Clinical Management of ALK+ Advanced NSCLC

Benjamin Levy, MD: There are multiple standard-of-care therapies for patients with advanced ALK-rearranged lung cancer. Crizotinib, the first, was developed as a MET inhibitor initially, but it had activity in ALK-rearranged lung cancer. When you compared crizotinib to chemotherapy, there was an improvement in progression-free survival [PFS] and intracranial-response rates for those who received crizotinib as compared with patients given chemotherapy. Thus, crizotinib has been the control arm of every subsequent trial that has solidified a next-generation ALK-directed therapy. Multiple trials have compared next-generation ALK-directed therapies with crizotinib. Of course, the ALEX trial compared alectinib with crizotinib and showed an improvement in PFS. Trends toward overall survival [OS] are also there. Because the ALEX trial came first, alectinib is considered a standard of care, and it is my standard of care for most patients with ALK-rearranged lung cancer. The ALTA-1L trial then compared brigatinib with crizotinib and showed similar outcomes. The data are not as mature as are those for the ALEX trial, but they show improvements in PFS and intracranial response. We’re following the OS and, again, trends toward OS. Because of that, brigatinib is also considered a front-line standard of care. The most recent data is from the CROWN study, which compared lorlatinib, another next-generation ALK-directed therapy, with crizotinib. Not surprisingly, the results showed an improvement in PFS. All of these trials showed improvements in response rates and in intracranial response rates, so lorlatinib is another potential option. These drugs have different toxicities. Because the ALEX trial offers the most mature data, and because I’m a creature of habit, I have generally used alectinib front line for most of my patients with ALK-rearranged lung cancer, but there are other options on the table. Right now, the front line data that we have is with alectinib as seen in the ALEX trial, with brigatinib in the ALTA-1L trial, and with lorlatinib in the CROWN trial. All are potential therapeutic options. Again, alectinib seems to be my go-to first drug for patients with ALK-rearranged lung cancer.

Mark A. Socinski, MD: Over the past several years, data sets addressing optimal therapy in the ALK-positive population have emerged. We have several studies with alectinib in different populations—the global ALEX trial, J-ALEX trial in Japan, and the ALESIA trial in China. All of these trials compared alectinib with crizotinib therapy and showed superiority of the primary outcome, which was largely PFS. We had a recent update on OS from the J-ALEX trial, which probably had the longest follow-up. The problem with interpreting the OS, which was not different between the crizotinib and alectinib arms, was that there was a remarkably high crossover rate to alectinib from the crizotinib arm. More than 70% of patients crossed over to alectinib, which may blur a survival advantage. When you look at the data from the ALEX trial, which did not allow crossover from the crizotinib arm, there is superior OS. In fact, the median survival on the alectinib arm has not yet been reached in follow up, and many patients are beyond 5 years. This is a population of patients that may live for years when diagnosed and treated appropriately. Following those alectinib trials, we have the ALTA-1L trial and the J-ALTA trial in Japan. They were looking at brigatinib, again comparing it with crizotinib as the control arm. And once again, crizotinib use produced inferior results. The primary end point was PFS. Very similar results were reported in ALTA-1L trial, and a small cohort in the J-ALTA trial showed the superiority of brigatinib over crizotinib. The most recent data set that was added to this experience was the CROWN trial, which compared lorlatinib with crizotinib. Again, the primary end point of PFS was superior with lorlatinib versus crizotinib. All 3 of these agents have beaten our former standard of care, crizotinib, when compared head-to-head. We need to give crizotinib some relief, because it was never intended to be an ALK inhibitor. It came into clinical early phase 1 trials as a MET inhibitor. True ALK inhibitors that have more specificity and potency for ALK are superior to the old standard of crizotinib. Interestingly, the 3 agents we've spoken about were initially proven in patients who had failed crizotinib. But now all 3 of them have shown superiority over crizotinib. Which is the best one to use in this setting now that we have 3 positive trials with these agents? It's very difficult to do cross-trial comparisons. The variant of ALK makes a difference. Co-mutations, such as P53, can make a difference in the survival outcomes. We may not know all of those specifics from all trials, which makes cross-trial comparisons somewhat treacherous in this setting. And toxicity profiles differ. They all target ALK and have similar efficacy end points, but they have different toxicity profiles, which demands consideration. For years, our standard, based on the results of the J-ALEX and the ALEX studies, has been alectinib. Personally, data from either the ALTA-1L trial or the CROWN trial would not change my first choice, which has been alectinib, in this population. All of these agents are highly active, and one can't be faulted for using any one of them in this setting. Tailoring the decision on the adverse effect profile instead of efficacy may be legitimate. 

A particular issue in the ALK-positive population of patients with NSCLC is the propensity for CNS [central nervous system] involvement at the time of diagnosis. We reviewed the results of the BFAST trial, in which about 40% of patients had brain metastases at the time of initial diagnosis; however, there is certainly a risk of developing brain metastases over time. Alectinib, brigatinib, and lorlatinib have quite good CNS penetration and CNS activity. The response rates are quite good. Response rates to alectinib in patients with brain metastases in the BFAST trial was in the 90% range, and that's also true for the other agents. CNS progression, particularly when it's symptomatic, can be devastating in certain patients. Importantly for radiation oncologists if brain metastases are diagnosed, the knee-jerk reflex often is to radiate them. These brain metastases are often asymptomatic. Initially, we can spare the patient the toxicity of brain radiation, particularly whole-brain radiation. The ALK-positive population tends to be a bit younger, and the median age is typically in the mid- to early-50s. These patients are typically never-smokers and otherwise healthy, so you don't want to expose them to the risk of CNS radiation toxicity unless necessary before they really need radiation. And many of these brain metastases can be controlled. When second-generation ALK inhibitors are compared specifically with crizotinib, which has much less CNS activity and penetration, the CNS progression rates are dramatically lower than found with crizotinib or chemotherapy in this population.

