Novel Small Molecule Inhibitors Show Efficacy in Endometrial Cancer

Data from 2 clinical trials of novel small molecule inhibitors, prexasertib (ACR-368) and ACR-2316, have demonstrated compelling efficacy signals, furthering therapeutic development in endometrial cancer.¹

An ongoing phase 2b trial (NCT05548296) evaluating prexasertib, a selective small molecule inhibitor targeting CHK1 and CHK2, demonstrated a compelling overall response rate (ORR) of 39% in patients with endometrial cancer (EC), with a notably high confirmed response rate of 67% in the serous subtype.²

The phase 2b study is driven by Acrivon Therapeutics’ proprietary Acrivon Predictive Precision Proteomics (AP3) platform. Efficacy was notably pronounced in patients with ≤2 prior lines of therapy (44% ORR), patients with a serous subtype with ≤2 prior lines of therapy (67% confirmed ORR), and patients with all-comer serous subtype with ≤2 prior lines of therapy (52% confirmed ORR).

The heightened sensitivity in serous tumors is consistent with a biological dependency on the G2-M checkpoint, as these tumors are frequently G1-S-deficient. Based on these findings, the trial's third arm will now exclusively enroll subjects with serous endometrial cancer who have received up to 2 prior lines of therapy. A Clinical Trial Application has been submitted for expansion in Germany, Italy, France, and Spain at over 20 selected sites. With this expansion into the European Union (EU), initial EU patient enrollment is expected in the first quarter of 2026.

Arm 3 will evaluate prexasertib combined with ultra-low dose gemcitabine as a tumor sensitizer. Enrollment will not require a pretreatment tumor biopsy, a feature expected to accelerate patient recruitment. The arm is designed for up to 90 subjects, with the potential for validation of clinical significance in as few as 40 subjects. Enrollment completion is anticipated in the fourth quarter of 2026.

“About a third of all second- and third-line [EC] cases are of serous subtype and represent a challenging patient population,” said Mansoor Raza Mirza, MD, chief medical officer of Acrivon, in a news release.¹ “Moreover, incorporating feedback from a Type B meeting in June 2025, we have recently submitted our [p]hase 3 confirmatory study protocol to the FDA for [prexasertib] in combination with anti–PD-1 therapy in frontline [patients with EC], building on the strong synergy observed preclinically between these [2] agents.”

In May 2023, prexasertib received fast track designation from the FDA for the treatment of patients with platinum-resistant ovarian cancer and EC.

Phase 1 Trial of ACR-2316

The company's second clinical asset, ACR-2316, a potential first-in-class WEE1/PKMYT1 inhibitor, showed a favorable tolerability profile and initial signs of efficacy in a phase 1 study (NCT06667141)³, including partial responses (PR) in tumor types not previously shown to be sensitive to this class of inhibitors.

The study has successfully established 2 weekly oral dosing regimens with a favorable tolerability profile. The regimens include 160 mg once daily (QD), 3 days on and 4 days off, and 240 mg QD, 2 days on and 5 days off. Adverse events were primarily transient, mechanism-based hematological events, predominantly neutropenia.

A biweekly regimen (2 days on / 12 days off) has been initiated to explore enhanced single-agent activity and provide future combination flexibility.

Tumor shrinkage was observed in 9 out of 20 evaluable patients at dose levels of 120 mg and above. Notably, PRs were seen in heavily pretreated patients across multiple tumor types prioritized by the AP3 platform.

A patient with high-grade Mullerian EC (BRCA1/2 wt), previously treated with platinum chemo and pembrolizumab (Keytruda) plus lenvatinib (Lenvima), achieved a confirmed PR and remained on therapy for 42 weeks.

A patient with small cell lung cancer, previously treated with cisplatin, durvalumab (Imfinzi), and tarlatamab (Imdelltra), achieved an unconfirmed PR with 50% tumor shrinkage at the first scan. A subsequent scan showed further target lesion shrinkage (69%), though nontarget liver metastases progressed after the EDC extract date.

A patient with squamous non–small cell lung cancer (BRCA1 mutated), who had received 4 prior lines of therapy, achieved an unconfirmed PR. This response was confirmed in a subsequent scan performed after the EDC extract date.

REFERENCES

1.Acrivon Therapeutics announces positive ACR-368 phase 2b endometrial cancer clinical data with EU expansion to accelerate enrollment, initial ACR-2316 clinical data, and ACR-6840, its next AP3-enables development candidate, targeting CDK11. News release. Acrivon Therapeutics. Published January 8, 2026. Accessed January 9, 2026. https://tinyurl.com/yu4vym7b

2.A phase 2 study of ACR-368 in endometrial adenocarcinoma. ClinicalTrials.gov. Updated September 23, 2025. Accessed January 9, 2026. https://clinicaltrials.gov/study/NCT05548296

3.Phase 1 study of ACR-2316 in specific advanced solid tumors. ClinicalTrials.gov. Updated October 21, 2025. Accessed January 9, 2026. https://clinicaltrials.gov/study/NCT06667141