Reference Detail

Ref Type Journal Article
PMID (29935304)
Authors Lin JJ, Zhu VW, Schoenfeld AJ, Yeap BY, Saxena A, Ferris LA, Dagogo-Jack I, Farago AF, Taber A, Traynor A, Menon S, Gainor JF, Lennerz JK, Plodkowski AJ, Digumarthy SR, Ignatius Ou SH, Shaw AT, Riely GJ
Title Brigatinib in Patients with Alectinib-Refractory ALK-Positive Non-Small Cell Lung Cancer: A Retrospective Study.
Journal Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Vol
Issue
Date 2018 Jun 20
URL
Abstract Text The second-generation ALK inhibitor alectinib recently demonstrated superior efficacy compared to the first-generation ALK inhibitor crizotinib in advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), establishing alectinib as the new standard first-line therapy. Brigatinib, another second-generation ALK inhibitor, has demonstrated substantial activity in patients with crizotinib-refractory ALK-positive NSCLC; however, its activity in the alectinib-refractory setting is unknown.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.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 nine patients in this study who underwent post-alectinib/pre-brigatinib biopsies, five had an ALK I1171X or V1180L resistance mutation; of these, one had a confirmed partial response and three 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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK rearrange ALK D1203N non-small cell lung carcinoma predicted - resistant Brigatinib Clinical Study Actionable In a clinical case study, ALK D1203N was identified at disease progression while on Alunbrig (brigatinib) treatment in a patient with ALK-positive non-small cell lung cancer (PMID: 29935304). 29935304
ALK rearrange ALK V1180L non-small cell lung carcinoma resistant Alectinib Clinical Study Actionable In a clinical case study, ALK V1180L was identified in post-progression biopsies of 2 non-small cell lung cancer patients harboring an ALK rearrangement after disease progression on Alecensa (alectinib) treatment (PMID: 29935304). 29935304
ALK rearrange non-small cell lung carcinoma sensitive Brigatinib Phase Ib/II Actionable In a Phase I/II trial, Alunbrig (brigatinib) treatment resulted in an objective response rate of 100% (8/8) in ALK inhibitor-naive ALK-rearranged non-small cell lung cancer (NSCLC) patients, 72% (51/71) in crizotinib-treated ALK-rearranged NSCLC patients, and 83% (5/6) in ALK-rearranged NSCLC patients with CNS metastases (PMID: 27836716). 27836716
ALK rearrange non-small cell lung carcinoma sensitive Brigatinib Clinical Study Actionable In a retrospective study, non-small cell lung cancer patients with brain metastases harboring an ALK rearrangement demonstrated prolonged survival following treatment with the combination of an ALK-targeted tyrosine kinase inhibitor, including Alunbrig (brigatinib), and radiotherapy (PMID: 26438117). 26438117
ALK rearrange non-small cell lung carcinoma sensitive Brigatinib FDA approved Actionable In a Phase II trial (ALTA) that supported FDA approval, Alunbrig (brigatinib) treatment resulted an overall response rate of 45% (51/112) in the 90mg arm and 54% (59/110) in the 180mg arm, and median progression-free survival of 9.2 and 11.0 months respectively, in ALK-rearranged non-small cell lung carcinoma patients who progressed on Xalkori (crizotinib) (PMID: 28475456; NCT02094573). 28475456
ALK rearrange non-small cell lung carcinoma sensitive Brigatinib Guideline Actionable Alunbrig (brigatinib) is included in guidelines as subsequent therapy for ALK rearranged non-small cell lung cancer patients whose disease progressed after Xalkori (crizotinib) therapy (NCCN.org). detail...
ALK rearrange non-small cell lung carcinoma sensitive Brigatinib Clinical Study Actionable In a retrospective analysis, Alunbrig (brigatinib) demonstrated limited efficacy, resulted in objective response in 17% (3/18) and stable disease in 50% (9/18) of patients with alectinib-refractory, ALK-positive non-small cell lung cancer, with a median progression-free survival of 4.4 months (PMID: 29935304). 29935304
ALK rearrange ALK I1171T non-small cell lung carcinoma predicted - resistant Brigatinib Clinical Study Actionable In a clinical case study, Alunbrig (brigatinib) treatment resulted in progressive disease in a patient with Alecensa (alectinib)-refractory, ALK-rearranged non-small cell lung cancer with an acquired ALK I1171T (PMID: 29935304). 29935304
ALK rearrange ALK I1171T non-small cell lung carcinoma predicted - resistant Alectinib Clinical Study Actionable In a clinical case study, ALK I1171T was identified in the post-progression biopsy of a non-small cell lung cancer patients harboring an ALK rearrangement after disease progression on Alecensa (alectinib) treatment (PMID: 29935304). 29935304
ALK rearrange ALK I1171N MET amp non-small cell lung carcinoma predicted - resistant Brigatinib Clinical Study Actionable In a clinical case study, MET amplification was identified together with a preexisting ALK I1171N at disease progression while on Alunbrig (brigatinib) treatment in a patient with ALK-positive non-small cell lung cancer (PMID: 29935304). 29935304
ALK rearrange ALK V1180L ALK L1196M ALK G1202R non-small cell lung carcinoma predicted - resistant Brigatinib Clinical Study Actionable In a clinical case study, ALK G1202R and ALK L1196M were identified at disease progression while on Alunbrig (brigatinib) treatment in liquid biopsy of a patient with ALK-positive non-small cell lung cancer also harboring an ALK V1180L (PMID: 29935304). 29935304
ALK rearrange ALK V1180L non-small cell lung carcinoma predicted - sensitive Brigatinib Clinical Study Actionable In a clinical case study, Alunbrig (brigatinib) treatment resulted in 1 partial response and 1 stable disease in 2 patients with Alecensa (alectinib)-refractory, ALK-rearranged non-small cell lung cancer with an acquired ALK V1180L (PMID: 29935304). 29935304
ALK rearrange ALK G1202R non-small cell lung carcinoma predicted - resistant Brigatinib Clinical Study Actionable In a clinical case study, Alunbrig (brigatinib) treatment resulted in progressive disease in a patient with ALK-rearranged non-small cell lung cancer refractory to Alecensa (alectinib) treatment, ALK G1202R was identified in post-brigatinib biopsy (PMID: 29935304). 29935304
ALK rearrange ALK I1171N non-small cell lung carcinoma predicted - sensitive Brigatinib Clinical Study Actionable In a clinical case study, Alunbrig (brigatinib) treatment resulted in stable disease in 2 patients with Alecensa (alectinib)-refractory, ALK-rearranged non-small cell lung cancer with an acquired ALK I1171N (PMID: 29935304). 29935304