1

Immunotherapy in GU Cancers

Dr Ravindran Kanesvaran

Medical Oncologist

National Cancer Centre Singapore

2

Disclosures

• Speaker Bureau: Pfizer, J&J, Sanofi, Novartis,

MSD

• Advisory Board/ Consultant: GSK, Novartis,

Bayer, J&J, Mundipharma, Astellas, MSD, BMS

• Research support: Sanofi, J&J, Astellas

3

Outline

• Introduction

• Immunotherapy in mBC

• Immunotherapy in mRCC

• Summary

4

Bladder and Kidney Cancers Singapore

Singapore Cancer Registry Interim Annual Report Trends in Cancer Incidence in Singapore 2010-2014

5

Metastatic Bladder Cancer

• Approximately 25% of patients will have muscle-invasive disease

and either present with or later develop metastases

6

Current Treatment : Chemotherapy

7

Current first line treatment

8

Carboplatin in patients “unfit” for

cisplatin

• Data suggests that CDDP > carbo in terms of efficacy

– MA Galsky Annals 2011 : CDDP > Carbo wrt CR, ORR

– Multiple phase II studies reveal CDDP > Carbo in terms of ORR

• EORTC 30896 (ASCO 2010)

– G/Carbo vs M-CAVI (M, V and Carbo) in pts CCT 30-60, PS 2

– OS same (about 8.5 mths); G/Carbo better tolerated

• Definition of pts unfit for CDDP (Galsky, JCO June 2011)

– ECOG 2

– CCT < 60

– ≥ G2 hearing loss or ≥ G2 neuropathy

– NYHA III CCF

9

Current Treatment: Immunotherapy

10

Role of immune system in advanced bladder

cancer

Martincorena I, Campbell PJ. Science. 2015;349:1483-9

High mutational load may correlate with immunogenicity, and provides valuable prognostic information

11

IMvigor 210: Study Design

• Single-arm phase II study with 2 cohorts

Pts with inoperable

advanced or metastatic

UC, predominantly TCC

histology, evaluable

tumor tissue for

PD-L1 testing

Cohort 1

Previously untreated,

cisplatin ineligible

Cohort 2

Prior platinum

treatment

Atezolizumab

1200 mg IV Q3W

until PD

Atezolizumab

1200 mg IV Q3W

until loss of benefit

Rosenberg JE, et al. Lancet. 2016;387:1909-1920

Primary endpoints: confirmed ORR by RECIST v1.1 (per central review), ORR per immune-modified RECIST (per investigator)Secondary endpoints: DoR, PFS, OS, safety

12

Post platinum – Responses

• Responses seen in all PD-L1 IC subgroups; higher response seen with higher PD-L1 status

• After a median follow-up of 11·7 months, the median duration of response was not yet reached in

any of the PD-L1 subgroups (range 2·0–13·7 months)

• At the time of the updated data cutoff, ongoing responses were reported in 38 (84%) of the 45

responding patients

• The median time to response was 2·1 months (95% CI 2·0–2·2)

13

Post platinum – Conclusion

• Targeting PD-L1 with atezolizumab is effective in heavily pretreated

patients with locally advanced or metastatic urothelial carcinoma

• Responses were seen in all PD-L1 expression subgroups

• Higher response rates in patients with higher levels of PD-L1

expression on immune cells

• Data led to FDA accelerated approval of atezolizumab for advanced

or metastatic UC after PD during or following platinum-based

therapy

14

Cohort 1 (Previously untreated and

cisplatin ineligible)

• Many patients are cisplatin ineligible due to poor

performance status, impaired renal function, or

comorbidities

• Non-cisplatin–based regimens associated with short

response duration, lack of survival benefit, high

discontinuation rate

• Many patients do not end up receiving systemic

treatment

15

Cisplatin ineligible – Survival

• No clear difference in OS between PD-L1 subgroups

• Median OS was not reached in patients with no risk factors

• 13·4 months in patients with one risk factor (either visceral metastases or ECOG 2)

• 6·2 months in patients with two risk factors

• 19·1 months median OS reported in the stable disease subgroup

16

Cisplatin ineligible – Conclusion

• Durable responses to atezolizumab in previously untreated cisplatin-

ineligible patients metastatic urothelial carcinoma

– Responses seen in all PD-L1 subgroup

• Survival to date appears favourable

• Low incidence of AE despite numerous co-morbidities

17

Was the accelerated approval too early?

