Sequencing Strategies for ALK-Targeted Therapy


Robert C. Doebele, MD, PhD: It’s possible to sequence multiple ALK inhibitors throughout a patient’s disease course, and we can do this partly based on disease monitoring, either through tumor biopsy or ctDNA [circulating tumor DNA] analysis. We know a lot of sensitivity and resistance information, both based on clinical data and laboratory data, that can help guide the selection of 1 inhibitor over the other. I say guide because I don’t think these are firmly set. However, it is possible to track this at each progression. For example, the patient starts on crizotinib and we see a gatekeeper mutation with L1196M on ctDNA analysis via liquid biopsy, we may want to switch that patient to alectinib or brigatinib. If we then see an ALK G1202R emerge at the next progression, we would want to perhaps switch that patient to lorlatinib to overcome that resistance. I do think it’s definitely possible to sequence these ALK TKIs [tyrosine kinase inhibitors] over the patient’s disease course and get long-term benefit with each of these agents.

I think 1 of the biggest benefits of the newer-generation of ALK inhibitors is their ability to penetrate into the CNS. We believe that much of the progression-free survival benefits observed in, for example, alectinib or brigatinib versus crizotinib is coming from the ability to both treat existing brain metastasis or prevent ones that have not yet occurred. That, I think, is critical for maintaining disease control in our patients who often may live multiple years, sometimes in excess of 5 years, with the ALK-positive non—small cell lung cancer.

I think almost all of us should be using next-generation inhibitors as our first-line ALK TKI, because in doing so we will either control existing brain metastases or prevent ones or delay ones that have not yet occurred. Similarly, when patients progressed on an ALK TKI, we should continue to use a CNS-penetrant ALK TKI if that’s what’s most appropriate, because we want to maintain control of brain metastases because we know that those can generate significant morbidity and mortality for our patients.

Thomas E. Stinchcombe, MD: As we’ve moved the next-generation ALK inhibitors to the frontline setting, 1 of the observations we’ve made is with crizotinib, about 25% of patients had an ALK tyrosine kinase mutation. With the next generations, the rate is around 50% or 60%. It varies depending on the series, and there’s a higher prevalence of the G1202R deletion mutation, which is a more potent resistance mutation. As we’ve increased ALK potency, we’ve also increased the rate of ALK-resistance mutations.

Going forward, I think there are a couple of things that intrigue me. I think we’re trying to triage the presence of the ALK mutation or the absence of predictive benefit for the ALK therapy. You could see the patients with the ALK tyrosine kinase mutation-negative. Do they have bypass tracks or other mechanisms of resistance, or is it just our sensitivity to biopsy was not sufficient to the ALK mutation? I think there’s going to be a lot of focus on that group of patients. I think we’re hoping that we’ll get a better understanding of the mutations and whether specific mutations can predict response to therapy.

Obviously, this is a complex medical situation in a relatively rare tumor type. But the NCI [National Cancer Institute] has launched the ALK protocol that will specifically look at patients, and they’ll get a biopsy, get testing of a next-generation sequencing, as well as collection of ctDNA. Then they’ll be assigned a specific therapy based on their mutation. It’s really determining if 1 of these next-generation tyrosine kinase inhibitors is more potent or more effective than the other related to the specific mutation. The patients without the mutation will be randomized to an ALK inhibitor versus chemotherapy, to really see if further ALK inhibition is going to be of benefit in the absence of a mutation. This will be a national effort that will hopefully address the sequencing, which I think is the biggest challenge. I think yesterday’s successes are today’s challenges, and I think the field has evolved very rapidly.

I think the development of chemotherapy and immunotherapy or single-agent immunotherapies have revolutionized the care of lung cancer. Importantly, in the ALK-rearrangement non—small cell lung cancer, there still continues to be questions about what the role of chemoimmunotherapy is, chemotherapy or immunotherapy. Looking at single-agent immunotherapy, we know the response rates are around 5% to 10%, very low response rates. I don’t think that single-agent immunotherapy has much of a role at this point. The question then becomes what about chemoimmunotherapy. And the 2 sort of combination therapies approved are the carboplatin-pemetrexed and pembrolizumab from KEYNOTE-189. Importantly, patients with an ALK-rearrangement were excluded from that trial, so we don’t have data on efficacy.

The second chemoimmunotherapy combination is carboplatin-paclitaxel-bevacizumab, and atezolizumab called the IMpower150 therapy. Patients with ALK and EGFR alterations were enrolled, but importantly they had to progress on a tyrosine kinase inhibitor. This may be an option for the ALK patient who has exhausted all the ALK tyrosine kinase inhibitors but maintains good performance status and wants further therapy. I think when I talk to the fellows, 1 of the things that I emphasize is that you’ve got to get the molecular testing first and then decide on whether you do immunotherapy. I think there’s sometimes an attraction from the PD-L1 [programmed death ligand 1] highs, and you’re basing decisions on that. You really do need to have the whole testing paradigm completed before you make a treatment decision.

Transcript Edited for Clarity

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