# Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became

Source: https://onco.cc/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/  
OnCo record `idea-lung-resistance-directed-sequencing-at-every-progression` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When a targeted drug stops working, the tumour has usually changed in a way you can read. Most patients still move to the next treatment on a protocol rather than on a test of what actually happened.

## Summary

Sequist's 37 re-biopsied patients showed that acquired resistance to EGFR inhibitors is a heterogeneous set of diagnoses: T790M, MET amplification, PIK3CA mutation, a change of cell state, and in 14 percent an outright transformation into small-cell lung cancer, which is sensitive to entirely different drugs. Three patients lost their resistance mechanism when the drug was withdrawn and responded again. Kobayashi's single patient in 2005 produced osimertinib.

Despite this, sequencing at progression is inconsistent: tissue re-biopsy is invasive and often declined, plasma testing is not reimbursed everywhere, and the result frequently arrives after the next line has started. The idea is to make a resistance profile, tissue where safe and plasma always, a required step before the next line, and to fund the pathway that makes it fast enough to act on.

## Fields

- Kind: Idea
- Last checked: 2026-09-25
- Tags: lung-evidence
- Hypothesis: Mandatory molecular profiling at progression on targeted therapy, with a turnaround short enough to choose the next line, improves survival after first progression compared with protocol-driven sequencing, chiefly by finding the histological transformations and the actionable bypass alterations that are currently missed.
- Rationale: The mechanisms are known, the assays exist, and at least one of them (small-cell transformation) changes treatment completely and is invisible without a biopsy. Amivantamab's activity against MET-driven bypass resistance, and the existence of drugs for MET, HER2 and RET alterations arising on treatment, mean a profile increasingly has somewhere to go. The reversibility finding also suggests a drug holiday is a testable strategy rather than a curiosity.
- Proposed test: A randomised strategy trial at first progression on a targeted therapy: profiling-directed next line (tissue plus plasma, result within 14 days) against physician's choice, with overall survival from progression as the primary endpoint and the rate of histological transformation detected as a key secondary. Plausible inside existing molecular tumour board networks; three to four years.
- Maturity: early-clinical
- Actor: clinic

## Connected records

- roadmaps: [ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment](https://onco.cc/roadmaps/ctdna-tests/), [Diagnostics roadmap: stains → gene panels → blood tests that decide treatment](https://onco.cc/roadmaps/diagnostics-roadmap/), [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/)
- cancers: [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Data silos](https://onco.cc/bottlenecks/b-data-silos/), [Fragmented care and guideline gaps](https://onco.cc/bottlenecks/b-care-fragmentation/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- key papers: [Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC](https://onco.cc/key-papers/paper-cho-mariposa-amivantamab-lazertinib-nejm-2024/), [EGFR mutation and resistance of non-small-cell lung cancer to gefitinib](https://onco.cc/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/), [Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors](https://onco.cc/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/), [Tracking the evolution of non-small-cell lung cancer](https://onco.cc/key-papers/paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017/)

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