The plan. Overview of clinical trials Current clinical trials in renal cancer Future treatment of renal cancer

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1 Relevant disclosure Bayer - consultancy GSK research funding, consultancy, speaker honoraria Novartis research funding Pfizer research funding, consultancy Roche / Genentech research funding, consultancy

2 The plan Overview of clinical trials Current clinical trials in renal cancer Future treatment of renal cancer

3 Clinical Trials: Why, How, What?

4 Why should we do Clinical Trials? To improve outcomes for future patients - To ensure that new treatments definitely do more harm than good - That the new treatment is better than the old treatment

5 Other motivations Gain experience of new treatments first Quality system is appealing Fame and glory Money

6 Why do patients take part? Access new treatments (esp where there is otherwise none) Hope that this may be the big breakthrough To help future sufferers To please their healthcare team? Because patients do better on clinical trials

7 How to do a clinical trial 1. Have a good question - Important to patients - There is reasonable doubt about the answer

8 How to do a clinical trial 1. Have a good question - Important to patients - There is reasonable doubt about the answer - It s possible to answer it

9 How to do a clinical trial 1. Have a good question 2. Find a way of answering it - which patients? - which intervention? - how big an improvement is important?

10 How to do a clinical trial 1. Have a good question 2. Find a way of answering it 3. Make sure everyone is doing it in the same way - write a clear protocol - choose and train different sites - monitor the activity at those sites - audit and inspection

11 How to do a clinical trial 1. Have a good question 2. Find a way of answering it 3. Make sure everyone is doing it in the same way 4. Collect the data - Case Report Forms - Database

12 How to do a clinical trial 1. Have a good question 2. Find a way of answering it 3. Make sure everyone is doing it in the same way 4. Collect the data 5. Pass on the results - publish - guidelines, etc.

13 Different types of clinical trials Different interventions: Drugs Operations Other interventions

14 Different types of clinical trials Phase III trials: Designed to show improvement that directly benefits patients Randomized Compares new treatment to standard treatment Minimal risk of chance finding

15 Overall survival N=800 Minimal risk of chance finding N=400 New Drug A +Placebo mrcc PS 0,1 No prior drug R N=400 Randomised Placebo +pazopanib Compare With SoC Direct benefit

16 Different types of clinical trials Phase III trials: Designed to show improvement that directly benefits patients Randomized Compares new treatment to standard treatment Minimal risk of chance finding A positive result should change practice

17 Different types of clinical trials Pre-phase III: Not practice-changing in themselves Safety / side effects Test doses / schedules Early signs of activity

18 Main areas of interest CARMENA How to manage small primary tumours Role and timing of cytoreductive nephrectomy Reducing risk of relapse after curative Sx Optimising drugs in advanced disease STAR SORCE

19 Role of cytoreductive nephrectomy: CARMENA

20 Overall survival Earlier Interferon mrcc No prior drug R 8.1 months Interferon + nephrectomy 11.1 months Flanigan et al. NEJM 2001

21 Overall survival CARMENA Sunitinib mrcc No prior drug R Sunitinib + nephrectomy Phase III could change practice away from surgery

22 Reducing risk of relapse after Curative surgery: SORCE

23 Relapse-free survival Earlier RCC No metastastases Intermediate or high risk of relapse < 90 days post nephrectomy R Interferon, Interleukin-2 5-fluorouracil No treatment No significant difference Aitchison et al. Eur J Caner 2013

24 Relapse-free survival SORCE Sorafenib Sorafenib Sorafenib RCC No metastastases Intermediate or high risk of relapse < 90 days post nephrectomy R Sorafenib Placebo Placebo Placebo Placebo Placebo

25 Optimising drugs in advanced disease: STAR Trials of first line TKI Give treatment continuously until progression, then stop In some patients causes high burden of chronic low grade toxicity The notion of treatment holiday is appealing But is it effective?

26 Holiday Holiday etc Progression free surviv al STAR TKI mrcc No prior drug R TKI TKI

27 Future treatments in RCC

28 Same drugs, different tricks: 1. Adjuvant treatment It works in many other cancers It may work particularly well with vascular targeted drugs.. It takes time to get the results Several trials in follow up SORCE (sorafenib) S-TRAC (sunitinib) Pazopanib Could result in major change in practice

29 Same drugs, different tricks: 2. Scheduling and sequencing STAR protocol and treatment holidays Which treatment to give next?

30 New Drugs: Immunotherapy We already know this approach works in RCC Newer, better immune-stimulating drugs

31 Thank you