18

IMvigor211: A Phase III Randomized Study

Examining Atezolizumab

vs. Chemotherapy for Platinum-Treated

Advanced Urothelial Carcinoma

Thomas Powles,1 Yohann Loriot,2 Ignacio Durán,3 Alain Ravaud,4 Margitta M. Retz,5

Nicholas J. Vogelzang,6 Sanjeev Mariathasan,7 Na Cui,7 Christina L. Derleth,7

Michiel S. van der Heijden8

1Barts Cancer Institute ECMC, Barts Health and the Royal Free NHS Trust, Queen Mary University of London,

London, UK; 2Département de Médecine Oncologique, Université Paris-Saclay

and Gustave Roussy, Villejuif, France; 3Department of Medical Oncology, Hospital Universitario Virgen del Rocío

and Institute of Biomedicine of Seville, Seville, Spain; 4Hôpital Saint-André CHU and Department of Medical

Oncology, Bordeaux University Hospital, Bordeaux, France; 5Department of Urology, Klinikum Rechts der Isar,

Technical University Munich, Munich, Germany; 6US Oncology Research, Comprehensive Cancer Centers of

Nevada, Las Vegas, Nevada, USA; 7Genentech, Inc., South San Francisco, CA, USA; 8Department of Medical

Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands

Powles T, et al. EAS 2017, IMvigor211.

19

Key Eligibility Criteria• 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)

IMvigor211 Study Design

▪ Primary endpoint

▪ OS, tested hierarchically

in pre-specified populations

19

Atezolizumab 1200 mg q3w

R1:1

No crossover permitted per protocol

Survival follow-up

Loss of clinical benefit

RECIST v1.1

progression

Stratification Factors• No. of risk factorsa (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 DOR

▪ Safety

▪ PROs: EORTC QLQ-C30

Chemotherapy (investigator’s choice)

• Vinflunine q3w• Docetaxel q3w• Paclitaxel q3w

aDefined by time from prior chemotherapy < 3 mo, ECOG performance status > 0 and hemoglobin < 10 g/dL.

20

OS Analysis: IC2/3 Population

20

HR = 0.87 (95% CI: 0.63, 1.21)

P = 0.41

Events/Patients

Median OS(95% CI)

12-mo OS Rate(95% CI)

Atezolizumab 72/116 11.1 mo (8.6, 15.5) 46% (37, 56)

Chemotherapy 88/118 10.6 mo (8.4, 12.2) 41% (32, 50)

No. at Risk

Atezolizumab 116 100 85 77 71 58 51 39 27 19 11 6 0

Chemotherapy 118 100 91 82 71 61 47 32 24 15 9 5 1

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Ove

rall

Surv

ival

100

Months

21

OS Analysis: ITT Population

Events/Patients

Median OS(95% CI)

12-mo OS Rate(95% CI)

Atezolizumab 324/467 8.6 mo (7.8, 9.6) 39% (35, 44)

Chemotherapy 350/464 8.0 mo (7.2, 8.6) 32% (28, 37)

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Ove

rall

Surv

ival

100

Months

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Ove

rall

Surv

ival

100

Months

HR = 0.85 (95% CI: 0.73, 0.99)

P = 0.038

No. at Risk

Atezolizumab 467 405 327 280 245 201 177 138 90 59 34 13 1

Chemotherapy 464 397 330 268 219 175 140 99 60 42 17 7 1

22

OS in Clinical and Treatment Subgroups

NE, not estimable. Unstratified hazard ratios are plotted. Dashed line refers to HR for ITT population.

