Diagnosing ALK+ NSCLC

Mark A. Socinksi, MD:Welcome to thisTargeted Oncologypresentation in precision medicine called “Advances in the Treatment Paradigm forALK+ Non—Small Cell Lung Cancer.”

We knowALKgene rearrangements occur in a small portion of patients with non—small cell lung cancer. Patients with tumors harboring such rearrangements are highly sensitive to ALK inhibitors. Our discussion today will be an overview of the biology ofALK-positive lung cancer, methods for diagnosingALK-positive non—small cell lung cancer, current FDA-approved ALK inhibitors, mechanisms of resistance to ALK inhibition, and potential strategies to combat resistance.

I am Dr Mark Socinksi, executive medical director of the AdventHealth Cancer Institute in Orlando, Florida. Joining me today is my colleague, Dr Thomas Stinchcombe, medical oncologist and professor of medicine at the Duke Cancer Center in Durham, North Carolina. Welcome, Dr Stinchcombe.

Thomas E. Stinchcombe, MD:Thank you for having me.

Mark A. Socinksi, MD:Let’s begin. You don’t mind if I call you Tom, do you?

Thomas E. Stinchcombe, MD:Please do.

Mark A. Socinksi, MD:Tom, it was 12 years ago, I believe, when the first reports ofALKrearrangements in adenocarcinoma of the lung came out. Some Japanese investigators originally described that. And it really defined a subset. What are your thoughts about that discovery and the importance of that? How many patients have this?

Thomas E. Stinchcombe, MD:I remember when that came out. I think it’s an excellent example in thoracic oncology of a rapid drug development paradigm. Crizotinib was studied in theALK-positive patients, and that led to promising activity and a very rapid approval in 2011. And then it was followed by 2 phase III trials, 1 in the second-line and 1 in the first-line, and very quickly we moved thisALK-targeted therapy, in this case crizotinib, to the preferred first-line therapy. I think it was a huge change in the landscape of how lung cancer was treated, because now we had 2 targeted therapies. I think it really pushed to the forefront the need for molecular profiling of all patients.

Mark A. Socinksi, MD:Interestingly, this is clinically a different set of patients. They tend to be younger. The median age in theALKstudies is always in the mid-50s. There’s nearly an equal distribution of men and women, which is not what we see withEGFRmutations, almost always or mostly exclusively adenocarcinoma in the never-smoker or light-smoking patient. So there is a different profile for this population. And so, clinicians should be suspicious if they see patients with lung cancer who fit that profile. Clearly, testing should be important. How do you test forALK? Or how do you find it?

Thomas E. Stinchcombe, MD:We have used theALKFISH [fluorescence in situ hybridization] probe, but I think there are some technical challenges with this test. You have to have 15% of the cells showing a split signal, and I think it takes some practice among your pathologists to get really proficient at this.

Mark A. Socinksi, MD:It’s a difficult technique.

Thomas E. Stinchcombe, MD:It’s a very difficult technique. I think as clinicians, we sometimes underestimate the technical challenges for our pathology colleagues.

Mark A. Socinksi, MD:One of my good friends, who’s the molecular pathologist at UPMC, said her least favorite thing to do is to read theALKFISH results because it’s not easy.

Thomas E. Stinchcombe, MD:It’s not easy, and I think they’ve tried to do some refinements with theALKIHC [immunohistochemistry] test which is on the VENTANA [software] platform. And I think now we’re looking more toward next-generation sequencing as a way to identify these patients—next-generation sequencing on the tumor as well as, potentially, the liquid biopsy, which I think has been a huge advance.

Mark A. Socinksi, MD:Yes, I think one of the take-home messages for that sort of thing is that at our place we screen with IHC. That now is an FDA-approved technique. Historically, we would do FISH in this setting. For a patient who had a positive IHC, I was going to put her on a clinical trial. Actually, the ALCHEMIST trial. The FISH result from the ALCHEMIST central testing came back negative. And so we had discrepant results here. I believed the IHC, so we actually sent off next-generation sequencing. It confirmed that she had theALKthing. The point is, if you’re suspicious ofALK, you should go through to do next-generation sequencing and not necessarily settle for a negative FISH result.

Thomas E. Stinchcombe, MD:I agree. And sometimes we get these FISH results that are 9% positive. Especially if they’re in the right patient profile, you really want to be diligent and follow up with additional testing.

Mark A. Socinksi, MD:You mentioned liquid biopsies. Give me your thoughts on liquid biopsies.

Thomas E. Stinchcombe, MD:Historically, I’ve used liquid biopsies in patients for whom there was insufficient tissue, or maybe they’ve had part of the molecular profiling done and we want a more comprehensive test. I think the advantage is that it’s very easy, in terms of clinical management of the patients. In clinic, you draw the blood. Generally, you get the results back in about a week. I think the challenge can be that if these are negative, we’re not confident that they are sensitive enough to really act upon. So it is important to consider the negative predictive value. Many times, people are doing either sequential tumor followed by liquid, or liquid followed by tumor to make sure that we never miss a patient. That’s the critical thing that we want to do.

Mark A. Socinksi, MD:I completely agree with you. I think the best thing an oncologist can do for a lung cancer patient is diagnose an oncogenic driver, particularly likeALK. To that extent, I think the other take-home message is that the only time the blood is helpful is if it’s positive. If it’s negative, is it truly negative or is it a false negative? Is there enough shedding of DNA from the tumor into the circulation to find it, or not? I think that is critical. In my practice, I do both tissue and blood at the same time, realizing that you will find things in blood that you don’t find in tissue, and vice versa. If you don’t want to ever miss an oncogenic driver, I think both compartments should be interrogated for these oncogenic drivers.

Thomas E. Stinchcombe, MD:You bring up a good point, too, because the tumor biopsies have always been considered the gold standard. There are concerns that sometimes you don’t get a big enough specimen. So it’s a false negative, or maybe the biopsy spot just doesn’t express….

Mark A. Socinksi, MD:Tumor heterogeneity.

Thomas E. Stinchcombe, MD:And I think more and more times, we’re going to have to do these complementary tests at this point. And so, I think you never want to miss one of these.

Mark A. Socinksi, MD:You mentioned before transitioning to the treatment of patients. Before we do that, it’s been my sense, clinically, that we see most of theseALKpatients with stage IV disease.

Thomas E. Stinchcombe, MD:That’s my impression. I know we touched on the ALCHEMIST trial. We’ve had trouble identifying patients. I’m not sure if it’s a difference in biology, or maybe these patients are young never-smokers, and maybe there’s a delay in the diagnosis? I tend to think it’s more of a difference in biology, personally, because about 20% to 30% of them present with brain metastases.

Mark A. Socinksi, MD:I was just going to ask you that. These patients seem to have a higher rate of brain metastases.

Thomas E. Stinchcombe, MD:We do check early stage patients. That’s debatable. We really have not found 1 of theALK-positives in the early stage patients.

Mark A. Socinksi, MD:I mentioned my patient who I just recently put on the ALCHEMIST trial. She had N1-positive disease, so she had stage II disease, it was tested internally at our place by IHC. It ended up being positive. But again, most of our experience has been with stage IV disease. And you mentioned the issue of brain metastases. This is a population that seems to be predisposed, I think because of the underlying biology, to have brain metastases.

Transcript edited for clarity.