Rozlytrek (entrectinib)

Tumors harboring these fusions respond dramatically to TRK inhibitors (e.g., larotrectinib, entrectinib, and repotrectinib), which selectively target the constitutively active fusion protein. Conclusively, this first report of three novel NTRK2 fusion transcript variants co-occurrence in an MTC patient expands the known spectrum of translocation partners in NTRK2 rearrangements. Prospective validation of their impact on TRK-targeted therapy efficacy and disease prognosis requires long-term follow-up.

P3, N=220, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

Inhibitors such as larotrectinib, entrectinib and repotrectinib are used when cancer cells harbor NTRK1, NTRK2 or NTRK3 fusion...Short courses of prednisone for the former and dexamethasone for the latter were initiated after failure of standard analgesia... For patients experiencing TRK inhibitor withdrawal pain, especially when tapering down the inhibitor is not an available strategy, a short course of corticosteroids can provide lasting relief. These cases emphasize the importance of better understanding the mechanism underlying the relationship between NRTK, NGF and nociception.

However, the clinically approved TRK inhibitors, including Larotrectinib and Entrectinib, are limited by insufficient efficacy and resistance due to kinase mutations. In the Km-12 xenograft model, DZX19 significantly suppressed tumor growth. These results indicate that DZX19 serves as a novel TRK-targeting lead compound for further investigation.

Multiple ROS1 tyrosine kinase inhibitors (TKIs)-from crizotinib to newer agents such as entrectinib, lorlatinib, repotrectinib, taletrectinib, and the highly selective zidesamtinib-have improved systemic and intracranial outcomes, although resistance remains inevitable and biologically diverse, involving both on-target kinase mutations and off-target mechanisms...Pemetrexed-based chemotherapy remains an effective option, whereas immune checkpoint inhibitors provide limited benefit...Looking ahead, priorities include optimizing sequencing strategies, evaluating perioperative targeted approaches, and incorporating genomic monitoring to anticipate resistance. These advances are reshaping the natural history of ROS1-rearranged NSCLC and supporting a more durable, precision-driven treatment paradigm.

P3, N=71, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

Current first-generation tyrosine kinase inhibitors (TKIs) such as crizotinib and entrectinib provide meaningful benefit but are limited by poor central nervous system (CNS) penetration and the development of resistance mutations, particularly G2032R. While its approval represents a significant advance for ROS1+ NSCLC, challenges remain, including resistance mechanisms such as L2086F, limited global access, and the absence of phase III confirmatory trials. Ongoing research into sequencing strategies, resistance profiling, and novel combination regimens will be essential to optimize patient outcomes.

This case highlights the potential of ROS1 as a therapeutic target in SCC, which has historically been considered rare, as ROS1-rearranged SCC accounts for only 0.2% according to the Foundation Medicine database. This underscores the importance of incorporating NGS into clinical practice, particularly for never smokers/light smokers or patients with advanced SCC of the lungs, to identify targetable mutations and guide personalized therapy.

P2, N=534, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2025 --> May 2026 | Trial primary completion date: Dec 2025 --> May 2026

P3, N=100, Recruiting, Hoffmann-La Roche | N=60 --> 100

Larotrectinib was used in 142 patients, demonstrating an 83.80% response rate, with low mortality (2.82%) and recurrence (2.11%) rates. Entrectinib had a lower response rate of 63.64%. We confirm the rarity of NTRK1-3 fusions in sarcomas. TRK inhibitors show high efficacy in sarcomas, emphasizing the necessity of genomic testing in all cases.Protocol registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024563594.

This case highlights the essential role of DNA methylation profiling in resolving diagnostic ambiguity and guiding targeted treatment in CNS tumors. It further supports the potential efficacy of entrectinib in NTRK fusion-positive glioneuronal tumors.