Roche’s next immuno-oncology combo is a big bet on Tigit

Almost in stealth mode the Swiss firm moves to begin a huge pivotal programme rivalling that of the IDO and IL-2 mechanisms.

Those who paid careful attention to Roche’s full-year financial presentation yesterday will have noticed that the company was moving its anti-Tigit antibody tiragolumab into a pivotal first-line small-cell lung cancer study in combination with Tecentriq. In terms of Roche’s ambitions, however, this is just the tip of the iceberg.

Speaking to Vantage yesterday the Swiss group revealed that the disclosed trial, Skyscraper-02, was one of no fewer than eight pivotal tiragolumab studies about to get under way. Nothing else is being revealed for competitive reasons – Merck & Co has a rival Tigit combo in phase II – but, after IDO and IL-2, Tigit has suddenly emerged as the industry’s next big immuno-oncology bet.

Of course, the quest for I-O mechanisms to boost PD-(L)1 blockade has been going on for years – without much success. Yervoy is still the only checkpoint blocker approved with an anti-PD-(L)1 drug, and Incyte’s epacadostat and Nektar’s bempegaldesleukin mark IDO and IL-2 respectively as the two biggest disappointments of this search so far.

Earlier in development, targeting such immune checkpoints as Tim3, Lag3 and Ox40 failed to deliver knockout data. If, as Roche hopes, tiragolumab comes to anything this could lead to renewed interest in biotechs including Arcus, Beigene and Compugen, which all have early-stage Tigit blockers in their pipelines.

Industry projects targeting Tigit
Project Company Trial Timing
Phase III
Tiragolumab (RG6058) Roche Skyscraper-02, Tecentriq + chemo combo in 1L SCLC Dosing to start w/c Feb 3, 2020; 7 other pivotal studies imminent
Phase II
MK-7684 Merck & Co Keynote-01A, Keytruda + chemo combo in 1L NSCLC 90 subjects; started Jan 15, 2020
BMS-986207 Bristol-Myers Squibb Monotherapy and Opdivo combo in various tumours 170 subjects; ends Dec 2022
Phase I
ASP8374 Astellas Pharma Monotherapy and Keytruda combo in various trumours 363 subjects; ends Jul 2021
AB154 Arcus Biosciences Monotherapy and AB122 (anti-PD-1) combo in various tumours 66 subjects; ends Jul 2020
BGB-A1217 Beigene Tislelizumab combo in various tumours 39 subjects; ends Apr 2021
Etigilimab (OMP-313M32) Mereo Biopharma Monotherapy and Opdivo combo in various tumours Mereo says study is "completing"; marked as "terminated" on
COM902 Compugen IND cleared to start phase 1 in 2020
IBI-939 Innovent IND cleared to start phase 1 in China
E0S884448 Iteos Therapeutics Was to have started phase 1 in 2019
AGEN1307 Agenus
CASC-674 Seattle Genetics
Source: EvaluatePharma & company presentations.

It is clear that work on Tigit has ramped up behind the scenes recently. Two weeks ago, and without the slightest fanfare, Merck & Co two begun Keynote-01A, a phase II study of that company’s anti-Tigit project MK-7684 in combination with Keytruda and chemo in first-line NSCLC.

Merck reported a 19% partial response rate in an earlier Keytruda combo study, though MK-7684’s monotherapy efficacy was negligible (SITC 2018 – The search for immuno-oncology combos continues, November 11, 2018). Beyond that data are scarce; Oncomed, now merged into Mereo, reported zero remissions in a study of etigilimab.

Given the lack of published data it is not immediately clear what has driven Roche’s enthusiasm here, though the group likely has an internal champion of Tigit. Genentech’s vice-president of oncology research, Ira Mellman, has spoken of Tigit as one of several I-O targets capable of synergising with PD-(L)1 blockade.

Neither is it known why SCLC is Roche’s first targeted indication. Tecentriq secured a first-line SCLC label on the back of the Impower-133 study, and its only threat here, Atrazeneca’s Imfinzi, looks like it might not amount to much (Surprise! There’s a tumour in which Keytruda doesn’t work, January 7, 2020).

Still, if numerous indications will be pursued perhaps SCLC just happens to have been the one that will start first. Roche has not revealed the design of Skyscraper-02, but more information will be available once the study is registered with; the first subject will be dosed next week, Roche told Vantage.

While virtually every checkpoint blockade approach after PD-(L)1 has underwhelmed, it is clear that companies are not giving up on next-generation I-O mechanisms just yet. The next move by Merck and others is keenly awaited.

This is an expanded version of an earlier story.

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