Maria Pia Vitale
Oncologia Medica
Azienda Ospedaliera Universitaria Policlinico di Modena
GRUPPO B
Ruolo dei checkpoint inhibitors nelle neoplasie renali e della vescica:
Le evidenze scientifiche e l’inserimento dei checkpoint inhibitors
nell’algoritmo decisionale
del carcinoma renale metastatico e della vescica
Ruolo dei checkpoint inhibitors nelle neoplasie renali Le evidenze scientifiche e l’inserimento
dei checkpoint inhibitors nell’algoritmo decisionale del carcinoma renale metastatico
1° Linea Metastatica
• Categoria di rischio sfavorevole/intermedio - Nivolumab + Ipilimumab
- Cabozantinib
• Categoria di rischio favorevole - Tki
• Atezolizumab-Bevacizumab
Dati di PFS significativi, OS non ancora maturi
• Tki + IO
Ruolo dei checkpoint inhibitors nelle neoplasie renali Le evidenze scientifiche e l’inserimento
dei checkpoint inhibitors nell’algoritmo decisionale del carcinoma renale metastatico
Progressione dopo VEGFr-inibitori - Nivolumab (seconda e terza linea)
Ruolo di PDL-1
- Dati discordanti tra Check-mate 025 e CA209-214 (setting diverso? Impiego di
ipilimumab?)
Courtesy of G. Procopio
CheckMate 214: Study design
IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status; Q2W, every 2 weeks; Q3W, every 3 weeks
Treatment until progression or unacceptable
toxicity
• Treatment-naïve advanced or
metastatic clear-cell RCC
• Measurable disease
• KPS ≥70%
• Tumor tissue available for PD-L1 testing
Treatment Patients
Randomize 1:1
Arm A
3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV Q3W
for four doses, then 3 mg/kg nivolumab IV Q2W
Arm B
50 mg sunitinib orally once daily for 4 weeks
(6-week cycles)
Stratified by
•IMDC prognostic score (0 vs 1–2 vs 3–6)
•Region (US vs Canada/Europe vs Rest of World)
• In IMDC intermediate- and poor-risk patients
– ORR (per independent radiology review committee, IRRC) – PFS (per IRRC)
– OS
• Statistical analyses
– Overall alpha is 0.05, split among the three co-primary endpoints – 0.001 for ORR, 0.009 for PFS, and 0.04 for OS
– PFS analysis had ~80% power and OS analysis had 90% power to detect a statistically significant difference between treatment arms
– The number of patients randomized was estimated to be ~1,070, 820 of whom would have IMDC intermediate/poor risk
Co-primary endpoints
• Secondary endpoints (in intention-to-treat [ITT] patients) – ORR
– PFS – OS
– Adverse event incidence rate (in all treated patients)
• PFS and OS secondary efficacy endpoints were subject to hierarchical testing, first testing in intermediate/poor-risk patients followed by testing in ITT patients, if significant
• Exploratory endpoints
– ORR, PFS, and OS in favorable-risk patients – Outcomes by tumor PD-L1 expression level
– HR QoL based on NCCN Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19)
Secondary and exploratory endpoints
ORR and DOR: IMDC intermediate/poor risk
N = 847
Outcome NIVO + IPI
N = 425
SUN N = 422 Confirmed ORR,a% (95% CI) 42 (37–47) 27 (22–31)
P < 0.0001 Confirmed BOR,a%
Complete response Partial response Stable disease Progressive disease
Unable to determine/not reported
9b 32 31 20 8
1b 25 45 17 12
aIRRC-assessed ORR and BOR by RECIST v1.1; bP < 0.0001
SUN NIVO + IPI No. at Risk
177 146 120 55 3
112 75 52 17 0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0 6 12 18 24
Months
Duration of Response(Probability)
Co-primary endpoint: ORR
Median duration of response, months (95% CI)
Patients with ongoing response, %
NIVO + IPI NR (21.8–NE) 72
SUN 18.2 (14.8–NE) 63
OS: IMDC intermediate/poor risk
Hazard ratio (99.8% CI), 0.63 (0.44–0.89) P < 0.0001
Median OS, months (95% CI) NIVO + IPI NR (28.2–NE)
SUN 26.0 (22.1–NE)
