Lung Cancer Therapy Based on Genomics Improves Survival

Fran Lowry

May 20, 2014

Treatment for lung cancer has traditionally been based on the tumor's histology, but the new approach of basing treatment on genomic features has now been shown to result in better survival.

Results from the Lung Cancer Mutation Consortium (LCMC) show that patients who received genotype-directed therapy lived more than a year longer than those who did not.

The results are published in JAMA.

"Although much remains to be done, the incorporation of genomic medicine into the study and treatment of lung cancer represents, at the very least, the end of the beginning for the care of these and other patients with cancer," write Boris Pasche, MD, PhD, of Wake Forest University, Winston-Salem, North Carolina, and Stefan C. Grant, MD, JD, MBA, of the University of Alabama at Birmingham, in an accompanying editorial.

The evidence that using targeted agents improves survival in lung cancer has been very difficult to show in clinical trials, but the current study shows that such an approach is not only feasible but successful. In fact, the study heralds a new era in the management of patients with a variety of cancers, Dr. Pasche told Medscape Medical News.

This theoretical juncture that we had discussed for many years has arrived. Dr. Boris Pasche

"We are at a critical juncture in oncology, and this study shows that this theoretical juncture that we had discussed for many years has arrived," Dr. Pasche said.

Genomics Improved Survival

The LCMC, a collaborative, 14-center study led by Mark G. Kris, MD, from Memorial Sloan-Kettering Cancer Center, in New York City, tested tumors from 1007 patients with metastatic lung adenocarcinomas for the presence 10 oncogenic driver mutations and then used the results to select agents that would target the drivers.

The study was conducted from 2009 through 2012, and the patients' tumors were tested for at least 1 gene, with full genotyping (testing for 10 genes) performed in 733 patients. For the other patients, the primary reason for the inability to test for all 10 genes was insufficient tissue.

Dr. Boris Pasche

An oncogenic driver was found in 466 (64%) of the patients who underwent full genotyping. KRAS mutations were the most frequent, found in 182 (25%), followed by sensitizing EGFR in 122 (17%) and ALK rearrangements in 57 (8%).

Less common drivers were other EGFR in 29 (4%), 2 or more genes in 24 (3%); ERBB2 (formerly HER2) in 19 (3%); BRAF in 16 (2%), PIK3CA in 6 (<1%), MET amplification in 5 (<1%), NRAS in 5 (<1%), and MEK1 in 1 (<1%).

These results were then used to guide the choice of targeted therapy.

Overall, among 938 patients with adequate data, the median survival was 2.7 years. For patients with an oncogenic driver treated with targeted therapy, the median survival was 3.5 years, for patients with an oncogenic driver who were not treated with targeted therapy, the median survival was 2.4 years, and for patients with no driver identified, the median survival was 2.1 years (P < .001).

Among the different drivers that were identified, the longest survival was seen in patients with ALK-positive tumors (4.3 years).

The fact that 14 centers could come together and help one another develop the ability to do such genetic testing simultaneously and share the information are important achievements, Dr. Kris noted in an earlier interview with Medscape Oncology.

"This has transformed the way we treat people with lung cancers," he said in a statement.

"It used to be that when lung cancers were diagnosed solely by a visual microscopic examination of tumor tissues by a pathologist, every patient received the same intravenous chemotherapy. But now, we are personalizing the care of these individuals by finding the genetic alterations in the tumor tissues that drive their cancers and giving medicines that specifically counteract the cancerous effects of those genes," Dr. Kris commented.

In an interview with Medscape Medical News, editorialist Dr. Pasche emphasized that the idea of genomics guiding therapy is no longer a theory ― it is now being used in clinical practice in many areas of oncology.

"We have come to the point where we can have informed information for patients that we never had before which would give us a better guess as to choosing therapies for patients who have no other option," he said. "For example, this morning I was discussing with a patient with triple negative breast cancer that failed all chemotherapies. She is still in very good condition, she has had her genome tested, and we found that she has mutations that would be targetable with everolimus [Afinitor, Novartis Pharmaceuticals Corporation], a drug that is approved by the FDA in other diseases. This is definitely a better option than any form of chemotherapy for her disease."

"We are at the point now where we may be able to offer patients other treatments by studying the genomic features of their cancer. Until recently, we could not afford to do it because it cost about a million dollars for one genome. Now it's as low as $900 to do the genome of a tumor, and it's likely that will become even cheaper. And with better software, we would also be able to assess the unique features of that tumor vs other tumors and vs the normal DNA of that patient, and this is really the major change," he said.

The study by Dr. Kris and colleagues is the first proof that it is feasible to do multiplex genetic testing, Dr. Pasche added. "It is no longer a hypothetical concept, it is proof of feasibility that is very elegantly showed."

Such an approach will, however, require a level of collaboration among investigators, institutions, funding agencies, and the pharmaceutical industry that presently does not exist, he said.

"Traditionally, to do clinical trials in common tumors like breast, colon, or lung cancer, you need several hundred patients. Until now, we would have to make sure that the patients all had the same type of cancer, and then we would randomize them to receive standard therapy plus a novel agent or a novel combination of agents," Dr. Pasche said.

Now, with the results of this study, such an approach becomes difficult, he said.

"If you look at the results from this study, you cannot do that anymore, because 64%, the majority of the patients, had mutations, and most were different. Even the largest institutions, like Sloan-Kettering and MD Anderson, which are the 2 largest cancer centers in the US by volume, would not be able to run a study of their own, even if they worked together," Dr. Pasche said.

Change the Way Clinical Trials in Oncology Are Done

Dr. Pasche predicted the need to have multiple institutions with multiple drugs available to do studies to assess the efficacy of drugs in patients who have mutations.

Probably in the next 10 years, what we have been doing traditionally is going to be looked at as ridiculous. Dr. Boris Pasche

"Without such collaboration, we will only have a small number of patients, or a case report, and that's not what we want. We want to move to the next step and be able to tell our patients who have cancers that are difficult to treat currently, for whom we have exhausted standard chemotherapy, that targeting their tumor intelligently may be an important option and much better than what we have always done in the past. Probably in the next 10 years, what we have been doing traditionally is going to be looked at as ridiculous. Now we'll be able to guess much better and have a good rationale for why we are using these agents in these patients."

The study was funded by the National Institutes of Health and the National Cancer Institute. Dr. Kris reports consulting for Ariad, AstraZeneca, Bind Biosciences, Boehringer Ingelheim, Chugai Pharma, Clovis, Covidien, Daiichi Sankyo, Esanex, Exelixis, Genentech, the National Lung Cancer Partnership (NLCP), Pfizer, PUMA, and Stand Up to Cancer (Massachusetts General Hospital), Novartis, Millenium, Roche, China, and Roche, Italy. Dr. Pasche reports receiving grant support from the National Cancer Institute, having served as the chair for the US Department of Defense Colorectal Cancer Grant review panel, serving as a member of the Cancer Genetics study section of the National Cancer Institute, as an ad hoc member of the Department of Defense Breast Cancer Review Panel, and as an ad hoc reviewer of the Cancer Genetics program of the University of Iowa Comprehensive Cancer Center in 2010; receiving awards from the National Cancer Institute and the National Institutes of Health, receiving payment for lectures from Novartis, Amgen, HudsonAlpha Institute, Hirslanden, University of Pennsylvania, Karmanos Cancer Institute, University of North Carolina at Chapel Hill, and LACORE, having 2 pending patent applications, receiving book royalties, and receiving travel support from the Bioelectromagnetics Society.

JAMA. 2014;311:1988-206. Full article, Editorial


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