Tracks 1-18

Track 1 Risk-benefit considerations in comparing bevacizumab/interferon to sunitinib and sorafenib Track 2 Second-line therapy after sunitinib Track 3 Tolerability of sunitinib or sorafenib Track 4 Study of intrapatient dose-escalated sorafenib for patients with mRCC Track 5 Hypertension associated with bevacizumab/TKI combination therapy in clinical trials Track 6 Rationale for investigating the combination of mTOR inhibitors and TKIs Track 7 Relationship between dosing and scheduling of the TKIs and therapeutic efficacy Track 8 TKI-associated hypothyroidism in RCC Track 9 Clinical trial of sunitinib/interferon alpha-2a and erlotinib in papillary RCC Track 10 Systemic therapy for papillary RCC Track 11 Proportion of patients with RCC treated with adjuvant therapy Track 12 Historical evolution of adjuvant clinical trials in RCC Track 13 Patterns of tumor progression in RCC Track 14 Patient acceptance of long-term adjuvant therapy with biologic agents Track 15 Time course of recurrence in RCC Track 16 Role of nephrectomy in mRCC Track 17 Wound-healing issues with biologic agents in RCC Track 18 Role of interleukin-2 in RCC

Select Excerpts from the Interview

Track 1

DR LOVE: What’s your take on the safety and toxicity issues with the major options for first-line treatment of metastatic RCC?

DR AMATO: That’s a good question. Let’s break it down. The predominant side effect with sunitinib is fatigue, thus the built-in break — four weeks on, two weeks off. Additional side effects occur, from skin reactions to gastrointestinal reactions, and occasionally you’ll obtain a hematologic profile with a decrease in counts. Those patients need the two-week rest period.

The clear issue with sorafenib is skin reactions associated with hand-foot syndrome. With both of these drugs, if you begin manipulating by lowering the dose to adjust for side-effect toxicity, you tend to lose efficacy. So you need to maintain at the approved doses.

Bevacizumab as a single agent is more manageable. Patients may exhibit some hypertension and proteinuria, but those are more manageable. With the addition of interferon to bevacizumab, the side-effect profile remains similar. If one evaluates this strictly from a tolerability standpoint, it would be fair to make the statement that interferon/bevacizumab is better tolerated than the oral TKIs.

DR LOVE: What about efficacy?

DR AMATO: It is unfair to say one is better than the other without conducting head-to-head trials. But if you compare across the board, they are similar. Phase II and Phase III data with sunitinib indicate anywhere from 30 to 40 percent activity, with an additional disease-stabilization portion (Motzer 2006a, 2007).

In trials evaluating sorafenib, activity is somewhere between five and 10 percent, but again with that stability portion (Escudier 2007c). Studies of interferon/bevacizumab reported approximately a 30 percent tumor response rate, again with a stability fraction (Escudier 2007b). With regard to progression- free survival, they’re all between five and 10 months.

Track 4

DR LOVE: Can you talk about your presentation at ASCO evaluating dose escalation of sorafenib (Amato 2007; [3.1])?

DR AMATO: The trial was for patients with clear cell component mRCC, who were started on sorafenib at 400 milligrams BID then had the dose escalated according to a prescribed schedule.

The study was based on Phase I data suggesting that at higher doses, sorafenib exhibited more activity, leading to the hypothesis that you might have more kinase inhibition at higher doses.

We reported a 16 percent complete response rate among 44 patients. Seven of 44 patients had a complete response, and another 17 had a partial response — a 55 percent objective response. The progression-free survival median was 8.4 months, which suggests that we now have a complete response rate population and partial response rate population similar to what we know of already, simply by increasing the dose.

DR LOVE: Do you believe that’s a reasonable strategy to implement currently in a clinical setting?

DR AMATO: Not at the present time. We are confirming the data. All the complete responders are approaching 15 to 24 months now, and we have added another 30 patients. Tune in at the next ASCO, and we will have the answers.

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Neil Love, MD

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Robert J Motzer, MD
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Daniel J George, MD
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Robert J Amato, DO
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Janice P Dutcher, MD
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