Combinations Among Different Immunotherapies (including ... · Brahmer J et al, NEJM: 373:123-35, 2015 Borghaei H et al, NEJM 373: 1627-39, 2015 Herbst RS et al, Lancet Oncol: 387,

Combinations Among Different

Immunotherapies (including simultaneous

PD-(L)1 and CTLA-4 blockade)

Karen Kelly, MD

Professor of Medicine

Associate Director for Clinical Research

Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon

Endowed Chair in Cancer Clinical Research

UC Davis Comprehensive Cancer Center

Royalty: UpToDate Author

Advisor: Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Clovis, Genentech, Lilly

Research: AbbVie, Celgene, EMD Serono, Genentech, Gilead, Lilly, Millennium, Novartis

Disclosures

Immune Checkpoint Inhibitors and NSCLC

Single agent PD-1 inhibitors produce superior PFS and OS

compared to chemotherapy in the first and second line

treatment setting.

This treatment benefit is limited to a subset of patients.

Immune evasive pathways are nonredundant; providing an

opportunity for therapeutic immune combinations.

PD-1 inhibitor ORR DOR 1 YR PFS 1 YR OS

Nivolumab

Squamous cell

20% NR

(3-20.5 m)

21% 42%

Nivolumab

Non-squamous cell

19% 17.2 m 19% 51%

Pembrolizumab

2 mg/kg

18% NR

(4.2-10.5 m)

20% 43%

Brahmer J et al, NEJM: 373:123-35, 2015

Borghaei H et al, NEJM 373: 1627-39, 2015

Herbst RS et al, Lancet Oncol: 387, 2016

Convert a non-T-cell inflamed tumor into an inflamed tumor

Expectations of Immune Combinations

IO

combinations

Enhance immune mediated tumor cell death

IO

combinations

?Anti-PD-1

inhibitor

Immune Signature

for IO combination

Understanding the Role of the Tumor

Microenvironment and Immunotherapy

Responsiveness

Luke, JJ et al ASCO 2016 abstr #3004

T cell-inflamed tumor microenvironment by tumor type in increasing frequency

NO CORRELATION WITH MUTATIONAL BURDEN

Immunotherapy Drug Classifications

Drugs that target immune evasion

•Blockade of negative immune

regulators

•Blockade of tolerogenic enzymes

Drugs that stimulate the immune

process

• Agonist of costimulatory

receptors

• Enhancers of antigen

presentation (vaccines)

• Exogeneous recombinant

cytokines

• Oncolytic viruses

• Cell therapies

Reference

Clinical Expectations of Immune Combinations

• Increased number of responding patients

• Deeper and more durable responses

• Longer PFS and OS

• An acceptable toxicity profile

Dual Immune Checkpoint Inhibitors

CTLA-4 Blockade (Ipilimumab)PD-1 Blockade(Nivolumab)

APC – T-cellInteraction

Activation(cytokine secretion, lysis,

proliferation, migration to tumor)

TumorMicroenvironment

Dendriticcell T cell Tumor cell

MHCTCR TCR

PD-L1

PD-L2

MHC

PD-1

PD-1

B7

B7 CD28

CTLA-4

anti-CTLA-4

+++

---

+++T cell

+++

---

---anti-PD-1

anti-PD-1

•Nivolumab and ipilimumab enhance T-cell antitumor activity through distinct but complementary mechanisms

•Preclinical data suggest synergy with dual CTLA-4 and PD-1 blockade vs either agent alone

–Increased proliferation of effector CD8+ and CD4+ T cells and decreased intratumoral T-regulatory cells vs single pathway blockade

•Combination FDA approved for untreated metastatic melanoma

CheckMate 012 Study Design: Nivolumab Plus Ipilimumab in First-line NSCLC

Primary endpoint: safety and tolerability

Secondary endpoints: ORR (RECIST v 1.1) and PFS rate at 24 wks

Exploratory endpoints: OS; efficacy by PD-L1 expression

Stage IIIB/IV NSCLC (any histology); no prior chemotherapy for advanced disease; ECOG PS 0 or 1

Nivo 3 mg/kg IV Q2W until

disease progression or

unacceptable toxicity

Nivo 1 mg/kg IV Q3W x 4

+

Ipi 1 mg/kg IV Q3W x 4

Nivo 1 mg/kg IV Q2W

+

Ipi 1 mg/kg IV Q6W

Nivo 3 mg/kg IV Q2W

+

Ipi 1 mg/kg IV Q12W

Nivo 3 mg/kg IV Q2W

+

Ipi 1 mg/kg IV Q6W

Until disease progression or unacceptable toxicity


Hellman MD et al, J Clin Oncol 34, 2016 (suppl; abstr 3001)

Nivo 3 Q2W + Ipi 1 Q12W

(n = 38)

Nivo 3 Q2W + Ipi Q6W

(n = 39)

Nivo 3 Q2W

(n = 52)

