An update from Merck & Co on its KeyVibe-002 trial featuring the TIGIT inhibitor vibostolimab, co-formulated with Keytruda (pembrolizumab), with or without docetaxel in second-line metastatic non-small cell lung cancer (NSCLC), revealed that the vibostolimab–Keytruda co-formulation alone did not increase progression-free survival (PFS) compared to docetaxel. Patients in this arm of the trial are now being switched to the standard of care.

However, the remaining arms of the trial are continuing to ascertain the efficacy of the co-formulation combined with docetaxel compared to docetaxel alone. Given that Lilly’s Cyramza (ramucirumab) in combination with docetaxel has already been shown to prolong overall survival compared to docetaxel alone in the Phase III REVEL trial, however, any improvement with the vibostolimab–Keytruda co-formulation would still lead to questions surrounding where this could be best utilised.

This data is the latest in a line of disappointing results from TIGIT inhibitors, following the high-profile failure of Roche’s tiragolumab in two Phase III trials in small-cell lung cancer (SKYSCRAPER-02) and first-line NSCLC (SKYSCRAPER-01) last year.

But with so much invested in this target already, there is a reluctance to completely abandon it. Both Merck & Co and Roche have indicated that they are still pursuing approvals for their TIGIT inhibitors. Several other candidates remain in multiple registrational trials, including Novartis/BeiGene’s ociperlimab. AstraZeneca is also backing TIGIT, with a Phase III trial of its PD-1/TIGIT bispecific rilvegostomig planned for 2023. Finally, Bristol Myers Squibb (BMS) and GSK, following multi-million dollar deals with Agenus and iTEOS respectively, have multiple Phase I/II trials ongoing.

Some slightly more positive news for this class came late last year, when Arcus/Gilead presented an update on their TIGIT inhibitor, domvanalimab, in first-line NSCLC at December’s meeting of the American Society of Clinical Oncology (ASCO). Although domvanalimab in combination with zimberelimab (Arcus’s PD-1 inhibitor) did show an increase in PFS compared to zimberelimab alone in the ARC-7 study, the data was ultimately underwhelming, with concerns raised about the efficacy of the zimberelimab control arm. It was therefore not likely to infuse great confidence in the class.

TIGIT inhibitors may yet prove valuable assets in the fight against cancer, but the initial enthusiasm for this target has certainly dampened, and expectations have been recalibrated. A more innovative approach could pay off: for example, Compugen is combining its TIGIT inhibitor COM902 (from which rilvegostomig is derived), with Keytruda and COM701, which targets another checkpoint inhibitor, PVRIG, which it is hoped will enhance efficacy.

With so much invested, and so many trials ongoing, a wealth of data can be expected on this class in the next few years, potentially revealing the patient subgroups which can benefit most from this therapy. However, none of these candidates are likely to replace the sizeable income stream lost once blockbuster PD-1 inhibitors lose patent protection towards the end of the decade.