Tracks 1-17

Track 1 Everolimus versus placebo after progression on sunitinib and/or sorafenib in mRCC Track 2 Toxicity and efficacy data with everolimus after sunitinib and/or sorafenib Track 3 Tolerability and efficacy of the mTOR inhibitors temsirolimus and everolimus Track 4 Efficacy of sunitinib compared to interferon in mRCC Track 5 Tolerability of TKIs in elderly patients Track 6 Updated AVOREN trial efficacy and toxicity data Track 7 Clinical trial of bevacizumab with or without erlotinib in mRCC Track 8 Bevacizumab monotherapy in the treatment of mRCC Track 9 Pitfalls of indirect comparisons of clinical trial data Track 10 Identifying surrogates to predict benefit from targeted therapies Track 11 In vitro data demonstrating a relationship between hypoxia-inducible factor (HIF) and tumor sensitivity to sunitinib Track 12 Antitumor effect of sunitinib Track 13 Correlation between HIF levels and rate of tumor regression in patients treated with sunitinib Track 14 Elevated HIF levels predict poor prognosis Track 15 Potential nonsynonymous single nucleotide polymorphisms (nsSNPs) associated with sunitinib-associated toxicity Track 16 Clinical trials combining bevacizumab and TKIs Track 17 Active clinical trials comparing monotherapy versus combination therapy in mRCC

Select Excerpts from the Interview

Track 5

DR LOVE: Can you discuss your presentation at ASCO 2008 evaluating sorafenib in older patients?

DR BUKOWSKI: It was an analysis of the Advanced Renal Cell Carcinoma Sorafenib (ARCCS) Expanded Access program. The question has been whether older patients experience the same benefits and toxicities as younger patients. The real issue is the definition of old, and no one agrees. The cutoff of 65 years old was chosen (Bukowski 2008). In this study with more than 2,500 patients enrolled by community doctors, we evaluated whether older patients and younger patients had similar progression-free survival (PFS) rates and toxicities associated with sorafenib.

It turns out that they did. An increase in toxicities did not appear in the individuals older than age 65 (Bukowski 2008; [3.1]).

Track 6

DR LOVE: Would you review the AVOREN trial and the update presented at ASCO 2008?

DR BUKOWSKI: The AVOREN trial was a straightforward study in which bevacizumab/interferon was compared to interferon alone as first-line therapy for mRCC. Last year, the presentation focused on efficacy and demonstrated that PFS was basically doubled when combining bevacizumab with interferon. The response rate was likewise doubled from 15 to 30 percent (Escudier 2007).

In the presentation this year, Dr Escudier evaluated the patients who had interferon dose reductions. As one would expect, patients tolerated lower doses of interferon better than higher doses. Outcomes were also studied. Although it was a subset analysis, which needs to be conducted in that context, it showed no difference between patients who had interferon dose reductions and those who did not (Escudier 2008; Melichar 2008; [3.2]).

Is a lower dose of interferon sufficient and clearly easier to tolerate than the one used in the study? These data support that. They even address the issue of whether interferon is completely necessary.

As you reduce the dose, perhaps you can almost eliminate the drug. We cannot, however, do so at this point. So lower doses of interferon are acceptable. I believe that most physicians who have used interferon recognize that you can administer two or three million units three times per week easily compared to nine or 18 million units, with which the toxicity is much higher.

Track 7

DR LOVE: You led a study evaluating bevacizumab alone versus bevacizumab with erlotinib. How much do you think interferon is contributing to the activity of bevacizumab?

DR BUKOWSKI: I wish we had an answer because it would make our lives easier as we begin to use bevacizumab for renal cancer in the United States. All we have are the data I presented and published, which included approximately 100 patients — half received bevacizumab alone, and the other half received bevacizumab and erlotinib (Bukowski 2007; [1.3]).

Erlotinib didn’t have any effect except the usual toxicity. The median PFS for the group as a whole was approximately nine months. We saw little difference in the median PFS between the two arms — one was a little less than nine months and the other a little more than nine months. The response rates in both arms were in the range of 13 to 14 percent (Bukowski 2007; [1.3]). This would be our de facto bevacizumab monotherapy experience that is available in a randomized, blinded setting.

When we view the data from AVOREN (Escudier 2007) and CALGB-90206 (Rini 2008; [3.3]) — two large groups of patients treated with the combination of bevacizumab and interferon — both show an effect on progression.

In the AVOREN study, the median PFS was approximately 10.2 months. In CALGB-90206, the median time to progression was 8.5 months.

You come away thinking that monotherapy with bevacizumab, if indeed one can extrapolate from the erlotinib/bevacizumab trial, is almost equivalent with perhaps a 1.5-month lower median PFS than with the combination of interferon and bevacizumab. You have the sense that the major contribution is from bevacizumab. My impression is that if we had a well-designed study in which we used bevacizumab monotherapy, we would see a median PFS of nine to 10 months.

Track 16

DR LOVE: Which new research strategies are currently receiving high priority?

DR BUKOWSKI: The data that keep coming out are with combinations, which is the next frontier. Can we combine these drugs in a fashion that enhances efficacy? We don’t know. I caution people against prematurely using combinations at this point because we have seen toxicity that is worrisome and problematic.

One paper, presented for the third time, was the Phase I trial of sorafenib and bevacizumab conducted by Jeff Sosman. The response rate remains robust at about 40 percent, but the toxicity is clearly problematic. One needs to reduce the doses of both bevacizumab and sorafenib to make the combination tolerable (Sosman 2008).

The other intriguing combination is sunitinib/bevacizumab, which has been studied at two centers — Memorial Sloan-Kettering (Feldman 2008) and the Cleveland Clinic (Cooney 2008). The outcomes at Memorial were such that you could administer full doses of both drugs, but within a cycle or two, toxicity developed that was a problem.

We saw three or four cases of hemolytic uremic syndrome, which is difficult to manage and could be life threatening. The combination at full doses was abandoned in terms of further studies.

At the Cleveland Clinic, we’ve not seen a single case of hemolytic uremic syndrome, but many of our patients, as they continue therapy, have had dose reductions because of other toxicities. You come away thinking that the tyrosine kinase inhibitors sorafenib and sunitinib are sometimes difficult to combine with other agents.

However, bevacizumab appears to be a drug that you can combine with other agents, especially with the mTOR inhibitors. A lot of interest exists for the combinations of bevacizumab with temsirolimus or everolimus.

Right now, it’s fair to say that the data on combinations are preliminary. We don’t have evidence to say that they are tolerated long term or that efficacy will be improved.

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Neil Love, MD

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Robert A Figlin, MD
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Gary R Hudes, MD
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Ronald M Bukowski, MD
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