Immunoterapia: carcinoma ovarico. Nicoletta Colombo University Of Milan-Bicocca European Institute of Oncology, Milan

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1 Immunoterapia: carcinoma ovarico Nicoletta Colombo University Of Milan-Bicocca European Institute of Oncology, Milan

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

3 Overall Survival (%) 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 tumorreactive T cells and antibodies The presence of intratumoural T cells is associated with better clinical outcome P<0.001 Intratumoral T cells No intratumoral T cells Month 1. Turner TB et al. Gynecol Oncol. 2016;142: Coukos G et al. Ann Oncol. 2016;27(suppl 1):i11-i Mandai M et al. Int J Clin Oncol. 2016;21: Zhang L et al. N Engl J Med. 2003;348:

4 The correlation between TILs and survival is supported by multiple clinical studies in OC Study or Subgroup Log [HR] SE Weight (%) Test for overall effect: p< CI, confidence interval; HR, hazard ratio; OC, ovarian cancer; SE, standard error; TILs, tumour-infiltrating lymphocytes HR [95% Cl] Zhang (2003) [ ] Sato (2005) [ ] Hamanishi (2007) [ ] Callahan (2008) [ ] Han (2008) [ ] Tomsova (2008) [ ] Adams (2009) [ ] Clarke (2009) [ ] Leffers (2009) [ ] Stumpf (2009) [ ] Total (95% Cl) [ ] Independent of tumour grade, stage or histologic subtype 1 TILs favour death HR [95% Cl] TILs favour survival Hwang et al. Gynecol Oncol 2012

5 Survival Other 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) T reg in ovarian cancer P< Low Medium High Months Curiel TJ et al. Nat Med. 2004; 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 Wei S et al. Cancer Res. 2005;. 7. Labidi-Galy SI et al. Cancer Res Kryczek I et al. Cancer Res Zhang QW et al. PLoS One Ray-Coquard I et al. Cancer Res. 2009;

6 What factors contribute to ovarian immunogenicity? HGOC: A Disease With High Copy Number and Genomic Instability High Mutation Rate Genomic instability increases TIL infiltration High Copy number Cirello G, et al. Nat Genet. 2013;45(10): Leary A, et al. Ann Oncol. 2017;29(Suppl 5): Abstract 948P.

7 CD8+ TILs Expressing PD-1 Are Increased in BRCA1/2 Ovarian Cancer CD8+ PD-1 P =.003 P =.005 P =.0024 Strickland K, et al. J Clin Oncol. 2015;33(suppl): Abstract 5512.

8 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):

9 Role of PDL-1 in ovarian cancer Intraepithelial TILs Define a Specific Class of Patients TIL-rich 50% TIL-poor 50% PD-L1 correlates with TILs PD-L1 expression >50% of advanced stages Deurloo R, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 950P.

10 Overall Survival PFS Higher PD-L1 Expression Is Associated With Poorer Prognosis in ovarian cancer PD-L1 low PD-L1 low p = PD-L1 high Years After Operation p = PD-L1 high Years After Operation 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, [0.011] 2.57, [0.027] PD-L1 was an independent poor prognostic factor for both OS and PFS.Hamanishi J et al. Proc Natl Acad Sci USA. 2007;104:

11 The rationale for targeting PD-L1 in OC OC is associated with mutational burden 1 5 Tumour mutations increase tumourspecific antigens 6 >50% of OC tumours show TILs at diagnosis 7 Increased expression of immune checkpoint modulators (PD-L1 and PD-1) 8 9 as a potential mechanism of resistance Anti-PDL1 or anti-pd1 Immunosuppressive tumour microenvironment Improved OC outcomes? OC, ovarian cancer; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TILs, tumour-infiltrating lymphocytes 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 Rooij et al. J Clin Oncol 2013; 6. Strickland et al. ASCO Zhang et al. N Eng J Med 2003; 8. Hamanishi et al. PNAS Abiko et al. Clin Cancer Res 2013

12 Immune Checkpoint Inhibitors in OC Nivolumab 1 Pembrolizumab Keynote 28 2 Avelumab 3 Atezolizumab 4 Durvalumab 5 N * Prior therapies PD-L1+ prevalence Overall Response Rate Duration 4: 55% 5: 38.5% 3: 65.3% 6: 58% Median: 4* 80% (IC 2/3) 100% ( 1% TC) 77% ( 1% TC) 83% (IC 2/3) >5% TC: 73% (11/15)* 15% 11.5% 9.7% 25% Not reported 4 (20%) > 24 wks 7 (30%) > 24 wks 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): Varga A, et al. J Clin Oncol. 2015;33(suppl): Abstract Disis ML, et al. J Clin Oncol. 2016;34(suppl): Abstract 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.

