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Spotlight

Luis E. Raez, MD, discusses the current liquid biopsy options for patients with lung cancer through assessing circulating tumor DNA.

Liquid Biopsy Techniques Test Lung Cancer MRD Level

Luis E. Raez, MD, medical director and chief scientific officer at Memorial Cancer Institute in Pembroke Pines, Florida, discusses the current liquid biopsy options for patients with lung cancer through assessing circulating tumor DNA (ctDNA).

These choices include identifying tumor-specific clones with tumor genotype-informed tests, such as Signatera, or detecting ctDNA in the blood with tumor genotype-uninformed tests. Raez highlights the debate between these 2 approaches, noting that tumor-informed biopsies are personalized and follow the tumor's evolution, while tumor-uninformed ctDNA detection only indicates cancer recurrence and is not patient specific.

Currently, Signatera is awaiting approval from the FDA as a molecular residual disease (MRD) test generally, but there are many ongoing studies using Signatera, emphasizing the potential benefits for patients. However, there is frustration for both patients and physicians when unable to determine if a patient will need additional systemic therapy post-surgery, according to Raez, underscoring the importance of accurate posttreatment assessments.

 We have 2 options now in liquid biopsies. One is to do tumor informed, meaning Signatera; we go to the tissue, and we identify among 16 different clones, which one or which ones the patient has, and we look for these tumor-specific clones. That's what we call them tumor informed. The other option, the other technologies that we use now, is only ctDNA. If we find ctDNA in your blood, it's because there is a recurrence. If there is no ctDNA in your blood, you are doing well, but that's tumor uninformed. So now we have the debate between which one of these technologies is better. Signatera looks very rational because you want to follow what your tumor has, and it's personalized because we do it patient by patient. So that's why—we will see, I guess. For lung cancer, that's what we do.

 We are waiting for FDA approval for MRD. To be fair, there are other MRD options, but this is something [where]...there is more than 80 or 90 studies ongoing with Signatera. That is why we're very excited that we may get some indications and validation and benefit for the patients. That's the most important thing because, as I said, if you have 100 patients with lung cancer, breast cancer, [etc], and after surgery, not knowing who is cured and who is not is something very frustrating—not only for the patients, but also for the doctors because we have to put them on treatment that they may not need.

What is your experience using brigatinib (Alunbrig) in patients with ALK-positive non–small cell lung cancer (NSCLC)?

Has anyone used brigatinib in your practice as first-line or second-line therapy? What have you seen in terms of efficacy and safety for these patients? I have patients who are on brigatinib now for several years and doing pretty well. I didn't see the pulmonary events in those 2 patients, but I wonder if anyone else used or has experience with brigatinib?

I have some patients who in the beginning I was treating with alectinib [Alecensa], but later on experienced progression prior to the lorlatinib [Lorbrena] data. They started on brigatinib. The patients tolerated it well, but did have hypertension, so we had to start on some hypertension medicines to manage and also had some dose reduction, but overall, the patient is doing well for the last few years.

What are your insights and perspectives of the ALEX trial (NCT02075840) of alectinib?

How do you monitor patients for myalgia and edema?

A lot of us have used alectinib in clinical practice. What is your interpretation of the outcomes that you see in the ALEX clinical trial? Does it sound like good treatment?

For alectinib, I've had a very good experience in patients with ALK-positive stage IV disease, and it is very well tolerated drug. I have been using alectinib before the approval of lorlatinib for first line. Many of my patients have been on alectinib for [a long time] with stable disease. If I have patients with ALK-positive stage IV disease, I usually start them on alectinib. That's my drug of choice; they can tolerate it [well].

If patients have brain metastases, then I would do lorlatinib in those cases. I also look at how much disease burden these patients have. If I feel that patients won't be able to tolerate lorlatinib, then alectinib becomes my treatment of choice, but I have been using alectinib, and then if the patient is on alectinib, then I reserve lorlatinib for second line.

