Karen Reckamp, 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?

: The challenge with high PD-L1, most of the trials have included very few patients with 

, 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 

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?

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

[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 

mutation, those patients could receive erlotinib versus placebo. That trial is powered for OS, and we await the data. There’s also an 

 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 

 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.

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

: If that. Are we going to wait 20 years to do something that we know we can do with the more common

 alteration? That extrapolation in some of these rare diseases is necessary.

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 

 positive and would not offer atezolizumab to a resected patient who was 

: 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?

Drug development is ripe for patients with 

 translocations, for combinations, a couple of trials with SHP inhibitors, with newer targeted therapies that are

 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 

 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.

: 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 

 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.

Videos

Karen Reckamp, MD, and Jyoti Patel, MD, discuss unmet needs, novel treatment strategies, and future perspectives for patients with ALK+ advanced NSCLC.

Unmet Needs and Future Directions

: Moving forward with CNS [central nervous system] activity, we’ve talked a lot about how we want to avoid radiation in these patients, and we want to talk about the data of why we can avoid radiation. As far as CNS metastases, you had mentioned that somewhere around one-third to a quarter of patients will have frontline metastases. Can you speak about the efficacy of the TKIs [tyrosine kinase inhibitors], listing them somewhat specifically, but more general categories? I know you did mention earlier that we can’t compare the efficacy, no cross-trial comparisons can be done, but talk about the efficacy of the TKIs in the brain.

Sure. We generally avoid crizotinib in patients who have CNS metastases, but if you look at the earliest trials, even crizotinib can have efficacy in the brain of about 40%. When we look at particular TKIs, brigatinib has had the most robust story with about a 79% CNS response rate, and alectinib is just under that in the mid-70% range. Again, these are drugs that are effective.

 The response rate for lorlatinib was 82% versus 23% for crizotinib.

Right, and 79% for brigatinib. Again, the volume and number of lesions would matter as you’re making these decisions.

Certainly, there are a number of early trials or investigator-initiated trials that have tried to couple these TKIs with VEGF inhibitors—ramucirumab and bevacizumab—to try to increase CNS efficacy, though when it’s that high, it’s hard to do. So it is more looking at CNS relapse rather than true response rate up front, and lorlatinib, with that deep hazard ratio, sort of wins there.

 With these drugs and the high response rates in the brain, what do we do for patients who do develop progression in the brain?

For new brain metastasis on lorlatinib, I would likely try, if I didn’t have an available trial, to add bevacizumab, if SRS [stereotactic radiosurgery] or limited resection were not feasible. Importantly, pemetrexed also has CNS penetration and chemotherapy does. If that’s the main site of progression and I didn’t have other local therapies available, then I’d switch to carboplatin and pemetrexed with or without bevacizumab.

Jyoti Patel, MD, and Karen Reckamp, MD, evaluate the treatment of patients with ALK+ advanced NSCLC with brain metastases.

Brain Metastasis in ALK+ NSCLC

: 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?

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.

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

 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 

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.

: 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?

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?

: 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.

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.

: 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 

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

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

How do you pick one of these? We get to see a fair number of patients with 

, [rearrangements] we have really enriched populations. But for many people who may be seeing 1 or 2 patients a year, how does this play out? On a very practical level, the world is changing quickly, and if you have something good, it’s hard to change because you’re keeping up with so many new drugs. I would say that for most of the patients that I see, who either generally have no CNS [central nervous system] metastasis or maybe very low burden, like a single CNS metastasis, I start those patients on alectinib. Overall, it’s well tolerated. Although it’s a lot of pills a day at the starting dose, 8 pills a day, I have many patients that come down on their dose. I also have patients historically, before lorlatinib, that we were able to bump the dose on with CNS disease. There’s some personalization there of dosing, which is nice. Certainly, this PFS [progression free survival] benefit is great in J-ALEX. There wasn’t an OS [overall survival] benefit, whether you get it afterwards, but again you want the best quality of life for as long as you can.

