Georgia Wilson, Carol Fraser-Browne, George Dranitsaris, Paul Oei, Peter C.C. Fong, Kerin Thompson, Fritha J. Hanning, Nicola Jane Mitchell, Steven Duffey, Jonathan Zwi, Reuben James Broom, and Mark J. McKeage
443 Background: Dovitinib is an anti-VEGFR tyrosine kinase inhibitor, differentiated by its inhibition of FGFR-1,-2,-3 and PDGFRβ. We evaluated its activity as 1st-line therapy in patients with metastatic clear-cell renal cell carcinoma (mCCRCC) in correlation with status of genes relevant to its mechanism of action. Methods: 31 treatment-naïve patients with mCCRCC were enrolled in this single-arm, single-site, phase II study (ACTRN12612000140853) and received dovitinib at 500mg 5 days on/2 days off until progression. Patients were offered an optional post-treatment biopsy to elucidate resistance mechanisms. The primary endpoint was progression free survival (PFS) using RECIST 1.1. Secondary endpoints include response rate (RR) and efficacy by FGFR gene status (FISH and DNA sequence using Sequenom OncoCarta panel). Results: Accrual occurred over 15 months from March 2012. Median patient age was 64 years and 72% were male. ECOG performance status was 0 in 45% and 1 in 55%. Heng prognostic group was favorable-risk in 38%, intermediate-risk in 52% and poor-risk in 10%. 38% of patients had bone metastases. Four patients stopped treatment due to toxicity and 1 patient withdrew (investigator decision). Median PFS was 6.2 months (inter quartile range: 3.3 to 8.2). Of 28 evaluable patients, best response was; PR (29%), SD (53%) and PD (18%). All-cause grade 3/4 adverse events (AE’s) occurring in ≥5% of patients were; fatigue (16%), abdominal pain (13%), pancreatitis (10%), gout (7%), diarrhea (7%), bone pain (7%), hypercalcaemia (7%), elevated lipase (7%) and pulmonary embolism (7%). No Grade 5 AE’s occurred. Pre-treatment tumor tissue is available for analysis from primary and metastatic sites from 93% and 54% of patients respectively. To date, 6 patients have donated post-progression tumor tissue. Gene status (FISH) for FGFR-1,-2,-3, PDGFβ and PDGFRβ is available for 20 primary and 17 metastatic specimens. Conclusions: Dovitinib has activity when administered in the 1st-line setting of mCCRCC with a tolerable safety profile at this dosing schedule. Correlation of this activity to relevant gene status in tumor samples from study patients will be presented. Clinical trial information: ACTRN12612000140853.