Unmet Needs and Future Directions

EP: 1.Overview of ALK+ NSCLC

EP: 2.Testing for the ALK Rearrangements

EP: 3.Mechanism of Action of ALK-targeting Therapies in NSCLC

EP: 4.Efficacy and Safety of Frontline Treatment Options for ALK+ NSCLC

EP: 5.Selecting the Appropriate Treatment in ALK+ NSCLC

EP: 6.Treatment Options for Patients with ALK+ NSCLC who Progress on First-line TKIs

EP: 7.Brain Metastasis in ALK+ NSCLC

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EP: 8.Unmet Needs and Future Directions

Jyoti Patel, MD: Thoughts about what happens next? Again, in real life, you see a patient who has been on lorlatinib for 6 or 7 months, has progressive disease. You rebiopsy, there’s nothing targetable. They have a high PD-L1 and have been through three TKIs [tyrosine kinase inhibitors]. What do you do?

Karen Reckamp, MD: The challenge with high PD-L1, most of the trials have included very few patients with ALK [rearrangements]. Outside of EGFR, where there’s very limited benefit, I’ve extrapolated to the light or never-smoking category, where there are some data that response to at least monotherapy with immunotherapy is 5% or less. I’m not certain what the immunotherapy is adding. As you mentioned, chemotherapy, especially pemetrexed-based chemotherapy, is very effective in this population, and potentially adding a VEGF receptor inhibitor may be more beneficial than adding immunotherapy. I have moved away from using immunotherapy in these patients, but I’m at equipoise for the patients who are ALK positive. In part, the immunotherapy has shown to increase interstitial lung disease for osimertinib, and when you combine it with some of these drugs, potentially increased toxicity, liver toxicity. But if you’re not combining it, it may not harm a patient to receive it, and some patients are really bent on receiving immunotherapy. I have a little more equipoise than thinking that I might be doing harm in this case, but I’m not certain that we’re adding anything, especially with the response rates to chemotherapy. I agree with you.

New therapies are needed. Information about when we might use immunotherapy would be helpful. But the other piece of this is we’re still not curing people. Five years is great, but these are young people, we want more than 5 years. How do we move this into the early stage setting?

Jyoti Patel, MD: Certainly our hope is that we diagnose more people at early stage disease, right? These are not patients we would routinely imagine would undergo CT screening. But as we develop biomarkers and there’s more awareness, we may see it at an earlier stage. But certainly, we cure patients with early stage disease. There has certainly been a large effort to include targeted therapies in the treatment paradigm for patients with lung cancer. Recently, osimertinib was approved for patients with EGFR [mutations] who underwent resection. You receive osimertinib for 3 years, and we know that’s a significant improvement in disease-free survival. We have yet to see what that looks like for OS [overall survival]. These studies take a long time. But it is certainly a standard of care to offer osimertinib for our patients.

Before that, there was a study called ALCHEMIST, and that’s our federal effort looking at marker-driven trials. Again, for resected patients, patients who underwent sequencing when it was still pretty novel, and had an EGFR mutation, those patients could receive erlotinib versus placebo. That trial is powered for OS, and we await the data. There’s also an ALK arm with crizotinib. Again, sort of historic. That has admittedly barely accrued. These patients are rare in the resection setting, and many of us have ambivalence about putting a patient on a less effective TKI. But certainly, that’s an answer that we’ll await.

It may be that you can extrapolate from other studies and provide a TKI. In a very real-world scenario, I recently had a discussion with a patient with really bulky stage III disease, who had undergone induction chemotherapy and resection, and had cleared N2 nodes, but still had N1 nodes and persistent tumor in the resection specimen, and the patient was ALK positive. We had a very long discussion about whether it would be reasonable to give the TKI out back, and there is no evidence to suggest it. But when we look at what we think a hazard ratio would be for the ADAURA [trial regimen], and how to extrapolate that for alectinib, certainly that was something that we talked about and talked about all our gaps in knowledge. But it was something that we went in with eyes open and did offer the patient a TKI.

Karen Reckamp, MD: With the right discussion, it seems worthwhile. We’re not going to get these answers for another decade, especially with ALK, right?

Jyoti Patel, MD: At least.

Karen Reckamp, MD: If that. Are we going to wait 20 years to do something that we know we can do with the more common EGFR alteration? That extrapolation in some of these rare diseases is necessary.

Jyoti Patel, MD: I would add that there are several efforts with the Lung Cancer Mutation Consortium that are looking at sort of proof of principal. These are single-arm studies in which patients get an induction TKI and then have surgery, then get appropriate chemotherapy and get the TKI out back, so we’ll have some phase 2 data to compare to historical norms. Again, remember atezolizumab was approved for patients who were high-PD-L1 positive, and likely I would know that a patient was ALK positive and would not offer atezolizumab to a resected patient who was ALK positive.

Karen Reckamp, MD: Right, I would agree with that, though there are very little data to support either way. It would be wrong to give it. With a person with 50% or more PD-L1, it would be a discussion. But from the metastatic setting, there’s very limited benefit in these patients from the immunotherapy.

Any other combinations you’re interested in? I know there is a drug that is looking at overcoming resistance to the solvent-front mutations from Turning Point [Therapeutics, Inc]. Outside of that, because these patients are so rare and there are many drugs available, it’s hard to develop in this area. The patients do so well, with progression-free survival of nearly 3 years. These are larger trials and prolonged trials that need to be done, unless you’re doing it in the refractory setting. As we spoke about, ensartinib is also in that frontline setting, but we have short follow-up, and it will take time to see if it measures up to the data we have from alectinib or even brigatinib. But obviously it seems incredibly efficacious, well tolerated, and has CNS [central nervous system] penetration that is excellent, similar to what we’ve seen with the other next-generation TKIs. What are your thoughts about next steps or final comments?

Jyoti Patel, MD: Drug development is ripe for patients with ALK translocations, for combinations, a couple of trials with SHP inhibitors, with newer targeted therapies that are ALK specific. Certainly, we’ll watch that. Other therapies that you can enroll your patients on now are consolidation trials. If you have limited disease or are induced oligometastatic, you’d be eligible for the NRG [Oncology] study in which you can have radiation to persistent sites of disease. In patients with EGFR mutations, an interesting strategy of looking at minimal residual disease is one that is being tested. If you don’t have such a deep response, can you intensify therapy with upfront chemotherapy to treat those persistent cells and then have a longer progression-free survival? There are a number of tools that we can integrate into our treatment with radiation and chemotherapy, and then still the effort to get better drugs.

Karen Reckamp, MD: That’s great. This has been extremely informative. Thank you, Dr Patel, for your insightful discussion, and thank you to our audience for watching this Targeted Oncology™ presentation on “ALK Gene Rearrangement as a Therapeutic Target in Non–Small Cell Lung Cancer.” We hope you’ve found this discussion to be useful and informative. Thank you.

Transcript edited for clarity.