Thanks for sharing your experience and insights. Myalgia is one of the most common adverse events [AEs] of alectinib and then edema, etc, and laboratory abnormalities like anemia, creatine elevation, and things like that [are also common]. Has anyone had patients who had severe myalgia or some of the hematological AEs?

I had a patient who [did not show] myalgia, but he was complaining of severe fatigue. He did have anemia. His hemoglobin dropped to 9 g/dL so I was concerned about the anemia. I was attributing his fatigue to anemia. I had discussed with him about the AE of myalgia. It can happen. He had creatine phosphokinase [CK] level tested by his primary care physician, and it was very high, in the 500s. I don't check CK levels unless I see a clinical presentation of myalgia in such patients. I did hold the drug for some time until his CK resolved. His fatigue was from anemia, and he had no symptoms. He had no muscle pain or tenderness. His creatinine was OK, but that that's something I have seen. Do you check CK level at frequent intervals with these patients?

I check once in a while, probably not every time. Sometimes I see them every 3 to 4 months, or sometimes every 6 months, depending on how they are doing. I think about checking. I always ask about myalgia. [I ask,] “Do you have any pain in the muscles?”

I have pretty good experience with alectinib. In patients I checked, the CK levels also slightly elevated. Patients are asymptomatic, and I just keep as is. I have 1 patient who developed hemolytic anemia, but the anemia is mild. I did some dose adjustments, and they are able to stay on the therapy.

I agree that dose interruption and then reduction, if necessary, is quite effective for further AEs.

What are your impressions of the efficacy data for lorlatinib?

What is your management approach for the lipid abnormalities associated with lorlatinib?

Do you use lorlatinib as first-line therapy at this point, or would you still prefer second-generation inhibitor therapy, such as alectinib or brigatinib in your in your practice? Have the 5-year progression-free survival data changed your practice at all?

I recently tried starting a patient on the third-generation [tyrosine kinase inhibitor (TKI)], but the insurance denied it. She presented with brain metastases [but] she had to try alectinib first and [not benefit] or not tolerate it before they would approve the third-generation TKI. But my previous experience with that drug has been great, [with] excellent intracranial control of disease.

[For] the lipid abnormalities, we check cholesterol, triglyceride levels, and then prescribe a statin. There are certain drug-drug interactions. You have to pick the right statin to use with lorlatinib. Weight gain and cognitive effects are usually dealt with dose reduction and interruption. There were some data presented in terms of supportive care for these AEs with the lorlatinib during the 2024 World Conference on Lung Cancer that I thought was helpful.

I used lorlatinib and saw an increase in cholesterol. Do you start them preemptively on some sort of cholesterol medication if they're not on it? If they're already on cholesterol medication, do you increase the dose?

I don't prescribe statin as a prophylactic approach. I check their cholesterol, and some people don't like to take a lot of medicines, which is understandable, and then they like to try lifestyle modification, diet, exercise, and I let that happen. But if that doesn't control the cholesterol then I start prescribing statin. That's been my practice. I don't know if anyone prescribes statin when you start lorlatinib from the beginning, or if you watch and then depending on the levels you can act on it.

What statin do you prefer for when patients experience hypercholesterolemia?

I think about using rosuvastatin [Crestor] or pitavastatin [Livalo]. I don't think atorvastatin [Lipitor] is a good choice because of the CYP3A pathway interaction.

1. Watson AS, Taormina JM, Yoder B, et al. Characterizing the severity and timing of real-world ALK-inhibitor associated weight gain in non-small cell lung cancer. 

. 2024;19(suppl 10):S643-644. doi:10.1016/j.jtho.2024.09.1213

2. Lorbrena. Prescribing information. Pfizer, 2023. Accessed December 10, 2024. 

https://labeling.pfizer.com/ShowLabeling.aspx?id=11140

During a Case-Based Roundtable® event, Chul Kim, MD, moderated a discussion on current use of ALK TKIs in lung cancer in the second article of a 2-part series.



Sequencing and Management Considerations for ALK TKIs in NSCLC

Oleg Gligich, MD, discusses utilizing circulating tumor DNA to assess patients with lung cancer.

