Lilly moves to overtake Relay

In the race to develop a wild-type sparing PI3Kα inhibitor Relay Therapeutics looked like it had pulled ahead of its bigger rival Lilly – but now Lilly has made a bold move that could see it overtake.

While Relay’s phase 3 trial, unveiled several months ago, is evaluating RLY-2608 in second-line breast cancer, Lilly has gone straight for the front line with its Scorpion-originated asset, tersolisib, a new clinicaltrials.gov listing has revealed.

New tune

The new study, Pikalo-2, is slated to begin in October in ER-positive, HER2-negative breast cancer with PIK3CA mutations. It will comprise two parts: the first will enrol patients with zero to two prior therapies, while the second will recruit treatment-naive subjects (although prior periadjuvant therapy is allowed).

However, the first portion is merely intended for dose optimisation, a Lilly spokesperson told ApexOnco. Pikalo-2 will compare tersolisib plus an endocrine therapy (eg, Faslodex) and CDK4/6 inhibitor like Kisqali against endocrine therapy plus CDK4/6 inhibitor alone. The primary endpoint is ORR (part one) and progression-free survival (part two).

Tersolisib was originated by Scorpion, where it was known as STX-478; Lilly acquired that company in January for an undisclosed up-front fee, a move that marked the big pharma’s third shot at PI3K inhibition.

That came not long after Scorpion reported data at ESMO from the phase 1/2 Pikalo-1 solid tumour trial, which found a 23% ORR with tersolisib monotherapy among 22 breast cancer patients. Most of these had previously received a CDK4/6 inhibitor.

Pikalo-1 is also testing a tersolisib/Faslodex doublet and a tersolisib/Faslodex/CDK4/6 inhibitor triplet; in December Scorpion additionally agreed to evaluate a triplet containing Pfizer’s CDK2 inhibitor atirmociclib, slated to begin in the second half.

No data appear to have been released yet with any of these combos. Presumably Lilly has some results in house, but the group looks like it’s taking a gamble by hurrying into combinations and into the front line.

Still discovering

Meanwhile, Relay seems to be taking a more measured approach. That group’s phase 3 trial, ReDiscover-2, will enrol post-CDK4/6 inhibitor patients, and test RLY-2608 plus Faslodex, versus AstraZeneca’s AKT inhibitor Truqap plus Faslodex.

The move is backed by the phase 1/2 ReDiscover trial, where the RLY-2608/Faslodex combo produced an ORR of 39% among 31 second-line-plus patients.

Meanwhile, Relay’s first-line plans are vague. Here the group is also evaluating a triplet, of RLY-2608 plus Faslodex plus either atirmociclib or Kisqali, with a view to starting a registrational trial. However, timings are unclear. Relay isn't short of cash, with $650m in the bank, enough to get it into 2029, but it clearly has less resources than Lilly, which might help explain its caution.

More selective?

A couple of PI3Kα inhibitors are approved in the US, namely Novartis’s Piqray and Roche’s Itovebi, though both hit wild-type as well as mutant forms of the protein, and come with warnings on their US labels.

It’s hoped that wild-type sparing projects could be less toxic. Others have gone further, developing molecules that targeting specific mutations; however, Lilly pulled back from the latter approach when it discontinued the H1047R mutant-specific LOXO-783 in August 2024.

Lilly had also been developing another wild-type sparing project, LY4045004, but that doesn’t appear to have entered the clinic. For now it's going all in with tersolisib, and the next couple of years should show whether this aggressive approach pays off.

Wild-type sparing PI3Kα inhibitors in PIK3CA-mutant ER+ve/​HER2-ve breast cancer

Note: Pikalo-2 details for part 2 only – part 1 intended for dose optimisation. Source: OncologyPipeline.