Expert Discusses Testing for Rare Genetic Mutations in Lung Cancer

While it is now standard practice to test patients with non-small cell lung cancer (NSCLC) for mutations such as EGFR, ALK and ROS1, testing for rarer mutations, including RET, BRAF, c-MET and NTRK, is not nearly as frequent.

Testing for these mutations is critical, according to Martin Dietrich, M.D., Ph.D., because they are not as “rare” as some in the oncology community might think.

“Especially in adenocarcinomas of NSCLC, rare mutations are not quite what the term applies,” said Dietrich. “You are looking at maybe 1 percent to 2 percent of a subset, but a subset of a very large portion of cancers. So, with 250,000 lung cancer diagnoses a year, 1 percent or 2 percent of patients affected includes several thousand patients a year. Therefore, ‘rare’ might not be the right term to phrase it.”

The significance of testing for these mutations is only increasing as new treatments that target these abnormalities are being explored. For example, the ongoing phase 2 basket STARTRK-2 trial that is examining the multikinase inhibitor entrectinib in patients with NTRK, ROS1 or ALK-positive tumors has already shown activity across solid tumors, including NSCLC (NCT02568267). Treatment with entrectinib achieved objective responses in 79 percent of patients who were enrolled in an earlier study, called STARTRK-1.

What are the major challenges for these patients with rare mutations?

Dietrich summarized the available treatments for these patient populations, as well as diagnostic and testing approaches. In an interview, Dietrich, a thoracic oncologist at Memorial Healthcare System, discussed these subtypes of rare mutations in NSCLC, the major challenges in treating these patients, and the hope that immunotherapy will be able to have a positive impact for these individuals.There are two major challenges. One is the availability of testing based on the availability of insurance coverage. That has been a huge concern, especially when those procedures and tissues are obtained in a hospital setting. There is a reimbursement issue.

Taking a look at the field of lung cancer overall, what particular areas are you excited about?

What ongoing trials in this area are you anticipating the results of?

The second major issue is the availability of sufficient tissue. We are looking at the most efficient tissue optimization. To the best extent possible, we must optimize the tissue available from biopsies from lung tissues that are not easily accessible.The main excitement in the field lies with immunotherapy. However, coming back to my lecture, the interesting next question to answer is how to make immunotherapy as a modality available to patients with one of these targetable mutations. This will make it more specific, and could allow not only impressive responses but could also induce lasting responses that are durable and would allow patients to live longer and even control their cancer. There are several. There is a CheckMate trial that is going to be very interesting. It essentially is looking at immunotherapy applications in unselected populations in the first-line setting. We have seen the introduction of so many new agents in this setting, but it’s now going to be the task to sort out the optimal sequence and patient population, as well as the optimal duration of therapy.

What do you see being accomplished in this area in the next five to 10 years?

Those are the next big challenges, now that we have so many new drugs entering the market to rearrange and optimize the application to the patient populations that we are defining better with each time that we have learned about these therapies. However, there is still a long way to go for determining the optimal approach.Ten years of lung cancer is about two or three generations worth of drugs. Therefore, we will see the introduction of several new targets in the immunotherapy field. We will see the combinations of different modalities, including radiation and immunotherapy. This will be standard of care in the next two or three years. Inflammatory response invoked by radiation therapy is certainly going to be a reasonable mechanism to enhance the immunotherapeutic effect of our newer agents.

The other question is, should we go back and repurpose our own chemotherapy drugs? We have docetaxel, which has become a whole new agent in prostate cancer. For us, we would have to look back at drugs such as pemetrexed and determine whether thymidylate synthase low-expressing squamous cell carcinomas would be a good target for those regimens.

Chemotherapy is not going to go away, but it is going to be used in a specific niche based on the better understanding of the biology of the cancers we are treating.