Le terapie a bersaglio molecolare nel carcinoma ovarico Napoli 20 Maggio 2016 Le terapie a bersaglio molecolare nel carcinoma ovarico Sandro Pignata Direttore Dip Uro Ginecologico Istituto Tumori di Napoli

Carcinoma ovarico 4800 nuovi casi nel 2015 in Italia 3251 decessi nel 2012 80 % III e IV stadi 20 % I e II stadi

Perché questa malattia è così letale? E’ impossibile la diagnosi precoce (eccetto che nelle pazienti BRCA mutate) I numerosi trattamenti disponibili hanno ritardato la progressione ma non ridotto la mortalità I farmaci biologici sono arrivati con ritardo a causa di una biologia estremamente complessa

OC subtypes: mutations 70 % 5% 2% 20% 5% Romero I et al. Endocrinology 2012; 153: 1593-1602

Low grade serous: Response to chemo Sources: Gonzalez-Martin et al. Ann Oncol 2005; Kushner et al. J Clin Oncol 2004; Mutch et al. J Clin Oncol 2007; Abushahin et al. J Clin Oncol 2006; Gershenson et al. Gynecol Oncol 2009 *75% received 1-2 prior chemo regimens

RAS/RAF Pathway nei LGSOC LGSOC frequent mutations in RAS/RAF. 40 -60% LGSOC KRAS or BRAF mutated Never LGSOC with both KRAS and BRAF BRAF decrease in advanced stages. Sources: a Singer et al. J Nat Canc Inst 2003; b Wong et al. Amer J Path 2010; c Grisham et al. Cancer 2012; d Jones et al. J Pathol 2012; e Farley et al. Lancet Oncol 2013

MEK Inhibitor in Low Grade Serous Ovarian Cancer Phase 3 trials: MILO MEK Inhibitor in Low Grade Serous Ovarian Cancer

High grade serous: The Post Genome Era Table of Contents 16 February 2001 Volume 291 Number 5507 The Human Genome

Molecula subtypes The Cancer Genome Atlas Research Network, Nature. 2011 Jun 29;474(7353):609-15

Serous Ovarian Cancer is a disease of DNA repair abnormalities and resulting ‘ “genomic instability” Subsets of high grade serous OC do not exist? Tumor can adapt rapidly may not be be able to be treated with “targeted agents” TKIs, antibodies etc May not be “predictable.”

Personalized medicine: angiogenesis

GOG-0218: Schema Arm I II III R A N D O M I S E Carboplatin (C) AUC 6 I Front-line: epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV N=1873 R A N D O M I S E Paclitaxel (P) 175 mg/m2 (CP) Placebo 1:1:1 Carboplatin (C) AUC 6 II Paclitaxel (P) 175 mg/m2 (CP + Bev) Bev 15 mg/kg Placebo Carboplatin (C) AUC 6 III Stratification variables GOG performance status Stage/debulking status Paclitaxel (P) 175 mg/m2 (CP + Bev  Bev) Bevacizumab 15 mg/kg 15 months OV = ovarian; PP = primary peritoneal FT = fallopian tube; Bev = bevacizumab Burger et al. ASCO 2010 15

GOG-0218: Investigator-Assessed PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 10.7 vs 11.2 vs 14.1 months p<0,0001 Proportion surviving progression free CP (Arm I) + BEV (Arm II) ap-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) 0 12 24 36 Months since randomization ASCO 2010 16

Edinburgh dataset; unsupervised hierarchical clustering Presented by:

Inferior OS in immune subgroup receiving bevacizumab OUTCOME OF “IMMUNE” AND “PRO-ANGIOGENIC” GROUPS OF OVARIAN CANCER IN ICON 7 Control arm ICON7 Immune and pro-angiogenic groups BEVACIZUMAB Adverse effect on PFS in the immune subgroup Benefit in pro-angiogenic group BEVACIZUMAB Adverse effect on OS in the immune subgroup Benefit in pro-angiogenic group Inferior OS in immune subgroup receiving bevacizumab Gourley et al, ASCO 2015.

MITO 16/MANGO OV2 project: Translational Project Chemotherapy associated genes Angiogenesis-related genes miRNA-machinery-related genes APE1, ERCC1, hMLH1,hMSH2 hOGG 1, RAD51 XPD,XRCC1 XRCC3,CYP3A4 CYP3A5, CYP1B1 CYP2C8, GSTM1 GSTT1, GSTM3 GSTP1, ABCG2 ABCC2, ABCB1 VEGF-A,VEGF-B VEGF-C,VEGF-D VEGF-E,VEGF-F IGF-1, IGF-2, IGFR-1,PIGF VEGF-R1, VEGF-R2, VEGF-R3,PGF PDGFa, PDGFb PDGFc,PDGFRa PDGFRb, NRP1 HLFB,HIF1α ADAR, Argonaute1 (EIF2C1), Argonaute 2 (EIF2C2), Argonaute4 (EIF2C4), CNOT1 (o NOT1), CNOT2 (o NOT2), CNOT3(o NOT3), CNOT4 (o NOT4), CNOT6 (o CCR4), DGCR8 (o Pasha),Dicer, EDC4 (oHEDLS/Ge-1), FMRP, GEMIN3 (o DDX20), GEMIN4, GEMIN5,HIWI,hnRNP-A1, LSM4, MOV10,p68 (DDX5 DEAD),POLR2A, Ran,RNASEN (Drosha), SMAD1, SMAD2 SMAD3, SMAD5, SND1 (o Tudor-SN), TNRC6A (o GW182), TNRC6B TRBP, TUT4, XPO5 (exportin-5)

