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AACR Annual Meeting 2026

April 17–22, 2026 · San Diego · 2418 items

After the meeting★★

Next-generation ADCs: payload innovation

48 people · 49 posts7 topics

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An ADC is an antibody as the courier and a toxin as the letter. The first three generations argued about linker stability and how toxic the payload was. This meeting argued about what the letter is: degraders, targeted drugs, dual payloads, even enzymes — not only cytotoxics.

Marketed T-DXd cut the risk of progression by nearly half in first-line HER2-positive breast cancer. The louder floor argument was still-unapproved: stuffing a pan-RAS inhibitor into an ADC, and the finding that a single IHC stain is no longer enough to pick patients.

A classic ADC is antibody–linker–cytotoxic, internalized, released in the lysosome, cell death. A DAC swaps in a degrader: after release it recruits an E3 and sends an “undruggable” protein to the proteasome. It deletes a protein rather than killing the cell, so the window can be wider and targets such as SMARCA2 come into range.

The other path is to take orally toxic kinase inhibitors (PI3K and the rest) and deliver them as payloads. Dual-payload ADCs hang two mechanisms on one antibody to beat cross-resistance among cytotoxics. The floor consensus: ADC competition has moved from “another target” to payload and pairing.

Analysis

Payload innovation is a field-level move this year, not a side quest. T-DXd is already rewriting the first-line standard. DAC clinical data are still thin — Prelude’s SMARCA2 degrader sits around a 15% response, a long way from a product.

The ADC clinical-trials plenary had a sharp line: in EGFR and CLDN6 programs, IHC expression did not predict benefit. “A unidimensional biomarker for a multidimensional drug” — internalization, payload sensitivity and spatial heterogeneity have to enter the model. Positive versus negative is not enough.

Still open
  • Whether DAC clinical responses clear the cytotoxic-ADC baseline by enough to matter.
  • Which multi-parameter model replaces IHC for patient selection.
  • Whether a pan-RAS ADC payload has a therapeutic window that survives first-in-human.
Key readout

T-DXd + pertuzumab · PFS HR 0.56 (40.7 vs 26.9 mo)DESTINY-Breast09 · 1L HER2+ mBC · Phase 3

Records

Drug / trialReadoutSetting
T-DXd + pertuzumabtrastuzumabHER2#BREASTCANCERPFS HR 0.56 (40.7 vs 26.9 mo)DESTINY-Breast09 · 1L HER2+ mBC · Phase 3
olaparib + T-DXdolaparibConfirmed PR 42.9%, mDOR 11.2 mo (n=28)Gapped schedule · endometrial / ovarian
risvutatugB7-H3 ADC, floor ORR ~47%GSK / Hansoh
zanidatamab 新辅助zanidatamabHER2No-chemo pCR 30%, HER2 down 56%NeoZanHER · early HER2+++
AVA6103 / pan-RAS ADCAVA6103CLDN18Tricomplex pan-RAS as payloadAmong the floor’s strongest ADC threads

Floor

Apr 23Thu
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  9. 2 more on this topicHER2 · 11
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Other directions

CBACBA Frontier Insights (CFI)Chinese Biopharmaceutical Association (CBA)www.cba-usa.org