Clinical Development of Rucaparib - ECMC Network NIHR... · Clinical Development of Rucaparib. Development of HRD/LOH Signature. Development Strategy Initial goal: ... Clovis Oncology

Rucaparib is an investigational product and not approved by any health authority.

Conclusions about efficacy and safety cannot be made

Clinical Development of Rucaparib

Development of HRD/LOH Signature

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 gBRCAmut

● Focus on ovarian cancer

● Initial hypothesis: HRD patients will

respond to rucaparib

− gBRCAmut - known

− sBRCAmut - not known

− BRCAWT but HRD (“BRCA-like”); not known

● Key issue: Defining BRCA-like

All Ovarian Cancer Patients

BRCAmut

HRD

gBRCAmut = germline mutation

sBRCAmut = somatic BRCA mutation

BRCAWT = BRCA wild type

HRD = homologous recombination deficient

3

BRCA1/2

RAD51

PALB2

PARP Inhibitors are Synthetically Lethal to BRCAmut and BRCA-Like Tumor

Cells with Homologous Recombination Deficiency (HRD)

Cell

death

Cell

deficient

in HR

Cell

survival

Cell

proficient

in HR

P

A

R

P

I

N

H

I

B

I

T

O

R

HR is a complex process requiring coordinated function of many

gene products

Genetic and epigenetic dysregulation cause HRD, resulting in tumor tissue BRCAmut 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

AAAAAAAAAAAAAAAAAAAAA

BBBBBBBBBBBBBBBBBBBBB

AAAAAAAAAAAAAAAAAAAAA

BAABBBBBBBBBBBBBAABBB

SNP profile of normal:

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.

SNP profile of LOH :

5

6

BRCAmut

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.

BRCAwt

● 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

NGS=next-generation sequencing; mut=mutation; wt=wild type.

Genome-Wide LOH Quantified by FoundationOne SNP NGS is employed for Prospective Patient Selection in ARIEL Studies

Kristeleit R et al. Presented at ECC-ESMO 2015. Abstract 2700.

HGSOC Patients can be Classified into Three Molecular Subgroups: BRCAmut,

BRCA-like, Biomarker Negative

Fre

qu

en

cy o

f Tu

mo

rs

Extent of Genomic LOH

Genomic LOH cutoff

Biomarker

NegativeBRCA-like

BRCAwt

BRCAmut

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 BRCAmut 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

BRCAmut, BRCA mutant; HRD, homologous recombination deficiency; PK, pharmacokinetics; AR; androgen-receptor

CO-338-010

NCT01482715

Treatment setting

Part 1Phase I

Dose escalation

Any solid tumor

Part 2 Part 3PK

ARIEL2/CO-338-017

NCT01891344

Treatment setting

Part 1 Part 2

ARIEL3/

CO-338-014

NCT01968213Maintenance

setting

ARIEL4

Treatment

setting

2A (Phase II)

• Platinum sensitive

• Relapsed ovarian

cancer (germline

BRCAmut)

• 2–4 prior

treatments

2B (Phase II)

• Relapsed ovarian

cancer (germline or

somatic BRCAmut)

• ≥3 prior

chemotherapy

regimens

Phase II

• Development of

HRD signature

• Relapsed

ovarian cancer

• Platinum

sensitive

• All comers

(Known germline

BRCAmut)

• >1 prior platinum-

based treatment

Phase III

• Randomized;

blinded rucaparib

(maintenance)

vs placebo after

response to

platinum-based

chemotherapy

• Confirmatory study

• ≥2 prior platinum-

based treatments

Phase III

• Randomized;

rucaparib vs

chemotherapy

• Confirmatory study

Phase II

• Refinement of

HRD signature

• Relapsed

ovarian cancer

• All comers

• ≥3 prior

chemotherapy

regimens

9

TRITON 2

Treatment

setting

TRITON 3

Treatment

setting

Phase II

• Metastatic

castrate-resistant

prostate cancer

• Biomarker

selected

• >2 prior therapies

including AR-

targeted and

taxane

Phase III

• Metastatic

castrate-resistant

prostate cancer

• Biomarker

selected

• Chemo-naïve,

progression

following one AR-

targeted therapy

• Randomised:

Rucaparib v

chemotherapy or

AR-targeted

therapy

Ovarian Cancer Prostate Cancer

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 gBRCAmut

-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(-), BRCAmut or BRCAwt/LOHHigh 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. Oza13

1University College London, Cancer Institute, London, UK; 2Sheba Medical Center, Ramat Gan, Israel; 3Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain;

4GINECO, Centre Léon Bérard and University Claude Bernard, Lyon, France; 5University of Pennsylvania,

Philadelphia, PA, USA; 6British Columbia Cancer Agency, Vancouver, BC, Canada; 7Gynecological Oncology,

Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA; 8Division of

Medical Oncology, London Regional Cancer Program, London, ON, Canada; 9Clinical Area of Gynecologic Oncology,

Valencian Institute of Oncology, Valencia, Spain; 10Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 11University of California Los Angeles, Los Angeles, CA, USA; 12Clovis Oncology, Inc., Boulder, CO, USA;

13Princess 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 (BRCAmut); 5%–7% harbour a somatic BRCAmut1–3

• The PARP inhibitor rucaparib has demonstrated clinical activity in BRCAmut high-

grade ovarian carcinoma (HGOC) in two phase 2 studies in the treatment

setting4,5

• Data from these studies, Study 10 (NCT01482715) and ARIEL2 (NCT01891344),

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 BRCAmut 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;27:1449-55; 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.

