Brigatinib Plus Local Consolidative Therapy Shows Promise in ALK+ NSCLC

Chul Kim, MD

Associate Professor

Georgetown University School of Medicine

Washington, DC

KEY TAKEAWAYS FROM CHUL KIM, MD

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

Chul Kim, MD: 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.¹ 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 P < .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; P < .0001].2

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; P < .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; P < .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; P = .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; P = .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 ALK fusion– positive NSCLC.³ 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.² 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.⁴ 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.

_References:

_{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. J Clin Oncol. 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. J Thorac Oncol. 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. Ann Oncol. 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. J Thorac Oncol. 2023;18(suppl 11):S96. doi:10.1016/j.jtho.2023.09.109}