NSCLC: Selecting a Frontline ALK-Targeted TKI Therapy


A panel of experts considers which factors best inform selection of first-line ALK TKI therapy in patients with non–small cell lung cancer.


Stephen Liu, MD: Is there a scenario where you might start a treatment before getting these molecular results? Jillian, I’ll go to you. Sometimes, there are other cases where we just have to go.

Jillian E. Thompson, NP: We have those cases where patients come in, and they are extremely symptomatic, and we need to get treatment started prior to getting those results back. Typically in those cases we can consider chemotherapy so that we have the options of other targeted therapies, immunotherapies, later with the benefit of not causing maybe more toxicities if we are treating with something and then later finding we have these targeted mutations.

Stephen Liu, MD: A good point, lung cancer sometimes presents in an advanced state and patients can be symptomatic. If you need to start therapy, you’re saying chemotherapy alone, it’s kind of an older treatment. Jyoti, can you explain, Jillian mentioned chemotherapy alone while waiting for the results. Why is that important?

Jyoti Patel, MD: Jillian did a nice job of alluding to the fact that sometimes we see increased toxicities. As a step back, we know monotherapy immunotherapy is not effective in patients with driver mutations. In combination with chemotherapy, it’s probably the chemotherapy that we’re seeing any responses with. However, once patient is given immunotherapy, often the antibody will have prolonged effects, and toxicities may last beyond that initial infusion. So there can often be a higher risk of irAEs [immune-related adverse events]. We know that’s been nicely delineated, particularly in patients with EGFR mutations who receive osimertinib, for example. After immunotherapy, the risk of hepatitis and pneumonitis is quite high. With ALK inhibitors, we also see higher rates of these irAEs, and they can persist again for weeks and preclude appropriate therapy and appropriate doses of therapy with the most active agents.

Stephen Liu, MD: Let’s go back to our case with this patient. We knew they were PD-L1 positive, we decided to wait for the full results. When the NGS [next-generation sequencing] did come back we saw the EML4-ALK fusion, and we saw wild type with the other alterations, which is what we’d expect, at least a diagnosis. The ALK fusion was not found in the blood. Sometimes the blood isn’t quite as good at [detecting] fusions, especially if there’s not a lot of extrathoracic disease, but as all of you have mentioned, we believe the tissue. The negative blood doesn’t stop us from waiting for the tissue results. This is an EML4-ALK fusion-positive non–small cell lung cancer.

Now, this is an area where we have a wealth of not just active drugs, but very effective drugs. The first drug approved in 2016 was crizotinib. We call that a first-generation inhibitor. It’s a versatile drug, approved also for ROS1 non–small cell lung cancer, and is very active in MET exon 14 lung cancer as well. Based on the phase 3 PROFILE study, we saw this drug originally approved on single-arm studies. We also have ceritinib, a second-generation agent, superior to chemotherapy in the frontline setting.

Then we move into the more modern agents. Alectinib, which was found to be superior to crizotinib. Brigatinib, superior to crizotinib. In the phase 3 ALEX and ALTA-1L trials, both [agents became approved]. More recently, lorlatinib, a next-generation ALK inhibitor, based on the phase 3 CROWN data, which were updated in early 2022, is also another potent option in that setting. We’ve got a lot of drugs, almost an embarrassment of riches. Ross, how do we choose? Is there 1 right answer here?

Ross Camidge, MD, PhD: No, there isn’t, which is good. Then we come back to the art of medicine. We know certain things are the wrong answer though. Having had 3 head-to-head studies vs crizotinib, we know crizotinib isn’t the right answer. Ceritinib, which was the first next-generation inhibitor approved, went head-to-head against chemotherapy, but I think most people feel its efficacy is not quite as good. Certainly, its efficacy in the brain is not quite as good as some of these newer drugs, and it has a whole bunch of toxicities. So, it’s really a choice between those 3 drugs: alectinib, brigatinib, and lorlatinib. As we dig into it, we start to play off efficacy vs toxicity for patients who are going to be on this drug potentially for years.

Stephen Liu, MD: Jillian, among all these different drugs, how do you make the choices between these?

