Phase II trial of bevacizumab and erlotinib in patients with metastatic renal carcinoma (RCC)

Reviewer: Maria Luisa Veronese, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2004

This presentation discusses off-label use of bevacizumab for RCC.  It also discusses the use of erlotinib for the treatment of RCC which has not been approved by the FDA.

Presenter: J.D. Hainsworth
Presenter's Affiliation: Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN
Type of Session: Scientific


The incidence of renal cell carcinoma (RCC) is increasing with aproximately 30,000 new cases expected this year.  The median survival of patients with metastatic renal cell carcinoma is approximately one year and only 10% of patients survive more than 2 years.  High-dose IL-2 and IFN-a produce responses in a minority of patients.  One of the most common genetic abnormalities in RCC is loss of the VHL protein which results in activation of HIFa and factors regulated by HIFa such as VEGF, PDGF, TGF, and EGF.  The rationale of this study rests on the hypothesis that combined VEGF and EGFR inhibition would result in more effective treatment.  Also, bevacizumab, an anti-VEGF antibody, has shown to prolong time to tumor progression (TTP) in second-line therapy of advanced RCC versus placebo. 

Materials and Methods

  • 62 patients with metastatic RCC who had failed 0 or 1 previous systemic regimens were entered to the study between 2/2003 and 1/2004
  • The median age was 61 and there were 50 males and 12 females
  • Most patients did not received prior chemotherapy treatment
  • All patients had prior nephrectomy
  • Most common sites of metastases: lung, liver, bones, lymph-nodes and adrenals
  • Motzer risk category: 26 patients (42%) low risk; 20 (32%) intermediate risk; 16 (26%) high 
  • No previous anti-angiogenesis agents or EGFR inhibitors were permitted
    bevacizumab 10 mg/kg IV every 2 weeks; erlotinib 150 mg PO daily
  • Evaluation for response after 8 weeks
  • Treatment continued until disease progression
  • Results

  • 58 patients were evaluable for response: CR 0 (0%), PR 12 (21%), SD/MR 38 (66%),  MR 12 (21%), PD 8 (13%)
  • Objective responses were observed in lung, liver, bone, lymph-node, and adrenal metastasis
  • No difference in response between the different risk category groups
  • Progression free survival (PFS) at 6 and 12 months was 67% and 50% respectively and overall survival (OS) was 92% and 81% respectively.
  • Most common severe toxicities (grade 3 or 4): rash (13%), diarrhea (10%), nausea/vomiting (6%), hypertension (8%), bleeding (5%) (mostly epistaxis), and proteinura (3%).
  • Author's Conclusions

  • The combination of bevacizumab and erlotinib has substantial clinical activity in RCC
  • The activity of the combination is superior to the activity of either agent when used  as monotherapy
  • Comparison of this combination with standard regimens is indicated
  • The use of agents targeting different pathways involved in the development of RCC is supported and further studies with different combinations are warranted
  • Clinical/Scientific Implications
    The study reports the results of a phase II clinical trial of a combination of two targeted agents, the monoclonal antibody targeting VEGF,bevacizumab, and the tyrosine kinase inhibitor, erlotinib.  Our understanding of the multiple genetic abnormalities and alterations of different biochemical pathways underlying the development of tumors has resulted in the discovery of novel agents targeting specific pathways.  Results of clinical trials with these agents as monotherapy have shown modest clinical activity in RCC.  The regimen bevacizumab/erlotinib has demonstrated substantial activity in this disease supporting the hypothesis that combining agents targeting multiple biochemical pathways results in more effective treatment.  It would be important to identify the patient population that will benefit from this or similar therapy and to predict early during treatment which patients will progress.  Efforts to define markers of response in subsequent trials are necessary.  Further study of this combination approach is warranted.

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