Novità sul trattamento delle neoplasie urologiche
CARCINOMA RENALE
ALKETA HAMZAJ
&
SERGIO BRACARDA
U.O.C. ONCOLOGIA MEDICA
Current treatment algorithm in mRCC (NCCN guidelines)
1-st line clear-cell RCC 2-nd line clear-cell RCC
Clinical trial Sunitinib [1]
Pazopanib [1]
Beva+INF-a [1]
High-dose IL-2 b Sorafenib †
Good or
intermediate risk Poor risk
Temsirolimusa Sunitinib [2b]
Sorafenib [3b]
Temsirolimus[3b]
Sunitinib [3b]
Sorafenib [3b]
Clinical trial
Sunitinib [2a]
Pazopanib [3]
Bevacizumab [2a]
IL-2 [2b]
Sorafenib [2a]
Clinical trial
Sunitinib [1]
Pazopanib [1]
Bevacizumab [2a]
IL-2 [2b]
Sorafenib [1]
Prior VEGF-TKI Prior cytokine
Everolimus [1]
Axitinib [1]
Temsirolimus [2b]
Axitinib [1]
Temsirolimus [2a]
Non clear cell RCC
[Category of evidence]; † selected patients ;
aCategory 1 for poor-prognosis patients; category 2B for selected patients of other risk groups; bPatients with excellent PS and normal organ function
NCCN Kidney Cancer Clinical Practice Guidelines v2.2014.
Targeted agents for mRCC, 1st-line therapy
1. Motzer 2007; 2. Motzer 2009; 3. Hudes 2007; 4. Escudier 2010; 5. Rini 2010; 6. Escudier 2009; 7. Sternberg 2010; 8.Sternberg 2011 9.Motzer 2012
*Poor risk patients, modified MSKCC criteria ( ) total patient population
1.Motzer 2012, 2.Motzer 2013, 3.Ravaud 2012, 4.Rini 2012 5.McDermott 2013, 6.Hutson 2013
Targeted agents for mRCC,
1st-line therapy
Sequential Therapy & Diferent Scheduling
The RECORD-3 study:
planned to identify the best sequence between TKI and mTOR
Motzer RJ et al. J Clin Oncol 2014;32:2765–2772
.
RECORD-3 study: first-line PFS & median OS
Motzer RJ et al. J Clin Oncol 2014;32:2765–2772.
SWITCH Trial:
Sequential study to evaluate the efficacy and safety of Sorafenib-Sunitinib vs Sunitinib-Sorafenib in mRCC
Michel et al, GU ASCO 2014;
Eichelberg C et al. European Urology, 2015
(A) total Progression-Free Survival and (B) Overall Survival (ITT population )
Overall crossover = 49%
SWITCH Trial:
Median first-line PFS and second-line PFS
More So-Su patients than Su-So patients reached protocol-defined second-line therapy (57% vs 42%)
Michel et al, GU ASCO 2014;
Eichelberg C et al. European Urology, 2015
Diferent Scheduling
Sunitinib 2/1 schedule
Neri 31 16.4mos 18.1mos
Int J Urol 2013
Atkinson 88 14.5mos 33mos
J Urol 2014*
Kletas 28 10mos 23mos
ASCO 2013
Bracarda 208 38.6mos NR
ASCO GU 2014*
Bracarda 41 9.6mos NR
ASCO GU 2014
N PFS, med OS, med
*changed to 2/1 schedule
J.L Lee et al. ASCO GU 2015
Retrospective Observational Study of Sunitinib
Administered on Schedule 2/1 in Patients With mRCC:
The RAINBOW Study 1
Eligibility:
Italian mRCC patients treated with sunitinib Schedule 2/1
Sunitinib 50 mg/day (Schedule 4/2)
Sunitinib
≤50 mg/day (Schedule 2/1) n=208
n=41
n=208
Sunitinib 50 mg/day (Schedule 2/1)
