CHICAGO – The newly minted Lung Cancer Mutation Consortium detected a driver mutation in 54% of lung adenocarcinoma tumors, allowing clinicians to use the information in real time to select erlotinib as initial therapy or to direct patients to trials targeting their specific mutation.
The collaborative effort points to the revolutionary changes taking place in the management of lung adenocarcinoma and the potential for personalized treatment in routine practice.
Dr. Mark G. Kris
"While an individual mutation may be quite rare, having a mutation of some kind that is actionable is very common in adenocarcinoma," said Dr. Mark G. Kris, who presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).
Earlier this year, the National Comprehensive Cancer Network and ASCO recommended epidermal growth factor receptor (EGFR) mutation testing to identify patients with advanced non-small cell lung cancer (NSCLC) who may benefit from EGFR tyrosine kinase inhibitors such as erlotinib (Tarceva) and gefitinib (Iressa). Adenocarcinoma is the most common form of NSCLC, accounting for up to 50% of cases in the United States.
Dr. Kris said new mutations can be quickly added to the testing process and that they plan to maintain and expand the scope of the consortium when federal funding ends for the National Cancer Institute–sponsored initiative made up of 14 cancer centers across the country.
"I think this can serve as a model for other institutions developing similar programs in lung cancer and for other cancers," said Dr. Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York.
A total of 1,234 patients with stage IV lung adenocarcinoma agreed to undergo testing for 10 known mutations using standard multiplexed assays and fluorescence in situ hybridization. Inadequate tissue in 170 patients (14%) resulted in a study group of 1,064 patients. Mutations were identified in 280 (54%) of 516 tumor specimens tested to date (95% confidence interval 50%-59%).
As suspected, the most common mutations were KRAS (22%), EGFR (17%), and EML4-ALK rearrangement (7%), Dr. Kris said. Other mutations were: BRAF (2%) and PIK3CA, HER2, MET amplification, MEK1, NRAS, and AKT1.
The vast majority (97%) of mutations were mutually exclusive. Of the 14 double-mutant tumors, the two molecular lesions most commonly seen together were MET amplification and PIK3CA, he said.
Four sites had testing available prior to the study, with seven additional sites now able to provide multiplex mutation testing. Preliminary data from 121 patients enrolled at a single site show that driver mutations were found in 60 (59%) of 102 patients in whom testing was completed. That information was used to direct therapy in 30% of patients – 19 to receive erlotinib up front and 16 to go on a trial of an agent targeting their specific mutation.
"In truth, we used it for every patient because when we did not find an EGFR mutation, we did not give them erlotinib," Dr. Kris said.
The turnaround time for mutational testing varied by site, but generally took only a few days. The great majority of time is in specimen acquisition, preparation, and submission to the molecular lab.
"Those are formidable obstacles that we all have to face," Dr. Kris said. "But I think with programs like this, we’ll get over those."
Invited discussant Dr. Ramaswamy Govindan, a professor of medicine at Washington University in St. Louis, said EGFR mutation testing is ready for routine clinical use and that EML4 ALK fusion testing will soon be ready. He pointed out that there are more than 15,000 NSCLC mutations alone in the Catalog of Somatic Mutations in Cancer database and that many questions remain, including the cost-effectiveness of mutational testing.
"It’s important to remember that not all mutations are created equal," he said.
Dr. Govindan described the most important aspect of the presentation as the linking of the consortium to targeted clinical trials. Last year he was coauthor of a review that found only 8% of nearly 500 ongoing clinical trials in NSCLC used biomarkers for patient selection (J Thorac. Oncol. 2010 Aug;5:1116-9). He contrasted that study with the observation that no fewer than 112 drugs were discussed at this year’s Targeted Therapies in Lung Cancer meeting.
Some of the agents being evaluated in trials linked to the consortium include: crizotinib for EML4-ALK rearrangements, tivantinib plus erlotinib for KRAS mutations, erlotinib plus the investigational agents OSI 906 or MM 121 for EFGR mutations and an afatinib trial targeting HER2 led by Dr. Kris.
The Lung Cancer Mutation Consortium was funded by an American Recovery and Relief grant. Dr. Kris reports consulting for ArQule, BI, Chugai Pharma and Pfizer. Dr. Govindan reports consulting for Taiho and honoraria from AstraZeneca, GlaxoSmithKline, and BI.