Initial data from the phase I study of WEE1 inhibitor zedoresertib and PKMYT1 inhibitor lunresertib demonstrated an expected and manageable safety profile in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A gene alterations, according to findings from the MYTHIC trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2026 (Abstract CT022). The combination regimen also demonstrated antitumor activity, especially among patients with ovarian cancer who had CCNE1 or FBXW7 alterations.
“This combination demonstrated strong synergy in preclinical studies, and we have now demonstrated its great potential as a novel therapeutic option for patients across multiple tumor types—especially for those with ovarian cancer,” said principal investigator Timothy Yap, MBBS, PhD, Professor of Investigational Cancer Therapeutics and Vice President and Head of Clinical Development in the Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center. “Patients with cancers harboring CCNE1 amplification and FBXW7 and PPP2R1A mutations represent areas of unmet clinical need, for which this combination could provide a new treatment option.”
Background and Study Methods
Zedoresertib and lunresertib are both oral highly selective inhibitors of WEE1 and PKMYT1, respectively. The combination demonstrated synthetic lethality in preclinical models, causing mitotic catastrophe.
The phase I MYTHIC trial enrolled patients with advanced solid tumors with CCNE1 amplification or FBXW7 or PPP2R1A deleterious mutations. Patients were treated with the combination at one of five dose levels from 150 mg to 260 mg of zedoresertib daily plus 60 mg or 80 mg of lunresertib on a 3-days-on/4-days-off schedule.
Endpoints included safety, tolerability, recommended combination doses, pharmacokinetics, pharmacodynamics, antitumor activity, and molecular response rate.
Key Findings
Among all 54 patients treated as of the cutoff date, grade 3 or higher treatment-related adverse events most commonly included anemia (9.3%), neutropenia (7.4%), and palmar-plantar erythrodysesthesia (7.4%). No grade 5 treatment-related events were reported.
Dose-limiting toxicities were experienced by four patients (9.3%), including grade 3 pain in extremity and grade 1 rash on 150-mg zedoresertib plus 60-mg lunresertib, grade 3 rash on 200-mg zedoresertib plus 80-mg lunresertib, grade 3 palmar-plantar erythrodysesthesia on 260-mg zedoresertib plus 60-mg lunresertib, and grade 3 vomiting on 260-mg zedoresertib plus 60-mg lunresertib.
Analysis of pharmacokinetics and pharmacodynamics demonstrated dose-dependent exposures for both agents and target engagement in many patients.
Of 44 evaluable patients, 24 (55.5%) achieved tumor shrinkage with 3 confirmed complete responses, 5 unconfirmed partial responses, 15 with stable disease, and 1 patient with progressive disease.
Sixteen evaluable patients had ovarian cancer with a CCNE1 amplification or FBXW7 mutation. Thirteen of these patients (81.3%) had tumor shrinkage with three confirmed complete responses, three unconfirmed partial responses, and seven with stable disease. The clinical benefit rate was 93.8%. Seven patients in this group were on treatment for at least 16 weeks. Four patients had CA-125 responses.
Twenty-three patients had post baseline circulating tumor DNA data available and 39% of these patients had a molecular response across all dose levels.
DISCLOSURES: The study was funded by Debiopharm and Repare Therapeutics. For full disclosures of the study authors, visit abstractsonline.com.
