These studies demonstrate that NTRK wild-type receptors are important drivers of brain metastatic colonization and progression in different subtypes of lung cancer, independent of their driver alterations. Thus, they provide rationale to expand the use of FDA-approved NTRK inhibitors with brain penetrance for the prevention of CNS metastases.

P3, N=71, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Sep 2033 --> Jun 2030 | Trial primary completion date: Aug 2032 --> Dec 2026

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

After adjuvant chemotherapy, maintenance larotrectinib was initiated based on proven TRK inhibitor efficacy in metastatic NTRK-fusion tumors and emerging evidence for targeted therapy benefit in driver-positive early stage lung adenocarcinoma. Our findings demonstrate the value of molecular pathology in the diagnostic journey of pulmonary malignancies, guiding rare fusion detection and supporting therapeutic decisions based on rare fusions in early stage disease.

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.

P=N/A, N=20, Completed, Grupo Espanol de Tumores Neuroendocrinos | Recruiting --> Completed

NCI-MATCH subprotocol Z1E demonstrates that larotrectinib offers clinically significant benefit with marked ORR across NTRK fusion-positive tumors with no clinically significant toxicities. These findings support the rationale for the US Food and Drug Administration's tissue-agnostic approval of larotrectinib for NTRK fusion-positive tumors. Our findings demonstrate the necessity of including NTRK1, NTRK2, and NTRK3 within comprehensive molecular assays of cancer to navigate patients to an easily administered and highly effective therapy.

In ROS1-positive NSCLC patients, taletrectinib has been effective and well tolerated, as evidenced by early clinical trials, including those that are resistant to crizotinib. It demonstrates potential for disease control, as it has excellent oral absorption and is able to combat the spread of neurological disorders. Taletrectinib is emerging as a promising candidate for enhancing the outcomes of patients with ROS1-positive lung cancer as the treatment landscape for this disease continues to evolve.

The best TRK inhibitor 5c had IC50 values of 0.75 and 0.96 nM against TRKAG595R and TRKAG667C, showing better potency than drugs larotrectinib (approximately 87- and 46-fold improvement) and selitrectinib (approximately 10- and 13-fold improvement). More importantly, 5c demonstrated favorable in vivo pharmacokinetic properties and antitumor efficacy (tumor growth inhibition (TGI) of 91% at 30 mg/kg and 115% at 60 mg/kg with 4 of 6 partial regression) in a BaF3-TMP3-TRKAG667C xenograft mouse model, which is greatly superior to that of selitrectinib (TGI of 2% at 30 mg/kg). Compound 5c exhibits significant potential to overcome clinical acquired multiple resistance to TRK inhibitors.

P2, N=173, Active, not recruiting, Nuvation Bio Inc. | Trial completion date: Dec 2025 --> Jun 2027

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