Brigatinib in the Therapy of Pretreated Patients with Advanced ALK-Positive NSCLC

Introduction

Oncogenic mutations in the gene for anaplastic lymphoma kinase (ALK) are present in 3−5% of patients with non-small cell lung cancer (NSCLC). Patients with mutations in the ALK gene (ALK⁺) are generally younger, non-smokers or light smokers, and histologically it is adenocarcinoma with a high risk of brain metastases at diagnosis or progression.

Brigatinib is a next-generation ALK inhibitor (ALKi) with increased intracranial efficacy and high effectiveness against mutations that cause resistance to ALK inhibitors. It was initially administered to patients pretreated with crizotinib. Later clinical studies showed the superiority of brigatinib over crizotinib, and it is now also administered as a first-line treatment for ALK⁺ patients with advanced NSCLC.

The Early Access Program for Brigatinib

The BrigALK retrospective study from real-world clinical practice analyzed the outcomes of ALK⁺ patients with advanced NSCLC enrolled in the French early-access program (FEAP). With 104 participants enrolled, an interim analysis was performed: the median follow-up was 6.7 months, investigator-assessed progression-free survival after initiation of brigatinib (invPFS) was 6.6 months (95% confidence interval [CI] 4.8−9.9), and the median overall survival (OS) was 17.2 months (95% CI 11.0 to not reached).

The BrigALK2 study analyzed the entire duration of FEAP including follow-up and focused on the efficacy of lorlatinib after brigatinib therapy. Patients aged 18 years or older with confirmed ALK⁺ advanced NSCLC and previous treatment with one ALKi were included. Data were retrospectively obtained from patients' medical records.

Results

In BrigALK2, data from 183 patients were analyzed. More than half (55.3%) had ≥ 3 metastatic sites, most commonly brain metastases (71.6%). The median time from the diagnosis of metastatic NSCLC to initiation of brigatinib therapy was 30.6 months (95% CI 17.0−34.6). Brigatinib was administered as second-line therapy to 7.7% of patients, third-line to 24%, fourth-line to 40.4%, and fifth-line to 27.9%. Before brigatinib therapy, 70.5% of patients underwent chemotherapy.

At the time of data cutoff (February 1, 2021), 21 patients were on treatment, and the median follow-up after initiation of brigatinib therapy was 40.4 months (95% CI 38.4−42.4). The median invPFS was 7.4 months (95% CI 5.9−9.6) and the median duration of treatment (DOT) with brigatinib was 7.3 months (95% CI 5.8−9.4). For patients pretreated with 1 (n = 14), 2−3 (n = 118), or > 3 (n = 51) ALK inhibitors, the median DOT was 13.8 (95% CI 3.8–26.4), 7.4 (95% CI 5.6–9.9), and 4.9 (95% CI 1.7–9.3) months, respectively. The median OS reached 20.3 months (95% CI 15.6−27.4) for the entire patient population. Both OS and DOT decreased with the number of prior ALK inhibitors. There was no significant difference in the median OS between patients with and without brain metastases: 20.3 (95% CI 14.7–27.4) vs. 22.6 (95% CI 12.6–37.5) months.

At the time of data collection, disease progression was observed in 112 patients (60.9%) during brigatinib therapy. After brigatinib, 106 patients started subsequent therapy, and clinical data were available for 92 of them. Lorlatinib was used in 68 patients, with 51 receiving it immediately after brigatinib and 17 receiving a second-generation ALKi and/or chemotherapy before lorlatinib. The interval between the diagnosis of advanced NSCLC and the initiation of lorlatinib therapy was 52.8 months (95% CI 43.2–60.3). The median follow-up was 29.9 months, the median DOT with lorlatinib was 5.3 months (95% CI 3.6–7.6), and the median OS from the start of lorlatinib therapy was 14.1 months (95% CI 10.3–19.2).

The median OS from the initial diagnosis of NSCLC was 75.3 months (95% CI 38.2–174.6). Advanced disease was revealed at diagnosis in 86.4% of patients.

Conclusion

The results of the analysis confirm the efficacy of brigatinib in real-world clinical practice in a population of patients previously treated with ALK inhibitors and highlight the therapeutic activity of lorlatinib after brigatinib administration.

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Source: Descourt R., Pérol M., Rousseau-Bussac G. et al. Brigatinib for pretreated, ALK-positive, advanced non-small-cell lung cancers: long-term follow-up and focus on post-brigatinib lorlatinib efficacy in the multicenter, real-world BrigALK2 study. Cancers (Basel) 2022 Mar 30; 14 (7): 1751, doi: 10.3390/cancers14071751.