1. Bracarda S, et al.
• Retrospective, observational, multicenter study (24 Italian local and referral centers)
• Data collected from November 2005 to August 2013
• Control group from the Gustave Roussy Institute treated with the standard 4/2 Schedule and no modifications other than dose related
• The main reasons for changing schedule were fatigue, mucositis, diarrhea, and hand-foot syndrome
Bracarda et al, ASCO GU 2014. J Clin Oncol 2014. 32:suppl 4; abstr 471
Toxicities (grade ≥3) were significantly reduced on Schedule 2/1 compared with the initial Schedule 4/2
(8% vs 46%, respectively; P<0.001) 1
Adverse Event, %
Schedule 4/2 (n=208)
Schedule 2/1
(n=208) P Value
All events 45.7 8.2 <0.001
Diarrhea 3.9 − 0.008
Fatigue 10.1 − <0.001
Mucositis 6.7 0.5 <0.001
Anorexia 2.4 − 0.063
Hand-foot syndrome 10.1 3.4 0.003
Hypertension 9.1 2.4 0.007
Heart failure 0.5 − 1.000
Thrombocytopenia 7.7 0.5 <0.001
Incidence of Grade 3–4 NCI-CTC Toxicity in Cohort 4:22:1 (Entire Cohort)
NCI-CTC=National Cancer Institute−Common Toxicity Criteria.
1. Bracarda S, et al.
Adverse Event, %
Schedule 4/2 (n=106)
Schedule 2/1
(n=106) P Value
All events 41.5 6.6 <0.001
Diarrhea 3.8 − 0.125
Fatigue 13.2 − <0.001
Mucositis 4.7 1.0 0.219
Anorexia 1.9 − 0.500
Hand-foot syndrome 13.2 1.9 0.002
Hypertension 5.7 1.9 0.289
Heart failure − − NA
Thrombocytopenia 4.7 1.0 0.219
Maximum toxicity (grade ≥3) was also significantly reduced when sunitinib 50 mg/day schedule 2/1 was modified to sunitinib 50 mg/day schedule 4/2 1
Incidence of Grade 3–4 NCI-CTC Toxicity in Cohort 4:22:1 Treated Without Dose Reduction (50 mg/day)
NA=not available; NCI-CTC=National Cancer Institute−Common Toxicity Criteria.
1. Bracarda S, et al.
RAINBOW Study: Efficacy Data 1
Group 4/22/1 Group 2/1 Control
Patients, n
208
106 with 50 mg on 2/1 102 with <50 mg on 2/1
41 211
Median treatment duration, mo
(interquartile range)
28.2 (14.2–70.8)
7.8 (5.8–22.4)
9.7 (5.3–16.7) mPFS, mo (interquartile
range)
30.2 (23.2–47.1)
10.4 (7.7–23.0)
9.7 (8.9–11.7)
mOS, mo
NR
(36-mo probability:
72.7%)
23.2 (10.6–NE)
27.8 (23.1–35.8)
mPFS=median progression-free survival; mOS=median overall survival; NE=not evaluable; NR=not reported.
1. Bracarda S, et al.
• Baseline characteristics were not balanced between study groups
• Schedule 4/22/1 had more favorable characteristics compared to the other 2 groups in terms of histology, burden of disease, and prognostic risk (Heng criteria)
• Patients in the 2/1 group had less favorable characteristics in terms of ECOG PS and
the presence of brain metastases
VEGF-R TKI
Current & Future Drug – “Classes” in mRCC
Anti-Angiogenic Agents
Immune Checkpoint Inhibitors
VEGF Inhibitors
m-TOR Inhibitors
anti PD-1/PD-L1
anti -CTLA-4
Checkpoint Inhibitor Therapy
Checkpoint Inhibitor Therapy
Both approaches activate anti-tumor T-cell activity
Nature, 2014
Nivolumab in metastatic RCC – phase II data
Nivolumab in metastatic RCC-phase II data
CheckMate-025:
Phase III study of Nivolumab vs Everolimus in locally advanced/mRCC with prior anti-angiogenic therapy 1,2
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, DOR, duration of OS in PD-L1-positive vs PD-L1-negative subgroups, safety, disease-related symptom progression rate
• Stratification: MSKCC risk criteria; number of prior anti-angiogenic therapies; region
Eligibility:• Advanced or mRCC with clear-cell component
• Received 1 or 2 prior anti-angiogenic therapies
• Progression on or after most recent therapy (within 6 months of study enrolment)
• Karnofsky PS ≥70
Nivolumab
3 mg/kg IV every 2 weeks
Everolimus 10 mg orally daily RA
N D O M
I SA
T I O N N=821
1:1
Treatment until disease progression or unacceptable toxicity
1. www.clinicaltrials.gov (NCT01668784);
2. Motzer et al. NEJM 2015
CheckMate-025: Patient demographics
Characteristic Nivolumab Group
(N = 410)
Everolimus Group (N = 411)
Median age, years (range) 62 (23–88) 62 (18–86)
Sex, %
Male Female
77 23
74 26 MSKCC risk group, %
Favourable Intermediate Poor
35 49 16
36 49 15 Number of prior anti-angiogenic regimens in advanced
setting, % 1 2
72 28
72 28 Region, %
US/Canada Western Europe Rest of world
42 34 23
42 34 24
Motzer et al. NEJM 2015 Sharma et al. ECC 2015 Oral presentation 3LBA
CheckMate-025: OS
Motzer et al. NEJM 2015 Minimum follow-up was 14 months
CheckMate-025: PFS
Motzer et al. NEJM 2015
CheckMate-025: Antitumour activity
Motzer et al. NEJM 2015 Motzer et al. NEJM 2015 Supplement
*For patients without progression, duration of response is defined as the time from first response date to date of censoring
Characteristic Nivolumab Group
(N = 410)
Everolimus Group (N = 411)
ORR,% 25 5
Odds ratio (95% CI) P value
5.98 (3.68‒9.72)
<0.001 Best overall response,%
Complete response Partial response Stable disease Progressive disease Not evaluated
1 24 34 35 6
<1 5 55 28 12 Median time to response, months (range) 3.5 (1.4‒24.8) 3.7 (1.5‒11.2) Median duration of response, months (range)* 12.0 (0‒27.6) 12.0 (0‒22.2)
Ongoing response, n/N (%) 49/103 (48) 10/22 (45)
CheckMate-025: OS by subgroup analysis
Motzer et al. NEJM 2015
CheckMate-025: OS by PD-L1 expression
Motzer et al. NEJM 2015
CheckMate-025: Safety summary
*Septic shock (1); bowel ischemia (1)
Nivolumab Group (N = 406)
Everolimus Group (N = 397)
Any Grade Grade 3 or 4 Any Grade Grade 3 or 4
Treatment-related AEs, % 79 19 88 37
Treatment-related AEs leading to
discontinuation, % 8 5 13 7
Treatment-related deaths, n 0 2*
44% of patients in the nivolumab arm and 46% of patients in the everolimus arm were treated beyond progression
Motzer et al. NEJM 2015 Sharma et al. ECC 2015 Oral presentation 3LBA
CheckMate-025: Treatment-related AEs in ≥10% of patients
Motzer et al. NEJM 2015 Treatment-related AE, %
Nivolumab Group (N = 406)
Everolimus Group (N = 397)
Any Grade Grade 3 or 4 Any Grade Grade 3 or 4
All events 79 19 88 37
Fatigue 33 2 34 3
Nausea 14 <1 17 1
Pruritus 14 0 10 0
Diarrhoea 12 1 21 1
Decreased appetite 12 <1 21 1
Rash 10 <1 20 1
Cough 9 0 19 0
Anaemia 8 2 24 8
Dyspnoea 7 1 13 1
Peripheral oedema 4 0 14 1
Pneumonitis 4 1 15 3
Mucosal inflammation 3 0 19 3
Dysgeusia 3 0 13 0
Hyperglycaemia 2 1 12 4
Stomatitis 2 0 29 4
Hypertriglyceridemia 1 0 16 5
Epistaxis 1 0 10 0
Current phase III immunotherapy trials challenging treatments paradigms for advanced clear-cell mRCC
Current phase III immunotherapy trials challenging
treatments for advanced clear-cell mRCC
IMmotion151 : (recruiting)
Randomized phase 3 study of Atezolizumab + Bevacizumab versus Sunitinib in patients with untreated mRCC
www. clinicaltrials.gov (NCT02420821))
MPDL3280A + BEVA
SUNITINIB
Treat until disease progression
•Primary endpoint: PFS
•Secondary endpoints: OS, ORR, TTD, safety DoR
N =550
Eligibility Criteria Advanced or Metastatic RCC
• Previously untreated in advanced or metastatic setting
• Tissue available for PD-1 testing.
Arm A:
Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV
Q3W x4
Arm B:
Sunitinib 50 mg PO 4/6 wks
1:1
Stratify by: IMDC Prognostic Score (0 vs 1-2 vs 3-6); Region
(US vs Canada/WEurope/
NEurope vs ROW)
Co-Primary endpoints: PFS and OS
• Secondary endpoints: PFS and OS in any-risk subjects with treatment naive mRCC, ORR, PK, safety
N=1070 pz
CheckMate 214:
Randomized phase 3 study of Nivolumab + Ipilimumab vs Sunitinib in previously untreated mRCC
Study design:
Continuous Nivolumab 3 mg/kg IV, Q2W
R A N D O M
I Z A T I O N
Start up June 2014
www. clinicaltrials.gov (NCT02231749)
