Present state of the art of immune checkpoint inhibitors ......Disclosures • I have provided consultation, attended advisory boards, and/or provided lectures for: Pfizer, MSD, BMS,

Present state of the art of immune

checkpoint inhibitors in oncology

John Haanen, MD PhD

ESMO Advanced course in Immuno-oncology, Amsterdam Febr 2018

Disclosures

• I have provided consultation, attended advisory boards,

and/or provided lectures for: Pfizer, MSD, BMS, IPSEN,

Novartis , Roche/Genentech, NEON Therapeutics

and Gadeta, for which NKI received honoraria

• Through my work NKI received grant support from BMS,

MSD, Novartis, and NEON Therapeutics

• I declare no conflict of interest

Immune Checkpoint inhibitors

• Immune checkpoints play an important role in

immune tolerance

• Cancer hijacks many of these peripheral tolerance

mechanism to escape the immune system

• Inhibition of a single immune checkpoint can be

enough to break this cancer induced tolerance

(anti-CTLA4, anti-PD-1/PD-L1)

• Combination of some of these inhibitors appear

more powerful

Value of enhancing endogenous tumor-specific T cell

responses: Checkpoint blockade

Adjusted from Drake et al., Nat Rev Clin Oncol 2014

Ipilimumab for treatment of

metastatic melanoma

Hodi et al 2010 NEJM

1 Year 2 Year

Ipi + gp100 N=403 44% 22%

Ipi + pbo N=137 46% 24%

gp100 + pboN=136 25% 14%

1 Year 2 Year 3 Year

Ipilimumab+ DTIC

N=25047.3 28.5 20.8

Placebo+

DTIC

N=252

36.3 17.9 12.2

Pre-treated-pts

+/- gp100

HLA-A2

3mg/kg

Re-induction possible

Robert et al NEJM 2011

naive-pts

+ DTIC

10 mg/kg

Maintenance possible

Updated OS results from CheckMate 066 trial in

BRAF wt advanced melanoma

Atkinson et al. abstract 3774 SMR 2015

Decrease of the risk of death 58% vs chemotherapy

Pembrolizumab vs ipilimumab as 1st line treatment of

metastatic melanoma

Robert et al NEJM 2015

Treatment Arm

Median

(95% CI), mo

Rate at

12 mo

HR

(95% CI) P

Pembrolizumab Q2W NR (NR-NR) 74.1% 0.63

(0.47-0.83)

<0.00001

Pembrolizumab Q3W NR (NR-NR) 68.4% 0.69

(0.52-0.90)

<0.00001

Ipilimumab NR (12.7-NR) 58.2% — —

Decrease of risk of death of pembrolizumab 31 to 37% vs ipilimumab

1. Daud A et al. 2015 ASCO; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. 2015 ASCO; 4. Plimack E et al. 2015 ASCO; 5.

Bang YJ et al. 2015 ASCO; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et

al. 2015 AACR; 9. Varga A et al. 2015 ASCO; 10. Ott PA et al. 2015 ASCO; 11. Doi T et al. 2015 ASCO.

-100

-80

-60

-40

-20

0

20

40

60

80

100

Ch

an

ge F

rom

Baseli

ne

in

T

um

or

Siz

e, %

Melanoma1 (N=655)

KEYNOTE-001

-100

-80

-60

-40

-20

0

20

40

60

80

100

NSCLC2 (N=262)

KEYNOTE-001

-100

-80

-60

-40

-20

0

20

40

60

80

100

Gastric5 (N=39)

KEYNOTE-012

-100

-80

-60

-40

-20

0

20

40

60

80

100

-100

-80

-60

-40

-20

0

20

40

60

80

100

H&N3 (N=132)

KEYNOTE-012

TNBC6 (N=32)

KEYNOTE-012

-100

-80

-60

-40

-20

0

20

40

60

80

100

cHL7 (N=29)

KEYNOTE-013

-100

-80

-60

-40

-20

0

20

40

60

80

100

Mesothelioma8 (N=25)

KEYNOTE-028

Anti-PD1 Demonstrates Broad Antitumor Activity

Urothelial4 (N=33)

KEYNOTE-012

-100

-80

-60

-40

-20

0

20

40

60

80

100

-100

-80

-60

-40

-20

0

20

40

60

80

100

Ovarian9 (N=26)

KEYNOTE-028

-100

-80

-60

-40

-20

0

20

40

60

80

100

SCLC10 (N=20)

KEYNOTE-028

-100

-80

-60

-40

-20

0

20

40

60

80

100

Esophageal11 (N=23)

KEYNOTE-028

Courtesy of G Long

Nivo

lung cancer

non-

squamous

2nd line with

biomarker

Pembro

lung

2nd line

with

biomarker

Nivo

kidney

2nd line

Nivo

lung cancer

squamous

2nd line

Nivo

Hodgkin

4th line

Atezo

bladder cancer

2nd line with

biomarker

Pembro

head/neck

2nd line

Pembro

lung cancer

1st line with

biomarker

Atezo

lung cancer

2nd line

Nivo

head/neck

2nd line

Nivo

bladder

2nd line

Pembro

Hodgkin

4th line

Avelumab

Merkel cell Ca

1st line

FDA approvals for immune checkpoint

blockers, diagnostic tests, and treatment

combinations

2011 20132012 201620152014 2017 2018

Pembrolizumab

2nd-line

Ipilimumab

monotherapy

Nivolumab

2nd-line

Nivo

1st-lineIpi

adjuvant

Nivo/ipi

combo

Pembro

1st-line

Nivo mel

biomarker

Durvalumab

bladder

2nd line

with

biomarker

Avelumab

bladder

2nd line

Pembro/chemo

NSCLC

combo

2nd line

Melanoma

Non-Melanoma

Pembro

bladder

2nd line

Pembro

MSI-hi tumors

2nd line

with biomarker

Nivo

MSI-hi CRC

2nd line

with biomarker

Courtesy of S. Topalian (JAMA 2017)

“Melanoma has become from a disease that gave

cancer a bad name to a ‘model’ disease for I-O”

Current I-O treatment options for melanoma

– Stage III disease

• Neo-adjuvant/adjuvant trials

– Stage IV disease

• combination therapy

EORTC 18071/CA184-029: Study Design

Stratification factors

– Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC ≥4 positive lymph nodes)

– Regions (North America, European countries, and Australia)

Enrollment Period: June 2008 to July 2011

Randomized, double-blind, phase 3 study evaluating the efficacy and safety of

ipilimumab in the adjuvant setting for high-risk melanoma

INDUCTION

Ipilimumab 10 mg/kg

Q3W × 4High-risk, stage III,

completely resected

melanoma

INDUCTION

Placebo

Q3W × 4

R

MAINTENANCE

Ipilimumab 10 mg/kg

Q12W up to 3 years

MAINTENANCE

Placebo

Q12W up to 3 years

Treatment up to a maximum of 3 years, or until disease progression, intolerable toxicity, or

withdrawal

N = 475

N = 476

Week 1 Week 12 Week 24

N = 951

Q3W = every 3 weeks; Q12W = every 12 weeks; R = randomization.

aStratified by stage provided at randomization.

CI = confidence interval.

Pa

tie

nts

A

live

a

nd

W

ith

ou

t R

ec

urr

en

ce

(

%)

Ipilimumab Placebo

Events/patients 264/475 323/476

HR (95% CI)a 0.76 (0.64, 0.89)

Log-rank P valuea 0.0008

Median RFS, months

(95% CI)

27.6

(19.3, 37.2)

17.1

(13.6, 21.6)

RFS (per IRC)

41%

30%

Years0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk

264 475 283 217 184 161 77 13 1

323 476 261 199 154 133 65 17 0

Ipilimumab

Placebo

Pa

tie

nts

A

live

(%)

aStratified by stage provided at randomization.

Ipilimumab Placebo

Deaths/patients 162/475 214/476

HR (95.1% CI)a 0.72 (0.58, 0.88)

Log-rank P valuea 0.001

OS

65%

54%

Years0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk

162 475 431 369 325 290 199 62 4

214 476 413 348 297 273 178 58 8

Ipilimumab

Placebo

Patient Disposition and Treatment

Ipilimumab (n = 471) Placebo (n = 474)

Discontinuation, % 100 100

Reasons for discontinuation, %

Normal completion (received study drug for

entire 3 years)13.4 30.2

Disease recurrence 28.7 59.5

AE related to study drug 49.7 1.9

Other reasonsa 8.2 8.4

Median doses, per patient, n 4.0 8.0

Receiving ≥1 maintenance dose, % 42.0 70.0

Receiving ≥7 doses (1 year of therapy), % 28.9 56.8

aIncludes AE unrelated to study drug, both related and unrelated to study drug, patient request, poor/noncompliance, death, pregnancy, patient

no longer eligible, other.

