AACR 2026: Breakthroughs in DNA Damage Repair Inhibition, Dual Payload ADCs, and AI-Driven Biomarkers

In a series of oral and poster presentations at the annual meeting of the American Association for Cancer Research (AACR), held April 17 – 22, 2026 in San Diego, CA, Debiopharm International unveiled a suite of innovative preclinical and clinical research findings, highlighting advances in DNA damage repair (DDR) inhibition, antibody-drug conjugate (ADC) technology, and AI-driven biomarker development.

MYTHIC: Synergy in DDR Inhibition
A major highlight is the first disclosure of clinical results from the MYTHIC study (NCT04855656), a Phase I trial evaluating the combination of Debiopharm’s highly selective WEE1 inhibitor zedoresertib (Debio 0123) and the PKMYT1 inhibitor lunresertib (Debio 2513) in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations.[1]

Presented by Timothy A. Yap, MBBS, Ph.D., FRCP, a Medical Oncologist and Physician-Scientist based at the University of Texas MD Anderson Cancer Center, this first-in-class synthetic-lethal combination demonstrated strong synergistic antitumor activity, particularly in patients with ovarian cancer and CCNE1 amplification or FBXW7 mutations. The results of the study confirmed that zedoresertib targets WEE1, a key DDR kinase, while lunresertib inhibits PKMYT1, inducing synthetic lethality in tumors with specific genetic vulnerabilities.

Fifty-four (54) participating patients (55.6% female; 1 – 9 prior lines of therapy, diagnosed with ovarian cancer (35.2%), colorectal cancer (31.5%), pancreatic cancer (7.4%), and breast cancer (5.6%)), were treated at 5 dose levels, ranging from 150 mg to 260 mg of zedoresertib plus 60 mg or 80 mg of lunresertib. A total of 55.5% of RECIST-evaluable patients achieved tumor shrinkage, and the combination showed a manageable safety profile. The most common ≥ Grade 3 treatment-related adverse events (TRAEs) were anemia (9.3%), neutropenia (7.4%), and palmar-plantar erythrodysesthesia (PPE) (7.4%). There were no Grade 5 TRAEs; 4 (9.3%) patients experienced dose-limiting toxicity. Notably, 81.3% of ovarian cancer patients with relevant genetic alterations experienced tumor shrinkage, and the clinical benefit rate was 93.8%.[1]

“These MYTHIC study results mark an important milestone—early data suggest strong synergy between zedoresertib and lunresertib, with tumor regressions observed in patients,” said Esteban Rodrigo Imedio, Executive Medical Director, Oncology, Debiopharm.

MLINK™ Duo Payload Technology
Debiopharm also presented preclinical advances in MultiLINK™ (MLINK) Duo ADC technology, which enables the combination of two distinct cytotoxic payloads (up to DAR 8+8) into a single antibody to enhance efficacy, tumor heterogeneity, and overcome resistance. [2] The dual-payload technology combines plasma stability and controlled tumor-specific dual-payload release and enables the conjugation of a diverse range of dual payloads to antibodies, including combinations of well-established cytotoxic agents such as DM1, DM4, MMAE, and exatecan, as well as innovative new payload combinations.[2]

Proof-of-concept studies with trastuzumab-based MLINK Duo ADCs that simultaneously deliver Monomethyl auristatin E (MMAE), a potent synthetic antineoplastic agent and anti-mitotic drug which inhibits cell division by targeting tubulin polymerization, and exatecan, a potent, water-soluble, synthetic analog of camptothecin that acts as a DNA topoisomerase I inhibitor, showed high plasma stability, controlled dual-payload release, and potent antitumor activity.[2]

MLINK Duo ADCs exhibited low aggregation, favorable pharmacokinetics, and synergistic therapeutic effects, suggesting a major step forward in addressing tumor heterogeneity and acquired resistance.

The study results confirmed the specific enzymatic cleavage mechanism of the MLINK Duo linker technology, demonstrating effective payload release. The trastuzumab-based MLINK Duo ADC showed enhanced anti-tumor activity in several Cell-Derived Xenograft (CDX) models, maintaining efficacy and achieving tumor regression in CDX models—even in models resistant to single-payload ADCs

Next-generation ADCs based on the MultiLINK™ Duo ADC technology demonstrated that combining two cytotoxic agents via a stable linker increases therapeutic efficacy and overcomes resistance.[2]

“Dual payload ADC technology has the potential to be a game changer for cancer patients. Our MLINK Duo research may reshape how complex cancers are targeted and treated,” added Antoine Attinger, Director, Translational Pharmacology.

AI-Driven and Spatial Biomarker Innovations
Debiopharm’s translational research included two poster presentations on digital pathology and multiplexed spatial profiling:

• The first one included the results discussing the development and validation of a Deep Learning-based virtual immunohistochemistry (vIHC) algorithm to predict overexpression of the Cyclin E1 (CCNE1) protein biomarker from routine hematoxylin and eosin (H&E)-stained whole-slide images in gynecological malignancy encompassing primarily high-grade serous ovarian carcinoma (HGSOC) and uterine serous carcinoma (USC), offering a scalable, tissue-sparing approach for patient selection in targeted therapy trials. Predicting CCNE1, a key cell-cycle regulator whose gene amplification (copy number ≥6) correlates strongly with protein overexpression (H-score >50) and enhanced sensitivity to WEE1 inhibitors, generally requires precious tissue and additional laboratory processing. In contrast, the virtual immunohistochemistry platform approach, which uses routinely available H&E slides, provided a scalable alternative to accelerate patient selection for targeted therapy. Using neural network models trained to learn morphological and nuclear features predictive of Cyclin E1 expression intensity (0-3+), the study demonstrated the feasibility of a deep learning-driven virtual biomarker for Cyclin E1 that can predict protein overexpression directly from H&E slides.[3]
• The second poster focused on advanced 3D cluster analysis and multiplexed spatial proteomics to resolve discrepancies between RNASeq, proteomics, and IHC data, refining target assessment for HER3 bispecific antibody and ADC development. This multifactorial approach supports the rational selection of models and patient populations for precision oncology strategies and highlights the target-specific variability in correlations among the different analytes, underscoring once again the importance of proper omics/IHC platform selection for each individual target. The outcomes demonstrated that once the appropriate expression values are identified, the 3D analysis tool allows dynamic adjustment of expression thresholds for multiple targets, potentially informing the sample-specific most promising (bs)Ab/ADC treatment options.[4]

The outcomes of these two studies demonstrated that virtual immunohistochemistry tools and spatial profiling can accelerate biomarker discovery, improve patient selection, and optimize targeted therapy development.

Overall, Debiopharm’s presentations at AACR 2026 highlight the company’s commitment to advancing precision oncology, with cutting-edge science spanning DDR inhibition, dual-payload ADCs, and AI-powered biomarker strategies. Ongoing clinical and translational work aims to establish new standards for treating hard-to-treat and genetically defined cancers.

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Clinical trials
Study of Lunresertib Alone or in Combination With RP-3500 or Debio 0123 in Patients With Advanced Solid Tumors (MYTHIC) – ClinicalTrials.gov ID NCT04855656

Reference
[1] Yap TA, Aggarwal R, Fontana E, Hojgaard M, Carneiro BA, Duska L, LoRusso P, Yadav S, Lheureux S, Mathews C, Moy RH, Lakhani N, Weiss M, Tymon-Rosario J, Colon-Otero G, Garrido-Laguna I, E. Lee EK, Rodrigo Imedio E, Wessen J, Piggott L, Dozio V, Luong N, Mas C, Schram AM. First data disclosure of the Phase I trial of the first-in-class combination of WEE1 inhibitor zedoresertib with PKMYT1 inhibitor lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr CT022.
[2] Attinger A, Marx L, Rocha Gomes DB, Gerusz V, Ma M, Postupalenko V, Monjardet A, Quesnot N, Chardonnens C, Wuttke R, Luong N. Enhancing therapeutic efficacy and overcoming resistance with a novel dual-payload antibody-drug conjugate technology. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr 1683 / 12
[3] Fuchs J, To K, Jackson C, Schobs L, Lyons R, Azhar R. Development of a virtual Cyclin E1 biomarker using Deep Learning from H&E slides for predicting Cyclin E1 overexpression in gynecological malignancy. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr 4155 / 5.
[4] Fuchs J, Mas C, Durandau E, Rocha Gomes D, Ma M, Attinger A, Pokorska-Bocci A. Beyond bulk: Resolving RNASeq/mass spectrometry/IHC discrepancies with multiplexed spatial profiling and 3D cluster analysis to refine HER3 (bs)Ab and (bs)ADC therapeutic strategies. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr 5738 / 27

Featured image: AACR 2018 Annual Meeting. Photo courtesy © 2018 – 2026 AACR/Scott Morgan. Used with permission.

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