Tracks 1-14

Track 1 AVOREN: Interferon-2a with or without bevacizumab as first-line therapy in mRCC Track 2 Use of bevacizumab monotherapy in RCC Track 3 Bevacizumab-associated side effects and toxicity Track 4 Potential antitumor mechanism(s) of bevacizumab Track 5 Treatment algorithm for patients with mRCC Track 6 Incorporation of bevacizumab into the management of mRCC Track 7 ECOG-E2805: Adjuvant sunitinib, sorafenib or placebo in resected RCC Track 8 Use of the mTOR inhibitor temsirolimus in patients with poor-risk RCC Track 9 Increasing doses of sunitinib or sorafenib in clinical practice Track 10 The Randomized Discontinuation clinical trial design Track 11 Studying combinations of molecularly targeted agents in RCC Track 12 Management of VEGF TKI-associated toxicities Track 13 Use of combined therapy in RCC Track 14 Targeting novel pathways in RCC

Select Excerpts from the Interview

Track 4

DR LOVE: What do we know about the mechanism of action of bevacizumab in renal cell cancer?

DR STADLER: Kidney cancer is distinctive in that these tumors express one of the highest levels of VEGF.

This is directly related to the pathophysiology of this tumor type, which is thought to involve inactivation of the von Hippel-Lindau (VHL) pathway leading to upregulation of the HIF transcription factor, which in turn leads to upregulation of VEGF.

These data, which were obtained from expression profiling, suggest a direct anti-angiogenic effect as the mechanism of action of bevacizumab in kidney cancer.

Tracks 5-6

DR LOVE: What’s your general algorithm right now for first- and second-line therapy in metastatic disease?

DR STADLER: For patients with good prognoses, the most mature front-line data are with the VEGF receptor TKIs — specifically with sunitinib — so that would be my choice for first-line therapy. That’s also driven by the fact that as of now, bevacizumab has not received full regulatory approval for treatment. I believe that once bevacizumab receives approval, whether one uses the TKIs, bevacizumab or temsirolimus first line remains an open question.

In the second line, we enroll patients on one of our trials. We’re considering the use of alternative VEGF receptor-targeting agents but also have a trial evaluating combinations of agents with bevacizumab. One of the combinations we’re studying is bevacizumab with gemcitabine and capecitabine, based on earlier work we conducted at our institution and through the CALGB.

DR LOVE: How would you ideally use it in renal cell cancer?

DR STADLER: Using it in the front line makes sense, especially for patients with good prognoses. My recommendation would be to use bevacizumab with interferon because that’s what the Phase III data tell us (Escudier 2007).

DR LOVE: How would you compare quality of life using sorafenib or sunitinib versus bevacizumab as a single agent?

DR STADLER: I believe the toxicities of sorafenib and sunitinib are broader than the toxicities of bevacizumab, in that the TKIs also produce skin and gastrointestinal (GI) toxicities. Certainly some patients have more difficulty with some of these skin and bowel toxicities from the TKIs, but many of our patients have tolerated these treatments for long periods.

Track 7

DR LOVE: Would you discuss the ongoing adjuvant trial evaluating sorafenib and sunitinib?

DR STADLER: This is an ECOG-sponsored trial (ECOG-E2805) for patients with high-risk cancer after surgery and no evidence of metastatic disease (2.1). Patients are randomly assigned to one year of sorafenib versus sunitinib versus placebo, with disease-free survival as the primary endpoint. The study also includes an opportunity to register patients prior to surgery in order to collect tumor specimens and evaluate potential molecular predictive markers.

DR LOVE: In this study, is it going to be evident which patients are receiving sorafenib or sunitinib and which patients are receiving placebo?

DR STADLER: I believe there is a concern that this study is not going to be truly blinded. Obviously if a patient has significant skin or diarrheal toxicities, it’s unlikely that the patient is receiving placebo. However, we’ve learned in conducting placebo-controlled trials that our accuracy in predicting which agent the patient was receiving is much less than we thought it would be.

DR LOVE: Do you have any predictions as to the outcome of the trial?

DR STADLER: I’m hopeful that the data will show that one of the oral TKIs will delay disease progression.

Track 11

DR LOVE: What are some of the clinical trial concepts being considered in renal cell cancer with regard to combinations of biologics?

DR STADLER: A lot of interest has been expressed with regard to combining VEGF pathway targeted agents — either the TKIs or bevacizumab — with the mTor (mammalian target of rapamycin) inhibitors, such as sirolimus, temsirolimus and everolimus. There is great interest in combining these classes of agents because they work on different but related pathways. ECOG is launching a randomized Phase II trial with multiple combinations, including bevacizumab, sorafenib and temsirolimus in various combinations (2.2).

I believe the biggest question is whether these combinations will prove to be any better than using the drugs in sequence, because we know that the combinations increase toxicity.

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Neil Love, MD

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David I Quinn, MBBS, PhD
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Walter Stadler, MD
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Mario Lacouture, MD
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Bernard J Escudier, MD
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