Immunotherapy in Ovarian Cancer

Antonio González Martín

Medical Oncology Department

Ovarian cancer

• The leading cause of death due to gynaecological

cancer in developed countries and the fifth cause

of death from cancer in women.

• 75–80% of patients will present with advanced

disease at the time of diagnosis

• Upfront therapy of ovarian cancer must be

performed by a multidisciplinary team and consists

of optimal upfront cytoreductive surgery followed

by paclitaxel-carboplatin chemotherapy.

Bookman, M. A. et al. J Clin Oncol 2009

60% survival at 5 years in R0 Vs 25-30% in > R0

NO residual disease after upfront debulking surgery is

the main prognostic factor

Learning Objectives

• Rational for immunotherapy in ovarian cancer.

• Clinical data with immunotherapy in ovarian cancer

and planned clinical trials

• Role of PD-L1 as predictive factor

• Combination with chemotherapy and bevacizumab

Ovarian cancer has far few mutations compared

with melanoma and NSCLC

Brown et al, Genome Research 2014

What is the rationale for immunotherapy in OC?

• Evidence of immune response against ovarian cancer.

10 studies

1815 patients

HR 2.24

(1.71-2.91)

Hwang et al. Gynecol Oncol 2012

Distribution and prognostic

impact of TIL subsets in HGSC.

Nelson. Current Opinion Inmunol 2015

What is the rationale for immunotherapy in OC?

• Evidence of immune response against ovarian cancer.

• PD-L1 expression is considered a mechanism of

immune-response evasion and has been associated to

a worse prognosis.

Hamanishi et al. PNAS 2007

PD-L1 (PD ligand-1)

48/70（68%）

What is the rationale for immunotherapy in OC?

• Evidence of immune response against ovarian cancer.

• PD-L1 expression is considered a mechanism of

immune-response evasion and has been associated to

a worse prognosis.

• Patients with HRD/BRCAmut may have higher neo-

antigen load

Levine D. The Cancer Genome Atlas, Molecular profiling of

serous ovarian cancer, 2011

Homologous recombination

(HR) deficient

Not HR deficient

BRCA1

germline

8%

BRCA2

germline

6%

BRCA1

somatic

3%BRCA2

somatic

3%

BRCA1

methylation

11%

EMSY

amplification

6%PTEN loss

5%Other HRD

7%

CCNE1

amplification 15%

MMR

germline

2%

Other

34%

20% HGSOC are BRCA 1/2 mut

• BRCA1/2 germline

mutation 14%

• BRCA1/2 somatic

mutation 6%

• Total 20%

Association and prognostic significance of BRCA1/2-mutation

status with neoantigen load, number of TIL and expression of

PD-1/PD-L1 in high grade serous ovarian cancer

Kyle C. Strickland et al. Oncotarget 2016

HR deficient tumors, either BRCA1/2-mut

or non- BRCA1/2-mut, demonstrated

significantly higher neoantigen loads than

HR proficient tumors

Lower neoantigen load is

associated with inferior overall

survival

Association and prognostic significance of BRCA1/2-mutation

status with neoantigen load, number of TIL and expression of

PD-1/PD-L1 in high grade serous ovarian cancer

Kyle C. Strickland et al. Oncotarget 2016

BRCA1/2-mutated HGSOCs harbor increased PD-1 and PD-L1 expression

compared to HR proficient HGSOCs

Association and prognostic significance of BRCA1/2-mutation

status with neoantigen load, number of TIL and expression of

PD-1/PD-L1 in high grade serous ovarian cancer

Kyle C. Strickland et al. Oncotarget 2016

Prognostic significance of BRCA1/2-mutation status and number of CD3+ TILs

229 m

56 m20 m

Learning Objectives

• Rational for immunotherapy in ovarian cancer.

