1. Nuovi Farmaci e Targets Emergenti nel Trattamento del CA Renale in Fase Avanzata  
Dario Giuffrida, Ivana Puliafito

2. Biological pathways in RCC

3. VEGFR Inhibitors Sunitinib I linea Sorafenib Pazopanib II linea
mPFS
Sunitinib: 11 m
IFNα: 5 m
Sorafenib
Pazopanib
II linea
I/II linea
mPFS
Sorafenib: 5,5 m
Placebo:2,8m
mPFS
Pazopanib: 9,2 m
Placebo: 4,2 m
Motzer,NEJM 2007; Escudier, NEJM 2007; Sternberg, JCO 2010

4. THE AXIS TRIAL RESULTS
Axitinib
Rini, Lancet 2011; 378:

5. Linee guida AIOM Update 1° linea I linea
Rischio basso-intermedio Negativa forte Negativa debole Positiva debole Positiva forte
Sunitinib
Pazopanib
Beva + IFN
Sorafenib
Il 2

6. Linee guida AIOM Update 2 Linea
2 linea dopo citochine Negativa forte Negativa debole Positiva debole Positiva forte
Axitinib
Sorafenib
Sunitinib
Pazopanib
2 linea dopo
Inibitore VEGF Negativa forte Negativa debole Positiva debole Positiva forte
Everolimus
Axitinib
Sorafenib

7. Key options upon disease progression on first-line therapy
VEGFr-TKI → mTOR

8. RECORD-4: a Multicenter Phase 2 Trial of Second-Line Everolimus in Patients With Metastatic Renal Cell Carcinoma
Robert J. Motzer,1 Anna Alyasova,2 Dingwei Ye,3 Andrey Karpenko,4 Hanzhong Li,5 Boris Alekseev,6 Liping Xie,7 Galina Kurteva,8 Ruben Kowalyszyn,9 Yeni Neron,10 Thomas Cosgriff,11 LaTonya Collins,12 Thomas Brechenmacher,13 Scott Segal,14 Liza Morgan,15 Lin Yang,16
1Memorial Sloan-Kettering Cancer Center, New York, New York, USA,2 Prevoljskiy Region Medical Centre, Novgorod, Russia, 3Fudan University Shanghai Cancer Center, Shanghai, China, 4Leningrad Regional Oncologic Dispensary, Saint-Petersburg, Russia, 5Peking Union Medical College Hospital, Beijing, China, 6Moscow Hertzen Oncology Institute, Moscow, Russia, 7First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Province, China, 8Center of Oncology, Sofia, Bulgaria, 9Centro de Investigaciones Clinicas Clinica Viedma, Rio Negro, Argentina, 10Centro de Pesquisas Oncológicas-CEPON, Florianopolis-SC,Brazil, 11Crescent City Research Consortium, Metairie, Louisiana, 12Novartis Oncology, East Hanover, New Jersey, USA, 13Novartis Pharma S.A.S., Rueil-Malmaison, France, 14Novartis Oncology, East Hanover, New Jersey, USA, 15Novartis Oncology, East Hanover, New Jersey, USA, 16Cancer Institute and Hospital, Chinese Academy of Medical Science, Beijing, China

9. Study Objectives
The RECORD-4 study was designed to prospectively assess everolimus in an exclusively second-line setting (ClinicalTrials.gov ID, NCT )
Efficacy and safety of everolimus was assessed in patients with mRCC whose disease progressed after first-line treatment with an anti-VEGF or a cytokine agent
Primary objective
To assess PFS of second-line everolimus in mRCC
Secondary objectives
PFS by first-line cohorts, OS, AE profile
Motzer RJ et al. ASCO Abstract 4518.

