Three Tigit players look to surprise in 2023
But two have already disappointed, and the third has shown little to suggest a positive outcome.
After Gilead/Arcus’s Arc-7 study of domvanalimab yielded its first results last month, 2023 promises more catalysts for this and two other anti-Tigit projects. However, there is little to suggest that this drug class’s disappointing track record is about to change.
Domvanalimab itself will yield a more mature data cut from Arc-7 at Asco, but it is the first look at overall survival from the Skyscraper-01 study of Roche’s tiragolumab, due in the current quarter, that has investors’ immediate attention. And Merck & Co will soon present the first pivotal data for vibostolimab, an asset about which little has been disclosed.
Vibostolimab is an anti-Tigit MAb in a phase 2/3 programme called Keyvibe, whose scale rivals that of Roche’s Skyscraper trials. What little early results have emerged so far about the Merck asset have not generated great expectations.
The 2020 Esmo meeting showed data from the uncontrolled phase 1 Keyvibe-001 trial. Here a Keytruda combo yielded a 29% ORR in PD-(L)1 treatment-naive NSCLC – an underwhelming result given the 27% ORR in front-line disease cited on Keytruda’s label. In PD-(L)1 pretreated patients the ORR was a disappointing 5% for the combo, or 7% for vibostolimab monotherapy.
The next trial to read out will be Keyvibe-002, in the first half, possibly at Asco. This trial tests vibostolimab plus Keytruda, with or without chemo, against chemo, in NSCLC patients who have already progressed after immunotherapy and chemo; given the Keyvibe-001 data this seems unlikely to succeed.
First-line NSCLC
But the data might be used to handicap the chances of a much more important vibostolimab/Keytruda combo trial, Keyvibe-003 in first-line NSCLC, which has a December completion date.
This is the same setting in which Roche’s Skyscraper-01 bombed last year, with one important distinction: Keyvibe-003 enrols a broader population, expressing PD-L1 as low as 1%, versus Skyscraper-01’s ≥50% requirement. There is some hope that it might be easier for Merck to detect a combination effect in lower PD-L1 expressers.
Skyscraper-01 failed for progression-free survival, but no actual numbers from it have been revealed, so it is impossible to gauge the failure numerically or statistically. First data from Skyscraper-01’s more important endpoint, overall survival, are due in the current quarter.
Evercore ISI’s Umer Raffat has suggested that Roche allocated the vast majority of statistical powering in the study to OS – as it had in the SCLC Skyscraper-02 trial. If this is the case then the PFS result might be strong numerically but fail on a very stringent statistical basis and, most importantly, a hit on OS is still possible.
However, Roche’s wording around the time of the PFS readout suggests that this is a long shot, as does detail from the earlier Cityscape study. Final analysis of Skyscraper-01 is expected some six months after the OS readout.
| A battle of three Tigits | |||
|---|---|---|---|
| Study | Skyscraper-01 | Keyvibe-002 | Arc-7 |
| Company | Roche | Merck & Co | Gilead/Arcus |
| Setting | 1st-line NSCLC (≥50% PD-L1) | Post-PD-(L)1/chemo NSCLC | 1st-line NSCLC (≥50% PD-L1) |
| Design | Tiragolumab + Tecentriq, vs Tecentriq | Vibostolimab + Keytruda +/- chemo, vs chemo | Domvanalimab + zimberelimab, vs zimberelimab |
| What do we know? | Failed for PFS (no data) | Keyvibe-001 underwhelmed | Positive for PFS but clinically disappointing |
| What's expected? | First OS data | First data (PFS & OS?) | More mature PFS data |
| When? | Q1 2023 (then final analysis in Q3 2023) |
Asco | Asco (then first OS data later in 2023) |
| Why is it important? | Could reignite interest in Tigit if most alpha was allocated to OS, leading to a positive result | First controlled data for vibostolimab, could help handicap Keyvibe-003 in 1st-line NSCLC | Improved dataset could suggest better activity if combined with a better PD-(L)1 drug |
| Source: company disclosures. | |||
Analysts generally believe that until OS data from Skyskraper-01 are revealed interest in Gilead/Arcus’s first-line NSCLC Arc-7 study will remain muted. The initial read of PFS and ORR data from Arc-7 was numerically positive but clinically underwhelming, and the next catalyst is a more mature cut of PFS data and biomarker analysis, and should come at Asco. OS data will likely come towards the end of the year.
Like with Skyscraper-01 Evercore’s Mr Raffat takes a contrarian view of Arc-7, for instance citing the possibility of extra as-yet unconfirmed remissions being reported later. He also plays down the value of comparing Arc-7 to the ultimately misleading result of Roche’s Cityscape trial, which he stresses was based on a subgroup analysis.
One problem for domvanalimab is that it is being studied on top of zimberelimab, which appears to be a substandard anti-PD-1 MAb. But if Merck’s Keyvibe-003 fails, one conclusion could be that Merck has a poor Tigit and good PD-1 drug, while Gilead/Arcus have a good Tigit and poor PD-1.
The bull case for domvanalimab is that such a scenario would see Merck come knocking on Gilead/Arcus’s door.
