In the Journals

Researchers track clinical course of EGFR-mutant transformed small cell lung cancer

Patients with epidermal growth factor receptor-mutant non-small cell lung cancer that transformed into small cell lung cancer experienced this transformation at an average of 17.8 months following diagnosis, according to results of retrospective study published in Journal of Clinical Oncology.

Further, EGFR-mutant transformed small cell lung cancer usually was characterized by RB1, TP53 and PIK3CA mutations; frequent central nervous system metastases; and responses to a platinum-etoposide regimen and taxanes, but not to checkpoint inhibitors.

“Approximately 3% to 10% of EGFR-mutant NSCLCs undergo transformation to small cell lung cancer,” Nicolas Marcoux, MD, medical oncologist and hematologist at Massachusetts General Hospital, and colleagues wrote. “Significant progress has been made in the past few years toward understanding the genetic mechanisms associated with such histologic transformation. ... Despite these advances, little is known about the clinical course of patients with EGFR-mutant cancer after small cell lung cancer transformation, which leads to uncertainty about appropriate treatments and prognostic implications for clinicians.”

Marcoux and colleagues analyzed 67 patients (median age at diagnosis, 56 years; women, n = 38; 49% white, 42% Asian; 73% never smokers) with a history of EGFR-mutant small cell lung cancer. EGFR mutations included exon 19 deletion (n = 46), L858R (n = 17) and other (n = 4).

A total of 58 patients had NSCLC at initial diagnosis, while nine had de novo small cell lung cancer or mixed histology. The patients with initial NSCLC received one or more EGFR tyrosine kinase inhibitor before small cell lung cancer transformation.

Median time to small cell lung cancer transformation was 17.8 months (95% CI, 14.3-26.2). Researchers observed high response rates to platinum-etoposide and taxanes after transformation, but no responses among 17 patients who received immunotherapy.

Results showed median OS from diagnosis of 31.5 months (95% CI, 24.8-41.3) and median OS from small cell lung cancer transformation of 10.9 months (95% CI, 8-13.7).

Fifty-nine patients had tissue genotyping at first evidence of small cell lung cancer, and all patients maintained their original EGFR mutation. Fifteen of 19 patients with prior EGFR T790M positivity were T790 wild type at transformation.

Recurrent mutations also included TP53 (79%), RB1 (58%) and PIK3CA (27%), with re-emergence of NSCLC clones occurring in some patients.

Researchers also reported frequent CNS metastases after transformation.

Limitations to the study included its retrospective nature and a lack of standardized treatment and response assessments across the cohort.

EGFR-mutant lung cancers that transform to small cell lung cancer or that have high-grade neuroendocrine histology at the time of diagnosis exhibit high response rates to platinum-etoposide, which should be considered the first-line therapy of choice, and also exhibit high response rates to taxanes,” Marcoux and colleagues wrote. “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.” – by John DeRosier

Disclosures: Marcoux reports honoraria from Bristol-Myers Squibb. Please see the study for all other authors’ relevant financial disclosures.

Patients with epidermal growth factor receptor-mutant non-small cell lung cancer that transformed into small cell lung cancer experienced this transformation at an average of 17.8 months following diagnosis, according to results of retrospective study published in Journal of Clinical Oncology.

Further, EGFR-mutant transformed small cell lung cancer usually was characterized by RB1, TP53 and PIK3CA mutations; frequent central nervous system metastases; and responses to a platinum-etoposide regimen and taxanes, but not to checkpoint inhibitors.

“Approximately 3% to 10% of EGFR-mutant NSCLCs undergo transformation to small cell lung cancer,” Nicolas Marcoux, MD, medical oncologist and hematologist at Massachusetts General Hospital, and colleagues wrote. “Significant progress has been made in the past few years toward understanding the genetic mechanisms associated with such histologic transformation. ... Despite these advances, little is known about the clinical course of patients with EGFR-mutant cancer after small cell lung cancer transformation, which leads to uncertainty about appropriate treatments and prognostic implications for clinicians.”

Marcoux and colleagues analyzed 67 patients (median age at diagnosis, 56 years; women, n = 38; 49% white, 42% Asian; 73% never smokers) with a history of EGFR-mutant small cell lung cancer. EGFR mutations included exon 19 deletion (n = 46), L858R (n = 17) and other (n = 4).

A total of 58 patients had NSCLC at initial diagnosis, while nine had de novo small cell lung cancer or mixed histology. The patients with initial NSCLC received one or more EGFR tyrosine kinase inhibitor before small cell lung cancer transformation.

Median time to small cell lung cancer transformation was 17.8 months (95% CI, 14.3-26.2). Researchers observed high response rates to platinum-etoposide and taxanes after transformation, but no responses among 17 patients who received immunotherapy.

Results showed median OS from diagnosis of 31.5 months (95% CI, 24.8-41.3) and median OS from small cell lung cancer transformation of 10.9 months (95% CI, 8-13.7).

Fifty-nine patients had tissue genotyping at first evidence of small cell lung cancer, and all patients maintained their original EGFR mutation. Fifteen of 19 patients with prior EGFR T790M positivity were T790 wild type at transformation.

Recurrent mutations also included TP53 (79%), RB1 (58%) and PIK3CA (27%), with re-emergence of NSCLC clones occurring in some patients.

Researchers also reported frequent CNS metastases after transformation.

Limitations to the study included its retrospective nature and a lack of standardized treatment and response assessments across the cohort.

EGFR-mutant lung cancers that transform to small cell lung cancer or that have high-grade neuroendocrine histology at the time of diagnosis exhibit high response rates to platinum-etoposide, which should be considered the first-line therapy of choice, and also exhibit high response rates to taxanes,” Marcoux and colleagues wrote. “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.” – by John DeRosier

Disclosures: Marcoux reports honoraria from Bristol-Myers Squibb. Please see the study for all other authors’ relevant financial disclosures.