Detecting and Treating ALK-Positive Lung Cancers

Posted by Samantha Powell on August 26th, 2014 |

Hello. This is Mark Kris, from Memorial Sloan Kettering Cancer Center in New York City. I want to spend a few minutes talking about the treatment of ALK-positive lung cancers and ROS1, another of the oncogene fusion-driven lung cancers.

We have had some recent data come out. I think the first piece to discuss is the observation from the Lung Cancer Mutation Consortium that ALK-positive cases are 8% of lung adenocarcinomas.[1] People have said that that is high — and it is one of the higher numbers reported — and people have said that the group at the consortium was somehow selected.

To the contrary, what the consortium found most commonly in this cohort of patients were people with RAS mutations; 25% of these patients had mutations in KRAS, which is what you would expect in a general cohort of lung cancers. Nonetheless, ALK-positive lung cancer is probably more common than you think.

Rapid Identification of ALK-Positive Cancer in the Next-Generation Testing Era

The second issue with ALK is, now that we are migrating to multiplex, next-generation testing, the time it takes to get that result is longer. In truth, getting a fluorescence in situ hybridization (FISH) test was not simple either, because sufficient tissue had to be obtained, and the FISH is probably the most labor-intensive test done in our pathology laboratories.

So, what do you do? How do you find people with ALK-positive disease? At our institution, we have used ALK immunohistochemistry, a strategy you may want to consider. While we are waiting for next-gen results, our pathologists routinely obtain immunohistochemistry tests for ALK and for L858R EGFR. The antibodies are available. They are quite reliable. They work well in CLIA labs (certified under the Clinical Laboratory Improvement Amendments) and can be rapidly set up. There is a huge body of literature about their accuracy, reliability, reproducibility, and concordance with FISH testing.[2] When you need to make sure that someone is or is not ALK positive, consider doing the immunohistochemistry test while the next-gen panel is cooking.

New Opportunities, New Challenges

Another amazing story in drug development is the approval of ceritinib by the US Food and Drug Administration a few months ago. It is amazing that an illness that was described only about 7 years ago already has 2 approved treatments, with another drug, alectinib, moving right along toward approval.

New drugs present new opportunities and new challenges to the oncologist. I refer you to the updated NCCN guidelines,[3] which have already added ceritinib and how to use it. I know we have a natural tendency to switch to the new agent as soon as we find [drug-resistant progression], but I urge you to be very careful and very patient-specific in how you use ceritinib in patients who have already receivedcrizotinib.

Dr. Kris Recommends…

For the asymptomatic patient with noncritical progression, clearly the best and recommended course is to continue the crizotinib. For patients who have single-site and easily approachable metastatic deposits, particularly patients with isolated CNS progression, we want to maintain good control in extra-CNS sites. For these patients, stop the crizotinib, give whole-brain radiotherapy, and continue with the crizotinib once that is done.

Again, there is no proof that switching too soon is a good strategy. We have seen many patients who have been maintained on a drug that is very well tolerated for a long period of time.

On the basis of our current information, this also applies to other fusion-directed cancers, particularly ROS1 cancer. For someone with ROS1 cancer who is receiving crizotinib but develops isolated CNS recurrence with good control everywhere else, stop the crizotinib, fix the brain, and then restart the crizotinib. This control can be maintained when the brain is taken care of.

Clearly, ceritinib can be effective in the brain, but please remember that isolated brain recurrence can be treated in other ways. Many of these drugs can penetrate into the brain. It is not that ceritinib is so much better; it is an effective drug and it works everywhere, but please use it at the right time.

We are having an amazing run in the treatment of lung cancers, diseases that were considered untreatable, or with very limited treatment options, and lots of toxicity. The landscape has changed tremendously. However, this has put more burden on the oncologist. We have many more decisions to make, but that is a good thing.

Date: 8/26/14
Outlet Full Name: Medscape
Author: Mark G. Kris, MD

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