I do use a fair bit of brigatinib and I was lucky I got to participate in the phase 1 study. I’m comfortable with brigatinib. To me, the nice upsides for brigatinib are the low incidence of severe toxicities usually happen soon, I know if it’s going to be the pulmonary event or the hypertension. But it’s well tolerated over years, months. I would say one piece I definitely keep in mind is if I have a younger patient or a patient who might have issues with compliance, once a day is nice. This is where patient-centered care is important. For some people, it’s just overwhelming to think about, okay, I’m taking 8 tablets a day for as long as I can, which is essentially the message we give, that we’re going to stay on this until it stops working. For some patients who may have sensitivity with pills, or I worry about getting all of the medication in, certainly I think brigatinib is a superior choice. In the absence of a clinical trial comparing both drugs in terms of efficacy and CNS disease, it’s really hard. We can opine on it a lot. Certainly, brigatinib has nice CNS penetration and good response, but there’s too much of a difference.

Lorlatinib in the frontline setting to me would be someone with a fair burden of CNS disease. We’ve all, unfortunately, met patients who present with leptomeningeal disease or numerous brain metastases, and at least in my practice that’s who I would reserve it for. What’s your take on it?

: I would agree with most of what you’ve said. Alectinib clearly has the longest follow-up, it’s an easy one to go to. I have also been using brigatinib more frequently and find it very tolerable. Both alectinib and brigatinib, in my mind, are the most tolerable choices we have and they are both excellent drugs with long progression-free time and excellent CNS penetration. Patients do well on these drugs.

Lorlatinib, again the toxicity profile, almost everybody starts to develop high triglycerides and hyperlipidemia. Then the CNS and mood effects that some patients have from this, as this also gets our neurotrophin tyrosine kinases, that can be challenging for patients. I would agree that those patients with a high CNS burden up front and symptomatic CNS disease up front, that those would be the best patients to have lorlatinib up front.

In terms of toxicity for these patients, there are some unique toxicities certainly with lorlatinib, right, like learning my statins, but there’s also been patients with arthralgias that we’ve had to manage, that are significant. The CNS toxicity for some people is troubling. It can be minor, maybe a little bit shorter fuse, maybe some troubles concentrating, but some patients, unfortunately, can have really deep personality changes, can have hallucinations. You need to, when you’re advising a patient about this, get their family buy in because sometimes they don’t even know it’s happening. But just really do a lot of prep work about what this could look like.

: I agree. And the weight gain, which is also a CNS-centric toxicity, is real. I had one patient who gained 20 pounds in a week. Dose reduction did help it, but it was a profound weight gain that we see.

There’s some weird endocrine stuff, too. Certainly, crizotinib we don’t use so often anymore, but people can have low testosterone. The weight gain with alectinib, we see it, and with brigatinib, where it is like full body edema, it’s insidious. Again, if you’re seeing patients over years, which is great, but you need to take into account even the minor toxicities, the grade 1 and 2 toxicities.

: Right, I agree. The low testosterone is important. It hadn’t been tested as thoroughly as the reports from crizotinib, but likely we are going to see it with the next generation 

 inhibitors, too. Considering that for people who have low energy or otherwise unexplained adverse effects when they’ve been on the drug over time.

Jyoti Patel, MD, and Karen Reckamp, MD, share insights on factors to consider when selecting the appropriate therapy for patients with ALK+ advanced NSCLC.

Selecting the Appropriate Treatment in ALK+ NSCLC

 Speaking about the clinical activity, let’s go into some of the studies that have been recently published or presented at some of the recent meetings, to talk about some of these subtle differences and the data we now know. The first 2 trials that have the longest follow-up are the global ALEX and the J-ALEX trial. The J-ALEX was done in Japan and was the first study done with alectinib. Both of these trials have significant follow-up time, and presented and published last year was the updated overall survival and progression-free survival for the global ALEX study. This was with follow-up of 48 months, so nearly 5 years follow-up, and the updated progression-free survival was 34.8 months versus 10.9 months, which is something similar to what we’re seeing, as we’ll talk about, in the J-ALEX trial. The overall survival is still not reached for alectinib, and it was 57.4 months in the crizotinib control arm. That’s remarkable, to see nearly 60 months even in the control arm for patients who received crizotinib. To see nearly a 5-year overall survival is impressive.

