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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