ADC Therapies at AACR 2026: What Cancer Patients Should Know
92 antibody-drug conjugate projects were presented at this year's AACR meeting. Here's what matters for patients looking for clinical trials.
What Are ADCs?
An antibody-drug conjugate (ADC) is a targeted cancer therapy that combines three components: an antibody that finds cancer cells, a linker that holds everything together, and a payload (a potent drug) that kills the cancer cell once delivered. Think of it as a guided missile — the antibody is the guidance system, and the payload is the warhead.
ADCs have already transformed treatment for several cancers. Trastuzumab deruxtecan (Enhertu) for HER2-positive breast cancer, sacituzumab govitecan (Trodelvy) for triple-negative breast cancer, and enfortumab vedotin (Padcev) for bladder cancer are among the most successful examples.
At AACR 2026, 92 ADC-related projects were presented — including 4 in the dedicated clinical trials plenary session — showing this field is accelerating faster than ever.
What's New: The Next Generation of ADCs
Bispecific ADCs: Targeting Two Proteins at Once
One of the biggest limitations of current ADCs is that cancer cells can escape by losing the target protein (antigen) on their surface. Bispecific ADCs solve this by targeting two different proteins simultaneously, making it much harder for cancer cells to evade treatment.
Notable bispecific ADCs presented at AACR 2026:
- NEOK001 (B7-H3 x ROR1) — achieved deep tumor regression in 53% of 38 patient-derived models, outperforming trastuzumab deruxtecan
- NEOK002 (EGFR x MUC1) — showed 78% tumor regressions in KRAS-mutant solid tumors, and synergized with the KRAS inhibitor sotorasib
- ATG-125 (B7-H3 x PD-L1) — a first-of-its-kind ADC that doubles as an immunotherapy, increasing immune cell infiltration into tumors
- VBC108 (CDH17 x CLDN18.2) — designed for GI cancers, covering >80% of gastric cancers without requiring tumor testing
Dual-Payload ADCs: Two Drugs in One
Another innovation is loading ADCs with two different payloads instead of one. This attacks cancer cells through two mechanisms simultaneously, reducing the chance of resistance.
Novel Payloads: Beyond Today's Standard Drugs
Most approved ADCs use one of two payload types: topoisomerase I (Topo I) inhibitors or MMAE. AACR 2026 showcased entirely new payload classes that work through different mechanisms — important because they can overcome resistance to existing ADCs.
| New Payload Type | How It Works | Why It Matters for Patients |
|---|---|---|
| Pan-RAS inhibitor | Blocks RAS signaling (a driver in ~30% of all cancers) | First time RAS-targeting drugs can be delivered directly to tumors via ADC |
| Amanitin | Stops RNA production — kills even dormant cancer cells | Works regardless of cell cycle stage; active in slow-growing tumors |
| RNA splicing modulator | Disrupts how cancer cells process genetic instructions | Overcomes Topo I resistance; also activates immune response |
| ATR inhibitor | Blocks DNA repair in cancer cells | Combined with DNA-damaging payload for dual attack (CLIO-8221) |
| Phosphonate | Activates immune T cells to attack nearby cancer cells | Novel approach: ADC delivers immune activation, not direct cell killing |
ADC Resistance: Why It Matters and How New ADCs Address It
A common concern for patients on ADC therapy is: what happens when it stops working? A landmark study published concurrently with AACR 2026 showed that resistance to ADCs like Enhertu and Trodelvy is primarily driven by efflux pumps — proteins that pump the drug back out of cancer cells — rather than loss of the target protein.
This is actually good news, because it means:
- Switching payload class can restore activity. If you progress on a Topo I-based ADC, an ADC with a different payload (like amanitin or MMAE) may still work.
- New payloads are being designed to resist efflux. For example, the Byondis antifolate payload has low affinity for efflux pumps.
- Dual-payload ADCs attack through two mechanisms at once, making resistance harder to develop.