Any

Grade

Grade

3-4

Any

Grade

Grade

3-4

Any

Grade

Grade

3-4

Treatment-related AEs, % 82 37 72 33 71 19

Treatment-related AEs

leading to discontinuation, %11 5 13 8 10 10


Safety Profile




(n = 38)


(n = 39)

Nivo 3 Q2W

(n = 52)

Confirmed ORR, % (95% CI) 47 (31, 64) 39 (23, 55) 23 (13, 37)

Median duration of response, mo (95% CI) NR (11.3, NR) NR (8.4, NR) NR (5.7, NR)

Median length of follow-up, mo (range) 12.9 (0.9-18.0) 11.8 ( 1.1-18.2) 14.3 (0.2-30.1)

Best overall response, %

Complete response

Partial response

Stable disease

Progressive disease

Unable to determine

0

47

32

13

8

0

39

18

28

15

8

15

27

38

12

Median PFS, mo (95% CI) 8.1 (5.6, 13.6) 3.9 (2.6, 13.2) 3.6 (2.3, 6.6)

1-year OS rate, % (95% CI) NC 69 (52, 81) 73 (59, 83)


Nivolumab + Ipilimumab

Increased number of responding patients

Deeper and more durable responses

Longer PFS (q 12 wk schedule)

? Longer OS

- An acceptable toxicity profile

Randomized Phase III Trials of Dual Immune Checkpoint Inhibitors

CheckMate 227

Primary endpoints OS and PFS

Nivolumab monotherapy

Ran

do

miz

e

Tumor PD-L1> 1%

Nivolumab + Ipilimumab3 mg/kg q 2wks + I mg/kg q 6 wks

Chemotherapy

Non-SQ: Pemetrexed + cisplatin

or carboplatin

SQ: Gemcitabine + cisplatin

or carboplatin

Treatmentuntil disease progression or unacceptable toxicity

Nivolumab + SOC

Ran

do

miz

e

Nivolumab + Ipilimumab3 mg/kg q 2 wks+ 1 mg/kg q 6 wks

Chemotherapy

Pemetrexed + cisplatin or carboplatin

Gemcitabine + cisplatin or carboplatin

Paclitaxel + carboplatin


Tumor PD-L1< 1%

Treatment-naïvepatients withstage IVor recurrentNSCLC

Anticipatedenrollment:approximately1980

CheckMate 032 Study Design: Nivolumab Plus Ipilimumab in Recurrent SCLC

Primary endpoint: ORR per RECIST v1.1

Secondary endpoints: Safety

Exploratory endpoints: PFS, OS, biomarker analysis

Patients with SCLC with progressive disease after ≥ 1 prior line of therapy, including a

platinum-based regimen in first line (unselected by PD-L1 expression) (N = 183)

Until disease progression or unacceptable toxicity

Nivo 1 mg/kg IV Q2W

+

Ipi 3 mg/kg IV Q4W


Nivo 3 mg/kg IV Q2W

Nivo 3 mg/kg IV Q2W

+

Ipi 1 mg/kg IV Q4W

Antonia S et al, Lancet Oncol 17, 883-95

Nivo 3 Q2W

(n = 98)


(n = 61)


(n = 54)

Grade

1-2

Grade

3

Grade

4

Grade

1-2

Grade

3

Grade

4

Grade

1-2

Grade

3

Grade

4

Treatment-related AEs, % 39 (40%) 9 (9%) 4 (4%) 30 (49%) 14 (23%) 4 (7%) 30 (56%) 8 (15%) 2 (4%)

Treatment-related AEs

leading to discontinuation, %

Dual Immune Checkpoint InhibitorsSafety Profile

Nivolumab 3 mg/kg

(n=98)

Nivolumab 1 mg/kg plus

ipilimumab 3 mg/kg (n=61)

Nivolumab 3 mg/kg plus

ipilimumab 1 mg/kg (n=54)

Objective response; 95% CI 10 (10%; 5-18) 14 (23%; 13-36) 10 (19%; 9-31)

Best overall response

Complete response 0 1 (2%) 0

Partial response 10 (10%) 13 (21%) 10 (19%)

Stable disease 22 (22%) 13 (21%) 9 (17%)

Progressive disease 52 (53%) 23 (38%) 29 (54%)

Unable to determine 12 (12%) 8 (13%) 6 (11%)

Med Dor NR (4.4-NR) 7.7 mos 4.4 mos

1 YR PFS 11% 19% NE

1 YR OS 33% 43% 35%


Efficacy


CheckMate 451


Nivolumab

Ran

do

miz

e

Nivolumab + Ipilimumab

Placebo

Treatmentuntil disease

progression or unacceptable

toxicity

ES SCLC with a response or stable disease after 4 cycles platinum-based therapy

N = 810


Treatment-naïvepatients with stage IV or recurrent NSCLC

Anticipated enrollment:approximately 1092

Durvalumab monotherapy

Ran

do

miz

e

Tumor PD-L1assessmentat screening

Durvalumab + Tremelimumab

Pemetrexed + cisplatin or carboplatin

Gemcitabine + cisplatin or carboplatin

Paclitaxel + carboplatin



MYSTIC

Durvalumab 20 mg/kg q 4 wks

and Tremelimumab 1 mg/kg

N=18

Treatment related AEs (any Grade)

