IMMUNOTERAPIA: L’ESPERIENZA ITALIANA NEL...
Transcript of IMMUNOTERAPIA: L’ESPERIENZA ITALIANA NEL...
II SESSIONE
IMMUNOTERAPIA: L’ESPERIENZA ITALIANA NEL mRCC
Giacomo Cartenì Direttore U.O.S.C. di Oncologia Medica e Responsabile
del Centro di Riferimento Oncologico Regionale
Polispecialistico
A.O. A. Cardarelli Napoli
Disclosure
Pfizer
Novartis
Bayer
BMS
MSD
Roche
Eisai
Ipsen
Consulting & advisory board
Esperienza italiana in mRCC
Expanded Access Named
Patient Program (NPP)
in mRCC
Three-Year Efficacy and Safety Update From the
Phase III CheckMate 025 Study of Nivolumab
Versus Everolimus in Patients With Advanced
Renal Cell Carcinoma
Padmanee Sharma,1 Scott S. Tykodi,2 Bernard Escudier,3 Michael Carducci,4 Stephane Oudard,5 Hans
J. Hammers,4 Saby George,6 Daniel Castellano,7 Ajjai S. Alva,8 Martin Eduardo Richardet,9 Christine
Chevreau,10 Elizabeth R. Plimack,11 Sandhya Srinivas,12 Giuseppe Procopio,13 Jeffrey A. Sosman,14
David F. McDermott,15 Toni K. Choueiri,16 Elmer Berghorn,17 Lingfeng Yang,17 Robert J. Motzer18 Da
vid F. 1MD Anderson Cancer Center, University of Texas, Houston, TX, USA; 2University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 3Gustave
Roussy, Villejuif, France; 4Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; 5Hôpital Européen Georges Pompidou, AP-HP, Paris, France; 6Roswell Park Cancer Institute, Buffalo, NY, USA; 7Hospital Universitario 12 De Octubre, Madrid, Spain; 8University of Michigan, Ann Arbor, MI, USA; 9Instituto Oncologico de
Cordoba, Cordoba, Argentina; 10IUCT-O Institut Claudius Regaud, Toulouse, France; 11Fox Chase Cancer Center, Philadelphia, PA, USA; 12Stanford Cancer Institute, Stanford,
CA, USA; 13Fondazione Istituto Nazionale Tumori, Milan, Italy; 14Vanderbilt University Medical Center, Nashville, TN, USA; 15Beth Israel Deaconess Medical Center, Dana-
Farber/Harvard Cancer Center, Boston, MA, USA; 16Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA, USA; 17Bristol-Myers Squibb, Princeton, NJ, USA; 18Memorial Sloan Kettering Cancer Center, New York, NY, USA
These data were presented at the 16th International Kidney Cancer Symposium; November 3–4, 2017; Miami, FL, USA
These slides are for personal use only
8
Results • Median OS remained significantly longer with nivolumab versus everolimus, with 3-year OS rates
of 39% versus 30%, respectively (Figure 1)
Results
9
• Tumor responses remained consistent with longer follow-up, with more ongoing responses with
nivolumab than with everolimus (Table 1)
Results
10
• A delayed benefit with nivolumab versus everolimus was seen in PFS (Figure 2)
Results
11
• Treatment-related AEs
occurred in 80% and
89% of patients
treated with nivolumab
and everolimus,
respectively (Table 2)
• Incidence of
treatment-related
select AEs is shown in
Table 2
Results
12
• The majority of nivolumab-related select AEs resolved (within 5.6–26.1 weeks), with the
exception of endocrine events (Table 3)
CheckMate-025: OS by subgroup analysis
Motzer et al. NEJM 2015
CheckMate-025: OS by PD-L1 expression
Motzer et al. NEJM 2015
OS: Number and sites of metastases
Subgroup
Nivolumab
Events/patients
Everolimus
Events/patients
Hazard ratio
(95% CI)
No. of sites of metastases
1
≥2
14/68
168/341
21/71
194/338
Bone metastases
Yes
No
42/76
141/334
45/70
170/341
Liver metastases
Yes
No
54/100
129/310
52/87
163/324
Nivolumab Everolimus
Favors
0 1 2
OS: Bone and liver metastases
Bone Median OS, months (95% CI)
Nivolumab 18.5 (10.2–NE)
Everolimus 13.8 (7.0–16.4)
HR (95% CI), 0.72 (0.47–1.09)
Liver Median OS, months (95% CI)
Nivolumab 18.3 (13.4–26.7)
Everolimus 16.0 (8.4–21.6)
