ALK Gene Rearrangements As A Therapeutic Target in Non-small Cell Lung Cancer - Episode 6

Treatment Options for Patients with ALK+ NSCLC who Progress on First-line TKIs

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Karen Reckamp, MD, and Jyoti Patel, MD, outline their treatment approaches for patients with ALK+ NSCLC who progress on frontline TKIs.

Karen Reckamp, MD: What about patients who progress on frontline treatments? Fortunately, they have very long progression-free time, but most of the patients will have tumors that develop resistance and have progression. What do you think about when you’re thinking about sequencing?

Jyoti Patel, MD: A lot has changed here. Certainly, we have approvals that are just based on line of therapy. There is benefit to doing molecular testing for our patients. Generally, the patient is progressing, I’ll end up doing a blood test as well as tissue if it’s safe. Sometimes if it’s progression in the brain alone, it’s a little bit more difficult, but I hope that can inform my treatment. Usually, it doesn’t because it’s usually progression after alectinib and I am usually going to move to lorlatinib.

In the Goto study in Japan, looking at claims data, most patients were treated with alectinib from J-ALEX, and then about half of patients at progression ended up getting lorlatinib.

Jyoti Patel, MD: The duration of response for these patients was about 5 months, again shorter than one would have expected from the clinical trials. But remember, there’s a myriad of reasons why patients come off of study. Probably their PS [performance status] and comorbidities weren’t as good as enrolling in a trial in the second-line setting.

And then interestingly, there’s also a study from France called the BrigALK2 study, and this was the study of brigatinib in the second line, and then also looked at a subset of patients who received lorlatinib after brigatinib, and it was essentially looking at patients who were on the EAP [expanded access program] for brigatinib. The duration of treatment for brigatinib was 7.3 months, and then it broke up in how many TKIs before brigatinib. It was about 13 months if you had only received one TKI, [tyrosine kinase inhibitors] presumably crizotinib, it was down to 4.9 months if you had 3 ALK TKIs before, again presumably ceritinib and alectinib and then brigatinib. The likelihood of response was lower. On that study on brigatinib, 74% of patients had disease control, certainly nice to see.

Of those patients that received brigatinib and progressed, about two-thirds of them went on to receive lorlatinib. Impressively, even with these early drugs, even if we’re looking at patients that were diagnosed in 2015, for example, the time from their diagnosis of non-small cell lung cancer [NSCLC] to lorlatinib start was 52.8 months. That, to me, is the real-world evidence that even off trials, that patients were doing this well.

Karen Reckamp, MD: Sometimes the real-world evidence does help to show us the advances that have been made, and even when clinical trial populations are very specific in this setting, this is something that is translated into patients. So that’s great. And there were also, unfortunately, all of the trials in the second-line setting were after crizotinib. We know these drugs work exceptionally well after crizotinib, but we have little data about how well they do after each other, other than the lorlatinib which has some of the best data and has approval in the post second/third generation TKI setting. We’re really extrapolating from small numbers of patients and this real-world data.

The J-ALTA study was a second-line study of patients getting brigatinib after alectinib, and this is a subset of this study. Forty-seven patients in that trial had prior alectinib, and in those patients the response rate was about 34%, with a progression-free survival of about 7 months. Disease control rate was very good at 79%. This is hinting at what we saw with lorlatinib post alectinib. In that study, only 1 of 72 patients had experienced pneumonitis, and then when they looked at the anti-tumor effects, they did see activity to the G1202R, the I1171N, the V1180L, and the L1196M mutations that we see, and the G1202R which can be incredibly difficult to treat. Brigatinib seems like a reasonable choice post alectinib, and we know that lorlatinib and brigatinib do have some of the most coverage of the resistance mutations that you do get post crizotinib and alectinib.

As you had mentioned, Dr Patel, from the BrigALK study, as we see the number of prior therapies you receive, the PFS goes down. We’re getting less and less a benefit. There have been multiple studies looking at liquid biopsies in tissue, and the complexity of alterations that occur in these patients who have received multiple therapies. That being said, many of them started with crizotinib. Most of the data we have is still a crizotinib starting point and then these other drugs, but we should be getting more information as obviously the alectinib trials have longer follow-up.

