Prospettive future nel trattamento medico del mRCC Cinzia Ortega Dipartimento di Oncologia Medica Fondazione del Piemonte per l’Oncologia I.R.C.C.S. Candiolo Lara, ASCO GU 2014 Divisione di Oncologia Medica, IRCCS Candiolo Results of mRCC treatments Improved clinical benefit 1st line PFS: 9-12 mos; OS: 10-29 mos 2nd line PFS: 4-6 mos Improved Quality of life More treatment alternatives available Acceptable costs vs benefits Have we reached a therapeutic plateau? Divisione di Oncologia Medica, IRCCS Candiolo Lara, ASCO GU 2014 Divisione di Oncologia Medica, IRCCS Candiolo Future strategies in mRCC Improve therapeutic index of TKIs Dose intensification (based on biomarkers ; ie HT), schedule Overcoming VEGFR-TKI Resistance Novel targets Novel immunotherapeutic strategies Treatment selection based on tumor biology Divisione di Oncologia Medica, IRCCS Candiolo RCC pathways and targets Rini, Atkins Lancet Oncology Intratumoral heterogeneity Difficult identification of therapeutic targets and biomarkers Divisione di Oncologia Medica, IRCCS Candiolo Stares, Educational session ASCO GU 2014 Novel targets and investigational Agents AGENT CLASS PRIMARY TARGETs Tivozanib TKI VEGFR1-3 Dovitinib TKI FGFR1-3, VEGFR1-3, PDGFRα/β Cabozantinib TKI MET, VEGFR2, RET Nintedanib TKI VEGFR1-3, PDGFRα/β, FGFR1-3, Regorafenib TKI VEGFR1-3, C-KIT, TIE-2, PDGFRβ, FGFR1, RET, RAF-1, BRAF, MAP kinase Cediranib TKI VEGFR1-3 Lenvatinib TKI VEGFR1-2, FGFR1, PDGFRβ, C-KIT Nivolumab Immune TX PD-1 IMA901 Immune TX 9HLAClass1-1HLAClass2 peptide vaccine AGS 003 Immune TX Dendritic cell-based vaccine Naptumomab estafenatox Immune TX Tumor target superantigen BE223S Kinase inhibitor PI3K,mTOR GDC-0980 Kinase inhibitor PI3K,mTOR MK2206 Kinase inhibitor Akt AMG386 Angiopoietin jnhibitor ANG1-2 Divisione di Oncologia Medica, IRCCS Candiolo Cabozantinib: synergistic approach of VEGF/c-Met blockade Oral TKI targeting VEGFR2, MET, RET • c-Met constitutively phosphorilated in clear cell RCC • Activated c-Met promotes tumor growth, invasion, metastasis 1 • High levels of HGF associated with decreased survival in RCC • MET has been implicated in acquired resistance to VEGF TT (Image Source: Exelixis, Inc.) Vaishampayan, Current Oncol Rep 2013 Divisione di Oncologia Medica, IRCCS Candiolo Divisione di Oncologia Medica, IRCCS Candiolo Choueiri, ASCO 2012 Cabozantinib and bone mets • Both HGF and MET are expressed by osteoblasts and osteoclasts in vitro and mediate cellular responses such as proliferation, migration, and differentiation. • Cabozantinib targets both MET and VEGFR2 in osteoblast/osteoclast cells. Targeting both the tumor and the bone microenvironment • Whether bone metastases in other tumors such as renal cancer will behave similarly is unknown at present. However, clinical trials in kidney cancer patients with bone metastases, appear to demonstrate similar clinical responses on bone scans. Divisione di Oncologia Medica, IRCCS Candiolo Choueiri, ASCO 2012; Vaishampayan, Current Oncol Rep 2013 Cabozantinib ongoing phase II study 1st line Divisione di Oncologia Medica, IRCCS Candiolo Choueiri, Kidney Cancer Symposium 2013 2nd line study Divisione di Oncologia Medica, IRCCS Candiolo Immunotherapy: PD-1 receptor and nivolumab Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation, suppresses T-cell activation by