SABCS 2024 – Lilly's PI3Kα push is no longer mutation-specific

It didn't take long for Lilly to renew its push into PI3Kα inhibition, after the recent discontinuation of the initial lead molecule LOXO-783. A poster at San Antonio Breast Cancer Symposium has revealed a slightly different mechanism of action for the group's second attempt at this target, LY4045004, which is expected to enter clinical trials next year.

LY4045004 has been revealed to be a "pan-mutant-selective" inhibitor, meaning that it is wild-type sparing, but – like competitors from Relay and Scorpion, but unlike LOXO-783 – it's not specific for a single PI3Kα mutation. That Lilly should have taken a step back like this is strange, as is the fact that LY4045004 has actually sat quietly in its pipeline for four years.

The molecule was originated by a private entity called Petra Pharma, which Lilly acquired in May 2020. The acquisition price wasn't disclosed, but Lilly had been required to make future payments – a liability Lilly extinguished in 2022, paying the sellers of Petra a one-off $334m, according to an SEC filing.

However, after buying out this liability Lilly proceeded with the development of LOXO-783, a molecule specific for the H1047R mutation in PI3Kα, while LY4045004 languished as a preclinical asset. LOXO-783 entered the phase 1 Pikasso-01 study in May 2022, but was discontinued this year, with Lilly saying it would focus on a next-generation asset – now revealed to be LY4045004.

3% response rate

A separate SABCS poster this week concerned LOXO-783, and showed why Lilly decided to scrap the molecule: among 32 patients with PIK3CA H1047R-mutant advanced breast cancer LOXO-783 monotherapy gave a response rate of just 3%, while in 79 subjects given LOXO-783 with endocrine therapy ORR was 6%.

ORRs were slightly better in combination with endocrine therapy and Verzenio (17%) and Taxol (24%), but the poster concluded that high rates of diarrhoea limited the ability to achieve the optimal, preclinically identified LOXO-783 dose.

Meanwhile, the SABCS poster on LY4045004 said this molecule had preclinically been shown to inhibit kinase and helical PI3Kα mutations, while sparing wild-type PI3Kα and not inhibiting other PI3K isoforms. In particular tumour regression was seen in PI3Kα H1047R and E545K-mutant breast cancer models.

As such LY4045004 employs a similar mechanism to Relay's RLY-2608 and Scorpion's STX-478, which both spare wild-type PI3Kα without being specific for a particular mutation. Both molecules impressed clinically in PIK3CA-mutated breast cancer earlier this year, Scorpion's as monotherapy and Relay's in combination with Faslodex.

Relay presented an update at SABCS, now reporting a 39% confirmed ORR among 31 patients, up from the 30% in 30 patients it press released in September. For its part Scorpion had a SABCS poster repeating the dataset it presented at its ESMO late-breaker.

Too specific?

The idea behind developing ever more specific PI3K inhibitors is to avoid toxicity. Two PI3Kα inhibitors are now approved, 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. 

Lilly's discontinuation of LOXO-783, and the successes of Relay and Scorpion, suggests that there might be a limit to this specificity. Where this now leaves companies like OnKure and Cogent, which are continuing to plough the mutant-specific furrow, is an open question.

The PI3Kα inhibitor evolution

Source: OncologyPipeline.