Alecensa (alectinib)

The results of the ADAURA trial led to the approval of osimertinib for adjuvant treatment of completely resected, EGFR-mutated NSCLC, while the ALINA trial provided the basis for the approval of alectinib in the adjuvant treatment of ALK-positive, completely resected NSCLC. This article discusses the current evidence regarding the perioperative use of targeted therapies, the recommendations for molecular testing in non-small cell lung cancer, and the resulting therapeutic implications, as well as ongoing research efforts in this evolving field.

This case adds to the limited body of evidence and underscores the importance of recognizing neuroendocrine differentiation in ALK-positive lung cancer cases which show clinical progression. Further studies are needed to elucidate the molecular drivers of this transformation and to optimize treatment strategies for affected patients.

This case illustrates the successful personalization of neoadjuvant alectinib by employing an imaging response-adapted strategy. This strategy utilized dynamic imaging assessments to guide the scheduling of the surgical procedure, culminating in a deep pathological response and prolonged disease-free survival, thereby offering a refined perioperative paradigm for ALK-rearranged NSCLC.

Despite robust evidence supporting ALK-targeted therapies, this study highlights substantial disparities in access to diagnostics and treatment for ALK-rearranged NSCLC in Brazil, particularly among patients reliant on the public health care system. Findings underscore the need for policies to strengthen testing infrastructure, ensure equitable access to guideline-recommended therapies, and enhance provider education. Addressing these gaps is essential for equitable precision oncology and improved outcomes.

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.

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.

In preclinical EML4-ALK models, tumor cell PD-L1 overexpression did not alter alectinib sensitivity, depth, or durability of response in vitro or in vivo High PD-L1 expression is associated with shorter PFS to first-line ALK TKIs without affecting the initial radiographic response. Preclinical findings suggest that PD-L1-intrinsic tumor cell signaling does not directly impair ALK TKI efficacy, implicating tumor microenvironment-mediated mechanisms in reduced response durability.

Oncologists should consider broad next-generation sequencing, including fusion detection, for patients with KRAS-wildtype PDAC. When an ALK fusion is identified, ALK inhibitor therapy can yield durable disease control.

P1/2, N=1000, Recruiting, Oslo University Hospital HF | N=6000 --> 1000

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.

Dynamic monitoring via ctDNA liquid biopsy and genomic profiling guides precision treatment. This review summarizes alectinib's value, resistance mechanisms, and tailored strategies to optimize care for ALK-positive NSCLC.