Clinical Development of Rucaparib

Transcription

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

2 Development of HRD/LOH Signature

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

4 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 PALB2 Cell proficient in HR P A R P Cell survival RAD51 BRCA1/2 Cell deficient in HR I N H I B I T O R Cell death 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 Abstract Confidential

5 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: AAAAAAAAAAAAAAAAAAAAA BBBBBBBBBBBBBBBBBBBBB SNP profile of LOH : LOH, loss of heterozygosity; NGS, next generation sequencing; SNP, single nucleotide polymorphism. Swisher E, et al. AACR Abstract CT339; McNeish I, et al. IGCS Abstract AAAAAAAAAAAAAAAAAAAAA BAABBBBBBBBBBBBBAABBB 5

6 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 BRCA wt BRCA-like Biomarker Negative Hypothesis 1: Ovarian cancer patients with high genomic LOH suggesting BRCA-like signature will respond to rucaparib. Hypothesis 2: Ovarian cancer patients who are Biomarker 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 Abstract

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

8 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

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

10 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 gbrca 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

11 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

12 Background Approximately 14% 18% of epithelial ovarian cancers harbour a germline BRCA1 or BRCA2 mutation (BRCA mut ); 5% 7% harbour a somatic BRCA mut1 3 The PARP inhibitor rucaparib has demonstrated clinical activity in BRCA mut highgrade ovarian carcinoma (HGOC) in two phase 2 studies in the treatment setting 4,5 Data from these studies, Study 10 (NCT ) and ARIEL2 (NCT ), were combined for an integrated efficacy and safety analysis These analyses further characterise the clinical benefit of rucaparib (600 mg BID) in the treatment setting in patients with BRCA mut HGOC who have received 2 prior chemotherapy regimens 1. The Cancer Genome Atlas (TCGA) Research Network. Nature. 2011;474:609-15; 2. Pennington KP et al. Clin Cancer Res. 2014;20:764-75; 3. Moschetta M et al. Ann Oncol. 2016;27: ; 4. Shapira-Frommer R et al. Eur J Cancer. 2015;51:S545; abstract 2746; 5. Coleman RL et al. J Clin Oncol. 2016;4(suppl 15):abstract 5540 BID, twice daily. 12

13 Efficacy and Safety Populations Safety Population (n=377) Criteria - Diagnosis of ovarian cancer (inclusive of primary peritoneal and fallopian tube cancer) - Enrolled at 600 mg BID dosing level and received 1 dose of rucaparib 600 mg Study 10 (NCT ) n=62 ARIEL2 (NCT ) n=315 Efficacy Population (n=106) Criteria - Received 2 prior chemotherapies, including 2 platinum-based regimens - Had a deleterious germline BRCA or somatic BRCA mutation - Enrolled at 600 mg BID dosing level and received 1 dose of rucaparib 600 mg n=42 n=64 Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). 13

14 Patient Characteristics Efficacy population n=106 Safety population n=377 Median age (range), years 59 (33 84) 62 (31 86) ECOG Performance Status, n (%) 0 65 (61.3) 233 (61.8) 1 41 (38.7) 144 (38.2) Cancer type, n (%) Epithelial ovarian 91 (85.8) 305 (80.9) Primary peritoneal 6 (5.7) 39 (10.3) Fallopian 9 (8.5) 33 (8.8) BRCA mutation, n (%) Germline 88 (83.0) 108 (28.6) Somatic 13 (12.3) 23 (6.1) Origin uncertain 5 (4.7) 12 (3.2) No mutation 0 (0.0) 234 (62.1) BRCA gene mutation, n (%) BRCA1 67 (63.2) NA BRCA2 39 (36.8) NA Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). ECOG, Eastern Cooperative Oncology Group; NA, not applicable. 14

15 Patient Characteristics Efficacy population n=106 Safety population n=377 Median number of prior chemotherapies (range) 3 (2 6) 2 (1 7) 1 prior therapy, n (%) (33.7) 2 prior therapies, n (%) 41 (38.7) 85 (22.5) 3 prior therapies, n (%) 65 (61.3) 165 (43.8) Median number of platinum-based therapies (range) 2 (2 5) 2 (1 5) 1 prior platinum-based therapy, n (%) (34.7) 2 prior platinum-based therapies, n (%) 60 (56.6) 144 (38.2) 3 prior platinum-based therapies, n (%) 46 (43.4) 102 (27.1) PFI from latest platinum regimen, n (%) <6 months 27 (25.5) 90 (23.9) 6 12 months 56 (52.8) 152 (40.3) >12 months 23 (21.7) 129 (34.2) Missing 0 6 (1.6) Platinum response (most recent therapy), n (%) Sensitive (recurrence after PFI 6 months) 79 (74.5) 283 (75.1) Resistant (recurrence after PFI <6 months) 20 (18.9) 67 (17.8) Refractory (progression on platinum, PFI <2 months) 7 (6.6) 26 (6.9) Unknown 0 1 (0.3) Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). PFI, progression-free interval. 15