Stephen Liu, MD: For ALK fusion-positive lung cancer, it really is an embarrassment of riches. We have a lot of very active, very effective, and well tolerated drugs available. Alectinib, brigatinib, and lorlatinib all have shown superior results when compared with crizotinib in randomized trials, but they do have some differences in terms of efficacy, safety, and convenience. They all are very effective with high response rates. They do have a lot in common. When compared with crizotinib, they all have been associated with better PFS. All are highly CNS-penetrating, which is particularly important in ALK fusion-positive lung cancer because of the high tropism for brain metastases with this subset. Use of any of these agents generally produces PFS and the durability of response of at least 3 years, on average, before initial resistance occurs. Certainly, there are differences between them. When comparing their PFS with that of crizotinib, the HR by investigator assessment for alectinib was 0.43 in the ALEX trial and for brigatinib was 0.43 in the ALTA-A1L trial; for lorlatinib, it was quite a bit lower at 0.28. There's no question that lorlatinib is a highly effective drug, possibly because it may have more CNS penetration. But this may be one of the rare cases in oncology where we choose not to use our most potent drug first, and that reflects the differences in toxicities. Lorlatinib can raise cholesterol [levels], which is usually straightforward but still can be a challenge for an oncologist. The toxicity of concern is the impact on cognition and neurologic function. It may cause mild and temporary dizziness or moodiness or something as serious as seizures, hallucinations, depression, or personality changes. I've seen a wide range of cognitive impact from lorlatinib therapy. Patients treated with lorlatinib must be watched closely, because the effects can be mitigated with dose reduction if they're recognized early. But sometimes they're subtle. In a busy clinic, we may not get to spend a lot of time with the patient, and we may miss that they're no longer able to balance their checkbook, that they get lost when they're trying to go home, or that they're wandering on the streets. If patients don't have a strong support system or people around them who can identify or report these changes, it can be concerning. When we look at alectinib, it's a very well-tolerated drug. Some patients notice myalgias, fatigue, and, sometimes, constipation. Liver function-test abnormalities are a little common. Brigatinib is also extremely well tolerated. It famously has a low incidence of early-onset pulmonary events in which the DLCO [diffusing capacity for carbon monoxide] transiently drops. Interestingly, these events self-resolve with continued dosing, and a lot of patients may not really notice them. With the current approved dosing of 90 mg given once daily for a week followed by 180 mg given daily, they're actually pretty rare. Overall, the drug is very well tolerated. There also are a few practical, nonclinical factors to consider. Alectinib therapy involves 8 pills each day, and brigatinib therapy involves 1 pill each day. Overall, however, they're both very effective, highly well-tolerated agents. And we're lucky to have all of them. I really don't think there's a wrong answer among all of those.

With so many options available for advanced ALK fusion-positive NSCLC, how do we choose among alectinib, brigatinib, or lorlatinib? Patients need to be watched a little more closely with different surveillance strategies, because I have some concerns about cognitive toxicity with lorlatinib therapy. I've seen some severe cases in the past. I'm probably a little less likely to use lorlatinib in the first-line setting, although I might consider it if there's a particularly heavy CNS burden. Generally, I'm looking to alectinib and brigatinib. When we look at patients with ALK-positive lung cancer, the PFS HR ratio for lorlatinib was the lowest among the 3 agents. The survival is much, much longer than any one drug's PFS on those studies, suggesting that patients really should receive multiple lines of therapy. Therefore, I'm pretty comfortable reserving a drug like lorlatinib for later use. Between alectinib and brigatinib, both drugs are excellent and very effective, offer fast responses, and are extremely well tolerated. Really, it's a coin flip. Some nonclinical factors that could be considered include pill burden and cost, and that's something that's unpredictable. If there are differences in out-of-pocket cost for a patient based on their insurance coverage, copays, or formularies, then that probably will sway me, because both are similar and effective. Looking forward, we must see if there are differences in terms of resistance to these drugs and how that might influence sequencing. But as of today, all of these are appropriate options

Benjamin Levy, MD: It’s easy to decide what to do with a patient with advanced stage ALK-rearranged lung cancer. We have multiple options, and we generally start with alectinib in my practice. But what do you do when there’s disease progression on alectinib? And the progression is heterogeneous. There can be oligoprogression where there’s just one site that’s growing, there can be progression only intracranially, or there can be systemic progression where you really need to think about a therapeutic switch. And that’s where we really talk about resistance and what’s going on. There are multiple ways that resistance occurs in patients with ALK-rearranged lung cancer. First, you can have amplification of the ALK fusion that can confer resistance to the drug you've given. Second, bypass signaling pathways, other pathways like EGFR or c-Kit, can be engaged and cause resistance. Perhaps one of the areas that’s being most studied as a mechanism of resistance is mutations in the ALK-kinase domain. And these occur following alectinib treatment. We’re starting to gather data on how common they are. One mutation that we look at is G1202R. And this is important, because this mutation may be targetable by a next-generation ALK-directed therapy, lorlatinib. At the time of progression, I generally test for mechanisms of resistance. We look for these secondary mutations in the ALK-kinase domain. And if there is a G1202R or other mutation, we generally will leverage lorlatinib. What to do for patients that don’t have mutations? That is where things get a little bit trickier. Chemotherapy or lorlatinib could be leveraged. We’re just beginning to scratch the surface on how to sequence therapies for ALK-rearranged lung cancer and what to do at the time of resistance.

Transcript edited for clarity.