Immunoterapia: carcinoma ovarico

Nicoletta Colombo University Of Milan-Bicocca

European Institute of Oncology, Milan

What do we know in Ovarian Cancer as a Target for Cancer Immunotherapy?

Effect of Immune System on OC

• Ovarian Cancer is an immunogenic

tumour1-4

– Strong immunosuppressive environment

present in OC

– Spontaneous antitumor immune response

can be detected in the form of tumor-

reactive T cells and antibodies

• The presence of intratumoural T cells

is associated with better clinical

outcome4

1. Turner TB et al. Gynecol Oncol. 2016;142:349-356. 2. Coukos G et al. Ann Oncol. 2016;27(suppl 1):i11-i15.

3. Mandai M et al. Int J Clin Oncol. 2016;21:456-461. 4. Zhang L et al. N Engl J Med. 2003;348:203–213.

Overa

ll S

urv

ival

(%)

Month

0

25

50

75

100

0 12 24 36 48 60 72 84 96 108 120 132

P<0.001

Intratumoral T cells

No intratumoral T cells

The correlation between TILs and survival is

supported by multiple clinical studies in OC

Hwang et al. Gynecol Oncol 2012

Test for overall effect: p<0.00001 CI, confidence interval; HR, hazard ratio; OC, ovarian cancer; SE, standard error; TILs, tumour-infiltrating lymphocytes

Study or Subgroup Log [HR] SE Weight (%)

HR

[95% Cl]

HR

[95% Cl]

Zhang (2003) 0.61 0.18 12.5 1.84 [1.29–2.62]

Sato (2005) 1.11 0.307 8.8 3.03 [1.66–5.54]

Hamanishi (2007) 2.031 0.518 4.8 7.62 [2.76–21.04]

Callahan (2008) 0.548 0.222 11.2 1.73 [1.12–2.67]

Han (2008) 0.563 0.258 10.1 1.76 [1.06–2.91]

Tomsova (2008) 1.308 0.296 9.1 3.70 [2.07–6.61]

Adams (2009) 0.694 0.315 8.6 2.00 [1.08–3.71]

Clarke (2009) 0.282 0.106 14.5 1.33 [1.08–1.63]

Leffers (2009) 1.02 0.251 10.3 2.77 [1.70–4.54]

Stumpf (2009) 0.895 0.258 10.1 2.45 [1.48–4.06]

Total (95% Cl) 100.0 2.24 [1.71–2.92] TILs favour death

0.1 0.2 0.5 1 2 5 10

TILs favour survival

Independent of tumour grade, stage or histologic subtype1

Other Immune Factors Correlate With Poor Prognosis

• Presence of Tregs in tumor1-4

• Accumulation of plasmacytoid

dendritic cells5-7

• Presence of immunosuppressive

macrophages expressing B7-H48,9

• Low level of circulating

lymphocytes (<1.0x109/L)10

1. Curiel TJ et al. Nat Med. 2004; 2. Wolf D et al. Clin Cancer Res. 2005; 3. Redjimi N et al. Cancer Res. 2012;. 4. Govindaraj C et al. Clin Immunol. 2013; 5. Zou W

et al. Nat Med. 2001. 6. Wei S et al. Cancer Res. 2005;. 7. Labidi-Galy SI et al. Cancer Res. 2011. 8. Kryczek I et al. Cancer Res. 2007. 9. Zhang QW et al. PLoS

One. 2012. 10. Ray-Coquard I et al. Cancer Res. 2009; S

urv

iva

l

Months

0

0.4

0.6

0.8

1.0

0

P<0.0001

0.2

20 40 60 80 100

Low

Medium

High

Treg in ovarian cancer

Curiel TJ et al. Nat Med. 2004;

What factors contribute to ovarian immunogenicity ?

Genomic instability

increases TIL

infiltration

Leary A, et al. Ann Oncol. 2017;29(Suppl 5): Abstract 948P. Cirello G, et al. Nat Genet. 2013;45(10):1127-1133.

