Prospettive future nel trattamento medico del mrcc. Francesco Massari Oncologia Medica Policlinico S Orsola-Malpighi Bologna
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1 Prospettive future nel trattamento medico del mrcc Francesco Massari Oncologia Medica Policlinico S Orsola-Malpighi Bologna 3 rd YOUNG SPECIALIST RENAL CARE Firenze, 09 Aprile 2016
2 Renal cell carcinoma Papillary type I 9% Papillary type II 6% Clear cell RCC 70% Non-Clear cell RCC 30% Chromophobe 4-5% Oncocytoma 3-5% Ducts of Bellini <1% Xp11 traslocation t(6,11) traslocation Associated to neuroblastoma Tubulo-papillary Tubulocystic Mucinous tubular Neuroendocr. tumors Mesenchymal Tubulocystic Her. leiomyomathosis Unclassified Massari F, Santoni M 2015
3 RCC is not a single disease Chromophobe (5%) Gene: BHD Papillary Type 1 (5%) Gene: C-Met Other Clear cell (75%) Gene: VHL Papillary Type 2 (10%) Gene: FH BHD = Birt-Hogg-Dubé FH = Fumarate hydratase VHL = von Hippel-Lindau A lot of new genes: SEDT2, PBRM1, BAP1, KMD61, NF2 Linehan WM, et al. In: Cancer: Principles and Practice of Oncology. 2006:
4 Renal cell carcinoma Papillary type I 9% Papillary type II 6% Clear cell RCC 70% Non-Clear cell RCC 30% Chromophobe 4-5% Oncocytoma 3-5% Ducts of Bellini <1% Xp11 traslocation t(6,11) traslocation Response to TKIs Prognosis Associated to neuroblastoma Tubulo-papillary Tubulocystic Mucinous tubular Slow progressor Primary refractory 10-20% Good risk 10-20% Intermediate risk 50-70% Poor risk 15-25% Late relapsing 10-13% Neuroendocr. tumors Mesenchymal Tubulocystic Her. leiomyomathosis «Good» poor risk 15% Interm. poor risk 40% «Poor» poor risk 45% Unclassified Massari F, Santoni M 2015
5 RCC classification based on 400 genes Brugarolas J., KCA Chicago 2014
6 Integrative Genomic Analyses of nccrcc Durinck S, Nature Genetics 2015; 47(1): 13-21
7 Integrative Genomic Analyses of nccrcc Exome sequencing: higher average of protein-coding alterations in nccrcc compared to ccrcc Modified by Ciccarese C, Journal Club Durinck S, Nature Genetics 2015; 47(1): 13-21
8 N Engl J Med Nov 4. [Epub ahead of print]
9 Papillary Renal Cell Carcinoma - Histology Type 1 prcc Type 2 prcc Single line of small basophilic cells with scanty cytoplasm Small, regular, round nuclei Often bilateral or multifocal Several layers of large eosinophilic cells coating papillae Irregular and polymorphic nuclei, with prominent nucleoli New entity characterization by pathologist Modified by Ciccarese C, Journal Club
10 Hereditary Papillary Renal Cell Carcinoma Type 1 prcc Type 2 prcc Autosomal dominant hereditary papillary RCC syndrome (HPRC) activating germline mutations of MET oncogene Hypovascularized, low-grade prcc, with slow growth rate, and low tendency to metastasize. [Schmidt LS, Nat Genet. 1997; 16: ] Hereditary leiomyomatosis and RCC syndrome (HLRCC) germline mutations of the fumarate hydratase (FH) gene High pathological grade and stage, aggressive behavior with shorter survival [Tomlison IP, Nat Genet. 2002; 30: ] Modified by Ciccarese C, Journal Club
11 Papillary RCC type I Met activation is common Distinct alterations involving MET in prcc Germline mutation TK domain Somatic mutation TK domain Copy number alteration Fusion Albiges L, Clin Cancer Res. 2014; 20(13):
12 Papillary RCC type II Escudier B, ECCO-ESMO 2015
13 The Somatic Genomic Landscape of Chromophobe RCC Combined mtdna and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtdna mutations in cancers relying on oxidative phosphorylation Davis CF et al, Cancer Cell 2014; 26: ,
14 Chromophobe RCC ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Davis CF et al, Cancer Cell 2014; 26: ,
15 Translocation RCC The genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing Malouf GG et al, Clin Cancer Res 2014; 20(15):
16 Clear Cell RCC is VHL driven AA Hakimi et al. Nature Genetics 2013, 45(8),
