TABLE 2.
Kinase Inhibitors: Investigational Agents and Results of Clinical Trials
| Agent | Manufacturer | Targets | ORR (%) | SDR (%) |
PFS/OS (mos) |
References | |
|---|---|---|---|---|---|---|---|
| Axitinib (AG-013736) | Pfizer | VEGF-R1-3, PDGF-Rβ, c-Kit | |||||
| phase 2 advanced (n=30 PTC, 15 FTC, 11 MTC, 2 ATC, 2 other) | DTC=31% MTC=18% ATC=50% |
DTC=42% MTC=27% ATC=0% |
18.1/na | 18 | |||
| AZD6244 (selumetinib) | AstraZeneca | MEK1/2 | |||||
| phase 2 RAI-resistant progressive PTC (n=32) | Overall=3% | Overall=66% | 13.4/na | 19 | |||
| Cediranib (Recentin, AZD2171) | AstraZeneca | VEGF-R1-3, PDGF-Rα/β c-Kit | |||||
| CEP-751 | Cephalon | RET, FLT3, TrkA-C | |||||
| E7080 | Eisai | VEGF-R1-3, PDGF-Rβ, c-Kit, FGF-R, SCF-R | |||||
| phase 1 incl. TC (preliminary)(n=?) | 3 PRs | 28 | |||||
| Gefitinib (Iressa, AZD1839) | AstraZeneca | EGF-R | |||||
| phase 2, advanced, RAI failure (n=11 PTC, 6 FTC, 4 MTC, 5 ATC, 1 HTC) | Overall=0% | Overall=48% | 3.7/ 17.5 | 4 | |||
| Imatinib (Gleevec, STI571) | Novartis | RET, Bcr-abl, c-Kit, PDGF-Rβ | |||||
| phase 2 metastatic MTC (n=5) | MTC=0% | MTC=80% | 5 | ||||
| phase 2 metastatic progressive MTC (n=8) | MTC=0% | MTC=88% | 6/na | 6 | |||
| Lestaurtinib (CEP-701) | Cephalon | RET, FLT3, JAK2, TrkA-C | |||||
| Motesanib (AMG 706) | Amgen/Takeba | VEGF-R1-3, RET, PDGF-Rβ, c-Kit, FLT3, JAK2, TrkA-C | |||||
| phase 1 (n=2 PTC, 1 FTC, 1 MTC, 1 ATC, 1 HTC, 1 F/PTC) | PTC=50% FTC=100% MTC=100% (others=0%) |
HTC=100% FTC=100% others=0% |
7 | ||||
| phase 2 advanced, progressive, RAI-resistant DTC; 57 PTC, 15 FTC, 17 HTC, 4 other | Overall=14% PTC=12% FTC=17% |
DTC=67% | 10/na | 22 | |||
| phase 2 advanced, progressive, RAI-resistant MTC; 91 eval pts | Overall=2% | Overall=81% | 12/na | 23 | |||
| Pazopanib (Votrient, GW786034) | GlaxoSmithKline | VEGF-R1-3, PDGF-Rα/β, c-Kit | |||||
| phase 2 progressive, RAI-resistant DTC, MTC, ATC (n=37 DTC) | Overall=49% FTC=73% PTC=33% HTC=45% |
11.7/na | 24 | ||||
| PLX4032 (RO5185426) | Roche/Plexxikon | BRAF (V600E mut > wt) | |||||
| phase 1 solid tumor; 3 PTC w/BRAF mut (preliminary) | PTC=33% | PTC=67% | 8+ months | 26 | |||
| PP1, PP2 (pyrazolo-pyrimidines) | TKI: Src family kinases (LCK, CSK, p38, p38β2, CK1δ), mutant RET (C634R, C634R/V804G) > RET | ||||||
| RPI-1 | Cell Therapeutics | RET, c-Met | |||||
| Semaxanib (SU5416) | Pharmacia / SUGEN | VEGF-R2, c-Kit, c-Kit mutants (D814Y, D814V, D818Y) | |||||
