Combination Therapies Based on PD-1 or PD-L1 Blockade

Melanoma BridgeNaples, Italy

December 4, 2014

Mario Sznol- Yale University (in Absentia)

Summary of Anti-PD-1/PD-L1 Activity in Metastatic Melanoma

Objective Response Rates

Median Duration of Response

Median PFS Median Survival 1/2/3 year survival

Nivolumab Treatment-Naive

40% (CR = 7.6%) NR 5.1 months NR 73%/x/x

Nivolumab (postipilimumab)

26-32% NR NA NA 70%/x/x

Nivolumab(prior Rx, not ipi)

32% 23 months 4 months 17 months 63%/48%/42%

PembrolizumabIpi-Naive

40% NR 5.6 months NR 74%/x/x

Pembrolizumab(post ipilimumab)

21-28% NR 2.9-5.4 months6mth – 34-38%

NR 65%/x/x

Possible Mechanisms for Innate Resistance to PD-1/PD-L1 Blockade

• No tumor antigen specific T-cells in tumor microenvironment• Don’t exist or;• Blocked from entry into tumor

• Insufficient tumor antigen specific T-cells in tumor microenvironment• Dysfunctional tumor antigen specific T-cells in tumor

microenvironment• Other checkpoints present in addition to PD1-PD-L1 pathway• Dysfunction driven by checkpoints other than PD1-PD-L1 pathway• Other mechanisms of T cell suppression

• IDO, TGF-beta, Treg, etc.

• Loss of tumor antigen presentation• Innate tumor cell resistance to immune mediated killing

Combinations Based on PD-1/PD-L1 Blockade • Multiple combinations supported by animal models

• Vaccines• Cytokines (IL-15, IL-21, IFN-alfa,…)• Immune checkpoints

• CTLA-4• LAG-3, TIM-3, B7-H3?

• Co-stimulatory agents – 4-1BB, OX40, CD27, ….• Adoptive Cell Transfer• Inhibitors of infiltrating suppressive MDSC and type 2 macrophages• Enzyme based suppression- IDO• Treg inhibition• Targeted agents• Chemotherapy• Radiation therapy • Anti-angiogenesis agents• HDAC Inhibitors

• No human data yet to reliably predict best combination for individual patient

Synergistic Activity with Anti-PD-1 and Anti-CTLA-4 Antibodies

0 5 10 15 20 250

250

500

750

1000

1250

1500

1750

days

med

ian

tum

or v

olum

em

m3

Control

aCTLA-4 MAb

aPD-1 MAb

Combination aPD-1 + aCTLA-4

Dosing

Combination of Non-Efficacious Doses of anti-PD1 and anti-CTLA-4 Antibodies is Efficacious in Mouse Model

Provided by Alan Korman, BMS

Rationale:Different roles in T cell Differentiation-Compensatory upregulationAnti-CTLA4 elimination of tumor TregAnti-CTLA4 induced tumor T cell infiltration

Phase 1 CA209-004 Cohorts

All dose units are mg/kg. Results from Cohorts 6 and 7 (sequenced treatment cohorts – ipilimumab followed by nivolumab) were reported previously (Kluger et al. ESMO 2014)Ipi = ipilimumab; Nivo = nivolumab; Q2W = every 2 weeks; Q3W = every 3 weeks; Q12W = every 12 weeks

Con

curr

ent

The

rapy

Q12W x 8Nivo 0.3 + Ipi 3Cohort 1

(N = 14)Nivo 0.3 Nivo 0.3 + Ipi 3

Nivo 1 + Ipi 3Cohort 2(N = 17)

Nivo 1 Nivo 1 + Ipi 3

Q3W x 4

Q3W x 4

Q3W x 4

Q3W x 4

Q12W x 8

Nivo 3 + Ipi 1Cohort 2a(N = 16)

Nivo 3 Nivo 3 + Ipi 1Q3W

x 4Q3W

x 4Q12W

x 8

Q2W x ≤48

Q2W x ≤48Prior

standard ipilimumab

therapy

Cohort 6(N = 17)

Nivo 1

Cohort 7(N = 16) Nivo 3

Seq

uenc

ed

The

rapy 4–12

weeksfrom last

dose

Nivo 3 + Ipi 3Cohort 3(N = 6)

Nivo 3 Nivo 3 + Ipi 3Q3W

x 4Q3W

x 4Q12W

x 8

Q2W x ≤48Nivo 3Cohort 8

(N = 41)Nivo 1 + Ipi 3 Q3W

x 4

6

Baseline Characteristics

*All treated patientsJUNE 2014 data analysis.ECOG = Eastern Cooperative Oncology Group.

Cohorts 1–3(N = 53)*

Cohort 8(N = 41)*

Median age, years (range) 57 (22–79) 55 (22–80)

Male, n (%) 60 44ECOG performance status, n (%)

01Not reported

83152

66295

Lactate dehydrogenase level, n (%)≤Upper limit of the normal range>Upper limit of the normal range

6238

6139

Systemic cancer therapy, n (%)ImmunotherapyBRAF inhibitor

194

297

Number of prior systemic cancer therapies, n (%)01≥2

602811

492724

7

Activity Summary

Cohort(s) Nivo (mg/kg) + Ipi (mg/kg) Nb ORR,a

% CR, % Aggregate Clinical Activity Rate, %

≥80% Tumor Burden Reduction at 36 Weeks,c %

1–3 53 42 17 72 42

1 0.3 + 3 14 21 14 57 36

2 1 + 3 17 47 18 65 53

2a 3 + 1 16 50 25 88 31

3 3 + 3 6 50 0 83 50

8d 1 + 3 41 44 7 56 29

All Concurrent Cohorts 94 43 13 65 36aPer modified World Health Organization (mWHO) criteria, [CR+PR]/Nx100. bNumber of response-evaluable patients. cBest overall response. dCohort 8 using the phase 2/3 trial dose schedule, started November 2013.

JUNE 2014 data analysis

8

Maximum Response in Target Lesions

Patient

0

50

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150

200

250

-50

-100

Max

imum

Res

pons

e Fr

om B

asel

ine

in T

arge

t Les

ion

(%)

April 2014 data analysis

Cohorts 1–3

Cohort 8

42% patients had ≥80% reduction in target lesion

29% patients had ≥80% reduction in target lesion

JUNE 2014 data analysis.

Patients

050

100

200

850900

-50

150

-100

9

Metastatic melanoma from anal mucosal primary, Cohort 2: response to ipilimumab 3 mg/kg + nivolumab 1 mg/kg; Received a single dose of combination due to early onset uveitis-responded to high dose steroids

Metastatic melanoma from anal mucosal primary, Cohort 2: response to ipilimumab 3 mg/kg + nivolumab 1 mg/kg; Received a single dose of combination due to early onset uveitis-responded to high dose steroids

Sienkiewicz, Dina, LSienkiewicz, Dina, LUnit#: MR2263994Unit#: MR2263994Acc#: E101524698Acc#: E101524698DOB: 10/7/1967DOB: 10/7/1967F/46 YEARF/46 YEAR

Yale New Haven Hospital Yale New Haven HospitalCT NP 2506 LightSpeed VCTCT NP 2506 LightSpeed VCT

CT CHEST ABDOMEN PELVIS W IV CONTRASTCT CHEST ABDOMEN PELVIS W IV CONTRAST6.1 CHEST - ABDOMEN - PELVIS WITHOUT AND/OR WITH6.1 CHEST - ABDOMEN - PELVIS WITHOUT AND/OR WITH

6/5/2014 1:42:41 PMTech: DMTech: DM

ORAL OMNI & 85CC OMNI 350ORAL OMNI & 85CC OMNI 350HELICAL MODE /1:42:41 PMHELICAL MODE /1:42:41 PMW: 400 C: 40 Z: 1.53W: 400 C: 40 Z: 1.53600 ---600 ---KVp: 120KVp: 120Tilt: 0Tilt: 0FFSFFS

