Transformed EGFR-mutant non-small cell lung cancer (NSCLC) had a mix of retained and new mutations, often responded to conventional chemotherapy, and did not respond well to immunotherapy, a multicenter retrospective study showed.
The study, one of the largest of its kind, found that NSCLC transformation to SCLC or neuroendocrine tumors occurred at a median year and a half after initial diagnosis, that these transformed cancers universally retained the founder EGFR mutation, and that transformation to SCLC was associated with the emergence of several new mutations.
The retrospective analysis corroborated previous evidence regarding the molecular underpinnings of transformed SCLC and provided new information about the clinical course of the disease, as reported online in the Journal of Clinical Oncology.
“There is a growing appreciation that EGFR-mutant NSCLC can undergo SCLC transformation,” Lecia Sequist, MD, of Massachusetts General Hospital Cancer Center in Boston, and co-authors concluded.
“Of importance, given the increasing use of cell-free DNA analysis at the time of acquired TKI [tyrosine kinase inhibitor] resistance, our data emphasize the continued role of tissue biopsy at progression for histologic examination, especially in cases in which no genetic resistance mechanism is identified by noninvasive means,” they continued. “Additional investigation and ongoing multicenter collaborations are needed to better elucidate optimal strategies for this group.”
Studies of mutation-focused repeat biopsy in EGFR-mutant NSCLC uncovered molecular mechanisms of resistance that led to development of next-generation treatment strategies. Studies of patients who underwent repeat biopsy showed that in 3% to 10% of cases, acquired resistance to TKIs is associated with histologic transformation to SCLC, the authors noted. Less commonly, EGFR mutations occurred in de novo SCLC.
Previous work demonstrated that EGFR mutation uniformly remains at the DNA level in transformed tumors but that EGFR protein is diminished, rendering the tumors unresponsive to EGFR-targeted TKIs. Additional evidence suggested that the SCLC clone diverged early from the founder clone and that transformation often was associated with inactivation of TP53 and RB1.
“We’ve known about transformation for quite awhile, but because it’s a rare occurrence, a single institution will have only a handful of patients, making it very hard to study,” said Zofia Piotrowska, MD, also of Massachusetts General Hospital Cancer Center.
To address the information void, investigators at eight North American cancer centers contributed data from records of patients with a history of EGFR-mutant SCLC or high-grade neuroendocrine carcinomas, collectively termed SCLC.
The analysis comprised data for 67 patients, whose EGFR mutations consisted of exon 19 deletion (69%), L858R (25%), and other (6%). At initial diagnosis, 58 of the 67 patients had NSCLC and the remaining nine had SCLC or mixed histology.
The patients with NSCLC at diagnosis received a median of two lines of therapy prior to transformation, including at least one EGFR TKI. Additionally, 23 patients received two or more EGFR TKIs, and 17 patients had an acquired EGFR T90M resistance mutation. Investigators determined that 15 of 19 patients with prior evidence of the T90M mutation did not harbor the mutation at transformation.
The median time on EGFR TKI therapy to transformation was 15.8 months, and the median interval from initial diagnosis to transformation was 17.8 months. All but five of the 58 patients with initial diagnoses of EGFR-mutant NSCLC were on an EGFR TKI at transformation.
Seven of nine patients with de novo SCLC had classic histology at transformation and the remaining two patients had large-cell neuroendocrine carcinoma, the authors reported. Five of the seven patients with classic histology harbored the T90M mutation, and two of the five had mixed NSCLC-SCLC histology.
Analysis of SCLC samples revealed TP53 mutations in 38 (79%) of 48 evaluable patients, RB1 in 18 (58%) of 31, and PIK3CA in 14 (27%) of 52. Mutation assessment by next-generation sequencing identified TP53 mutations in 32 of 35 patients. Three patients had BRCA1 mutations, but none had point mutations thought to be associated with cancer predisposition.
After SCLC transformation (or de novo SCLC diagnosis), patients received a median of two lines of systemic therapy, most often a platinum-etoposide doublet (n=53). In 46 evaluable patients, the overall response rate was 54%. None of 17 patients responded to an immune checkpoint inhibitor, either as monotherapy or in a combination. Half of 20 evaluable patients responded to treatment with a taxane.
The patients had a median post-transformation follow-up of 8.1 months (range 0.0-26.9). Median overall survival from initial diagnosis was 31.5 months, and the median survival from transformation was 10.9 months.
“We still have a lot to learn about these cancers and how they are related to regular small cell lung cancer and what the optimal treatments are,” Piotrowska told MedPage Today. “One of the things that I hope will come from this study, seeing the number of patients we can get with this type of cross-institutional collaboration, is that it makes us hopeful that we might be able to design clinical trials specifically for patients with small cell, transformed, EGFR-mutant lung cancer.”
Sequist disclosed relationships with AstraZeneca, Genentech, Bristol-Myers Squibb, Pfizer, Merrimack Pharmaceuticals, Boehringer Ingelheim, Clovis Oncology, Novartis, Johnson & Johnson, Merck, Guardant Health, and Incyte.