Overall Survival (Probability)
425 399 372 348 332 318 300 241 119 44 2 0
422 387 352 315 288 253 225 179 89 34 3 0
No. at Risk NIVO + IPI
SUN
Months 1.0
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
18 21 24 27 30 33
15 9 12
6 3
0
Co-primary endpoint
0 3 6 9 12 15 18 21 24 27 30
PFS per IRRC: IMDC intermediate/poor risk
Hazard ratio (99.1% CI), 0.82 (0.64–1.05) P = 0.0331
Median PFS, months (95% CI) NIVO + IPI 11.6 (8.7–15.5)
SUN 8.4 (7.0–10.8)
Progression-Free Survival (Probability)
425 304 233 187 163 149 118 46 17 3 0
422 282 191 139 107 86 57 33 11 1 0
No. at Risk NIVO + IPI
SUN
Months 1.0
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Co-primary endpoint
ORR, PFS, and OS: Intention to treat
a23% of patients in the NIVO + IPI arm and 25% of patients in the SUN arm had tumor PD-L1 expression ≥1%
bIRRC-assessed by RECIST v1.1
cIRRC-assessed
N = 1,096a
Outcome NIVO + IPI
N = 550
SUN N = 546 Confirmed ORR,b% (95% CI) 39 (35–43) 32 (28–36)
P = 0.0191 PFS,cmedian (95% CI),
months
12.4 (9.9–16.5) 12.3 (9.8–15.2) HR (99.1% CI) 0.98 (0.79–1.23)
P = 0.8498
550 523 492 464 443 426 404 339 197 71 4 0 546 506 471 432 402 363 334 283 173 66 6 0
Overall Survival (Probability)
0.8 0.9 1.0
0.4 0.5 0.6 0.7
0 6 12 18 24
0.1 0.0 0.2 0.3
33 30
3 9 15 21 27
Months No. at Risk
NIVO + IPI
HR (99.8% CI) 0.68 (0.49–0.95) P = 0.0003
Median OS, months (95% CI) NIVO + IPI NR (NE–NE)
SUN 32.9 (NE–NE)
Secondary endpoint
ORR and PFS: IMDC favorable risk
a11% of patients in both arms had tumor PD-L1 expression ≥1%
bIRRC-assessed by RECIST v1.1
cIRRC-assessed
N = 249a
Outcome
NIVO + IPI N = 125
SUN N = 124
Confirmed ORR,b% (95% CI) 29 (21–38) 52 (43–61)
P = 0.0002
PFS,c median (95% CI), months 15.3 (9.7–20.3) 25.1 (20.9–NE) HR (99.1% CI) 2.18 (1.29–3.68)
P < 0.0001
Exploratory endpoint
284 202 155 119 102 90 70 23 9 1 0
278 200 138 105 83 67 43 25 11 1 0
PFS by PD-L1 expression: IMDC intermediate/poor risk
PD-L1 <1% (n = 562) PD-L1 ≥1% (n = 214)
HR (95% CI) 0.48 (0.28–0.82) P = 0.0003
Median PFS, months (95% CI) NIVO + IPI 22.8 (9.4–NE) SUN 5.9 (4.4–7.1)
HR (95% CI) 1.00 (0.74–1.36) P = 0.9670
Median PFS, months (95% CI) NIVO + IPI 11.0 (8.1–14.9) SUN 10.4 (7.5–13.8)
NIVO SUN No. at
Risk
100 77 61 54 50 48 41 21 8 2 0
114 63 40 24 17 13 9 4 0 0 3
0.8 0.9 1.0
0.4 0.5 0.6 0.7
0 3 6 9 12 15 18 21 24 27 30
0.1 0.0 0.2 0.3 0.8
0.9 1.0
0.4 0.5 0.6 0.7
0 3 6 9 12 15 18 21 24 27 30
0.1 0.0 0.2 0.3
Progression-Free Survival (Probability)
Months Months
Exploratory endpoint
Treatment-related adverse events: All treated patients
NIVO + IPI N = 547
SUN N = 535
Event, % Any grade Grade 3–5 Any grade Grade 3–5a
Treatment-related adverse events in ≥25% of patients 93 46 97 63
Fatigue 37 4 49 9
Pruritus 28 <1 9 0
Diarrhea 27 4 52 5
Nausea 20 2 38 1
Hypothyroidism 16 <1 25 <1
Decreased appetite 14 1 25 1
Dysgeusia 6 0 33 <1
Stomatitis 4 0 28 3
Hypertension 2 <1 40 16
Mucosal inflammation 2 0 28 3
Palmar-plantar erythrodysesthesia syndrome 1 0 43 9
Treatment-related AEs leading to discontinuation, % 22 15 12 7
Treatment-related deaths n = 7b n = 4c
aTwo patients had grade 5 cardiac arrest. bPneumonitis, immune mediated bronchitis, lower GI hemorrhage, hemophagocytic syndrome, sudden death, liver toxicity, lung infection. cCardiac arrest (n = 2), heart failure, multiple organ failure
Secondary endpoint
IMmotion151: A Randomized Phase III Study <br />of Atezolizumab Plus Bevacizumab vs Sunitinib <br />in Untreated Metastatic Renal Cell Carcinoma
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Study Objectives
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Study Design