ADC Clinical Trials by Cancer Type
ADC trials are expanding across nearly every cancer type. Here are some notable results from AACR 2026:
| Cancer Type | ADC | Target | Key Result |
|---|---|---|---|
| NSCLC (lung) | Risvutatug rezetecan + adebrelimab | B7-H3 + PD-L1 | 47% response rate, 94% disease control, 14-month PFS |
| Ovarian (platinum-resistant) | QLS5132 | CLDN6 | >50% response rate, 94% disease control, no ILD |
| Nasopharyngeal (NPC) | SYS6010 | EGFR | 32% response rate, 87% disease control |
| GI cancers | IPN60300 | ITGA2 (new target) | Clinical trials plenary presentation |
| Prostate (mCRPC) | HDP-103 | PSMA | Superior to standard ADC in preclinical models |
What ADC Combinations Are Being Tested?
The field is moving from ADC monotherapy toward rational combinations:
- ADC + checkpoint immunotherapy: The most common combination. Risvutatug rezetecan + anti-PD-L1 showed 47% response in NSCLC. Multiple trials are open combining ADCs with pembrolizumab, nivolumab, or durvalumab.
- ADC + targeted therapy: NEOK002 + sotorasib (KRAS G12C inhibitor) showed extended tumor regression lasting 58 days in models.
- ADC + DNA repair inhibitor: Combinations with PARP inhibitors (like olaparib) are being tested, or built directly into the ADC (CLIO-8221).
Safety Improvements
A major concern with current ADCs is toxicity — particularly interstitial lung disease (ILD) with Topo I-based ADCs and neuropathy with MMAE-based ones. Several innovations at AACR 2026 addressed this:
- QLS5132 (ovarian cancer ADC) reported zero ILD cases and zero treatment discontinuations
- Plinabulin reduced severe neutropenia from 33% to 5% when combined with ADCs — potentially a universal companion drug
- AND-gate logic ADCs (like PBS293) only release their payload when both target proteins are present on the same cell, reducing off-target damage to normal tissue
What This Means for Patients Seeking Trials
If you're looking for clinical trials, here's what the AACR 2026 ADC landscape means for you:
- More options after progression. If you've progressed on a standard ADC (Enhertu, Trodelvy, Padcev), next-generation ADCs with different payloads or bispecific designs may be an option.
- Biomarker testing matters. Many ADC trials require specific targets (HER2, TROP2, EGFR, B7-H3, Nectin-4, CLDN18.2). Ask about comprehensive genomic profiling and IHC testing.
- ADCs are entering earlier lines. Originally used after multiple prior therapies, ADCs are now being tested as first-line combinations with immunotherapy.
- Rare cancers benefit too. Bispecific and pan-tumor ADCs (targeting B7-H3, ROR1, CDH17) are enrolling broadly across solid tumor types.
ClinTrialFinder can help you find ADC trials matched to your specific cancer type, biomarkers, and treatment history.
Find ADC Trials for Your Cancer
Disease-Specific Trial Pages
Browse recruiting trials for cancers with active ADC development:
- Breast Cancer Trials — HER2-targeted ADCs, TROP2 ADCs for TNBC
- Lung Cancer (NSCLC) Trials — B7-H3, EGFR, HER2 ADCs
- Cholangiocarcinoma Trials — HER2 ADCs, bispecific ADCs
- Ovarian Cancer Trials — FOLR1, TROP2, CLDN6 ADCs
- Colorectal Cancer Trials — CDH17, EGFR bispecific ADCs
- Gastric Cancer Trials — HER2, CLDN18.2, CDH17 ADCs
- Glioblastoma Trials — B7-H3 ADCs crossing blood-brain barrier
- Browse All Disease Trials
This article summarizes publicly presented data from the AACR 2026 Annual Meeting (April 2026, Chicago). It is intended for educational purposes and does not constitute medical advice. Always discuss treatment options with your oncologist.