13

Efficacy and Safety Populations

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

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

Study 10

(NCT01482715)

n=62

n=42

ARIEL2

(NCT01891344)

n=315

n=64

Safety Population (n=377)

Efficacy Population (n=106)

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).

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



ECOG, Eastern Cooperative Oncology Group; NA, not applicable.

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 (%) 0 127 (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 (%) 0 131 (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)



PFI, progression-free interval.

16

Progression-Free Survival in the Efficacy Population

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)

Median (months) 95% CI Range

10.0 7.3–12.5 0.0–22.1+

+ Censored; Censoring rate: 47%

• 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


CI, confidence interval.

17

Progression-Free Survival in the Efficacy Population


10.0 7.3–12.5 0.0–22.1+

+ Censored; Censoring rate: 47%

Progression-free at 6 months:

79%

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


CI, confidence interval.

18

Investigator-Assessed ORR in the Efficacy Population

Parameter

Study 10

n=42

ARIEL2

n=64

Efficacy population

n=106

n (%)

[95% CI]

Investigator-assessed RECIST ORR

(confirmed CR+PR)

25 (59.5)

[43.3–74.4]

32 (50.0)

[37.2–62.8]

57 (53.8)

[43.8–63.5]

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)

[61.1–79.2]


CR, complete response; GCIG, Gynecologic Cancer InterGroup; NE, not evaluable; ORR, objective response rate; PR, partial response;

RECIST, Response Evaluation Criteria In Solid Tumors.

19

Response by Subgroups

ORR, % (95% CI)

53.8 (43.8–63.5)

53.4 (42.5–64.1)

46.2 (19.2–74.9)

80.0 (28.4–99.5)

53.7 (41.1–66.0)

53.8 (37.2–69.9)

68.3 (51.9–81.9)

53.8 (43.8–63.5)

65.0 (51.6–76.9)

53.8 (43.8–63.5)

18.5 (6.3–38.1)

62.5 (48.6–75.1)

73.9 (51.6–89.8)

0 (0.0–41.0)

25.0 (8.7–49.1)

65.8 (54.3–76.1)


20

Best Response for Target Lesions in the Efficacy Population

*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.


++

+++

++ ++++ +

+ ++

+ + + +

++ + ++ + +++++++

+

++++

-120

-100

-80

-60

-40

-20

0

20

40

60

80

Ch

an

ge f

rom

Bas

eli

ne

in

Su

m o

f th

e D

iam

ete

r o

f Ta

rge

t L

es

ion

s†

(%)

N=103*

+ = Ongoing

BRCA1

BRCA2

21

Best Response for Target Lesions in the Efficacy Population

++

+++

++ ++++ +

+ ++

+ + + +

++ + ++ + +++++++

+

++++

-120

-100

-80

-60

-40

-20

0

20

40

60

80

Ch

an

ge f

rom

Bas

eli

ne

in

Su

m o

f th

e D

iam

ete

r o

f Ta

rge

t L

es

ion

s†

(%)

N=103*

+ = Ongoing

BRCA1

BRCA2

BRCA mutation origin uncertain

Somatic BRCA mutation

Germline BRCA mutation

*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.


22

Duration of Response in the Efficacy Population


9.2 6.6–11.7 1.7–19.8+

+ 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

23

Safety Summary: All Ovarian Cancer Patients Who Received ≥1 Dose

of Rucaparib 600 mg

Parameter


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)†

*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.

• Median dose intensity (actual dose received/first dose received) was 0.92 (range, 0.1–1.3)• 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%)

24

Treatment-Emergent Adverse Events: ≥20% All Grade

Term


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.

25

Laboratory Abnormalities: Shifts from Baseline

Term


n=375*

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.


SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase.

26

Conclusions

• Rucaparib is active in patients with germline or somatic BRCAmut 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 6.6–11.7)

• 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;

NCT01968213)

– In the treatment setting in comparison to standard chemotherapy (ARIEL4; NCT02855944)

Clinical Development of Rucaparib - ECMC Network NIHR... · Clinical Development of Rucaparib. Development of HRD/LOH Signature. Development Strategy Initial goal: ... Clovis Oncology

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