In brief
- Of 28,244 patients with non-small cell lung cancer (NSCLC) and next-generation sequencing data, 195 (0.7%) carried the TP53 Y220C mutation.
- That prevalence is higher than the 0.4% average the authors give for solid tumours, and similar to that of other low-abundance actionable alterations in NSCLC.
- Half of the Y220C-positive patients carried no known driver alteration.
- Y220C was more frequent in EGFR-mutant than in EGFR-wild-type tumours (1.7% vs 0.7%; p=0.029), and showed no significant association with gender, smoking status, histology or stage.
- A second TP53 mutation was present in 17.0% of Y220C-positive patients, which the authors consider possibly associated with intrinsic resistance.
Study at a glance
- Design: Retrospective, multicentre, ETOP-sponsored
- Cohort: 28,244 patients with NSCLC and next-generation sequencing data, from several European institutions
- Prevalence: 195 patients (0.7%) with TP53 Y220C, against an average of 0.4% across solid tumours
- Other drivers: None known in half of the Y220C-positive patients
- EGFR status: Y220C in 1.7% of EGFR-mutant vs 0.7% of EGFR-wild-type tumours (p=0.029)
- Clinical features: No significant association with gender, smoking status, histology or stage
- TP53 co-mutation: A second TP53 mutation in 17.0% of Y220C-positive patients
- Not reported: In the abstract, treatment received, outcomes or survival of Y220C-positive patients; the sequencing panels used
PYNNACLE tested rezatapopt without a single patient with NSCLC
TP53 is the most frequently mutated gene in human cancer, and drugs that target specific mutant p53 proteins have been developed. Rezatapopt reactivates the Y220C p53 protein. It was evaluated in the Phase I PYNNACLE trial in patients with solid tumours, with results the authors describe as promising.
That trial enrolled no patients with NSCLC. Little was known about the clinicopathological characteristics or the genetic profile of patients whose lung tumours carry Y220C, and the ETOP study was set up to describe them.
195 Y220C carriers among 28,244 sequenced patients
The investigators collected data retrospectively from NSCLC patients from several European institutions, and included only those with next-generation sequencing data available.
At 0.7%, the prevalence in NSCLC exceeds the 0.4% average the authors give for solid tumours. Because the data were gathered retrospectively, the figure describes patients who already had sequencing results.
A higher rate in EGFR-mutant tumours, and no clinical profile to select patients by
Y220C was found in 1.7% of EGFR-mutant tumours, against 0.7% of EGFR-wild-type tumours (p=0.029). No significant association was observed with gender, smoking status, histology or stage.
Half of the Y220C-positive patients carried no known driver alteration. No clinical feature in the cohort pointed to the mutation, and the authors call for patients with NSCLC to be screened for it.
A second TP53 mutation in 17% of carriers, a possible route to resistance
The authors propose that these second TP53 mutations might be associated with intrinsic resistance, and they recommend that TP53 co-mutations be analysed alongside Y220C itself.
A frequency on a par with other rare actionable alterations in NSCLC
The authors note that TP53 Y220C has a frequency similar to other low-abundance, actionable alterations in NSCLC, and conclude:
“Patients with NSCLC should be screened and included in future trials of Y220C reactivators.”Molina-Vila et al., Journal of Thoracic Oncology (2026)
The evidence is retrospective and descriptive. Whether a Y220C reactivator is active in NSCLC is a question for prospective trials.
Sources
- Journal of Thoracic Oncology. Brief Report: Characterization of the Potentially Actionable TP53 Y220C Mutation in Non-Small Cell Lung Cancer. A Multicenter, European Thoracic Oncology Platform Study (2026-10-01). doi.org
Featuring Lung Summit faculty
This study was co-authored by Lung Summit faculty Rolf A. Stahel, Lukas Bubendorf, Lizza Hendriks, Solange Peters and Stephen Finn.
This article was produced independently by the Lung Summit editorial team, without industry funding or input.