• Clinical data with immunotherapy in ovarian cancer

and planned clinical trials

Galuzzi et al. Oncotargets 2014

Inmunomoduladory

Mabs

(Check point inh)

Monoclonal Antibodies Directed Against PD-1, or

its Ligands PD-L1/2, Promote T cell Activation

mAb with clinical data in OC

• Anti PD-1

– Nivolumab

– Pembrolizumab

• Anti PD-L1

– Avelumab

– Durvalumab

– Atezolizumab

• Anti CTLA-4

– Ipilimumab

Nivolumab

• Fully humanized IgG4

monoclonal antibody

targeting the PD-1

• Platinum-resistant

Hananishi et al. J Clin Oncol 2015

Nivolumab

Dose

Number of

Patients Response

1 mg/kg/ 2 weeks 10 1 PR (10%)

3 mg/kg/ 2 weeks 10 2 CR (20%)

Complete responders

A) HGSOC B) Clear Cell Carcinoma

Mananishi et al. J Clin Oncol 2015

Pembrolizumab

Phase 1b Keynote 028

• Anti-PD-1 humanized IgG4 monoclonal antibody

• 10 mg/kg / 2 weeks

• 26 patients

• No candidates for standard therapy

• PD-L1 in 1% of tumor nests or PD-L1 expression in

stroma

• ORR 11.5% with 1 CR, 2 PR , and 23% SD

• Responses lasting > 24 weeks

Varga A et al. ASCO 2015. #5510.

Pembrolizumab clinical development

Phase II trials

NCT02440425 Dose Dense Paclitaxel With Pembrolizumab

(MK-3475) in Platinum Resistant Ovarian Cancer

NCT02520154 Pembrolizumab in Combination With

Chemotherapy in Frontline Ovarian Cancer

NCT02766582 Pembrolizumab/Carboplatin/Taxol in

Epithelial Ovary Cancer

NCT02674061 Efficacy and Safety Study of Pembrolizumab

(MK-3475) in Women With Advanced Recurrent

Ovarian Cancer (MK-3475-100/KEYNOTE-100)

Cohort A: 1-3 prior lines

Cohort B: 4-6 prior lines

AvelumabPhase Ib (NCT01772004, Javelin solid tumor study)

• Fully humanized monoclonal anti-PD-L1 IgG1 antibody.

• 124 patients with refractory or recurrent OC (progression within

6 months, or after 2nd/3rd line)

• 10 mg/kg every 2 weeks

Disis ML, et al. J Clin Oncol. 2016;34(suppl): Abstract 5533.

ORR 9,7% (12/124)

12.3% in PD-L1+ tumors

5.9% in PD-L1- tumors

(based on > =1%

threshold)

JAVELIN 100

Outcomes

Primary endpoint: PFS from randomization (A vs B, A vs C)

Secondary endpoints: PFS from randomization (B vs C)

Maintenance PFS, OS, ORR, duration of response, PROs, safety, PK

Stratification:

• - weekly vs Q3W taxol

• - residual vs no residual disease vs neoadjuvant

• - Region – North America vs other

Observation

Avelumab Q2W

Chemotherapy

Chemotherapy

Chemotherapy Maintenance

Chemotherapy

+ Avelumab Q3WAvelumab Q2W

1o analysis

1o analysis

2o analysis

(if both

1o analyses

positive)

R

A

N

D

O

M

I

Z

A

T

I

O

N

n = ~951 (388 PFS events) 272 events

within each of the 2 main comparisons

• Anticipated start: Feb 2016

• Target PFS: HR=0.65

• Arm A mPFS: 23 mo

• Arms B and C mPFS: 35.4 mo

• Accrual rate = 40 pts/mo

• Accrual duration = 27 mo.

• IA of PFS for efficacy or futility =

~30 mo. 2/3 of events

• Expected PFS readout at 41 mo

1:1:1

Patients whose tumor was not progressing as per RECIST 1.1 criteria (CR, PR, or SD) will be allowed to continue onto the maintenance portion of the study

Enrollment Criteria

• Previously untreated

• Stage II-IV

• Prior debulking surgery or plan for neoadjuvant chemotherapy

• ECOG PS 0 or 1

• Mandatory archival tissue

Chemotherapy: Choice of carboplatin q3w, paclitaxel, OR carboplatin + weekly paclitaxel as per JGOG 3016.

Maintenance avelumab up to 2 years.

Arm A

Arm B

Arm C

JAVELIN 200Avelumab (anti-PDL1) in Platinum Resistant/Refractory Ovarian Cancer

Randomized Phase 3 Study

1:1:1

Primary Endpoint:

Enrollment Criteria• Progression ≤ 6 mo or no response

to most recent platinum-based

therapy

• No more than 3 prior therapies for

platinum-sensitive disease, and no

prior therapies for platinum-

resistant disease

• Measurable disease

• Adequate bone marrow, renal, liver

and cardiac function

• ECOG PS 0 or 1

• No prior immune checkpoint

inhibitor therapies

• Available tissue at baseline

Arm A

Avelumab

Arm C

Doxil

R

A

N

D

O

M

I

Z

A

T

I

O

N

Secondary Endpoints: ORR, PFS, Duration of response, PROs, Safety

n = ~550 (282 events)

(200 events for each comparison)

OS

Stratification: Platinum refractory vs resistant, #prior therapies, bulky disease.

