Professor Martin Gore • • • • • • Martin has devoted his career to improving outcomes in cancer He is internationally recognised in kidney cancer, melanoma and ovarian cancer He cofounded the EIKCS in 2004 and has been an outstanding friend and supporter of the KCA He has been Medical Director of the Royal Marsden Hospital since 2006 He has inspired and mentored a generation of Medical Oncologists in the UK and abroad He is a staunch advocate for the Marsden, for the National Health Service and most importantly, for patients Ninth European International Kidney Cancer Symposium Dublin – 25-26 April 2014 Eugene P. Schonfeld Lecture EIKCS Dublin, April 2014 Treatment of kidney cancer 2024 Martin Gore PhD FRCP Royal Marsden Hospital Institute of Cancer Research London Bill Hendry 1938-2012 Tim Christmas 1956-2011 Bill Bro, CEO KCA Eugene P. Schonfeld 1943 - 1997 1967 BA in Communications Arts, University of Notre Dame 1968 Masters, Science in Journalism 1975 PhD in management Northwestern University He taught advertising at Northwestern and marketing at the College of Business Administration at the University of Illinois He formed a consulting company Schonfeld Associates 1989 - diagnosed with RCC 15 cm 1989 - founding President and Chief Executive Officer KCA, travelled the US organising KCA groups and began a strong advocacy program urging FDA approval of IL-2 1992 - FDA approves IL 2, the first agent for the treatment of RCC 1997 - dies of metastatic RCC aged 54 6 Eugene P. Schonfeld 1943 - 1997 ''Gene was a remarkable advocate for cancer patients and demonstrated that patient activism is essential in cancer drug development,'‘ Patty Delaney Associate Director, Cancer Liaison Program, FDA 7 Eugene P. Schonfeld 1943 - 1997 8 You don’t know where you are going to… …if you don’t know where you have come from 2004 40th ASCO, New Orleans 2004 Oral Presentation Session Carbonic Anhydrase IX (CAIX) expression predicts for renal cell cancer (RCC) patient response and survival to IL-2 therapy M Atkins Update of a phase 1 study of intravenous CCI-779 given in combination with interferon{alpha} to patients with advanced renal cell carcinoma JW Smith Infliximab: A phase II trial of the tumour necrosis factor (TNF{alpha}) monoclonal antibody in patients with advanced renal cell cancer (RCC) NR Maisey A phase II study of gemcitabine (G) and capecitabine (C) in patients with metastatic renal cell cancer (mRCC): A report of Cancer and Leukemia Group WM Stadler Low dose interferon-{alpha}2b (IFN) + thalidomide (T) in patients (pts) with previously untreated renal cell cancer (RCC). Improvement in progression-free survival (PFS) but not quality of life (QoL) or overall survival (OS). A phase III study of the Eastern Cooperative Oncology Group (E2898) MS Gordon Redman, ASCO Education Book 2004 RENAL CELL CANCER PERCY QUATTRO, Negrier 2007 MPA vs IFN vs IL-2 vs IFN + IL-2 100 Survival (%) 80 60 MPA 2.5% 4.4% 4.1% 10.9% 40 IFN 20 IL2 n = 492 IFN + IL-2 0 0 6 12 18 24 30 36 42 48 RENAL CELL CARCINOMA Immunotherapy-induced durable CRs IFN vs IFN+IL2+FU Gore 2010, 1006 pts RCT IL2 high dose, iv bolus 186 pts, Durable CR 7% McDermott 2005 Proportion without progression 1.00 0.75 0.50 0.25 0.00 RCT IL2 high dose, iv bolus 306 pts, Durable CR 8% Yang 2003 Complete Responders - by treatment CR = 2% 0 6 11 10 8 9 12 18 24 30 36 42 48 54 Time since complete response (months) 60 Number at risk IFN only IFI 7 8 4 7 2 5 2 5 IFN only 2 4 2 2 0 2 0 1 0 1 IFI Duration of complete response IFN-α: 3, 4, 5, 6+, 12, 12, 16, 18+, 20+, 34+, 44+ IFI: 3, 7, 12+, 19+, 22, 35+, 36+, 36+, 52+, 65+ Treatment 2024 Targeted agents • TKIs won’t be used as they are now • novel VEGF targets to be discovered • new targets eg from chromosome 3 (PBRM1, BAP1) BUT REMEMBER… CNS disease Rini and Atkins, Lancet Oncol 2009 Immunotherapy Interferon Interleukin 2 +++ --CTLA4 PD1 Immunotherapy is an… Automated, continuous, personalised, molecular identification, patient selection, IMP synthesising, GMP-compliant manufacturing, treatment delivery system in vivo Melanoma 5-year OS analysis DTIC +\- ipilimumab Maio, ESMO 2013 1.0 DTIC + 10 mg/kg Ipi Censored 0.9 DTIC + Placebo Censored Proportion Alive 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 Months Treatment group Median OS, months Overall survival rate, % 1-year 2-year 3-year 4-year 5-year Ipi + DTIC 11.2 47.6% 28.9% 21.3% 19.1% 18.2% Plac + DTIC 9.1 36.4% 17.8% 12.1% 9.7% 8.8% PLATEAU Phase 1 Nivolumab: Melanoma, n = 107 OS, PFS, PFS responders ? Plateau or