A first for CCR8

It’s been two years since CCR8 emerged as a highly interesting target for the development of anticancer therapies, so it might come as a surprise that it’s only now that a molecule with this mechanism is set to start a phase 3 trial.

The honour belongs to Sino’s cafelkibart, which a new clinicaltrials.gov listing reveals will begin a pivotal Chinese study in CCR8-positive gastric and gastroesophageal junction adenocarcinoma in April. The development is of note to investors in Coherus, much of whose investment case rests on an anti-CCR8 project, and whose stock has risen 50% this year, partly on its promise.

Coherus picked up the anti-CCR8 MAb tagmokitug through its 2023 acquisition of the distressed biotech Surface Oncology. Last month Oppenheimer initiated coverage of Coherus, citing the potential of tagmokitug to deliver phase 1 readouts, in combination with Loqtorzi, this year; the settings include gastric/GEJ adenocarcinoma.

Combo promise

This sellside initiation might have helped drive up Coherus’s shares, but tagmokitug appears to be inactive as monotherapy, yielding zero responses among 19 subjects.

But the real promise of blocking CCR8, a protein expressed on T regulatory cells and thus thought to have an immunosuppressive action, is as part of a combination; this is why Coherus is betting on a Loqtorzi combo, though for now there’s little beyond mechanistic theory to suggest that tagmokitug will deliver here.

That’s obviously also the bet being made with Sino’s cafelkibart, whose phase 3 trial will test only a combination with Loqtorzi in the active cohort, and compare this against paclitaxel chemo. The planned 400 patients must all have CCR8 positivity confirmed by central laboratory – a novel requirement – and the study’s primary endpoint is overall survival.

Formally the trial’s sponsor is LaNova, the company that originated cafelkibart. But the molecule’s owner is Sino, which earlier held a 5% stake in LaNova, and last year paid up to $951m to acquire the remainder, presumably at least in part driven by the promise of cafelkibart as what was then a mid-stage pipeline asset.

And validation?

It’s cafelkibart that’s probably done more than any other anti-CCR8 project to validate clinically the promise of CCR8 as a target to be hit in combination with PD-(L)1.

Last year’s ASCO saw presentation of pooled data from two phase 1/2 trials in pancreatic cancer, where combination with Loqtorzi (China cohort) or with Keytruda (Australia) yielded an 18% confirmed response rate among 74 patients. Meanwhile, activity among 19 subjects given cafelkibart monotherapy was a far less impressive 5%, and that cohort was terminated.

In gastric cancer, a relevant setting given the new phase 3, cafelkibart plus PD-1 blockade delivered a 36% ORR among 36 patients, roughly half of whom had already progressed after PD-1 therapy. Presenters also argued that activity broadly correlated with CCR8 expression.

Several big names featured in the flurry of interest in CCR8 a couple of years ago, including Bristol Myers Squibb with imzokitug, Roche with RO7502175, Amgen with the Five Prime-originated AMG 355, Gilead with denikitug (ex Jounce) and BeOne with BGB-A3055. None of these early to mid-stage projects has yet yielded any meaningful human data.

The phase 2 & 3 anti-CCR8 MAb pipeline

Notes: ADC; *small molecule; the rest are naked MAbs. Source: OncologyPipeline.