10. until disease progression or intolerable toxicity
RECORD-4 Study Design
Primary objective
PFS (all patients)
Secondary objectives
PFS (by first-line cohorts) OS
ORR
AE profileb
Cohort 1: First-line sunitinib
Cohort 2: Other first-line anti-VEGF therapya
Cohort 3: First-line cytokine-based therapy
Everolimus 10 mg/day
until disease progression or intolerable toxicity
aOther first-line anti-VEGF therapy was sorafenib, bevacizumab, pazopanib, tivozanib, and axitinib.
bGrade 3 and 4 AEs were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Grade 1 and 2 AEs were recorded only if they led to dose modification or interruption.
ClinicalTrials.gov ID, NCT
Data cutoff was Sept 1, 2014
Motzer RJ et al. ASCO Abstract 4518.

11. PFS by First-Line Treatment Cohort (Investigator Assessment)
K-M Median PFS, months
First-line sunitinib
5.7 95% CI, 3.7, 11.3
Other first-line anti-VEGF
7.8 95% CI, 5.7, 11.0
First-line cytokines
% CI 2.6, NE)
100 80 60 40 20 2 4 6 8 10 12 14 16 18 22 24
Progression-free survival, %
Time, months
First-line sunitinib (n/N = 43/58)
Other first-line anti-VEGF therapy (n/N = 38/62)
First-line cytokine therapy (n/N = 7/14)
Number of patients still at risk
Prior sunitinib 58 41 30 23 20 17 14 9 5 4
Other prior anti-VEGF 62 49 37 29 13 7 6 3 1
Prior cytokines 12 10 2
NE, non-estimable; n/N, number of patients who progressed or died/total number of patients.
Other first-line anti-VEGF therapy was sorafenib, bevacizumab, pazopanib, tivozanib, and axitinib.
Motzer RJ et al. ASCO Abstract 4518.

12. OS by First-Line Treatment Cohort (Immature)
100 80 60 40 20 3 6 9 12 15 18 21 24 27 30
Overall survival, %
Time, months
First-line sunitinib (n/N = 20/58)
Other first-line anti-VEGF therapy (n/N = 24/62)
First-line cytokine therapy (n/N = 2/14)
K-M Median OS, months
First-line sunitinib NE
Other first-line anti-VEGF
% CI, 11.7, NE
First-line cytokines
Number of patients still at risk
Prior sunitinib 58 56 52 44 28 19 12 5 1
Other prior anti-VEGF 62 46 32 20 17 9 6
Prior cytokines 14 13 10 8 7 2
NE, non-estimable; n/N, number of patients who died/total number of patients.
Other first-line anti-VEGF therapy was sorafenib, bevacizumab, pazopanib, tivozanib, and axitinib.
Motzer RJ et al. ASCO Abstract 4518.

13. Conclusions
RECORD-4 results confirm the PFS benefit of everolimus in the second-line setting1
PFS benefit with second-line everolimus was observed for patients treated with first-line sunitinib and with various other first-line anti-VEGF therapies1
The grade 3−4 AE profile was similar to that reported in RECORD-12
1. Motzer RJ et al. ASCO Abstract 4518; 2. Motzer RJ et al. Cancer. 2010;116:

14. Final Overall Survival Analysis for the RECORD-3 Study of First-Line Everolimus Followed by Sunitinib Versus First-Line Sunitinib Followed by Everolimus in Metastatic RCC
Jennifer J. Knox,1 Carlos H. Barrios,2 Tae Min Kim,3 Thomas Cosgriff,4 Vichien Srimuninnimit,5 Ken Pittman,6 Roberto Sabbatini,7 Sun Young Rha,8 Thomas W. Flaig,9 Ray D. Page,10 J. Thaddeus Beck,11 Foon-yiu Cheung,12 Sunil Yadav,13 Poulam Patel,14 Lionel Geoffrois,15 Edward M. Schiff,16 Julie Niolat,17 Noah Berkowitz,18 Maurizio Voi,19 Robert J. Motzer20
1Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada, 2PUCRS School of Medicine, Porto Alegre, Brazil, 3Seoul National University Hospital, Seoul, Korea,4Crescent City Research Consortium, Metairie, Louisiana, USA, 5Siriraj Hospital, Mahidol University, Mahidol, Thailand, 6 The Queen Elizabeth Hospital, Woodville, South Australia, Australia, 7AOU Policlinico di Modena, Modena, Italy , 8Yonsei Cancer Center, Seoul, Korea, 9University of Colorado School of Medicine, Aurora, CO, USA, 10The Center for Cancer and Blood Disorders, Fort Worth, Texas, USA, 11Highlands Oncology Group, Fayetteville, Arkansas, USA, 12Queen Elizabeth Hospital, Hong Kong, China, 13Saskatoon Cancer Center, University of Saskatchewan, Saskatoon, Saskatchewan, Canada, 14University of Nottingham, Nottingham, UK, 15 Médicale Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy Cedex, France,16Novartis Oncology, East Hanover, New Jersey, USA, 17Novartis Pharma SAS, Rueil-Malmaison, France, 18Novartis Oncology, East Hanover, New Jersey, USA, 19Novartis Oncology, East Hanover, New Jersey, USA, 20Memorial Sloan-Kettering Cancer Center, New York, New York, USA

