Guest Column | March 23, 2026

What's Next For ADCs: How Combinations Will Help Define The Future Of Treatment

Pedro Valencia, Ph.D., vice president, Asset Strategy Leadership, Oncology, AbbVie

Human lung cancer under microscope-GettyImages-2207680068

As the number of approved and investigational antibody-drug conjugates (ADCs) continues to grow, so does the conversation around how to continue advancing innovation in this area.1–6 With ADCs having demonstrated meaningful clinical activity, the field has moved beyond simply establishing their efficacy to deepening the understanding of how best to utilize these therapies to align more closely with tumor biology and patient needs.1,3,6 Advances in linker chemistry, payload engineering, and antibody selection have matured the structural foundation of ADCs — and the field’s attention has correspondingly shifted to the harder questions: how resistance emerges, how sequencing decisions affect durability, and how biological context determines which patients will benefit most.1,6

To advance the development of ADCs and move toward a future where chemotherapy is less essential for the treatment of certain cancers, we are actively identifying effective strategies to broaden the application of ADCs by combining multiple targets in one molecule and identifying complementary partners for novel combination approaches with ADCs.

Thoughtful Combination Designs

ADCs that are designed to target a key cancer biomarker can deliver potent toxins and target agents directly to cancer cells.1 However, to drive an optimal and durable anti-tumor response, these ADCs should overcome various challenges, including primary or acquired resistance, effective tumor penetration, and variable immune activation that may limit their full potential.1,4

Some of these challenges may be addressed by implementing rational combination strategies with other therapies.1,4 By thoughtfully aligning ADC mechanisms with complementary therapies, we can potentially achieve deeper and more lasting responses for patients, maximizing efficacy at the tumor site while sparing healthy tissues from unnecessary toxicity. This may be especially beneficial for patients whose cancer does not respond to current monotherapies.1,6 Checkpoint inhibitors, for instance, may impact the tumor microenvironment to make it more susceptible to ADCs, addressing tumor heterogeneity that monotherapy alone may not overcome.2,7,8

Effective combination design involves far more than simply adding agents together. It requires an understanding and integrated alignment of mechanisms of action, payload potency, and tumor biology to create synergistic and durable therapies. Smart and strategic combination approaches demand clear insight into how these mechanisms interact within the tumor and how resistance may evolve over time.1,3

Payload choice is also crucial to this process. Topoisomerase-1 (Top1) inhibitor payloads, for example, induce immunogenic cell death and demonstrate meaningful bystander activity, making them well suited to combination with checkpoint blockade.2,8–10

At AbbVie, for example, researchers are exploring combinations of ADCs with immuno-oncology agents and other targeted therapies — not through default pairings but by leveraging mechanistic rationale, early durability indicators, and translational data to guide decisions. The goal is to build regimens that help patients for longer durations, while minimizing unnecessary adverse effects.

To put this into perspective, many tumors may initially respond to a single agent but ultimately adapt through changes in signaling pathways or immune context. In such cases, combining ADCs with immuno-oncology or targeted agents may simultaneously address multiple aspects of tumor biology.1,10

Looking ahead, the evolution of ADC combinations will be guided not by increasing intensity but by advancing precision — selecting the right partners, in the optimal sequence, for each unique biological landscape.

Lung Cancer As An Emerging Area Of Exploration

AbbVie is focused on advancing ADCs to deliver more durable, deeper responses for patients across multiple cancer types, including colorectal cancer and lung cancer. At the forefront of these efforts is lung cancer, the leading cause of cancer-related deaths worldwide.11,12 This area serves as a strong proof point for the use of ADC combinations for certain patients — with encouraging results seen around response rate, durability, and overall safety profile.6

Although approved monotherapy treatment options have produced significant clinical benefits in biomarker-selected lung cancer patients, durable responses remain limited, with many patients experiencing either primary resistance or disease progression following initial response.12 This underscores the need for novel agents such as ADCs. Lung cancer patients also often have comorbidities that require careful dose and administration choices.13 Across the spectrum of lung cancer subtypes — from epidermal growth factor receptor (EGFR)-mutant and KRAS-driven adenocarcinomas to squamous cell carcinomas with few targeted therapies, as well as small cell lung cancer where rapid resistance to first-line platinum-based treatments persists as a major challenge14 — disease resistance mechanisms are well understood but remain inadequately addressed by current therapies.15 This landscape highlights a clear biological rationale: ADC combinations are uniquely positioned to deliver the most meaningful incremental therapeutic benefit for these patient populations.

In our own work developing ADC strategies for lung cancer, we’re looking at target expression patterns across subtypes, evaluating drug payload classes for their fit with specific tumor biology, and testing combinations that aim to extend immunotherapy benefit or restore sensitivity after monotherapy failure while prioritizing safety. Our early-stage trials are currently investigating multiple ADCs with Top1 inhibitor payloads, for example, to identify regimens that may have the potential to deliver durable benefit and remain practical in real‑world settings. As biology and data mature, we believe this current work in lung cancer may inform future development in additional tumor types, where each specific cancer will require its own biological rationale and combination logic.

