A Phase I Study of Bevacizumab, Everolimus, and Panitumumab for Patients With Advanced Solid Tumors

EGFr inhibition has been shown to have down-regulatory effects on VEGF expression and angiogenesis. The combination of anti-VEGF and anti-EGFr targeting is clinically rational, and preliminarily has shown at least additive, if not synergistic effects [12, 13]. Further, preclinical data has shown that constitutive activation of the AKT pathway is a mechanism of resistance to EGFr inhibitors [14]. Therefore, inhibition of both EGFr and AKT pathways by panitumumab and RAD001 may create a synergistic antitumor effect. There is also rationale that RAD001 and anti-VEGF therapies may be synergistic. Preliminary results from a Phase I dose escalation study of bevacizumab in combination with RAD001 has reported a recommended Phase II dose of this combination, and has described a minor response in a colorectal cancer patient previously refractory to bevacizumab-based therapy, and over 10 months of stable disease in another colorectal cancer patient previous refractory to bevacizumab-based therapy [15].

Bevicizumab (Avatstin) is a humanized monoclonal antibody to VEGF. VEGF is known to play a pivotal role in tumor angiogenesis and is a significant mitogenic stimulus for arterial, venous and lymphatic endothelial cells. The addition of bevacizumab to chemotherapy has been shown to increase overall response rate, duration of response and survival for patients with metastatic colon cancer (4) and is beneficial in first line non-small cell lung cancer and metastatic breast cancer [1, 2], and second line metastatic colorectal cancer (7). VEGF signals through phosphoatidylinositol 3-kinase (PI3K) and Akt as well as through the extracellular regulated kinase (ERK 1/2), a mitogen activated protein kinase (MAPK). VEGF's multiple biologic actions may be mediated by different pathways. Erikkson demonstrated that VEGF induced hyperpermeability was highly dependent on activation of the AKT pathway, while the angiogenic effect was largely unaffected by blocking this pathway and likely depended on ERK activation [3].

RAD001 (Everolimus), an oral derivative of rapamycin, selectively inhibits mTOR (mammalian target of rapamycin), an intracellular protein kinase implicated in the control of cellular proliferation of activated T-lymphocytes or neoplastic cells. mTOR is considered to be a downstream component of the PI3K/AKT/TSC pathway, a signalling module known to be heavily deregulated in many human cancers[4, 5]. In this context, there is an increasing body of evidence suggesting that AKT regulates mTOR activity[5-7], and that the activation status of the PI3K/AKT pathway may be indicative of responsiveness to rapamycins such as RAD001. Specifically, loss of PTEN or constitutive/hyper-activation of AKT has been suggested to sensitize tumors to the effects of inhibition of mTOR[6-8]. Indeed, RAD001 preferentially inhibits the proliferation of tumor cells displaying high AKT activity and totally reverses AKT-driven prostate intraepithelial neoplasia in a mouse transgenic model[7]. Rapamycins also inhibit downstream signaling pathways of VEGF. The rapamycin-regulated PI3K and p70s6 pathways are known to be involved in mediating VEGF's effects on endothelial cells [9]. In animal models, rapamycins modestly decrease tumor VEGF expression, and significantly blunt typical angiogenic responses to VEGF. Everolimus has been shown to inhibit tumor growth and reduce number of blood vessels in a murine melanoma model, indicating that RAD001 has direct antiangiogenic effects [10].

Panitumumab (Vectibix) is a fully humanized monoclonal antibody directed against epidermal growth factor receptor (EGFr), which is a 170-kD transmembrane glycoprotein with a cytoplasmic protein kinase domain essential for tumor growth and division. The receptor binds multiple ligands including epidermal growth factor and transforming growth factor-alpha (TGF-alpha). The tyrosine kinase intracellular domain of the receptor is activated via binding of a ligand to EGFr, which in turn initiates a cascade of intracellular signals. These downstream signaling pathways again include the phosphorylation of mitogen-activated protein kinase (MAPK) through the ras/raf pathway. Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively[11].

1. Sandler, A.B., et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial- E4599. in Proc Am Soc Clin Oncol. 2005.
2. Miller, K.D., et al. E2100: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first line threapy for locally recurrent or metastatic breast cancer. in American Society for Clinical Oncology. 2005. Orlando, FL.
3. Eriksson, A., et al., Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. Circulation, 2003. 107(11): p. 1532-8.
4. Vivanco, I. and C.L. Sawyers, The phosphatidylinositol 3-kinase-akt pathway in human cancer. Nature Cancer, 2002. 2: p. 489-501.
5. Krymskaya, V.P., Tumor suppressors hamartin and tuberin: intracellular signaling. Cell Signal, 2003. 15: p. 729-739.
6. Bjornsti, M.-A. and P.J. Houghton, The TOR pathway: A target for cancer chemotherapy. Nat Rev Cancer, 2004. 4: p. 335-348.
7. Majumder, P.K., et al., mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med, 2004. 10: p. 594-601.
8. Noh, W.C., et al., Determinants of rapamycin in breast cancer cells. Clin Cancer Res, 2004. 10: p. 1013-1023.
9. Yu, Y. and J.D. Sato, MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J Cell Physiol, 1999. 178(2): p. 235-46.
10. Lane, H., et al. Antiangiogenic activity of RAD001, an orally active anticancer agent. in Proc AACR. 2002.
11. Ciardiello, F. and G. Tortora, A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clin Cancer Res, 2001. 7: p. 2958-2970.
12. Spigel, D.R., et al. Bevacizumab and erlotinib in the treatment of patients with metastatic renal cell cancer (RCC): Update of a phase II multicenter trial. in Proc Am Soc Clin Oncol. 2005.
13. Saltz, L.B., et al. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. in Proc Am Soc Clin Oncol. 2005.
14. She, Q.B., et al., Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. Clin Cancer Res, 2003. 9(12): p. 4340-6.
15. Zafar, Y., et al. Preliminary results of a phase I study of bevacizumab (BV) in combination with everolimus (E) in patients with advanced solid tumors. in Proc Am Soc Clin Oncol. 2006.