Reference Detail

Ref Type

Journal Article

PMID

(36096442)

Authors

Ou SI, Nishio M, Ahn MJ, Mok T, Barlesi F, Zhou C, Felip E, de Marinis F, Kim SW, Pérol M, Liu G, Migliorino MR, Kim DW, Novello S, Bearz A, Garrido P, Mazieres J, Morabito A, Lin HM, Yang H, Niu H, Zhang P, Kim ES

Title

Efficacy of Brigatinib in Patients With Advanced ALK-Positive NSCLC Who Progressed on Alectinib or Ceritinib: ALK in Lung Cancer Trial of brigAtinib-2 (ALTA-2).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer	17	12	2022 Dec	1404-1414	J Thorac Oncol

URL

Abstract Text

Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors.In this single-arm, phase 2, ALK in Lung Cancer Trial of brigAtinib-2 (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (after 7-d 90-mg lead-in). Primary end point was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed.Among 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 [0.5-17.7] mo), confirmed IRC-ORR was 26.2% (95% confidence interval [CI]: 18.0-35.8), median duration of response, 6.3 months (95% CI: 5.6-not reached), and median progression-free survival (mPFS), 3.8 months (95% CI: 3.5-5.8). mPFS was 1.9 months (95% CI: 1.8-3.7) in patients with ctDNA-detectable baseline ALK fusion (n = 64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8-39.9); mPFS was 3.8 months (95% CI: 1.9-5.4). Resistance mutations were present in 33.3% (26 of 78) of baseline ctDNA; 54% (14 of 26) of mutations were G1202R; 52% (33 of 64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg once daily) was 85.9%.In ALK in Lung Cancer Trial of brigAtinib-2, brigatinib was found to have a limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. mPFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ALK	V1180Y	missense	unknown	ALK V1180Y lies within the protein kinase domain of the Alk protein (UniProt.org). V1180Y has been identified in the scientific literature (PMID: 36096442), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Apr 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK I1171T ALK G1269A	lung non-small cell carcinoma	predicted - sensitive	Brigatinib	Case Reports/Case Series	Actionable	In a Phase II trial (ALTA-2), Alunbrig (brigatinib) therapy resulted in a partial response lasting at least 7.4 months in a patient with advanced non-small cell lung cancer harboring EML4-ALK, ALK G1269A, and ALK I1171T who previously progressed on Alecensa (alectinib) therapy (PMID: 36096442; NCT05421936).	36096442
ALK V1180L	lung non-small cell carcinoma	predicted - sensitive	Brigatinib	Case Reports/Case Series	Actionable	In a Phase II trial (ALTA-2), Alunbrig (brigatinib) therapy resulted in a partial response, with a progression-free survival of 11 months, in a patient with advanced non-small cell lung cancer harboring ALK V1180L who previously progressed on Alecensa (alectinib) therapy (PMID: 36096442; NCT05421936).	36096442
ALK positive	lung non-small cell carcinoma	no benefit	Brigatinib	Phase II	Actionable	In a Phase II trial (ALTA-2), Alunbrig (brigatinib) therapy demonstrated limited efficacy in ALK-positive advanced non-small cell lung cancer patients who previously progressed on Alecensa (alectinib) or Zykadia (ceritinib) therapy, with an objective response rate (ORR) of 26.2% (27/103, 1 complete (CR) and 26 partial responses), duration of response of 6.3 mo, median progression-free survival of 3.8 mo, and intracranial ORR of 15% (8/55, 1 CR) in patients with CNS metastases (PMID: 36096442; NCT05421936).	36096442
EML4 - ALK ALK V1180Y	lung non-small cell carcinoma	predicted - sensitive	Brigatinib	Case Reports/Case Series	Actionable	In a Phase II trial (ALTA-2), Alunbrig (brigatinib) therapy resulted in a partial response, with a progression-free survival of 7.4 months, in a patient with advanced non-small cell lung cancer harboring EML4-ALK and ALK V1180Y who previously progressed on Alecensa (alectinib) therapy (PMID: 36096442; NCT05421936).	36096442