Arm B

Doxil + Avelumab

Confidential

Atezolizumab

Bendell JC, et al. J Clin Oncol. 2016;34(suppl): Abstract 3502.

Fc-engineered, humanized, nonglycosylated

IgG1 kappa monoclonal antibody targetin PD-L1

83% were PD-L1+

25% (2/8) ORR

All IHC 2-3 for PDL-1

Learning Objectives

• Rational for immunotherapy in ovarian cancer.

• Clinical data with immunotherapy in ovarian cancer

and planned clinical trials

• Role of PD-L1 as predictive factor

Classification of Tumors Into 4 Groups• Aimed at predicting effective treatment with immune

checkpoint inhibitors based on melanoma studies1,2

– Only Type I is likely to respond

1. Taube JM, et al. Sci Transl Med. 2012;4(127):127ra37. 2. Teng MW, et al. Cancer Res. 2015;75(11):2139-2145.

Type I: Adaptive immune

resistance

TIL+

PD-L1+

Type II: Immunologic

ignorance

TIL-

PD-L1-

Type III: Intrinsic induction

TIL-

PD-L1+

Type IV: Tolerance

TIL+

PD-L1-

Objective response by PD-L1 expression with nivolumab

Hananishi et al. J Clin Oncol 2015

ORR by PD-L1 Expression With Avelumab

• Differences in ORR not statistically significant between PD-L1+ and PD-L1- groups

* Nonevaluable specimens (n = 50) include those that were missing, of poor quality, or otherwise not available to provide results.

Staining Cut-Off Level(n = 74)*

PD-L1 Expression

Status

Prevalence, %

ORR, n (% )[95% CI]

≥1% Tumor cells

PD-L1+ 777 (12.3%)

[5.1, 23.7]

PD-L1- 231 (5.9%)[0.1, 28.7]

Disis ML, et al. J Clin Oncol. 2016;34(suppl): Abstract 5533.

Learning Objectives

• Rational for immunotherapy in ovarian cancer.

• Clinical data with immunotherapy in ovarian cancer

and planned clinical trials

• Role of PD-L1 as predictive factor

• Combination with chemotherapy and bevacizumab

TILTumor-Infiltrating

Lymphocytes

HOT: TIL-Rich

T-lymphocytes are present,

but not working

COLD: TIL-

Poor

T-lymphocytes are just

absent in the tumor!

How Do We Sensitize “Cold” Tumors?

Tumor

expression

of VEGF

Reduce lymphocyte adhesion

to vessel walls

Associated with absence of

tumor-infiltrating T cells

Lymphocyte do not penetrate the tumor:

TIL are not present

Local immunosuppression:

TIL are present but not working

VEGF is correlated with

expression of PD-1 on CD8+

cells

VEGFR2 is selectively expressed

on immunosuppressive Treg

Angiogenesis and Immunosuppression Programs Collaborate to Facilitate Tumor Growth

VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor

Recurrentlate relapse

N = 405

•Nonmucinous histology

•TFI p (platinum-free interval)

>6 months

•One or 2 prior lines of Cx

•ECOG ≤1

Chemotherapy-based schedule options (investigator’s choice): Carboplatin AUC5 + PLD* (30 mg/m² q 4 wks) or paclitaxel (175

mg/m² q3 wks) or gemcitabine (1000 mg/m² D1&D8 q 3wks).

Bevacizumab 15 mg/kg q3 wks or 10 mg/kg q2 wks. ATEZO/PLACEBO: 1200 mg, IV q3 wks or 800 mg q2 wks.

Carboplatin combo

R

2:1R

BIOPSY

Stratification factors

•PDL-1 expression•TFI p (6-12 months, >12

months)

•Chemotherapy cohort

PI: J.E. Kurtz

Carboplatin combo

Bevacizu

mab

Summary

• There is substantial rationale for the development of

immunetherapy in OC

• Activity is limited (ORR 10-15%) but with long term

responders in recurrent setting

Future challenge

• Selection of patients

• When in the clinical course (first line vs recurrence)

• Combinations (anti-angiogenic, PARPi, chemotherapy…)

Thank you