17 VHL has a key role in Angiogenesis and in Therapy VHL = HIF mtor Bevacizumab Temsirolimus VEGF PDGF TGF-α Everolimus VEGFR PDGFR EGFR Raf Raf Sorafenib Sorafenib Sunitinib Pazopanib Sorafenib mtor = mammalian target of rapamycin EGFR = endothelial growth factor receptor VEGFR = VEGF receptor; PDGFR = PDGF receptor Kaelin WG. Nat Rev Cancer 2002;2:673 82
18 Treatment might be different in the future based on observed mutation
19 BAP1 activity in RCC Santoni M, Massari F, Expert Rev. Mol. Diagn Early online, 1 10
20 BAP1 and PBRM1 are mutually exclusive Peña-Llopis S et al. Nat Genetics 2012
21 BAP1 and PBRM1 as prognostic factor for OS Lancet Oncol 2013; 14:
22 Rini BJ et al. J Clin Oncol 2009; 27(19):
23 Full blockade of Pi3K/AKT/mTOR pathway is attractive Ortolani S, Ciccarese C et al. Future Oncol. 2015;11(12):
24 Full blockade of Pi3K/AKT/mTOR pathway is attractive but NOT efficient! 1. Powles T et al, ASCO Symposium 2014; Abs # Powles T et al, ASCO-GU Symposium 2015; Abs #409
25 Hitting both mtorc-1 and -2 looked smart
26 Timing is everything If mtorc2 is activated, as an escape mechanism, when mtorc1, which is Rapamycin-sensitive, is blocked by Everolimus then, does make sense to administer a dual mtorc1 and mtorc2 inhibitor from the very beginning? Probably really a bad study design
27 A better study would have been Everolimus 10 mg o.d. PROGRESSION RANDOMIZATION mtorc-1/2 inhibitor BSC or 3 rd line Tx
28 Rini BJ et al. J Clin Oncol 2009; 27(19):
29 Some drugs inhibit directly HIF CRLX101 is a dual inhibitor of HIF1a and HIF2a Phase I/II reported in 22 patients PFS 9.9 months in refractory patients (Keefe et al., ASCO 2015) Further development is ongoing
30 Rini BJ et al. J Clin Oncol 2009; 27(19):
31 Should we continue to investigate more potent VEGF inhibitor? Less potent VEGFR-1 VEGFR-2 VEGFR More potent Tivozanib1,2 Axitinib3 Cediranib3 Motesanib3 ABT-8693 Sorafenib3 Vandetanib3 Sunitinib3 Pazopanib3 Vatalanib3 IC50, half-maximal inhibitory concentration. 1. Eskens F et al. Presented at 2008 annual meeting of the American Association for Cancer Research (abstract); 2. Nakamura K et al. Cancer Res. 2006;66: ; 3. Chow LQ, Eckhardt SG. J Clin Oncol. 2007;25:
32 Drugs to overcome resistance Modified by Ellis L M, Hicklin D J Clin Cancer Res 2009;15:
33 FGF Mediates Escape From Antiangiogenic Therapy Massari F, Ciccarese C et al. Expert Rev Anticancer Ther Nov 14:1-3
34 Third-line Trial in mrcc: Dovitinib vs Sorafenib Phase III, randomised, open-label, multi-centre trial Eligibility criteria Advanced clear cell or a component of clear cell mrcc 1 measurable lesion N = 550 by CT or MRI 1 prior anti-vegf and 1 prior mtor inhibitor Karnofsky PS 70 R A N D O M I S A T I O N Principal Investigator: Dr Robert Motzer Trial Sites: United States, Canada, Germany Dovitinib 500 mg/day 5 days on/2 days off Sorafenib 400 mg bid Primary end point: PFS Secondary end points: OS, ORR, safety, and patient-reported outcomes Motzer RJ et al, Lancet Oncol. 2014;15(3):
35 Motzer RJ et al, Lancet Oncol. 2014;15(3):
36 Lenvatinib ± Everolimus in mrcc: Study Design Randomized open-label phase II trial compared lenvatinib ± everolimus vs everolimus aloneinrccptswhoprogressedonvegftherapy Courtesy of Ciccarese C Motzer R, et al. ASCO Abstract 4506.
37 Lenvatinib ± Everolimus in mrcc: Patients Characteristics Characteristic Lenvatinib/ Everolimus (n = 51) Lenvatinib (n = 52) Everolimus (n = 50) Male, % Median age, yrs 61 (44-79) 64 (41-79) 59 (37-77) ECOG PS 0/1, % Low hemoglobin, % 53/47 56/44 56/ Corrected serum calcium < 10 mg/dl, % Prior VEGF therapy, % Sunitinib Pazopanib Sorafenib Other Courtesy of Ciccarese C Motzer R, et al. ASCO Abstract 4506.
38 Lenvatinib ± Everolimus in mrcc: Efficacy Response Lenvatinib/ Everolimus (n = 51) ORR, % 43 P<.001 vs everolimus Median PFS, mos 14.6 HR: 0.40;P<.001 vs everolimus Median OS, mos 25.5 HR: 0.51; P=.024 vs everolimus Lenvatinib (n = 52) 27 P=.007 vs everolimus 7.4 HR: 0.61; P=.048 vs everolimus 19.1 HR: 0.68; P=.118 vs everolimus Everolimus (n = 50) Courtesy of Ciccarese C Motzer R, et al. ASCO Abstract 4506.