Timing of MRD Testing in Lung Cancer Affects Patient Outcomes

Oleg Gligich, MD, assistant professor at the Columbia University Division of Hematology/Oncology at Mount Sinai Medical Center, discusses utilizing circulating tumor DNA (ctDNA) to assess patients with lung cancer.

With ctDNA testing, various stages of cancer treatment can be assessed for minimal residual disease, including in the neoadjuvant, adjuvant, and metastatic settings. Gligich explains that ctDNA testing is performed before chemotherapy and after each subsequent cycle of therapy. This testing can be prognostic and correlates with pathologic complete response (CR).

Testing is recommended immediately after surgery in the adjuvant setting, according to Gligich. Following key time points to monitor efficacy, plus using longitudinal testing is emphasized to improve test sensitivity. After completing therapy, testing every 3 months is recommended to detect recurrence.

 ctDNA can be done in the neoadjuvant space, it can be done in the adjuvant space, and it could be done in the metastatic space for monitoring of either worsening disease or recurrence. In the neoadjuvant space, we like to test patients before the initiation of chemotherapy, especially if you have enough tissue. Then we like to test with each subsequent cycle, because we know that that's very prognostic.... We know from prospective observational data that patients who clear their ctDNA by cycle 2 day 1 will do significantly better as compared to patients who don't. We also know that cycle 4 day 1 correlates very well to pathologic CR and that most likely will be a much better surrogate marker as compared to doing pathological response rates after surgery.

 In the adjuvant setting, I like to test right after surgery, so your landmark time points in most clinical trials will be day 10 to day 120 and I think it's crucial that testing occurs, because then you'll have something to follow, whether that's ctDNA positivity or negativity. If it's positive, you definitely know you have a lot more work to do, and maybe your treatment algorithms may not be appropriate if you don't clear. Then what's important is that you continue following. We've learned that longitudinal time points are super important to improve the sensitivities of your tests. So I follow until completion of therapy, and then subsequently every 3 months to determine recurrence. We know that that lead time for lung cancer is about 6 months.

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

Targeted Oncology: Please discuss the long-term data from the KEYNOTE-407 trial (NCT02775435) evaluating chemotherapy plus pembrolizumab.

Data from the KEYNOTE-407 study led to FDA approval of the combination of chemotherapy plus pembrolizumab [Keytruda] for patients who were treatment naive with non–small cell lung cancer [NSCLC] and squamous histology.

 In this trial, patients who had stage IV disease and had no symptomatic brain metastases were included.

Patients were a randomly assigned 1:1 to receive pembrolizumab plus chemotherapy with the backbone of carboplatin plus paclitaxel followed by pembrolizumab maintenance for up to 31 cycles vs placebo plus chemotherapy and followed by placebo maintenance. In this study, they did allow optional crossover of pembrolizumab for up to 35 cycles. The primary end points were progression-free survival [PFS] and overall survival [OS].

The 5-year OS and PFS data from the KEYNOTE-407 trial showed sustained benefit in the squamous cell population with an OS of 18.4% with pembrolizumab vs 9.7% with placebo and an HR of 0.71.

 The PFS was also improved in the treatment arm at 10.8% months vs 3.5%, respectively.

How does PD-L1 expression affect the efficacy for patients with NSCLC?

When evaluating the breakdown by PD-L1 expression, what has been demonstrated across the KEYNOTE trials is that the higher the PD-L1 expression, the greater the magnitude of benefit from the combination.

In the population with a PD-L1 expression of 50% or greater, the 5-year updated OS rate is 23% [in the experimental arm] vs 8.3%. In the population with a PD-L1 of 1% to 49%, the OS update is 20.6% vs 7.5%. In the population with a PD-L1 negative expression, the OS rates are 10.7% vs 13%, and the median was 15 months of follow-up. For the PD-L1 negative subgroup, especially in frontline, monotherapy is not recommended.

During a Case-Based Roundtable® event, Ticiana Leal, MD, discusses phase 3 trials of combinations in the non–small cell lung cancer setting in the second article of a 2-part series.

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