antonio gonzález martín medical oncologydepartment · bookman, m. a. et al. j clin oncol 2009 60%...
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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