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Spotlight

This roundtable series reviews the treatment of patients with advanced 

-positive non–small cell lung cancer, as discussed by key opinion leaders and participants at virtual live events.

Patients With ALK+ Lung Cancer Given Targeted Therapy

The ALTA-1 trial showed benefit of brigatinib over crizotinib in all patients with ALK-positive lung cancer and those with brain metastases.

Real-world data demonstrated most patients received another ALK-TKI after brigatinib if they experienced disease progression.

The BRIGHTSTAR study showed efficacy of adding local consolidative therapy to brigatinib and a randomized trial is underway.

Targeted Oncology: Could you discuss the outcomes of the ALTA-1 trial (NCT02737501) in patients with 

-positive non–small cell lung cancer (NSCLC)?

Brigatinib [Alunbrig] is a second-generation ALK inhibitor. We give a 90-mg daily dose for 7 days as a lead-in followed by 180 mg once a day if that 7-day, 90-mg dose is well tolerated. In the ALTA-1 trial, brigatinib was compared with crizotinib [Xalkori] in a randomized fashion. A few things to notice in the trial was that 1 line of prior systemic therapy was allowed for patients with locally advanced or metastatic NSCLC, so a patient could have gotten a dose or few cycles of chemotherapy before enrollment in the trial, and crossover was permitted at the time of progression if the patient was assigned to crizotinib. The primary end point was the blinded independent review committee [BICR]–assessed progression-free survival [PFS].

The objective response rate was better numerically, 74% with brigatinib and 62% with crizotinib.

 That didn’t change much based on presence or absence of brain metastases and so this is certainly an active drug in this space.

In the intent-to-treat [ITT] population, the investigator-assessed PFS was a median of 30.8 months [for brigatinib] vs 9.2 months with crizotinib with a HR of 0.43 [95% CI, 0.31-0.58; log-rank 

 < .0001]. Then the BICR-assessed PFS was 24 months with brigatinib vs 11 months with crizotinib [HR, 0.48; 95% CI, 0.35-0.66; 

Looking at those patients with baseline brain metastasis, intracranial PFS in the ITT population, there was more CNS [central nervous system] activity with brigatinib compared with crizotinib and more CNS progression in those patients who were assigned to crizotinib [HR, 0.44; 95% CI, 0.30-0.65; 

 < .0001], and then in patients who had baseline metastasis, the benefit was greater in favor in brigatinib [HR, 0.29; 95% CI, 0.17-0.51; 

 < .0001]. Crizotinib doesn't have a lot of CNS activity and that is being reflected in the Kaplan-Meier curves.

For overall survival [OS], there was a crossover from crizotinib to brigatinib so in the ITT population, there was no difference in OS with an HR of 0.81 [95% CI, 0.53-1.22; 

 = .305]. There may be a little bit more difference in OS in those with baseline brain metastases [HR, 0.43; 95% CI, 0.21-0.89; 

 = .020], but overall in the ITT population, there was no OS difference.

What real-world data are there for post-brigatinib treatment?

They looked at treatment patterns and outcomes after brigatinib therapy for 

Thirty patients received second-line ALK-TKI [tyrosine kinase inhibitor], and then 16 out of the 30 received second-line lorlatinib [Lorbrena]. If you look at the time to treatment discontinuation, patients were able to stay on the second-line ALK-TKI a total of 34.7 months, but in the patients who received lorlatinib it was 37.2 months so a little better.

What is the safety profile of brigatinib?

There are adverse events that we need to monitor with brigatinib.

 The first is the creatine phosphokinase elevation, and then hypertension. Brigatinib has some VEGF inhibition, and then also EGFR [inhibition]. In this case, there was rash that happened. Blood pressure is something we need to monitor. We also talk about the early onset pulmonary events, where patients can develop early onset but usually transient pulmonary events such as shortness of breath. Rarely, some patients require oxygen, but this can be treated with dose interruption, and some people can stay on the treatment with supportive care; that is seen in about probably 3% to 5% of patients.

What additional research is being done with brigatinib in this setting?

This brings us to another study. This is the BRIGHTSTAR study [NCT03707938], and this is a clinical trial of brigatinib plus local consolidative therapy [LCT] in stage IV or recurrent ALK fusion–positive NSCLC. This was not a randomized trial. Patients received brigatinib for 8 weeks, then had a scan. If there was no progressive disease, then they received brigatinib until progression, but also got local consolidative therapy, so if they had less than 3 active sites, then they got LCT to all sites. For more than 3 active sites, they [received] LCT to sites at the discretion of the treating physician.

If you look at the PFS rate across the 1-year, 2-year, or 3-year marks, although we shouldn’t do cross-trial comparison, numerically, there's a better PFS rate with the incorporation of LCT on top of brigatinib first-line treatment.

 There is an ongoing randomized trial that compares brigatinib alone and then intensification on top of brigatinib, adding LCT or chemotherapy; that is BRIGHTSTAR-2 [NCT06522360]. It was overall safe, and then showed us some promising results. BRIGHTSTAR-2 is a randomized trial that compares between those treatment intensification strategies on top of brigatinib.

1. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in advanced alk inhibitor-naive ALK-positive non-small cell lung cancer: second interim analysis of the phase III ALTA-1L trial. 

. 2020;38(31):3592-3603. doi:10.1200/JCO.20.00505

2. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. 

. 2021;16(12):2091-2108. doi:10.1016/j.jtho.2021.07.035

3. Delmonte A, Ahn M, Ghosh S, et al. Real-world treatment patterns and effectiveness of subsequent treatments following first-line (1L) brigatinib for patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) from ALTA-1L. 

. 2024;9(suppl 3):1-53. doi:10.1016/esmoop/esmoop102569

4. Elamin Y, Gandhi S, Saad M, et al. BRIGHTSTAR local consolidative therapy with brigatinib in tyrosine kinase inhibitor-naïve ALK-rearranged metastatic NSCLC. 

. 2023;18(suppl 11):S96. doi:10.1016/j.jtho.2023.09.109

During a Case-Based Roundtable® event, Chul Kim, MD, discussed the ALTA-1 trial and BRIGHTSTAR trials of brigatinib in ALK+ lung cancer in the first article of a 2-part series.

Brigatinib Plus Local Consolidative Therapy Shows Promise in ALK+ NSCLC

A 53-year-old Asian American woman presents to her primary care physician with complaints of a persistent, productive cough mixed with scant amounts of blood and associated with chest discomfort upon deep inspiration. ​She denied fever, night sweats, headache, or recent upper respiratory infection. ​She is a never smoker with no family history of malignancy.

Chest X-ray showed right, upper lobe opacity and mediastinal enlargement. She was referred to a thoracic oncologist for further evaluation. CT of chest, abdomen, and pelvis revealed multiple peripheral nodules in the right upper lobe, the largest measuring 3.7 cm ´ 3.4 cm in diameter with ipsilateral mediastinal lymphadenopathy of varying nodal size between 2.2 cm and 2.8 cm. There was no evidence of hepatic involvement.

Contrast-enhanced staging MRI of the brain demonstrated discreet intracranial lesions in the parietal (2.6 cm) and frontal (1.2 cm) lobes. Her disease staging was T2aN2M1b (metastatic). She underwent endobronchial ultrasound-guided transbronchial needle aspiration and endoscopic ultrasound-guided fine needle aspiration of the lungs and mediastinal lymph nodes. The disease’s histopathology included tumor cell clusters with high nucleus to cytoplasmic ratio; pleomorphic nuclei and granular chromatin; acinar structure with signet-ring cell morphology consistent with adenocarcinoma; and short axis diameter of mediastinal node specimen of 2.1 cm. Immunohistochemistry showed the disease was TTF-1+, Napsin A+; CEA+; PD-L1 tumor proportion score = 27%

Tissue next-generation sequencing revealed an (

fusion​; the remainder of the broad-based panel was negative.

