Lorbrena (lorlatinib)

Despite the lack of formal evidence for alternative formulations, pharmacokinetic data suggest adequate absorption. Crushed lorlatinib administered through a nasogastric tube represents a practical and effective option for dysphagic patients with ALK-positive NSCLC requiring early target-directed therapy.

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.

The achievement of over 24 months of disease control underscores lorlatinib's potent activity against these complex molecular profiles. Our findings highlight the importance of recognizing and targeting rare ALK fusion variants-even when coexisting with other ALK rearrangements and resistance-associated mutations and expand the therapeutic landscape of precision oncology for advanced NSCLC.

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.

This case supports studying the inclusion of newer ALK inhibitors in upfront therapy for pediatric ALK+ ALCL and supports the use of Lorlatinib to treat CNS relapse of ALK+ ALCL.

P2, N=9, Completed, University of Milano Bicocca | Recruiting --> Completed | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P=N/A, N=24, Recruiting, Centro de Tratamiento e Investigación sobre Cáncer, Luis Carlos Sarmiento Angulo

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.

A 63-year-old female underwent radical resection for stage IA lung adenocarcinoma (ALK-positive) and received adjuvant ensartinib...The patient was subsequently treated with lorlatinib combined with stereotactic radiotherapy...This case highlights that during long-term follow-up of patients with malignancies, a new intracranial lesions may warrant consideration of a second primary cancer (SPC), particularly when the treatment response is not consistent with the expected biology of the original tumor. Timely pathological confirmation and multidisciplinary review may help reduce diagnostic delay and improve treatment selection.

P1, N=102, Not yet recruiting, Chugai Pharmaceutical

With median PFS yet to be reached after 7 years of follow-up in CROWN, lorlatinib continues to show unprecedented long-term benefit in patients with advanced ALK-positive NSCLC. Patients without progression within 24 months on lorlatinib have a low risk of progression or death at year 7 and may continue long-term treatment. Findings suggest that sustained long-term disease control with first-line lorlatinib may enable advanced ALK-positive NSCLC to evolve toward a chronic condition.