CLEOPATRA Protocol review OS Study Title A Phase

CLEOPATRA Protocol review & OS 분석결과

Study Title • A Phase III, Randomized, Double-Blind, Placebo. Controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER 2 Positive Metastatic Breast Cancer (WO 20698 B) • 이전에 치료받은 적이 없는 Her 2 -양성 전이성 유방암에 서 퍼투주맙 + 트라스트주맙 + 도세탁셀 vs. 위약 + 트 라스트주맙 + 도세탁셀의 유효성과 안전성을 평가하는 제 3상, 무작위배정, 이중 맹검, 위약 대조 임상시험 (WO 20698 B)

HER 2 Biology • The Human Epidermal growth factor Receptor-2 gene is a protooncogene mapped to chromosome 17 q 11. 2 q 21 [ it encodes a 185 -k. D transmembrane glycoprotein, the HER 2 receptor (1225 aa)] • HER 2 is member of the HER family consisting of 4 tyrosine kinase receptors (HER 1 -4) • HER 2 is amplified/over-expressed in ~25 -30 % of breast cancers HER 2 overexpression worsens prognosis of breast cancer (Slamon etal. , 1987 and 1989). • HER 2 is also over-expressed in many other tumors, e. g. gastric, NSCLC, CRC, bladder etc

Pertuaumab & Trastuzumab Pertuzumab Trastuzumab • Activates antibodydependent cellular cytotoxicity (ADCC) • Has a major effect on role of HER 2 as a coreceptor with HER 3 or EGFR • Inhibits multiple HERmediated signaling pathways • Activates ADCC • Prevents HER 2 domain cleavage • Inhibits HER 2 -mediated signaling pathways

Study Objectives • Primary – To compare progression free survival (PFS) based on tumor assessments by independent review facility (IRF) between pts Placebo + Trastuzumab + Docetaxel and Pertuzumab + Trastuzumab + Docetaxel • Secondary: To compare between the two arms – Overall survival (OS) – PFS based on investigator assessment – Objective response rate and duration of response – Safety profile – Time to symptom progression (FACT Trial Outcome Index) – Evaluate biomarkers and correlate with clinical outcomes

Cleopatra Study Schema 400 pts A Placebo + Trastuzumab + Docetaxel * R 400 pts B 1: 1 randomization Study dosing q 3 wks until Progressive Disease (PD) or unacceptable toxicity. Pertuzumab + Trastuzumab + Docetaxel * *At least 6 cycles of Docetaxel

Key Eligibility Criteria(1) • Inclusion: - Male & female patients � 18 years - Histologically or cytologically confirmed adenocarcinoma breast with locally recurrent or metastatic disease • Pts with de-novo Stage IV disease are eligible • Pts with measurable and/or non-measurable disease are eligible - FFPE tissue for central testing / 25 unstained slides - Centrally confirmed over expressing HER 2 -positive BC • IHC 3+ • FISH positive - Baseline LVEF 50% (ECHO or MUGA) within 42 days of randomization - ECOG 0, 1 - Signed Informed Consent

Key Eligibility Criteria(2) • • - Exclusion History of anticancer therapy for MBC one prior hormonal regimen permitted Disease-free interval from completion of systemic adjuvant treatment (including Herceptin) < 12 months Cumulative dose of equivalent doxorubicin > 360 mg/m 2 LVEF decline to < 50% during previous trastuzumab therapy CNS metastases Other malignancy (except ca in situ cervix or basal skin cancer) Inadequate hematologic function Impaired liver or renal function

Concomitant Therapy • - Excluded therapies: Anticancer therapies (including targeted) Investigational Products Initiation of herbal remedies • - Avoid where possible: Chronic or High dose corticosteroid therapy Immuno-suppressants TNF-inhibitors Anti-T cell antibodies

Screening Assessments • • • Informed Consent Medical History Complete Physical exam ECOG Performance Status Chest X-ray 12 -Lead ECG Echocardiogram or MUGA LVEF values during and post prior trastuzumab therapy (on e-CRF; protocol version B) FFPE tumor sample for HER 2 status(Targos) Tumor assessment Bone Scan SAEs if related to study procedures

Screening Examination • • • Hematology & Biochemistry INR and a. PTT Pregnancy test Serum for trastuzumab PK Serum for antibodies to pertuzumab Serum sample (ECD/HER 2, HER ligands), Blood sample for clinical genotyping - (FC�polymorphism) FACT-B Qo. L (females only) SAE if related to study procedure Optional BSR serum and plasma Optional metastatic tumor sample for biomarkers Optional whole blood for DNA research

