Clinical Development of Rucaparib Rucaparib is an investigational - PowerPoint PPT Presentation

Clinical Development of Rucaparib Rucaparib is an investigational product and not approved by any health authority. Conclusions about efficacy and safety cannot be made

Development of HRD/LOH Signature

Development Strategy ● Initial goal: Identify all rucaparib responsive patients using tumor DNA sequence data All Ovarian Cancer Patients ● Partnership with Foundation Medicine ● Conduct trials in all-comer populations, not just gBRCA mut ● Focus on ovarian cancer BRCA mut ● Initial hypothesis: HRD patients will respond to rucaparib − gBRCA mut - known HRD sBRCA mut - not known − BRCA WT but HRD (“BRCA - like”); not known − ● Key issue: Defining BRCA-like gBRCA mut = germline mutation sBRCA mut = somatic BRCA mutation BRCA WT = BRCA wild type HRD = homologous recombination deficient 3

PARP Inhibitors are Synthetically Lethal to BRCA mut and BRCA-Like Tumor Cells with Homologous Recombination Deficiency (HRD) HR is a complex process requiring coordinated function of many gene products P A Cell Cell R proficient survival P in HR PALB2 I N RAD51 H I B BRCA1/2 Cell I Cell deficient T death in HR O R Genetic and epigenetic dysregulation cause HRD, resulting in tumor tissue BRCA mut and BRCA -like tumors that are sensitive to PARP inhibitors HR, homologous recombination; HRD, HR-deficient; PALB2, partner and localizer of BRCA2; RAD51, homolog of the bacterial RecA protein. Kristeleit R, et al. ECC-ESMO 2015. Abstract 2700. 4 | Confidential

Loss of Heterozygosity (LOH) is a Marker of Genomic Scarring in HRD Ovarian Cancer ● Loss of heterozygosity (LOH) is a large-scale (Mbp) chromosomal event resulting in the loss of varying lengths of DNA that represents a phenotypic marker of Homologous Recombination Deficiency (HRD). ● Increased LOH correlates with BRCA mutation and platinum sensitivity in HGSOC ● LOH can be quantified by analysis of single nucleotide polymorphisms (SNPs) across the genome ● Clovis partnered with Foundation Medicine to develop a CoDx evaluating tumor genome-wide LOH and BRCA mutation status Normal chromosome pair (diploid) Chromosome pair with LOH SNP profile of normal: SNP profile of LOH : AAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAA BAABBBBBBBBBBBBBAABBB BBBBBBBBBBBBBBBBBBBBB LOH, loss of heterozygosity; NGS, next generation sequencing; SNP, single nucleotide polymorphism. Swisher E, et al. AACR 2014. Abstract CT339; McNeish I, et al. IGCS 2014. Abstract 0211. 5

Genome-Wide LOH Quantified by FoundationOne SNP NGS is employed for Prospective Patient Selection in ARIEL Studies ● TCGA and AOCS ovarian genomic data and overall survival data was used to develop LOH cutoff to prospectively identify HGSOC patients with a BRCA-like signature in ARIEL2 study BRCA mut Hypothesis 1 : Ovarian cancer patients with high genomic LOH BRCA-like suggesting BRCA-like signature will respond to rucaparib. BRCA wt Hypothesis 2 : Ovarian cancer patients who Biomarker are “Biomarker Negative” Negative (ie, with low genomic LOH) will not respond to rucaparib. NGS=next-generation sequencing; mut=mutation; wt=wild type. Kristeleit R et al. Presented at ECC-ESMO 2015. Abstract 2700. 6

HGSOC Patients can be Classified into Three Molecular Subgroups: BRCA mut , BRCA-like, Biomarker Negative BRCA wt Frequency of Tumors Biomarker BRCA-like Negative BRCA mut Genomic LOH cutoff Extent of Genomic LOH Kristeleit R et al. Presented at ECC-ESMO 2015. Abstract 2700 7

Summary ● BRCA -like phenotype considers the whole genomic signature of patients with ovarian cancer to predict treatment response to PARP inhibitors − HRD leads to LOH across the genome, the extent of which is used to define BRCA -like phenotype ● Clovis Oncology and Foundation Medicine have collaborated to develop an NGS-based HRD companion diagnostic test − This HRD test incorporating analyses of both tumor tissue BRCA mut and BRCA -like (in later version) signatures may identify additional patients with ovarian cancer who may be likely to respond to rucaparib ● The ARIEL clinical development program is underway and aims to identify and prospectively test the utility of the HRD diagnostic test in the treatment (ARIEL2) and maintenance (ARIEL3) settings NGS, next-generation sequencing. 8

