What can we expect from running phase III trials: will all of them alter the current treatment algorithm?

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1 What can we expect from running phase III trials: will all of them alter the current treatment algorithm? 8 th European International Kidney Cancer Symposium Budapest, May 2013 Martin Gore PhD FRCP Royal Marsden Hospital Institute of Cancer Research London

2 Why do clinical trials? Patients tell us how to treat patients a stepwise change make the best of what we have Intervention licence new drugs Budget health economics efficiency Biology

3 Renal cell carcinoma 1 st line, Progression-free survival INF-α alone INF-α+IL-2+5-FU Sunitinib Pazopanib Sorafenib Axitinib Tivozanib Temsirolimus Bevacizumab + Temsirolimus Bevacizumab + Everolimus Immunotherapy VEGFF-targeted agent Combinations Bevacizumab + INF-α Kane 2006 review Gore 2010 Motzer 2012 Motzer 2009 Motzer 2012 Sternberg 2009 Hutson Rini Motzer Escudier Hutson 2013 Motzer 2012 Hudes 2007 Rini 2012 Ravaud 2012 Rini 2012 Ravaud 2012 Rini 2009 Escudier Time (months)

4 Targeted Agents for mrcc RCTs vs new therapies, First line Agent n Median PFS (months) Median OS (months) Pazopanib vs sunitinib 1 (COMPARZ) vs vs 29.3 Tivozanib vs sorafenib Bevacizumab + everolimus vs bevacizumab + IFN 3 (RECORD-2) Bevacizumab + temsirolimus vs bevacizumab + IFN 4 (INTORACT) Bevacizumab vs bevacizumab + temsirolimus vs bevacizumab + sorafenib vs sorafenib + temsirolimus 5 (BeST) 12.7 vs 9.1 p = (28.8 vs 29.3) vs 10 NR vs vs vs Axitinib vs sorafenib 6 (AGILE 1051) vs 7.3 vs 11.3 vs vs 6.5 p =.038 N/A 1.Motzer 2012, 2.Motzer 2013, 3.Ravaud 2012, 4.Rini McDermott 2013, 6.Hutson 2013

5 Targeted Agents for mrcc RCTs vs new therapies, Relapse disease Agent n Median PFS (months) Median OS (months) Axitinib vs sorafenib 1 (AXIS) vs 4.7 P < vs 19.2 Temsirolimus vs sorafenib 2 (INTORSECT) vs vs 16.6 P = Rini 2011, 2.Hutson 2012

6 Combination vs single agent, second line trial NCT PI Philips mrcc 1 prior VEGFR (n=700) Everolimus 10mg od Everolimus 10mg od + Bevacizumab D1+15, q28 Primary endpoint OS

7 Sequential therapy, third line trial NCT (GOLD) 3 rd line mrcc (1 VEGF+1mTOR) (n=550) Dovitinib 500 mg od orally 5/2 days, 28-day cycle Sorafenib 400mg BID continuous dosing Primary endpoint PFS

8 Relapse therapy how often? 2 nd -line = 131/251 patients 1 (52%) 2 nd -line = 109/272 patients 2 (40%) 3 rd -line = 47/251 patients 1 (36%) 1.Levy Eur J Cancer 2013, 2.Heng ASCO GU 2011

9 Guidance 1 st line MSKCC Risk Recommended Other Options Good or intermediate Poor Sunitinib Bevacizumab + IFNα Pazopanib Temsirolimus High-dose IL-2 Sorafenib Clinical trial Sunitinib Clinical trial Clinical trial should always be consider in all scenarios Escudier Ann Oncol 2012 NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer v1 2013

10 Guidance 2 nd line Prior therapy Recommended Other Options Cytokine-refractory Sunitinib Sorafenib Pazopanib Axitinib Sunitinib Bevacizumab + IFNα Temsirolimus TKI-refractory Everolimus Axitinib Sunitinib Sorafenib Pazopanib Bevacizumab + IFNα Temsirolimus Clinical trial should always be consider in all scenarios Escudier Ann Oncol 2012 NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer v1 2013

11 Nonclear cell renal cell carcinoma Chromophobe Medullary Translocation Papillary type1 Mucinous tubular and spindle cell Collecting duct Papillary type2

12 Nonclear cell RCC, RCTs Intervention NCT no. Histology n Endpoint Everolimus vs Sunitinib (ASPEN) Mixed 108 PFS at 6, 12, 24 mos Temsirolimus vs Sunitinib Mixed 22 PFS Gemcitabine vs Gem+sunitinib Sarcomatoid 100 PFS

13 Fill the basket trials for subtypes Subtype A Organ-defined eg RCC R A N D O M I S E Drug 1 Drug 2 Subtype B Subtype C Subtype D Subtype A Subtype B Subtype C Subtype D

14 Real time post randomisation review and reallocation Fill the basket trials for subtypes Subtype A Organ-defined eg RCC R A N D O M I S E Drug 1 Drug 2 Subtype B Subtype C Subtype D Subtype A Subtype B Subtype C Subtype D

15 Questions I ask myself in clinic 1. Who to treat? 2. When to start treatment? 3. When to stop a treatment? 4. How best to use what is available? 5. Hello old friend?

