P3.02b-109 Molecular Profiling of EGFR-Positive NSCLC with Secondary T790M Resistance Mutation and Tertiary Transformation into Small-Cell Lung Cancer: Topic: EGFR RES

Abstract

In advanced stage NSCLC, activating EGFR-mutations are prognostic and predictive factors for treatment with an EGFR-tyrosine kinase inhibitor (TKI). However, invariably, resistance to EGFR-TKI develops. Resistance is primarily driven by T790M mutations present in approximately 50% of EGFR-mutation positive NSCLC at progression. A different mechanism of EGFR-TKI-resistance is transformation into SCLC which has been reported in very rare cases. Employing Sanger sequencing and targeted next generation sequencing, we performed full histopathological workup and molecular profiling of all tumor biopsies obtained during the course of disease. Both molecular and histopathological data were correlated with the clinical course. We report the case of a 70 year old patient, ECOG 1, presenting with dyspnea and fatigue due to a predominantly acinar adenocarcinoma with extensive metastatic disease. Using Sanger sequencing, we detected a del Exon19-EGFR mutation. Based on fulfilled response criteria for EGFR-TKI therapy, erlotinib 150mg was initiated with rapid improvement of dyspnoe and fatigue. After one month, erlotinib was reduced to 100mg due to dermatotoxicity. After 5 weeks, CT showed partial remission. After 4½ months, CT revealed mixed response with resolved pleural effusion but slowly progressive pulmonary metastases. The brain metastases present at diagnosis had regressed but a new lesion was detected. Due to ongoing clinical benefit, erlotinib was continued beyond progression. After 7 months, the patient deteriorated clinically (ECOG 2) with CT showing progression of all tumor sites including. FNAC of a progressive mediastinal lymph node was submitted for histopathological and molecular work-up. In parallel one cycle of systemic chemotherapy with carboplatin/gemcitabine was given, and cerebral radiation was delivered. Following detection of a T790M mutation, chemotherapy was stopped and therapy with osimertinib 80mg (CUP) was started with prompt improvement of the clinical state. CT after 6 weeks confirmed partial remission. However, 10 weeks later, the patient’s condition rapidly deteriorated. CT detected complete remission of brain metastasis but rapid progression of the primary tumor, mediastinal lymphadenopathy, and hepatic metastases. An endobronchial kryobiopsy revealed small cell lung cancer as the underlying cause. EGFR analysis revealed the presence of the original exon19 mutation which had been present in the previous biopsies showing NSCLC histology. Complementing these preliminary results, a full molecular workup using next generation sequencing is currently being performed across all biopsies and will be presented. Integrated analysis of clinical, histopathological and molecular characteristics reveals tumor evolution over time and leads to highly individual therapeutic management benefiting the patient.