**4. New agents in clinical development**

The results with early TKIs in metastatic RCC has led to a number of small molecules multitargeted agents being investigated in phase II and III studies. [68] These include tivozanib which targets VEGFR -1, -2, and -3, PDGFR and c-kit, dovitinib (VEGFR -1, -2, -3 and PDGFRbeta) and regorafenib. [69]

### **4.1. Tivozanib**

In a phase II study, two hundred and seventy two patients with advanced RCC treated who had not received prior VEGF targeted therapy received tivozanib. [70] Patients took tivozanib 1.5 mg daily for 16 weeks, and according to response were then stratified into stopping or continuing tivozanib. Those with stable disease were randomised between tivozanib and placebo (and this group could re-start tivozanib if they developed progressive disease, or completed the double blind phase). Overall, by week 16, 84% of patients demonstrated PR or SD, ORR was 30%, disease control rate (DCR) was 85% and median PFS 11.7 months. Best results were achieved in patients with clear-cell histology who had undergone a nephrectomy. These patients achieved an ORR of 36%, DCR of 88% and median PFS of 14.8 months. Com‐ monest adverse effects included hypertension (45%) which was grade 3-4 in 12%, and dys‐ phonia (22%). [70]

Twenty-eight patients with advanced RCC and clear-cell variant, who had failed up to one prior VEGF-targeted therapy, were treated in a phase Ib open-label study of tivozanib combined with temsirolimus. [71] Tivozanib was administered orally daily for 3 weeks on and 1 week off. Intravenous temsirolimus was given once weekly. A standard 3+3 dose escalation design was used at four levels from 0.5 mg to 1.5 mg per day and 15 to 25 mg per week of tivozanib and temsirolimus, respectively. Twenty-eight patients (26 male) of median age 62 years and Karnofsky Performance Status from 100 to 80 were participated in the study. Median duration of treatment was 21.1 weeks. PR was seen in 28%, SD in 64% and DCR (PR and SD > 24 weeks) in 48% of the treated population. Treatment-related adverse events seen in ≥ 10% of patients were: fatigue, decreased appetite, stomatitis, thrombocytopenia, diarrhea, nausea, constipation and dyspnea. There were no grade 4 events, and no dose limiting toxicities. [71]

Preliminary results of a phase III trial comparing tivozanib to sorafenib in stage IV RCC as first line treatment were made available at the ASCO 2012 annual meeting. [72] Tivozanib in comparison with sorefenib resulted in an improvement in PFS (HR 0.80; median 12 vs. 10 months respectively; p=0.04) and higher ORR (33 vs. 23%). Patients on tivozanib experienced a higher incidence of grade 3 or 4 hypertension (26 vs. 17%), higher rates of dysphonia (21 vs. 5 %) and back pain (14 vs. 7%). However, tivozanib had less diarrhea (24 vs. 38%), hand and foot syndrome (15 vs. 71%) and alopecia (2 vs. 21%). [72]

### **4.2. Dovitinib**

was found with everolimus over placebo. [67] However there was no statistically significant difference for median OS (14.8 months vs. 14.4 months) as majority (80%) of patients in the placebo plus best supportive arm were allowed to cross over after the unbinding at the second interim analysis. RECORD-1 trial proved the efficacy of mTOR inhibitors following VGEF therapy and as such received FDA approval for patients who have progressed following

The results with early TKIs in metastatic RCC has led to a number of small molecules multitargeted agents being investigated in phase II and III studies. [68] These include tivozanib which targets VEGFR -1, -2, and -3, PDGFR and c-kit, dovitinib (VEGFR -1, -2, -3 and PDGFR-

In a phase II study, two hundred and seventy two patients with advanced RCC treated who had not received prior VEGF targeted therapy received tivozanib. [70] Patients took tivozanib 1.5 mg daily for 16 weeks, and according to response were then stratified into stopping or continuing tivozanib. Those with stable disease were randomised between tivozanib and placebo (and this group could re-start tivozanib if they developed progressive disease, or completed the double blind phase). Overall, by week 16, 84% of patients demonstrated PR or SD, ORR was 30%, disease control rate (DCR) was 85% and median PFS 11.7 months. Best results were achieved in patients with clear-cell histology who had undergone a nephrectomy. These patients achieved an ORR of 36%, DCR of 88% and median PFS of 14.8 months. Com‐ monest adverse effects included hypertension (45%) which was grade 3-4 in 12%, and dys‐

Twenty-eight patients with advanced RCC and clear-cell variant, who had failed up to one prior VEGF-targeted therapy, were treated in a phase Ib open-label study of tivozanib combined with temsirolimus. [71] Tivozanib was administered orally daily for 3 weeks on and 1 week off. Intravenous temsirolimus was given once weekly. A standard 3+3 dose escalation design was used at four levels from 0.5 mg to 1.5 mg per day and 15 to 25 mg per week of tivozanib and temsirolimus, respectively. Twenty-eight patients (26 male) of median age 62 years and Karnofsky Performance Status from 100 to 80 were participated in the study. Median duration of treatment was 21.1 weeks. PR was seen in 28%, SD in 64% and DCR (PR and SD > 24 weeks) in 48% of the treated population. Treatment-related adverse events seen in ≥ 10% of patients were: fatigue, decreased appetite, stomatitis, thrombocytopenia, diarrhea, nausea, constipation and dyspnea. There were no grade 4 events, and no dose limiting toxicities. [71] Preliminary results of a phase III trial comparing tivozanib to sorafenib in stage IV RCC as first line treatment were made available at the ASCO 2012 annual meeting. [72] Tivozanib in comparison with sorefenib resulted in an improvement in PFS (HR 0.80; median 12 vs. 10 months respectively; p=0.04) and higher ORR (33 vs. 23%). Patients on tivozanib experienced

sunitinib / sorafenib. [67]

166 Renal Tumor

beta) and regorafenib. [69]

**4.1. Tivozanib**

phonia (22%). [70]

**4. New agents in clinical development**

The highest tolerated dose of dovitinib is 500 mg daily on a 5-day on/ 2 day off schedule in 28 day cycles. A phase II study of dovitinib in clear-cell metastatic RCC and in patients previously treated with a VEGFR inhibitor and/or mTOR inhibitor was reported in 2011. [73] In 51 patients overall responses were PR in 8%, and SD ≥ 4 months in 37%. Median PFS and OS were 6.1 and 16 months respectively. The most common adverse events were nausea (73%; grade 3:9%), diarrhea (64%; grade 3:9%), vomiting (56%; grade 3: 5%), decreased appetite (48%; grade 3:7%), asthenia (36%; grade 3:12%), and fatigue (36%; grade 3: 10%). An on-going phase 3 trials is comparing dovitinib with sorafenib in patients who have had one previous VEGF- and mTORtargeted therapy.

### **4.3. Regorafenib**

A phase II of regorafenib in previously untreated metastatic or unresectable RCC patients has recently been published. [69]. Forty-eight of 49 patients enrolled were available for assessment of tumour response. Nineteen of these had an objective response (partial); (39.6%, 90% CI 27.7-52.5). Side-effects were noted in 98% of patients, and 35% experienced serious drugrelated events. Two patients had grade 4 adverse events related to treatment including two cardiac ischaemia or infraction, one hypomagnesaemia, and one chest/thoracic pain. The authors advise close monitoring. [69]