15. Background/Study Objective
Current treatment guidelines for patients with mRCC recommend a first-line VEGF inhibitor, including the VEGFR-TKI sunitinib, followed by an agent such as the mTOR inhibitor everolimus at progression1-3
RECORD-3 (ClinicalTrials.gov ID, NCT ) was a multicenter, randomized phase 2 trial that compared first-line everolimus followed by sunitinib (everolimus → sunitinib) with first-line sunitinib followed by everolimus (sunitinib → everolimus) at PD in patients with mRCC4
In the final primary analysis comparing progression-free survival (PFS) of everolimus and sunitinib as first-line therapy, the noninferiority margin was not achieved; therefore, the primary end point was not met
1. NCCN Clinical Practice Guidelines in Oncology Kidney Cancer ( 2. Ljungberg B et al. EAU Guidelines on Renal Cell Carcinoma. Update ( 3. Escudier B et al. Ann Oncol. 2014;25(suppl 3):iii49-iii56; 4. Motzer RJ et al. J Clin Oncol. 2014;32:

16. Key eligibility criteria
Study Design
Primary objective
PFS first-line
Secondary objectives
PFS combined
ORR first-line OS
Safety
Final OS analysis
Key eligibility criteria
Clear cell or non-clear cell mRCC
Measurable disease
Did or did not undergo nephrectomy
No prior systemic therapy
KPS ≥70% R A N D O M I Z E
Everolimus
10 mg/day continuous
Sunitinib
50 mg/day schedule 4/2
First Line
Second Line
N=471
1:1
Crossover upon progressiona
aTo occur within 35 days of progression
Motzer RJ et al. J Clin Oncol. 2014;32:

17. Combined PFS (Final Analysis)
Knox JJ et al. ASCO Abstract 4554.

18. OS (Final Analysis)
Knox JJ et al. ASCO Abstract 4554.

19. Safety Profile Updated
Most frequently reported AEs during first-line everolimus and sunitinib, respectively,
Stomatitis (53% and 58%), fatigue (47% and 53%), and diarrhea (40% and 58%)
Grade 3−4 AEs suspected to be related to treatment
First-line therapy, 47% with everolimus and 63% with sunitinib
Second-line therapy, 47% with everolimus and 57% with sunitinib
Within each treatment sequence, 62% with everolimus → sunitinib and 71% with sunitinib → everolimus
On-treatment deaths
Safety population: 34 (14%) in the first-line everolimus arm (n = 238) and 15 (6%) in the first-line sunitinib arm (n = 231)
Second-line safety population: 11 (9%) with everolimus (n = 116) and 12 (9%) with sunitinib (n = 128)
Knox JJ et al. ASCO Abstract 4554.