Page: 22 of 51Page: 22 of 51 IM: 22 SE: 601 IM: 22 SE: 601Compressed 8:1Compressed 8:1

--- ------ ---XY: 8.60XY: 8.60

THK: 5THK: 5ASIR: SS20ASIR: SS20

NI: 135NI: 135

RR LL

HH

FF cm cm

Sienkiewicz, Dina, LSienkiewicz, Dina, LUnit#: MR2263994Unit#: MR2263994Acc#: E101726672Acc#: E101726672DOB: 10/7/1967DOB: 10/7/1967F/46 YEARF/46 YEAR

Yale New Haven Hospital Yale New Haven HospitalCT NP 2506 LightSpeed VCTCT NP 2506 LightSpeed VCT

CT CHEST ABDOMEN PELVIS W IV CONTRASTCT CHEST ABDOMEN PELVIS W IV CONTRAST6.1 CHEST - ABDOMEN - PELVIS WITHOUT AND/OR WITH6.1 CHEST - ABDOMEN - PELVIS WITHOUT AND/OR WITH

8/16/2014 10:53:26 AM 8/16/2014 10:53:26 AMTech: mtTech: mt

ORAL OMNI & 85CC OMNI 350ORAL OMNI & 85CC OMNI 350HELICAL MODE /10:53:26 AMHELICAL MODE /10:53:26 AMW: 409 C: 39 Z: 1.22W: 409 C: 39 Z: 1.22600 ---600 ---KVp: 120KVp: 120Tilt: 0Tilt: 0FFSFFS

Page: 25 of 54Page: 25 of 54 IM: 25 SE: 601 IM: 25 SE: 601Compressed 8:1Compressed 8:1

--- ------ ---XY: 6.61XY: 6.61

THK: 5THK: 5ASIR: SS20ASIR: SS20

NI: 135NI: 135

RR LL

HH

FF cm cm

Metastatic melanoma from anal primary –Relapse after approx. 2 years, re-induction with 4 combination doses to near CR;No recurrence of uveitis

Cohort 8, Ipilimumab + nivolumab, response at 12 weeks

Prior therapy with HD-IL2, multiple resections, Vemurafenib, and RT; LDH > 2000 at baseline; LDH nearly normal within 3 weeks

Yale Ipi/Nivo Cohorts 1-3• N=25

– Confirmed PR/CR – 10 (40%)• 7 ongoing near CR• 1 CR ->PD at approx. 2.5 years -> reinduced -> near CR • 1 PD in node and then in brain, DOD at approx. 2 years• 1 PD DOD at > 4 years after multiple therapies

– Of 15 PD/unconfirmed OR:• Mixed response (early brain met), then later bowel mets – now NED

with gamma knife RT + surgery • Mixed Resp at 12 weeks -> off due to tox (lipase) CR with further ipi

alone, single local recurrence resected• uPR -> off due to LFTsPD on steroids stable PR with further ipi alone• 1 prolonged irPR—PD reinduction-> alive with PD• 1 inevaluable – response in brain mets and small systemic DZ (lung/liver)

-2 brain mets RX with GK-RT now NED > 1 year• 1 irSD PD reinduced at approx 3.5 years• 1 SD PD PR to TIL

– 10 total deaths (6 non-responders)• 4 at dose level 1• 1 ocular primary

• Follow-up ≥ 2 years• 8/10 PR/CR remain in CR/near

CR (one required re-induction at 2.5 years)

• 4 with mixed response or transient response remain with NED with additional ipi alone, ipi + surgery, or GKRT + surgery

• 1 with SD x 1 year remains progression-free after TIL

• 2 with waxing and waning disease and slow progression on continued therapy and re-induction

Tail of curve at 50% survival?

Overall Survival

JUNE 2014 data analysis.

