IMMUNOTERAPIA: L’ESPERIENZA ITALIANA NEL...

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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

Transcript of IMMUNOTERAPIA: L’ESPERIENZA ITALIANA NEL...

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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

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Disclosure

Pfizer

Novartis

Bayer

BMS

MSD

Roche

Eisai

Ipsen

Consulting & advisory board

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Esperienza italiana in mRCC

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Expanded Access Named

Patient Program (NPP)

in mRCC

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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

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Results • Median OS remained significantly longer with nivolumab versus everolimus, with 3-year OS rates

of 39% versus 30%, respectively (Figure 1)

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Results

9

• Tumor responses remained consistent with longer follow-up, with more ongoing responses with

nivolumab than with everolimus (Table 1)

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Results

10

• A delayed benefit with nivolumab versus everolimus was seen in PFS (Figure 2)

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Results

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• 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

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Results

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• The majority of nivolumab-related select AEs resolved (within 5.6–26.1 weeks), with the

exception of endocrine events (Table 3)

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CheckMate-025: OS by subgroup analysis

Motzer et al. NEJM 2015

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CheckMate-025: OS by PD-L1 expression

Motzer et al. NEJM 2015

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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

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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

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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.

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Association of Overall Survival With Baseline HRQoL and

Improvement in HRQoL up to 12 Weeks

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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

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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

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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

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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

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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

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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

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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

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Checkmate 025 Baseline Characteristics (3)

Motzer NEJM 2015

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Expanded Access Named

Patient Program (NPP)

in mRCC

Clinical Activity

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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

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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

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Expanded Access Named

Patient Program (NPP)

in mRCC

Overall Survival

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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%

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Clinical Activity & OS

in Subgroups of Patients:

Pluri-treated patients

Elderly patients

Brain metastases

Bone metastases

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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

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Efficacy (cont’d.)

• Disease control rates are shown in Figure 1.

3

4

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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

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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

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Figure 2. Overall survival based on age subgroups

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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

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Table 3. Safety results

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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

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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)

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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.

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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)

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Expanded Access Named

Patient Program (NPP)

in mRCC

Discontinuation

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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)

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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

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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