ESMO 2024 – Scorpion joins Relay in the alpha club
What Relay managed with a combo Scorpion might be able to do with STX-478 monotherapy.
What Relay managed with a combo Scorpion might be able to do with STX-478 monotherapy.
The recently rekindled field of alpha-specific PI3K inhibition just got a new entrant. First-in-human data with Scorpion’s STX-478, presented as an ESMO late-breaker on Sunday, showed a level of monotherapy activity in breast cancer that could rival the data Relay put up last week with its contender, RLY-2608, in combination with Faslodex.
Though this is a cross-trial comparison the patient characteristics are reasonably similar, and the latest data support STX-478’s promotion to Scorpion’s pipeline lead, ahead of EGFR inhibitors. At a time when the likes of Lilly are showing an interest in inhibitors that spare wild-type PI3Kα the focus is on whether Scorpion and Relay alike can do this relatively safely.
Increasing selectivity
Toxicity has long been a problem with PI3K inhibitors, leading to developers seeking ever more selective molecules. The only PI3Kα inhibitor to be launched is Novartis’s Piqray, while Roche’s inavolisib faces a 27 November PDUFA date. These both hit mutant as well as wild-type PI3Kα, while Scorpion and Relay are working on allosteric inhibitors that spare the wild-type form.
Scorpion’s first-in-human study of STX-478 recruited patients with several solid tumours, and the headline number across all 43 who were efficacy evaluable was a 21% ORR; these were all partial responses, nearly half of which were unconfirmed – though all were subsequently confirmed after the June 2024 data cutoff.
The most common cancer in the study was ER-positive HER2-negative breast cancer, and these 22 patients yielded a 23% ORR. An even better response rate was seen in gynaecological tumours, but this concerned just nine patients, four of whom developed partial responses.
For Relay, the RLY-2608/Faslodex combo has given a 30% confirmed ORR in a broadly similar population of patients with PIK3CA kinase and non-kinase mutations, and excluding those with PTEN/AKT co-mutations. Not only did Relay’s data come from a combo, they concerned just the RLY-2608 recommended phase 2 dose, whereas Scorpion’s include all doses tested.
Relay vs Scorpion in PI3Kα inhibition
RLY-2608 + Faslodex | STX-478 | |
|---|---|---|
| Trial | NCT05216432 | NCT05768139 |
| ER+/HER2- breast cancer patients | 30 | 22 |
| Dose | 600mg BID (RP2D) | 20-160mg QD |
| Prior CDK4/6 inhibitor | 100% | 97% |
| Prior Faslodex/novel SERD | 52% | ? |
| Prior PI3Kα or mTOR or AKT inhibitor | 0% | 41% |
| PIK3CA kinase mutation | 50% | 59% |
| PIK3CA non-kinase mutation | 50% | 41% |
| PTEN/AKT co-mutation | 0% | 0% |
| Confirmed ORR* | 30% | 23% |
| Hyperglycaemia | 47% (2% gr 3) | 23% (0% gr 3/4) |
| AST/ALT elevation | 0% | 13% (10% gr 3/4) |
| Creatinine increase | 33% (0% gr 3) | 0% |
| AEs leading to discontinuation | 3% | 0% |
Note: *includes responses confirmed after data cutoff. Source: Relay presentation & ESMO.
The issue of STX-478 dosing is live, because while up to 160mg daily was tested that caused two dose-limiting toxicities – liver enzyme elevations – and 100mg was decided on as the maximum tolerated dose, Dr Alberto Montero from Seidman Cancer Center in Cleveland, told ESMO.
Even if this raises concerns about future toxicities emerging at lower dosing, STX-478 has substantial target coverage even three dose levels down from 100mg, said the ESMO discussant, Memorial Sloan Kettering’s Dr Alexander Drilon, giving Scorpion flexibility in choosing its go-forward dose.
STX-478 and RLY-2608 are both specific for mutant PI3Kα, but there’s an even more selective approach in this field, and that’s Lilly's work on inhibitors that hit only a particular type of PI3Kα mutation – in Lilly’s case H1047R. While the big pharma group remains focused on this, it recently discontinued its lead clinical project, LOXO-783.
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