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Progression-Free Survival in PD-L1+
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Progression-Free Survival in ITT
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Objective Response Rate
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Objective Response Rate
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Objective Response Rate
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Overall Survival in ITT
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Overall Survival in PD-L1+
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Treatment-related AEs<br />≥ 20% frequency in either arm and > 5% difference between arms
Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
CheckMate 025 Study Design
aPatients were allowed to continue treatment beyond progression if investigator-assessed clinical benefit was achieved and treatment had an acceptable side-effect profile.
AE, adverse event; CNS, central nervous system; IV, intravenous; KPS, Karnofsky performance status; mTOR, mammalian target of rapamycin; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; PO, oral; qd, once daily; q2w, every 2 weeks;
R, randomized; RCC, renal cell carcinoma.
1. Motzer RJ et al. N Engl J Med 2015;373:1803–13. 2. Clinicaltrials.gov. NCT01668784. Accessed April 26, 2017.
Phase 3, randomized, open-label study of nivolumab vs everolimus in patients with advanced or metastatic clear cell RCC who have received prior anti-angiogenic therapy.1
Nivolumab
3 mg/kg IV q2w Until progression,a unacceptable toxicity, withdrawal of consent, or end of study
Key Inclusion Criteria1
• Advanced/metastatic clear cell RCC
• ≤3 total prior regimens
• 1 or 2 prior anti-angiogenic therapies
• Progression <6 months before enrollment
• KPS ≥70
• No CNS metastases
• No prior therapy with mTOR inhibitor
• No condition requiring glucocorticoids
R 1:1
Everolimus 10 mg PO qd
Primary Endpoint: OS
Secondary Endpoints: ORR, PFS, OS by PD-L1 expression, incidence of AEs Start Date: September 20122
Estimated Trial Completion Date: September 20182 Primary Completion Date: May 20152
Status: Ongoing but not recruiting2 Trial Director: Bristol-Myers Squibb2
N=821
Safety and Efficacy of Nivolumab for Metastatic Renal Cell Carcinoma:
Real-World Data From an Italian Expanded Access Program
Ugo De Giorgi,1Sarah Scagliarini,2Umberto Basso,3Luca Galli,4 Claudia Mosillo,5Claudia Caserta,6 Sabrina Rossetti,7Annalisa Guida,8Alessandra Bearz,9 Sebastiano Buti,10 Giovanni Lo Re,11 Francesca
Valcamonico,12Alketa Hamzay,13 Francesco Cognetti,14Francesca Rastelli,15Giuseppe Fornarini,16 Camillo Porta,17 Gabriella Del Bene,18 Daniele Turci,19Giuseppe Procopio20; the Italian EAP RCC Group
1Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy; 2AORN A. Cardarelli, Napoli, Italy; 3Istituto Oncologico Veneto, Padova, Italy; 4AOU Pisana Spedali Riuniti di S. Chiara, Pisa, Italy; 5Policlinico Umberto I, Roma, Italy; 6AO Santa Maria, Terni, Italy;
7Istituto Pascale, Napoli, Italy; 8AOU di Modena, Modena, Italy; 9Istituto Nazionale Tumori, Aviano, Italy; 10AOU di Parma, Parma, Italy; 11AO Santa Maria degli Angeli, Pordenone, Italy; 12ASST Spedali Civili di Brescia, Brescia, Italy; 13Azienda USL 8, Arezzo, Italy; 14IFO Regina Elena, Roma, Italy; 15UOC Oncologia Fermo Area Vasta 4, Fermo, Italy; 16Ospedale San Martino IST Genova, Genova, Italy; 17IRCCS San Matteo, Pavia, Italy;
18San Camillo Forlanini, Roma, Italy; 19Ospedale Santa Maria delle Croci, Ravenna, Italy; 20Istituto Nazionale Tumori, Milano, Italy
Abstract #4577
Methods
• Nivolumab was made available upon physician request through the EAP
