More bad vibes kill off Merck’s TIGIT and Lag3

TIGIT and Lag3 have looked liked dead ends for some time, and Merck is finally admitting defeat, discontinuing its contenders vibostolimab and favezelimab respectively.

Both assets, which were being investigated as fixed-dose combinations alongside Keytruda, have had various blow-ups. The final straw for vibostolimab was the failure of the important first-line non-small cell lung cancer trials Keyvibe-003 and Keyvibe-007, which Merck disclosed on Monday evening.

The company said that in a planned analysis both studies had met futility criteria for the primary endpoint of overall survival. Merck also said there were more immune-mediated adverse events with the combo versus Keytruda alone, mirroring previous experience with vibostolimab.

Following these disappointments, Merck has also discontinued the Keyvibe-006 study in stage III NSCLC, where vibostolimab plus Keytruda was being tested against AstraZeneca’s PD-L1 blocker Imfinzi.

Other recent flops for vibostolimab include Keyvibe-002 in third-line NSCLC, Keyvibe-010 in adjuvant melanoma and, most recently, Keyvibe-008 in small-cell lung cancer. At the time there were questions about why Merck started Keyvibe-008 at all, given the failure of Roche’s troubled TIGIT contender tiragolumab in a similar study back in 2022.

Mid to late-stage Keyvibe trials of vibostolimab + Keytruda fixed-dose combo

Source: OncologyPipeline & clinicaltrials.gov.

And now there will be questions about why Merck, and others, persevered for so long with this mechanism. Tiragolumab is still in play, but only just, following the recent flop of Skyscraper-01 first-line NSCLC trial.

Other companies still active in TIGIT include Arcus/Gilead, GSK/iTeos, BeiGene and AstraZeneca. Astra recently started another phase 3 trial with its anti-TIGIT x PD-1 MAb rilvegostomig, a move that might end up looking rash.

Lag3 lack

Lag3 has had more success, with the approval of Bristol Myers Squibb’s Opdualag, a fixed-dose combination of relatlimab and Opdivo. However, that drug has disappointed outside its marketed melanoma use, most recently in NSCLC.

Merck’s own contender, favezelimab, also recently fell short in colorectal cancer, where it was being tested alongside Keytruda in the Keyform-007 trial.

The company is now stopping enrolment into Keyform-008, in classical Hodgkin lymphoma patients progressed on prior PD-1 inhibitors – the only Keyform trial that hasn’t yet read out.

The trigger for this decision, according to Merck, was a “thorough evaluation” of the data on favezelimab, and wasn’t spurred by toxicity concerns.

Merck isn’t the only one to have pulled out of this class recently: Roche slipped the discontinuation of its PD-1 x Lag3 bispecific tobemstomig into its Pharma Day presentation at the end of September.

Plenty of Lag3 projects are still in development, though. Notably, Regeneron’s contender fianlimab might have an edge over Opdualag in melanoma, while a key test in NSCLC is approaching. Other players include BeiGene and Akeso, which has two shots here, with Lag3 x PD-1 and Lag3 x CD73 projects.