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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