1.0

Atezolizumab better Chemotherapy better

SubgroupPD-L1 status IC2/3

IC1/2/3

ITT

Tobacco use history Current

Previous

Never

ECOG PS 0

1

Primary tumor site Bladder

Urethra

Renal pelvis

Ureter

Liver metastases Yes

No

Lymph node–only metastases Yes

No

Chemotherapy stratification Taxane

Vinflunine

Atezolizumab mOS Chemotherapy mOS11.1 mo 10.6 mo

8.9 mo 8.2 mo

8.6 mo 8.0 mo

9.2 mo 6.7 mo

8.4 mo 8.2 mo

10.4 mo 8.1 mo

12.0 mo 10.1 mo

6.1 mo 6.4 mo

8.9 mo 7.7 mo

NE 12.5 mo

5.9 mo 8.5 mo

8.9 mo 8.1 mo

4.0 mo 5.2 mo

10.1 mo 9.7 mo

17.4 mo 12.2 mo

8.1 mo 7.2 mo

8.3 mo 7.5 mo

9.2 mo 8.3 mo

23

IMvigor211 – Conclusion

• The primary endpoint of OS was not met in the IC2/3 population

• Due to delayed separation of the Kaplan-Meier curves, the

differences in mOS and HR do not fully reflect the clinical activity

achieved with atezolizumab

• The safety data showed no new safety signals and demonstrated a

more favorable safety profile for atezolizumab than for

chemotherapy

24

Nivolumab in mBC

25

Overall Survival

• At a median follow-up of 7·00

months (IQR 2·96–8·77),

median OS was 8·74 months

(95% CI 6·05 to not reached)

in the overall population,

• Median OS 11·30 months

(8·74 to not reached) in the

subgroup of patients with PD-

L1 expression of > 1%

• Median OS 5·95 months

(4·30–8·08) in the subgroup

with PD-L1 expression of < 1%

26

Pembrolizumab K-045

27

Stratification Factors

• ECOG PS (0/2 vs 2)

• Hemoglobin level (<10 vs ≥10 g/dL)

• Liver metastases (yes vs no)

• Time from last chemotherapy dose (<3 vs ≥3

mo)

KEYNOTE-045: Study Design

Pembrolizumab

200 mg IV Q3W

For 2 years

Paclitaxel 175 g/m2 Q3W (n=84)

OR

Docetaxel 75 mg/m2 Q3W (n=84)

OR

Vinflunine 320 mg/m2 Q3W (n=87)

R (1:1)

N=542

Key End Points

Primary: OS and PFS in total and PD-L1 CPS ≥10% populations

Secondary: OR and DOR in total and PD-L1 CPS ≥10%

populations; safety in total population

n=270

n=272

Key Eligibility Criteria

• Urothelial carcinoma of the renal pelvis, ureter,

bladder, or urethra

• Transitional cell predominant

• PD after platinum-based chemo for advanced

disease or recurrence within 12 mo of

perioperative platinum-based therapy for

localized muscle-invasive disease

• ECOG PS 0-2

• Provision of tumor sample for biomarker

assessment

CPS = combined positive score; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; IV = intravenous; OS = overall survival; PD =

progressive disease; PD-L1 = programmed death ligand 1; PFS = progression-free survival; PS = performance status; Q3W – every 3 weeks; R = randomization.

28

† ECOG PS scores range from 0 to 5, with 0 indicating no symptoms and higher scores indicating greater disability.‡ PD-L1 CPS: the percentage of tumor and infiltrating immune cells with PD-L1 expression out of the total number of tumor cells.§Risk factors include the Bellmunt risk factors: ECOG PS score >0; hemoglobin concentration <10 g/dL; presence of liver metastases,2 plus time since the completion/discontinuation of previous therapy <3 mo.3

CPS = combined positive score; ECOG = Eastern Cooperative Oncology Group; PD-L1 = programmed death ligand 1; PS = performance status.

1. Bellmunt J, et al. N Engl J Med. 2017; February 17 [Epub ahead of print]; 2. Bellmunt J, et al. J Clin Oncol. 2010;28:1850-1855; 3. Sonpavde G, et al. Eur Urol. 2013;63:717-723.

KEYNOTE-045: Baseline Characteristics

29

CI = confidence interval; CPS = combined positive score

KEYNOTE-045: Overall Survival

• The median OS was 10.3 months (95% CI, 8.0 to 11.8) in the pembrolizumab group vs 7.4 months

(95% CI, 6.1 to 8.3) in the chemotherapy group

• In patients who had a tumor PD-L1 CPS of 10% or more, the median OS was 8.0 months (95%

CI, 5.0 to 12.3) in the pembrolizumab group vs 5.2 months (95% CI, 4.0 to 7.4) in the

chemotherapy group

Total Population CPS ≥10% Population

30

KEYNOTE-045: Overall Survival in Key

Subgroups

31

KEYNOTE-045: Conclusion

• Pembrolizumab significantly improved OS over chemotherapy in patients

with advanced urothelial carcinoma following first-line platinum-based

therapy: OS benefit observed in all PD-L1 populations

• No significant difference in PFS between pembrolizumab and chemotherapy

• ORR significantly higher and responses more durable with pembrolizumab

• Lower incidence of treatment-related AEs of any grade (60.9% vs 90.2%)

and grade 3-5 severity (15.0% vs 49.4%) with pembrolizumab

• Updated results after 22.5 mths follow-up remained consistenta

• Responses ongoing at data cutoff:– All patients: 57.9% in the pembrolizumab arm; 20.0% in the chemotherapy arm