16 Who to treat?

17 Who to treat? mrcc POPULATION IMMUNOTHERAPY TARGETED THERAPY

18 TARGETs, Escudier ECCO 2005 PFS, subset analysis Age <65 years Age 65 years Low MSKCC score Intermediate MSKCC score No prior IL-2/IFN Prior IL-2/IFN Metastasis in lung at baseline Metastasis in liver at baseline Time from diagnosis 1.5 years Time from diagnosis >1.5 years 0 Sorafenib benefit Placebo benefit Hazard ratio MSKCC = Memorial-Sloan Kettering Cancer Center IL-2 = interleukin; IFN = interferon Escudier ECCO 2005

19 Poor risk patients, first line trial NCT PI Tannir mrcc (n=90) TKI \ mtor naive Pazopanib 800mg od po Temsirolimus 25mg iv q28 Primary endpoint PFS

20 Biomarkers in RCC bfgf HGF PIGF VEGF-A VEGF-C VEGF-D ANG-2 PDGF-AA PPDGF-BB IGFBP1 IGEFBP3 PEDF svegfr1 svegfr2 CAIX HIF CXCR4 VHL S6 SNPs MMP2 MMP9 TGFβ1 TGFβ2 Osteopontin TSP1 TSP2 Tissue Factor PAI-1 Active PAI-1 Total CRP D-dimer VonW Factor Gro-α IL-6 IL-8 P-selectin E-selectin SDF-1b ICAM-1 VCAM-1 MCP-1 E-cadherin TNF-α IFN-y NT-proBMP CXCR4 PDL-1

21 Fishing is futile

22 Fishing is futile Signals for stopping early

23 Phase III Studies Sunitinib and Nephrectomy SURTIME PI Bex Patients with synchronous mrcc and primary tumour in situ n=458 R A N D O M I S A T I O N Nephrectomy Sunitinib 50 mg/day (Schedule 4/2) Sunitinib 50 mg/day (Schedule 4/2) Nephrectomy CARMENA PI Mejean Metastatic clear-cell RCC n=576 R A N D OM I S A T I O N Nephrectomy Sunitinib 50 mg/day (Schedule 4/2) Sunitinib 50 mg/day (Schedule 4/2)

24 Mr DH 47 years old

25 When to start treatment?

26 mrcc Adjuvant Therapy RCTs, Targeted Agents Trial Intervention n Duration Endpoint Accruing /Closed S-TRAC ASSURE Sunitinib vs Placebo Sunitinib vs Sorafenib vs Placebo year DFS C year DFS C SORCE EVEREST Sorafenib Meta-analysis? vs 3 years DFS C vs Placebo Everolimus vs year RFS A Placebo ATLAS PROTECT ARISER Axitinib vs Placebo Pazopanib vs Placebo c250muab vs Placebo (Rencarex) years DFS A year DFS A weeks DFS/OS C

27 Observation is a valid treatment approach in mrcc

28 Observation is a valid treatment approach in mrcc Patients n Observation pre Rx median, mos Median PFS post Rx median, mos Median OS post Rx median, mos ALL Sunitinib Interferon Fisher 2012

29 When to stop a treatment?

30 Slow growth past RECIST PD August 08 July 09 January 10 October 10

31 Tumour vol Turning mrcc into a chronic disease Larkin and Gore, Lancet 2010 Time

32 Differential response March 2007 July 2010

33 Differential response March 2007 July 2010 RFA Cyberknife

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35 How best to use what is available?

36 Sequential therapy, switch trials NCT (PI Michel SWITCH, Germany) NCT (PI Tomita, Japan) First-line mrcc (n=346 & 120) Sunitinib OR Sorafenib PD or toxicity Sorafenib OR Sunitinib NCT (RECORD-3) First-line mrcc (n=460) Everolimus OR Sunitinib PD or toxicity Sunitinib OR Everolimus NCT (PI Jänich Switch-II) First-line mrcc (n=544) Pazopanib OR Sorafenib PD or toxicity Pazopanib OR Sorafenib Primary Endpoints nd

37 Sequential therapy, alternating trials SUNRISES NCT PI Bellmunt First-line mrcc (n=115) Sunitinib 50mg/day (4\2, 12weeks) Sunitinib 50mg/day (50mg/day, 4\2) Everolimus 10 mg/day (12weeks) 1 st PD 1 st PD Everolimus (10mg/day) Sunitinib 50mg/day (50mg/day, 4\2) Everolimus (10mg/day) 2 nd PD 2 nd PD Primary Endpoint PFS at 1 year Secondary Endpoint 1 st PFS altn arm vs 2 nd PFS seqeuntial arm