Treatment related AEs (Grade 3-4)

11 (61%)

3 (17%)

Treatment related AEs leading to

discontinuation

3 (17%)

There was one treatment related death due to a pericardial effusion

Durvalumab 10-20 mg/kg every 2 wks

or 4 wks + tremelimumab 1 mg/kg

All evaluable patients with ≥ 24 weeks of follow-up

Objective response 6/26 (23% [9-44])

Disease control 9/26 (35% [17-56])

PD-L1 positive (≥ 25%)



PD-L1 negative (< 25%)



PD-L1 negative (0%)



PD-L1 status unknown




Pembrolizumab + Ipilimumab in Second Line NSCLC

Gubens M et al. ASCO 2016 #9027

Ipilimumab 4 doses

Week 0 3 6 9 12 15 18 21 24 27 30 33 // 105

Pembrolizumab 2 or 10 mg/kg Q3W for up to 2 years

Pembrolizumab and Ipilimumab Dosing

Pembrolizumab 2 mg/kg + Ipilimumab 1 mg/kg (n=44)

Total population

n=44

TPS ≥50%

n=6

TPS ≥1%

n=24

TPS <1%

n=20

ORR, n (%) [95% CI] 11 (25) [13-40] 1 (17) [<1-64] 7 (29) [13-51] 4 (20) [6-44]

DCR, n (%) [95 % CI] 28 (64) [48-78] 2 (33) [4-78] 14 (58) [37-78] 14 (70) [46-88]

Best overall response, n (%)

CR 2 (5) 1 (17) 1 (4) 1 (5)

PR 9 (21) 0 6 (25) 3 (15)

SD 17 (39) 1 (17) 7 (29) 10 (50)

PD 8 (18) 1 (17) 4 (17) 4 (20)

No assessment 8 (18) 3 (50) 6 (25) 2 (10)

Duration of response,

median (range), months13.8 (1.8+ to 13.8) 3.5 (3.5 to 3.5) NR (1.8+ to 12.7+) 13.8 (2.5+ to 13.8)

Dual Immune Checkpoint Agonist and Antagonist

Infante J et al. ASCO 2016 abst #101


Agonist Antagonist N GR 3 AE ORR Comment

OX40

MOXR 0916

.8-1200mg q 3 wk

Atezolizumab

1200mg IV q 3 wk

51

9 prior PD/PDL1

4 prior OX40

1-pneumonitis 4%

2/51 durable

NO DLT

NO DDI

4-IBB/CD137

Utomilumab

.045 – 5 mg/kg q 3 wk

Pembrolizumab

2 mg/kg q 3 wk

23

6-NSCLC

1-SCLC

Prior ICI allowed

1-adrenal

insufficiency

1 hypokalemia

26%

6/23 durable

NO DLT

NO DDI

PD-L1 Modulation

pembrolizumab)

Drug Class of Agonist Combination ASCO Session

MOXR0916 OX40 + atezolizumab Abstract 101 CSS 6/4

MEDI0562 OX40 + tremelimumab

+ durvalumab

-

GSK3174998 OX40 + pembrolizumab Abstract 3017 6/5

PF-04518600 OX40 + utolomumab Abstract 3079 6/5

MEDI6383 OX40 ligand

fusion protein

+ durvalumab -

Utomilumab IBB + pembrolizumab Abstract 3002


Immune Checkpoint Inhibitors + IDO Inhibitors

ORR 53% (8/15 pts) ORR 17% (2/12 pts)

Indoximod 1200 mg po bid daily, Ipilimumab 3 mg/kg

x 4 doses, Standard anti- PD-1 administration

Yousef Z, et al. ASCO 2016 #3075Adverse event data not reported

Responses with Indoximod and Ipilimumab

Immune Checkpoint Inhibitors + Vaccines

TG4010 – MVA-MUC1-IL2 vaccine

TIME Trial

Quoix E. et al Lancet Oncology 2016

Primary endpoint: ORR

UC Davis, UCSF, COH and UCSD

Previously treated

advanced stage

nonsquamous cell

NSCLC

(N=

Cycles 1-3

TG4010 q weekly

+ Nivolumab

q 2 weekly

Subsequent Cycles

TG4010 q 2 weekly

+ Nivolumab

q 2 weekly

Progression

Understanding Mechanisms of

Immune Evasion

Spranger S et al Nature 2015

Luke JJ et al. J Clin Oncol, 2016 (suppl; abstr 3004)

Documents

Combinations Among Different Immunotherapies (including ... · Brahmer J et al, NEJM: 373:123-35, 2015 Borghaei H et al, NEJM 373: 1627-39, 2015 Herbst RS et al, Lancet Oncol: 387,