High

Mutation

Rate

High

Copy

number

HGOC: A Disease With High Copy Number and Genomic

Instability

CD8+ TILs Expressing PD-1 Are Increased in BRCA1/2 Ovarian Cancer

CD8+ PD-1

Strickland K, et al. J Clin Oncol. 2015;33(suppl): Abstract 5512.

P = .0024

P = .003 P = .005

Tumoral PD-1 Expression Differs According to Histologic Type

High-Grade

Serous Endometrioid

Clear

Cell

Webb JR, et al. Cancer Immunol Res. 2015;3(8):926-935.

Role of PDL-1 in ovarian cancer

Intraepithelial TILs Define a Specific Class of Patients

TIL-rich

50%

TIL-poor

50%

Deurloo R, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 950P.

PD-L1

expression

>50% of

advanced

stages

PD-L1 correlates with TILs

Higher PD-L1 Expression Is Associated With Poorer Prognosis in ovarian cancer

.Hamanishi J et al. Proc Natl Acad Sci USA. 2007;104:3360-3365.

PD-L1

Expression

Patient Number OS Risk Ratio,

95% CI [P-value]

PFS Risk Ratio,

95% CI [P-value]

Low 22 (31.5%) 1 1

High 48 (68.5%) 4.26, 1.39-12.94 [0.011] 2.57, 1.11-5.93 [0.027]

PD-L1 was an independent poor prognostic factor for both OS

and PFS

1.0

Ove

rall

Su

rviv

al 0.8

0.6

0.4

0.2

0 0 2 4 6 8 10 12

Years After Operation

p = 0.016

PD-L1 high

PD-L1 low

1.0

PF

S

0.8

0.6

0.4

0.2

0 0 2 4 6 8 10 12

Years After Operation

p = 0.038

PD-L1 high

PD-L1 low

The rationale for targeting PD-L1 in OC

1. Lawrence et al. Nature 2013; 2. Imielinski et al. Cell 2012; 3. Chen et al. Clin Cancer Res 2012; 4. Seghal et al. Cancer Res 2008

5. Rooij et al. J Clin Oncol 2013; 6. Strickland et al. ASCO 2015 7. Zhang et al. N Eng J Med 2003; 8. Hamanishi et al. PNAS 2007

9. Abiko et al. Clin Cancer Res 2013 OC, ovarian cancer; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TILs, tumour-infiltrating lymphocytes

OC is associated with mutational burden1–5

Tumour mutations increase tumour-specific antigens6

>50% of OC tumours show TILs at diagnosis7

Improved OC outcomes?

Immunosuppressive

tumour

microenvironment

Anti-PDL1

or anti-PD1 Increased expression of

immune checkpoint

modulators

(PD-L1 and PD-1)8–9 as a

potential mechanism of

resistance

Nivolumab1 Pembrolizumab

Keynote 28 2 Avelumab3 Atezolizumab4 Durvalumab5

N 20 26 124 12 20*

Prior

therapies ≥4: 55% ≥5: 38.5% ≥3: 65.3% ≥6: 58% Median: 4*

PD-L1+

prevalence 80% (IC 2/3) 100% (≥1% TC) 77% (≥1% TC) 83% (IC 2/3)

>5% TC: 73%

(11/15)*

Overall

Response

Rate

15% 11.5% 9.7% 25% Not reported

Duration

4 (20%) > 24

wks

7 (30%) > 24 wks 16.1% @24

wks

mPFS ~12 wks Not reported

* Includes ovarian cancer (n = 15), triple-negative breast cancer (n = 2), cervical cancer (n = 2), and uterine leiomyosarcoma patients (n = 1)

CI, confidence interval; DCR, disease-control rate; IC, immune cell; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TC, tumor cell; TRAE, treatment-related adverse event, Tx, treatment

1. Hamanishi J, et al. J Clin Oncol. 2015;33(34):4015-4022. 2. Varga A, et al. J Clin Oncol. 2015;33(suppl): Abstract 5510. 3. Disis ML, et al. J Clin Oncol. 2016;34(suppl): Abstract 5533. 4. Infante JR, et al. Ann Oncol. 2016;27(Suppl 6): Abstract 871P. 5. Lee J-M, et al. J Clin Oncol. 2016;34(suppl): Abstract 3015.