38 Sequential therapy, alternating trials ROPETAR NCT PI Voest First-line mrcc (n=100) Everolimus (10mg/day, 8weeks) Pazopanib (800mg/day) Pazopanib (800mg/day, 8weeks) 1 st PD 1 st PD Everolimus (10mg/day) Pazopanib (800mg/day, 8weeks) Everolimus (10mg/day) 2 nd PD 2 nd PD Primary Endpoint PFS to earliest PD Secondary Endpoint Time to second PD, from first PD

39 Hypertension as a biomarker of sunitinib efficacy in mrcc Max Systolic BP >140 (n=441) Max Systolic BP <140 (n=93) p value ORR % 54.6% 9.7% < PFS, months < OS, months < Rini JNCI 2011

40 AGILE 1046 (NCT ) Axitinib first line First-line mrcc (n=200) Axitinib 5 mg BID 4 weeks, 1 cycle BP 150/90 mmhg 2 concurrent BP meds No grade 3\4 axitinib tox No dose reduction NO Axitinib <5mg BID Axitinib 5mg BID + Axitinib dose titration Primary Endpoint ORR Secondary Endpoint PFS, OS, safety profile, response duration, PK YES Axitinib 5mg BID + Placebo dose titration Rini 2012

41 Quality of Life

42 Quality of Life Toxicity is a patient not a doctor issue Grade 1\2 toxicities matter

43 Quality of Life Toxicity is a patient not a doctor issue Grade 1\2 toxicities matter

44 Sequential therapy, preference trials TAURUS NCT First-line mrcc (n=160) Sunitinib (50mg/day, 4/2 days) Tivozanib (1.5 mg od 3/1 weeks) Tivozanib (1.5 mg od 3/1 weeks) 12 week swiitch Sunitinib (50mg/day, 4/2 days) Primary endpoint: Preference tivozanib\sunitinib Secondary endpoint: Tox, dose reductions\ interruptions \ QoL 12 week assess

45 Scheduling, first line trial NCT PI Kim 1 st line mrcc (n=80) Sunitinib 50mg 4\2 weeks Sunitinib 50mg 2\1 weeks Primary endpoint: treatment failure (PD, death, toxicity)

46 Sequential therapy, intermittent trials STAR EudraCT PI Brown Sunitinib (50mg/day, 4/2 days) First-line mrcc (n=1000) OR Pazopanib (800 mg od) To maximun response Minimum 4 cycles Continue treatment until PD Treatment break until PD - then restart Co-Primary endpoints: Survival at 2 years QoL

47 Hello old friend? Immunotherapy s?

48 Immunotherapy, first line AGS-003 Autologous dendritic vaccine Leucopharesis in AGS-003 arm NCT (ADAPT) PI Figlin\Wood mrcc (n=450) 2:1 Sunitinb x1 then Sunitinb+AGS-003 x8 (48 weeks) No PD Sunitinib +AGS-003 3monthly until PD Sunitinb (48 weeks) Sunitinb until PD Primary endpoint OS

49 Immunotherapy, first line IMA901 Tumour-associated peptides,tumaps NCT IMPRINT PI Rini\Eisen mrcc (n=330) Sunitinib x 1cycle 3:2 Sunitinib + Cyclo x1 then IMA901 id x10 in 4mos Sunitinib Primary endpoint OS

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51 PD-1 \ PDL-1

52 Change in Target Lesions from Baseline (%) Immunotherapy, RCC phase 1 Nivolumab\BMS , 10mg/kg Weeks since initiation of treatment McDermott KCS Chicago, Yang NEJM Oct

53 Immunotherapy, second line Nivolumab\BMS NCT mrcc <2 prior VEGFi < 3 lines (n=822) Nivolumab 3 kg/mg iv q14 Everolimus 10 mg od po Primary endpoint OS

54 Targeting PD-1 and PD-L1 ANTI-PD-1 MDX-1106/BMS /Nivolumab fully human IgG4 anti-pd1 mab BMS CT-011 humanized IgG1 anti-pd1 mab CureTech/Teva MK-3475 human IgG4 anti-pd1 mab Merck ANTI-PDL-1 MPDL3280A/RG7446 humanized mab Genentech BMS fully humanized IgG4 mab inhibits PD-1 and B7.1 BMS AMP-224 a B7-DC/IgG1 fusion protein licensed to GSK

55 LICENCE Trial objectives Novel agents+ Clinical trials+ The clinical trialist s journey Phase 2\3 Phase 2\3

56 LICENCE Trial objectives Novel agents+ Clinical trials+ Biology Novel agents The clinical trialist s journey Phase 2\3 Serial sampling