Died/Treated Median OS (95% CI)

Cohort 2 4/17 NR (26.8–NR)

Cohorts 1–3 14/53 NR (39.7–NR)

Cohort 8 8/41 NR (10.5–NR)

• Cohort 8 uses the same dosing schedule that is being tested in the phase 3 trial (CA209-067)

Month

OS

(%)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

1-yr OS 94% 2-yr OS

88%

1-yr OS 85% 2-yr OS

79%

Patients at Risk175341

175240

174931

164716

16450

14420

14370

14300

13250

7160

4110

370

350

350

010

010

000

Cohort 2 (Nivo 1 + Ipi 3)Cohorts 1–3Cohorts 8 (Nivo 1 + Ipi 3)

Cohort 2 (N=17)

Cohorts 1–3 (N=53)Cohort 8(N=41)

Lowest survival in cohort 1 –Dose response for nivo versus patient selection

15

Cohort(s) [N*] EvaluableSample, N

ORR, n/N (%)BRAF WT BRAF MT

1–3 [53] 51 18/39 (46) 3/12 (25)8 [41] 39 10/27 (37) 6/12 (50)

*Number of patients treated. MT=mutant (BRAFT V600 mutation positive); WT=wild-type (BRAF V600 mutation negative).

JUNE 2014 data analysis.

ORR and Tumor Burden Change by BRAF Mutation Status

Cohorts 1–3 Cohort 8

-100

50

100

150

200

250

-50

0

BRAF MT BRAF WT BRAF Unknown

Max

imum

Res

pons

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om B

asel

ine

in T

arge

t Les

ion

(%)

900

-100

0

50

100

-50

800

16

ORR and Tumor Burden Change by PD-L1 Status

Cohort(s) [N*] EvaluableSample, N

ORR, n/N (%)PD-L1 Positive† PD-L1 Negative†

1–3 [53] 37 8/14 (57) 8/23 (35)8 [41] 21 0/0‡ 8/21 (38)

*Number of patients treated. †5% cut-off, tumor cell surface staining. ‡None of the 21 evaluable patient samples was test positive for PD-L1 by 5% tumor cell surface staining cutoff

Cohorts 1–3 Cohort 8

JUNE 2014 data analysis.

PD-L1+ PD-L1- PD-L1 Unknown

Max

imum

Res

pons

e Fr

om B

asel

ine

in T

arge

t Les

ion

(%)

-100

50

100

150

200

250

-50

0

900

-100

0

100

800

17

Treatment-Related AEs Reported in ≥ 15% of Patients*Patients with an event, %

Cohorts 1–3 (N=53) Cohort 8 (N=41)Any Grade Grade 3/4 Grade 5 Any Grade Grade 3/4 Grade 5

All drug-related 97 63 0 98 66 2†Rash 62 4 0 66 10 0Pruritus 57 0 0 46 0 0Fatigue 43 2 0 46 0 0Diarrhea 42 4 0 34 12 0Nausea 23 2 0 24 2 0Lipase increased 26 19 0 17 10 0AST increased 25 13 0 12 7 0Pyrexia 23 0 0 22 0 0ALT increased 23 11 0 12 12 0Amylase increased 21 6 0 12 7 0Vitiligo 15 0 0 7 0 0Abdominal pain 9 0 0 20 2 0Arthralgia 9 0 0 20 0 0*Listing adverse events reported in ≥ 15% of patients in cohorts 1–3 or in cohort 8, sorted by any grade frequency in cohort 1–3; †One patient died due to grade 5 multi-organ failure related to study treatment in cohort 8ALT = alanine aminotransferase; AST = aspartate aminotransferase.

JUNE 2014 data analysis. 18

Treatment-Related Immune-Mediated* AEs

Patients with an event, %

Cohorts 1–3 (N=53) Cohort 2 (N=17) Cohort 8 (N=41)Any

GradeGrade

3/4Any

GradeGrade

3/4Any

GradeGrade

3/4

Skin 79 4 88 0 78 17

Gastrointestinal 43 9 35 12 37 20

Hepatic 30 15 35 18 15 12

Endocrine 17 4 24 6 24 4

Pulmonary 8 2 12 6 5 2

Renal 6 6 6 6 0 0

Hypersensitivity /InfusionReaction 2 0 6 0 2 0

*Immune-mediated adverse events are events with potential immunologic causes and those that require more frequent monitoring or intervention with immune suppression or hormone replacementJUNE 2014 data analysis.