– CPS ≥10: 73.3% in the pembrolizumab arm; 33.3% in the chemotherapy arm

aR de Wit, et al. ESMO Poster Presentation 2017

32

Pembrolizumab K-052

33

KEYNOTE-052: Study Design

34

KEYNOTE-052: Baseline Characteristics

35

KEYNOTE-052: Objective Responses

• Median time to response was 2 months

36

KEYNOTE-052: PFS

• Median PFS was 2 months (95% CI 2–3); 6 month PFS of 30% (25–35)

• 6 month OS was 67% (95% CI 62–73)

37

KEYNOTE-052: Conclusion

• First-line pembrolizumab demonstrated clinically meaningful

antitumor activity in cisplatin-ineligible patients with advanced

urothelial cancer

• No new safety signals were identified

38

Avelumab

39

Durvalumab

40

Summary of IO (2nd line) trials

Chism D. J Natl Compr Canc Netw 2017;15(10):1277–1284

41

Summary of cisplatin-ineligible first line trials

Chism D. J Natl Compr Canc Netw 2017;15(10):1277–1284

42

Comparing Toxicities between PD-1 and PD-L1

inhibitors

Pillai RN. Cancer 2017 Sep 28. doi: 10.1002/cncr.31043

43

Summary

• Chemotherapy still has an important role in the management of mBC

• We have 5 IO drugs with some data for use in mUC but only one with phase III trial data to support its use (Pembrolizumab)

• Biomarker studies seem to show a relationship but not clear

• Accelerated approval does not guarantee phase 3 trial success

• More IO drugs and combination trials are ongoing

• Cost will play a big role in its usage and access in non reimbursable markets

44

Outline

• Current standards

• Immunotherapy in mBC

• Immunotherapy in mRCC

• Summary

Rationale for Immunotherapy in RCC

• Spontaneous remissions attributed to the immune system of advanced RCC have been observed1

• RCC exhibits immune cell infiltrates, and several immune escape mechanisms have been reported in RCC2,3

• Historically, the mainstay of treatment for patients with mRCC was immunotherapy with interleukin-2 or interferon-α1

• Immuno-Oncology (I-O) is an evolving treatment modality encompassing agents designed to directly harness the patient’s own immune system to fight cancer7,8

Tregs CD45+ Memory T Cells CD8+ T Cells CD4+ T Cells

Studies have documented alterations in various immune cell types in RCC, including3-6:

levels: Poor

prognosis

levels: Fair/Poor prognosis

levels: Fair/Poor

prognosis/no association

levels: Fair/Poor prognosis

RCC=renal cell carcinoma; mRCC=metastatic renal cell carcinoma; Treg=regulatory T cell.1. Escudier B. Ann Oncol. 2012;23(Suppl 8):viii35-viii40 2. Noessner E et al. OncoImmunology. 2012;1(8):1451-1453. 3. Bockorny B et al. Expert Opin Biol Ther. 2013;13(6):911-925. 4. Hotta K, et al. Br J Cancer. 2011;105(8):1191-1196. 5. Nakano O et al. Cancer Res. 2001;61(13):5132-5136. 6. Igarashi T et al. Urol Int. 2002;69(1):51-56. 7. Ascierto PA et al. J Trans Med. 2014;12:141. doi: 10.1186/1479-5876-12-141. 8. Eggermont A et al. OncoImmunol. 2014;3(1):e27560.

46

NCCN 2017

47

Phase III, randomized, open-label trial of nivolumab vs everolimus in subjects with advanced or metastatic clear cell RCC who have received prior anti-angiogenic therapy

* Patients may continue treatment beyond progression (RECIST 1.1) if investigator-assessed clinical benefit is achieved and treatment is well tolerated.

Nivolumab3 mg/kg IV q2w Until progression*,

unacceptable toxicity, withdrawal of

consent, or end of trial

Key Inclusion Criteria▪ Advanced/metastatic clear cell RCC▪ No more than 3 total prior regimens in

advanced/metastatic setting▪ 1 or 2 prior anti-angiogenic therapy

regimens in advanced/metastatic setting▪ Karnofsky PS ≥70%; No CNS metastases▪ No prior therapy with mTOR inhibitor▪ No glucocorticoid use (equivalent to >10 mg

of prednisone daily)

R

1:1Everolimus10 mg PO qd

• Primary Outcome Measure: OS• Secondary Outcome Measures: PFS, ORR, DOR etc

N=821

Safety and Efficacy of Nivolumab for Metastatic Renal Cell Carcinoma: Real-World Data From an Italian Expanded Access Program

Key Inclusion Criteria

▪ ≥18 years with advanced or metastatic RCC

▪ ≥1 prior systemic treatment in the advanced or metastatic setting

▪ Patients with untreated CNS metastases or active autoimmune disease were excluded

N=389

Nivolumab3 mg/kg IV q2w

Until progression*, unacceptable toxicity, withdrawal of consent

• This analysis included all patients who received ≥1 dose of nivolumab

• AEs monitored and graded using the National Cancer Institute CTCAETerminology Criteria for Adverse Events v4.0

• ORR, PFS), and OS were evaluated

1. Motzer RJ et al. N Engl J Med. 2015. doi:10.1056/NEJMoa1510665.

Characteristic Nivolumab (N = 389)

Male, n (%) 291 (75)

Median age, years (range)≥75, n (%)

65 (34–85)70 (18)

ECOG PS, n (%)012NA

176 (45)174 (45)

24 (6)15 (4)

Histology, n (%)Clear cellNon-clear cellNA

356 (92)26 (7)7 (2)

Metastasis site, n (%)BoneLiverCNS

193 (50)128 (33)

32 (8)

Number of prior systemic therapies, n (%)

12≥3

80 (21)137 (35)170 (44)

NA = not available, percentages may not add to 100% due to rounding

Characteristic Nivolumab (N=410)

Everolimus(N=411)

Total ( N=821)

Male, n (%) 315 (77) 304 (74) 619 (75)

Median age, years (range) 62 (23–88) 62 (38–86) 62 (34–85)

Karnofsky performance status – no (%)

<70708090100

2(<1)22 (5)

110 (27)150 (17)126 (31)

1 (<1)30 (7)

116 (28)130 (32)134(33)

3 (<1)52 (6)24 (6)15 (4)

260 (12)

Disease sites that could be evaluated - no (%)1≥2

68 (17)341 (83)

71 (17)338 (82)

139 (17)679 (83)

Metastasis site, n (%)LungLiverBone

278 (68)100 (24)76 (19)

273 (66)87 (21)70 (17)

551 (67)187 (23)146 (18)

Number of prior systemic therapies, n (%)

SunitinibPazopanibAxitinib

246 (60)119 (29)51 (12)

242 (59)131 (32)50 (12)

488 (59)250 (30)101 (12)

Previous nephrectomy -no. (%)Yes No

364 (89)46 (11)

359 (87)52 (13)

723 (88)98 (12)

NA = not available, percentages may not add to 100% due to rounding

CheckMate 025

Baseline Patient Characteristics

Real-World Data

Overall Survival

Median OS at 2 years follow-up,

months (95% CI)

Nivolumab 26.0 (22.2–29.6)

Everolimus 19.7 (17.6–22.3)

HR (95% CI): 0.73 (0.61–0.88);

P=0.0006

• Median follow-up was 33.6 months

• Median OS was not reached

• With a (range: 1–17). 6-month and 9-month OS rates were 80% and 73%, respectively.

CheckMate 025 Real-World Data

Median follow-up of 9.2 months

1. Motzer RJ et al. N Engl J Med. 2015. doi:10.1056/NEJMoa1510665.

50

Progression-Free Survival

Median PFS, months (95% CI)

Nivolumab 4.6 (3.7–5.4)

Everolimus 4.4 (3.7–5.5)

HR=0.88 (95% CI, 0.75–1.03) P=0.11

No. of patients at riskNivolumab 410 230 145 116 81 66 48 29 11 4 0Everolimus 411 227 129 97 61 47 25 16 3 0 0

0 3 6 129 15

Months

18 21 24 27 30

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

gre

ssio

n-F

ree

Su

rviv

al (

Pro

bab

ility

)

Nivolumab

Everolimus

1. Motzer RJ et al. N Engl J Med. 2015.doi:10.1056/NEJMoa1510665.

• In an ad hoc sensitivity analysis of patients who had not progressed or died at 6 months, median PFS was 15.6 months for Nivolumab versus 11.7 months for Everolimus (HR=0.64; 95% CI, 0.47–0.88)1

