Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial.

IMPORTANCE: Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC). OBJECTIVE: To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor. DESIGN, SETTING, AND PARTICIPANTS: This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC. INTERVENTIONS: Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily. MAIN OUTCOMES AND MEASURES: The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC. RESULTS: A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P < .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P < .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02767804.

Phase I, First-in-Human, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Vorolanib in Patients with Advanced Solid Tumors.

LESSONS LEARNED: Pharmacokinetic results underscore that the vorolanib (X-82) study design was successful without the need for further dose escalation beyond 400 mg once daily (q.d.).Therefore, the recommended dose of X-82 as a single agent in patients with advanced cancer is 400 mg q.d. BACKGROUND: Vorolanib (X-82) is a novel, oral, multikinase vascular endothelial growth factor (VEGF) receptor/platelet-derived growth factor (PDGF) receptor inhibitor that was developed on the same chemical scaffold as sunitinib, but designed to improve upon the safety profile while maintaining the efficacy of sunitinib. By targeting the VEGF and PDGF receptors, X-82 was expected to disrupt tumor angiogenesis and be active in a broad spectrum of solid tumors. Therefore, we determined the maximum tolerated dose (MTD) and characterized the preliminary pharmacokinetics and clinical tumor response of X-82 as a single agent in patients with advanced solid tumors. METHODS: Adult patients with advanced solid tumors received X-82 as tablets or capsules (once daily [q.d.] or b.i.d.) every 4 weeks. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. RESULTS: Fifty-two patients received study treatment in 17 cohorts. X-82 capsule dosing was as follows: cohorts 1-6 (20-400 mg q.d.) and cohorts 7-8 (140-200 mg b.i.d.). Patients in cohorts 9-17 received 50-800 mg q.d. tablet dosing. The median time on treatment was 58 days. X-82 blood pharmacokinetics appeared dose-independent with a t 1/2 of 5.13 hours and 6.48 hours for capsule and tablet formulations, respectively. No apparent accumulation was observed after 21 days of daily dosing. CONCLUSION: X-82 had a safety profile consistent with its mechanism of action. It has a short half-life and was well tolerated by most patients. Study enrollment ended prior to the determination of the MTD because of the apparent saturation of absorption at 400-800 mg. The recommended dose of X-82 as a single agent in patients with advanced cancer is 400 mg q.d.

Pharmacodynamic study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel.

BACKGROUND: A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82. METHODS: Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1-14, a treatment break on days 15-20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200 mg) or high-dose X-82 (400 mg) arm. Patients were scheduled to undergo four 3'-deoxy-3'-18F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models. RESULTS: 14 patients were enrolled and treated with median 3.5 cycles (range 0-12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUVmax decreased by - 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUVmax decreased - 44% (p = 0.03). CONCLUSIONS: The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy.