Small cell transformation in EGFR-mutated non-small cell lung cancer: DLL3 expression and efficacy of immune checkpoint inhibitors or tyrosine kinase inhibitors combined with chemotherapy

Highlights•Small cell transformation occurs about 1.5 years after start of targeted therapy•Immunotherapy was associated with a non-significant trend towards longer survival•Efficacy of treatment lines after platinum/etoposide is limited•The majority of tumors acquires DLL3 expression with small cell transformationAbstractIntroductionSmall cell transformation (SCT) is a typical mechanism of adaptive resistance to third generation epidermal growth factor receptor inhibitors (EGFRi) which have become the standard of care for EGFR-driven non-small cell lung cancer (EGFR+ NSCLC). Little is known about the optimal management of SCT patients. This study aimed to compare outcomes under platinum/etoposide chemotherapy alone (chemo) or in combination with EGFR inhibitors (EGFRi+chemo) or immune checkpoint inhibitors (ICI+chemo). In addition, DLL3 expression was explored as potential novel therapeutic target.MethodsWe conducted a retrospective study on patients with EGFR+ NSCLC and SCT treated at 19 centers in Europe and the United States. A total of 47 patients were included of whom 17 received chemo, 20 ICI+chemo, and 10 EGFRi+chemo. We analyzed DLL3 expression by immunohistochemistry.ResultsIn the entire cohort, median overall survival (OS) from start of first SCT therapy was 11 months (95% confidence interval [95%CI] 9.1-12.9) and median progression-free survival (PFS) was 5 months (95%CI 4.2-5.8). Median PFS was similar in all three groups (chemo and ICI+chemo 4 months, EGFRi+chemo 6 months), and 12-months PFS was 12% (95%CI 2%-31%), 13% (95%CI 0%-43%), and 0% for ICI+chemo, EGFRi+chemo, and chemo, respectively. Median OS in the ICI+chemo group was 13 months (95%CI 5.5-20.5) compared to 10 months (95%CI 7.6-12.4) with chemo and EGFRi+chemo (95%CI 8.1-11.9), respectively. Before and after SCT, 0% and 93% of tumors were DLL3-positive.ConclusionsOur results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT.Presented elsewherePart of this work has been presented at ESMO annual meeting in Madrid, Spain in October 2023 (Poster 1336P).