Small Cell Transformation of EGFR-Mutant NSCLC Treated with Tyrosine Kinase Inhibition
by
, , , , ,
Adam Rock
1
,
Isa Mambetsariev
1,
Siddhika Pareek
1,
Jeremy Fricke
1,
Xiaochen Li
2,
Javier Arias-Romero
1,
Waasil Kareem
3,
Leonidas Arvanitis
4,
Debora S. Bruno
5,
Stacy Gray
1 and
Ravi Salgia
1,*
1
Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
2
Division of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
3
Department of Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
4
Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
5
Department of Medical Oncology & Therapeutics Research, City of Hope Cancer Center Atlanta, Newnan, GA 30265, USA
*
Author to whom correspondence should be addressed.
Curr. Oncol. 2025, 32(10), 554; https://doi.org/10.3390/curroncol32100554
Submission received: 28 August 2025
/
Revised: 30 September 2025
/
Accepted: 30 September 2025
/
Published: 3 October 2025
(This article belongs to the Section Thoracic Oncology)
Simple Summary
Histologic transformation represents the conversion of a baseline cancerous cell into a new cell, leading to resistance to specific treatments. Small cell transformation is an example of resistance to tyrosine kinase inhibition in epidermal growth factor mutant lung cancer. This retrospective review focuses on genomic alterations at various time points observed in patients with epidermal growth factor mutant lung cancer who underwent histologic transformation. We observed various recurrent genomic alterations that may contribute to the development of small cell lung cancer in the setting of targeted therapy for EGFR mutations. Relevant data pertaining to outcomes and therapeutic interventions are described in detail to aid clinicians in addressing this rare and clinically challenging phenomenon.
Abstract
Introduction: Epidermal growth factor receptor (EGFR) alterations exist in 15–50% of non-small cell lung cancer (NSCLC) diagnoses. Although effective therapeutics have been developed in the form of tyrosine kinase inhibitors (TKI), various mechanisms of resistance lead to treatment failure after exposure to EGFR TKI-based therapy. Of these, histologic transformation (HT) into small cell lung cancer (SCLC) represents approximately 14% of cases. Methods: Within a single institution, we retrospectively reviewed longitudinal data from both tissue and liquid biopsies of patients with histologic transformation after a diagnosis of EGFR-mutant NSCLC. We sought to further characterize the baseline and emergent genomic alterations after HT to SCLC in the context of TKI exposure, along with germline alterations that may contribute to lineage plasticity and outcomes. Results: Fifteen patients were included in our analysis. Of these, EGFR exon 19 deletions were the most frequent (n = 11, 73.3%), followed by L858R (n = 3, 20%) and L861Q (n = 1, 6.7%). The median time for transformation was 17 months (95%CI, 8.9–41.9 months). The median OS of our cohort was 51.6 months (95%CI, 26.3—NE) with a median OS post-transformation of 13.4 months. Recurrent genomic alterations included TP53, Rb1, PIK3CA, and BRAF. Germline testing revealed a pathogenic alteration in FBN1, with a recurrent variant of unknown significance (VUS) in PALLD. Conclusion: Post-transformation somatic mutation testing and germline testing at presentation revealed unique mutational profiles not previously reported in the setting of HT to SCLC. Further investigations are required to determine the optimal treatment and sequencing following HT.