13 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 N=124 Treatment Avelumab (10 mg/kg) by IV Q2W until disease progression, unacceptable toxicity, or other criteria for withdrawal 3 prior therapies: 65.3% 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 Primary Endpoint Secondary Endpoint Safety 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 Abstract 5533.

14 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.

15 KEYNOTE-028: Multicohort Phase Ib Trial of Pembrolizumab (Anti-PD-1): Efficacy Antitumoral activity Patients (n = 26) Best response n % IC 95 Response rate CR PR SD PD DCR 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.

16 Change in Target Lesions From Baseline (%) Best Overall Response with Nivolumab in Platinum- Resistant Advanced ovarian cancer 150 PD 1 mg/kg (n=10) 3 mg/kg (n=10) PD PD PD PD PD PD SD SD PD PD SD SD SD NE PD PR SD CR CR 15% ORR (3 of 20 patients) Median PFS=3.5 months, median OS=20.0 months for pooled cohort Hamanishi J et al. J Clin Oncol. 2015;33(34):

17 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%) 2 cases with a CR Hamanishi J, et al. J Clin Oncol. 2015;33(34):

18 Change in Target Lesions From Baseline (%) Best Overall Response With Nivolumab in ovarian cancer mg/kg (n=10) 3 mg/kg (n=10) PR SD CR CR Time (days) 15% ORR (3 of 20 patients) Median PFS=3.5 months, median OS=20.0 months for pooled cohort Hamanishi J et al. J Clin Oncol. 2015;33(34):

19 Phase Ib Trial of Atezolizumab (Anti-PD-L1) 83% of tumor specimens were PD-L1+ 25% (2/8) ORR in IC 2/3 patients Bendell JC, et al. J Clin Oncol. 2016;34(suppl): Abstract 3502.

20 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

21 Searching for Rational Combinations Combination With Chemotherapy

22 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.

23 Chemotherapy Increases release of tumor antigens Increases TIL and PD-L1 expression Mesnage S, et al. Ann Oncol. 2017;28(3):

24 Immunogenic Cell Death Inducers Drug Bleomycin Bortezomib Cyclophosphamide Doxorubicin Epirubicin Idarubicin Mitoxantrone Oxaliplatin Indications Cervical cancer, HNSCC, lymphoma, penile cancer, testicular cancer Mantle cell lymphoma, multiple myeloma Breast cancer, leukemia, lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, retinoblastoma ALL, AML, bladder cancer, bone sarcoma, breast cancer, gastric cancer, lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, SCLC, soft tissue sarcoma, thyroid cancer, Wilms tumor Breast cancer AML AML, breast cancer, NHL, prostate cancer 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):e

25 Synergistic Antitumor Responses of Pegylated Liposomal Doxorubicin and Anti-PD-1 Complete response was achieved in more colon cancer mouse models treated with both PLD and anti-pd-1 compared to single agents CR, complete response; PLD, pegylated liposomal doxorubicin Rios-Doria J, et al. Neoplasia. 2015;17:

26 JAVELIN 200 Avelumab in Platinum-Resistant/Refractory OC Randomized Phase III Study (NCT ) 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 n = ~550 R A N D O M I Z A T I O N 1:1:1 Arm A Avelumab Arm B PLD + Avelumab Arm C Pegylated Liposomal Doxorubicin (PLD) Stratification: P6 refractory vs resistant, number of prior therapies, bulky disease Primary Endpoint: Coprimary OS and PFS Secondary Endpoints: ORR, duration of response, PROs, safety ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PROs, patient-reported outcomes

27 Alteration of the immunological landscape Combining immune checkpoint inhibitors with chemotherapy Emens and Middleton Cancer Immunol Res 2015

