Unecritinib

This phase I/II trial characterized the tolerability, safety, and antitumor activities of unecritinib, a novel derivative of crizotinib and a multi-tyrosine kinase inhibitor targeting ROS1, ALK, and c-MET, in advanced tumors and ROS1 inhibitor-naive advanced or metastatic non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements. Eligible patients received unecritinib 100, 200, and 300 mg QD, and 200, 250, 300, and 350 mg BID in a 3 + 3 design during dose escalation and 300 and 350 mg BID during expansion. Phase II trial patients received unecritinib 300 mg BID in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) per independent review committee (IRC). Key secondary endpoints included intracranial ORR and safety. The ORR of 36 efficacy evaluable patients in the phase I trial was 63.9% (95% CI 46.2%, 79.2%). In the phase II trial, 111 eligible patients in the main study cohort received unecritinib. The ORR per IRC was 80.2% (95% CI 71.5%, 87.1%) and the median progression-free survival (PFS) per IRC was 16.5 months (95% CI 10.2, 27.0). Additionally, 46.9% of the patients who received recommended phase II dose of 300 mg BID experienced grade 3 or higher treatment-related adverse events. Treatment-related ocular disorders and neurotoxicity occurred in 28.1% and 34.4% of patients, respectively, but none was grade 3 or higher. Unecritinib is efficacious and safe for ROS1 inhibitor-naive patients with ROS1-positive advanced NSCLC, particularly patients with brain metastases at baseline, strongly supporting that unecritinib should become one of the standards of care for ROS1-positive NSCLC.ClinicalTrials.gov identifier: NCT03019276 and NCT03972189.

Background: TQ-B3101 is a novel kinase inhibitor currently in development for the treatment of advanced malignant solid tumor and relapsed or refractory ALK-positive anaplastic large cell lymphoma.Methods: A population pharmacokinetic model was developed using data collected from a Phase 1 study and a Phase 2 study to characterize the pharmacokinetic of TQ-B3101 and its active metabolite (TQ-B3101M). The final model was used to optimize dosing of TQ-B3101 for pediatric patients (6-<18 years) with anaplastic large cell lymphoma.Results: The pharmacokinetic of TQ-B3101 and TQ-B3101M was adequately described by a 1-compartment model with first-order absorption and elimination for parent drug coupled with a 2-compartment model with time-dependent clearance for the metabolite. The clearance of TQ-B3101M decreased over time with a maximum fractional reduction of 0.41. The estimated apparent clearance and apparent volume of distribution of TQ-B3101 were 2850 L/h and 4200 L, respectively. The elimination half-life of TQ-B3101 was 1.0 h. The distribution and elimination half-lives of TQ-B3101M at steady state were 4.9 and 39.4 h, respectively. The projected exposure of TQ-B3101M in virtual pediatric population following the body surface area tiered dosing regimen was similar to that in children pediatric patients after the recommended pediatric dose of crizotinib (280 mg/m2 twice daily), an analog of TQ-B3101M.Conclusion: A population pharmacokinetic model was developed to provide optimal dose of regimen for further development of TQ-B3101 in pediatric patients with anaplastic large cell lymphoma.