More Than Half of NSCLC Patients Have Actionable Mutations, Lung Cancer Consortium Reports

Field: Medicine (Health Sciences)

Lung Cancer Mutation ConsortiumPersonalized cancer care requires that clinicians know what mutation or mutations drive an individual patient's tumor so the patient can be treated according to that genetic alteration. However, few institutions are currently equipped to run the rapid molecular tests necessary to support that approach. To overcome that barrier, researchers from 14 institutions formed the lung cancer mutation consortium (LCMC) and set out to test non-small cell lung adenocarcinomas from 1,000 patients in real time, and use the information to guide therapy. Thus far, the LCMC has completed testing on 516 patients and identified driver mutations in more than half of the tumors, according to data presented at the ASCO Annual Meeting. As planned, physicians used the individual patient information to direct the patients to treatment with an approved targeted agent, to an appropriate clinical trial, or to standard treatment with chemotherapy. Moreover, the LCMC used American Recovery and Reinvestment Act grant money to establish CLIA-certified molecular testing facilities at seven participating institutions, which will support future care and research.MARK G. KRIS, MD: “We detected an actual mutation in 54% of individuals with lung adenocarcinoma and used this in real time to select erlotinib therapy and direct patients to clinical trials. In reality, all patients had benefit, because if we didn't find a mutation or a patient didn't qualify for a clinical trial, they got chemotherapy, which for them was a better choice.”“We did it,” said Mark G. Kris, MD, Chief of Thoracic Oncology Service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center, who presented the LCMC data. “We detected an actual mutation in 54% of individuals with lung adenocarcinoma and we used this in real time to select erlotinib therapy and to direct patients to clinical trials. In reality, all patients had benefit, because if we didn't find a mutation or a patient didn't qualify for a clinical trial, they got chemotherapy, which for them was a better choice.” A Process Established The investigators used a combination of sequencing and fluorescent in situ hybridization (FISH) tests to evaluate each patient's tumor. They tested for alterations in 10 previously identified driver gene, including KRAS, EGFR, BRAF, HER2, PIK3CA, AKT1, NRAS, MEK1, EML4-ALK, and MET amplification.RAMASWAMY GOVINDAN, MD: “With the exception of the EGFR inhibitors, the mutations are not ready for prime time, so the linking of the mutation consortium to clinical trials is the most important thing. Fortunately we have a number of drugs that need to be explored.”Out of 1,234 patients who agreed to participate, 170 (14%) did not have adequate tissue available. As of May 13, the team had completed analysis of 516 samples, 294 had sequence analysis completed but not FISH, and 82 had FISH analysis completed but not sequencing, and another 172 were awaiting both tests. The most common mutation was in KRAS (22%), followed by EGFR (17%), EML4-ALK (7%), and BRAF (2%). Mutations in other genes were found less frequently, and tumors carrying more than one mutation were rare, occurring in just 3% of tumors. ‘Singular Data’ “This is singular data,” Dr. Kris said. “This is perhaps the only time that every test for every mutation was done on every specimen.” That complete analysis provides a picture of lung cancer mutations across a relatively large population, and enables the community to see their frequency, and how infrequently two or more driver mutations occur in a single tumor. “The good news is that even though some of these mutations are rare, when you look at the totality of mutations, from a patient's standpoint, something is usually found that can be used to guide care,” Dr. Kris said. Moreover, the investigators have established a connection between the academic lung cancer community and the pharmaceutical companies that are testing drugs designed to block these key driver mutations. Instead of setting up a clinical trial system of its own, the LCMC contacted companies that already had trials open and recommended that their patients participate in those studies. In an interview with OT, Dr. Kris said he thinks this approach benefits patients because it facilitates their entry into the most appropriate trial with fewer tests or hurdles. Also, because the system is efficient, it could be used as a model for future efforts. “By just linking ourselves to the pharmaceutical company trials, we shifted that burden to the companies, rather than running them ourselves, or duplicating their efforts,” he said. The value of that strategy was seconded by the study's Discussant, Ramaswamy Govindan, MD, Professor and Co-Director of the Section of Medical Oncology at Washington University School of Medicine, Siteman Cancer Center. “With the exception of the EGFR inhibitors, the mutations are not ready for prime time, so the linking of the mutation consortium to clinical trials is the most important thing,” he said. “Fortunately we have a number of drugs that need to be explored.” Facilities Established When the consortium was first set up, three institutions had CLIA-certified molecular labs and one was in the process of setting one up. A key aspect of the grant, therefore, was to establish CLIA laboratories at the other centers so that each institution could analyze its own samples, sharing information on a National Cancer Institute database. Eleven of the 14 sites now have testing labs. “Some sites did share specimens, but the goal was that each site would analyze their own specimens and establish a labor-atory where this testing could be ongoing even after the grant ends, Dr. Kris said. “I believe it is safe to say that after the life of this grant, this testing will continue and be a care-and-research resource there.” When asked after his presentation whether the test delayed care substantially, Dr. Kris said the testing itself was pretty rapid. “The great majority of time is in specimen acquisition, specimen preparation, and getting an adequate specimen to the molecular lab. Those are very formid-able obstacles that we all have to face. I think with more programs like this we will get over those. But it was not an issue of technology. The technology turns around very quickly.” A Strategy to Lower Costs? During his discussion of the LCMC data, Dr. Govindan, who is OT's Clinical Advisory Editor for Oncology, noted that at a recent meeting there were close to 100 experimental targeted agents being discussed, and the costs of both drug development and cancer care are increasing. A key question, therefore, is whether molecularly directed patient care, like the LCMC strategy, can reduce costs. Data presented by French researchers at a meeting in Brussels in May suggest that it can, Dr. Govindan said. With 28 French clinics participating, 1.7 million euro were used for EGFR testing. However, only those patients whose tumors carry an EGFR mutation received treatment with a targeted agent. Therefore, the drug cost for front-line gefitinib dropped from more than ?100 million to ?35 million. “This is fairly early data, and it is unclear if the patients will get erlotinib or gefitinib later,” Dr. Govindan said. “But the point is that if you do testing earlier on, and select patients, it is possible you will save costs significantly. We will be seeing these kinds of cost analyses in the coming years.” Memorial Sloan-Kettering and some of the Boston institutions are already set to include molecular testing for patients on a regular basis, Dr. Kris noted. Instead of testing the 10 common driver mutations the LCMC focused on, though, the institutions will run a testing panel including 200 to 300 genes, which are known drivers in a variety of cancers. “I think it is going to be much more efficient that way,” he said. “The truth is that you can do 250 genes without a lot more effort than you can do 10. The machinery and technology to do that are already in place in Boston hospitals and our place.”