57 LICENCE Trial objectives Novel agents+ Clinical trials+ Biology Novel agents The clinical trialist s journey Phase 2\3 Serial sampling Phase 2\3

58 end

59 Change in Target Lesions from Baseline (%) Immunotherapy, phase 1 Nivolumab\BMS , 10mg/kg Weeks since initiation of treatment McDermott KCS Chicago, Oct 2012

60 Trial objectives TOXICITY LICENCE CLINIC BIOMARKERS TOXICITY The drug journey

61 Targeted Agents for mrcc RCTs vs old therapies, First-line therapy Agent n ORR (%) Sunitinib vs 12 vs IFN-α 1,2 p< Temsirolimus vs 4.8 vs IFN-α 3* ns Bevacizumab + IFN-α vs 12 vs IFN-a 4 p= Bevacizumab + IFN-α vs IFN-a Sorafenib vs IFN-α Pazopanib vs placebo 7, vs 13 p< vs 8.7 ns 32 vs 4 p<0.001 Median PFS (months) 11 vs 5 p< vs 3.1 p< vs 5.4 p< vs 4.9 p< vs 5.6 p= vs 2.8 p<0.001 Median OS (months) 26.4 vs 21.8 p= vs 7.3 p= vs 21.3 p= vs 17.4 p=0.069 NA (22.9 vs 20.5) ns *Poor risk patients, modified MSKCC criteria ( ) total patient population 1. Motzer 2007; 2. Motzer 2009; 3. Hudes 2007; 4. Escudier 2010; 5. Rini 2010; 6. Escudier 2009; 7. Sternberg 2010; 8.Sternberg 2011

62 Targeted Agents for mrcc RCTs vs placebo, Relapse disease Agent n ORR (%) Median PFS (months) Median OS (months) Sorafenib vs Placebo 1,2 cytokine) (post vs 2 p< vs 2.8 p< vs 14.3* p= Everolimus vs Placebo 3 (post VEGFtargeted) vs 0 ns 4.9 vs 1.9 p< vs 14.4 ns Pazopanib vs Placebo 4 (post cytokine) vs 3 p< vs 4.2 p<0.001 (22.9 vs 20.5) ns *crossover censoring ( ) total patient population 1. Escudier 2007; 2.Escudier 2009; 3. Motzer 2010; 4. Sternberg 2010

63 Surgical trials Stratify Surgery 1. Immediate Metastases + anytime Primary in situ 2. Delayed No surgery Endpoints 1. Reason for timing: inoperability,not fit, paraneoplastic syndrome control 2. Time to 2nd line treatment 3. No 2nd line treatment 4. Overall survival 5. PFS to 1st line treatment 6. Number of lines of treatment

64 Nonclear cell mrcc Adjuvant Therapy RCTs, Targeted Agents Trial n Result Everolimus 1 (RAPTOR) Sunitinib 2 (SUPAP) mos mpfs 61 12% ORR, 12.5% mos mos Foretinib % ORR (50% Resp c-met. 9.3% mos mos Erlotinib % ORR, 27 mos 1.Escudier ESMO 2012, 2.Ravaud ESMO,2012, 3.Chouieri JCO 2013, 4.Gordon JCO 2009

65 Sequential therapy, switch trials NCT First-line mrcc (n=540) Sunitinib (50mg/day 4/2 schedule) Sorafenib (400mg BID) PD or toxicity Sorafenib (400mg BID) Sunitinib (50mg/day 4/2 schedule) RECORD-3 First-line mrcc (n=460) Everolimus (10mg/day) Sunitinib (50mg/day 4/2 days) PD or toxicity Sunitinib (50mg/day 4/2 schedule) Everolimus (10mg/day)

66 Quality of Life

67 Sequential therapy Study n AGENTS START NCT (1 0 endpoint = 2 nd PFS) 240 Pazopanib Bevacizumab vs Pazopanib Everolimus vs Everolimus Bevacizumab vs Everolimus Pazopanib vs Bevacizumab Pazopanib vs Bevacizumab Everolimus

68 Change in tumour measurements (%) Clinical patterns of resistance to targeted therapy Change in tumour measurements (%) Change in tumour measurements (%) Clonal Escape SD\PR + PD SD\PR + new lesion Primary refractory (2 3 months of treatment) Early progressors (6 12 months of treatment) Late progressors Intrinsic resistance Evasive resistance Rini BI and Flaherty K, Urol Oncol 2008

69 AGILE 1046 (NCT ) Axitinib first line Investigator assessed Total (N=213) Arm C not eligible for dose titration (n=91) Arms A + B eligible for dose titration (n=112) mpfs, mo ORR 48% 59% 43% Rini 2012

70 HIGH VS LOW DOSE BEVACIZUMAB VS PLACEBO n = 116pts Yang N Engl J Med 2003