EGFR-Mutant Small-Cell Lung Cancer Research Articles

Characteristics and prognosis of EGFR mutations in small cell lung cancer patients in the NGS era

PurposeTargeted therapy has not been effective for small cell lung cancer (SCLC) patients. Although some studies have reported on EGFR mutations in SCLC, a systematic investigation into the clinical, immunohistochemical, and molecular characteristics and prognosis of EGFR-mutated SCLCs is lacking.MethodsFifty-seven SCLC patients underwent next-generation sequencing technology, with 11 in having EGFR mutations (group A) and 46 without (group B). Immunohistochemistry markers were assessed, and the clinical features and first-line treatment outcomes of both groups were analyzed.ResultsGroup A consisted primarily of non-smokers (63.6%), females (54.5%), and peripheral-type tumors (54.5%), while group B mainly comprised heavy smokers (71.7%), males (84.8%), and central-type tumors (67.4%). Both groups showed similar immunohistochemistry results and had RB1 and TP53 mutations. When treated with tyrosine kinase inhibitors (TKIs) plus chemotherapy, group A had a higher treatment response rate with overall response and disease control rates of 80% and 100%, respectively, compared to 57.1% and 100% in group B. Group A also had a significantly longer median progression-free survival (8.20 months, 95% CI 6.91–9.49 months) than group B (2.97 months, 95% CI 2.79–3.15), with a significant difference (P = 0.043). Additionally, the median overall survival was significantly longer in group A (16.70 months, 95% CI 1.20–32.21) than in group B (7.37 months, 95% CI 3.85–10.89) (P = 0.016).ConclusionEGFR-mutated SCLCs occurred more frequently in non-smoking females and were linked to prolonged survival, implying a positive prognostic impact. These SCLCs shared immunohistochemical similarities with conventional SCLCs, and both types had prevalent RB1 and TP53 mutations.

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer.

Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called “bypass activation”). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.

EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes.

Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized. We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed. We included 67 patients-38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation. 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.

MS18.03 Treatment of SCLC transformed from EGFR Mutant Adenocarcinoma

MS18.03 Treatment of SCLC transformed from EGFR Mutant Adenocarcinoma

1531PD - Clinical outcomes for EGFR-mutant adenocarcinomas (AC) that transform to small cell lung cancer (SCLC)

Background: About 5-10% of EGFR-mutant lung ACs transform to SCLC at the time of acquired resistance. The clinical course of patients (pts) with this finding is poorly characterized. Methods: We retrospectively reviewed the records of all 16 pts with EGFR-mutant SCLC that have been seen at our center under an IRB-approved protocol and summarized demographics, disease features, and clinical outcomes. Results: Among 16 pts, 10 were women. 15 had AC histology at diagnosis; one had de novo SCLC with EGFR del19. 11 were never-smokers. All but the de novo case received an EGFR tyrosine kinase inhibitor (TKI) prior to transformation (7 had > 1 prior TKI; 6 received a 3rd-gen TKI) and 14/15 were on a TKI when the SCLC was noted. Median time from diagnosis to SCLC was 29.6 mo (95% CI 10.8-38.1). 15/16 of the SCLC tumors were genotyped; all kept their founder EGFR mutation and none had T790M, including 5 pts with prior T790M-positivity. Not all samples were assessed for genotype by the same assay, though recurrent mutations observed in at least 25% of cases were TP53, PIK3CA and RB1 (full genetic data will be shown at meeting). The most common therapy given directly after SCLC diagnosis was platinum-etoposide (n = 9); all SCLC treatment lines considered, platinum-etoposide had a clinical response rate of 72% (8/11) and progression-free survival of 4.6 mo (95% CI 2.0-5.5). Seven pts also had a taxane at some point after the diagnosis of SCLC, and 4/7 (57%) responded. Median overall survival (mOS) from initial cancer diagnosis was 38.2 mo (95% CI 24.5-43.9) and mOS from time of SCLC diagnosis was 12.4 mo (95% CI 4.0-16.6). Conclusions: EGFR-mutant AC that transforms to SCLC uniformly maintains its founder EGFR mutation and is mutually exclusive with T790M (though both can be observed sequentially). In our cohort, the median time from initial lung cancer diagnosis to transformation was 2.5 years. The mOS of 12.4 mo following diagnosis of SCLC is similar to that seen among pts with non-EGFR-mutant SCLC. Likewise, responses to platinum-etoposide were frequent, but transient. 4 pts also responded to a taxane. Interestingly, mOS from diagnosis was similar to expected mOS for pts that never transform to SCLC at 38.2 mo. Further investigation is needed to better elucidate optimal strategies for this group. Legal entity responsible for the study: Lecia V Sequist Funding: None Disclosure: Z. Piotrowska: Advisory board/consulting honoraria from AstraZeneca, Boehringer-Ingelheim and Ariad Pharmaceuticals. A.F. Farago: Consulting for Pharmamar, Abbvie, Takeda, Merrimack, Intervention Insights. Honorarium from Foundation Medicine. A.N. Hata: Amgen - consulting and research support Novartis - research support L. Sequist: Consulting for AZ, Ariad, BMS and Genentech – and research support from Clovis, AZ, BI, Novartis, Merrimack, Pfizer, Genentech, Merck, Johnson & Johnson. All other authors have declared no conflicts of interest. Keywords: metastatic non-small lung cancer, SCLC, small cell transformation, EGFR mutations

Small-Cell Carcinoma With an Epidermal Growth Factor Receptor Mutation in a Never-Smoker With Gefitinib-Responsive Adenocarcinoma of the Lung

Activating mutations in the epidermal growth factor receptor (EGFR) gene are extremely rare in small-cell lung cancer (SCLC). Here, we present a case of an EGFR-mutant gefitinib-responsive non–small-cell lung cancer (NSCLC) of adenocarcinoma histology occurring in a never-smoker followed by subsequent diagnosis of metastatic SCLC carrying an EGFR mutation. Although gefitinib therapy of the primary NSCLC resulted in disease control for over 3 years, the patient subsequently developed metastatic SCLC to the liver. Epidermal growth factor receptor mutation analysis revealed that the exon 21 L858R activating mutation was present in both the original lung adenocarcinoma and the metastatic SCLC. We hypothesize that SCLC either evolved from the previously diagnosed NSCLC or that both arose from a common precursor. Further comparative molecular analysis of these histologically distinct tumors would be of value to better understand the potential role of EGFR in the pathogenesis of SCLC in never-smokers, and the role of selection for an EGFR-mutant SCLC subclone as an unusual mechanism of acquired resistance to EGFR inhibitors in NSCLC.