interacting with its ligands (PD-L1/2) expressed by tumor cells, stromal cell or both. An estimated 24–37% of patients with ccRCC have high levels of PD-L1 expression and these patients are characterized by an aggressive tumor phenotype and poor prognosis. Pts with PD-1-positive tumor infiltrating lymphocytes (TILs) have poor prognosis NIVOLUMAB T cell + • High affinity for PD-1, blocks binding of PD-L1 and PD-L2 Tumour APC T cell PD-L1 PD-1 T cell priming Divisione di Oncologia Medica, IRCCS Candiolo • Fully-human PD-1-blocking antibody • Promotes anti-tumour response Suppression (anergy, exhaustion, death) Thompson Cancer Res 2007, Topalian, NEJM 2012 1. McDermott DF, et al. J Clin Oncol 2013;31 (suppl 6; abstr 351). Nivolumab in patients with advanced solid tumours 296 pts 34 RCC Dose, mg/kg n ORR, n (%) Median response duration, months (95% CI) SD ≥24 weeks, n (%) PFS rate at week 24, % 1 18 5 (28) 12.9 (9.2–NE) 4 (22) 50 10 16 5 (31)* 12.9 (8.4–NE) 5 (31) 67 All 34 10 (29)* – 9 (27) 58 Divisione di Oncologia Medica, IRCCS Candiolo *1 CR 1. McDermott DF, et al. J Clin Oncol 2013;31 (suppl 6; abstr 351). Nivolumab: adverse events (immune-related causes) Divisione di Oncologia Medica, IRCCS Candiolo 1. McDermott DF, et al. J Clin Oncol 2013;31 (suppl 6; abstr 351). A phase I study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in combination with sunitinib, pazopanib, or ipilimumab in patients (pts) with metastatic renal cell carcinoma (mRCC). Ongoing Phase 1 dose-escalation and expansion study evaluating combination of nivolumab with sunitinib, pazopanib or ipilimumab in pts with mRCC. The primary objectives are to assess safety and tolerability, and to determine the recommended Phase 2 dose in pts with mRCC. The secondary objective is to assess preliminary antitumor activity (objective response rate and response duration per RECIST 1.1). Exploratory objectives are to evaluate overall survival, pharmacodynamics, and predictive biomarkers for the combinations, and pharmacokinetics and immunogenicity of nivolumab. Clinical trial information: NCT01472081. Divisione di Oncologia Medica, IRCCS Candiolo J Clin Oncol 31, 2013 (suppl; abstr TPS4593) Nivolumab vs. everolimus after VEGF-TKI therapy: Phase III study design • Advanced or metastatic RCC with clear-cell histology • Measurable disease • 1 or 2 prior VEGFTKI therapy • No prior mTOR inhibitor R A N D O M I S A T I O N • Estimated enrolment: 822 • Estimated completion: February 2016 • Primary endpoint: OS • Secondary endpoints: PFS, ORR, Safety 1. NCT01668784. http://www.clinicaltrials.gov Nivolumab 3 mg/kg Iv Q 2 weeks Everolimus oral once-daily J Clin Oncol 31, 2013 (suppl; abstr TPS4592) Tumor vaccines mRCC Current generation of studies employ novel vaccines: IMA -901: mixture synthetic tumor associated peptides AGS 003: autologous dendritic cells Divisione di Oncologia Medica, IRCCS Candiolo Conclusions Cabozantinib: for selected bone mets patients? Nivolumab: opportunity for selection of patients for immunotherapy on the basis of tumor markers (PD-1 and PD-L1 expression in tumors) Tumor vaccines? Divisione di Oncologia Medica, IRCCS Candiolo Lara, ASCO GU 2014 Divisione di Oncologia Medica, IRCCS Candiolo [email protected] Divisione di Oncologia Medica, IRCCS Candiolo
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