HR (95% CI), 0.81 (0.55–1.18)
Nivolumab
0.0
0 3 6 1 2 9 1 5
Months
1 8 2 1 2 4 2 7 3 0 3 3
0.1
0.8
0.9
100 83 62 43 15 1
87 60 50 30 11 0
Everolimus
0.2
0.3
0.4
0.5
0.6
0.7
1.0
Everolimus
Nivolumab
0 3 6 1 2 9 1 5
Months
1 8 2 1 2 4 2 7 3 0 3 3
No. of patients at risk
Nivolumab 76 58 46 32 9 1
Everolimus 70 49 35 20 3 0
Ove
rall
Su
rviv
al
(Pro
ba
bil
ity)
0.0
0.1
0.8
0.9
0.2
0.3
0.4
0.5
0.6
0.7
1.0
A clinically meaningful and statistically significant improvement in QoL was seen with nivolumab vs everolimus for the duration of the study
Questionnaire completion rate: ≥ 80% during the first yr of follow-up
CheckMate-025: Change From Baseline in
QoL Scores
FK
SI-
DR
S:
Me
an
Ch
an
ge
Fro
m B
as
eli
ne
Nivolumab
Everolimus
4 0 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104
Wks
-6
0
-4
-2
2
4
6
Pts at Risk, n Nivolumab 362 334 302 267 236 208 186 164 159 144 132 1 19 1 12 97 90 89 81 72 63 59 53 44 43 31 30 26 20 Everolimus 344 316 270 219 191 157 143 122 102 97 87 74 73 63 58 49 44 35 30 28 24 21 15 12 12 9 9
Wo
rse
B
ett
er
Motzer R, et al. N Engl J Med. 2015;373:1803-1813.
Association of Overall Survival With Baseline HRQoL and
Improvement in HRQoL up to 12 Weeks
KEY INCLUSION CRITERIA: • Patients with histologically confirmed advanced or metastatic RCC • Must have received at least 1 prior therapy regimens in the
advanced or metastatic setting. • Karnofsky Performance Score (KPS) ≥ 70% • Patients are eligible if CNS metastases are adequately treated and
patients are neurologically returned to baseline for at least 2 weeks prior to first dose of program medication. In addition, patients must be either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first dose of program medication.
KEY EXCLUSION CRITERIA: • Patients with untreated CNS metastases are excluded • Patients with an active, known or suspected autoimmune
disease. • Patients with a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first program dose.
• Prior treatment with an anti-PD-1, anti-PD-L1, anti PD L2, anti-CD137, or anti CTLA 4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
Expanded Access Named Patient Program
Expanded Access Named Patient Program
3 mg/kg OPDIVO
TREATMENT REGIMEN AND SCHEDULE: • The dose and schedule of nivolumab is 3
mg/kg IV every 2 weeks • Patients treated to a maximum of 24 months
• For patients treated with nivolumab it is
permitted to continue treatment beyond initial progressive disease as long as they meet predefined criteria
EAP Baseline Characteristics (1)
Nivolumab (n = 389) Median age, years (range)
≥70 years, n (%) ≥75 years, n (%)
65 (34, 85) 125 (32) 70 (18)
Male, n (%) Female, n (%)
291 (75) 98 (25)
ECOG PS, n (%) 0 1 2 NA
176 (47) 174 (47)
24 (6) 15
Number of prior systemic regimens, % 1 2 3 ≥4 NA
80 (21)
136 (35) 101 (26) 69 (18)
3
In total, 389 Italian patients
received at least one dose of
nivolumab in EAP across 108 sites
Nivolumab (n = 389) Histology
Clear cell Non-clear cell NA
346 (92) 32 (8)
11 Metastatic sites, n (%)
Bone Nodes Brain Liver Lung
193 (50) 238 (61)
32 (8) 128 (33) 286 (73)
EAP Baseline Characteristics (2)
In total, 389 Italian patients
received at least one dose of
nivolumab in EAP across 108 sites
CheckMate 025 Study Design
Previously treated
mRCC
Stratification factors
Region
MSKCC risk group
Number of prior anti-
angiogenic therapies
Nivolumab
3 mg/kg intravenously
every two weeks
Everolimus
10 mg orally
once daily
Ra
nd
om
ize
1:1
Patients were treated until progression or intolerable toxicity occurred
Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted
Sharma at ESMO 2015
Nivolumab N = 410
Everolimus N = 411
