AACR 2025 preview – Roche's TIGIT postmortem

A post-mortem of the failed Skyscraper-01 study of Roche's anti-TIGIT MAb tiragolumab features at one of the highest-profile plenaries at next month's AACR conference. Tiragolumab had once been hotly touted, but its almost total failure has accompanied setbacks with other large clinical programmes targeting TIGIT.

Skyscraper-01 is among a handful of studies that will be unveiled at clinical trial plenaries during AACR, and these will also include the surprisingly successful Keynote-689, on the back of which Keytruda has been filed for perioperative head and neck cancer, as well as a first-in-human trial of another Roche project, the Werner helicase inhibitor RO7589831.

Though much of the AACR programme was unveiled on Tuesday after market, the most important data details remain embargoed. This is the case for all clinical trial plenaries, for which only the abstract titles are available at present.

Survival mystery

For Roche much is already known about Skyscraper-01, an extensively delayed study that combined tiragolumab with Tecentriq in first-line PD-L1-high lung cancer, and was said to have failed the final analysis of its OS co-primary endpoint last November.

Among key question to be answered at the AACR postmortem will be whether the OS data deteriorated meaningfully from an interim data cut, leaked in 2023 and found to have delivered a 0.81 hazard ratio. It's possible, for instance, that the early result was flattered by censoring. PFS was already known to have been a bust, and perhaps more will be revealed about the extent of this flop.

Though data from failed trials are largely of academic interest, Skyscraper-01 was a key litmus test of the TIGIT craze, whose fall from grace featured the discontinuation of Merck's vibostolimab in phase 3, and setbacks at BeiGene and Arcus/Gilead.

The company most invested in TIGIT now is AstraZeneca, with the bispecific rilvegostomig, while GSK put the iTeos-derived belrestotug into phase 3 recently. Tiragolumab's only realistic remaining hope is first-line liver cancer, where the Skyscraper-14 trial could deliver data over the next 12 months.

Selected presentations at AACR's clinical trials plenaries

Merck had more success with Keytruda in head and neck cancer, where Keynote-689, testing neoadjuvant Keytruda followed by adjuvant Keytruda plus chemo and radiotherapy, was said last October to have met its primary endpoint of event-free survival versus chemo/radiotherapy alone.

The data have been filed for US approval, and the FDA has set a 23 June PDUFA date. Should a decision to approve be made before this, the numbers will be published for all to see on Keytruda's label, thus scooping the AACR plenary on 27 April.

Among other clinical trial plenaries at the conference, Roche is to reveal what look like first-in-human data for its Werner helicase inhibitor RO7589831, an asset licensed in 2020 from Vividion for $135m up front. This synthetic lethality mechanism has generated some interest, with GSK licensing Ideaya's IDE275/GSK4418959, for instance, though as yet there's been little definitive proof of its potential.

Also in the spotlight is Revolution's RAS(on) G12D inhibitor zoldonrasib, due to deliver data from a NSCLC cohort of a solid tumour trial that yielded results in pancreatic cancer at last year's Triple meeting. And first-in-human results are due from on Joyo's ROS1 inhibitor JYP0322, a molecule said to overcome G2032R, a resistance mechanism seen with drugs like Lorbrena.

AACR takes place in Chicago on 25-30 April.