This overall survival benefit with alectinib is seen in both patients with and without brain metastases, and it’s important to know that this study is done with the global dosing of 600 mg BID [twice a day]. In this trial, there was very limited crossover, only about 20%, because as we start talking about survival in some of the other studies, we don’t see as dramatic differences in survival.

Moving on to the J-ALEX trial, in this trial again they used 300 mg [twice a day], which is the Japanese dosing for alectinib, and in this study they now have 68 months of follow-up. Based on that, they did not find a significant difference in the overall survival. It was about 60.8 months versus 64 months with crizotinib. In this study, again a differing factor, 78% crossed over and went on to receive alectinib and quit the crizotinib arm. That does tell us about sequencing, that as long as you’re getting access to these drugs, you may be able to extend your survival regardless of what you ended up starting with, which is a helpful piece of information to know. Again, the progression-free survival is very similar, 10 months for the control arm and 34 months in the alectinib arm, and again with good brain penetration.

Dr Patel, would you like to tell us about updates for the ALTA-1 trial and brigatinib?

Yes. The ALTA-1 trial was a frontline trial, brigatinib versus crizotinib, and updates were presented at ESMO [European Society for Medical Oncology annual meeting] this year. Similarly, we’re looking at high progression-free survival at 12 months, a response rate of 79%, an intracranial response rate of 78%. Early toxicity, I mentioned before, was low, grade 3/4 events with ILD [interstitial lung disease] or pneumonitis was 0.7% in this trial. This is something to keep in mind, very unusual, but real.

The overall survival at 4 years was incredible. Patients with CNS [central nervous system] metastasis had a 4-year overall survival of 64%, and those who did not have CNS metastasis at diagnosis, 71%. It was about 66% in all-comers; there was a high rate of brain metastases in these patients. It’s certainly exciting.

It’s important in both of these trials to think about discontinuation. The number of patients who had to drop doses in both the ALEX studies as well as in brigatinib remained low. There was a little bit of dose reduction in ALEX compared to brigatinib, but overall these drugs were very well tolerated.

 That’s very helpful. As you mentioned, the lorlatinib data were recently presented and published from the CROWN study, and unlike the brigatinib and alectinib data, this is based on an interim analysis and relatively short follow-up. Knowing that, we see these overall survivals nearing 5 years, it’s going to be a while before we have full data. But as you had mentioned before, what’s really profound is the CNS data. The median progression-free survival was not reached as we would expect, and it was 9.3 months for crizotinib. Again, similar to what we’ve seen for the control arm, maybe a little bit lower.

Those patients without CNS progression of all-comers within the first 12 months was 96% without CNS metastasis versus 60% in the crizotinib arm, and the hazard ratio, an impressive 0.07. Seeing that hazard ratio tells you that the extent of activity, even as the duration of the follow-up goes on, that level of activity is profound. The CNS penetration is one of the things to watch with lorlatinib as we start to see some of the data mature for this drug.

Karen Reckamp, MD, and Jyoti Patel, MD, review currently available frontline treatment options for ALK+ advanced NSCLC and discuss updated efficacy and safety data from key clinical trials of these agents in advanced NSCLC.

Efficacy and Safety of Frontline Treatment Options for ALK+ NSCLC

 Based on this, we do have many drugs approved in the frontline and the second-line setting. I’ll present them in the order that they were approved: crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib, and then there are also data for ensartinib in the frontline setting, though not FDA approved at this time. Can you tell us about the mechanisms of action, how they might be different from each other, and some of the aspects of the drugs up front?