Angiogenesis No predictive biomarker No biomarker for resistance All patients treated

Personalized medicine: BRCA

Study 19: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer 0.6 0.8 0.9 0.1 0.2 0.3 0.4 0.5 0.7 1.0 3 6 9 12 15 18 Probability of progression-free survival Time from randomization (months) Primary analysis (58% maturity; n=154/265) PFS HR=0.35 (95% CI, 0.25–0.49) P<0.00001 Randomized treatment* Placebo (n=129) Olaparib 400 mg bd monotherapy (n=136) Interim OS analysis (38% maturity): HR=0.94; 95% CI, 0.63–1.39; P=0.75 Ledermann J et al. N Engl J Med 2012;366:1382–1392

PFS by BRCA mutation status BRCAm (n=136) Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) Median PFS, months 11.2 4.3 HR=0.18 95% CI (0.11, 0.31); P<0.00001 1.0 0.9 0.8 0.7 0.6 Proportion of patients progression-free 0.5 0.4 0.3 Olaparib BRCAm 0.2 Placebo BRCAm 0.1 3 6 9 12 15 Time from randomization (months) Number at risk Olaparib BRCAm 74 59 33 14 4 Placebo BRCAm 62 35 13 2 82% reduction in risk of disease progression or death with olaparib Ledermann JA et al . J Clin Oncol 2013;31(15S); abstr 5505

Study 19: Time to second subsequent therapy BRCAm (n=136) Olaparib Placebo Events: total pts (%) 42:74 (57%) 49:62 (79%) Median TSST, months 23.8 15.2 HR=0.44 95% CI: 0.29, 0.67; p<0.00013 1.0 0.9 0.8 0.7 0.6 Proportion of patients receiving study treatment or first subsequent therapy 0.5 0.4 0.3 Olaparib BRCAm 0.2 Placebo BRCAm The risk of time to second subsequent therapy or death was significantly reduced in the olaparib group compared with placebo (median 23.8 vs 15.3 months; HR=0.46; 95% CI: 0.30, 0.70; p=0.00027) This suggested that in patients with BRAC mutated ovarian cancer the treatment benefit provided by olaparib maintenance treatment in prolonging PFS (and TDT and TFST) is maintained when patients continue onto a subsequent therapy 0.1 5 10 15 20 25 30 35 40 45 Time from randomisation (months) Number at risk Olaparib BRCAm 74 70 65 50 38 33 30 23 9 Placebo BRCAm 62 60 46 31 21 18 11 9 2 Ledermann J et al. Lancet Oncol 2014 A uso esclusivo Medical Affairs – riservato – non promozionale AstraZeneca raccomanda l'uso dei propri prodotti secondo il Riassunto delle Caratteristiche di prodotto

Solo 1 Olaparib Carbo-taxolo Placebo Studio multicentrico di Fase III, randomizzato, in doppio cieco, controllato con placebo, per valutare il trattamento di mantenimento con Olaparib in monoterapia dopo una prima linea di chemioterapia a base di platino in pazienti con carcinoma ovarico in stadio avanzato (stadio FIGO III-IV) e mutazione del gene BRCA

PAOLA1 Platine, Avastin and OLAparib in 1st line of advanced high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer   Randomized, Double-blind, Phase III Trial of olaparib vs. placebo in combination with bevacizumab in women following first-line chemotherapy plus bevacizumab for advanced high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer

BRCA PARP inhibitors More patients tested for BRCA mutation Useful for selecting chemotherapy All old trials should be revised?

BRCAness and genetic instability

PARP Inhibition in HRD deficient

61 % response rate in platinum sensitive BRCA mut 32 % response rate in High LOH 8% response rate in Low LOH Rucaparib Ariel 3

Stroma Islet CD3+ TIL Present 55% TIL Absent 40% Zhang, et al. N Engl J Med 2003

CD8 T -lymphocytes in Ovarian Cancer Intratumoral T cells Intratumoral T cells No intratumoral T cells No intratumoral T cells Zhang, Conejo-Garcia, Katsaros, Gimotty, Massobrio, Regnani, Makrigiannakis, Gray, Schlienger, Liebman, Rubin, Coukos. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003

Clinical Efficacy of Nivolumab in Platinum-resistant Ovarian Cancer Response by Recist Among the 18 patients shown on this waterfall blot, 2 had a complete response, one partial response and 5 stable disease providing an overall disease control rate of 44 %, an impressive clinical outcome in this highly platinum resistant ovarian cancer population. How does this compare to Nivolumab in melanoma? Hamanishi, ASCO 2014 38

AVELUMAB and OC Response by subgroup

PEMBROLIZUMAB and OC CHANGE FROM BASELINE IN TUMOR SIZE A. Varga, S. et al JCO ASCO Annual Meeting 2015

Tumor infiltrating and peritumoral T cells and expression of PD-L1 in BRCA1/2-mutated high grade serous OC These findings support trials of immune-checkpoint inhibitors targeting the PD1/PDL1 pathway in BRCA1/2-mutated OC An elevated number of CD3+ and CD8+ in BRCA1/2-mutated OC may provide an additional explanation for the improved clinical outcomes associated with these mutations

Conclusions Ovarian cancer is a heterogenous disease. BRCA Serous cancers have genomic instability. Integration of genomics and clinical biomarkers for prognosis and treatment. Personalized medicine and immunotherapy is coming?