16 Progression-Free Survival in the Efficacy Population Median (months) 95% CI Range Censored; Censoring rate: 47% At risk (events) 106 (0) 93 (9) 85 (14) 69 (19) 43 (37) 31 (40) 21 (43) 14 (49) 8 (54) 3 (55) 3 (55) 2 (56) 0 (56) Of 106 patients, 50 did not have an event of disease progression or death at the data cutoff dates Of these 50 patients, 32 were still on treatment, and 18 discontinued treatment for reasons other than disease progression or death at the data cutoff dates Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). CI, confidence interval. 16

17 Progression-Free Survival in the Efficacy Population Progression-free at 6 months: 79% Median (months) 95% CI Range Censored; Censoring rate: 47% Progression-free at 12 months: 41% At risk (events) 106 (0) 93 (9) 85 (14) 69 (19) 43 (37) 31 (40) 21 (43) 14 (49) 8 (54) 3 (55) 3 (55) 2 (56) 0 (56) Of 106 patients, 50 did not have an event of disease progression or death at the data cutoff dates Of these 50 patients, 32 were still on treatment, and 18 discontinued treatment for reasons other than disease progression or death at the data cutoff dates Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). CI, confidence interval. 17

18 Investigator-Assessed ORR in the Efficacy Population Study 10 n=42 ARIEL2 n=64 Efficacy population n=106 Parameter n (%) [95% CI] Investigator-assessed RECIST ORR (confirmed CRPR) 25 (59.5) [ ] 32 (50.0) [ ] 57 (53.8) [ ] CR 4 (9.5) 5 (7.8) 9 (8.5) PR 21 (50.0) 27 (42.2) 48 (45.3) SD 12 (28.6) 24 (37.5) 36 (34.0) PD 2 (4.8) 7 (10.9) 9 (8.5) NE 3 (7.1) 1 (1.6) 4 (3.8) Investigator-assessed RECIST/GCIG CA-125 ORR 75 (70.8) [ ] Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). CR, complete response; GCIG, Gynecologic Cancer InterGroup; NE, not evaluable; ORR, objective response rate; RECIST, Response Evaluation Criteria In Solid Tumors. PR, partial response; 18

19 Response by Subgroups ORR, % (95% CI) 53.8 ( ) 53.4 ( ) 46.2 ( ) 80.0 ( ) 53.7 ( ) 53.8 ( ) 68.3 ( ) 53.8 ( ) 65.0 ( ) 53.8 ( ) 18.5 ( ) 62.5 ( ) 73.9 ( ) 0 ( ) 25.0 ( ) 65.8 ( ) Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). 19

20 Change from Baseline in Sum of the Diameter of Target Lesions (%) Best Response for Target Lesions in the Efficacy Population N=103* = Ongoing BRCA1 BRCA *Three patients did not have a post baseline scan; For unconfirmed responses; includes the best percent change from baseline up to and including the first overall response of progressive disease. Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). 20

21 Change from Baseline in Sum of the Diameter of Target Lesions (%) Best Response for Target Lesions in the Efficacy Population N=103* = Ongoing BRCA1 BRCA2 Germline BRCA mutation 20 0 Somatic BRCA mutation BRCA mutation origin uncertain *Three patients did not have a post baseline scan; For unconfirmed responses; includes the best percent change from baseline up to and including the first overall response of progressive disease. Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). 21

22 Duration of Response in the Efficacy Population Median (months) 95% CI Range Censored; censoring rate: 47% At risk (events) 57 (0) 57 (0) 52 (1) 50 (1) 44 (4) 41 (5) 27 (15) 25 (16) 19 (19) 17 (20) 12 (23) 11 (24) 9 (26) 6 (28) 3 (29) 2 (29) 2 (29) 2 (29) 2 (29) 1 (30) 0 (30) Of the 57 patients with a response, 27 did not have an event of disease progression or death at the data cutoff dates Of these 27 patients, 20 were still on treatment, and 7 discontinued treatment for reasons other than disease progression or death at the data cutoff dates Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). 22