Phase III trials in the adjuvant setting for stage III and IV disease

• A Phase 3, Randomized, Double-blind Study of Adjuvant

Immunotherapy With Nivolumab Versus Ipilimumab After

Complete Resection of Stage IIIb/c or Stage IV Melanoma in

Subjects Who Are at High Risk for Recurrence (CheckMate-238)

• Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody

Pembrolizumab Versus Placebo After Complete Resection of

High-risk Stage III Melanoma: A Randomized, Double- Blind Phase

3 Trial of the EORTC Melanoma Group (KEYNOTE-054)

• A Phase III Randomized Trial Comparing Physician/Patient Choice

of Either High Dose Interferon or Ipilimumab to Pembrolizumab

in Patients With High Risk Resected Melanoma

CA209-067: Study Design CA209-238: Study Design

Patients with high-risk,

completely resected stage

IIIB/IIIC or stage IV melanoma

Enrollment period: March 30, 2015 to November 30, 2015

Follow-up

Maximum

treatment

duration of

1 year

NIVO 3 mg/kg IV Q2W

and

IPI placebo IV

Q3W for 4 doses

then Q12W from week 24

IPI 10 mg/kg IV

Q3W for 4 doses

then Q12W from week 24

and

NIVO placebo IV Q2W

1:1

n = 453

n = 453

Stratified by:

1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c

2) PD-L1 status at a 5% cutoff in tumor cells

Study Overview

Primary endpoint

• RFS: time from randomization until first recurrence (local, regional, or distant

metastasis), new primary melanoma, or death

Secondary endpoints

• OS

• Safety and tolerability

• RFS by PD-L1 tumor expression

• HRQoL

Current interim analysis

• Primary endpoint (RFS), safety, and HRQoL

– DMFS (exploratory)

• Duration of follow-up: minimum 18 months; 360 events

DMFS = distant metastasis-free survival; HRQoL = health-related quality of life

Baseline Patient Characteristics

• Most of the patients had cutaneous melanoma (85%), and 4% had acral and 3% had mucosal melanoma

• All 905 patients are off treatment; median doses were 24 (1-26) in the NIVO group and 4 (1-7) in the IPI group

• 397 patients completed 1 year of treatment (61% of the NIVO group and 27% of the IPI group)

NIVO(n = 453)

IPI(n = 453)

Median age, years 56 54

Male, % 57 59

Stage, IIIB+IIIC, % 81 81

Macroscopic lymph node involvement (% of stage IIIB+IIIC) 60 58

Ulceration (% of stage IIIB+IIIC) 42 37

Stage IV, % 18 19

M1c without brain metastases (% stage IV) 17 17

PD-L1 expression ≥5%, % 34 34

BRAF mutation, % 41 43

LDH ≤ ULN, % 91 91

Primary Endpoint: RFS

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

453 353 311 249 5 0399 332 291 71NIVO

453 314 252 184 2 0364 269 225 56IPI

Number of patients at risk

NIVO

IPI

NIVO IPI


Median (95% CI) NRNR (16.6,

NR)

HR (97.56% CI) 0.65 (0.51, 0.83)

Log-rank Pvalue

<0.0001

66%

53%

71%

61%

PD-L1 Expression Level <5% PD-L1 Expression Level ≥5%

NIVO IPI


Median (95% CI) NR 15.9 (10.4, NR)

HR (95% CI) 0.71 (0.56, 0.91)

NIVO IPI


Median (95% CI) NR NR

HR (95% CI) 0.50 (0.32, 0.78)

Subgroup Analysis of RFS: PD-L1 Expression Level R

FS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

NIVO

IPI

275 204 171 129 3 0242 189 159 41NIVO

286 184 139 100 2 0219 153 124 31IPI


RF

S (

%)

Months

152 130 122 105 2 0135 125 114 26NIVO

154 120 105 78 0 0133 108 93 21IPI


64%

54%

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

NIVO

IPI

82%

74%

RFS: Prespecified Subgroups

Subgroup

No. of events/no. of patients Unstratified

HR (95% CI)

Unstratified HR

(95% CI)NIVO 3 mg/kg IPI 10 mg/kg

Overall Overall 154/453 206/453 0.66 (0.53, 0.81)

Age <65 years 106/333 147/339 0.65 (0.51, 0.84)

≥65 years 48/120 59/114 0.66 (0.45, 0.97)

Sex Male 99/258 133/269 0.68 (0.53, 0.88)

Female 55/195 73/184 0.63 (0.44, 0.89)

Stage (CRF) Stage IIIb 41/163 54/148 0.67 (0.44, 1.00)

Stage IIIc 79/204 109/218 0.65 (0.49, 0.87)

Stage IV M1a-M1b 25/62 35/66 0.63 (0.38, 1.05)

Stage IV M1c 8/20 8/21 1.00 (0.37, 2.66)

Not reported 1/2 0/0

Stage III: Ulceration Absent 58/201 94/216 0.59 (0.42, 0.82)

Present 60/153 64/135 0.73 (0.51, 1.04)

Not reported 2/15 5/15 0.39 (0.07, 2.00)

Stage III: Lymph node

involvement

Microscopic 41/125 55/134 0.71 (0.47, 1.07)

Macroscopic 72/219 101/214 0.62 (0.46, 0.84)

Not reported 7/25 7/18 0.60 (0.21, 1.72)

PD-L1 status <5%/indeterminate 123/300 149/299 0.71 (0.56, 0.90)

≥5% 31/152 57/154 0.50 (0.32, 0.78)

BRAF mutation status Mutant 63/187 84/194 0.72 (0.52, 1.00)

Wild-type 67/197 105/214 0.58 (0.43, 0.79)

Not reported 24/69 17/45 0.83 (0.45, 1.54)

NIVO IPI

0 1 2

Exploratory Endpoint: DMFS for Stage III Patients

DM

FS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

369 309 280 214 3 0335 292 264 62NIVO

366 284 239 176 1 0312 254 217 51IPI


NIVO

IPI

NIVO IPI


Median (95% CI) NR NR

HR (95% CI) 0.73 (0.55, 0.95)

Log-rank P value 0.0204

80%

73%

Treatment-Related Select Adverse Events

• Median time to onset of treatment-related select AEs was generally shorter for patients

receiving IPI (range 2.6-10 weeks) than for those receiving NIVO (range 3.3-14.2 weeks)

AE, n (%)

NIVO (n = 452) IPI (n = 453)

Any grade Grade 3/4 Any grade Grade 3/4

Skin 201 (44.5) 5 (1.1) 271 (59.8) 27 (6.0)

Gastrointestinal 114 (25.2) 9 (2.0) 219 (48.3) 76 (16.8)

Hepatic 41 (9.1) 8 (1.8) 96 (21.2) 49 (10.8)

Pulmonary 6 (1.3) 0 11 (2.4) 4 (0.9)

Renal 6 (1.3) 0 7 (1.5) 0

Hypersensitivity/infusion reaction 11 (2.4) 1 (0.2) 9 (2.0) 0

Endocrine

Adrenal disorder 6 (1.3) 2 (0.4) 13 (2.9) 4 (0.9)

Diabetes 2 (0.4) 1 (0.2) 1 (0.2) 0

Pituitary disorder 8 (1.8) 2 (0.4) 56 (12.4) 13 (2.9)

Thyroid disorder 92 (20.4) 3 (0.7) 57 (12.6) 4 (0.9)

Conclusions

• Nivolumab showed a clinically and statistically significant improvement in

RFS vs the active control of high-dose ipilimumab for patients with

resected stages IIIB/IIIC and stage IV melanoma at high risk of

recurrence (HR = 0.65, P < 0.0001)

– 18-month RFS rates were 66% for nivolumab and 53% for ipilimumab

– Benefit for nivolumab was observed across the majority of prespecified

subgroups tested, including PD-L1 and BRAF mutation status

• Nivolumab has a superior safety profile in comparison with ipilimumab,

with fewer grade 3/4 AEs and fewer AEs leading to treatment

discontinuation

• Nivolumab has the potential to be a new standard treatment option for

patients with resected stage IIIB, IIIC, and IV melanoma regardless of

BRAF mutation

New developments in adjuvant and neoadjuvant trials

• An Open-label, Phase IB Study of NEO-PV-01 + AdjuvantWith Nivolumab in Patients With Melanoma, Non-Small CellLung Carcinoma or Transitional Cell Carcinoma of the Bladder

• Phase II Study to Identify the Optimal neoadjuvantCombination Scheme of Ipilimumab and Nivolumab in Stage III Melanoma Patients (OPACIN-neo)

• A Phase II, Randomised, Open Label Study of NeoadjuvantDabrafenib, Trametinib and / or Pembrolizumab in BRAF V600 Mutant Resectable Stage IIIB/C Melanoma

• A Phase 1b Trial of Neoadjuvant CXCR4 antagonist (X4P-001) Alone and With Pembrolizumab in Patients WithResectable Melanoma

Antonia et al., NEJM 2017

PACIFIC: Study Design

Phase III, Randomized, Double-blind, Placebo-

controlled, Multicenter, International Study

*Defined as the time from randomization (which occurred up to 6 weeks post-cCRT) to the first documented event of tumor progression or death in the absence of progression.

ClinicalTrials.gov number: NCT02125461 BICR, blinded independent central review; cCRT, concurrent chemoradiation therapy; DoR, duration of response;

NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PROs, patient-reported outcomes;

PS, performance status; q2w, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization

• Patients with stage III, locally

advanced, unresectable NSCLC

who have not progressed following

definitive platinum-based cCRT

(≥2 cycles)

• 18 years or older

• WHO PS score 0 or 1

• Estimated life expectancy of

≥12 weeks

• Archived tissue was collected

All-comers population

Durvalumab

10 mg/kg q2w for

up to 12 months

N=476

Placebo

10 mg/kg q2w for

up to 12 months

N=237

2:1 randomization,

stratified by age, sex,

and smoking history

N=713Key secondary endpoints

• ORR (per BICR)

• DoR (per BICR)

• Safety and tolerability

• PROs

Co-primary endpoints

• PFS by BICR using RECIST v1.1*

• OS

R

1–42 days

post-cCRT


Baseline Characteristics (ITT)

Durvalumab

(N=476)

Placebo

(N=237)

Age Median (range), years

≥65 years, %

64 (31–84)

45.2

64 (23–90)

45.1

Male, % 70.2 70.0

WHO performance status score, %* 0 / 1 49.2 / 50.4 48.1 / 51.5

Smoking status, % Current / Former / Never 16.6 / 74.4 / 9.0 16.0 / 75.1 / 8.9

Disease stage, %† IIIA / IIIB 52.9 / 44.5 52.7 / 45.1

Histology, % Squamous / Non-squamous 47.1 / 52.9 43.0 / 57.0

PD-L1 status, % Known: TC <25% / TC ≥25%

Unknown‡

39.3 / 24.2

36.6

44.3 / 18.6

37.1

Prior chemotherapy, % Induction / Definitive cCRT 25.8 / 99.8 28.7 / 99.6

Prior radiotherapy, %* <54 Gy

54 to ≤66 Gy

>66 to ≤74 Gy

0.6

92.9

6.3

0

91.6

8.0

Best response to prior cCRT, %¶ CR / PR / SD / PD 1.9 / 48.7 / 46.6 / 0.4 3.0 / 46.8 / 48.1 / 0

*Not reported or missing (durvalumab, placebo, total): WHO performance status (0.4% each), prior radiotherapy (0.2%, 0.4%, 0.3%). †Other: durvalumab, 2.5%; placebo, 2.1%; total, 2.4%. ‡No sample collected or no valid test result. ¶Not evaluable/not applicable: durvalumab, 2.3%; placebo, 2.1%; total, 2.2%.

cCRT, concurrent chemoradiation therapy; CR, complete response; ITT, intention-to-treat; PD, progressive disease; PD-L1, programmed cell death ligand-1; PR, partial response; SD, stable disease;

TC, tumor cell; TC ≥25%, ≥25% PD-L1 expression on tumor cells; TC <25%, <25% PD-L1 expression on tumor cells; WHO, World Health Organization


Patient Disposition

• Median follow-up was 14.5 months (range 0.2–29.9)

Durvalumab

(N=476)

Placebo

(N=237)

Received treatment, n (%) 473 (99.4) 236 (99.6)

Completed 12 months of treatment, n (%) 202 (42.7) 71 (30.1)

Discontinued study treatment, n (%)

Patient decision

Adverse event

Severe non-compliance to protocol

Disease worsening

Development of study specific discontinuation criterion

Other

241 (51.0)

14 (3.0)

73 (15.4)

1 (0.2)

148 (31.3)

1 (0.2)

4 (0.8)

153 (64.8)

12 (5.1)

23 (9.7)

1 (0.4)

116 (49.2)

1 (0.4)

0

Received subsequent therapy after discontinuation, n (%) 145 (30.5) 102 (43.0)

Progressed by BICR as of data cutoff for interim PFS analysis, n 214 157


PFS by BICR (Primary Endpoint; ITT)P

FS

pro

babili

ty

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 3 6 9 12 15 18 21 24 27

Time from randomization (months)

Placebo

Durvalumab

476 377 301 264 159 86 44 21 4237 163 106 87 52 28 15 4 3

10

No. at riskDurvalumab

Placebo

Durvalumab

(N=476)

Placebo

(N=237)

Median PFS (95% CI), months 16.8 (13.0–18.1) 5.6 (4.6–7.8)

12-month PFS rate (95% CI) 55.9% (51.0–60.4) 35.3% (29.0–41.7)

18-month PFS rate (95% CI) 44.2% (37.7–50.5) 27.0% (19.9–34.5)

Stratified hazard ratio, 0.52 (95% CI, 0.42–0.65)Two-sided P<0.0001


PFS Subgroup Analysis by BICR (ITT)

Durvalumab Placebo Unstratified HR*

No. of patients (95% CI)

All patients 476 237 0.55 (0.45–0.68)

SexMale 334 166 0.56 (0.44–0.71)

Female 142 71 0.54 (0.37–0.79)

Age at randomization<65 years 261 130 0.43 (0.32–0.57)

≥65 years 215 107 0.74 (0.54–1.01)

Smoking statusSmoker 433 216 0.59 (0.47–0.73)

Non-smoker 43 21 0.29 (0.15–0.57)

Disease stageStage IIIA 252 125 0.53 (0.40–0.71)

Stage IIIB 212 107 0.59 (0.44–0.80)

HistologySquamous 224 102 0.68 (0.50–0.92)

Non-squamous 252 135 0.45 (0.33–0.59)

Best response to

cCRT

CR 9 7 –

PR 232 111 0.55 (0.41–0.75)

SD 222 114 0.55 (0.41–0.74)

PD-L1 status≥25% 115 44 0.41 (0.26–0.65)

<25% 187 105 0.59 (0.43–0.82)

Unknown 174 88 0.59 (0.42–0.83)

EGFR statusMutant 29 14 0.76 (0.35–1.64)

Wild-type 315 165 0.47 (0.36–0.60)

Unknown 132 58 0.79 (0.52–1.20)

*Hazard ratio and 95% CI not calculated if the subgroup has less than 20 events.

BICR, blinded independent central review; CI, confidence interval; CR, complete response; HR, hazard ratio; ITT, intention-to-treat; EGFR, epidermal growth factor receptor

0.25 0.5 1 2

Favors durvalumab Favors placebo


Time to Distant Metastasis or Death by BICR (ITT)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1 3 6 9 12 15 18 21 24 27 30

Pro

babili

ty o

f death

or

dis

tant m

eta

sta

sis

Time from randomization (months)

Placebo

Durvalumab

No. at riskDurvalumab

Placebo476 407 336 288 173 91 46 22 4 1 0237 184 129 106 63 32 16 5 4 0 0

Durvalumab Placebo

14.6 (10.6–18.6)23.2 (23.2–NR)Median time (95% CI),

months

Stratified hazard ratio, 0.52 (95% CI, 0.39–0.69)Two-sided P<0.0001


Pneumonitis or Radiation Pneumonitis

Safety analysis set (all-causality). *Pneumonitis/radiation pneumonitis was assessed by investigators with subsequent review and adjudication by the study sponsor.

In addition, pneumonitis, as reported in the table, is a grouped term, which includes acute interstitial pneumonitis, interst itial lung disease, pneumonitis, and pulmonary fibrosis.

Two patients randomized to placebo received at least one dose of durvalumab and were considered part of the durvalumab arm for safety reporting.

Pneumonitis (grouped terms) or radiation

pneumonitis, n (%)*

Durvalumab

(N=475)

Placebo

(N=234)

Any grade 161 (33.9) 58 (24.8)

Grade 3/4 16 (3.4) 6 (2.6)

Grade 5 5 (1.1) 4 (1.7)

Leading to discontinuation 30 (6.3) 10 (4.3)


Summary• Durvalumab demonstrated a statistically significant and robust

improvement in PFS versus placebo (HR 0.52; P<0.0001; median

improvement of >11 months) at a planned interim analysis

• PFS improvement with durvalumab was observed across all pre-

specified subgroups

• Durvalumab demonstrated a clinically meaningful benefit in ORR

(28.4% vs 16.0%; P<0.001), with durable responses versus placebo

(median DoR not reached vs 13.8 months)

• Patients receiving durvalumab had a lower incidence of new lesions,

including new brain metastases, compared with patients receiving

placebo

• The safety profile of durvalumab was consistent with that of other

immunotherapies and with its known safety profile as monotherapy in

patients with more advanced disease;1 no new safety signals were

identified

• The study remains blinded to OSAntonia et al., NEJM 2017

“Melanoma has become from a disease that gave

cancer a bad name to a ‘model’ disease for I-O”

Current I-O treatment options for melanoma

– Stage III disease

• Neo-adjuvant/adjuvant trials

– Stage IV disease

• combination therapy

Why combining

(immuno)therapies?

Tumor foreignnessMutational load

General immune statusLymphocyte count

Immune cell infiltration

Intratumoral T cells

Absence of CheckpointsPD-L1

Absence of soluble inhibitorsIL6->CRP/ESR

Tumor sensitivity to immune effectors

MHC expression

IFN-g sensitivity

Absence of inhibitory tumor metabolism

LDH, glucose utilization

Cancer Immunogram

Blank, Haanen et al. Science 2016

Chen & Mellman Nature 2017

Cancer Immunophenotypes

Combinations with immunotherapy

Melero, Haanen Nat Rev Canc 2015

Most combinations have anti-PD1/PDL1 as

backbone

Melero, Haanen Nat Rev Canc 2015

Combinations

• Anti-CTLA4 + anti-PD1/PDL1

• IDO1/2 inhibitor + anti-PD1

• Oncolytic virus + anti-PD1

• Anti-LAG3 + anti-PD1

• Combination with angiogenesis inhibitors

– IMpower 150 (NSCLC)

– IMmotion 151(RCC)

PD1 blockade synergizes with aCTLA-4

Curran et al., PNAS 2010

Immunotherapy melanoma – CTLA4 + PD-1

blockade (ipilimumab + nivolumab)

Wolchok et al.

ASCO 2013 # 9012

Overall Survival Results From a Phase III Trial

of Nivolumab Combined With Ipilimumab in Treatment-naïve

Patients With Advanced Melanoma (CheckMate 067)

James Larkin,1 Vanna Chiarion-Sileni,2 Rene Gonzalez,3 Piotr Rutkowski,4 Jean-Jacques Grob,5

C. Lance Cowey,6 Christopher D. Lao,7 Dirk Schadendorf,8 Pier Francesco Ferrucci,9 Michael Smylie,10

Reinhard Dummer,11 Andrew Hill,12 John Haanen,13 Michele Maio,14 Grant McArthur,15 Dana Walker,16

Linda Rollin,16 Christine Horak,16 F. Stephen Hodi,17,* Jedd D. Wolchok18,*

1Royal Marsden Hospital, London, UK; 2Oncology Institute of Veneto IRCCS, Padua, Italy; 3University of Colorado Cancer Center, Denver, CO,

USA; 4Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland; 5Hospital de la Timone, Marseille, France; 6Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA; 7University of Michigan, Ann Arbor, MI, USA; 8Department of

Dermatology, University of Essen, Essen, Germany; 9European Institute of Oncology, Milan, Italy; 10Cross Cancer Institute, Alberta, Canada; 11Universitäts Spital, Zurich, Switzerland; 12Tasman Oncology Research, QLD, Australia; 13Netherlands Cancer Institute, Amsterdam, The

Netherlands; 14University Hospital of Siena, Siena, Italy; 15Peter MacCallum Cancer Centre, Victoria, Australia; 16Bristol-Myers Squibb,

Princeton, NJ, USA; 17Dana-Farber Cancer Institute, Boston, MA, USA; 18Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; *Contributed equally to this study.

Presented at AACR 2017 by Larkin

Unresectable or

Metatastic Melanoma

• Previously untreated

• 945 patients

CA209-067: Study Design CheckMate 067: Study Design

Treat until

progression or

unacceptable

toxicity

NIVO 3 mg/kg Q2W +IPI-matched placebo

NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO

3 mg/kg Q2W

IPI 3 mg/kg Q3W for 4 doses +

NIVO-matched placebo

Randomize

1:1:1

Stratify by:

• BRAF status

• AJCC M stage

• Tumor PD-L1 expression <5% vs ≥5%*

N=314

N=316

N=315

Randomized, double-blind,

phase III study to compare NIVO+IPI

or NIVO alone to IPI alone*

*The study was not powered for a comparison between NIVO and NIVO+IPI

Database lock: Sept 13, 2016 (median follow-up ~30 months in both NIVO-containing arms)


NIVO+IPI(N=314)

NIVO(N=316)

IPI(N=315)

ORR, % (95% CI)* 58.9 (53.3–64.4) 44.6 (39.1–50.3) 19.0 (14.9–23.8)

Best overall response — %

Complete response 17.2 14.9 4.4

Partial response 41.7 29.7 14.6

Stable disease 11.5 9.8 21.3

Progressive disease 23.6 38.6 51.1

Unknown 6.1 7.0 8.6

Median duration of response, months (95% CI)

NR (NR–NR) 31.1 (31.1–NR) 18.2 (8.3–NR)

Response To Treatment

*By RECIST v1.1; NR = not reached.

• At the 18-month DBL, the CR rate for NIVO+IPI, NIVO and IPI was 12.1%, 9.8% and 2.2%, respectively

Database lock: Sept 13, 2016, minimum f/u of 28 months

Progression-Free Survival

Wolchok et al., NEJM 2017

NIVO+IPI (N=314) NIVO (N=316) IPI (N=315)

Median PFS, mo (95% CI)

11.7 (8.9–21.9)

6.9 (4.3–9.5)

2.9 (2.8–3.2)

HR (95% CI) vs. IPI0.42

(0.34–0.51)0.54

(0.45–0.66)--

HR (95% CI) vs. NIVO0.76

(0.62–0.94)-- --

Overall Survival

*P<0.0001

Wolchok et al., NEJM 2017

NIVO+IPI (N=314) NIVO (N=316) IPI (N=315)

Median OS, mo (95% CI)

NRNR

(29.1–NR)20.0

(17.1–24.6)

HR (98% CI) vs. IPI0.55

(0.42–0.72)*0.63

(0.48–0.81)*--

HR (95% CI) vs. NIVO0.88

(0.69–1.12)-- --

NIVO+IPI(N=314)

NIVO(N=316)

IPI(N=315)

Any subsequent therapy, n (%)* 129 (41) 169 (54) 225 (71)

Systemic therapy 100 (32) 140 (44) 196 (62)

Anti-PD-1 agents 30 (10) 32 (10) 132 (42)

Anti-CTLA-4 19 (6) 83 (26) 12 (4)

BRAF inhibitors 40 (13) 57 (18) 68 (22)

MEK inhibitors 30 (10) 38 (12) 39 (12)

Investigational agents** 8 (3) 6 (2) 15 (5)

Median time to subsequent systemic therapy, mo (95% CI)

NR (NR‒NR) 26.8 (18.0‒NR) 8.5 (7.3‒9.7)

2 year % of pts free of subsequent therapies

65.8 53.8 24.7

Subsequent Therapies: All Randomized

Patients

*Patients may have received more than 1 subsequent therapy (e.g. radiation, surgery and systemic therapies)

**Other than investigational immunotherapy, BRAF inhibitors, and MEK inhibitors


<1% PD-L1NIVO+IPI NIVO IPI

Median OS,

mo (95% CI)

NR

(26.5–NR)

23.5

(13.0–NR)

18.6

(13.7–

23.2)

HR (95% CI)

vs NIVO

0.74

(0.52–

1.06)

─ ─

≥1% PD-L1NIVO+IPI NIVO IPI

Median OS,

mo (95% CI)NR NR

22.1

(17.1–

29.7)

HR (95% CI)

vs NIVO

1.03

(0.72–

1.48)

─ ─

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39363330272421181512963

60%

49%

41% OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39363330272421181512963

113 0IPI 11032434450576171798796

117 0NIVO 216505557596265737686103

123 0NIVO+IPI 4186672747479828291102113

164 0IPI 2216474778389102115126138155

171 0NIVO 13698109112117122131139148158165

155 0NIVO+IPI 3278599101102105112116127132144

67%

67%

48%

Outcomes Observed at PDL1 1% Cutoff

PD-L1 Expression Level <1% PD-L1 Expression Level ≥1%

Patients at risk: Patients at risk:

• ORR of 65.2% for NIVO+IPI and 55.0% for NIVO • ORR of 54.5% for NIVO+IPI and 35.0% for NIVO


Safety Summary• With an additional 19 months of follow-up, safety was consistent with the initial

report1

• Most select AEs were managed and resolved within 3-4 weeks (85–100% across

organ categories)

• ORR was 70.7% for pts who discontinued NIVO+IPI due to AEs, with median OS

not reached

NIVO+IPI(N=313)

NIVO

(N=313)IPI

(N=311)

Patients reporting event, % Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4

Treatment-related adverse event (AE) 95.8 58.5 86.3 20.8 86.2 27.7

Treatment-related AE leading to discontinuation 39.6 31.0 11.5 7.7 16.1 14.1

Treatment-related death, n (%) 2 (0.6)a 1 (0.3)b 1 (0.3)b

aCardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >100 days after the last treatment.bNeutropenia (NIVO, n=1); colon perforation (IPI, n=1).1

1. Larkin J, et al. NEJM 2015;373:23‒34.

Rapid complete remission after combination

immunotherapy with anti-CTLA4 and anti-PD1

Chapman et al., NEJM 2015

Conclusions (1)

• Combination of ipilimumab + nivolumab is highly

effective in patients with metastatic melanoma

with ORR of 58.9%, PFS of 11.7 months and 2

year OS rate of 58%

Conclusions (2)

• NIVO+IPI and NIVO significantly improved OS and PFS vs. IPI alone in

patients with untreated advanced melanoma

• In descriptive analyses, NIVO+IPI resulted in numerically higher OS, PFS and

ORR vs. NIVO alone

• Results consistently favored NIVO+IPI across clinically relevant subgroups,

including PD-L1 expression <5% or <1%, mutant BRAF, and elevated LDH

– Although similar prolongation of OS was observed with NIVO and NIVO+IPI for

PD-L1 expression ≥5% or ≥1%, NIVO+IPI resulted in higher ORR regardless of

PD-L1 expression

• For NIVO+IPI, median DOR and time to subsequent therapy are still not

reached

• The safety profile of the combination showed high rate of grade 3-4 IR toxicity,

but early discontinuation due to AEs did not preclude benefit

Epacadostat Plus Pembrolizumab in Patients

With Advanced Melanoma: Phase 1 and 2

Efficacy and Safety Results From ECHO-

202/KEYNOTE-037

• O. Hamid,1 T. F. Gajewski,2 A. E. Frankel,3 T. M. Bauer,4 A. J. Olszanski,5 J. J. Luke,2 A.

S. Balmanoukian,1

E. V. Schmidt,6 B. Sharkey,7 J. Maleski,7 M. M. Jones,7 T. C. Gangadhar8

• 1The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 2University of

Chicago, Chicago, IL, USA; 3University of Texas Southwestern Medical Center, Dallas,

TX, USA*; 4Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; 5Fox Chase Cancer Center, Philadelphia, PA, USA; 6Merck & Co., Inc., Kenilworth, NJ, USA; 7Incyte Corporation, Wilmington, DE, USA; 8Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA

Presentation #1214O

Session: Melanoma and Other Skin Tumours

Presented at the ESMO Annual Meeting 2017

Madrid, Spain

September 9, 2017

IDO1 Enzyme and Epacadostat

• Tumors may evade immunosurveillance

through numerous mechanisms (eg,

immune checkpoint inhibition of T-cell

activation and upregulation of the IDO1

enzyme)

• IDO1 is an IFNγ-induced intracellular

enzyme that catalyzes the first and rate-

limiting step of tryptophan degradation in

the kynurenine pathway1

• In tumors, depletion of tryptophan and

production of kynurenine and other

metabolites shift the local TME to an

immunosuppressive state that helps tumor

cells evade immunosurveillance1

• Epacadostat is a potent and specific oral

inhibitor of the IDO1 enzyme2

• Combining epacadostat with an immune

checkpoint inhibitor may improve patient

outcomes

IDO1, indoleamine 2,3 dioxygenase 1; IFNγ, interferon gamma; PD-1, programmed death 1; PD-L1, programmed death ligand 1.

1. Moon YW, et al. J Immunother Cancer. 2015;3:51. 2. Liu X, et al. Blood. 2010;115(17):3520-3530.

Objective and Study Design

• ≥18 years of age

• Histologically or cytologically

confirmed melanoma

• Life expectancy >12 weeks

• ECOG PS 0 or 1

• ALT, AST, ALP <2.5x ULN;

conjugated bilirubin <2.0x ULN

• No previous IDO inhibitor or

immune checkpoint inhibitor

treatment

• Phase 2 requirements

– Documented BRAF V600E-

mutation status or consent for

BRAF mutation testing during

screening

– Ocular melanoma excluded

Phase 1/2 Melanoma Patients (N=65)

Epacadostat 25 mg BID

+

Pembrolizumab 2 mg/kg

Q3W

Epacadostat 300 mg

BID

+

Pembrolizumab 200 mg

Q3W


+


Q3W

Epacadostat 300 mg

BID

+


Q3W


+


Q3W

Epacadostat 100 mg

BID

+


Q3W

Epacadostat 100 mg

BID

+


Q3W

Dose

Escalation

Safety

Expansion

Open-Label

Cohort

Expansion

Phase 1b Phase 2

Epacadostat

100 mg BID

+

Pembrolizumab

200 mg Q3W

Tumor cohorts

Melanoma, SCCHN,

UC, NSCLC (TPS

≥50%,* TPS <50%),

RCC, TNBC, OC,

MSI-High CRC,*†

DLBCL,* GC,* HCC*†

Objective: To report the efficacy, safety, and tolerability data for epacadostat plus pembrolizumab

in patients with advanced melanoma in the phase 1/2 ECHO-202/KEYNOTE-037 study

(NCT02178722)

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; CRC, colorectal cancer;

DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; GC, gastric cancer; HCC,

hepatocellular carcinoma; IDO, indoleamine 2,3 dioxygenase; MSI, microsatellite instability; NSCLC, non-small cell lung cancer; OC, ovarian

cancer; Q3W, every 3 weeks; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; TNBC, triple-negative

breast cancer; TPS, tumor proportion score; UC, urothelial cancer; ULN, upper limit of normal.

* Ongoing patient enrollment at data cutoff (June 9, 2017). † Ongoing patient enrollment at time of European Society for Medical Oncology

presentation (September 9, 2017).

Patient Disposition Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma

* Patients received 24 months of study treatment or achieved complete response and elected to discontinue treatment following the protocol-

defined minimum amount of treatment (≥24 weeks before discontinuation and ≥2 cycles of combination treatment beyond the date of initial

complete response).

Median (range) follow-up: 45+ (2 to 144+) weeks

Median (range) epacadostat exposure: 34+ (<1 to 145+) weeks

Treatment Ongoing

(n=32)

• Disease progression

(n=15)

• Adverse event (n=6)

‒ Treatment related

(n=4)

• Death (n=3)

• Patient decision (n=1)

• Other (n=2)

Treatment

Discontinued

(n=27)

Phase 1/2 Melanoma

(N=65; Enrollment

Complete)

Treatment Completed*

(n=6)

Best Objective Response by RECIST v1.1Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma

All

Patients

(N=65)

Treatment-Naive for

Advanced Disease, All E

Doses

(n=54)

Treatment-Naive for

Advanced Disease, E 100

mg

(n=39)

Per-protocol evaluable,* n

(%)n=63 n=53 n=38

ORR (CR+PR) 35 (56) 29 (55) 22 (58)

CR 9 (14) 7 (13) 3 (8)

PR 26 (41) 22 (42) 19 (50)

SD 10 (16) 9 (17) 6 (16)

DCR (CR+PR+SD) 45 (71) 38 (72) 28 (74)

PD or death 18 (29) 15 (28) 10 (26)

Not evaluable† n=2 n=1 n=1

• For all patients, based on irRECIST (n=63*): ORR=59% (9 CR, 28 PR); DCR=75% (10 SD)

• BRAF-mutation–positive (n=18) vs –negative (n=43): 50% vs 56% ORR

• LDH normal (n=39) vs elevated (n=23): 62% vs 48% ORR

Response Observed Across Patient Subgroups (N=63*)

• Liver metastases yes (n=24) vs no (n=39): 46% vs 62% ORR

• M1c (n=35) vs non-M1c (n=28): 49% vs 64% ORR

Best Percentage Change From Baseline in Target Lesions

Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma

CR, complete response; DCR, disease control rate; E, epacadostat, irRECIST, immune-related RECIST; MEL, melanoma; ORR, objective

response rate; PD, progressive disease; PD-L1, programmed death ligand 1; PR, partial response; RECIST, Response Evaluation Criteria in Solid

Tumors; SD, stable disease.

Note: PD-L1 positive defined as MEL Score 2 (membranous PD-L1 expression in ≥1% of tumor cells or inflammatory cells in nests of tumor cells)

as assessed by immunohistochemistry using the 22C3 antibody. * SD per target lesion but PD per RECIST v1.1. † PR per target lesion but PD per

RECIST v1.1. ‡ PR per target lesion but SD per RECIST v1.1. § PD per target lesion per RECIST v1.1 (PR per irRECIST). ǁ CR per target lesion

but PD per new lesion per RECIST v1.1 (PR per irRECIST); ¶ CR per target lesion but PR per RECIST v1.1 (nontarget lesions still present).

Treatment-Naive Patients

E 100 mg BID

Other E Doses

All Patients

PD-L1 Positive

PD-L1 Negative

PD-L1 Unknown

Percentage Change From Baseline in Target Lesions Over TimeAll Patients

Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma

BID, twice daily; E, epacadostat.

All Treatment-naive, All E Doses

Treatment-naive E 100 mg BID

All Patients

Progression-Free SurvivalEpacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma

Immune related adverse eventsEpacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma

Adverse Event,* n (%)

All Grade

(N=65)

Grade 3/4

(N=65)

Total 12 (19) 6 (9)

Hypothyroidism 4 (6) 0

Severe skin reactions† 4 (6) 3 (5)

Colitis 2 (3) 2 (3)

Uveitis‡ 2 (3) 0

Autoimmune hepatitis§ 1 (2) 1 (2)

* Adverse events of special interest include adverse events with an immune-related cause, regardless of attribution

to study treatment by the investigator. † Includes grade ≥3 rash generalized, rash maculopapular, rash pruritic, and erythema multiforme minor. ‡ Includes iritis and uveitis. § Includes grade 3 elevations of alanine aminotransferase and aspartate aminotransferase, and biopsy confirmed.

• Epacadostat plus pembrolizumab demonstrated promising antitumor activity in

patients with advanced melanoma

• Epacadostat plus pembrolizumab demonstrated a favorable safety profile in

these phase 1/2 melanoma patients that is consistent with previous reports;1,2

the incidence of related grade 3/4 toxicity was 20%

• These results support the ongoing phase 3 investigation of epacadostat plus

pembrolizumab in patients with advanced melanoma (ECHO-301/KEYNOTE-

252; N=706, fully accrued)

ConclusionsEpacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma

• 55% ORR (13% CR)

• 72% DCR

• 22.8 month median PFS*

• 52% landmark 18-month

PFS*

Treatment-Naive for Advanced

Disease, All E Doses (n=53)

Treatment-Naive for Advanced

Disease, E 100 mg (n=38)

• 58% ORR (8% CR)

• 74% DCR

• Median PFS not reached*


PFS*

• 56% ORR (14% CR)

• 71% DCR

• 12.4 month median PFS*


PFS*

All Patients (n=63)

Oncolytic Virotherapy Promotes Intratumoral T Cell

Infiltration and Improves Anti-PD-1 Immunotherapy

Ribas et al., Cell 2017

Study design: Phase 1b study

21 patients with stage IIIB/C or IV melanoma


Best overall response


Objective responses observed in all

stages


PFS and OS


Converting Cold into Hot Tumors by Combining

Immunotherapies

Haanen Cell 2017

Efficacy of BMS-986016 (relatlimab), a Monoclonal

Antibody That Targets Lymphocyte Activation Gene-3

(LAG-3), in Combination With Nivolumab in Patients With

Melanoma Who Progressed During Prior Anti–PD-1/PD-L1

Therapy in All-Comer and Biomarker-Enriched Populations

• Paolo Antonio Ascierto,1 Petri Bono,2 Shailender Bhatia,3 Ignacio Melero,4 Marta Nyakas,5 Inge Marie

Svane,6 James Larkin,7 Carlos A. Gomez-Roca,8 Dirk Schadendorf,9 Reinhard Dummer,10 Aurélien

Marabelle,11 Christoph Hoeller,12 Matthew Maurer,13 Christopher Harbison,13 Priyam Mitra,13 Satyendra

Suryawanshi,13 Kent Thudium,13 Eva Muñoz-Couselo14

1Istituto Nazionale Tumori Fondazione "G. Pascale," Napoli, Italy; 2Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; 3University of Washington, Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA; 4Clinica Universidad de Navarra, Pamplona, Spain;

5Oslo University Hospital, Oslo, Norway; 6Copenhagen University Hospital, Herlev, Denmark; 7Royal Marsden Hospital, NHS Foundation Trust, London, United Kingdom; 8Institut Universitaire du Cancer, Oncopole, Toulouse, France; 9Westdeutsches Tumorzentrum, University Hospital Essen & German Cancer

Consortium, Essen, Germany; 10UniversitätsSpital Zürich, Skin Cancer Center University Hospital, Zürich, Switzerland; 11Gustave Roussy, Paris, France; 12Medical University of Vienna, Vienna, Austria; 13Bristol-Myers Squibb, Princeton, NJ; 14Vall d´Hebron Institute of Oncology, Barcelona, Spain

Presented at ESMO 2017 by Ascierto

Potential Role of LAG-3 in T-Cell Exhaustion

and Anti–PD-1 Resistance

PD-L1

LAG-3

MHC II

Effector

CD4+/CD8+

T cell

Acquired

resistance

Tumor or other

infiltrating cell

+ Antigen

PD-1

PD-1

LAG-3 MHC II

PD-L1

PD-1

+ Nivolumab+ Nivolumab

+ Relatlimab

+ Nivolumab

+ Relatlimab

I-O therapy naive:

LAG-3 may limit I-O response

I-O therapy experienced:

LAG-3 may contribute to

resistance

• LAG-3 regulates a checkpoint pathway that limits the activity of T cells1

• LAG-3 and PD-1 receptors are overexpressed and/or co-expressed on tumor-infiltrating lymphocytes in melanoma2,3

Nivolumab

Relatlimab

(BMS-986016/anti–LAG-3) I-O, immuno-oncology; MHC II, major histocompatibility complex class II; PD-1, programmed death-1; PD-L1, programmed death ligand 1.

1. Grosso JF et al. J Clin Invest. 2007;117:3383‒3392. 2. Goding SR et al. J Immunol. 2013;190:4899–4909. 3. Taube JM et al. Clin Cancer

Res. 2015;21:3969–3976.

Study Rationale and Design

• Relatlimab + nivolumab demonstrated tolerability, peripheral T-cell activation, and preliminary clinical

activity in advanced solid tumors (dose-escalation cohort; NCT01968109)1

• Antitumor activity was previously reported in 55 patients with melanoma who progressed during prior

anti–PD-1/PD-L1 therapy (ORR, 12.5%; DCR, 54%)—LAG-3 expression correlated with higher rates

of response and disease controla,2

• Updated results in this ongoing study are presented (median follow-up, not reached

[range, 0.1+ to 53+ weeks])

DCR, disease control rate; IV, intravenous; ORR, objective response rate; PD, pharmacodynamics; PK, pharmacokinetics; Q2W, every 2 weeks; QTc, corrected QT interval. aLAG-3 expression was evaluated by IHC. bSixty-one patients were response evaluable.

1. Lipson E et al. J Immunother Cancer. 2016;4(suppl 1):173. 2. Ascierto et al. J Clin Oncol. 2017;35(suppl) [abstract 9520].

Relatlimab (80 mg) +

Nivolumab (240 mg) IV Q2W

Efficacy: Melanoma

(progressed during

prior I-O) n = 68b

Dose

Expansion

N = 262

Study Endpoints

(dose expansion)

• Co-Primary: Preliminary

efficacy and safety/tolerability

• Other: Immunogenicity, QTc,

PK, PD, biomarkers

Dose

Escalation

N = 8

(advanced

solid tumors)

Safety: All patients

Prior Therapies

aFour patients received anti–PD-1/PD-L1 + anti–CTLA-4, 8 patients

received anti–CTLA-4 after anti–PD-1/PD-L1, and 33 patients received

anti–CTLA-4 before anti–PD-1/PD-L1; prior anti–CTLA-4 therapy was not

reported in 2 patients bThirty-three patients received nivolumab, 33

patients received pembrolizumab, and 2 patients received other

therapies. cResponse in 1 patient was reported as not applicable.

• Patients in the melanoma prior

PD-(L)1 cohort were heavily

pretreated, with approximately 77%

having ≥ 2 prior therapies

• Most patients (57%) also received

prior anti–CTLA-4 therapy

• 46% of patients had a best response

of PD to prior anti–PD-1/PD-L1

therapy

Mel Prior PD-(L)1n = 68

Prior radiotherapy, n (%) 19 (28)

Prior systemic therapy, n (%) 68 (100)

Immunotherapy 68 (100)

Anti–CTLA-4a 39 (57)

Anti–PD-1/PD-L1b 68 (100)

Best response to prior anti–

PD-1/PD-L1c

CR 1 (1.5)

PR 12 (18)

SD 20 (29)

PD 31 (46)

BRAF inhibitors 19 (28)

MEK inhibitors 13 (19)

Number of systemic regimens

1 16 (24)

2 21 (31)

≥ 3 31 (46)

Median (range) 2 (1–5)

Antitumor Activity of Relatlimab + Nivolumab

• ORR was 11.5% and DCR was 49%

• LAG-3 expression (≥ 1%) enriched

for response

• Median duration of response was

not reached (range, 0.1+ to 39+)

BOR, best overall response. aResponse-evaluable patients; all progressed during prior anti–PD-1/PD-L1 therapy. bImmune-cell LAG-3 expression (percent of positive cells within invasive margin, tumor, and stroma)

evaluated by IHC in tumor sections with antibody clone 17B4. cTumor response evaluated by investigator per Response Evaluation Criteria in Solid Tumors v1.1. dOne response was

unconfirmed. eOccurred prior to first radiographic scan.

Mel Prior PD-(L)1a

All

n = 61

LAG-3 ≥ 1%b

n = 33

ORR, n (%)c

95% CI7 (11.5)d

4.7, 226 (18)d

7, 35.5

BOR, n (%)c

CR 1 (1.6) 1 (3.0)

PR 6 (9.8)d 5 (15)d

SD 23 (38) 15 (45)

PD 25 (41) 8 (24)

Clinical progressione 6 (9.8) 4 (12)

DCR (CR + PR + SD), n (%)c

95% CI

30 (49)36, 62

21 (64)45, 80

Pink: PD-L1 ≥ 1% Blue: PD-L1 < 1% Gray: PD-L1 unknown

100

80

60

40

20

0

-20

-40

-60

-100

-80

100

80

60

40

20

0

-20

-40

-60

-100

-80

100

80

60

40

20

0

-20

-40

-60

-100

-80

45% with tumor

reduction

24% with tumor

reduction

13% with tumor

reduction

Be

st

pe

rce

nt

ch

an

ge

in s

um

of

targ

et

les

ion

dia

me

ters

fro

m b

as

eli

ne

a,b

aSix patients with clinical progression prior to their first scan and 1 with PD due to a new symptomatic brain metastasis prior to getting full scans were not included. bOne patient with best change from baseline > 30% had a best response of SD.

LAG-3 ≥ 1%n = 29

LAG-3 < 1%n = 17

LAG-3 Unknownn = 8

Best Change in Target Lesion Size by LAG-3

and PD-L1 Expression

Summary

• With additional follow-up, clinically meaningful antitumor activity with

relatlimab + nivolumab was observed in a heavily pretreated population

of patients with melanoma who had progressed during prior anti─PD-1/PD-L1

therapy

• Responses were more likely in patients with LAG-3 expression ≥ 1%, while

PD-L1 expression did not appear to enrich for response

• The combination is well tolerated, with a safety profile similar to that of

nivolumab monotherapy

• Further investigations of the combination of relatlimab + nivolumab are ongoing,

in melanoma and other tumor types, in both I-O–naive and I-O–experienced

patients

esmo.org

ESMO IMMUNO-ONCOLOGY CONGRESS

2017

Primary PFS and safety analyses of a randomised Phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150) Martin Reck,1 Mark A. Socinski,2 Federico Cappuzzo,3 Francisco Orlandi,4 Daniil Stroyakovskii,5

Naoyuki Nogami,6 Delvys Rodríguez-Abreu,7 Denis Moro-Sibilot,8 Christian A. Thomas,9

Fabrice Barlesi,10 Gene Finley,11 Claudia Kelsch,12 Anthony Lee,12 Shelley Coleman,12 Yijing Shen,12

Marcin Kowanetz,12 Ariel Lopez-Chavez,12 Alan Sandler,12 Robert Jotte13

Reck M, et al. IMpower150 PFS analysis.

4. Trafficking of T cells

to tumours (CTLs)

5. Infiltration of T cells into tumours

(CTLs, endothelial cells)

6. Recognition of

cancer cells by T cells

(CTLs, cancer cells)

7. Killing of cancer cells

(immune and cancer cells)1. Release of cancer cell antigens

(cancer cell death)

2. Cancer antigen presentation

(dendritic cells/ APCs)

3. Priming and activation (APCs

and T cells)

Rationale for combining atezolizumab + bevacizumab

• In addition to its known anti-angiogenic effects, bevacizumab’s inhibition of VEGF has immune

modulatory effects

• Atezolizumab’s T-cell mediated cancer cell killing may be enhanced through bevacizumab’s reversal of

VEGF-mediated immunosuppression

1. Ferrara N, et al. Nat Rev Drug Discov, 2004. 2. Gabrilovich DI, et al. Nat Med, 1996. 3. Oyama T, et al. J Immunol, 1998. 4. Goel S, et al. Physiol Rev, 2011.

5. Motz GT, et al. Nat Med, 2014. 6. Hodi FS, et al. Cancer Immunol Res, 2014. 7. Wallin JJ, et al. Nat Commun, 2016. 8. Gabrilovich DI, Nagaraj S. Nat Rev

Immunol, 2009. 9. Roland CL, et al. PLoS One, 2009. 10. Facciabene A, et al. Nature, 2011. 11. Voron T, et al. J Exp Med, 2015.

Figure adapted from Chen DS, Mellman I. Immunity, 2013.

Establishing an

immune-permissive

tumour microenvironment

by decreasing MDSC and

Treg populations7-11

Promotion of T-cell priming

and activation via

dendritic cell maturation2-3

Normalisation of the tumour

vasculature for increased

T-cell tumour infiltraton4-7


a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance of treatment

with one or more approved targeted therapies. b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w.

IMpower150 study design

Arm A

Atezolizumabb +

Carboplatinc +

Paclitaxeld

4 or 6 cycles

Atezolizumabb

Arm C (control)

Carboplatinc +

Paclitaxeld

+ Bevacizumabe

4 or 6 cycles

Bevacizumabe

Su

rviv

al fo

llo

w-u

p

Stage IV or

recurrent metastatic

non-squamous NSCLC

Chemotherapy-naivea

Tumour tissue available

for biomarker testing

Any PD-L1 IHC status

Stratification factors:

• Sex

• PD-L1 IHC expression

• Liver metastases

N = 1202

R

1:1:1

Arm B

Atezolizumabb +

Carboplatinc +

Paclitaxeld

+ Bevacizumabe

4 or 6 cycles

Atezolizumabb

+

Bevacizumabe

Maintenance therapy

(no crossover permitted)

Treated with

atezolizumab

until PD by

RECIST v1.1

or loss of

clinical benefit

AND/OR

Treated with

bevacizumab

until PD by

RECIST v1.1

The principal question is to assess whether the addition of atezolizumab to Arm C provides clinical benefit

Reck M, et al. IMpower150 PFS analysis.The T-effector (Teff) gene signature is defined by expression of PD-L1, CXCL9 and IFNγ and is a surrogate of both

PD-L1 IHC expression and pre-existing immunity (Kowanetz M, et al. WCLC, 2017).

IMpower150 study populations and objectives

ITTAll randomised

patients

Teff-high WTa

High T-effector gene signature expression

Teff-low WTa

Low T-effector gene signature expression

Co-primary objectives• Investigator-assessed PFS in ITT-WT

• Investigator-assessed PFS in Teff-high WT

• OS in ITT-WT

1

EGFR/ALK +(13% of patients)

ITT-WTa

(87% of patients)

a WT refers to patients without EGFR

or ALK genetic alterations.

Reck M, et al. IMpower150 PFS analysis.1. Kowanetz M, et al. WCLC 2017 [abstract MA 05.09]. 2. Rittmeyer A, et al. Lancet, 2017.

Biomarkers in IMpower150

• IMpower150 provided the opportunity to evaluate multiple strategies to

enrich for PFS, including T-effector (Teff) gene signature expression and

PD-L1 IHC

• The Teff gene signature is defined by mRNA expression of 3 genes (PD-

L1, CXCL9 and IFNγ) and is a surrogate for both PD-L1 expression and

pre-existing immunity

– In the OAK study, the Teff gene signature appeared to be a more sensitive biomarker

of PFS benefit for monotherapy atezolizumab vs docetaxel than PD-L1 IHC

expression1

• PD-L1 expression was evaluated using the SP142 IHC assay, as defined

in the Phase III OAK study of atezolizumab vs docetaxel2


IC, tumour-infiltrating immune cells; TC, tumour cells.a The Teff gene signature high cut-off ≥ ‒1.91 was used. b 1 patient in Arm A had unknown PD-L1 IHC expression.

TC2/3 or IC2/3 = TC or IC ≥ 5% PD-L1+; TC1/2/3 or IC1/2/3 = TC or IC ≥ 1% PD-L1+; TC0 and IC0 = TC and IC < 1% PD-L1+.

Data cutoff: September 15, 2017

Baseline characteristics in ITT

Baseline characteristicsArm A:

atezo + CP(N = 402)

Arm B:atezo + bev + CP

(N = 400)

Arm C (control):bev + CP(N = 400)

Median age (range), years 63 (32-85) 63 (31-89) 63 (31-90)

Sex, male, n (%) 241 (60%) 240 (60%) 239 (60%)

ECOG PS, 0, n (%) 180 (45%) 159 (40%) 179 (45%)

Tobacco use history, n (%)Current smoker | Previous smokerNever smoker

98 (24%) | 227 (57%)

77 (19%)

90 (23%) | 228 (57%)

82 (21%)

92 (23%) | 231 (58%)

77 (19%)

Liver metastases, yes, n (%) 53 (13%) 53 (13%) 57 (14%)

EGFR mutation, positive, n (%) 46 (11%) 35 (9%) 45 (11%)

ALK rearrangement, positive, n (%) 9 (2%) 13 (3%) 21 (5%)

Teff gene signature expression, high, n (%)a 177 (44%) 166 (42%) 148 (37%)

Of those tested 124 106 115

KRAS mutation, positive, n (%) 36 (29%) 47 (44%) 38 (33%)

PD-L1 expression, n (%)b

TC2/3 or IC2/3TC1/2/3 or IC1/2/3TC0 and IC0

137 (34%)213 (53%)188 (47%)

140 (35%)209 (52%)191 (48%)

133 (33%)195 (49%)205 (51%)


INV-assessed PFS in ITT-WT (Arm B vs Arm C)

INV, investigator.


6.8 mo(95% CI: 6.0, 7.1)

8.3 mo(95% CI: 7.7, 9.8)

HR, 0.617 (95% CI: 0.517, 0.737)

P < 0.0001Minimum follow-up: 9.5 mo

Arm B: atezo + bev + CP

Arm C: bev + CP

Reck M, et al. IMpower150 PFS analysis.INV, investigator.


INV-assessed PFS in Teff-high WT (Arm B vs Arm C)

6.8 mo(95% CI: 5.9, 7.4)

11.3 mo(95% CI: 9.1, 13.0)

HR, 0.505 (95% CI: 0.377, 0.675)

P < 0.0001Minimum follow-up: 9.5 mo

Landmark PFS, %Arm B:

atezo + bev + CP

Arm C:

bev + CP

6-month 72% 57%

12-month 46% 18%


0

10

20

30

40

50

60

70

80


Arm C:bev + CP

Re

sp

on

se

(%

)

a Investigator-assessed ORR.b Censored value.


ORRa and DOR in ITT-WT and Teff-high WT

0

10

20

30

40

50

60

70

80


Arm C:bev + CP

Re

sp

on

se

(%

)

CR/PR:

1%/47%

CR/PR:

4%/60% CR/PR:

2%/51%

CR/PR:

4%/65%

CR

PR

ORR: 48%

ORR: 64%

ORR: 54%

ORR: 69%

ITT-WT Teff-high WT

CR

PR

Median DOR

(range), mo 9.0 (0.4-24.9b) 5.7 (0.0b-22.1)Median DOR

(range), mo 11.2 (0.5-24.9b) 5.7 (0.0b-22.1)

Arm B:

atezo + bev + CP

Arm B:

atezo + bev + CP

Arm C:

bev + CP

Arm C:

bev + CP


a Including fatal haemorrhagic AEs: Arm C: haemoptysis n = 1, pulmonary haemorrhage n = 2; Arm B haemoptysis n = 3,

pulmonary haemorrhage n = 2, haemorrhage intracranial n = 1; Arm A: haemoptysis n = 1, haemorrhage intracranial n = 1.b Investigator text for AEs encoded using MedDRA v20.1.


Safety summary

Arm A:atezo + CP(n = 400)

Arm B:atezo + bev +

CP(n = 393)

Arm C (control):bev + CP(n = 394)

Median doses received (range), nAtezolizumabBevacizumab

10 (1-37)NA

12 (1-38)10 (1-38)

NA8 (1-33)

All cause AE, n (%)Grade 3-4Grade 5

389 (97%)226 (57%)10 (3%)

385 (98%)242 (62%)23 (6%)

390 (99%)230 (58%)21 (5%)

Treatment-related AE, n (%)Grade 3-4Grade 5a

372 (93%)170 (43%)

3 (1%)

371 (94%)219 (56%)

11 (3%)

376 (95%)188 (48%)

9 (2%)

Serious AE, n (%)Treatment-related serious AE

155 (39%)77 (19%)

165 (42%)100 (25%)

134 (34%)76 (19%)

AEs of special interest, n (%)b

Grade 3-4Grade 5

184 (46%)37 (9%)2 (1%)

199 (51%)45 (11%)

0

108 (27%)13 (3%)

0

AE leading to withdrawal from any treatment

56 (14%) 128 (33%) 98 (25%)

AE leading to dose interruption or modification

203 (51%) 235 (60%) 189 (48%)


AEs of special interest, n

(%)

Arm A:

atezo + CP

(n = 400)

Arm B:

atezo + bev + CP

(n = 393)

Arm C (control):

bev + CP

(n = 394)

All grade Grade 3-4 All grade Grade 3-4 All grade Grade 3-4

Rash 114 (29%) 14 (4%) 113 (29%) 9 (2%) 52 (13%) 2 (1%)

Hepatitis

Laboratory

abnormalities

39 (10%)

34 (9%)

12 (3%)

10 (3%)

54 (14%)

47 (12%)

19 (5%)

16 (4%)

29 (7%)

29 (7%)

3 (1%)

3 (1%)

Hypothyroidism 30 (8%) 1 (<1%) 50 (13%) 1 (<1%) 15 (4%) 0

Infusion-related reactions 16 (4%) 3 (1%) 13 (3%) 2 (1%) 11 (3%) 3 (1%)

Pneumonitis 21 (5%) 7 (2%) 11 (3%) 6 (2%) 5 (1%) 2 (1%)

Hyperthyroidism 11 (3%) 0 16 (4%) 1 (<1%) 5 (1%) 0

Colitis 3 (1%) 2 (1%) 9 (2%) 5 (1%) 2 (1%) 2 (1%)

Severe cutaneous reaction 3 (1%) 3 (1%) 4 (1%) 0 1 (<1%) 0

Adrenal insufficiency 2 (1%) 0 2 (1%) 1 (<1%) 3 (1%) 1 (<1%)

Pancreatitis 2 (1%) 2 (1%) 5 (1%) 2 (1%) 0 0


Immune-related AEs of special interest in

≥ 5 patients across arms


Summary

• IMpower150 is the first phase III immunotherapy-based combination study

to demonstrate a statistically significant and clinically meaningful

improvement in PFS in all-comer 1L NSQ mNSCLC, providing a potential

new standard of care for patients

• PFS benefit was demonstrated with the addition of atezolizumab to

bevacizumab + CP (Arm B) vs bevacizumab + CP (Arm C) in all

populations tested, including patients with sensitising EGFR or ALK

genetic alterations, Teff-low tumours, PD-L1–negative tumours and

liver metastases

• Atezolizumab in combination with chemotherapy ± bevacizumab appears

to be well tolerated and its safety profile is consistent with known safety

risks

• OS data, while not mature, are promising in Arm B vs Arm C; next interim

analysis for all arms is anticipated in 1H 2018

mNSCLC, metastatic NSCLC; NSQ, non-squamous.

Documents

Present state of the art of immune checkpoint inhibitors ......Disclosures • I have provided consultation, attended advisory boards, and/or provided lectures for: Pfizer, MSD, BMS,