Lorbrena (lorlatinib)

Drug likeness analysis results revealed that chalcone derivatives CD5, CD8, and CD9 and reference standard drugs lorlatinib and topotecan showed no violations against all five drug likeness rules. Current study overcomes these challenges by employing green nanocatalysts (Al(OH)₃ and Ti/Fe@Al(OH)₃) for eco-friendly, high-yield synthesis and computational screening to design potent, multi-target lung cancer therapeutic chalcone compounds. The online version contains supplementary material available at 10.1007/s40203-026-00599-3.

After about 20 years of exciting improvements in treatment efficacy outcomes of advanced epidermal growth factor receptor (EGFR) mutant and anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC), also combined with a progressively better safety profile, from chemotherapy to new generation tyrosine kinase inhibitors (TKIs) (osimertinib, alectinib, brigatinib), the recent MARIPOSA and CROWN trials have changed this trend. The story would be easy and totally positive if these two innovative, amazing treatments were not associated with new peculiar features in safety profiles that must be discussed with patients, because they potentially affect their quality of life. When treating these patient populations, the peculiar safety profiles of amivantamab plu lazertinib and lorlatinib require a well-structured shared decision making, "where and when", both the high probability of a longer survival and the risk of worse quality of life must be well announced and explained to our patients before the shared final treatment choice.

A number of BM treatment-effective drugs have shown BM-preventive effects: In NSCLC, the EGFR-inhibitor osimertinib and ALK inhibitors like alectinib, brigatinib and lorlatinib lower the incidence of BM. In HER2-positive breast cancer, tucatinib and trastuzumab deruxtecan have preventive activity in patients without BM at baseline...Preventing BM requires a personalized, multidisciplinary approach, integrating tumor biology, individual risk assessment, and therapeutic advances. Secondary prevention in patients with BM is as vital as tertiary prevention, warranting prospective validation of preclinical concepts.

We report a 19-year-old male with ALK-rearranged, radioiodine-refractory PDTC who started systemic therapy with ceritinib, achieving a complete metabolic response. Treatment with the third-generation ALK inhibitor led to a deep and durable complete metabolic response, sustained for more than four years, including persistence of remission after treatment discontinuation, with minimal toxicity. This case highlights the potential role of sequential ALK inhibition to overcome acquired resistance in ALK-rearranged TC and underscores the importance of comprehensive molecular profiling to guide personalized treatment strategies in rare aggressive thyroid cancers.

This TPR-ALK fusion-driven IMT demonstrates that disease progression after an initial response to crizotinib can be effectively overcome with lorlatinib, resulting in rapid and durable clinical benefit. These findings add to emerging evidence supporting next-generation ALK inhibitors as effective treatment options for ALK-rearranged IMT after crizotinib failure.

Although PCNSTL is exceptionally rare, we identified distinct neuroimaging patterns showing highly aggressive features on MRI but hypometabolic PET imaging, which may assist in identifying future PCNSTL cases. Despite the limited cohort size, our findings suggest that MTX-based chemotherapy with ASCT may translate into favorable outcome. We report on an ALK1-positive PCNSTL case with sustained complete remission after targeted therapy with lorlatinib.

P1, N=15, Recruiting, Nationwide Children's Hospital | Active, not recruiting --> Recruiting

Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, was started which showed significant disease regression at 18-month follow-up. This report highlights the favorable response to targeted ALK inhibition in central nervous system ALK-positive histiocytosis.

After two years of therapy, the child has sustained partial tumor regression on MRI and no new neurological symptoms. We conclude that comprehensive multi-omics analyses are required for correct molecular diagnosis in childhood CNS tumors and can radically impact patient outcome by identifying molecular targets for precision treatment.

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026

Among patients with advanced non-small cell lung cancer (NSCLC), ALK-positive disease accounts for roughly 5% of cases We conducted a systematic search of PubMed, Embase, Cochrane, Web of Science, and ClinicalTrials.gov for randomized controlled trials comparing first-line ALK inhibitors with crizotinib or platinum-based chemotherapy and reporting intracranial outcomes. The safety profile was comparable between second- and third-generation ALK TKIs, with alectinib reporting fewer grade ≥3 adverse events (RR 0.72, 95% CI 0.58-0.88). These findings support the use of second- and third-generation ALK TKIs, particularly lorlatinib, as preferred first-line options for patients presenting with brain metastases at diagnosis.