• Median PFS was 4.6 months (95% CI: 3.6, 5.7;)

• 6-month and 9-month PFS rates were 44% and 35%, respectively

CheckMate 025 Real-World Data

51

Objective Response Rate

• Nivolumab was associated with a greater number of objective responses1

Nivolumab n=410

Everolimusn=411

Objective response rate, %1 26 5

Odds ratio (95% CI)6.13(3.77–9.95)

P<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 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 (0–36.8) 12.0 (0–33.0)

Ongoing response, n/N (%) 30/105 (29) 3/22 (14)

1. Motzer RJ et al. N Engl J Med. 2015. doi:10.1056/NEJMoa1510665.

Best response N = 389

ORR, n (%)

95% CI (%)

86/389 (22)

18, 26

Best objective response, n (%)

CR

PR

SD

PD

Not determined

2 (<1)

84 (22)

120 (31)

144 (37)

39 (10)

CR = complete response; PD = progressive disease

CheckMate 025 Real-World Data

52

Checkmate 025: Overall Survival by Number and Sites of Metastasis

SubgroupNivolumab

Events/patients, nEverolimus

Events/patients, n

No. of sites of metastasis

1 14/68 21/71

≥2 168/341 194/338

Bone metastases

Yes 42/76 45/70

No 141/334 170/341

Liver metastases

Yes 54/100 52/87

No 129/310 163/324

0 21

Nivolumab Everolimus

Favors

Motzer RJ et al. Oral presentation at ASCO GU 2016. 498.

53

Checkmate 025: Treatment-Related AEs in ≥15% of Patients

Nivolumabn=406

Everolimusn=397

Any grade Grade 3 Grade 4* Any grade Grade 3 Grade 4†

Treatment-related AEs1, % 79 19 1 88 33 4Fatigue 34 2 0 34 3 0Nausea 15 <1 0 17 1 0Pruritus 14 0 0 10 0 0Diarrhea 14 1 0 21 1 0Decreased appetite 12 <1 0 20 1 0Rash 10 <1 0 20 1 0Cough 9 0 0 19 0 0Anemia 8 2 0 24 8 1Dyspnea 7 1 0 13 <1 0Peripheral edema 4 0 0 14 <1 0Pneumonitis 4 1 <1 15 3 0Mucosal inflammation 3 0 0 19 3 0Dysgeusia 3 0 0 13 0 0Hyperglycemia 2 1 <1 12 3 <1Stomatitis 2 0 0 29 4 0Hypertriglyceridemia 1 0 0 16 4 1Epistaxis 1 0 0 10 0 0

* Grade 4 AEs not listed in table: increased blood creatinine (1), acute kidney injury (1), anaphylactic reaction (1).† Grade 4 AEs not listed in table: increased blood triglycerides (2), acute kidney injury (1), sepsis (1), chronic obstructive pulmonary disorder (1), increased blood cholesterol (1), neutropenia (1), pneumonia (1).1. Motzer RJ et al. N Engl J Med. 2015.doi:10.1056/NEJMoa1510665.

Treatment-related AE Any grade (N = 389) Grade 3–4 (N = 389)

Total, n (%) 124 (32) 27 (7)

General, n (%)Fatigue/astheniaPyrexiaLack of appetite/anorexia

60 (15)49 (13)12 (3)5 (1)

9 (2)9 (2)

01 (<1)

Skin and mucosal, n (%)Rash

38 (10)34 (9)

2 (<1)2 (<1)

Gastrointestinal, n (%)DiarrheaNausea/vomiting

33 (8)18 (5)8 (2)

5 (1)3 (1)

2 (<1)

Pain, n (%) 7 (2) 0

Endocrine, n (%)HypothyroidismHyperthyroidismAutoimmune hypophysitis

12 (3)6 (2)6 (2)

1 (<1)

1 (<1)00

1 (<1)

Respiratory/pulmonary, n (%)Pneumonitis

7 (2)3 (1)

3 (1)1 (<1)

Hematologic, n (%)Anemia

11 (3)9 (2)

3 (1)3 (1)

Hepatic/pancreatic, n (%)Increased transaminase

9 (2)5 (1)

00

Real world data: Treatment-related AEs in ≥1% of patients

• Treatment-related grade 3–4 AEs occurred in 27 (7%) patients• AEs were generally manageable with treatment according to protocol-specified guidelines• No treatment-related deaths were reported

Checkmate 025 - Conclusions

➢ Nivolumab significantly improved efficacy compared to everolimus in previously treated pts with advanced metastatic RCC.