Immune Checkpoint Inhibitors in OC

Ovarian cancer subset of JAVELIN Solid Tumor

study: Avelumab Phase 1b Study Study Objective: To assess safety and tolerability of avelumab in the subset of patients

with refractory or recurrent advanced OC

Enrollment Criteria • Recurrent OC with disease

progression within 6 months of

platinum-based therapy or after

subsequent therapy

• RECIST 1.1 measurable disease

• ECOG PS 0 or 1

• Availability of fresh biopsy or tumor

archival material for analysis of PD-

L1 expression

Evaluation • Efficacy assessed by RECIST

every 6 weeks

• Time-to-event endpoints (Kaplan-

Maier)

• Blood collection for CA-125

• BRCA 1/2 mutational status

recorded from medical records

• AEs assessed throughout the

trial by NCI-CTCAE 4.0

Treatment • Avelumab (10 mg/kg) by IV

Q2W until disease progression,

unacceptable toxicity, or other

criteria for withdrawal

N=124

Primary Endpoint Safety

Secondary Endpoint

Best overall response, progression-free survival, overall survival, evaluation of

association between PD-L1 expression on tumor cells and immune cells within

tumor and clinical activity of avelumab

Disis ML et al. ASCO 2016. Abstract 5533.

≥3 prior therapies: 65.3%

Response to Avelumab by Subgroup (N = 75)

N = 75

ORR by RECIST 1.1

n (%) 95% CI

Tumor burden (median sum of longest diameter = 58 mm)

> Median (n = 35) 2 (5.7%) (0.7, 19.2)

≤ Median (n = 40) 6 (15.0%) (5.7, 29.8)

# of prior treatment lines

≥3 (n = 51) 4 (7.8%) (2.2, 18.9)

2 (n = 10) 1 (10.0%) (2.5, 44.5)

≤1 (n = 14) 3 (21.4%) (4.7, 50.8)

Platinum resistance/sensitivity†

Resistant (<6 months of PFI; n = 44) 4 (9.1%) (2.5, 21.7)

6 to 12 months of PFI (n = 18) 2 (11.1%) (1.4, 34.7)

Sensitive (>12 months of PFI; n = 10) 2 (20.0%) (2.5, 55.6)

†Defined based on platinum-free interval (PFI) since last line of platinum: <6 months, 6 to 12 months, and >12 months; PFI could not be determined for 3 patients.

Disis ML, et al. J Clin Oncol. 2015;33(suppl). Abstract 5509.

KEYNOTE-028: Multicohort Phase Ib Trial of Pembrolizumab (Anti-PD-1): Efficacy

Antitumoral activity

Patients

(n = 26)

Best response n % IC95

Response rate 3 11.5 2.4-30.2

CR 1 3.8 0.1-19.6

PR 2 7.7 0.9-25.1

SD 6 23.1 9.0-43.6

PD 17 65.4 44.3-82.8

DCR 9 34.6 17.2-55.7

Of the 3 patients who responded, their responses endured for ≥24 weeks

CR, complete response; DCR, disease control rate; PD, progressive disease; PR, partial response; SD, stable disease

Varga A, et al. J Clin Oncol. 2015;33(suppl): Abstract 5510.

Best Overall Response with Nivolumab in Platinum-Resistant Advanced ovarian cancer

Hamanishi J et al. J Clin Oncol. 2015;33(34):4015-4022.

