Influence of Molecular Pathology on Ovarian Cancer Treatment Now and - PowerPoint PPT Presentation

Influence of Molecular Pathology on Ovarian Cancer Treatment Now and in the Future Charlie Gourley Professor of Medical Oncology University of Edinburgh Cancer Research Centre Edinburgh Cancer Research UK Centre MRC Institute of Genetics and Molecular Medicine www.igmm.ac.uk

Disclosures  Personal interests:  Roche, PharmaMar, Boehringer Ingelheim, Caris Life Sciences, Almac Diagnostics  Non-personal interests:  Roche, AstraZeneca, GlaxoSmithKline, Cyclacel

Ovarian cancer; standard first-line treatment  Maximal debulking surgery  6 cycles of carboplatin and paclitaxel chemotherapy  ‘One size fits all’ approach  Histological subtypes differ in response to chemotherapy, survival, genetics and tissue of origin

Which predictive biomarkers have made it into ‘standard’ practice?

Which predictive biomarkers have made it into ‘standard’ practice? 1. Histological subtype Kurman and Shih, Human Pathol 2011

Which predictive biomarkers have made it into ‘standard’ practice? 1. Histological subtype 2. ER expression Bowman et al, 2001 Smyth et al, 2007

Influence of molecular pathology on ovarian cancer clinical research 1) Biological agents in early development which have a defined target (patients selected on basis of molecular test) 2) Biological agents in later development which have a defined MOA but for whom the selection criteria remain unclear 3) Licensed agent(s) currently given to all patients but for whom the ability to select patients would be beneficial

Example 1 Low grade serous ovarian cancer

Low grade serous ovarian cancer • Often presents early in association with serous borderline tumour • Increased risk in patients with a history of endometriosis (HR 2.11, 1.39 – 3.20, p<0.0001) • Median/mean age: 43/45 years • Comprises 10 – 15% of serous carcinoma • For stage II – IV disease – median PFS: 19 months median OS: 81 months • Often calcified disease Gershenson D, et al. Gynecol Oncol 2009;114:48 – 52; Wong K-K, et al. Am J Pathol 2010;177:1611 – 7; Pearce CL, et al. Lancet Oncol 2012;13:385 – 94.

Systemic treatment of low-grade serous ovarian cancer: Retrospective data • Response to platinum-based chemotherapy: <5% • First line: 4% response, 88% disease stabilization 1 • Second line: 3.7% response, 60% disease stabilization 2 • Response to hormonal therapy: around 10% • Response to endocrine therapy: 9% in retrospective analysis 2 • ER+/PR+ had longer TTP than ER+/PR – (p=0.053, 64 patients) ER = oestrogen receptor; PR = progesterone receptor; TTP = time to progression. 1 Schmelet KD, et al. Gynecol Oncol 2008;108:510 – 4. 2 Gershenson D, et al. Gynecol Oncol 2009;114:48 – 52.

Mutation profile of low versus high grade serous ovarian cancer KRAS/BRAF/ERBB2 Mutation TP53 Mutation % % % % ERBB2 12 bp ins 75 75 75 75 75 75 75 75 BRAF BRAF BRAF BRAF BRAF BRAF 50 50 50 50 50 50 50 50 ? ? 25 25 25 25 25 25 25 25 KRAS KRAS KRAS KRAS KRAS KRAS SBT LG HG SBT LG HG SBT LG HG SBT = serous borderline tumours; LG = low grade; HG = high grade. Singer G, et al. J Natl Cancer Inst 2003;95:484 – 6; Singer G, et al. Am J Pathol 2002;160:1223 – 8; Nakayama K, et al. Cancer Biol Ther 2006;5:779 – 85.

cadherin ERRB2 mutations RTK b -catenin PI3K PTEN KRAS mutations AKT BRAF mutations b -catenin mTOR MEK b -catenin MAPK (ERK) cyclin E LEF/TCF cyclin D1 GLUT1 Progression Survival Proliferation TP53

Low grade with KRAS/BRAF mut more sensitive to MEKi in vitro than high grade Mutation status KRAS BRAF wt wt OSE wt wt Stroma wt mut MPSC1 mut wt OVPC-1 wt mut SBT/LG OVPC-2 mut wt OVPC-3 wt mut OVPC-4 wt wt OVPC-5 wt wt OVPC-6 wt wt OVPC-7 wt wt OVPC-8 HG wt wt CAOV3 wt wt SKOV3 wt wt OVCAR3 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 Cell number (% of DMSO controls) Pohl lG, et al. Cancer Res 2005;65:1994 – 2000.

GOG 239 study • Phase II study of MEK inhibitor AZD 6244, (selumetinib) 100 mg b.i.d. • 52 patients • Primary endpoint: response rate • Heavily pretreated (58% at least 3 prior treatment regimens) • 15% response rate, 65% stable disease • Median PFS: 11 months • 6% BRAF, 41% KRAS, 15% NRAS mutations • No correlation of mutation status with response Farley et al, Lancet Oncol 2013 Farley J, et al. Int J Gynecol Cancer 2011;21(Suppl. 3):S38 (Abstract).

