Introduction
Approved TKIs with Anti-VEGFR Activity
Selectivity and Potency of VEGFR Inhibitors
Agent | Study design | Activity | Grade ≥3 adverse events (active treatment arms) |
---|---|---|---|
Axitinib | Phase 2, single-arm, 52 patients with clear cell mRCC [25•] | ORR 44%; TTP 15.7 months; OS 29.9 months | Hypertension (8%), diarrhea (5%), fatigue (4%), anorexia (1%), limb pain (2%), arthralgia (1%), myalgia (1%), stomatitis (1%) |
Phase 2, single-arm, 62 patients with sorafenib-refractory clear cell mRCC [26•] | ORR 23%; PFS 7.4 months; OS 13.6 months | Hand-foot syndrome (16%), fatigue (16%), hypertension (16%), dyspnea (15%), diarrhea (15%), dehydration (8%), hypotension (7%) | |
Tivozanib | Phase 2, randomized discontinuation study of 272 patients with locally advanced or mRCC (all histologies) [20•] | ORR 27%; PFS 11.8 months | Hypertension (9%), asthenia (2%) |
Randomized, placebo-controlled phase (n = 111) [21•] | Tivozanib: PFS 12.1 months | ||
Placebo: PFS 6.3 months | |||
Cediranib | Phase 2, randomized, placebo-controlled; 71 patients with advanced RCC [37] | Cediranib: tumor size −20%; ORR 34%; PFS 12.1 months | Fatigue (19%), hypertension (19%), diarrhea (13%) |
Placebo: tumor size +19%; PFS 2.7 months |
Second-Generation VEGFR TKIs
Tivozanib
Axitinib
Cediranib
Other TKIs in Development with VEGFR Affinity
Conclusions
All grades (grades 3–4) | Sunitinib [62] (n = 375) | Sorafenib [63] (n = 451) | Pazopanib [15••] (n = 290) | Axitinib [25•] (n = 52) | Tivozanib [20•] (n = 272) |
---|---|---|---|---|---|
Adverse events | |||||
Mucositis/stomatitis | 43% (10%) | NA | NA | 9% (1%) | 4% (<1%) |
Hand-foot syndrome | 21% (5%) | 30% (6%) | NA | NA | 4% (<1%) |
Rash/desquamation | 27% (1%) | 40% (1%) | NA | 6% (0%) | 6% (1%) |
Fatigue | 58% (9%) | 37% (6%) | 19% (2%) | 27% (4%) | 8% (2%) |
Diarrhea | 58% (6%) | 43% (2%) | 52% (4%) | 31% (5%) | 12% (2%) |
Dose reduction | 32% | 13% | NA | 29% | 10% |
Dose interruption | 38% | 21% | 14% | NA | 4% |