Jillian E. Thompson, NP: I think something he mentioned, toxicity profile, is a big part of that, but also, we’ve learned that with these medications coverage of brain metastasis is something to consider as well in the choice. Also, when we look at toxicity profiles we’re looking at any comorbidities, any baseline abnormalities that are already there, so there’s a number of things to consider when making those choices.

Stephen Liu, MD: So, maybe safety profiles and efficacy, they’re all very effective agents. Jyoti, if I were to ask a specific question to you, does the presence of brain metastases influence your TKI [tyrosine kinase inhibitor] choice for ALK lung cancer today?

Jyoti Patel, MD: I think we have good evidence that, particularly alectinib, brigatinib, and lorlatinib, all have high efficacy in the CNS [central nervous system]. We see deep response rates. Perhaps in a patient who had symptomatic brain metastases or leptomeningeal disease at presentation, I may, again because of the high CNS penetration, use lorlatinib. But I feel very comfortable with alectinib and brigatinib also causing nice CNS regressions. Other than that, to me, they’re pretty similar, and choice is very nuanced based on patient preference, toxicities, and provider familiarity.

Stephen Liu, MD: I think that’s an important point, we hear about lorlatinib and CNS, there’s a strong link, and there’s no question that’s a very CNS-active drug. But I remember one of my earlier cases was a patient who had surgery for an ALK lung cancer, he presented with a massive burden of metastases only in the brain. It was to the point where he was starting to herniate. They couldn’t do radiation because radiation would worsen the herniation. They were afraid of taking him to surgery, so they gave him alectinib. That was probably about 6 years ago, and he’s still on [alectinib]. He had an immediate response, and I know from firsthand experience alectinib is a very good drug in the brain. I can’t imagine that it would have been any different with any of those drugs. So they’re all active the brain. Has that been your experience as well, Ross?

Ross Camidge, MD, PhD: Yes, I remember you would see patients come in with highly symptomatic disease with a midline shift. The surgeons [would say], “I have to operate,” or the radiation oncologists [would say], “I have to irradiate.” [I would tell them], “I can put this patient on a pill, and they will feel better before they get into your clinic.”

Stephen Liu, MD: Absolutely.

Ross Camidge, MD, PhD: When that did happen, I usually had to send the patient back to them so they would believe me.

Stephen Liu, MD: That’s absolutely correct. Let me ask you this question, it’s little more nuanced. Jyoti, we know there are some different fusion variants for EML4-ALK, sort of numbered in the order they were identified. Does fusion variant, comutation status, do those influence your treatment today, or is that still investigational?

Jyoti Patel, MD: Certainly there has been some discussion of whether variant status affects PFS [progression-free survival], and it likely does, but how that’s impacted by TKIs remains investigational. So I don’t know if it’s a prognostic marker rather than a predictive marker of response, and I’m not sure what to do with it right now. At this juncture it has not affected my prescribing habits.

Stephen Liu, MD: It’s not available if you’re doing FISH [fluorescence in situ hybridization], but if you’re doing NGS, it may not show up in the report, but you certainly can ask about that. We know from some published works that different variants might have different outcomes with drugs, and mutations like TP53 might command a worse prognosis. But I agree, I’m not sure exactly how to use that in practice. Ross, when you get that information, is it just something you take note of, or do you does it influence what you do?

Ross Camidge, MD, PhD: I think what we’re really saying is these things are subtle modifiers of risk. But we all know that you can have somebody who has high-risk features and nothing bad happens. The other thing is we don’t have anything specific to do differently. I still think we are missing a piece of information, which is how to tell a patient sitting in front of you [their] future is definitely going to look good or bad before we put them on the TKI. The variant and the co-mutation status for TP53 isn’t enough to tell us that yet.

Stephen Liu, MD: There is some heterogeneity there. We’re getting a little closer hopefully, but we’re not quite there yet. If we look at the NCCN [National Comprehensive Cancer Network] guidelines, when we detect an ALK fusion in metastatic non–small cell lung cancer, our preferred initial therapy is alectinib, brigatinib, or lorlatinib. All of them have received category 1 recommendations for frontline settings as preferred options.

Transcript edited for clarity.

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