no plateau Topalian, JCO 2014 Anti-PD-1 MoAb MK-3475: Melanoma PFS: Independent Central Review Progression-Free Survival, % 100 80 Median, mo Rate, 6 mo Rate, 12 mo PD-L1+ 10.6 57% 45% PD-L1– 2.9 35% 18% 60 40 20 0 0 20 40 60 80 Time, weeks • PFS was significantly longer in patients with PD-L1+ tumors: HR, 0.52; 95% CI, 0.32–0.86; P = 0.0051 • n = 125 Daud AACR 2014 21 Advanced Melanoma Nivolumab + ipilimumab concurrent Wolchok NEJM 2013, n = 53 pts Melanoma LDH prognostic factor for ipilimumab 3mg/kg n Survival at 1 year Survival 4 cycles of ipi at 2 years completed Low LDH <2xULN 182 51.2% 34.6% 66% High LDH >2xULN 42 4.8% 0% 24% Med OS = 14.7mos LDH = N Med OS = 3.7mos LDH >ULN p < 0.001 Kelderman, Cancer Immunol Immunother 2014 Advanced Melanoma NCT01515189 Ipilimumab 3mg/kg 1st line R A N D O M I S E Ipilimumab 10mg/kg Advanced Melanoma Checkmate 067 Ipilimumab 1st line R A N D O M I S E Nivolumab Ipilimumab + Nivolumab Approved immunosuppressive agents Corticosteroids Calcineurin inhibitors Cyclosporine A Tacrolimus Anti-proliferative drugs (MTX,cyclo) Azathioprine Mycophenolate mofetil Rapamycin Anti-lymphocyte polyclonal Abs ATGAM Thymoglobulin Anti-CD3 MoAbs Campath OKT3 Anti-interleukin 2 receptor MoAbs Daclizumab Basiliximab Infliximab Combinatorial immunotherapy, 2024 Cytokines IFN IL2 IL7 IL21 GmCSF Adoptive Tcell therapy Activated TCR engineered CARs Vaccination DC DNA RNA Immuocyte depletion Treg MDSC MoAb-conjugates Combinatorial immunotherapy, 2024 Caveats ‘Meet the new boss, same as the old boss’ from Who’s Next? The Who 1971 ‘Old’ immunotherapies will be resurrected by new technologies Bad habits will be repeated ‘Immune monitoring’ will re-emerge Patient selection will be routine PET technology with probes specific for inflammatory markers BUT REMEMBER…CNS disease Combinatorial immunotherapy, 2024 Clinical trials • trial design based on biological OR systematic rationale • examine dose and schedule early • always randomise, even at phase 1 • time point comparisons •‘raising the plateau’ end point • collection of post study data eg treatment will be mandated by ‘regulators’ ‘Maintenance’ trial design Elective continual maintenance Patients in CR following induction therapy R A N D O M I S E Elective intermittent maintenance Relapse-direct ‘maintenance’ Combinatorial immunotherapy, 2024 Clinical trials • trial design based on biological OR systematic rationale • examine dose and schedule early • always randomise, even at phase 1 • time point comparisons •‘raising the plateau’ end point • collection of post study data eg treatment will be mandated by ‘regulators’ IMMUNOTHERAPY vs TARGETED AGENTS it is not a competition IMMUNOTHERAPY + TARGETED AGENTS will be sequential\alternating not combinatorial Radiotherapy, 2024 Ohno, EPMA Journal 2013 SBRT\Carbon-ion RT Abscopal effect (Mole 1953) Oligometastatic disease Replace RFA Translational research 2024 Pharmacogenomics Toxicity, efficacy, ethnicity Genotype OR 95% CI P 0.046 40 Any toxicity > grade 2 n = 183 35 VEGFR2 1191C/T CC TC TT 2.39 1.02 to 5.60 ABCG2 haplotype ξ TT-TT+TT-other vs other-other 0.38 0.17 to 0.83 AA AG GG 4.03 1.24 to 13.09 0.021 TTT-TTT+TTTother vs other-other 0.39 0.16 to 0.94 0.035 30 Sunitinib vs IFN Sunitinib EAP S.Korea 25 20 15 10 Mucosal inflammation n = 193 CYP1A1 2455A/G 5 0.016 Hand foot syndrome n = 182 0 Hb Neutro Plats ABCB1 haplotype∞ Kim Oncology 2011; van Erp JCO 2009 ‘Fishing’ for a biomarker will cease by 2024 therapeutic target molecule is not a biomarker it is a self fulfilling prophecy eg ER, HER2, BRAF • poor history of ‘searching’ for biomarker • need to be ‘all or nothing’ ie 80% predictive not enough • early diagnosis of ‘response’ in first 4 weeks The patients …then, now and always Quality of Life PATIENTS’ PREFERENCES MATTER 120 Breast cancer 100 80 % 60 Doctors' views of patients' preference Patients' views 40 20 0 Lee at al 2010 PATIENTS’ PREFERENCES MATTER Wanless Report Securing our Future Health: Taking a long-term view UK Department of Health 2002 • patient preference • based on maximum patient engagement • estimated annual savings 16% of projected budget by 2022 • total saving £30 billion 2024 Health dollar/research resource shift out of EU Institut Gustave Roussy 2024 Dr Escudier will still be interviewing for Fellows Institut Gustave Roussy 2024 Dr Escudier will still be interviewing for Fellows Team 2014 Jaqui Moore James Larkin Lynda Pyle Tim Eisen Lisa Pickering David Nicol A very big ‘thank you’ to all my patients and their families