Download BACKGROUND SUMMARY

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]