20. Conclusions
Results of this final OS analysis are consistent with initial results and further support the sequence of VEGFR-targeted therapy followed by everolimus, in clear cell and non-clear cell mRCC, at PD
Median OS 29.5 months for sunitinib → everolimus
Low rate of crossover to second-line therapy (50−54%) surprising; but the median combined PFS of 22.2 months for sunitinib → everolimus is a novel end point that was not previously established in prospective trials, and it can serve as a new benchmark in sequential therapy
Because of high censoring rates, there are limitations to the interpretation of combined PFS results
AE profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals
Knox JJ et al. ASCO Abstract 4554.

21. Nivolumab: Mechanism of Action
Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 up-regulation on tumour
Priming and activation of T cells through MHC/antigen & CD28/B7 interactions with antigen-presenting cells
IFNγ
IFNγR
T cell receptor
T cell receptor
MHC
MHC
PI3K
Shp-2
NFκB
Dendritic cell
Other
CD28 B7
Tumour
cell
PD-L1
T cell
PD-1
PD-L1
PD-L2
PD-1
PD-L2
PD-1
PD-1
Nivolumab blocks the PD-1 receptor
Adapted from Pardoll 2012.[1]
CD28/B7, cluster of differentiation 28/B7; IFNγ, interferon-gamma; IFNγR, IFNγ receptor; NFκB, nuclear factor kappa B; PD-1, programmed death-1; PD-L1, PD ligand-1; PI3K, phosphoinositide-3 kinase; Shp-2, ubiquitously expressed tyrosine-specific protein phosphatase.
Pardoll DM. Nat Rev Cancer. 2012;12(4):

22. CheckMate 025: A randomized, open-label, phase III study of nivolumab versus everolimus in advanced renal cell carcinoma
Padmanee Sharma, Bernard Escudier, David F. McDermott, Saby George, Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey A. Sosman, Giuseppe Procopio, Elizabeth R. Plimack, Daniel Castellano, Howard Gurney, Frede Donskov, Petri Bono, John Wagstaff, Thomas C. Gauler, Takeshi Ueda, Li-An Xu, Ian M. Waxman, Robert J. Motzer, on behalf of the CheckMate 025 investigators

23. Introduction
No phase III clinical trial has demonstrated an OS benefit versus standard therapy in previously treated patients with mRCC to date; this highlights a significant unmet need
Nivolumab, a PD-1 immune checkpoint inhibitor, demonstrated encouraging OS and acceptable safety in a phase II study in previously treated patients with mRCC1
This phase III study compared nivolumab versus everolimus in patients with mRCC after prior anti-angiogenic treatment (NCT )
1. Motzer RJ. J Clin Oncol 2015.

24. 3 mg/kg intravenously every two weeks
Study design
Nivolumab
3 mg/kg intravenously every two weeks
Everolimus
10 mg orally
once daily
Randomize 1:1
Previously treated mRCC
Stratification factors
Region
MSKCC risk group
Number of prior anti- angiogenic therapies
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.

25. Study endpoints Primary endpoint Overall survival (OS)
Secondary endpoints included
Objective response rate (ORR)
Progression-free survival (PFS)
Adverse events
Quality of life (QoL)
OS by PD-L1 expression

27. Overall survival by subgroup analyses
Nivolumab
n/N
Everolimus
MSKCC risk group
Favorable
45/145
52/148
Intermediate
101/201
116/203
Poor
37/64
47/60
Prior anti-angiogenic regimens 1
128/294
158/297 2
55/116
57/114
Region
US/Canada
66/174
87/172
Western Europe
78/140
84/141
Rest of the world
39/96
44/98
Age, years
<65
111/257
118/240
≥65 to <75
53/119
77/131
≥75
19/34
20/40
Sex
Female
48/95
56/107
Male
135/315
159/304
Nivolumab
0.25
0.5
0.75
1.5
2.25 1
Everolimus
Favors
Analyses based on interactive voice response system data.
Note: none of the treatment-by-subgroup interactions (including the PD-L1 subgroups in the previous slide) are statistically significant.