28 Immunotherapy is Moving As First-Line

29 JAVELIN Ovarian 100: Avelumab + Platinum Combo (Frontline) Randomized Phase III Study (NCT ) Enrollment Criteria Previously untreated Stage III-IV Prior debulking surgery or plan for neoadjuvant chemotherapy ECOG PS 0 or 1 Mandatory archival tissue n = ~951 R A N D O M I Z A T I O N 1:1:1 Arm A Arm B Arm C Chemotherapy Chemotherapy Chemotherapy Chemotherapy + Avelumab q3w Maintenance Observation Avelumab q2w Avelumab q2w Primary Endpoint: PFS Secondary Endpoints: Maintenance PFS, OS, ORR, duration of response, pcr, PROs, safety, PK 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

30 Rationale for Combining Cancer Immunotherapy With Anti-VEGF Reduce TILs Immunosuppressive Induces abnormal tumor vasculature Reducing T-cell trafficking and infiltration into the tumor bed 5,6 Reduces lymphocyte adhesion to vessel walls Decreases immune-cell recruitment to the tumor site 4 VEGF Inhibits T-cell function Binds to VEGFR2 on T cells 1 Kills T cells by tumor endothelium-produced FasL 2 Stimulates immunosuppressive regulatory T cells 2 Inhibits dendritic cell function Drives them into an immature state 3 VEGF(R), vascular endothelial growth factor (receptor) 1. Gavalas NG, et al. Br J Cancer. 2012;107(11): Terme M, et al. Cancer Res. 2013;73(2): Coukos G, et al. Br J Cancer. 2005;92(7): Bouzin C, et al. J Immunol. 2007;178(3): Shrimali RK, et al. Cancer Res. 2010;70(15): Chen DS, et al. Immunity. 2013;39(1):1-10.

31 Pre-clinical data for combining anti-pdl1 and VEGF blockade Tumour volume (mm 3 ) 2000 anti-pdl1 Combined treatment with these two agents synergistically inhibited tumour growth in the Cloudman mouse tumour model Control anti-vegf anti-pdl1 + anti-vegf Day Irving. 1 st Annual Expert Forum on Immuno-oncology, 2013

32 NRG-GY009: PLD With Atezolizumab and/or Bevacizumab in Platinum-Resistant Recurrent OC Enrollment Criteria Recurrent, platinum-resistant OC High-grade OC 2 prior regimens Measurable disease ECOG PS 0 or 1 Randomized Phase II/III Study (NCT ) Mandatory submission of tumor tissue samples Primary Endpoint: Secondary Endpoints: DLT, OS, PFS ORR, safety R A N D O M I Z A T I O N 1:1:1 Arm A PLD + atezolizumab Arm C PLD + bevacizumab n = ~488 Arm B PLD + atezolizumab + bevacizumab 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

33 ATALANTE Study Design Primary endpoint: PFS

34 IMagyn050: Study Design in Primary Cohort n = ~1350

35 The Next Future in Ovarian Cancer

36 1. Gatalica Z, et al. J Clin Oncol. 2015;33(suppl): Abstract Turner N, et al. Nat Rev Cancer. 2004;4(10): Cancer Genome Atlas Research Network. Nature. 2011;474(7353): Snyder A, et al. N Engl J Med. 2014;371(23): Strickland KC et al. J Clin Oncol. 2015;33(suppl). Abstract 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

37 Anti-PD-L1 and PARPi Synergy In Vivo Robillard L, et al. Cancer Res. 2017;77(13 Suppl): Abstract 3650.

38 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

39 TOPACIO- niraparib and pembrolizumab Percentage change in lesion size in (A) Recurrent Ovarian (B) TNBC Konstantinopoulos et al ESMO 2017

40 Population Select trials combining PARP-I with immune checkpoint inhibitors March 30 - April 2, 2014 Sheraton Sonoma County Petaluma, California NCT TOPACIO/ keynote 162 Advanced TNBC or recurrent ovarian cancer NCT NCT NCT Advanced solid tumor or recurrent ovarian cancer Recurrent BRCAm ovarian cancer Recurrent/ persistent ovarian cancer NCT MEDIOLA Advanced solid tumors included gbrcam ovarian cancer Several front-line trials planned!!! NCT 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

41 In Preparation First-line and second-line combinations with PARPi and anti-pd-l1/pd1

42 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 singleagent therapy from larger trials Development of predictive biomarkers is critical to optimizing patient selection and treatment outcomes