23 Safety Summary: All Ovarian Cancer Patients Who Received 1 Dose of Rucaparib 600 mg Parameter Ovarian cancer patients n=377 Any all-grade AE, n (%) 377 (100.0) Treatment-related all-grade AE, n (%) 360 (95.5) Any grade 3 AE, n (%) 229 (60.7) Treatment-related grade 3 AE, n (%) 177 (46.9) AE leading to dose interruption, n (%) 221 (58.6) AE leading to dose reduction, n (%) 173 (45.9) Treatment-related AE leading to dose reduction, n (%) 167 (44.3) AE leading to treatment discontinuation*, n (%) 50 (13.3) Treatment-related AE leading to discontinuation, n (%) 30 (8.0) Any AE leading to death, n (%) 9 (2.4) Malignant neoplasm progression, n (%) 8 (2.1) Nonprogression AE leading to death, n (%) 1 (0.3) Median dose intensity (actual dose received/first dose received) was 0.92 (range, ) Primary reasons for dose reduction: anemia/decreased hemoglobin (17.2%), asthenia/fatigue (14.1%), and nausea (11.1%) Primary reasons for treatment discontinuation: asthenia/fatigue (2.4%), small intestinal obstruction (1.9%), and nausea (1.3%) *Excludes patients who discontinued due to disease progression; Patient died of sepsis, which was assessed by the investigator as not related to rucaparib. Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016) AE, adverse event. 23

24 Treatment-Emergent Adverse Events: 20% All Grade Term Ovarian cancer patients n=377 All grade, n (%) Grade 3/4, n (%) Nausea 290 (76.9) 19 (5.0) Asthenia/fatigue* 289 (76.7) 41 (10.9) Vomiting 174 (46.2) 15 (4.0) Anaemia* 165 (43.8) 94 (24.9) ALT/AST increased* 156 (41.4) 41 (10.9) Constipation 150 (39.8) 6 (1.6) Decreased appetite 148 (39.3) 10 (2.7) Dysgeusia 148 (39.3) 1 (0.3) Diarrhoea 130 (34.5) 9 (2.4) Abdominal Pain 119 (31.6) 13 (3.4) Dyspnoea 81 (21.5) 2 (0.5) Thrombocytopoenia* 79 (21.0) 17 (4.5) Blood creatinine increased 79 (21.0) 2 (0.5) Myelodysplastic syndrome/acute myeloid leukemia was reported in <1% of patients *Combined terms. Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016) ALT, alanine aminotransferase; AST; aspartate aminotransferase. 24

25 Laboratory Abnormalities: Shifts from Baseline Ovarian cancer patients n=375* Term Any worsening shift from baseline, n (%) Maximum shift to grade 3/4, n (%) Increase in creatinine 347 (92.5) 5 (1.3) Increase in ALT 279 (74.4) 47 (12.5) Increase in AST 276 (73.6) 17 (4.5) Decrease in haemoglobin 251 (66.9) 88 (23.5) Decrease in lymphocytes 168 (45.3) 26 (7.0) Increase in cholesterol 150 (41.0) 9 (2.5) Decrease in platelets 147 (39.2) 23 (6.1) Decrease in neutrophils 132 (35.2) 37 (9.9) Increases in AST (SGOT) and ALT (SGPT) levels normalised over time with continued treatment Elevations in creatinine likely result from inhibition of the renal transporters MATE1 and MATE2-K *Data shown for patients with both baseline and post-baseline results; n=371; n=366. Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase. 25

26 Conclusions Rucaparib is active in patients with germline or somatic BRCA mut high-grade ovarian cancer who have received 2 prior chemotherapies in the treatment setting Response rates were highest in patients who had a PFI 6 months (65.8%) or were limited to 2 prior lines of therapy (68.3%) Response to rucaparib was durable (median duration of response, 9.2 months; 95% CI ) Rucaparib has a manageable safety profile Adverse events were managed with treatment interruption or dose modification Two randomised, phase 3 confirmatory trials are ongoing In the maintenance setting in patients with relapsed high-grade ovarian cancer (ARIEL3; NCT ) In the treatment setting in comparison to standard chemotherapy (ARIEL4; NCT ) 26