Ch

an

ge

in

Ta

rge

t L

es

ion

s

Fro

m B

as

eli

ne

(%

)

150

100

50

0

-50

0

PD

PD PD PD PD PD PD SD SD PD PD SD SD SD NE PD

PR

SD CR

CR

1 mg/kg (n=10)

3 mg/kg (n=10)

• 15% ORR (3 of 20 patients)

• Median PFS=3.5 months, median OS=20.0 months for pooled cohort

2 cases with a CR

Nivolumab (Anti-PD-1) in Ovarian Cancer

Nivolumab

Dose

Number of

Patients Response

1 mg/kg 10 1 PR (10%)

3 mg/kg 10 2 CR (20%)

Hamanishi J, et al. J Clin Oncol. 2015;33(34):4015-4022.

Best Overall Response With Nivolumab in ovarian cancer

• 15% ORR (3 of 20 patients) • Median PFS=3.5 months, median OS=20.0 months for pooled cohort

1 mg/kg (n=10)

3 mg/kg (n=10)

Ch

an

ge

in

Ta

rge

t L

es

ion

s

Fro

m B

as

eli

ne

(%

)

200

150

50

0

-50

-100

PR SD

CR CR

Time (days)

100

50 100 150 200 250 300 350 400

Hamanishi J et al. J Clin Oncol. 2015;33(34):4015-4022.

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

Phase Ib Trial of Atezolizumab (Anti-PD-L1)

83% of tumor specimens were PD-L1+

25% (2/8) ORR in IC 2/3 patients

Summary single-agent therapy with immune checkpoint inhibitors

• Modest response rates

• Disease control prolonged in some patients

• Heterogeneous group of patients

• Some evidence that benefit is greater ⎻ Platinum-sensitive tumours

⎻ Fewer lines of chemotherapy

⎻ PDL1 + ve tumours

Searching for Rational Combinations Combination With Chemotherapy

Immunogenicity of chemotherapy

Chemotherapy has been shown to

Enhance antigen presentation

Enhance immunogenicity (release of adjuvants by cells)

Increase susceptibility to immune attack

Zitvogel L et al. Immunity. 2013;39:74-88.

Chemotherapy

Increases release of tumor

antigens

Increases TIL and PD-L1

expression

Mesnage S, et al. Ann Oncol. 2017;28(3):651-657.

Immunogenic Cell Death Inducers Drug Indications

Bleomycin Cervical cancer, HNSCC, lymphoma, penile cancer, testicular cancer

Bortezomib Mantle cell lymphoma, multiple myeloma

Cyclophosphamide Breast cancer, leukemia, lymphoma, multiple myeloma, neuroblastoma,

ovarian cancer, retinoblastoma

Doxorubicin ALL, AML, bladder cancer, bone sarcoma, breast cancer, gastric cancer,

lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, SCLC, soft

tissue sarcoma, thyroid cancer, Wilms tumor

Epirubicin Breast cancer

Idarubicin AML

Mitoxantrone AML, breast cancer, NHL, prostate cancer

Oxaliplatin Colorectal cancer

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; HNSCC, head and neck squamous cell carcinoma; NHL, non-Hodgkin lymphoma; SCC, squamous

cell carcinoma; SCLC, small cell lung carcinoma

Pol J, et al. Oncoimmunology. 2015;4(4):e1008866.

Synergistic Antitumor Responses of Pegylated Liposomal Doxorubicin and Anti-PD-1

CR, complete response; PLD, pegylated liposomal doxorubicin

Rios-Doria J, et al. Neoplasia. 2015;17:661-670.

