Efficacy, safety and pharmacokinetics of Unecritinib (TQ-B3101) for patients with ROS1 positive advanced non-small cell lung cancer: a Phase I/II Trial

Abstract

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.

Fig. 1

Pharmacokinetics characteristics. Mean plasma concentration-time curves of unecritinib M (a) after a single oral administration at 100 and 200 mg (linear scale). Mean plasma concentration-time curves of unecritinib M (b) after once daily multiple oral administrations at 100, 200, and 300 mg (linear scale). Mean plasma concentration-time curves of unecritinib M (c) after twice-daily multiple oral administrations at 200, 250, 300, and 350 mg (linear scale). The dotted lines indicate IC₅₀ (0.8 nm [0.4 ng/mL], green) and IC₉₀ (6.2 nm [2.8 ng/mL], black) of unecritinib M for wildtype ROS1

Fig. 2

Treatment responses. Waterfall plots of the best percentage changes for the sum of target lesion diameters after unecritinib treatment are shown for individual patients with the best objective response assessed by the independent review committee (IRC) per RECIST v1.1 as indicated by the color codes. The dotted line indicates a 30% reduction in the target lesion size. Each bar represents one patient in the efficacy-evaluable population in phase I trial (a) and phase II trial (b). Treatment responses in (b) are also color-coded for gene fusion partners CD74-ROS1, non-CD74-ROS1 fusions, and indeterminate. Swimmer plot of duration of treatment duration (months) of individual patients in phase I trial (c). Each bar represents one efficacy evaluable patient who had attained partial response. Deaths are marked in solid cycles. Patients receiving ongoing treatment are marked with an arrow. d The Kaplan–Meier curve for estimated progression-free survival (PFS) in the intention-to-treat population of phase II trial patients treated with unecritinib. Vertical lines on the survival curve indicate censoring of data. NE not evaluable

Fig. 3

The Kaplan–Meier curve for estimated progression-free survival (PFS) in the intention-to-treat population of phase II trial patients treated with unecritinib, patients with (a) and without (b) CD74-ROS1 rearrangements. Vertical lines on the survival curve indicate the censoring of data

Fig. 4

a Forest plot analysis of objective response rates (ORR) per patient subgroups in the main study cohort (n = 111). RTHYN, prior receipt of radiotherapy; SMKYN, prior or current smokers. The Kaplan–Meier curve for estimated PFS in the intention-to-treat population of phase II trial with (b) and without (c) baseline brain metastases who were treated with unecritinib. d The Kaplan Meier curve for estimated intracranial PFS. Vertical lines on the survival curve indicate the censoring of data