29. Treatment-related AEs in ≥10% of patients
Nivolumab
N = 406
Everolimus
N = 397
Any grade
Grade 3
Grade 4a
Grade 4b
Treatment-related AEs, % 79 18 1 88 33 4
Fatigue 2 34 3
Nausea 14
<1 17
Pruritus 10
Diarrhea 12 21
Decreased appetite
Rash 20
Cough 9 19
Anemia 8 24
Dyspnea 7 13
Edema peripheral
Pneumonitis 15
Mucosal inflammation
Dysgeusia
Hyperglycemia
Stomatitis 29
Hypertriglyceridemia 16
Epistaxis
a Grade 4 AEs not listed in table: increased blood creatinine (1), acute kidney injury (1), anaphylactic reaction (1).
b Grade 4 AEs not listed in table: increased blood triglycerides (2), acute kidney injury (1), sepsis (1), chronic obstructive pulmonary disorder (1), increased blood cholesterol (1), neutropenia (1), pneumonia (1).

30. Conclusions
CheckMate 025 met its primary endpoint, demonstrating superior OS with nivolumab versus everolimus
This is the only phase III trial to demonstrate a survival advantage in previously-treated patients with mRCC versus standard therapy
Survival benefit with nivolumab was consistent across subgroups and irrespective of PD-L1 expression
Nivolumab was associated with fewer grade 3 and 4 treatment- related AEs and fewer treatment-related AEs leading to discontinuation than everolimus
The superior survival and favorable safety profile in this phase III trial provide evidence for nivolumab as a potential new treatment option for previously treated patients with mRCC

38. Cabozantinib as new drug in RCC

39. Cabozantinib as new drug in RCC

43. L’oncologo nel nuovo scenario di II linea
PFS come end point surrogato della OS nei pazienti con ca. renale metastatico
Con le immunoterapie la PFS non può essere usata come end point surrogato
Lo studio meteor potrebbe confermare la PFS come end point surrogato

44. Current RCC Treatment Algorithm
Regimen
Setting
Recommended
Therapy
Other Options
Treatment-naive patient (1st line)
MSKCC risk: Good or intermediate
Pazopanib
Sunitinib Bevacizumab + IFN-α
High-dose IL-2
Sorafenib
Clinical trial
MSKCC risk: Poor
Temsirolimus
Sunitinib
Treatment-refractory
patient (≥2nd line)
Cytokine-refractory
Axitinib
Bevacizumab + IFN-α
TKI-refractory
Everolimus
IL-2, interleukin 2; MSKCC, Memorial Sloan-Kettering Cancer Center; TKI, tyrosine kinase inhibitor.
Escudier B et al. Ann Oncol 2014; 25 (Suppl. 3): iii49-iii56.
Ljungberg B et al
NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. V3.2015

45. Sistema prognostico IMDC o criteri di Heng
Sistemi prognostici
Karnosky PS
< 80%
Tasso di emoglobinemia
< limite inferiore range di riferimento
Calcio corretto
> 10 mg dl
Periodo dalla diagnosi al trattamento
< 1 anno
Conta assoluta neutrofili
> Limite superiore normalità
Conta piastrinica
Sistema prognostico IMDC o criteri di Heng
Prognosi
N. fattori
Sopravvivenza mediana
Sopravvivenza a 2 anni
Favorevole NR
75%
Intermedia
1-2
27 mesi
53%
Sfavorevole
3-6
8.8 mesi 7%
Sistema prognostico Heng : categorie di rischio e sopravvivenza mediana

46. Possibile futuro scenario terapeutico
Sunitinib Axitinib
Everolimus
Cabozantinib
Nivolumab
Pazopanib Everolimus

47. Conclusioni Prima linea:
Sunitinib e Pazopanib sono standard di cura per i pazienti con malattia a cellule chiare a prognosi buona ed intermedia
L’utilizzo di schedule alternative di sunitinib è consigliabile nella sola gestione della tossicità
Seconda linea: l’immunoterapia condizionerà il trattamento di seconda linea
Axitinib rimarrà uno standard a progressione da sunitinib
Ad oggi le opzioni restano everolimus ed axitinib

48. Grazie per l’attenzione