Median age (range), years 62 (23–88) 62 (18–86)
Sex, % Female Male
23 77
26 74
MSKCC risk group, % Favorable 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 the world
42 34 23
42 34 24
Checkmate 025 Baseline Characteristics (1)
Sharma at ESMO 2015
Checkmate 025 Baseline Characteristics (2)
Adapted from Sharma at ESMO 2015
Subgroup Nivolumab n/N
Everolimus n/N
MSKCC risk group
Favorable Intermediate Poor
45/145 101/201
37/64
52/148 116/203
47/60
Prior anti-angiogenic regimens
1 2
128/294 55/116
158/297 57/114
Region
US/Canada Western Europe Rest of the world
66/174 78/140 39/96
87/172 84/141 44/98
Age, years
<65 ≥65 to <75 ≥75
111/257 53/119 19/34
118/240 77/131 20/40
Sex
Female Male
48/95 135/315
56/107 159/304
Checkmate 025 Baseline Characteristics (3)
Motzer NEJM 2015
Expanded Access Named
Patient Program (NPP)
in mRCC
Clinical Activity
EAP Clinical Activity
Nivolumab (n = 389)
BORR, n (%) 67/389 (17)
Best overall response, % Complete response Partial response Stable disease Mixed response Progressive disease Unable to determine
1 (<1)
66 (17) 121 (31)
7 (2) 133 (34) 61 (16)
o 82 (21%) patients on nivolumab were treated beyond progression
Checkmate 025 Clinical Activity
Item Nivolumab Everolimus
Objective response rate, % 26 5
Odds ratio (95% CI)
P value 6.13 (3.77–9.95)
<0.0001
Best overall response, %
Complete response
Partial response
Stable disease
Progressive disease
Not evaluated
1
25
34
35
6
<1
5
56
27
11
Median duration of response,
months (range) 12.0
(0.0–36.8+) 12.0
(0.0+–33.0+)
Ongoing response, n/N (%) 30/105 (29) 3/22 (14)
+ indicates censored observation
Plimack KCS 2016
Expanded Access Named
Patient Program (NPP)
in mRCC
Overall Survival
EAP Overall Survival
6-months OS: 83.3%
9-months OS: 76.6%
Median Follow-up 6.6 months (Max 15.9 months)
9-months OS: 76.6%
6-months OS: 83.3%
Clinical Activity & OS
in Subgroups of Patients:
Pluri-treated patients
Elderly patients
Brain metastases
Bone metastases
Sergio Bracarda,1 Luca Galli,2 Marco Maruzzo,3 Giovanni Lo Re,4 Sebastiano Buti,5 Adolfo Favaretto,6 Francesco Di Costanzo,7 Cosimo Sacco,8 Marco Merlano,9 Claudia Mucciarini,10 Elena Zafarana,11 Sante
Romito,12 Antonio Maestri,13 Carmelo Giannitto Giorgio,14 Maria Teresa Ionta,15 Daniele Turci,16 Ugo De Giorgi,17 Giuseppe Procopio,18 Enrico Cortesi,19 Camillo Porta20
1Azienda USL Toscana SudEst, Arezzo; 2AOU Pisana “Spedali Riuniti di S. Chiara,” Pisa; 3Istituto Oncologico Veneto, IOV IRCCS, Padua; 4Oncologia Pordenone-S.Vito, CRO Aviano, Pordenone; 5Azienda Ospedaliero-Universitaria di Parma, Parma; 6AULSS 2 Marca Trevigiana, Treviso; 7AOU Careggi, Florence; 8AOU “Santa Maria della
Misericordia,” Udine; 9AO “S. Croce e Carle,” Cuneo; 10Ospedale di Carpi, Carpi; 11AUSL4 - Nuovo Ospedale di Prato, Prato;12Ospedali Riuniti di Foggia, Foggia; 13Ospedale “S.Maria della Scaletta,” Imola; 14Ospedale “Gravina e Santo Pietro,” Caltagirone; 15AOU di Cagliari, Cagliari; 16Presidio Ospedaliero “S. Maria delle Croci,”
Ravenna; 17Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola; 18Istituto Nazionale dei Tumori, Milan; 19Policlinico Umberto I, Rome; 20IRCCS Policlinico “S.Matteo,” Pavia, Italy
Negative Prognostic Factors and Resulting Clinical Outcome in Patients With Metastatic
Renal Cell Carcinoma Included in the Italian Nivolumab Expanded Access Program
Abstract #887P Presented at the European Society for Medical Oncology (ESMO) Congress; 8–12 September 2017; Madrid,
Spain
Bristol-Myers Squibb has obtained the appropriate permissions to externally share this material with healthcare professionals upon request
Efficacy (cont’d.)
