Epidermal growth factor receptor (EGFR)–mutant non–small cell lung tumors transformed to small cell disease an average of 17.8 months after diagnosis, and this shift often involved Rb1, TP53, and PIK3CA mutations, according to the findings of a multicenter retrospective study of 67 patients.
After transformation, platinum-etoposide, paclitaxel, and nab-paclitaxel each yielded clinical response rates of 71%, while patients did not respond to programmed death-1 or programmed death-ligand 1 checkpoint inhibition, reported Nicolas Marcoux, MD, of Massachusetts General Hospital in Boston and his associates. “Indeed, none of the 17 patients [who received a checkpoint inhibitor] even seemed to derive clinical benefit from these therapies, as the longest time to progression was only 9 weeks,” the researchers wrote in the Journal of Clinical Oncology.
Interestingly, docetaxel produced no responses among six treated patients. Transformation often led to central nervous system metastases and patients survived a median of 10.7 months after transformation (95% confidence interval, 8.0-13.7 months).
Repeat biopsies showed that 3%-10% of EGFR-mutant non–small cell lung cancers transformed to small cell lung cancers. However, the subsequent clinical course has not been well characterized. Patients in this study were treated at eight cancer centers, had a history of EGFR-mutant small cell lung cancer, and most (87%) had non–small cell histology at diagnosis and received at least one EGFR tyrosine kinase inhibitor. The other nine patients had de novo small cell lung cancer or mixed histology.
All 59 patients with tissue genotyping at first evidence of small cell lung cancer retained their founder EGFR mutations, Dr. Marcoux and his associates reported. Among 19 patients with a history of EGFR T790M positivity, 15 patients were T790 wild-type at transformation. “Other recurrent mutations included TP53, Rb1, and PIK3CA,” they wrote.
The study supports the first-line use of platinum-etoposide for EGFR-mutant lung cancers that transform to small cell lung cancer, the researchers concluded. “Conversely, these tumors do not respond well to checkpoint inhibitors and the use of these therapies outside of a clinical trial should currently be discouraged.”
Funders included the National Institutes of Health, LungStrong, Targeting a Cure for Lung Cancer, Be a Piece of the Solution, the Susanne E. Coyne Memorial Fund, and a STOP Cancer Carrie Scott Grant. Dr. Marcoux disclosed honoraria from Bristol-Myers Squibb.
SOURCE: Marcoux N et al. J Clin Oncol. 2018 Dec 14. doi: 10.1200/JCO.18.01585.