Lorbrena (lorlatinib)

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.

P4, N=29, Not yet recruiting, Hunan Cancer Hospital

P=N/A, N=160, Not yet recruiting, Sun Yat-sen University

This multicentre real-world cohort describes longitudinal ROS1 management with evolving treatments. Favourable survival likely reflects reflex molecular testing, access to ROS1i, and high clinical trial enrolment.

After an uneventful 5-day hospitalization without complications, the patient remains disease-free at the 12-month follow-up. This is the first report of neoadjuvant lorlatinib followed by uniportal VATS achieving pCR predicted by CMR in stage IIIB ALK-positive NSCLC, given the limitations of short-term follow-up and a single-case design.

P4, N=80, Not yet recruiting, Qiming Wang

This multinational registry-based analysis highlights evolving global treatment patterns, supports newer TKIs' effectiveness, and identifies clinical and molecular factors associated with treatment duration.

The efficacy of tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, lorlatinib, entrectinib, and repotrectinib was systematically evaluated. Our findings underscore that although G2032R and L2026M mutations reside within the kinase active site, their impact extends far beyond steric hindrance, altering overall kinase domain dynamics. Collectively, these data establish a robust panel of patient-derived ROS1 cell lines that recapitulate clinical resistance patterns and, together with complementary computational modeling, provide a valuable framework to dissect ROS1 tumor biology and support rational design of next-generation inhibitors.

P=N/A, N=35, Completed, Pfizer | Active, not recruiting --> Completed

We report the case of a 61-year-old woman diagnosed with stage IV lung adenocarcinoma with brain metastasis harboring an EGFR exon 19 deletion (p.E746_A750del), who acquired resistance to osimertinib through a ROS1 fusion bypass pathway. The patient achieved a survival of over 6.5 years from initial diagnosis through ongoing adjustments to targeted therapy, including sequential treatment with crizotinib, entrectinib, and lorlatinib...Notably, we observed an interesting phenomenon with both crizotinib and entrectinib: while initial treatment led to intolerable adverse reactions requiring discontinuation, subsequent reintroduction of the same agent was well-tolerated. This case report aims to provide potential treatment strategies for patients with similar complex co-mutations.

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.