Updated Results of ARIEL2, a Phase 2 Open-Label Study to Identify Ovarian Cancer Patients Likely to Respond to Rucaparib Abstract 0211 BACKGROUND − Clovis Oncology and Foundation Medicine have partnered to develop an NGS-based HRD test to identify such patients • The ARIEL program aims to identify tumor genetic characteristics predictive of rucaparib response using a novel translational-clinical approach In Study CO-338-010, rucaparib demonstrated robust clinical activity in platinum-sensitive OC patients with gBRCA1/2 mutations BRCA mutations and BRCAness lead to the same phenotype Homologous recombination: genetic defects BRCA – 85% RECIST/CA-125 response rate – 88% disease control rate at 24 weeks Overall response rates, n/N (%) Other homologous recombination defects Non-BRCA HR pathway Gene expression miRNA Disease control rates, n/N (%) RECIST CR, PR or SD >24 weeks 15/20 (75%) 18/20 (90%) 15/17 (88%)* BRCAness causes HRD, resulting in genomewide LOH that can be quantified by NGS Translocations Amplifications • Rucaparib is well tolerated at the recommended Phase 2 dose (600 mg BID) – The most frequent adverse events (AEs) are primarily mild to moderate and include gastrointestinal toxicities, fatigue/asthenia, AST/ALT elevation, and myelosuppression – AEs are manageable and no patients have discontinued due to an AE LOH 14% BRCA1 germline 100 The rucaparib-sensitive population is defined as patients whose tumors have BRCA mutations or BRCAness Predicted to be rucaparib-sensitive Change from baseline (%) Predicted to be rucaparib-resistant 0 -20 -40 -60 The ARIEL program is designed to prospectively identify rucaparib-sensitive patients -100 In Study CO-338-010, CA-125 decreased by >50% in 93% of patients with elevated CA-125 (>70 U/mL) at baseline Foundation Medicine has developed a computational method for predicting germline vs. somatic variant status from NGS of tumor tissue without a matched normal control (Sun et al. AACR 2014) • High-grade, platinum-sensitive, relapsed ovarian cancer (≥1 prior platinum-based regimen) Lock down HRD test • Progression-free survival (PFS) in HRD subgroups • In ARIEL2, approximately two-thirds of patient tumors had either a tBRCA1/2 mutation (germline or somatic) or exhibited BRCAness – these patients are predicted to benefit from rucaparib treatment • ARIEL2 clinical outcome data will be presented on November 20, 2014 at the 26th EORTC-NCIAACR Symposium on Molecular Targets and Cancer Therapeutics (Barcelona, Spain) • The HRD test developed from ARIEL2 will be prospectively applied to the primary PFS analysis of pivotal study ARIEL3 (NCT01968213) Phase 2 Study (ARIEL2) • Single-arm, rucaparib 600 mg BID • An HRD test that incorporates analyses of both tumor BRCA1/2 mutations and BRCAness may identify additional women with ovarian cancer who are likely to respond to rucaparib • Confirm pre-specified HRD signature to optimize definition of rucaparib-sensitive patients 100 80 Change from baseline (%) BRCA2 somatic SUMMARY 20 BRCA2 BRCA2 germline High-grade ovarian cancer Biomarker-negative 40 BRCA1 somatic 27% tBRCAMUT RECIST ORR = 75% 45% • Foundation Medicine’s NGS assay sequences BRCA1/2 genes in tumor • The assay also sequences single-nucleotide polymorphisms (SNPs) • SNP analysis identifies and quantifies genomic LOH In Study CO-338-010, target lesion regressions have been observed in 95% of patients BRCA1 Germline/somatic results from 29 tBRCA mutant patients Next-generation sequencing (NGS) BRCAness -80 Since the number of known gBRCAmut patients is capped in ARIEL2, the frequency of BRCA mutant cases identified in the tumor may not reflect the actual frequency in the overall high-grade