But at least we know they work, they can work after each other. To me, this tells me that after 2, that’s when I tend to bring in chemotherapy or other therapies. We can talk more about that and when you stop the TKIs. But you can always go back to these TKIs. Cycling through and understanding sequencing can be helpful, and doing liquid biopsy or tissue biopsy if you’re able to, to try and understand which mutations are there, may help us to decide how to sequence these. What are your thoughts about sequencing?

Jyoti Patel, MD: That’s great. Certainly, you want the biology to dictate the drug that you use, and these multiple biopsies over time can help you understand if there’s tumor heterogeneity, particularly in the blood biopsies. I tend to start with alectinib or brigatinib. If a patient has been on alectinib and progressing, then I want to see where the resistance mechanism is. Generally, lorlatinib will have good coverage. At the time of progression with lorlatinib, I will usually biopsy, but I have not found a drug I can go back to after lorlatinib. It really is what is happening in the second-line space. Am I trying brigatinib or moving to lorlatinib is practically speaking what my decision is?

But after lorlatinib, then I’d agree with you, generally we’re looking at doing some chemotherapy at that juncture. For most patients, I’ll start chemotherapy with carboplatin and pemetrexed. We know that pemetrexed is a preferred platinum doublet from early trials with crizotinib, knowing that pemetrexed had longer PFS than docetaxel. For fusion-positive cancers, that’s across the board. I’ll usually do carboplatin and pemetrexed and often keep the lorlatinib going if I can, particularly if there’s CNS [central nervous system] disease. Usually, I’ll do a short course depending on response, I might just do 4 cycles of carboplatin and then do a lorlatinib maintenance, or do PEM/lorlatinib [pemetrexed] afterwards.

One of the biggest issues for our patients is CNS metastasis and what that looks like over multiple years. We know that 20, a fifth to a third of patients have CNS metastasis at the time of diagnosis. That’s the piece in which holding tight and waiting until you get an answer can be a little bit tough. For an asymptomatic patient, when you’re waiting for NGS [next generation sequencing] to come back, certainly I would say hold tight because these drugs are so CNS active. For a symptomatic patient or someone with large volume of disease, often you’re forced to move forward. But the paradigm for these patients has switched to try to do systemic therapy first. If you must, do limited radiation like SRS [stereotactic radiosurgery] or resection, and then sort of that last piece is in extreme circumstances, and I can’t think of any patients in the past few years that I’ve had to do whole-brain radiation early on. But the implications are that we’re seeing some patients that were treated with whole-brain radiation 6, 7 years ago, it has impacted their quality of life, now with good systemic control. It’s balancing that piece of being patient and letting the systemic therapy work for you. Thoughts about that?

Karen Reckamp, MD: I would agree. Interestingly, as we see that patients are living for years, and we’re seeing this for many types of advanced non-small cell lung cancer, that survival is increasing, the way you think about whole-brain radiation and the potential toxicities. In the past, patients lived 6 months, the toxicities were about the immediate toxicities and not so much about the longer-term sequelae. These tend to be younger patients, they tend to be working and productive in society, and so avoiding those long-term effects of whole-brain radiation I think are important. We are moving toward more aggressive SRS in these patients and rarely, rarely do whole-brain radiation in most of these patients. Again, fortunately we have drugs that work very well and are very CNS penetrant.

Jyoti Patel, MD: The other piece is that, yes, we use SRS a lot, that a lot of these patients over time, particularly if you add a new drug on, will end up with things like radiation necrosis. It’s very multidisciplinary in how to handle what could be progression that truly is treatment response. We’ll use systemic therapies like bevacizumab for a couple of cycles, or now LITT, which is essentially laser ablation, at which time you can get a biopsy to make sure that it’s not progressive disease versus radiation necrosis. It’s become much more of a team-based sport in many ways. There are a lot of touch points with multiple providers, everyone from endocrinology to your neurosurgeon to radiation oncology, and then your entire care team as you’re managing these patients.

Karen Reckamp, MD: Many patients who ended up going to surgery in some of these trials did have necrosis rather than growth of their tumor. But the necrosis can be just as difficult symptomatically for a patient as growth of a tumor. I agree with you that this multidisciplinary care and continued follow-up care is incredibly important.

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.