 [mutations] is instructive on many levels, seeing the clinical observation in a trial that may not have been enriched for patients with 

mutations, to now a drug in which there are a multitude of very specific targeted therapies. Crizotinib was the first TKI [tyrosine kinase inhibitor] that was approved for 

 and remember crizotinib is a great MET inhibitor, and that’s where it was being developed. In a patient on an early trial, there was a very deep response to crizotinib, and then subsequent therapy ensued from that clinical observation. Crizotinib is effective, it’s more effective than chemotherapy, but it shouldn’t be used unless nothing else is available or there are toxicity issues. It’s a multitargeted TKI and is probably the least potent of the drugs.

The next drug that was approved was ceritinib. Ceritinib is also quite potent. It’s probably less preferred than alectinib and brigatinib. Initially it was difficult, it was approved after crizotinib at a dose of 750 mg per day. Importantly, there was a randomized, open-label study that demonstrated efficacy at a lower dose, at 450 mg with food versus 750 mg without food; it was much better tolerated. When we first started using ceritinib, many of us would say let’s start low and then titrate up. Many of our patients had a lot of GI [gastrointestinal] effects. There is a cost savings with a lower dose; it’s a drug that nonetheless is exciting, but probably has moved to an older drug status in the United States in particular.

Alectinib is the drug that’s used commonly in the United States, and it’s approved in the frontline setting as well as after progression on crizotinib. Alectinib is overall well tolerated, there’s efficacy in patients with CNS [central nervous system] metastasis, in patients who have impaired performance status. Generally, it’s well tolerated. It’s given in split dosing. The formulation of the pill is a little bit tougher, the starting dose is 600 mg twice a day, that’s 4 tablets twice a day. And there are unique adverse effects for it. There can be some GI upset, some edema, but generally, again, well tolerated.

More recently, brigatinib was another next-generation ALK inhibitor. It targets a very broad range of 

mutations and has demonstrated activity after crizotinib and in the frontline setting. Initially, in the early studies, there was a little pulmonary toxicity noted. We call it a pulmonary event, patients would have some edema. But the dosing was changed in which it was stepped up, and when that’s the case it’s quite rare, it’s less than 1% of patients. It’s once-a-day dosing, which is certainly nice for some patients. It has some toxicities like higher myalgias, which most of these drugs do, but your CPK [creatine phosphokinase] can get high, you can have some hypertension. But again, it’s generally well tolerated. Brigatinib and alectinib have never been compared head-to-head, so everything we talk about is to a comparator arm, which is dated. It makes it difficult to talk about significant differences between these trials. The number of patients enrolled is certainly small, but ethnicity might be different, comorbidities might be different, and it’s important to keep in mind.

Then finally, most recently lorlatinib was approved. It’s now approved in the frontline setting, certainly after progression on other TKIs was the first indication. In the frontline setting, we know it’s an active drug. It’s highly CNS penetrant and has a real role for some of our patients. But many of us would not necessarily jump on it as a frontline drug because of some of the AEs [adverse events], like the neurocognitive and mood effects as well as hypercholesterolemia. We’re talking about patients, again as Dr Reckamp mentioned, who are on these drugs chronically, hopefully for years, so even low-grade toxicities are ones that we have to keep in mind.

Certainly, all these drugs work as tyrosine kinase inhibitors, and they’re all small molecules. Chemically, their structures are quite similar. Some of the structures are different in that they’re more CNS penetrant, but there are tweaks. For most of us, we would say that the clinical activity probably trumps the biochemical structure when we’re making a decision.

Jyoti Patel, MD, elucidates the mechanism of action of various ALK targeting agents in NSCLC and the optimal formulations and dosing strategies in patients with advanced NSCLC.

Karen Reckamp, MD | Authors

Articles

Unmet Needs and Future Directions

Brain Metastasis in ALK+ NSCLC

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

Selecting the Appropriate Treatment in ALK+ NSCLC

Efficacy and Safety of Frontline Treatment Options for ALK+ NSCLC

Mechanism of Action of ALK-targeting Therapies in NSCLC