No checkpoint glory for Acrivon
Prexasertib data worsen again, and biomarkers are up in the air.
Prexasertib data worsen again, and biomarkers are up in the air.
Having teased last month that it would reveal some sort of update covering the checkpoint kinase CHK1/2 inhibitor prexasertib in January, Acrivon did so last week. However, the data failed to enthuse investors, and the company’s attempt to capitalise on the hype surrounding the JP Morgan healthcare conference fell flat.
Acrivon has proposed a path to filing prexasertib in endometrial cancer – the one remaining indication after failures in ovarian and bladder cancers. But the strategy is confused by patients' biomarker status, and some of the data have deteriorated from an already disappointing earlier update; the company fell 40% over two days to end the week with a market cap of just $55m.
Last March Acrivon outlined a plan to split endometrial cancer patients in this study into two groups, based on baseline testing with its Oncosignature assay: likely responders (so-called BM+) and non-responders (BM-). BM+ patients received prexasertib monotherapy, while BM- patients got prexasertib plus ultra low-dose gemcitabine (ULDG).
Into the subgroups
At the time the company cited a 35% confirmed response rate among 20 BM+ patients – a figure that had deteriorated from an initial 63%, albeit in just eight subjects. Now the numbers have waned further still, with Acrivon last week revealing that 31 patients were now evaluable, but only 10 had confirmed responses, giving an ORR of 32%.
Acrivon attempted to put things in a better light by focusing on subgroups, limiting analysis to 25 BM+ patients on no more than two prior therapy lines (ORR of 36%), and to a further subgroup of these subjects who additionally had the serous type of endometrial cancer (12 patients, ORR 67%).
Among 23 patients with serous endometrial cancer and no more than two prior therapies – but irrespective of BM status – the ORR was 52%, Acrivon said. But here the situation gets even more confusing.
After earlier highlighting the possibility of BM+ patients providing a path to accelerated approval, Acrivon is now starting a new phase 2 cohort, enrolling 90 patients with just the serous subtype, no more than two prior therapy lines – but unselected for BM, and who will all be given prexasertib plus ULDG irrespective of BM status.
The relevance of the Oncosignature assay is therefore again up in the air. A confirmatory phase 3 study, Acrivon disclosed, will enrol patients with first-line endometrial cancer – including serous and other subtypes – combine prexasertib with PD-1 blockade, and use Oncosignature status only for stratification.
Analysts at Jones Research wrote that it was unclear whether the BM all-comers approach would work or whether Acrivon would have to turn back to biomarker-positive patients only. They also called the clinical results only “modestly” better than standard treatments, and said these would likely worsen further in a larger dataset.
The note to investors cited ORRs of 50% for Genmab’s rinatabart sesutecan in second-line plus endometrial cancer, 37% for Hutchmed/Takeda’s Fruzaqla plus Tyvyt in the serous subtype, and 57% for Enhertu in HER2-positive disease.
Summary of data from prexasertib’s phase 2 study in relapsed endometrial cancer
| Cohort 1 | Cohort 2 | Cohort 3 | ||
|---|---|---|---|---|
| BM status | BM+ | BM- | BM unselected, ≤2 prior lines, serous | |
| Regimen | Prexasertib | Prexasertib + ULDG | Prexasertib + ULDG | |
| Data | ORR 32% (n=31) | ORR not disclosed | Cohort to start enrolling in Q1 2026 | |
| Subgroup 1 | BM+, ≤2 prior lines | BM-, ≤2 prior lines | ||
| Data | ORR 36% (n=25) | ORR 23% (n=35) | ||
| Subgroup 2 | BM+, ≤2 prior lines, serous | BM+, ≤2 prior lines, non-serous | No split given by serous/non-serous for BM- cohort | |
| Data | ORR 67% (n=12) | ORR 8% (n=12) | ||
| Cohort 1& 2 | BM unselected | |||
| Subgroup | BM unselected, ≤2 prior lines, serous | BM unselected, ≤2 prior lines, non-serous | ||
| Data | ORR 52% (n=23) | ORR 14% (n=37) | ||
Notes: BM=biomarker, as determined by Acrivon’s Oncosignature assay; ULDG=ultra-low dose gemcitabine. Source: Acrivon.
Acrivon might now officially be a micro-cap biotech, but it’s not about to be called a one-trick pony, additionally highlighting its dual Wee1 and PKMYT1 inhibitor ACR-2316, and presenting ACR-6840, a CDK11 inhibitor, as its next preclinical development candidate.
However, the best that can currently be said about ACR-2316 is that it’s produced just two confirmed responses among 20 evaluable patients with various solid tumours.
Prexasertib is thus set to remain in focus for remaining investors, who will no doubt be aware that the molecule had already been discontinued by Lilly, and that early Acrivon data in ovarian cancer were uncompetitive, and in bladder cancer not enough potential responders could be identified. The clock is now ticking for the endometrial indication.
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