Roche’s Tigit fail poses a big question for Merck

 The failure of Roche’s tiragolumab in front-line small-cell lung cancer is not the end of the world for Tigit blockade, or for Roche’s extensive programme here, but it raises a key question for Merck & Co: should Merck even bother with a rival study in the same setting?

By coincidence Merck’s Keyvibe-008 trial is due to begin tomorrow, according to its clinicaltrials.gov listing. The study is analogous to Skyscraper-02, which Roche today said had failed, in a virtually identical setting and with the same comparator; and there is reason to believe that Merck’s chances of success are even lower than Roche’s.

Both trials aim to show that combined Tigit and PD-(L)1 blockade plus chemo can beat Tecentriq plus chemo. Roche this morning said that in Skyscraper-02 its anti-Tigit contender tiragolumab had failed to add anything to the Tecentriq/chemo standard in terms of progression-free or overall survival.

Keyvibe-008 seeks to test Keytruda plus Merck’s anti-Tigit vibostolimab and chemo in first-line SCLC, also against Tecentriq plus chemo. Crucially, however, Keytruda plus chemo has itself already failed to beat chemo in first-line SCLC, courtesy of the phase 3 Keynote-604 study. Tecentriq plus chemo did manage this in the registrational Impower-133 trial.

Put bluntly: Merck is trying to show that Tigit, a mechanism that just failed in this setting, added to Keytruda, a drug that earlier failed in this setting, can beat a newly established standard of care.

Of course, there are caveats. For a start, not every Tigit blocker works in an identical way. Keynote-604 did not fail by much – it showed a statistical benefit on PFS; OS was missed in all-comers, but on an as-treated basis it was a hit. Finally, Skyscraper-02 and Keyvibe-008 are not identical, with subtle differences in patient profiles and dosing schedules.

Asked whether Merck would go ahead with Keyvibe-008 the company confirmed to Evaluate Vantage that it had initiated the trial.

Roche and Merck square up in Tigit
Setting	Roche trials with tiragolumab…		…Merck & Co trials with vibostolimab
1L SCLC	Skyscraper-02	Tigit + Tecentriq + chemo, vs Tecentriq + chemo	Keyvibe-008	Tigit + Keytruda + chemo, vs Tecentriq + chemo
1L PD-L1+ve NSCLC	Skyscraper-01*	Tigit + Tecentriq, vs Tecentriq	Keyvibe-003	Tigit + Keytruda, vs Keytruda
Stage III NSCLC	Skyscraper-03**	Tigit + Tecentriq, vs Imfinzi	Keyvibe-006	Tigit + Keytruda + CRT, vs Imfinzi + CRT
1L NSCLC chemo combo	Skyscraper-06^	Tigit + Tecentriq + chemo, vs Keytruda + chemo	Keyvibe-007	Tigit + Keytruda + chemo, vs Keytruda + chemo
Notes: CRT=chemoradiotherapy; *PD-L1 "high"; **after, but not progressed on, CRT; ^non-squamous. Source: company filings.

For Roche Skyscraper-02 was always a long shot. The phase 3 study was one of several launched as the Swiss company ramped up its investment in the Tigit programme, but tiragolumab had no precedent against SCLC in earlier trials.

Here Roche’s other big 2022 tiragolumab readout, the Skyscraper-01 trial in PD-L1-high NSCLC, differs. The earlier phase 2 Cityscape study showed a 77% reduction in risk of death with the combo versus Tecentriq alone in PD-L1 ≥50% expressers.

Merck’s analogous trial in this setting is Keyvibe-003, testing vibostolimab plus Keytruda versus Keytruda alone, though the precise level of PD-L1 expression patients need to have is not clear; this might be ≥1%, since this is what Keytruda’s front-line NSCLC monotherapy label requires. Both companies will also duel in chemo combo NSCLC trials, and in stage III disease.

Roche, which is the more advanced of the two, has 2022 Tigit readouts in two other settings, cervical and oesophageal cancers, where Merck is testing vibostolimab as part of the phase 2 basket study Keyvibe-005. Both companies clearly think there is still much to play for.

Other studies in the Skyscraper and Keyvibe Tigit programmes
Study	Setting	Design	Primary endpoint	Results?
Tiragolumab (Roche)
Skyscraper-04	2L PD-L1+ve cervical cancer	Tecentriq combo, vs Tecentriq	ORR	Data in 2022
Skyscraper-02C*	1L SCLC (China)	Tecentriq + chemo combo, vs Tecentriq + chemo	PFS & OS	Ends Jun 2022
Skyscraper-08*	1L oesophageal cancer	Tecentriq + chemo combo, vs chemo	PFS & OS	Data in 2022
Skyscraper-09	1L PD-L1+ve sq head & neck carcinoma	Tecentriq combo, vs Tecentriq	ORR	Ends Jan 2023
Skyscraper-07*	Oesophageal squamous cell carcinoma maintenance	Tecentriq combo vs placebo, Tecentriq vs placebo	PFS & OS	Ends Dec 2024
Skyscraper-05	Neoadjuvant & adjuvant NSCLC	Tecentriq +/- chemo combo	Safety & mPR^	Ends Feb 2027
Vibostolimab (Merck & Co)
Keyvibe-002	2L NSCLC	Keytruda +/- chemo combo, vs chemo	PFS	Ends Mar 2023
Keyvibe-004	R/r haematological cancers	Keytruda combo	ORR**	Ends Sep 2024
Keyvibe-001	Solid tumours	Various combos	ORR**	Ends Jan 2025
Keyvibe-005	Solid tumours	Various combos	PFS & ORR	Ends Feb 2025
Note: *ph3 study, all others being ph1 or ph2; ^major pathological response; **secondary endpoint, primary being safety. Source: clinicaltrials.gov & company statements. https://www.evaluate.com/vantage/articles/news/trial-results/roches-tigit-fail-poses-big-question-merck