Brigatinib in Patients With Alectinib-Refractory ALK-Positive NSCLC

Abstract

Introduction: The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib recently showed superior efficacy compared to the first-generation ALK inhibitor crizotinib in advanced ALK-rearranged NSCLC, establishing alectinib as the new standard first-line therapy. Brigatinib, another second-generation ALK inhibitor, has shown substantial activity in patients with crizotinib-refractory ALK-positive NSCLC; however, its activity in the alectinib-refractory setting is unknown.

Methods: A multicenter, retrospective study was performed at three institutions. Patients were eligible if they had advanced, alectinib-refractory ALK-positive NSCLC and were treated with brigatinib. Medical records were reviewed to determine clinical outcomes.

Results: Twenty-two patients were eligible for this study. Confirmed objective responses to brigatinib were observed in 3 of 18 patients (17%) with measurable disease. Nine patients (50%) had stable disease on brigatinib. The median progression-free survival was 4.4 months (95% confidence interval [CI]: 1.8-5.6 months) with a median duration of treatment of 5.7 months (95% CI: 1.8-6.2 months). Among 9 patients in this study who underwent post-alectinib/pre-brigatinib biopsies, 5 had an ALK I1171X or V1180L resistance mutation; of these, 1 had a confirmed partial response and 3 had stable disease on brigatinib. One patient had an ALK G1202R mutation in a post-alectinib/pre-brigatinib biopsy, and had progressive disease as the best overall response to brigatinib.

Conclusions: Brigatinib has limited clinical activity in alectinib-refractory ALK-positive NSCLC. Additional studies are needed to establish biomarkers of response to brigatinib and to identify effective therapeutic options for alectinib-resistant ALK-positive NSCLC patients.

Keywords: ALK; Alectinib; Brigatinib; NSCLC; Resistance.

Figure 1.. Brigatinib activity in alectinib-refractory ALK-positive NSCLC.

(A) Best confirmed tumor responses of 18 ALK-positive patients who received brigatinib and had baseline measurable disease. All patients received and progressed on prior alectinib. The bars show best percent change in the target tumor burden from baseline. The dotted horizontal line shows the 30% threshold for partial response. The red dot indicates a patient who had best overall change from baseline of 0%, with new lesions. PD, progressive disease; SD, stable disease; PR, partial response. (B) Progression-free survival (PFS) on brigatinib for 22 patients. Vertical tick marks on the PFS curve indicate censoring of data. Dotted lines show the median PFS. (C) Swimmer plots demonstrating the duration of brigatinib treatment for each patient in the study cohort. Arrows indicate patients continuing on brigatinib at the time of data cutoff. * indicates patients with evaluable but non-measurable disease. + indicates a patient who required early permanent discontinuation of brigatinib due to pneumonitis and was therefore not evaluable for response to brigatinib.

Figure 2.. Individual duration of brigatinib treatment in patients with post-alectinib/prebrigatinib biopsies.

Patients who achieved a confirmed partial response (PR) are represented in blue; stable disease (SD), in green; progressive disease (PD), in red. One patient (marked with *) had evaluable but non-measurable disease. WT indicates wild-type ALK (no ALK mutation identified in the resistant specimen). ^# indicates testing by liquid (rather than tumor) biopsy; all cases not marked with ^# underwent a tumor biopsy. Arrows indicate patients still receiving brigatinib at the time of data cutoff.

Figure 3.. Examples of tumor responses to brigatinib in ALK-positive cases with ALK resistance mutations.

(A) Confirmed response of a supraclavicular lymph node to brigatinib in a patient with a V1180L resistance mutation detected in the post-alectinib/pre-brigatinib biopsy. This patient remained on treatment at the time of data cutoff. (B) Progressive disease with enlarging and new hepatic and splenic metastases after one month of treatment in a patient with ALK G1202R detected in the post-alectinib/pre-brigatinib biopsy. (C) Progressive disease with an enlarging right lung mass in a patient who did not undergo a post-alectinib/pre-brigatinib biopsy. This patient experienced disease relapse after approximately one month of therapy, and had a post-brigatinib liquid biopsy revealing a G1202R mutation (allele frequency of 3.2%).

Figure 4.. Proposed sequential treatment approach to ALK-positive patients with acquired resistance to alectinib.

This schema is based on the available preclinical and clinical data. Once patients experience disease progression on first-line alectinib, repeat biopsies should be pursued, if feasible, in order to determine the ALK resistance mutation status. Cases with an ALK resistance mutation can be treated with sequential lorlatinib therapy. In a specific subset of cases with an I1171X, V1180L, or L1196M mutation, brigatinib may serve as an additional potential option; ceritinib could also be considered in this setting, although not preferred given its lower CNS activity. In the absence of an ALK resistance mutation, patients may be treated with chemotherapy or combination strategies.