39 MET and Acquired Resistance to VEGF-targeted Therapies Hypoxia triggers increase in cmet expression and activity: Cell invasion and migration Cell proliferation Cell survival Inhibition of cmet may help overcome acquired resistance to the VEGF pathway Dual inhibitors of cmet and VEGFr2 such as Cabozantinib are active Aftab DT et al. Clin Transl Oncol, 2011; 13: 703-9
40 cmet expression in clear cell RCC Courtesy of Bin Teh
41 Patients with localised renal-cell carcinoma and the MET polymorphism rs might have an increased risk of recurrence after nephrectomy Lancet Oncol 2013; 14: 81 87
42 CABOZANTINIB (XL 184) in Patients with Metastatic, Refractory RCC Choueiri T et al. J Clin Oncol 30, 2012 (suppl; abst 4504)
43 METEOR Study Eligibility: mrcc with clear-cell component At least 1 prior VEGFR TKI Progression on prior VEGFR TKI within 6 months of study enrolment Karnofsky PS 70 R A N D O M I S A T I O N N=658 1:1 Cabozantinib 60 mg orally daily Everolimus 10 mg orally daily Primary endpoint: PFS Secondary endpoints: OS, ORR Exploratory endpoints: safety, tolerability, tumour MET status, circulating tumour cells, serum bone markers and plasma biomarkers, skeletal-related events, and HRQoL Stratification: MSKCC risk criteria; number of prior VEGFR TKIs Choueiri T et al. NEJM 2015
44 METEOR Study: PFS Choueiri T et al. NEJM 2015
45 METEOR Study: OS *Interim analysis(49% information fraction) Medians cannot yet be estimated due to frequent early censoring Choueiri T et al. NEJM 2015
46 ALK 1: a new target Activin receptor-like 1 (ALK1) and its high-affinity ligand, bone morphogenetic protein 9 (BMP9), are TGF-beta superfamily members ALK1 is selectively expresses on vascular and lymphatic endothelial cell
47 ALK 1: a new target Escudier B; ECCO-ESMO 2015
48 Phase I ongoing study Escudier B; ECCO-ESMO 2015
49 Phase I ongoing study Escudier B; ECCO-ESMO 2015
50 Blocking PD-1/PD-1L in RCC tumor microenvironment Massari F, Santoni M, Ciccarese C. et al, Cancer Treat Rev. 2015;41(2):
51 CheckMate 025 Previously treated mrcc Stratification factors Region MSKCC risk group Number of prior antiangiogenic therapies Randomize 1:1 Nivolumab 3 mg/kg intravenously every two weeks Everolimus 10 mg orally once daily Patients were treated until progression or intolerable toxicity occurred Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted MSKCC, Memorial Sloan-Kettering Cancer Center. Motzer RJ et al, N Engl J Med. 2015; 373(19):
52 Overall Survival (Probability) CheckMate 025: Overall survival Nivolumab Median OS, months (95% CI) 25.0 (21.8 NE) Everolimus 19.6 ( ) HR (98.5% CI): 0.73 ( ) P = Everolimus Nivolumab No. of patients at risk Months Nivolumab Everolimus Minimum follow-up was 14 months. NE, not estimable. Motzer RJ et al, N Engl J Med. 2015; 373(19):
53 CheckMate 025: Overall survival by PD-L1 expression PD-L1 1% (n = 24%) PD-L1 <1% (n = 76%) Median OS, months (95% CI) Median OS, months (95% CI) Nivolumab 21.8 ( ) Everolimus 18.8 ( ) Nivolumab Everolimus 27.4 (21.4 NE) 21.2 ( ) HR (95% CI): 0.79 ( ) HR (95% CI): 0.77 ( ) Overall Survival (Probability) Everolimus Nivolumab Everolimus Nivolumab No. of patients at risk Months Nivolumab Everolimus Months Motzer RJ et al, N Engl J Med. 2015; 373(19):
54 PD-Lomas Courtesy of Escudier B ECCO-ESMO 2015 Marabelle A et al,oncoimmunology 2015
55 PD-1 blockade: alone or in combination? PD-1 blockade is a promising strategy for mrcc patients However, it is still unclear if this approach may be used alone or in combination with other strategies
56 PD-1 blockade.in combination with? Anti PD-L1 MEDI4736 DC vaccines Anti LAG3 BMS Tyrosin kinase inhibitors PD-1 blockade Anti-CTLA-4 Ipilimumab Tremelimumab IDO1 inhibitors 41BB agonist monoclonal antibody NK cell therapy Modified by Santoni M, AIOM 2014
57 Hammers H et al. ESMO 2014; Abstract 7843 (Presentation 1050O)
58 Ipilimumab + Nivolumab in mrcc Hammers H et al. ESMO 2014; Abstract 7843 (Presentation 1050O)
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