Phase II basket trial of brigatinib for <i>ALK</i> fusion–positive solid tumors: ALLBREAK trial (WJOG15221M).

3105 Background: ALK fusions occur in approximately 0.2% of solid tumors other than non-small cell lung cancer (NSCLC) and are associated with poor outcomes. Prospective evidence for ALK tyrosine kinase inhibitors in this rare condition is limited. Methods: This phase II basket trial evaluated brigatinib (90 mg once daily for 7 days, then 180 mg once daily) using a decentralized clinical trial platform. Eligible patients had advanced solid tumors other than NSCLC with ALK fusions detected in tumor tissue or circulating tumor DNA (ctDNA). The initial planned sample size was 14, with an objective response rate (ORR) of 50% considered promising and 12% unacceptable (one-sided α = 0.025; β = 0.09). Enrollment was expanded to 28 patients due to rapid accrual. ctDNA analyses were performed at baseline, cycle 2, and progressive disease (PD). Results: Twenty-eight patients from ten hospitals were enrolled from May 2022 to March 2025; one was excluded from the full analysis set (FAS) due to clinical deterioration before treatment initiation. The FAS (n = 27) included patients with biliary tract cancer (BTC), colorectal cancer (CRC), thyroid cancer (TC), inflammatory myofibroblastic tumor (IMT), or other solid tumors (n = 7, 5, 3, 3, and 9, respectively). ECOG PS was 0 or 1 (18/9). The number of prior lines of therapy was 0–2 and ≥3 in 20 and seven patients, respectively. ALK fusions were detected by next-generation sequencing (NGS) or fluorescence in situ hybridization (22/5). Among NGS-detected cases, fusion partners included EML4 (n = 8), STRN (n = 2), and others (including CEP44 , HOOK1 , TPM3 , and RRBP1 ; n = 12). The confirmed ORR in the FAS was 63.0% (95%CI, 42.4–80.6), with ORRs of 57% in BTC, 60% in CRC, and 67% each in TC, IMT, and other tumors. For the first 14 patients enrolled as per initial study design, the ORR was 57.1% (95% CI, 28.9–82.3%). In the FAS, the disease control rate was 92.6%, and the median progression-free survival, duration of response, and overall survival were 9.7, 14.4, and 19.5 months, respectively. At data cutoff, 11 patients remained on treatment. ORR varied with fusion partner: 38% for EML4 , 100% for STRN, and 75% for other partners. ORR was comparable between patients with and without baseline ctDNA detection of ALK fusions (67% vs. 64%). At PD, acquired ALK mutations (G1202R, E1028K, and L1502L) were detected in 23% (3/13) of patients; alterations in EGFR, KRAS, or MET were observed in 23% (3/13) of patients. The most common grade 3–4 adverse events were increased creatine phosphokinase (11%) and hypertension (11%). Interstitial lung disease occurred in 7% of patients (grade 1 only; no grade 3–4). No treatment-related deaths occurred. Conclusions: Brigatinib shows a high, durable response rate and manageable toxicity in non-NSCLC ALK fusion–positive solid tumors, supporting its use as a tumor-agnostic therapeutic agent in this rare molecular subset. Clinical trial information: jRCT2041210148.