Transformation of EGFR-Mutant NSCLC to SCLC


Key Points

  • All patients with initial NSCLC had received ≥ 1 EGFR tyrosine kinase inhibitor prior to SCLC transformation.
  • Median time to transformation was 17.8 months.

In a study reported in the Journal of Clinical Oncology, Marcoux et al provided further evidence that EGFR-mutant non–small cell lung cancer (NSCLC) can undergo transformation to small cell lung cancer (SCLC) and identified factors associated with such transformation. It has been estimated that such transformation occurs in 3% to 10% of EGFR-mutant NSCLCs.

The study involved data from 67 patients (38 women and 29 men) with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at 8 North American sites. EGFR mutations included exon 19 deletion (69%), L858R (25%), and others (6%). At initial lung cancer diagnosis, 58 patients had NSCLC and 9 had de novo SCLC or mixed histology.

Characteristics of Transformation

At the time of transformation for the 58 patients with initial NSCLC or at time of diagnosis for the 9 cases of de novo SCLC, histology was reported as classic SCLC in 97% of cases and as large-cell neuroendocrine carcinoma in the remaining 2 cases. All patients with initial NSCLC had received at least one EGFR tyrosine kinase inhibitor prior to SCLC transformation. Among these patients, median total time on EGFR tyrosine kinase inhibitors before transformation was 15.8 months (range = 1.3–53.4 months), and median time from diagnosis of advanced NSCLC to SCLC transformation was 17.8 months. Overall, 93% of patients were receiving an EGFR tyrosine kinase inhibitor at the time of transformation.

After transformation, the clinical response rate was 54% among 46 evaluable patients treated with platinum/etoposide and 50% among 20 evaluable patients receiving taxane regimens. No clinical responses were observed among 17 patients receiving immune checkpoint inhibitors, including 8 receiving nivolumab/ipilimumab; the longest time to progression in these 17 patients was 9 weeks. Median overall survival was 31.5 months from diagnosis and 10.9 months from the time of SCLC transformation.

Among 59 patients with tissue genotyping at first evidence of SCLC, all maintained their founder EGFR mutation after transformation, although 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Common mutations identified in SCLC samples after transformation were TP53 (79% of 48 evaluable patients), Rb1 (58% of 31 patients), and PIK3CA (27% of 52 patients).

NSCLC clones were observed to reemerge in some cases. Central nervous system (CNS) metastases were frequent after transformation to SCLC, with 64% of 59 patients with follow-up radiographic information having progression in the CNS after SCLC diagnosis.

The investigators concluded, “There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis, and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum/etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.”

Lecia V. Sequist, MD, MPH, of Massachusetts General Hospital, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by the National Institutes of Health, LungStrong, Targeting a Cure for Lung Cancer, and others. The study authors’ full disclosures can be found at

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