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Tumor Discovery HIF1α treatments in renal cell carcinoma

References 17-19 22,23 21,24,25 26,27 20,28,29 30,31 32,33 34,35 42 21,43 47,48

10% discontinued dose reduction 38% required dose interruption; 32% Grade 3 or 4 – 79% versus 61% 3% versus 1% due to toxicities versus 71.5% Grade 3 or 4 – 67% versus 68% Grade 3 or 4 – 61% versus 70% versus 71.8% Grade 3 or 4 – 67% versus 78% Grade 3 or 4 – 71% versus 50% Grade 3 or 4 – 15%
AE treatment; 13% required required dose reduction discontinued treatment Grade 3 or 4 – 71.2% Grade 3 or 4 – 82.4%

FDA Approval 2005 2006 2009 2009 2012 2017 2021 2021 2007 2009 2021

10% versus 2% 31% versus 6% – 36% versus 23% 31.6% versus 12% – – 41% versus 6% 49%
PRR 50.7% versus 23.4% 54.9% versus 331.9%

<1% versus 0% 0% versus 0% – 0% versus 0% 4.4% versus 2.1% 1.3% versus 0% – – 2% versus 0% 0%
CRR 16.1% versus 4.2%

10% versus 2% 31% versus 6% 31% versus 13% 36% versus 23% 33% versus 12% 71% versus 36% 8.6% versus 4.8% 43% versus 6% 49%
ORR 55.2% versus 25.5% 33.1% versus 23.3% Abbreviations: CRR: complete response rate; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PRR: partial response rate; IFN-α: Interferon-alpha, VEGFR: Vascular endothelial growth factor receptor; TKI: Tyrosine kinase inhibitor; HIF: Hypoxia-inducible factor; RCC: Renal cell carcinoma; ccRCC: Clear cell renal cell carcinoma, mTOR:

(months) 19.3 versus 14.4 versus 11.6 versus 30.3 versus 29.3 versus 10.9 versus 25.5 versus
OS 15.9 – – 8.9 10.7 21.8 28.8 – 7.3 17.5 –

(months) 5.5 versus 2.8 11 versus 5 10.2 versus 5.4 9.8 versus 4.3 13.8 versus 8.4 8.2 versus 5.6 11.9 versus 9.1 23.9 versus 9.2 3.8 versus 1.9 14.6 versus 5.5
PFS VHL- syndrome 96% at 24 months
Table 1. Comparison of HIF pathway inhibitors
Approved use Advanced RCC Advanced RCC mRCC mRCC Advanced ccRCC after failure of one prior systemic therapy Advanced RCC Advanced RCC following two or more prior systemic therapies Advanced RCC mRCC RCC following prior TKI failure associated solid tumors Mammalian target of rapamycin, VHL: Von Hippel–Lindau, AE: Adverse events.

Therapy target VEGF inhibitor VEGFR inhibitor anti-VEGF antibody VEGFR inhibitor VEGFR inhibitor VEGFR inhibitor VEGFR inhibitor VEGFR inhibitor mTOR inhibitor mTOR inhibitor HIF2-α inhibitor

Experimental arm Sorafenib versus placebo Sunitinib versus IFN-α Bevacizumab +IFN-α versus single- agent IFN-α Pazopanib versus sunitinib Axitinib+ Avelumab (anti-PD-L1 antibody) versus sunitinib Cabozantinib versus sunitinib Tivozanib versus sorafenib Lenvatinib+ Pembrolizumab (immunotherapy) versus sunitinib Temsirolimus versus IFN-α Everolimus+ Lenvatinib (VEGFR TKI) versus single-agent everolimus Belzutifan

Volume 3 Issue 4 (2024) 5 doi: 10.36922/td.4346