Collaboration Between Teams Accelerates Learning

Partnerships — whether with academic centers, peer organizations, or medical institutions — play a vital role in driving forward the science of ADC combinations. By collaborating, partners can access complementary targets, payloads, and technology platforms, accelerating the exploration of biological hypotheses and deepening collective insight across the field. The modular architecture of ADCs, where antibody, linker, and payload can each be independently optimized, makes them particularly suited to co-development partnerships that pool distinct molecular expertise, enabling collaborations that could ultimately expand the number of patients who can benefit from these innovative treatments.1,3

Sharing knowledge and expanding R&D collaboration efforts introduces new opportunities to explore combination regimens that can address different types of cancers with high unmet need.

Translating Scientific Progress Into Better Outcomes

The next generation of oncology therapies is being driven by disciplined, biology-led combination strategies in R&D. Insights gained from advancing ADC combination therapies in lung cancer, alongside collaborative partnerships that deepen the field’s collective understanding, are now shaping innovative approaches across multiple tumor types and accelerating efforts to develop chemotherapy-sparing regimens. In this evolving landscape, the true measure of success will not rest on the presence of an ADC alone but on the precision and rationale with which it is paired and deployed.

Our ambition is to go beyond incremental gains and set new standards of care, prioritizing treatment paradigms that help patients avoid the limitations and adverse effects of traditional chemotherapy. The focus is on developing combination strategies that are both biologically informed and evidence-based, delivering longer-lasting and more profound responses across diverse cancers. The path forward demands not just scientific ambition but rigorous translational discipline — ensuring that every combination regimen is built on a clear mechanistic hypothesis, tested against defined resistance signatures, and evaluated with endpoints that reflect what matters most to patients: deeper responses, longer remissions, and a meaningful reduction in the treatment burden that has defined oncology care for far too long.

References

  1. Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat Rev Clin Oncol. 2021;18(6):327–344. doi: 10.1038/s41571-021-00470-8.
  2. Giugliano F, Corti C, Tarantino P, et al. Bystander effect of antibody–drug conjugates: fact or fiction? Curr Oncol Rep. 2022;24:809–817. doi: 10.1007/s11912-022-01266-4.
  3. Maecker H, Jonnalagadda V, Bhakta S. Exploration of the antibody–drug conjugate clinical landscape. mAbs. 2023;15(1):2229101. doi: 10.1080/19420862.2023.2229101.
  4. Fujii T, Matsuda Y. Novel formats of antibody conjugates: recent advances in payload diversity, conjugation, and linker chemistry. Expert Opin Biol Ther. 2023;23(11):1053–1065. doi: 10.1080/14712598.2023.2276873.
  5. Sands J, Subramanian J. Treating patients with platinum‑sensitive extensive‑stage small‑cell lung cancer in a real‑world setting. Front Oncol. 2023;13:1161931. doi: 10.3389/fonc.2023.1161931. 
  6. Tsuchikama K, Anami Y, Ha SYY, et al. Exploring the next generation of antibody–drug conjugates. Nat Rev Clin Oncol. 2024;21(3):203–223. doi: 10.1038/s41571-023-00850-2.
  7. Ouyang P, Wang L, Wu J, et al. Overcoming cold tumors: a combination strategy of immune checkpoint inhibitors. Front Immunol. 2024;15:1344272. doi: 10.3389/fimmu.2024.1344272.
  8. Guo Y, Shen Z, Zhao W, et al. Rational identification of novel ADC with high bystander killing effect against heterogeneous tumors. Adv Sci. 2024;11(13):e2306309. doi: 10.1002/advs.202306309. Epub 2024 Jan 25.
  9. Forveille S, Leduc M, Sauvat A, et al. Datopotamab deruxtecan induces hallmarks of immunogenic cell death. Cell Stress. 2025;9;194-200. doi: 10.15698/cst2025.08.311
  10. Iwata TN, Ishii C, Ishida S, et al. A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018;17(7):1494–1503. doi: 10.1158/1535-7163.MCT-17-0749.
  11. IARC/WHO. Global cancer burden growing, amidst mounting need for services. Press Release No. 345; Feb 1, 2024. Accessed March 2026. https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing--amidst-mounting-need-for-services.
  12. IARC. Lung cancer—cancer type overview. Page updated 2025–2026. Accessed March 2026. https://www.iarc.who.int/cancer-type/lung-cancer/
  13. Buja A, Di Pumpo M, Rugge M, et al. Patterns of comorbidities in lung cancer patients and survival. Cancers (Basel). 2025;17(9):1577. doi: 10.3390/cancers17091577
  14. Ying Q, Fan R, Shen Y, et al. Small Cell Lung Cancer—An Update on Chemotherapy Resistance. Curr Treat Options Oncol. 2024;25:1112–1123. doi: 10.1007/s11864-024-01245-w.
  15. Yu LY, Yang RY, Long Z, et al. Targeted therapy of non-small cell lung cancer: mechanisms and clinical trials. Front Oncol. 2024;26:14. doi: 10.3389/fonc.2024.1451230.

About The Author

Pedro Valencia, Ph.D., is VP of asset strategy leadership, oncology at AbbVie. He oversees the oncology asset leadership team and the lifecycle of oncology assets across AbbVie’s solid tumor and blood cancer portfolio. Prior to his current role, he was the VP of solid tumor pipeline strategy at AbbVie. He oversaw solid tumor asset leadership and project management and was a key player in defining and advancing the overall solid tumor strategy and pipeline. He holds a Ph.D. and MS in chemical engineering from MIT, where he worked on novel nanotherapeutics. He holds a BS in chemical engineering from the University of Wisconsin-Madison, where he graduated first in his class with highest honors.