Alunbrig (brigatinib)

P1, N=5, Active, not recruiting, City of Hope Medical Center | Trial completion date: Apr 2026 --> Mar 2027 | Trial primary completion date: Apr 2026 --> Mar 2027

ALK inhibitors, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib has significantly improved clinical outcomes in ALK-rearranged NSCLC patients. To overcome these resistance mechanisms, the development of novel therapeutic strategies are required. By integrating structural biology, mutation evolution patterns, and emerging therapeutic approaches, this review underscores the need for next-generation inhibitors to overcome resistance and improve long-term outcomes in patients with ALK-positive NSCLC.

P2, N=118, Completed, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Active, not recruiting --> Completed

P2, N=25, Recruiting, University Health Network, Toronto | Not yet recruiting --> Recruiting

While second- and third-generation ALKi (including alectinib, brigatinib, ensartinib, envonalkib, and lorlatinib) have demonstrated superior efficacy compared with the first-generation inhibitor crizotinib in randomized trials, the absence of direct head-to-head comparisons limits the definition of their relative clinical benefit. This indirect comparison indicates that lorlatinib provides the most durable PFS and the strongest intracranial disease control, although ALKis are characterized by distinct toxicity profiles. In the absence of clear OS differences at present, first-line treatment selection should integrate efficacy, intracranial activity, tolerability, and emerging molecular features within a personalized therapeutic framework.

High-level evidence, including prospective interventional studies, supports exposure-guided dosing for imatinib and sunitinib, demonstrating improved molecular or clinical outcomes when predefined trough concentration targets are achieved. For alectinib, cabozantinib, trametinib, and lenvatinib, consistent exposure-response or exposure-toxicity relationships and pragmatic concentration thresholds support selective implementation, although randomized validation remains limited. For agents such as osimertinib, brigatinib, olaparib, and niraparib, monitoring appears most clinically relevant in toxicity-driven scenarios rather than for efficacy optimization. In contrast, lorlatinib currently lacks a clearly defined therapeutic window, limiting routine applicability...In conclusion, therapeutic drug monitoring and model-informed precision dosing are ready for selective clinical adoption in a subset of oral targeted therapies. Future prospective trials integrating pharmacometric tools with patient-centered outcomes are required to refine exposure targets and expand evidence-based implementation.

Notably, C479 exhibited in vitro inhibitory activity comparable to Brigatinib. All the results indicate that the candidate compounds not only possess inhibitory activity similar to that of Brigatinib, but may also help diversify the existing repertoire of ALK-targeted agents and provide additional options for NSCLC research.

Although rare, GI perforation, represents a clinically relevant adverse event associated with alectinib, particularly in patients with diverticulosis or other predisposing conditions. It is essential to optimize safety and long-term disease control by raising awareness of early warning symptoms, conducting a baseline GI evaluation in high-risk patients and carefully sequencing therapy after discontinuation.

Three patients were treated with imatinib (one later switched to nilotinib and then dasatinib), while one patient each received osimertinib and brigatinib. When interstitial pneumonia occurs during TKI administration and does not respond to drug withdrawal and corticosteroid treatment, careful analysis of chest imaging features, along with bronchoalveolar lavage and/or bronchoscopic lung biopsy, is necessary for a definitive diagnosis. This case series and literature review suggest that nebulized GM-CSF or whole lung lavage (WLL) may be effective treatment options for TKI-induced autoimmune PAP.

For EGFR-mutant NSCLC, sequential development of tyrosine kinase inhibitors (TKIs) from first- to third-generation agents-culminating in osimertinib-has markedly improved survival. Similarly, successive generations of ALK inhibitors, including alectinib, brigatinib, and lorlatinib, have extended disease control, particularly within the central nervous system. The introduction of antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan for HER2-mutant NSCLC, and emerging TKIs like zongertinib, represent new therapeutic milestones...Beyond lung cancer, our group, in collaboration with Juntendo University ARO (academic research organization) and fifteen institutions in Japan, conducted the MARBLE phase II trial of atezolizumab plus chemotherapy for thymic carcinoma, achieving a 56% objective response rate and 9.6-month median progression-free survival, supporting potential ICI approval in Japan...The DLL3-targeted BiTE tarlatamab significantly improved overall survival to 13.6 months in the phase III DeLLphi-304 trial for relapsed SCLC, with manageable cytokine release syndrome. Collectively, these advances signify a shift toward biologically driven, molecular-targeted or immune-integrated therapy, aiming to transform lung cancer into a chronic, manageable disease in the future, hopefully.

Patients were treated with crizotinib, alectinib, or brigatinib. Our results highlight the high efficacy of ALKi in achieving disease control (DC) in patients with ALK-positive NSCLC, regardless of the specific fusion variant or treatment regimen. However, the subtle differences in stable disease (SD) and PD rates among fusion variants suggest that genetic profiling may be useful in predicting the durability of response.

VS biology reflects integrated genetic and epigenomic dysregulation. Advancing care will require multi-omic classification, biomarker-driven trials, and combination therapies targeting both signaling and epigenetic vulnerabilities. Future management is expected to shift toward personalized, mechanism-based strategies aimed at durable tumor control while preserving hearing and quality of life.