Histologic transformation of EGFR-mutant non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of acquired resistance to EGFR-targeted tyrosine kinase inhibitors (TKIs) that occurs in approximately 3% to 10% of EGFR mutant NSCLCs. However, the natural history and clinical course of SCLC after transformation from NSCLC is poorly understood. A retrospective analysis sought to better characterize disease features and outcomes of 67 patients with EGFR-mutated SCLC and other high-grade neuroendocrine carcinomas.
The majority of patients (87%) included in the analysis had NSCLC at initial diagnosis, while 9 (13%) had de novo SCLC or mixed histology. All patients had EGFR mutations at diagnosis (exon 19 deletion 69%, L858R 25%, and other 6%), and those with NSCLC had been treated with at least one EGFR TKI. The median time to SCLC transformation was 17.8 months. Among 59 patients with tissue genotyping upon development of SCLC, all maintained founder EGFR mutation. A total of 19 patients had prior evidence of EGFR T790M mutation, but 15 of these patients were T790M wildtype following transformation. The most common mutations associated with transformation to SCLC included TP53 (79%), Pb1 (58%), and PIK3CA (27%).
Following development of SCLC (either de novo or transformation), patients received a variety of systemic therapies, with platinum-etoposide as the most common treatment. Platinum-etoposide was associated with an overall response rate (ORR) of 54% and a median progression-free survival (PFS) of 3.4 months. Of note, among 17 patients who received immunotherapy with a PD-1 or PD-L1 inhibitors, there were no responses and all patients progressed rapidly. Taxane chemotherapy was the most common treatment for patients progressing on platinum-etoposide chemotherapy, and was associated with a ORR of 50% and a median PFS of 2.7 months. Central nervous system (CNS) metastases occurred in 64% patients following transformation to SCLC. The median overall survival (OS) from diagnosis was 31.5 months, and median OS from transformation was 10.9 months.
The investigators concluded that transformation to SCLC occurs in a small but important subset of patients with EGFR mutated NSCLC and is frequently associated with Rb1, TP53, and PIK3CA mutations. While chemotherapy yields impressive response rates in these patients, they generally have poor outcomes. The authors also highlighted that tissue biopsy still plays an important role in NSCLC, in particular in cases where no genetic mechanisms of acquired resistance is identified by noninvasive methods such as cell-free DNA.