Lunresertib and Other PKMYT1 Inhibitors Show Promise in Gynecologic Malignancies

The inhibition of protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1) represents a unique treatment opportunity by offering a novel target for patients with endometrial and ovarian cancers whose disease harbors genetic alterations in CCNE1, FBXW7, and/or PPP2R1A, which often correspond with poor prognosis, according to Alison Schram, MD.

“PKMYT1 is an important protein that regulates cell division, particularly in the presence of cellular stress,” Schram, a gynecologic medical oncologist and associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, explained in an interview with OncLive®. “PKMYT1 inhibitors, in combination with other therapies that target the cell cycle, enhance CDK1 activation, which allows for premature mitosis and chromosomal catastrophe.”

Lunresertib Plus Camonsertib Shows Early-Phase Activity

The first-in-class PKMYT1 inhibitor lunresertib (RP-6306) has already displayed promising efficacy with a manageable safety profile in combination with camonsertib (RP-3500) for treating patients with ovarian and endometrial cancers.1 Preclinical data have shown that lunresertib is synthetically lethal in tumors with CCNE1 amplifications, as well as those with FBXW7 and PPP2R1A deleterious mutations. Further preclinical data have shown that ATR inhibition with camonsertib is synergistic with lunresertib and enhances antitumor activity.

Lunresertib plus camonsertib is being evaluated for the treatment of patients with solid tumors, including ovarian and endometrial cancers, in the phase 1 MYTHIC trial (NCT04855656). The study enrolled patients aged at least 12 years who were resistant or intolerant to standard therapy, had tumors harboring CCNE1 amplifications or FBXW7 and PPP2R1A deleterious alterations per next-generation sequencing, an ECOG performance status of 0 or 1, and adequate hemoglobin, platelet, and absolute neutrophil counts.

“We initially explored lunresertib as monotherapy and, after establishing the safety profile and recommended dosing schedule, went on to [evaluate the agent] in combination with camonsertib,” Schram said. “Lunresertib in combination with other agents that also promote cell division prior to adequate DNA repair can cause synthetic lethality in cancers that harbor genetic alterations in this pathway.”

Findings from MYTHIC presented during the 2025 American Association for Cancer Research Annual Meeting demonstrated that patients with endometrial cancer (n = 33) who received the combination achieved an overall response rate (ORR) per RECIST 1.1 criteria of 24.2% (95% CI, 11.1%-42.3%) and a clinical benefit rate (CBR) of 48.5% (95% CI, 30.8%-66.5%). The median time to response was 5.6 weeks (range, 5.1-21.3), and the 24-week progression-free survival (PFS) rate was 38.3% (95% CI, 18.5%-57.9%).

Among patients with ovarian cancer (n = 32), the ORR per RECIST 1.1 criteria was 31.3% (95% CI, 16.1%-50.0%) and the CBR was 68.8% (95% CI, 50.0%-83.9%). The median time to response was 6.9 weeks (range, 5.1-18.1), and the 24-week PFS rate was 41.2% (95% CI, 21.8%-59.7%).

Notably, both patient populations were heavily pretreated, having received a median of 3.0 (range, 1-10) prior lines of therapy. Molecular responses were observed in 69% (n = 34/49) of evaluable patients with ovarian or endometrial cancer. The median time to first molecular response was 22 days.

“Early molecular responses were associated with an improved PFS,” Schram added. “Patients with a molecular response had a median PFS of 19.1 weeks. In contrast, those that did not have a molecular response had a median PFS of 13.7 weeks. Molecular responses were observed across different genotypes and in patients with endometrial and ovarian cancer.”

In terms of safety, patients with endometrial or ovarian cancer who received the combination at the recommended phase 2 dose after schedule optimization (n = 74) experienced any-grade adverse effects (AEs) at a rate of 98.6%. Grade 3 and 4 AEs were reported at rates of 50.0% and 2.7%, respectively. Common any-grade AEs included anemia (78.4%), nausea/vomiting (62.2%), and rash (48.6%).

Serious treatment-related AEs (TRAEs) occurred in 6.8% of patients. TRAEs leading to dose reduction (55.4%), interruption (58.1%), and discontinuation (5.4%) were all reported. Notably, no patients experienced a TRAE leading to death.

In June 2024, the FDA granted fast track designation to the combination of lunresertib and camonsertib for the treatment of adult patients with CCNE1-amplified, or FBXW7- or PPP2R1A-mutated, platinum-resistant ovarian cancer.2

“It’s exciting that lunresertib has demonstrated a proof of concept for patients to receive PKMYT1-targeted therapy,” Schram said. “There’s a clear signal of efficacy with this ATR inhibitor–containing combination. From a clinical perspective, there is an opportunity to further develop the lunresertib/camonsertib combination.”

Development of Other PKMYT1-Directed Agents Is Under Way

Another PKMYT1 inhibitor, ACR-2316, which also targets WEE1, is being examined for the treatment of patients with advanced solid tumors in a phase 1 study (NCT06667141).3 The agent was designed to overcome the limitations of presently available WEE1 and PKMYT1 inhibitors and to have a superior therapeutic index and potent single-agent activity.4 The first-in-human, open-label trial is enrolling adult patients who experienced disease progression following prior therapy with an ECOG performance status of 0 or 1, measurable disease per RECIST 1.1, and adequate organ function.3 

The study includes dose-escalation and dose-expansion phases; ACR-2316 will be administered via a 3-week schedule in both portions. The primary end point in the dose-escalation phase is determining the maximum tolerated dose of ACR-2316; determining the recommended phase 2 dose is the primary end point of the dose-expansion phase. Secondary end points include safety and tolerability and pharmacokinetic measures.

In March 2025, Acrivon Therapeutics announced that a safety review committee cleared patients treated with ACR-2316 at dose levels 1 and 2 without safety concerns of dose-limiting toxicities.4 Clinical data from the phase 1 study of ACR-2316 are expected to be reported in the second half of 2025, according to the company.

“[The development of PKMYT1 inhibitors] opens a lot of doors for novel synthetic lethal biomarkers,” Schram said. “For the longest time, PARP inhibitors have been held up as the example of synthetic lethality in our field, but we haven’t been able to replicate that with other biomarkers. [These agents] are proof of concept for a novel target.”

References

1. Schram AM, Lee EK, Højgaard M, et al. Efficacy and safety of the combination PKMYT1-inhibitor lunresertib and ATR-inhibitor camonsertib in patients with ovarian and endometrial cancers: phase I MYTHIC study (NCT04855656). Cancer Res. 2025;85(8 suppl 2):CT262. doi:10.1158/1538-7445.AM2025-CT262
2. Repare Therapeutics announces fast track designation granted by the FDA for lunresertib in combination with camonsertib for the treatment of platinum-resistant ovarian cancer. News release. Repare Therapeutics. June 4, 2024. Accessed August 28, 2025. https://ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-announces-fast-track-designation-granted-fda
3. Phase 1 study of ACR-2316 in specific advanced solid tumors. ClinicalTrials.gov. Updated August 13, 2025. Accessed August 28, 2025. https://clinicaltrials.gov/study/NCT06667141
4. Acrivon Therapeutics provides program updates and fourth quarter and full year 2024 financial results. News release. Acrivon Therapeutics. March 27, 2025. Accessed August 28, 2025. https://ir.acrivon.com/news-releases/news-release-details/acrivon-therapeutics-provides-program-updates-and-fourth-quarter