIT regimen but not in the control cohort. As such, the study is unable to show what additional benefit tiragolumab provides on top of the checkpoint inhibition that is now standard of care. The benefit of the antibodies was “generally consistent” across patients with different PD-L1 status, a factor that influences the efficacy of checkpoint inhibitors. 

Roche is running another esophageal cancer study, SKYSCRAPER-07, that could clear up the uncertainty. That phase 3 trial is assessing tiragolumab and Tecentriq in patients who have not progressed following definitive concurrent chemoradiotherapy. One third of patients are taking both drugs. Another third are on placebo plus Tecentriq. And the final third are receiving two placebos. The trial is running until 2027. 

The study is one of seven phase 3 trials that Roche started in 2020 to evaluate tiragolumab in a range of settings, and part of a broader, multi-company push to show the effect of TIGIT blockade on cancer. Gilead and Merck & Co. are among the companies running phase 3 trials of rival anti-TIGIT antibodies. Setbacks have raised doubts about the mechanism, but the frontrunners have decided to stay the course.