MOAs - INLYTA and pembrolizumab

Mechanisms of Action – 
INLYTA® (axitinib) and pembrolizumab 

The combination of a TKI and IO acts on 2 different pathways: VEGF and PD-1

INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3, in vitro and in preclinical models

VEGF is constitutively upregulated in RCC, making it a primary driver of the disease1,2

  • Preclinical evidence demonstrates that the VEGF pathway plays a key role in continued RCC tumor growth and spread3,4
  • Preclinical models suggest that the VEGF pathway contributes to tumor growth and cancer progression by stimulating pathological angiogenesis and impacting immune cell activity in the tumor microenvironment5

Preclinical activity does not necessarily correlate with clinical outcomes.

Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth6

RCC is an immunogenic tumor in which PD-L1 expression can contribute to the inhibition of the antitumor response.7 Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production6

Preclinical activity does not necessarily correlate with clinical outcomes.

IO=immuno-oncology; PD-L1=programmed death-ligand 1; VEGF=vascular endothelial growth factor; VEGFR=vascular endothelial growth factor receptor.

References
  1. Brieger J, Weidt EJ, Schirmacher P, Störkel S, Huber C, Decker HJ. Inverse regulation of vascular endothelial growth factor and VHL tumor suppressor gene in sporadic renal cell carcinomas is correlated with vascular growth: an in vivo study on 29 tumors. J Mol Med (Berl). 1999;77(6):505-510.
  2. Linehan WM, Vasselli J, Srinivasan R, et al. Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res. 2004;10(18 Pt 2):6282S-6289S.
  3. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14(22):7272-7283.
  4. Han KS, Raven PA, Frees S, et al. Cellular adaptation to VEGF-targeted antiangiogenic therapy induces evasive resistance by overproduction of alternative endothelial cell growth factors in renal cell carcinoma. Neoplasia. 2015;17(11):805-816.
  5. Yuan H, Cai P, Li Q, et al. Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation. Biomed Pharmacother. 2014;68(6):751-756.
  6. KEYTRUDA [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc., 2020.
  7. Massari F, Santoni M, Ciccarese C, et al. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev. 2015;41(2):114-121.
BAVENCIO is a registered trademark of Merck KGaA, Darmstadt, Germany. All other trademarks are property of their respective owners.