▪ Median OS: 26 months (Nivolumab) vs 19.7 months (Everolimus) (hazard ratio, 0.73; P = 0.002).

▪ ORR 25% (nivolumab) vs 5% (Everolimus) (OR: 1.72; P = .0246)

➢ All-grade and grade 3/4 toxicity were lower with nivolumab compared to everolimus.

➢ The survival improvement and favorable safety profile demonstrated provides evidence for nivolumab as a potential new treatment option for previously treated patients with mRCC.

56

Real world data - Conclusions

• The EAP population included some subgroups that were poorly represented or

not represented at all in the pivotal CheckMate 025 study3

• 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 trial3

• As in CheckMate 025,4 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 trial3

• 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

56

3. Motzer RJ et al. N Engl J Med. 2015;373:1803-1813.4. Escudier B et al. Eur Urol. 2017. doi: 10.1016/j.eururo.2017.03.037.5. Escudier B et al. Eur Urol. 2017. doi: 10.1016/j.eururo.2017.02.010.

5757

Phase III, randomized, open-label trial of nivolumab combined with ipilimumab vs sunitinib monotherapy in treatment-naïve patients with advanced or metastatic clear cell RCC1

• Primary Outcome Measures: PFS and OS• Key Secondary Outcome Measures: ORR, safety• Select Exploratory Outcome Measure: HRQoL, HRU, predictive

biomarkers

N=1070

Start Date: October 2014Estimated Trial Completion Date: September 2019Estimated Primary Completion Date: June 2019Status: Ongoing, not recruitingStudy Director: Bristol-Myers Squibb

R

1:1

Sunitinib

50 mg PO qd for 4 weeks

( 6 week cycles)

Nivolumab

3 mg/kg IV q3w for 4 doses, then q2w

Key Inclusion Criteria

• Advanced/metastatic clear cell RCC

• No prior systemic therapy for RCC

• Prior adjuvant/neoadjuvant therapy allowed if the agent did not target the VEGF pathway, and recurrence occurred ≥6 months after last dose

• Karnofsky PS ≥70%

• Available FFPE archival or recent tumor tissue sample

• No prior treatment with VEGF pathway agents or agents targeting T-cell costimulation or checkpoint pathways

• No current or history of CNS metastases

Ipilimumab

1 mg/kg IV q3w for 4 doses

Until progression*, unacceptable

toxicity, withdrawal of

consent, or end of trial (up to 5 years)

* Patients may continue treatment beyond progression (RECIST 1.1) if investigator-assessed clinical benefit is achieved and treatment is well-tolerated.2

1. Clinicaltrials.gov. NCT02231749. Accessed November 9, 2016. 2. Hammers H et al. Poster presentation at ASCO 2015. TPS4578.See speaker notes for abbreviations.

Checkmate 214: 1L Nivolumab + Ipilimumab

58

Results of Checkmate-214

59

1st line Phase III trials of combination IO based

therapies in mRCC

Therapeutic target Control

arm

Experimental arm(s)

PD-1 and CTLA-4 Sunitinib Nivolumab + Ipilimumab x 4

Nivolumab

PD1 and IDO-1 Sunitinib

or

Pazopanib

Pembrolizumab + Epacadostat

PD-1 and VEGF Sunitinib Bevacizumab + Atezolizumab

PD-L1 and VEGF Sunitinib Axitinib + Avelumab

PD-L1 and VEGF Sunitinib Axitinib + Pembrolizumab

VEGF/FGF and (PD1 or

mTOR)

Sunitinib Lenvatinib + Pembrolizumab

OR

Lenvatinib + Everolimus

Vaccine (DC+autologous

tumor)

Sunitinib Sunitinib + AGS-003

(rocapuldencel-T)Modified from G. Sonpavde

60

Outline

• Current standards

• Immunotherapy in mBC

• Immunotherapy in mRCC

• Summary

61

Summary

• IO has an established role in the treatment of mRCC( Nivolumab)

• New standard established with recent IO data in first line mRCC ( int/ poor risk)

• A number of ongoing studies in the first line setting with IO combination studies show promise

• Cost and access present a major challenge which needs to be overcome

62

Thank youRavindran.Kanesvaran@singhealth.com.sg