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Table 1 Principal clinical trials for the approval of anti-angiogenesis receptor tyrosine kinase inhibitors (TKIs)

From: Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy

Drug (company) Indication Pivotal study Study design PFS OS ORR Approval time
Sorafenib (Bayer and Onyx) RCC NCT00073307 [27] Phase III, sorafenib vs. placebo HR = 0.44, p < 0.01 HR = 0.77, p = 0.02 10% vs. 2% 2005 (FDA)
HCC NCT00105443 [28] Phase III, sorafenib vs. placebo HR = 0.58, p < 0.001 HR = 0.69, p < 0.001 2% vs. 1% 2007 (FDA)
DTC NCT00984282 [29] Phase III, sorafenib vs. placebo HR = 0.59, p < 0.0001 HR = 0·80, p = 0·14 12.2% vs. 0.5% 2013 (FDA)
Sunitinib (Pfizer) GIST NCT00075218 [32] Phase III, sunitinib vs. placebo HR = 0.33, p < 0.0001 HR = 0·49, p = 0·007 7% vs. 0% 2007 (FDA)
RCC NCT00098657 NCT00083889 [33, 34] Phase III, sunitinib vs. INF-a HR = 0.42, p < 0.001 HR = 0.82, p = 0.05 31% vs. 6% 2007 (FDA)
pNETs NCT00428597 [35] Phase III, sunitinib vs. placebo HR = 0.42, p < 0.001 NA 9.3% vs. 0% 2011 (FDA)
Pazopanib (GlaxoSmith Kline) RCC NCT00720941 [37] Phase III, pazopanib vs. placebo HR = 0.46, p < 0.0001 NA 30% vs. 3% 2009 (FDA)
STS NCT00753688 [42] Phase III, pazopanib vs. placebo HR = 0.31, p < 0.0001 HR = 0.86, p = 0.25 9% vs. 0% 2012 (FDA)
Axitinib (Pfizer) RCC NCT00678392 [43, 44] Phase III, axitinib vs. sorafenib HR = 0.67, p < 0.0001 HR = 0.97, p = 0.37 19% vs. 9% 2012 (FDA)
Regorafenib (Bayer) CRC NCT01103323 [47] Phase III, regorafenib vs. placebo HR = 0.49, p < 0.0001 HR = 0.77. p = 0.005 1.0% vs. 0.4% 2012 (FDA)
NCT01584830 [48] Phase III, regorafenib vs. placebo HR = 0.31, p < 0.0001 HR = 0.55, p = 0.0002 4% vs. 0%
GIST NCT01271712 [49] Phase III, regorafenib vs. placebo HR = 0.27, p < 0.0001 HR = 0.77, p = 0.199 4.5% vs. 1.5% 2013 (FDA)
HCC NCT01774344 [50] Phase III, regorafenib vs. placebo HR = 0.46, p < 0.0001 HR = 0.63, p < 0.0001 11% vs. 4% 2017 (FDA)
Cabozantinib (Exelixis) MTC NCT00704730 [53] Phase III, cabozantinib vs. placebo HR = 0.28, p < 0.001 HR = 0.98 28% vs. 0% 2012 (FDA)
RCC NCT01865747 [55, 56] Phase III, cabozantinib vs. everolimus HR = 0.58, p < 0.001 HR = 0.66, p = 0.0003 21% vs.5% 2016 (FDA)
Nintedanib (Boehringer) IPF NCT00514683 [60] Phase II, nintedanib vs. placebo NA NA NA 2014 (FDA)
NCT01335464 NCT01335477 [61] Phase III, nintedanib vs. placebo
NSCLC NCT00805194 [63] Phase III, docetaxel + nintedanib vs. docetaxel + placebo HR = 0.79, p = 0.0019 HR = 0.94, p = 0.27 4.4% vs. 3.3% 2014 (EMA)
Lenvatinib (Eisai ) DTC NCT01321554 [67] Phase III, lenvatinib vs. placebo HR = 0.21, p < 0.001 HR = 0.73, p = 0.10 64.8% vs. 1.5% 2015 (FDA)
RCC NCT01136733 [68] Phase II, lenvatinib + everolimus vs. lenvatinib vs. everolimus HR = 0.4, p = 0.0005* HR = 0.51, p = 0.024* 43% vs. 27% vs. 6% 2016 (FDA)
HCC NCT01761266 [69] Phase III, lenvatinib vs. sorafenib HR = 0.64, p < 0.0001 HR = 0.92 40.6% vs. 12.4% 2018 (FDA)
Apatinib (Hengrui) GC NCT01512745 [73] Phase III, apatinib vs. placebo HR = 0.709, p = 0.015 HR = 0.444, p < 0.001 2.8% vs. 0% 2014 (CFDA)
Anlotinib (Chia-taiTianqing) NSCLC NCT02388919 [76] Phase III, anlotinib vs. placebo HR = 0.25, p < 0.001 HR = 0.68, p = 0.002 9.2% vs. 0.7% 2018 (CFDA)
Fruquintinib (Hutchison) CRC NCT02314819 [80] Phase III, fruquintinib vs. placebo HR = 0.26, p < 0.001 HR = 0.65, p < 0.001 4.7% vs. 0% 2018 (CFDA)
  1. Abbreviation: RCC renal cell carcinoma, HCC hepatocellular carcinoma, DTC differentiated thyroid cancer, GIST gastro-intestinal stromal tumor, pNETs pancreatic neuroendocrine tumors, STS soft tissue sarcoma, CRC colorectal cancer, MTC medullary thyroid cancer, IPF idiopathic pulmonary fibrosis, NSCLC non-small cell lung cancer, GC gastric cancer, PFS progression-free survival, OS overall survival, ORR objective response rate, NA not available, FDA US Food and Drug Administration, CFDA China Food and Drug Administration, EMA European Medicines Agency
  2. *Lenvatinib + everolimus vs. everolimus