# Combination baskets defined by resistance mechanism rather than by cancer type

Source: https://onco.cc/ideas/idea-tr2-resistance-mechanism-baskets/  
OnCo record `idea-tr2-resistance-mechanism-baskets` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Group patients by why their last drug stopped working, then test the combination designed to fix that specific failure, whatever the cancer.

## Summary

Progression biopsies and ctDNA now reveal resistance mechanisms (SLFN11 loss for topoisomerase-1 payloads, MET amplification for EGFR inhibitors, RB loss for CDK4/6 inhibitors). A basket trial enrolling by mechanism would test the matched rescue combination (for example ATR inhibitor plus the same ADC for SLFN11-low tumours) across histologies, converting a resistance hypothesis into a trial in months.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Mechanism-defined baskets will achieve objective response rates at least twice those of unselected post-progression combination cohorts of the same agents.
- Rationale: Histology-agnostic approvals (NTRK, MSI-high) proved that biology can define a population; resistance mechanisms are the same idea applied after progression.
- Proposed test: A three-cohort basket: SLFN11-low after a TOP1 ADC, MET-amplified after EGFR TKI, and RB1-loss after CDK4/6 inhibitor, each with a pre-specified rescue combination and a Simon two-stage design.
- Maturity: preclinical-evidence
- Actor: research

## Sources

- Bottleneck evidence (Too many combinations to test): Palmer & Sorger, Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy (Cell 2017): https://doi.org/10.1016/j.cell.2017.11.009

## Connected records

- ideas: [Payload-class switching as the rule for ADC sequencing](https://onco.cc/ideas/idea-payload-switching/), [Sequential multiple-assignment randomised trials to find the best order of ADCs](https://onco.cc/ideas/idea-tr2-smart-sequencing-adc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [CDK4/6 inhibitors](https://onco.cc/technologies/cdk46-inhibitor/)
- terms: [Drug efflux pumps (ABC transporters)](https://onco.cc/terms/efflux-pump/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/)
- key papers: [Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy](https://onco.cc/key-papers/paper-palmer-cell/)
- roadmaps: [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

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