A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC).

Abstract

8019 Background: The detection of driver mutations in the EGFR and ALK genes and targeted therapy has transformed treatment of lung cancer. The LCMC was established in 2009 to assay lung adenocarcinomas for driver genomic alterations in 10 genes and to study and treat patients by their molecular subtypes. Methods: The 14-member LCMC enrolled patients with metastatic adenocarcinoma of the lung and tested their tumors in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using multiplexed assays, and for ALK rearrangements and MET amplifications using fluorescence in situ hybridization (FISH). Results: 1,102 eligible patients were enrolled; 1,007 underwent testing for at least one genomic alteration with 733 undergoing testing for all 10 genes. 600 patients were women (60%) with a median age of 63; 341 were never smokers (34%) and 589 former smokers (58%). A driver alteration was detected in 622 (62%) of the 1,007 with any genotyping, and in 465 (63%) of the 733 fully genotyped cases. Among the tumors with full genotyping, drivers were found as follows: KRAS 182 (25%), sensitizing EGFR 107 (15%), ALK rearrangements 56 (8%), other EGFR 43 (6%), two genes 29 (4%), BRAF 16 (2%), HER2 15 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), and AKT1 0 (0%). Results were used to select targeted therapy or targeted trials in 279 patients with a driver alteration (28% of 1,007 total). Among 938 patients with clinical follow-up and treatment information, 264 with a driver alteration treated with a targeted agent had a median survival of 3.5 years; 313 with a driver who did not receive targeted therapy had a median survival of 2.4 years; while 361 without an identified driver had a median survival of 2.1 years (p<0.0001). Conclusions: An actionable driver alteration was detected in 62% of tumors from patients with lung adenocarcinomas, leading to use of a targeted therapy in 28%. The patients with an identified driver treated with a targeted agent lived longer than those patients who did not receive targeted therapy. Multiplexed genomic testing can aid physicians in matching patients with targeted treatments and appropriate clinical trials.

BRAF Mutations: Signaling, Epidemiology, and Clinical Experience in Multiple Malignancies

“…29 Among patients with lung adenocarcinoma, driver mutations have been identified in 62% of patients undergoing testing for at least 1 genomic alteration. 100 Mutations in BRAF arise in 1.6% to 4.9% of adenocarcinomas. 1,12,13,101,102 Unlike melanoma, PTC, and HCL in which most BRAF mutations are V600E, mutations in lung adenocarcinomas can be separated into either V600E (50%-56.8%) and non-V600E (43.2%-50%).…”

Frequency of Epidermal Growth Factor Mutation Status and Its Effect on Outcome of Patients with Adenocarcinoma of the Lung

“…However, our survival in chemotherapy arm was consistent with survival data reported in chemotherapy trials. A meta-analysis that included individual patient data from 2968 patients in nine trials, comparing cisplatin based to carboplatin based chemotherapy showed median survival of (median 8.4 vs. 9.1 months, HR for death 1.07, 95% CI 0.99 -1.15) [16].…”

Personalizing Therapy in Advanced Non–Small Cell Lung Cancer

“…Data from the Lung Cancer Mutation Consortium (LCMC) identified an oncogenic driver in 62% of lung adenocarcinomas that undergo molecular profiling for 10 of the most common oncogenic drivers and that these oncogenic drivers are 97% mutually exclusive. 21 When tissue availability is an issue, it is reasonable to do molecular testing concurrently for the currently actionable genotypes (EGFR and ALK), then proceed to more extensive profiling if these initial tests are negative, to triage a patient to a clinical trial for a potentially actionable mutation. 21 If tissue and resources allow, one can also consider testing more broadly as part of the initial oncogenic screen, and consider utilizing a next-generation sequencing (NGS) platform, which includes both the actionable and the putative oncogenic drivers, as well as genotypic abnormalities for which the functional or therapeutic significance is as yet unknown.…”

“…1). 21,23 The recognition of the central role of targeted therapy in EGFR-mutant lung adenocarcinoma is rooted in the landmark Iressa Pan-Asia Study (IPASS), a randomized phase 3 clinical trial that evaluated the efficacy of gefitinib versus carboplatin/paclitaxel as first-line therapy in patients clinically selected on the basis of adenocarcinoma histology, Asian ethnicity, and never-or light-smoking status. 24 The IPASS clinical trial illustrates first and foremost that targeted therapy with the EGFR TKI gefitinib is superior to conventional chemotherapy in the EGFR mutant population and is associated with a 71.2% response rate (RR) and a 52% relative risk reduction for progression-free survival (PFS) compared with chemotherapy (p < 0.001; ►Table 1).…”

“…1). 21 Crizotinib, a multitargeted small molecule TKI that inhibits not only ALK but MET and ROS 1 as well, was approved by the U.S. Food and Drug Administration (FDA) in 2011 based on phase 1 and 2 clinical trial data. The first results of the phase 1 trial were presented by Kwak et al, in which 82 ALK positive NSCLC patients received crizotinib with an RR of 57%.…”