• Disease control rates are shown in Figure 1.
3
4
Efficacy (cont’d.)
• Kaplan–Meier estimates of overall survival (OS) are shown in Figure 2; median OS has not yet been reached in any of the subgroups.
3
5
Roberto Sabbatini,1 Luca Galli,2 Sandro Pignata,3 Giovanni Lo Re,4 Francesca
Valcamonico,5 Carlotta Defferrari,6 Massimiliano Spada,7 Daniele Santini,8 Cristina
Masini,9 Libero Ciuffreda,10 Enzo M. Ruggeri,11 Aldo Chioni,12 Lorenzo Livi,13 Daniele
Fagnani,14 Andrea Bonetti,15 Lucio Giustini,16 Simona Duranti,17 Giuseppe Procopio,18
Claudia Caserta,19 Giacomo Cartenì 20
1AOU Policlinico, Modena; 2AOU Pisana Istituto Toscano Tumori, Pisa; 3IRCCS, Fondazione G. Pascale, Naples; 4AO, Santa Maria degli
Angeli, Pordenone; 5ASST, Spedali Civili di Brescia, Brescia; 6Ospedali Galliera, Genoa; 7Fondazione Istituto Giglio, Cefalù; 8Campus Bio-
Medico, Rome; 9IRCCS, AO Arcispedale Santa Maria Nuova, Reggio Emilia; 10Città della salute e della Scienza, Turin; 11 Ospedale Belcolle,
Viterbo; 12USL 9 Presidio Ospedaliero Misericordia, Grosseto; 13AOU Careggi, Florence; 14ASST, Vimercate; 15Ospedale Mater Salutis,
Legnago; 16UOC, Oncologia Area Vasta 4, Fermo; 17Azienda ASL8, Arezzo; 18Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan; 19AO
Santa Maria, Terni; 20AO A. Cardarelli, Naples, Italy
Efficacy and Safety data in Elderly Patients
with Metastatic Renal Cell Carcinoma
Included in the Nivolumab Expanded
Access Program In Italy
Abstract #897P Presented at the European Society for Medical Oncology (ESMO) Congress; 8–12 September 2017; Madrid,
Spain
Bristol-Myers Squibb has obtained the appropriate permissions to externally share this material with healthcare professionals upon request
Figure 2. Overall survival based on age subgroups
Safety
• The safety outcomes for all patients, and patients ≥70 and ≥75 years of age, are shown in
Table 3
• Overall, discontinuations due to treatment-related adverse events (AEs) in elderly and very
elderly patients are consistent with those observed in the overall population
Table 3. Safety results
Treatment Beyond Progression in Patients With Advanced Renal Cell Carcinoma
Participating in the Expanded Access Program
Enrico Cortesi,1 Federico Cappuzzo,2 Luca Galli,3 Alessandra Bearz,4 Sandro Pignata,5 Alfredo Berruti,6 Giampaolo Tortora,7 Davide Tassinari,8 Stefano Panni,9 Antonio Pazzola,10 Giammarco Surico,11 Michele Maio,12 Luciano Latini,13 Giovanni
Schinzari,14 Vincenzo Adamo,15 Enrico Ricevuto,16 Francesco Cognetti,17 Ugo De Giorgi,18 Giacomo Cartenì,19 Umberto Basso20
4
0
1Policlinico Umberto I, Rome; 2AUSL Romagna, Ravenna; 3AOU Pisana “Spedali Riuniti di S. Chiara,” Pisa; 4Istituto Nazionale Tumori, Aviano; 5Istituto Pascale, Naples; 6ASST Spedali Civili di Brescia, Brescia; 7AOU Integrata, Verona;
8AUSL della Romagna, Rimini; 9Istituti Ospitalieri, Cremona; 10Ospedale Civile SS Annunziata, Sassari; 11Ospedale Vito Fazzi, Lecce; 12Policlinico Le Scotte, Siena; 13Ospedale di Macerata, Macerata; 14Policlinico Gemelli, Rome;
15Ospedale Papardo di Messina, Messina; 16Rete Oncologica ASL 1, L’Aquila; 17IFO Regina Elena, Rome; 18Istituto Romagnolo per lo studio e la cura dei Tumori, Meldola; 19AO “A. Cardarelli,” Naples; 20Istituto Oncologico Veneto,
Padova, Italy
892P
Presented at the European Society for Medical Oncology (ESMO) Congress; 8–12 September 2017; Madrid,
Spain
Bristol-Myers Squibb has obtained the appropriate permissions to externally share this material with healthcare professionals upon request
Results (cont’d.)
