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 tumour 1-4
– 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
outcome 4
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.
O v erall Surv iv al (% )
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 subtype
1Other Immune Factors Correlate With Poor Prognosis
• Presence of T regs in tumor 1-4
• Accumulation of plasmacytoid dendritic cells 5-7
• Presence of immunosuppressive macrophages expressing B7-H4 8,9
• Low level of circulating
lymphocytes (<1.0x10 9 /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;
Surv iv a 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
T reg 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
Ov er al l Su rv iv al
0.80.6 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 burden
1–5Tumour mutations increase tumour- specific antigens
6>50% of OC tumours show TILs at
diagnosis
7Improved OC outcomes?
Immunosuppressive tumour
microenvironment Anti-PDL1 or anti-PD1
Increased expression of immune checkpoint
modulators
(PD-L1 and PD-1)
8–9as a potential mechanism of
resistance
Nivolumab
1Pembrolizumab
Keynote 28
2Avelumab
3Atezolizumab
4Durvalumab
5N 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 % IC
95Response 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.
C h an g e in T ar g et L esi o n s F ro m B aseli n e (% )
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)
C h an g e in T ar g et L esi o n s F ro m B aseli n e (% )
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:
PFSSecondary Endpoints:
Maintenance PFS, OS, ORR, duration of response, pCR, PROs, safety, PKRandomized 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 cells
1Kills T cells by tumor
endothelium-produced FasL
2Stimulates
immunosuppressive regulatory T cells 2
Inhibits dendritic cell function
Drives them into an immature state
3Reduces lymphocyte
adhesion to vessel walls
Decreases immune-cell recruitment to the tumor site
4Induces abnormal tumor vasculature
Reducing T-cell trafficking and infiltration into the tumor bed
5,6VEGF(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. 1
stAnnual Expert Forum on Immuno-oncology, 2013
T umo ur vo lu me (mm
3)
1500
1000
0 2000
500
30 20
0 10 40 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