Phase I trial of fruquintinib in patients with advanced solid tumors: Results of the dose escalation phase

Abstract Background Fruquintinib is a potent, highly selective, novel vascular endothelial growth factor receptor (VEGFR) -1, -2, and -3 tyrosine kinase inhibitor. In the phase 3 FRESCO trial1 that led to the drug’s approval in China, fruquintinib improved the median overall survival in patients with metastatic colorectal cancer (mCRC) in a third-line or later setting when compared to placebo (9.3 vs 6.6 months); hazard ratio was 0.65 (95% CI, 0.51-0.83; P  Methods This is a phase 1, open-label, dose escalation/dose expansion study conducted in the United States. The primary objectives are to evaluate the safety and tolerability in patients (pts) with advanced solid tumors and to determine the recommended phase 2 dose (RP2D). A secondary objective is to evaluate anticancer activity. The dose cohorts, 3 mg and 5 mg qd, were each on a 3 weeks on, 1 week off (3/1) schedule. Results There were 7 pts (6 evaluable) in each dose cohort (14 total). One patient in the 3 mg cohort had a dose-limiting toxicity (DLT) of grade 4 hypertension, and no patient in the 5 mg cohort had a DLT. The RP2D was determined to be 5 mg qd (3/1). Two other serious adverse events, colon obstruction and left breast cellulitis, were reported; neither was suspected to be drug-related. All 14 pts reported AEs; the most common were vomiting (57%), nausea (50%), constipation (50%, proteinuria (50%), hypertension (50%), dysphonia (43%), anorexia (36%), and dyspepsia (36%). Of the 10 pts evaluable for best objective response, 3 had a partial response, 5 had stable disease, and 1 had disease progression. Objective response rate was 3/14 (21.4%) and disease control rate was 9/14 (64.3%). Mean duration on study drug was 5.3 months. Conclusions Fruquintinib is generally well-tolerated in heavily pretreated patients, with the safety profile consistent with that of other anti-angiogenic tyrosine kinase inhibitors. The RP2D in US pts is 5 mg qd (3/1), which is also the approved dose in China. Preliminary anticancer activity was evident in these pts with advanced solid tumors. The dose expansion phase of the study is ongoing. Further investigation of fruquintinib in pts with mCRC is planned. 1 JAMA 2018; 319:2486. Clinical trial identification NCT03251378. Editorial acknowledgement Hoang-Lan Nguyen, PhD, Hutchison MediPharma (US), Inc. Legal entity responsible for the study Hutchison MediPharma, Limited. Funding Hutchison MediPharma, Limited. Disclosure A. Wang-Gillam: Advisory / Consultancy: Tyme; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bristol-Myer Squibb; Advisory / Consultancy: Jacobio. H. Park: Research grant / Funding (institution): Ambrx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Array Biopharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daichi Pharmaceutical; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Gilead; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Hoffman-LaRoche; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Millenium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Vertex Pharmaceuticals; Research grant / Funding (institution): Xencor. F. Songhua: Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. N.P. Sauter: Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. M. Kania: Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. All other authors have declared no conflicts of interest.