Carcinoma renale metastatico

(1)

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

(2)

Disclosure

 Pfizer

 Novartis

 Bayer

 BMS

 MSD

 Roche

 Eisai

 Ipsen

Consulting & advisory board

(3)

Esperienza italiana in mRCC

(4)

Expanded Access Named Patient Program (NPP)

in mRCC

(5)

(6)

(7)

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. Motzer

¹⁸

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)

8 Results

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

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

(9)

Results

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

nivolumab than with everolimus (Table 1)

(10)

Results

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

(11)

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

(12)

Results

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

exception of endocrine events (Table 3)

(13)

CheckMate-025: OS by subgroup analysis

Motzer et al. NEJM 2015

(14)

CheckMate-025: OS by PD-L1 expression

Motzer et al. NEJM 2015

(15)

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

(16)

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 9 1 2 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 9 1 2 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

Overall Survival (Probability)

0.0 0.1 0.8 0.9

0.2 0.3 0.4 0.5 0.6 0.7 1.0

(17)

 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

FKSI-DRS: Mean Change From Baseline

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

WorseBetter

Motzer R, et al. N Engl J Med. 2015;373:1803-1813.

(18)

Association of Overall Survival With Baseline HRQoL and

Improvement in HRQoL up to 12 Weeks

(19)

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

(20)

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

(21)

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

(22)

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

(23)

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 ndom 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

(24)

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

(25)

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

(26)

Checkmate 025 Baseline Characteristics (3)

Motzer NEJM 2015

(27)

Expanded Access Named Patient Program (NPP)

in mRCC

Clinical Activity

(28)

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

(29)

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

(30)

Expanded Access Named Patient Program (NPP)

in mRCC

Overall Survival

(31)

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%

(32)

Clinical Activity & OS

in Subgroups of Patients:

Pluri-treated patients Elderly patients Brain metastases

Bone metastases

(33)

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 Porta

²⁰

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

(34)

Efficacy (cont’d.)

• Disease control rates are shown in Figure 1.

3 4

(35)

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

(36)

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

(37)

Figure 2. Overall survival based on age subgroups

(38)

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

(39)

Table 3. Safety results

(40)

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

Basso

²⁰

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

(41)

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)

(42)

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.

(43)

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)

(44)

Expanded Access Named Patient Program (NPP)

in mRCC

Discontinuation

(45)

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)

(46)

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 2

^a

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

(47)

(48)

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. Motzer

¹⁹

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