Rucaparib Company-Sponsored Clinical Development Program Prostate Cancer Ovarian Cancer CO-338-010 ARIEL2/CO-338-017 ARIEL3/ ARIEL4 TRITON 2 TRITON 3 NCT01482715 NCT01891344 CO-338-014 Treatment Treatment Treatment Treatment setting Treatment setting NCT01968213 setting setting setting Maintenance setting Part 2 Part 3 Part 1 Part 1 Part 2 Phase I PK Dose escalation Any solid tumor 2A (Phase II) 2B (Phase II) Phase II Phase II Phase III Phase III Phase II Phase III • • • • • • • • Platinum sensitive Relapsed ovarian Development of Refinement of Randomized; Randomized; Metastatic Metastatic cancer (germline or HRD signature HRD signature blinded rucaparib rucaparib vs castrate-resistant castrate-resistant • Relapsed ovarian somatic BRCA mut ) (maintenance) chemotherapy prostate cancer prostate cancer • • cancer (germline Relapsed Relapsed vs placebo after • ≥3 prior • • • BRCA mut ) ovarian cancer ovarian cancer Confirmatory study Biomarker Biomarker response to chemotherapy selected selected platinum-based • 2 – 4 prior • • Platinum All comers regimens chemotherapy • • treatments sensitive >2 prior therapies Chemo-naïve, • ≥3 prior including AR- progression • Confirmatory study • All comers chemotherapy targeted and following one AR- (Known germline regimens • ≥2 prior platinum - taxane targeted therapy BRCA mut ) based treatments • Randomised: • >1 prior platinum- Rucaparib v based treatment chemotherapy or BRCA mut , BRCA mutant; HRD, homologous recombination deficiency; PK, pharmacokinetics; AR; androgen-receptor AR-targeted therapy 9

Investigator Initiated Trials (IIT’s) ● Clovis Oncology supports ethical, independent, investigator initiated research designed to advance scientific knowledge of the disease state, patient populations and medical treatments in alignment with Clovis Oncology’s clinical and non -clinical areas of interest as outlined in the previous slides. ● Clovis Oncology supports the funding of IIT’s with defined processes and governance measures in place, with independent investigators and co-operative groups. The IIT is conducted independently of Clovis Oncology with the following focus: -Identify all rucaparib responsive patients using tumor DNA sequence data -Conduct trials in all-comer populations, not just g BRCA mut -Company sponsored studies and supportive studies in ovarian and prostate cancer indications - Identify which Homologous Recombination Deficient (HRD) patients will respond to rucaparib and defining “ BRCA -like ” tumours -Identify combination therapies which may provide incremental patient benefit ● Approval of an IIT in a specific indication does not preclude other IIT proposals being considered in that indication provided there is strong clinical or non clinical rationale for the question, that has not already been addressed. Areas where IIT’s have been supported as of October 2016 include HER2 (-), BRCA mut or BRCA wt /LOH High breast cancer ; neoadjuvant triple ● negative breast cancer ; 1L maintenance oesophago-gastric and 1L maintenance ovarian cancer , Prostate cancer, Pancreatic cancer, Solid Tumour Basket studies, Mesothelioma and Radiotherapy Combinations. This list is being constantly updated as new proposals are received and reviewed and therefore is a snap shot view. Investigators should discuss proposals with Clovis Oncology when an IIT concept is being developed. 10

Clinical Activity of the Poly(ADP-Ribose) Polymerase (PARP) Inhibitor Rucaparib in Patients with High-Grade Ovarian Carcinoma and a BRCA Mutation: Analysis of Pooled Data from Study 10 (Parts 1, 2a, and 3) and ARIEL2 (Parts 1 and 2) Rebecca S. Kristeleit, 1 Ronnie Shapira-Frommer, 2 Ana Oaknin, 3 Judith Balmaña, 3 Isabelle Ray-Coquard, 4 Susan Domchek, 5 Anna V. Tinker, 6 Cesar Castro, 7 Stephen Welch, 8 Andres Poveda, 9 Kathy Bell-McGuinn, 10 Gottfried Konecny, 11 Heidi Giordano, 12 Lara Maloney, 12 Sandra Goble, 12 Lindsey Rolfe, 12 Amit M. Oza 13 1 University College London, Cancer Institute, London, UK; 2 Sheba Medical Center, Ramat Gan, Israel; 3 Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 4 GINECO, Centre Léon Bérard and University Claude Bernard, Lyon, France; 5 University of Pennsylvania, Philadelphia, PA, USA; 6 British Columbia Cancer Agency, Vancouver, BC, Canada; 7 Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA; 8 Division of Medical Oncology, London Regional Cancer Program, London, ON, Canada; 9 Clinical Area of Gynecologic Oncology, Valencian Institute of Oncology, Valencia, Spain; 10 Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 11 University of California Los Angeles, Los Angeles, CA, USA; 12 Clovis Oncology, Inc., Boulder, CO, USA; 13 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada