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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

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

2. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. 

. 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 

. 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187

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.



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

 What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for treating a patient with non–small cell lung cancer whose disease is positive for an 

The NCCN guidelines…differentiate between a patient where 

 gene rearrangements are discovered to prior first-line systemic therapy, where the preferred 3 agents are alectinib [Alencsa], brigatinib [Alunbrig], and lorlatinib [Lorbrena], vs if the 

 gene rearrangement was discovered while the patient is getting chemotherapy.

 Then, the NCCN gives the option of continuing systemic therapy, including maintenance, or interrupting and switching to an ALK tyrosine kinase inhibitor [TKI].

 I think most of us, even if we gave 1 cycle of chemotherapy, tend to interrupt and switch to an ALK TKI once the fusion has been discovered.

What data led to the approval of brigatinib in this setting?

The first trial that the oncologists [on the NCCN panel] probably used to [recommend] brigatinib is the ALTA-1L trial [NCT02737501].

-positive lung cancer were randomly assigned to crizotinib [Xalkori] which was the standard of care at the time vs brigatinib. Brigatinib is given the usual way, for 7 days at the 90 mg dose, then 180 mg after 1 week, and that is to account for the early lung toxicity. The treatment in this trial was continued until progressive disease or unacceptable toxicity and the primary end point was progression-free survival [PFS] by blinded independent review as measured by RECIST [criteria].

As you'd expect, most patients were never-smokers, a majority had stage IV disease, and a majority had adenocarcinoma.

 Approximately one-third of the patients in each arm had brain metastases at baseline. [This is] reflective of our typical patients with lung cancer, where we see frequent brain metastases in these patients who typically present with stage IV disease and are never-smokers.

What were the efficacy outcomes in this trial, and how did patients with brain metastases respond?

The confirmed objective response rate [ORR] in the brigatinib arm was 74% compared with 62% in the crizotinib arm.

 If you look at patients with measurable brain metastases at baseline, the numbers are small, only 18 in the brigatinib arm and 23 in the crizotinib arm, [but] the ORR is 78% in the brigatinib arm and 26% in the crizotinib arm. If you look at any baseline brain metastases by independent review, you will see that the ORR in the brigatinib arm was 66% vs 16% with crizotinib, confirming what we all know that these next-generation ALK inhibitors have greater intracranial efficacy when compared with crizotinib. Five of the 18 patients on the brigatinib arm had a complete response intracranially.

In the intent-to-treat [ITT] population, the investigator-assessed median PFS was 30 months in the brigatinib arm compared with 9 months in the crizotinib arm.

 If you look at the blinded independent review, it's 2 years in the brigatinib arm and 11 months in the crizotinib arm. The investigator-assessed HR was 0.43 compared with 0.48 by the independent review.

[In the ITT population], the intracranial PFS was 44 months with brigatinib with a HR of 0.44 [95% CI, 0.30-0.65; log-rank 

 < .0001], similar to what we see extracranially. In patients with brain metastases, the intracranial PFS was 24 months, very similar to what we've seen extracranially, with a hazard ratio of 0.29 [95% CI, 0.17-0.51; 

In the final overall survival [OS] data, in the ITT population the 2 [Kaplan-Meier] curves are overlapping [HR, 0.81; 95% CI, 0.53-1.22; log-rank 

 =.305], but the 4-year survival rate in the brigatinib arm was 66% compared with 60% in the crizotinib arm. Interestingly, in the patients with brain metastases, you could see clear separation between the curves, confirming the superiority of brigatinib over crizotinib in terms of brain efficacy, and showing this early separation between the curves suggesting that we've lost many of these patients due to intracranial progression, reinforcing the importance of having a drug with potent intracranial activity to treat these patients.

What is the toxicity profile of brigatinib based on this trial?

I want to focus on the severe toxicities. In the brigatinib arm, 70% of the patients had a grade 3 or 4 toxicity [vs 56% with crizotinib], then in terms of adverse events [AE] leading to treatment discontinuation, we've seen this in 13% of the patients [vs 9%, respectively], and 44% of the patients required a dose reduction [vs 25%, respectively].

 Some of the common AEs that we've seen are increased in creatine phosphokinase and lipase, and also we've seen severe hypertension in 14% of the patients treated with brigatinib [vs 4% with crizotinib].

Despite [the fact that] that early lung toxicity was an issue in some patients, overall, it wasn't a major limitation of the drug, and the rate of pneumonitis overall was low. It turns out that if these patients managed the first week without the lung toxicity, then they could go on the drug for several months and years without major challenge there.

1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 5.2024. Accessed April 25, 2024. 

https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

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

3. 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

4. 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. 

During a Case-Based Roundtable® event, Yasir Y. Elamin, MD, discussed the intracranial efficacy of brigatinib from the ALTA-1L trial for patients with ALK+ non–small cell lung cancer in the first article of a 2-part series.