Intracranial Response Data Supports Use of Brigatinib 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

Targeted Oncology: 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 ALK gene rearrangement?

YASIR Y. ELAMIN, MD: The NCCN guidelines…differentiate between a patient where ALK 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 ALK gene rearrangement was discovered while the patient is getting chemotherapy.¹ Then, the NCCN gives the option of continuing systemic therapy, including maintenance, or interrupting and switching to an ALK tyrosine kinase inhibitor [TKI].¹ 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].² In this trial, patients with TKI-naive ALK-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.² 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.³ 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.⁴ 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 P < .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; P < .0001].

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 P =.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].⁴ 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.

_References:

_{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. N Engl J Med. 2018;379(21):2027-2039. doi:10.1056/NEJMoa1810171}

_{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. J Clin Oncol. 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. J Thorac Oncol. 2021;16(12):2091-2108. doi:10.1016/j.jtho.2021.07.035}