Differences in TKIs May Sway Choice of First-Line Therapy in ALK+ NSCLC

Yasir Y. Elamin, MD

Assistant Professor, Department of Thoracic/Head and Neck Medical Oncology

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX

.DISCUSSION QUESTIONS

• Do the intracranial responses to brigatinib (Alunbrig) in patients with ALK-positive metastatic non–small cell lung cancer (mNSCLC) plus baseline brain metastases resonate with your own clinical experience?​
• With respect to reduced risk of disease progression or death, how does the early separation between the brigatinib and crizotinib (Xalkori) progression-free survival (PFS) end points influence your treatment decisions for patients with ALK-positive mNSCLC?​
• Which tyrosine kinase inhibitor (TKI) related adverse events (AEs) most concern you and what mitigation strategies do you apply for pulmonary, hepatic, and/or cardiovascular events?​

YASIR Y. ELAMIN, MD: Do [the data from the ALTA-1L trial (NCT02737501)] resonate with your activity? I'm sure many of you have used crizotinib in the past.

GARY WEISS, MD: I don't see enough patients [with brain metastases] to have this resonate with my own experience. If I see 1 ALK-positive patient per year, that means I'm going to get a brain metastasis approximately every 5 years, [in my experience]. I don't have large numbers to say that something works better than something else. With various studies that have come out, crizotinib, which is what I used when it was the only drug available, has dropped out of my regimens. All the other drugs seem to be better for [patients with] brain metastases. I often don't know [the mutational status] at the time I'm making my initial decision. Sometimes I know before, and with that in mind, I try…to see if there were any changes since I last saw that situation. [It is] the same with AEs. I read the numbers and I use those in my decisions, but I don't have the experience, and I don't think I will ever have the experience, because when I get my next [ALK-positive] patient with brain metastases, [there may be] 2 new drugs on the market and another [like] crizotinib that has gone into retirement.

ELAMIN: It’s a good problem to have that we have too many options and newer, better drugs. Dr Bhandari, what are your thoughts on treating these patients with brain metastases, and what do you think of the data you've seen in relation to the intracranial activity of brigatinib?

ARUN BHANDARI, MD: I had a few patients many years ago where I used crizotinib and they responded very well. I wish the comparison was [between brigatinib and] alectinib [Alecensa] because that’s what we are using currently. Is it superior? I can’t say. I have used alectinib many times and it is fairly well tolerated. I don’t see as many patients with lung cancer as you. I’m used to managing the AEs, [but] I think either one will be fine.

ELAMIN: I agree with you. When it comes to intracranial activity, there is no doubt that both brigatinib and [alectinib], and even lorlatinib, are superior to crizotinib and they are all acceptable frontline options, with subtle differences between the 3.^1-3 Dr Gupta, have you used brigatinib? What are your thoughts in terms of intracranial activity and the safety of the drug, if you have used it before?

MAHENDRA GUPTA, MD: I have not used the drug. My common first-line [drug] is alectinib. But based on the data [from ALTA-1L], and there is significant toxicity with [brigatinib], including 70% grade 3 and 4 toxicities and 8 deaths, I think it's a [more] toxic drug then alectinib.^1,2 If we have a comparative study that says that it is more effective than alectinib, we can use it, but I don't plan to use it as a first line.

ELAMIN: In my mind, I've used a lot of brigatinib, and I've used a lot of alectinib, as I see a fair number of patients with ALK-positive lung cancer, [which] is probably skewed because I do a lot of clinical research there. But the point I want to make here is that if you look at the trials, whether at the ALTA-1L trial or the ALEX [NCT02075840] data for alectinib, the data in terms of efficacy look almost identical. The HR [for PFS]…is 0.48 [by blinded independent central review in ALTA-1L] and the other is [0.47 in ALEX].^1,2 So, I do think that they're almost identical.

Also, when it comes to toxicity, with brigatinib you see a lot of liver enzyme abnormality, and creatine phosphokinase changes and lipase changes, which is going to force you to do a dose reduction. But with alectinib, you also see profound fatigue, especially for those patients who stay on it for years and years.^1,2 So between the 2, I agree with what everyone else said that there isn't a way of knowing which drug is better tolerated, or which drug is better overall. We unfortunately have to use this cross-trial comparison and I personally view [each drug] as fairly similar, even identical in many ways. I agree that lorlatinib [Lorbrena] is probably more potent, but it has a lot of AEs when it comes to that. But in terms of central nervous system activity, potency, and PFS, I think we are going to see that lorlatinib is probably superior to the 2 [other] drugs.³

REFERENCES:

1. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018;379(21):2027-2039. doi:10.1056/NEJMoa1810171

2. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829-838. doi:10.1056/NEJMoa1704795

3. Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187