Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.

P3, N=68, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Dec 2026 --> Jun 2030

Entrectinib was administered, and an excellent response was observed. This case emphasizes the relevance of performing NGS in cases with unusual clinicopathological findings to identify potential treatment options. Importantly, the morphology deviated from the classic fibrosarcoma-like appearance described in most adult NTRK3-fused neoplasms and broadens the morphological spectrum in which these neoplasms should be considered.

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

Targeted therapies with TRK inhibitors (TRKi), including larotrectinib and entrectinib, have shown promising efficacy with rapid and durable responses for patients with LGGs and HGGs. Overall, TRKi represent a significant advance for treating NTRK fusion-positive CNS tumors, especially in pediatric populations, offering new hope for patients with limited treatment options. Further studies are required to optimize their use and address unresolved challenges.

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

For patients prioritizing the maximization of QALYs and with the necessary financial resources, first-line taletrectinib prior to chemotherapy may be a preferred option. Conversely, for those with limited financial capacity or in contexts prioritizing cost-containment, second-line taletrectinib after crizotinib could be more suitable.

P1, N=13, Active, not recruiting, OHSU Knight Cancer Institute | Trial completion date: Jun 2026 --> Dec 2026

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.