AACR: Zedoresertib and lunresertib combination shows promising antitumor activity

MD Anderson Research News April 19, 2026

  • Phase I trial provides early clinical proof-of-concept supporting the combination of zedoresertib and lunresertib in certain advanced solid tumors
  • Zedoresertib, which targets WEE1, and lunresertib, a PKMYT1 inhibitor, are both investigational therapies that create synthetic lethality by blocking cell cycle proteins
  • Combination achieved notable responses in ovarian cancer at the preliminary recommended Phase II dose, with a 50% overall response rate across all patients and a 60% rate in patients with CCNE1 amplification
  • This combination has been granted FDA Fast Track Designation in patients with ovarian cancer harboring CCNE1 amplification, FBXW7 or PPP2R1A deleterious mutations

ABSTRACT: CT022

For patients with advanced solid tumors harboring specific genetic alterations, the first-in-class synthetic lethal combination of WEE1 inhibitor zedoresertib plus PKMYT1 inhibitor lunresertib demonstrated promising antitumor activity and was generally well-tolerated, according to Phase I MYTHIC trial data reported by researchers at The University of Texas MD Anderson Cancer Center.

Based on these data, the combination was granted Food and Drug Administration (FDA) Fast Track Designation in patients with ovarian cancer harboring these genetic alterations. Results were presented today in the clinical trials plenary session at the American Association for Cancer Research (AACR) Annual Meeting 2026 by principal investigator Timothy Yap, M.B.B.S., Ph.D., professor of Investigational Cancer Therapeutics and vice president and head of clinical development in UT MD Anderson’s Therapeutics Discovery division.

“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,” Yap said. “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.”  

More information on all UT MD Anderson AACR Annual Meeting content can be found at MDAnderson.org/AACR.  

What are zedoresertib and lunresertib, and how do they work?

Zedoresertib, developed by Debiopharm, is a highly selective and brain-penetrant WEE1 kinase inhibitor. The WEE1 protein is a critical gatekeeper of the cell cycle that can help cancer cells survive DNA damage by ensuring that DNA repair occurs before cell division takes place. Inhibiting WEE1 with zedoresertib, therefore, pushes cancer cells with DNA damage – such as those with CCNE1 amplification-induced replication stress – into mitosis earlier, leading to cell death through apoptosis.

Similarly, lunresertib, developed by Repare Therapeutics and licensed to Debiopharm, is a highly selective PKMYT1 kinase inhibitor that regulates the cell cycle via a different pathway, creating synthetic lethality in tumors with specific genetic mutations, such as FBXW7 or PPP2R1A, or CCNE1 amplification.

Both zedoresertib and lunresertib work well together in multiple tumor types in vivo, showing durable regressions following both continuous and intermittent zedoresertib treatment. The combination was also well-tolerated in preclinical studies.

What were the main objectives and who was treated in the MYTHIC trial?

The primary objectives of the Phase I MYTHIC trial were to determine the safety and tolerability of zedoresertib plus lunresertib, as well as to identify the maximum tolerated dose. Additionally, the researchers evaluated preliminary antitumor activity, pharmacokinetics and pharmacodynamics.

The ongoing trial had enrolled 62 patients at data cutoff with advanced resistant/refractory solid tumors harboring CCNE1 amplification and/or FBXW7 and/or PPP2R1A mutations, including but not limited to patients with ovarian, colorectal, pancreatic and breast cancer. Investigators are examining treatment doses from 150 mg. to 260 mg. daily of zedoresertib plus 60 mg. or 80 mg. of lunresertib on a three-on-four-off schedule.

What were the results of combining zedoresertib and lunresertib?

The overall disease control rate for 54 evaluable patients across all dosing levels was 68.5%. In 51 patients with target lesions, 26 showed tumor shrinkage and 10 patients achieved a radiological response.

Among patients with advanced ovarian cancers harboring CCNE1 amplification, FBXW7 or PPP2R1A mutations, 80% showed consistent tumor shrinkage, with durable responses observed. At least 10 patients (37%) remained on treatment for more than 16 weeks, and five patients (18.5%) remained on treatment for longer than 32 weeks.

The molecular response rate (MRR) was 47% for all patients across all dose levels. In patients with advanced ovarian cancer, the MRR was 67%.

The safety profile was manageable and consistent with either inhibitor as a monotherapy. The most commonly reported side effects were Grade 1 or 2 nausea, vomiting and asthenia, or generalized fatigue.

Given the promising antitumor activity and manageable safety profile, researchers will continue to optimize dosing and scheduling of this combination across the various tumor types represented in this study.

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The study was funded by Debiopharm and Repare Therapeutics. A complete list of collaborating authors and their disclosures can be found with the abstract.