M. Ladanyi

Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing

BACKGROUND EGFR T790M is the most common mutation associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Baseline EGFR T790M mutations in EGFR TKI-naïve patients have been reported, but the frequency and their association with response to EGFR TKIs remain unclear. PATIENTS AND METHODS The frequency of baseline EGFR T790M as detected by routine molecular genotyping was determined by reviewing clinical results obtained at our institution from 2009 to 2013. We also collected outcome data for treatment with EGFR TKIs. RESULTS To define the incidence of EGFR T790M, we reviewed 2774 sequentially tested patients with lung cancer who underwent molecular testing using a mass spectrometry-based assay, and 11 (0.5%) had baseline EGFR T790M. Compiling results from several molecular techniques, we observed EGFR T790M in tumors from 20 patients who had not previously been treated with an EGFR TKI. In all cases, EGFR T790M occurred concurrently with another EGFR mutation, L858R (80%, 16/20), or exon 19 deletion (20%, 4/20). Two percent of all pre-treatment EGFR-mutant lung cancers harbored an EGFR T790M mutation. Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. The response rate was 8% (1/13, 95% confidence interval 0%-35%). For the patients who received erlotinib, the median progression-free survival was 2 months and the median overall survival was 16 months. CONCLUSIONS De novo EGFR T790M mutations are rare (<1%) when identified by standard sensitivity methods. TKI therapy for patients with baseline EGFR T790M detected by standard molecular analysis has limited benefit.

Nomogram to predict the presence of EGFR activating mutation in lung adenocarcinoma

Epidermal growth factor receptor (EGFR) tumour genotyping is crucial to guide treatment decisions regarding the use of EGFR tyrosine kinase inhibitors in nonsmall cell lung cancer (NSCLC). However, some patients may not be able to obtain tumour testing, either because tissue is limited and/or tests are not routinely offered. Here, we aimed to build a model-based nomogram to allow for prediction of the presence of EGFR mutations in NSCLC. We retrospectively collected clinical and pathological data on 3,006 patients with NSCLC who had their tumours genotyped for EGFR mutations at five institutions worldwide. Variables of interest were integrated in a multivariate logistic regression model. In the 2,392 non-Asian patients with lung adenocarcinomas, the most important predictors of harbouring EGFR mutation were: lower tobacco smoking exposure (OR 0.41, 95% CI 0.37–0.46), longer time interval between smoking cessation and diagnosis (OR 2.19, 95% CI 1.71–2.80), advanced stage (OR 1.58, 95% CI 1.18–2.13), and papillary (OR 4.57, 95% CI 3.14–6.66) or bronchioloalveolar (OR 2.84, 95% CI 1.98–4.06) histologically predominant subtype. A nomogram was established and showed excellent discriminating accuracy: the concordance index on an independent validation dataset was 0.84. As clinical practices transition to incorporating genotyping as part of routine care, this nomogram could be highly useful to predict the presence of EGFR mutations in lung adenocarcinoma in non-Asian patients when mutational profiling is not available or possible.

Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium

The advent of effective targeted therapy for BRAFV600E‐mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced‐stage BRAF‐mutant lung adenocarcinomas.

Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers

BACKGROUND RET rearrangements are targetable, oncogenic lung cancer drivers. While previous series have shown durable clinical benefit with pemetrexed-based therapies in ALK- and ROS1-rearranged lung cancers, the benefits of pemetrexed-based treatments in patients with RET-rearranged lung cancers relative to other genomic subsets have not previously been explored. PATIENTS AND METHODS A retrospective review of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas and evidence of a RET, ROS1, or ALK rearrangement, or a KRAS mutation was conducted. Patients were eligible if they received treatment with pemetrexed alone or in combination. The primary outcome of progression-free survival (PFS), and secondary outcomes of overall response rate (ORR, RECIST v1.1), time to progression (TTP), and time to treatment discontinuation were compared between RET-rearranged and groups of ROS1-rearranged, ALK-rearranged, and KRAS-mutant lung cancers. RESULTS We evaluated 104 patients. Patients with RET-rearranged lung cancers (n = 18) had a median PFS of 19 months [95% confidence interval (CI) 12-not reached (NR)] that was comparable with patients with ROS1- (23 months, 95% CI 14-NR, n = 10) and ALK-rearranged (19 months, 95% CI 15-36, n = 36) lung cancers, and significantly improved compared with patients with KRAS-mutant lung cancers (6 months, 95% CI 5-9, P < 0.001, n = 40). ORR (45%), median TTP (20 months, 95% CI 17-NR), and median time to treatment discontinuation (21 months, 95% CI 6-NR) in patients with RET-rearranged lung cancers were not significantly different compared with patients with ALK- and ROS1-rearranged lung cancers, and improved compared with patients with KRAS-mutant lung cancers. CONCLUSION Durable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.

1463OPROSPECTIVE MOLECULAR EVALUATION OF SMALL CELL LUNG CANCER (SCLC) UTILIZING THE COMPREHENSIVE MUTATION ANALYSIS PROGRAM (MAP) AT MEMORIAL SLOAN KETTERING CANCER CENTER (MSKCC)

ABSTRACT Aim: Recent studies using next generation sequencing (NGS) on resected SCLC specimens have led to insights into the molecular heterogeneity of this disease. However, comprehensive, prospective molecular profiling of patients (pts) with advanced SCLC using the biopsy specimens available in clinical practice has not been performed. Methods: Utilizing an IRB-approved protocol, we prospectively are evaluating SCLC tumors (SCLC-MAP) of pts in active treatment. These biopsies are evaluated by: fluorescence in situ hybridization (FISH) for FGFR1 and MET copy number; point mutation genotyping for known oncogenes by a mass spectrometry based assay (Sequenom); and NGS with a panel of 300 cancer-related genes. We first tested the feasibility of this approach in a series of pts with SCLC identified retrospectively, with matched tumor and normal pairs, and performed NGS, confirming the findings by FISH. Results: In the feasibility cohort, 21 pts with SCLC had FFPE samples available. After histologic review and DNA extraction, 10 pts had adequate material for NGS. We observed recurrent mutations in RB1 (N=7) and TP53 (N=8) and amplifications of FGFR1 (N=2) and MET (N=1), using as little as 15 nanograms of DNA. FISH confirmed FGFR1 and MET amplification in the identified cases. Since 2/2013, SCLC pts undergoing active treatment, with sufficient archived tissue, are providing consent for SCLC-MAP. Thus far, 36 pt samples have been tested. Sequenom (N=32) identified an AKT1 E17 mutation (N=1) and a PIK3CA E542K mutation (N=1). NGS (N=25) has yielded the following: loss of RB1 (N=18 mutations; N=4 deletions); mutations in TP53 (N=24), MLL3 (N=9), and EPHA 5 (N=9); and amplifications of CDKN2C (N=5), MYCL1 (N=3), SOX2 (N=2), and FGFR1 (N=1, confirmed by FISH). 4 pts had insufficient material. Conclusions: Comprehensive molecular evaluation of SCLC is feasible on clinical specimens. Prospective collection of SCLC tumor samples and mutational analyses continue. Such analyses will allow us to characterize the molecular diversity of SCLC, identify pts who will be candidates for targeted therapies, and ascertain clinical characteristics. Funded, in part, by the Lung Cancer Research Foundation. Disclosure: All authors have declared no conflicts of interest.