In this case of non–small cell lung cancer (NSCLC), what would you select as first-line therapy?​

 of baseline central nervous system (CNS) metastases influence your treatment choice?​

-positive lung cancer with 2 brain metastases. Assuming that we may do stereotactic radiosurgery or Gamma Knife [radiation] to the brain, what ALK inhibitor would you have chosen?

I have good luck with alectinib [Alecensa]. In our 3 patients right now, it's very well tolerated. There are some data of it preventing CNS metastases with that phase 3 trial.

 So I think the third-generation ALK [TKI; tyrosine kinase inhibitor] would be my preference.

You don't differentiate if a patient has brain metastases or no brain metastasis? You're comfortable enough with using alectinib for both indications, which most of us do?

I would use alectinib as well in this situation. When I moved here 2 years ago, I saw a patient who was already treated with lorlatinib [Lorbrena]. I struggled to find what [to give] next after the patient’s disease progressed. I referred the patient for clinical trials with fourth-generation [TKIs] if we could find them, but eventually I had to treat the patient with chemotherapy. So I think the best thing is alectinib, and we have other options if the patient's disease did not respond to alectinib.

Exactly. We have 3 drugs approved by the FDA. Lorlatinib, brigatinib [Alunbrig], and alectinib.

Do the intracranial responses to brigatinib in patients with 

-positive metastatic NSCLC with baseline brain metastases resonate with your own clinical experience?​

Considering the data, do the intracranial responses to brigatinib in ALK-positive lung cancer with or without baseline metastases influence your decision when it comes to selecting which ALK inhibitor to use?

I think the newer-generation TKIs have better CNS penetration, so they make a big difference. This is applicable even for the 

-positive population. I've had a couple of patients on crizotinib [Xalkori] who were doing so well, and they were so comfortable that when the newer-generation drugs appeared, they were reluctant to change. I [now] use alectinib, but I don't have experience with brigatinib.

Do you have experience with lorlatinib? It has CNS activity, [so] it seems that lorlatinib may have an edge there.

Yes, I have. I have a couple of my patients who had CNS progression who I recently transitioned to lorlatinib. Interestingly, in one of them, I did molecular testing because they had resection of lung and brain lesions, and they had a 

 exon 14 [skipping mutation]. I'm still trying to figure out what to do for her, but this is short term. I haven't seen any major issues with toxicity that caught my eye.

Maybe I'm just lucky, but I don't see too many patients who have 

 positive intracranial disease. The data are impressive. I've only [treated these patients] twice. One was [treated with] crizotinib back when that was the only [option]. They did OK with it. I’ve used brigatinib once, but I don't know how the patient did because they moved out of state afterwards.

Gadgeel S, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. 

. 2018;29(11):2214-2222. doi:10.1093/annonc/mdy405

During a Case-Based Roundtable® event, Yasir Y. Elamin, MD, discussed with participants how they select treatment for a patient with ALK+ non–small cell lung cancer and brain metastases in the first article of a 2-part series.

CNS Activity of Third-Generation ALK TKIs Influence Approach in NSCLC

Do the intracranial responses to brigatinib (Alunbrig)

-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 

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?​

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.

I don't see enough patients [with brain metastases] to have this resonate with my own experience. If I see 1 

-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 [

-positive] patient with brain metastases, [there may be] 2 new drugs on the market and another [like] crizotinib that has gone into retirement.

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?

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.

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.

 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?

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.

 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.

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 

-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].

 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.

 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.

1. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. 

. 2018;379(21):2027-2039. doi:10.1056/NEJMoa1810171

During a Case-Based Roundtable® event, Yasir Y. Elamin, MD, asked participants their perspectives on the use of targeted agents for patients with ALK+ non–small cell lung cancer in the second article of a 2-part series.