• Complete response was achieved in more colon cancer mouse models treated with both PLD and anti-PD-1 compared to single agents

Randomized Phase III Study (NCT02580058)

1:1:1

Primary Endpoint:

Enrollment Criteria

• Progression ≤6 mo or no response to most recent platinum-based

therapy

• Up to 3 lines of chemotherapy for platinum-sensitive disease, most

recently platinum-containing, and no prior therapy for platinum-resistant

disease

• Measurable disease

• ECOG PS 0 or 1

• No prior immune checkpoint inhibitor therapies

• Doxil-resistant (disease progression within 6 mo) excluded

• Mandatory archival tissue

• Baseline biopsy required unless contraindicated

Arm A

Avelumab

Arm C

Pegylated Liposomal

Doxorubicin (PLD)

R

A

N

D

O

M

I

Z

A

T

I

O

N

Secondary Endpoints: ORR, duration of response, PROs, safety

n = ~550

Coprimary OS and PFS

Stratification: P6 refractory vs resistant, number of prior therapies, bulky disease

Arm B

PLD + Avelumab

ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PROs, patient-reported outcomes

JAVELIN 200 Avelumab in Platinum-Resistant/Refractory OC

Alteration of the immunological landscape Combining immune checkpoint inhibitors with chemotherapy

Emens and Middleton Cancer Immunol Res 2015

Immunotherapy is Moving As First-Line

JAVELIN Ovarian 100: Avelumab + Platinum Combo (Frontline)

1:1:1

• Patients with SD or better will be allowed to continue to maintenance

• Chemotherapy: Choice of q3w carboplatin-paclitaxel OR carboplatin + weekly paclitaxel

• Maintenance avelumab up to 2 years

Enrollment Criteria

• Previously untreated

• Stage III-IV

• Prior debulking surgery or plan for

neoadjuvant chemotherapy

• ECOG PS 0 or 1

• Mandatory archival tissue

Observation

Avelumab q2w

Chemotherapy Maintenance

Chemotherapy

+ Avelumab q3w Avelumab q2w

R

A

N

D

O

M

I

Z

A

T

I

O

N

Arm A

Arm B

Arm C

Primary Endpoint: PFS

Secondary Endpoints: Maintenance PFS, OS, ORR, duration of response, pCR, PROs, safety, PK

Randomized Phase III Study (NCT02718417)

Chemotherapy

Chemotherapy

n = ~951

Rationale for Combining Cancer Immunotherapy With Anti-VEGF

VEGF

Inhibits T-cell function

Binds to VEGFR2 on T cells1

Kills T cells by tumor endothelium-produced FasL2

Stimulates

immunosuppressive

regulatory T cells2

Inhibits dendritic cell function Drives them into an immature state3

Reduces lymphocyte

adhesion to vessel walls Decreases immune-cell recruitment to the tumor site4

Induces abnormal tumor

vasculature Reducing T-cell trafficking and infiltration into the tumor bed5,6

VEGF(R), vascular endothelial growth factor (receptor)

1. Gavalas NG, et al. Br J Cancer. 2012;107(11):1869-1875. 2. Terme M, et al. Cancer Res. 2013;73(2):539-549. 3. Coukos G, et al. Br J Cancer.

2005;92(7):1182-1187 4. Bouzin C, et al. J Immunol. 2007;178(3):1505-1511. 5. Shrimali RK, et al. Cancer Res. 2010;70(15):6171-6180. 6. Chen DS, et al.

Immunity. 2013;39(1):1-10.

Immunosuppressive Reduce TILs

Pre-clinical data for combining anti-PDL1 and VEGF blockade

Irving. 1st Annual Expert Forum on Immuno-oncology, 2013

Tum

our

volu

me (

mm

3)

1500

1000

0

2000

500

30 20 0 40 10 50 Day

anti-VEGF

anti-PDL1

Control

anti-PDL1 +

anti-VEGF

Combined treatment with

these two agents

synergistically inhibited

tumour growth in the

Cloudman mouse tumour

model

NRG-GY009: PLD With Atezolizumab and/or Bevacizumab in Platinum-Resistant Recurrent OC

1:1:1

Enrollment Criteria

• Recurrent, platinum-resistant OC

• High-grade OC

• ≤2 prior regimens

• Measurable disease

• ECOG PS 0 or 1

• Mandatory submission of tumor tissue samples

Arm A

PLD + atezolizumab

Arm C

PLD + bevacizumab

R

A

N

D

O

M

I

Z

A

T

I

O

N

Randomized Phase II/III Study (NCT02839707)

