Relay passes the baton to atirmociclib

It’s a sign of the perceived future importance in breast cancer of Pfizer’s CDK4 inhibitor atirmociclib that another company has selected this to be its combo partner, in preference to an established CDK4/6 inhibitor like Ibrance or Novartis’s Kisqali.

That company is Relay Therapeutics, which on Monday revealed plans for a phase 3 study of its pan-mutant PI3Kα inhibitor zovegalisib, plus atirmociclib and an aromatase inhibitor, in first-line PI3Kα-mutated disease. Here Relay is behind Lilly, which put its pan-mutant PI3Kα inhibitor, tersolisib, into the first-line Pikalo-2 study last year; that trial, however, tests a combo with a CDK4/6 inhibitor.

Thus an interesting split is developing between Lilly and Relay, with the former going on top of the established standard of care, and the latter betting on a possible future – though currently unapproved – one. Similar bets on atirmociclib combos in first-line breast cancer have been made by Olema with palazestrant, and by Arvinas with vepdegestrant, though the latter plan was abandoned.

Risks

The big risk for such approaches is that atirmociclib might yet fail to make it to market, a concern not helped by Pfizer dialling back some work on this molecule last year. It’s possible that Relay feels the need to take a risk on this given that it’s fallen behind Lilly, a situation that won’t be helped by the fact its planned phase 3 trial won’t even start until 2027.

And that’s not the only risk Relay is now taking. The company doesn’t appear ever to have tested a zovegalisib/atirmociclib/aromatase triplet in first-line patients, and is instead citing second-line plus data, in addition to pharmacokinetic findings backing its molecule’s “combinability”, positive drug interaction and relatively good tolerability.

Pan-mutant PI3Kα inhibition has become a big deal after Lilly pulled back from a mutant-specific approach in favour of tersolisib, which it gained through the acquisition of Scorpion. More recently this field has seen Novartis acquire Synnovation for $2bn, and OnKure discontinue the H1047R mutation-specific molecule OKI-219 to focus on a yet unnamed pan-mutation project.

The race between Relay and Lilly has seen the lead change several times. Zovegalisib was first into the clinic with a pivotal trial, but that was the Rediscover-2 study, in patients refractory to one line of CDK4/6 therapy; Lilly counterattacked shortly afterwards, taking tersolisib into the first-line Pikalo-2 trial last October.

Pivotal trials of tersolisib & zovegalisib

Source: OncologyPipeline.

On Monday Relay cited phase 1 data with the atirmociclib-containing triplet in patients after a median two therapies, claiming a 44% response rate. Across trials this compared favourably against around 30% for Roche's approved PI3Kα-selective inhibitor Itovebi plus Faslodex and either Kisqali or Verzenio; meanwhile, first-line CDK4/6 inhibition plus aromatase inhibition gives ORRs of 53-55%, Relay said.

For its part Scorpion’s phase 1/2 Pikalo-1 solid tumour trial found a 23% ORR with tersolisib monotherapy among 22 breast cancer patients, most of whom had previously received a CDK4/6 inhibitor. That trial also tests tersolisib/Faslodex/atirmociclib and tersolisib/Faslodex/CDK4/6 inhibitor triplets; no data have been released on these, though Lilly will likely have some in house.

The only other PI3Kα pan-mutant (wild-type sparing) inhibitor in pivotal development appears to be Junshi Biosciences’ JS105, though little is known about this molecule.