Bevacizumab/Erlotinib Combinations in the Treatment of Metastatic Renal Cell Carcinoma (RCC)
Presenter: John D. Hainsworth, M.D.
Presenter's Affiliation: Sarah Cannon Research Institute, Nashville, TN
Type of Session: Scientific
- Most clear cell renal cancers have mutations or inactivations of the von Hippel Landau (VHL gene).
- As a result, multiple tumor growth-signaling agents are overexpressed, including VEGF, EGF, TGF alpha, and PDGF beta.
- Active tumors need access to nutrients and a blood supply, and the process of new blood vessel formation is called angiogenesis.
- Considerable research has demonstrated the importance of angiogenesis for tumor growth and development.
- Growing tumors secrete molecules that signal for the initiation and maintenance of angiogenesis.
- One of the main molecules that signals for angiogenesis is called vascular endothelial growth factor (VEGF).
- Hypoxia, inflammatory molecules, and growth factors can all cause tumor cells to begin expressing VEGF.
- VEGF has 3 known receptors by which it can transmit the signal for angiogenesis to occur.
- A novel strategy to block tumor growth involves disrupting tumor angiogenesis by either decreasing VEGF levels or blocking VEGF receptors.
- Bevacizumab, a humanized anti-VEGF antibody which binds to the major ligand of the VEGFR1 receptor, has shown single agent activity in refractory RCC, prolonging progression-free survival (PFS) from 2.5 months to 4.8 months when compared to placebo.
- Additional inhibition of other pertinent signaling pathways, such as EGFR or PDGFR, may improve treatment efficacy.
- Erlotinib is a small molecule inhibitor of the EGFR tyrosine kinase receptor.
- Adding erlotinib to bevacizumab could potentially improve response rates in renal cell carcinoma.
- A multicenter phase II trial enrolled 63 patients between Jan 2003 and Jan 2004.
- Median follow-up is 27 months.
- Eligibility criteria included: a diagnosis of clear cell renal cell carcinoma; metastatic or unresectable locally recurrent cancer; 0 or 1 previous systemic therapies; previous nephrectomy; and no active CNS metastases.
- Bevacizumab (10mg/kg IV infusion q 2 weeks) was given with erlotinib (150mg PO daily).
- Patients were re-evaluated every 2 months.
- Treatment was continued until there was disease progression.
- Median patient age was 61, and the most common sites of metastasis were to the lung, liver, and bones.
- 2/3 of the patients had not had previous treatment for their cancer.
- With 59 patients evaluable, 25% of patients had either a complete or partial response.
- 61% of patients had stable disease or a minor response, and 14% had disease progression.
- Objective responses were observed in lung, liver, bone and adrenal metastases.
- Median PFS was 11 months.
- Following this study, a multicenter phase II trial added imatinib (Gleevec) to bevacizumab/erlotinib, and enrolled 91 patients between June 2004 and March 2005.
- The rationale was that inhibition of the PDGFR by imatinib may produce superior outcomes.
- This trial enrolled patients with the same eligibility criteria and dosing of bevacizumab and erlotinib as the previous trial. A brief phase I trial was performed to establish the proper imatinib dose - 400mg orally given daily.
- Median follow-up for this trial is 12 months.
- 83 patients are currently evaluable, and the trial showed partial response in 13%, stable disease or minor response rate in 63%, and progressive disease in 24% of patients.
- Median PFS is 9.9 months.
- When compared to the initial bevacizumab/erlotinib trial, the 3-drug trial with imatinib had higher rates of grade 3/4 toxicity, particularly diarrhea (41% vs 13%), rash (27% vs 13%), and nausea/vomiting (18% vs 10%).
- Bevacizumab/erlotinib is an active and well-tolerated treatment for patients with metastatic clear cell RCC.
- The activity of this combination appears greater than that of either drug alone.
- Although active, bevacizumab/erlotinib/imatinib is a substantially more toxic regimen, with increased diarrhea, fatigue and skin rash.
- At this time, there is no suggestion of increased efficacy by adding a third drug.
- Further combination inhibition of pertinent targets is indicated in RCC and other cancers.
Dr. Hainsworth presented the results of two trials examining multi-drug combinations of targeted therapies for metastatic renal cell carcinoma. These data illustrate a number of important points. First, many clinicians have the incorrect idea that targeted therapies are always well tolerated, especially when compared with cytotoxic chemotherapy. At least with the second trial (the 3 drug regimen), the rates of grade 3 or 4 toxicity were quite high. It appears that if one adds together enough of these biologic agents, one can come up with a fairly toxic regimen.
The second important point to take away from these data is that simply because something "makes sense" in a laboratory setting, does not mean it will translate well to the clinic, in a human population. The logic behind adding imatinib to the other two drugs is certainly sound, but in practice it did not appear to change outcomes. Perhaps we need to learn more about exactly what these compounds do, and how various cellular pathways affect one another when inhibited, before we can be optimally "rational" about our drug design. Imatinib is an excellent drug for CML, but at least in the way it was prescribed here, it did not significantly improve outcome. Furthermore, given the added cost of this agent, the 3-drug combination is likely going to be shelved (at least for now). However, the preliminary results of the bevacizumab/erlotinib trial are certainly quite interesting, and there is little doubt that further research will eventually validate these findings.