In brief
- A prospective trial gave first-line osimertinib with platinum and etoposide to patients with EGFR-mutant lung adenocarcinoma whose tumours were TP53/RB1-deficient, a group at high risk of transformation to small cell lung cancer.
- Five of the 11 patients developed SCLC transformation despite the SCLC-directed chemotherapy.
- Median progression-free survival was 11 months and median overall survival 33 months.
- Genomic and single-cell transcriptomic profiling found mesenchymal and squamous histologies as well as SCLC transformation, linked to progressive disruption of the RB pathway.
Study at a glance
- Design: Prospective trial, single treatment regimen
- Population: Metastatic EGFR-mutant lung adenocarcinoma, TP53/RB1-deficient (11 patients in the transformation count)
- Treatment: First-line osimertinib with platinum and etoposide
- SCLC transformation: 5 of 11 patients
- Survival: mPFS 11 months; mOS 33 months
- Translational work: Genomic and single-cell transcriptomic profiling of patient samples
- Not reported: in the abstract, response rates, adverse events and follow-up time
Small cell transformation in 5 of 11 patients
The trial enrolled patients with EGFR-mutant lung adenocarcinoma carrying TP53 and RB1 deficiency, the comutation pattern the authors identify with a high risk of histological transformation, and treated them from the first line with osimertinib plus platinum and etoposide. Platinum and etoposide are a chemotherapy pair directed at SCLC.
Transformation to SCLC still occurred in five patients. Median progression-free survival was 11 months and median overall survival 33 months. With 11 patients and one treatment arm, these figures describe this cohort and carry no comparison with osimertinib alone.
Mesenchymal and squamous change alongside SCLC
Profiling of patient samples at the genomic and single-cell transcriptomic level found plasticity associated with the TP53/RB1 comutations, some of it clinically evident and some subclinical. Besides transformation to SCLC, tumours showed mesenchymal and squamous histologies.
The authors connect these shifts to a progressive disruption of the RB pathway. In their analysis this disruption altered chromatin accessibility and switched on transcriptional programmes of neuronal differentiation and epithelial-to-mesenchymal transition, and osimertinib treatment intensified those programmes further.
“These findings provide insights into the role of plasticity in mediating drug tolerance.”Morrill Gavarró et al., Science Translational Medicine (2026)
Resistance to EGFR inhibitors through a change of histology
EGFR inhibitors are highly effective in EGFR-mutant lung adenocarcinoma, the authors note, but resistance emerges, and histological transformation to SCLC is a particularly aggressive form of it. The trial added SCLC-directed chemotherapy from the first line in the patients most exposed to that route.
Sources
- Science Translational Medicine. Osimertinib, platinum, and etoposide for patients with metastatic EGFR / TP53 / RB1 -mutant lung cancers at risk for histological transformation (2026-11-11). doi.org
Featuring Lung Summit faculty
This study was co-authored by Lung Summit faculty Charles Rudin.
This article was produced independently by the Lung Summit editorial team, without industry funding or input.
