Lorbrena (lorlatinib)

P=N/A, N=200, Not yet recruiting, Pfizer

P2, N=30, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Aug 2026 --> Apr 2026

P=N/A, N=50, Not yet recruiting, Pfizer

Probabilistic sensitivity analysis showed an almost 98,40% probability of cost-effectiveness at Italian willingness-to-pay thresholds. From both NHS and societal perspectives, lorlatinib represents a cost-saving and clinically superior first-line treatment option compared with alectinib for patients with ALK-positive advanced NSCLC in Italy.

We report the case of a 50-year-old woman with advanced ALK-positive NSCLC who experienced rapid tumor regression after 1 month of treatment with ensartinib, complicated by mild bilateral interstitial pneumonitis...Following progression on second-line chemotherapy, she was rechallenged with lorlatinib, which induced severe cutaneous toxicity that responded to corticosteroids...These findings highlight the need for heightened vigilance, multidisciplinary management, and the development of predictive biomarkers for TKI-associated toxicities. Future prospective studies are essential to guide safe rechallenge strategies and personalize toxicity monitoring in ALK-positive NSCLC.

Deulorlatinib demonstrated encouraging anti-tumor activity in patients with advanced ALK-positive NSCLC after failure of second-generation ALK inhibitors, including those with the G1202R mutation. Given its favorable safety profile, deulorlatinib represents a promising new option for this population.

Although FDA (Food and Drug Administration) approved inhibitors such as crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib have improved clinical outcomes, their efficacy is often challenged by resistance mechanisms, including secondary kinase domain mutations and activation of bypass pathways. Binding free energies and per-residue contributions were computed using MMGBSA. Boltz-2 machine learning platform to predict KD values and the top three hits were validated using PCA and free energy landscape.

P2, N=10, Terminated, National Cancer Institute (NCI) | Trial completion date: Mar 2027 --> Mar 2026 | Active, not recruiting --> Terminated; Inadequate accrual rate

However, the observed outcomes should be interpreted within the context of patient selection. The enrichment for prior responders limits the generalizability to unselected post-TKI populations, including those with primary resistance.

Recent innovations include antibody-drug conjugates (ADCs) such as TROP-2-targeting agents and HER3-DXd, which show promising efficacy in refractory disease. Next-generation tyrosine kinase inhibitors (TKIs), including lorlatinib, tepotinib, and glecirasib, have shown improved outcomes for patients with oncogene-driven NSCLC...Future efforts must prioritize overcoming resistance through combination strategies and ADCs, validating biomarkers using AI and ctDNA, streamlining CGP implementation, and addressing the unique needs of special populations. Bridging these biological and systemic challenges is essential for improving survival outcomes and ensuring equitable benefits for all NSCLC patients.

Psychiatric manifestations were most pronounced: olfactory hallucinations (0.14%, ROR: 91.44, PRR: 91.31), auditory hallucinations (1.3%, ROR: 22.0, PRR: 21.7), and acute psychosis (0.2%, ROR: 22.12, PRR: 22.07).ConclusionsLorlatinib exhibits a multidimensional neuropsychiatric profile with rare but highly specific events. Proactive monitoring of cognitive, mood, speech, and psychotic domains is recommended in clinical practice.

Finally, nutritional management is discussed, as is the role of adapted physical activity. In conclusion, this article highlights the importance of proactive monitoring and management of adverse cardiovascular events in patients treated with lorlatinib.