• Standard safety guidelines available to manage immune-mediated AEs with immune suppressing medication

19

PD-1/PD-L1 Blockade + anti-CTLA-4Next Steps and Questions• Randomized trials versus ipilimumab (069) and versus ipilimumab or

nivolumab (067) were completed • Concurrent versus sequential

• Gene expression (Dhodapkar et al, SITC 2014) suggest concurrent administration produces unique biological effects

• Management of adverse events • Predictive biomarkers? • Biology of acquired resistance?• Safe triple combinations? (anti-VEGF, others)

20

Antigen Presenting Cell or Tumor T-lymphocyte Function (excluding Treg)

Peptide-MHC T cell receptor Signal 1

CD80/CD86 (B7.1, B7.2) CD28/CTLA-4 Stimulatory/inhibitory

CEACAM-1 and TIM-3 CEACAM-1 inhibitory

CD70 CD27 stimulatory

LIGHT HVEM stimulatory

HVEM BTLA, CD160 inhibitory

PD-L1 (B7-H1) PD-1 and CD80 Inhibitory (Th1)

PD-L2 (B7-DC) PD1 and ? Inhibitory (Th2) or stimulatory

OX40L OX40 stimulatory

4-1BBL CD137 stimulatory

CD40 CD40L Stimulatory to DC/APC

B7-H3 ? Inhibitory or stimulatory

B7-H4 ? inhibitory

PD-1H (Vista) ? inhibitory

GAL9 TIM-3 inhibitory

MHC class II LAG-3 inhibitory

B7RP1 ICOS stimulatory

MHC class I KIR Inhibitory or stimulatory

GITRL GITR stimulatory

CD48 2B4 (CD244) inhibitory

HLA-G, HLA-E ILT2, ILT4; NKG2a inhibitory

MICA/B, ULBP-1, -2, -3, and -4+- NKG2D Inhibitory or stimulatory

CD200 CD200R inhibitory

CD155 TIGIT/CD226 Inhibitory/stimulatory

IDOTregMDSCMacrophagesTGF-beta

VaccinesCytokines

Non-ImmunotherapyVEGF/VEGFRiRTMolecular targetsChemoRx

In our melanoma gene expression database, high levels of:CEACAM-1B7-H3CD200CD155 (PVR)

TIM3

Hirano et al, Cancer Res, Feb, 2005

41BB + anti-PDL1

PD-1 Pathway BlockadeCombinations in Development

• Ipilimumab (anti-CTLA-4)• Tremelimumab (anti-CTLA-4)• Bevacizumab• IFNs – RCC/melanoma• IL-21 – terminated?• IL-2 (proposed)• anti-LAG3• anti-KIR• peptide vaccines• Oncolytic viruses (Tvec)• Anti-OX40 (proposed)• Anti-CD27• Anti-CD137• Treg inhibitors - mogamulizumab• Adoptive Cell Therapy • Dabrafenib +/- Trametinib• Vemurafenib +/-Cobimetinib• RT

Response to Ipi-Nivo

June 2013 July 2013 Feb 2014

Pt recently progressed on ACT*

Conclusions

• If phase 3 trials confirm early data, anti-PD-1 + anti-CTLA4 will become SOC for metastatic melanoma (wtBRAF and mBRAF)

• Following for long term survival • Toxicity high but manageable (similar to ipi 10 mg/kg)

• Approaches to improve ipi/nivo not immediately obvious• Multiple combinations supported by animal model data

• But clinical correlative data not yet available to select ‘best’ regimens for subsets of patients

• Clinical endpoints for studies may need to evolve• 3-year survival rates? • ‘Durable’ CR or near CR?

Credits

• CA209-004• Jedd Wolchok• Margaret Callahan• Harriet Kluger• Michael Atkins• John Kirkwood• Mary Ruisi• Ashok Gupta• Alan Korman• Many others