Patients
• A total of 389 patients with advanced RCC were enrolled in the Italian cohort of the EAP
between August 2015 and April 2016 and treated with nivolumab.
– The median number of nivolumab doses was 12 (range, 1–35)
– Median duration of follow-up was 9.2 months (range, 0.1–17.0)
• Of these 389 enrolled patients, 231 (59%) developed PD; 100 (43%) were treated beyond PD
and 131 (57%) were not (Table 1)
Results (cont’d.)
Efficacy Beyond First PD
• Of the 100 patients treated beyond PD, 32 (32%) achieved a subsequent tumor burden
reduction or a stabilization in tumor lesions (Table 3)
• It is noteworthy that of the 75 patients who showed no initial response to nivolumab (ie, best
response was PD), 24 (32%) achieved at least disease stabilization (including 6 [8%] achieving
a subsequent PR) with continued nivolumab treatment.
Figure 1. Kaplan-Meier estimates of OS for patients
treated beyond PD and patients not treated beyond
PD
• One-year overall survival was 73.5% in patients treated beyond PD
and 43.5% for patients not treated beyond PD (Figure 1)
Expanded Access Named
Patient Program (NPP)
in mRCC
Discontinuation
EAP Treatment discontinuation
TOTAL 192/389
REASON FOR
DISCONTINUATION
Adverse events
PD/Death
Other/UK
18 (5%)
156 (40%)
18 (5%)
Median number of doses: 10 (1-31)
Checkmate 025 discontinuation
Nivolumab
N = 406
Everolimus N = 397
Any Grade Grade 3-4 Any Grade Grade 3-4
Treatment-related AEs, % 79 19 88 37
Treatment-related AEs leading to discontinuation, %
8 5 13 7
Treatment-related deaths, n 0 2a
a Septic shock (1), bowel ischemia (1).
• 44% of patients in the nivolumab arm and 46% of patients in the everolimus arm were treated beyond progression
Sharma, ESMO 2015
Bernard Escudier,1 Nizar M. Tannir,2 David F. McDermott,3 Osvaldo Arén Frontera,4 Bohuslav Melichar,5 Elizabeth R. Plimack,6 Philippe Barthelemy,7 Saby George,8 Victoria Neiman,9 Camillo Porta,10
Toni K. Choueiri,11 Thomas Powles,12 Frede Donskov,13 Pamela Salman,14 Christian K. Kollmannsberger,15 Brian Rini,16 Sabeen Mekan,17 M. Brent McHenry,17 Hans J. Hammers,18 Robert J. Motzer19
1Gustave Roussy, Villejuif, France; 2University of Texas, MD Anderson Cancer Center Hospital, Houston, TX, USA; 3Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA; 4Centro Internacional de Estudios Clinicos, Santiago, Chile; 5Palacky
University, and University Hospital Olomouc, Olomouc, Czech Republic; 6Fox Chase Cancer Center, Philadelphia, PA, USA; 7Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 8Roswell Park Cancer Institute, Buffalo, NY, USA; 9Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, Tel Aviv, Israel; 10IRCCS San Matteo University Hospital Foundation, Pavia, Italy; 11Dana-
Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA; 12Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London, UK; 13Aarhus
University Hospital, Aarhus, Denmark; 14Fundación Arturo López Pérez, Santiago, Chile; 15British Columbia Cancer Agency, Vancouver, BC, Canada; 16Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 17Bristol-Myers Squibb, Princeton, NJ, USA; 18Sidney Kimmel
Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA; 19Memorial Sloan Kettering Cancer Center, New York, NY, USA
CheckMate 214: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Sunitinib for Treatment-Naïve Advanced or Metastatic Renal Cell Carcinoma, Including IMDC Risk and PD-L1 Expression Subgroups