| Sorafenib (Nexavar, BAY 43-9006) | Bayer/Onyx | VEGF-R2-3, RET, PDGF-Rβ, BRAF (wt and V599E mut), c-Kit, FGF-R1, p38 | |||||
| phase 2 metastatic, RAI-resistant (n=41 PTC, 11 FTC/HTC, 4 ATC) | PTC=15% FTC/HTC=0% ATC=0% |
PTC=61% FTC=82% ATC=25% |
PTC=10-16/na FTC=4.5/na | 27, 28, 29 | |||
| phase 2 metastatic or advanced MTC (n=15 sporadic, 5 hereditary) | MTC(sporadic)=6% MTC(hereditary)=20% |
sporadic=88% hereditary=80% |
17.9/na | 30 | |||
| phase 2 progressive post-RAI, metastatic DTC (n=13 PTC, 15 FTC, 4 other) | Overall=25% PTC=22% FTC=49% other=67% |
Overall=34% PTC=67% FTC=36% other=0% |
14.5/na | ||||
| pilot metastatic MTC (n=5) | MTC=40% | MTC=60% | 31 | ||||
| phase 2 ATC post-chemoTx (n=15) | ATC=13% | ATC=27% | 5.1/na | 27, 32 | |||
| phase 2 metastatic, progressive, RAI-resistant (n=18 PTC, 9 FTC/HTC, 1 MTC, 2 ATC) | Overall=23% PTC=22% FTC=33% MTC=0% ATC=0% |
Overall=53% PTC=61% FTC=44% MTC=100% ATC=0% |
17.9/na | ||||
| phase 1 + tipifarnib in solid tumors incl. MTC (n=6) (preliminary) | Overall=50% | ? | 33, 34 | ||||
| phase 2 + tipifarnib; advanced TC, metastatic DTC (n=22 DTC, 13 MTC) | DTC=4.5% MTC=38% |
DTC=36% MTC=31% |
18/na | 33, 34 | |||
| Sunitinib (Sutent, SU011248) | Pfizer | VEGF-R1-3, PDGF-R, c-Kit, RET, FLT3, CSF-1R | |||||
| phase 2 progressive/refractory post chemoTx, surgery, or RAI (n=31 DTC, 23 MTC) | DTC=14% MTC=35% |
DTC=68% MTC=57% |
38, 39 | ||||
| phase 2 progressive/refractory post-RAI (n=12 PTC, 8 MTC) | PTC=8% MTC=12% |
PTC=67% MTC=88% |
33, 40 | ||||
| phase 1 solid tumor, (n=1 PTC [post-RAI], 1 FTC [RAI-res.], both progressive, metastatic) | PTC=100% FTC=0% |
PTC=0% FTC=100% |
|||||
| Vandetanib (Zactima, ZD6474) | AstraZeneca | VEGF-R1-3, RET, EGF-R | |||||
| phase 2 advanced hereditary MTC (w/ RET germline mut) (n=30) | MTC=20% | MTC=53% | 27.9/na | 41 | |||
| phase 2 advanced hereditary MTC (RET germline mut) (n=19) | MTC=16% | MTC=32% | 42, 43 | ||||
| phase 3 advanced MTC, hereditary or sporadic (n=231) | MTC=45% | 20.5 months | 44 | ||||
| Vatalanib (PTK787, ZK222584) | Bayer Schering/Novartis | VEGF-R1-3, PDGF-Rβ, c-Kit, cFMS | |||||
| XL184 (cabozantinib) | Exelixis | VEGF-R2, RET, MET | |||||
| phase 1 advanced MTC (n=37) | MTC=29% | MTC=51% | 45 | ||||
| XL281 | Exelixis | BRAF (wt and V600E mut) | |||||
| phase 1 FTC (n=10) (preliminary) | FTC=0% | FTC=20% | 27 | ||||
KEY:
na = not assessed
ORR = Overall Response Rate
SDR = Stable Disease Rate
PFS/OS = Progression-free Survival/Overall Survival