LOGS study • Randomized 2-arm Phase II/III of MEK inhibitor trametinib vs control in relapsed low-grade serous ovarian cancer • Control arm nominated prior to randomization • Weekly paclitaxel • Pegylated liposomal doxorubicin • Weekly topotecan • Letrozole • Tamoxifen • 80 centres across USA and UK • 250 patients • Translational plans include NGS, gene expression microarray analysis, proteomics and optional biopsies at relapse (investigation of MEKi and hormonal sensitivity/resistance) CTAAC = Clinical Trials Advisory and Awards Committee

Example 2 PARP inhibition in the treatment of high grade serous ovarian cancer

Poly (ADP-Ribose) Polymerase (PARP)

PARP inhibition and tumour-selective synthetic lethality γ H2AX SSB PARPi DSB DNA replication fork arrest and collapse Normal HR repair RAD51 HR-based repair Chromosome stability Cell survival Slide provided with permission DSB, double-strand break; HR, homologous recombination; SSB, single-strand break; by Andrew Tutt Farmer H et al. Nature 2005;434:917 – 921; Bryant HE et al. Nature 2005;434:913 – 917

PARP inhibition and tumour-selective synthetic lethality γ H2AX SSB PARPi DSB DNA replication fork arrest and Impaired HR collapse Normal HR repair repair Alternative error-prone RAD51 repair HR-based repair Chromosome stability Chromosomal instability Cell survival Cell death DSB, double-strand break; HR, homologous recombination; SSB, single-strand break; Farmer H et al. Nature 2005;434:917 – 921; Bryant HE et al. Nature 2005;434:913 – 917

BRCA1 -/- and BRCA2 -/- cells are extremely sensitive to PARP inhibition BRCA2 +/+ BRCA1 +/+ BRCA2 +/- BRCA1 +/- BRCA1 -/- BRCA2 -/- No difference in sensitivity between heterozygous and wild-type BRCA cells Targeted inhibition  selective and less toxic therapy Farmer et al. Nature 2005; 434:917-21

• Non-toxic, oral therapy • Specifically active in BRCA1/2-deficient patients • 70% response rate in platinum sensitive patients • 44% response rate in platinum resistant patients • 18% response rate in platinum refractory patients • A number of patients remain in remission 36 months into treatment

Is it only BRCA1/2 germline mutation carriers who benefit from PARP inhibitors?

Is it only BRCA1/2 germline mutation carriers who benefit from PARP inhibitors? TCGA, Levine et al, Nature 2011

Study aim and design • To assess the efficacy of oral olaparib as a maintenance treatment in patients with platinum-sensitive high-grade serous ovarian cancer • Randomized, double-blind, placebo-controlled Phase II study • Multinational study; 82 sites in 16 countries Patient eligibility: • Platinum-sensitive high-grade serous ovarian cancer Olaparib •  2 previous platinum regimens 400 mg po bid • Last chemotherapy: platinum-based with a maintained Treatment response until disease Randomized 1:1 • Stable CA125 at trial entry progression • Randomization stratification factors: – Time to disease progression on penultimate Placebo platinum therapy po bid – Objective response to last platinum therapy Ledermann et – Ethnic descent al, ASCO 2011

Ledermann et al, NEJM, 2012 Progression-free survival Olaparib Placebo 1.0 60:136 (44.1) 93:129 (72.1) No. of events: Total patients (%) 0.9 Median PFS (months) 8.4 4.8 Proportion of patients 0.8 progression free Hazard ratio 0.35 (95% CI, 0.25 – 0.49) 0.7 P <0.00001 0.6 0.5 0.4 0.3 0.2 Randomized treatment Placebo 0.1 Olaparib 400 mg bid 0 0 3 6 9 12 15 18 Time from randomization (months) At risk (n) Olaparib 136 104 51 23 6 0 0 Placebo 129 72 23 7 1 0 0

Results: BRCA testing tBRCA Mutated Wild type* Not available TOTAL Mutated 71 3 22 96 gBRCA Wild type* 20 79 23 Not available 20 16 11 265 – 136 (51.3%) patients had a known deleterious BRCAm (BRCAm dataset) – 118 (44.5%) patients were defined as BRCA1/2 wild type for this analysis – 11 (4.2%) patients had neither a tumour nor a germline result available • The number of patients with a known BRCAm status increased from 97 (36.6%) to 254 (95.8%) out of 265 *Wild-type group includes patients with no known BRCAm or a mutation of unknown significance (a non-deleterious mutation) Presented by: Jonathan Ledermann

PFS by BRCAm status BRCAm (n=136) Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) 1.0 Median PFS, months 11.2 4.3 0.9 HR=0.18 Proportion of patients 0.8 95% CI (0.11, 0.31); progression-free P <0.00001 0.7 0.6 0.5 0.4 0.3 Olaparib BRCAm Placebo BRCAm 0.2 0.1 0 0 3 6 9 12 15 Time from randomization (months) Number at risk Olaparib BRCAm 74 59 33 14 4 0 Placebo BRCAm 62 35 13 2 0 0 • 82% reduction in risk of disease progression or death with olaparib Presented by: Jonathan Ledermann