ovarian cancer patient population In ARIEL2, tumor analysis identifies both germline and somatic BRCA1/2 mutations Normal chromosomes Mutations (eg, BRCA) Biomarker-negative 42% Deletions tBRCA mutant BRCAness HR deficiency Examples of DNA aberrations 25% 33% CR, complete response; PR, partial response; SD, stable disease *3 patients with SD have not reached 24 weeks 60 HRD analysis of tumors from 121 enrolled patients 14% CR, PR or SD >12 weeks 80 In ARIEL2, the majority of BRCA wild-type patient tumors exhibit BRCAness Methylation “BRCAness” • Impressive response and disease control rates 17/20 (85%) 1. Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; 2. The University of Texas MD Anderson Cancer Center, Houston, TX; 3. Princess Margaret Hospital, Toronto, Canada; 4. University of California, Los Angeles (UCLA), Los Angeles, CA; 5. The Ohio State University, James Cancer Center, Columbus, OH; 6. Flinders Medical Centre, Bedford Park, Australia; 7. Royal Melbourne Hospital, Melbourne, Australia; 8. Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain; 9. Institut Bergonié, Bordeaux, France; 10. St Jude Crosson Cancer Institute, Fullerton, CA; 11. Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; 12. Clovis Oncology, San Francisco, CA; 13. Clovis Oncology, Cambridge, UK; 14. Clovis Oncology, Boulder, CO; 15. Foundation Medicine Inc., Cambridge, MA; 16. University of Washington School of Medicine, Seattle, WA ARIEL PROGRAM OVERVIEW AND ARIEL2 PRELIMINARY RESULTS • Rucaparib, a potent oral PARP inhibitor (PARPi), has demonstrated activity in germline (g) BRCA1/2 ovarian cancer (OC) patients in the ongoing Clovis Study CO-338-010 (NCT01482715) • Predicting response to a PARPi beyond gBRCA1/2 mutation is currently challenging, and platinum sensitivity is a poor surrogate, with frequent false positives/negatives • Rucaparib may also be effective in tumors exhibiting "BRCAness" (ie, tumors with homologous recombination deficiency [HRD] due to mechanisms other than a BRCA1/2 mutation) • HRD related to a BRCA1/2 mutation or BRCAness leads to genomic loss of heterozygosity (LOH) that can be quantified in fixed tumor tissue using a next-generation sequencing (NGS) assay • Molecular analysis of tumor tissue to assess both germline and somatic BRCA1/2 mutations (tBRCAmut) and BRCAness could identify additional patients likely to respond to PARPi therapy RECIST and CA-125 Iain McNeish1, Robert L. Coleman2, Amit Oza3, Gottfried Konecny4, David M. O’Malley5, Ganessan Kichenadasse6, Clare L. Scott7, Ana Oaknin8, Anne Floquet9, David Park10, James D. Brenton11, Kevin Lin12, Sanjay Shetty12, Heidi Giordano12, Mitch Raponi12, Lindsey Rolfe13, Jeff Isaacson14, Roman Yelensky15, Andrew Allen12, and Elizabeth Swisher16 60 Test all ARIEL3 tumor samples; classify HRD status 40 20 0 Pivotal Study (ARIEL3) -20 -40 • High-grade, platinum-sensitive, relapsed ovarian cancer (≥2 prior platinum-based regimens; response to last platinum) -60 • Randomization (2:1), rucaparib vs. placebo -80 • Blinded treatment until progression by RECIST -100 • PFS in prospectively defined HRD subgroups 960.8 151.7 785 109 269.6 869 226 100.4 500.6 212.9 136 963 6149.6 6590 Final analysis Electronic copies of posters for other rucaparib studies can be accessed via the link below http://www.clovisoncology.com/productscompanion-diagnostics/scientific-presentations/ 3669.5 Baseline CA-125 (U/mL) Presented at the 15th Biennial Meeting of the International Gynecologic Cancer Society (IGCS), Melbourne, Australia, November 8-11, 2014 For more information on the ARIEL studies, please visit: www.arielstudy.com or contact Clovis Oncology Medical Information at: [email protected]