Secondary Endpoints:

n = ~488

DLT, OS, PFS

Arm B

PLD + atezolizumab +

bevacizumab

ORR, safety

• ARM A: Patients receive PLD IV on day 1 and atezolizumab IV on days 1 and 8

• ARM B: Patients receive PLD IV on day 1, bevacizumab IV on days 1 and 8, and atezolizumab IV on days 1 and 8

• ARM C: Patients receive PLD IV on day 1 and bevacizumab IV on days 1 and 8

• In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity

Primary Endpoint:

Primary

endpoint:

PFS

ATALANTE Study Design

n = ~1350

IMagyn050: Study Design in Primary Cohort

The Next Future in Ovarian Cancer

Genomic Instability Increases Immunogenicity

DNA repair

defect

Increased

mutation

burden

Increased

neoantigens

Increased

activity of

checkpoint

inhibitors

Demonstrated

for others tumors (MSI)

Suggested for

ovarian cancer

1. Gatalica Z, et al. J Clin Oncol. 2015;33(suppl): Abstract 3597. 2. Turner N, et al. Nat Rev Cancer. 2004;4(10):814-819. 3. Cancer Genome Atlas Research

Network. Nature. 2011;474(7353):609-615. 4. Snyder A, et al. N Engl J Med. 2014;371(23):2189-2199. 5. Strickland KC et al. J Clin Oncol. 2015;33(suppl).

Abstract 5512.

Anti-PD-L1 and PARPi Synergy In Vivo

Robillard L, et al. Cancer Res. 2017;77(13 Suppl): Abstract 3650.

Durvalumab with olaparib or cediranib

Modest response rate

Prolonged therapy in some patients

Ovarian Cancer

10/12 (83%) D +O

9/14 (64%) D+C

Lee J-M et al J Clin Oncol 2017

TOPACIO- niraparib and pembrolizumab

Konstantinopoulos et al ESMO 2017

Percentage change in lesion size in (A) Recurrent Ovarian (B) TNBC

March 30 - April 2, 2014

Sheraton Sonoma County

Petaluma, California

Select trials combining PARP-I with immune checkpoint inhibitors

NCT02657889

TOPACIO/

keynote 162

NCT02484404 NCT02571725 NCT02485990 NCT02734004

MEDIOLA NCT03101280

Population

Advanced

TNBC or

recurrent

ovarian cancer

Advanced solid

tumor or

recurrent ovarian

cancer

Recurrent

BRCAm ovarian

cancer

Recurrent/

persistent ovarian

cancer

Advanced solid

tumors included

gBRCAm ovarian

cancer

Part I.

Advanced gyn

cancers

Part II:

Plat-sensitive

ovarian cancer

Design Phase I-II Phase I-II Phase I/II Phase I PhaseI/II Phase I

Regimen Niraparib +

pembrolizumab

Durvalumab +

cediranib or

olaparib

Olaparib +

Tremelimumab

Tremelimumab +/-

olaparib

Olaparib +

Durvalumab

Rucaparib +

atezolizumab

End point DLT/RR Recommeded

dose/ORR

Recommeded

dose/ORR Safety

Disease control

rate

Safety

Safety

Several front-line trials planned !!!

In Preparation

First-line and second-line combinations

with PARPi and anti-PD-L1/PD1

Conclusions

Ovarian cancer is a good candidate for immunotherapy

Correlation between immune microenvironment and clinical outcomes

observed

Clinical trials with immune checkpoint inhibitors in ovarian cancer have demonstrated limited efficacy (~10-15% ORR) but some patients have prolonged stabilisation of disease

Rationale for combining immune checkpoint inhibitors with chemotherapy, bevacizumab and PARP inhibitors

The wave of immune checkpoint inhibitors has reached GYN oncology and is stimulating many phase II/III trials, despite the absence of results with single-agent therapy from larger trials

Development of predictive biomarkers is critical to optimizing patient selection and treatment outcomes