• Eligible patients were aged ≥18 years with advanced or metastatic RCC that had relapsed after ≥1 prior systemic treatment in the advanced or metastatic setting
• ECOG PS had to be ≤2
• Patients with untreated CNS metastases or active autoimmune disease were excluded
• Nivolumab 3 mg/kg was administered intravenously every 2 weeks for up to 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent
• Treatment beyond RECIST v1.1- defined progression was allowed in the absence of rapid disease progression in patients who were deriving investigator-assessed clinical benefit while also tolerating treatment
• This analysis included all patients who received ≥1 dose of nivolumab
• Adverse events (AEs) were monitored throughout the program and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0
• Objective response rate (ORR), progression-free survival (PFS), and OS were evaluated; the method and timing of assessments were at investigator discretion
• The association between baseline patient characteristics and efficacy outcomes was explored using a Cox regression model
Results: Patients
39
Kaplan–Meier estimate of OS
43
Kaplan–Meier estimate of PFS
44
Results: Impact of Baseline Characteristics on Efficacy
• Response rates were comparable among patient subgroups based on previous lines of therapy, age, histology, and brain or bone metastasis
ORR in select subpopulations
Conclusions
• The EAP population included some subgroups that were poorly represented or not represented at all in the pivotal CheckMate 025 study
• Despite these differences, comparison of the survival curves suggests that the 9- month OS rate (73%) in the EAP approached that observed in the nivolumab arm of the CheckMate 025 trial
• As in CheckMate 025, some patients treated beyond progression derived further benefit with improved tumor response
• The safety profile of nivolumab appeared consistent with that reported in the CheckMate 025 trial
• As in CheckMate 025, nivolumab treatment in the EAP benefited subgroups of patients who were elderly or had bone metastases
• Noting the limitations of this study type, preliminary data from this EAP appear to confirm data from the pivotal trial and suggest that nivolumab is effective for the treatment of metastatic RCC in routine clinical practice
50
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Ruolo dei checkpoint inhibitors nelle neoplasie vescicali Le evidenze scientifiche e l’inserimento
dei checkpoint inhibitors nell’algoritmo decisionale del carcinoma vescicale metastatico
1° Linea Metastatica
- Pz cis-platino eleggibili: Cis-Platino-Gemcitabina
- Pz cis-platino ineleggibili: Atezolizumab/Pembrolizumab in alternativa a Carboplatino/Gemcitabina
2°Linea
- 5 immunoterapici approvati da FDA → pembrolizumab
Key Eligibility Criteriaa
• mUC with progression during or following platinum-based chemotherapy
– ≤ 2 prior lines of therapy
• Measurable disease per RECIST v1.1
• ECOG PS 0-1
• Evaluable sample for PD-L1 testing
• TCC histology as primary component (N = 931)
Primary endpoint
• OS, tested hierarchically in pre-specified populations
IMvigor211 Study Design
60
Atezolizumab
1200 mg q3w
R 1:1
No crossover permitted per protocol
Survival follow-
up
Loss of clinical benefit
RECIST v1.1 progression Stratification Factors
• No. of risk factorsb(0 vs. 1/2/3)
• Liver metastases (yes vs. no)
• PD-L1 status (0/1 vs. 2/3)
• Chemotherapy (vinflunine vs. taxanes)
▪ Additional endpoints
– Efficacy: RECIST v1.1 ORR, PFS and DORc – Safety
– PROs: EORTC QLQ-C30
Chemotherapy (investigator’s choice)
• Vinflunine q3w
• Docetaxel q3w
• Paclitaxel q3w
Powles T, et al. EAS 2017