Drug Administration • Pertuzumab/ Placebo – – Cycle 1, Day 1 loading dose 840 mg Subsequent cycles 420 mg Administered every 3 weeks Dose may be delayed for AE (e. g. Cardiac Event, myelo-suppression) – No dose reduction allowed

Drug Administration • Trastuzumab – Cycle 1, Day 2 (24 hrs after pertuzumab and observation period); loading dose 8 mg/kg – Subsequent cycles 6 mg/kg – Weight change ± 10 % recalculate – Administered every 3 weeks – Dose may be delayed for AE – No dose reduction allowed

Drug Administration • Docetaxel - Cycle 1, Day 2 dose (24 hrs after pertuzumab and observation period)75 mg/m 2 • Administer only if neutrophil count > 1500 cell/mm 3 - If dose tolerated after Cycle 1, may increase dose 100 mg/m 2 EXCEPT if the following are present: » Febrile neutropenia » Grade 4 neutropenia > 5 days » ANC < 100/μL for more than 1 day » Other non-hematologic toxicities of Grade > 2 (NCI-CTCAE, Version 3) - Administered every 3 weeks - Given for at least 6 cycles if tolerated

Docetaxel Dose Modification • Dose reduction - reduce by 25% – febrile neutropenia or neutrophils < 500 cell/mm 3 for more than one week – Platelets < 100, 000 cell/mm 3 – Non-hematological toxicities > Grade 2 Permanently discontinue docetaxel: Severe hypersensitivity Severe/cumulative cutaneous reaction despite dose of 55 mg/m 2 Febrile neutropenia/neutrophils < 500 cells/mm 3 or platelets < 100 cells/mm 3 or total bilirubin > ULN without recovery – AST/ALT levels > 1. 5 x ULN concurrent with Alk phos > 2. 5 x ULN without recovery – Peripheral neuropathy �Grade 3 • – – –

Drug Administration: Key Information • • Treatment start – within 3 days of randomization Sequence of drug administration: �pertuzumab (P) trastuzumab (H) docetaxel If admin of three agents well tolerated at Cycle 1, subsequent cycles can be given on same day. Dose delay of one drug for a day or more– all therapy is delayed Reload P + H if dosing > 6 wks, therapies given as in Cycle 1 (pertuzumab/placebo Day 1, and trastuzumab/docetaxel Day 2 If > two cycles delayed→ Discontinued from study If docetaxel delayed >1 cycle w/o recovery, discontinue docetaxel and continue P+H

Summary of Efficacy from the Randomized Trial Parameter (independent review) No. of patients with an event Median months Overall Survival (interim analysis) No. of patients with an event Objective Response Rate (ORR) No. of patients analyzed Objective response (CR + PR) Complete response (CR) Partial Response (PR) Median Duration of Response (months) PERJETA + trastuzumab + docetaxel n=402 Placebo + trastuzumab + docetaxel n=406 191 (47. 5%) 18. 5 242 (59. 6%) 12. 4 69 (17. 2%) 96 (23. 6%) 343 275 (80. 2%) 19 (5. 5%) 256 (74. 6%) 20. 2 336 233 (69. 3%) 14 (4. 2%) 219 (65. 2%) 12. 5 HR (95% CI) p-value 0. 62 < 0. 0001 (0. 51, 0. 75) 0. 64 (0. 47, 0. 88) 0. 0053* 　 　 * The HR and p-value for the interim analysis of Overall Survival did not meet the pre-defined stopping boundary (HR £ 0. 603, p £ 0. 0012).

Kaplan-Meier Curve of IRF-Assessed Progression-Free Survival for the Randomized Trial

Kaplan-Meier Curve of Overall Survival for the Randomized Trial

Most Common Adverse Reactions (ARs) (>30%) Placebo + trastuzumab + docetaxel n=397 PERJETA + trastuzumab + docetaxel n=407 Diarrhea 46. 3% 66. 8% Alopecia 60. 5% 60. 9% Neutropenia 49. 6% 52. 8% Nausea 41. 6% 42. 3% Fatigue 36. 8% 37. 6% Rash 24. 2% 33. 7% Peripheral neuropathy 33. 8% 32. 4% 　

Conclusions • The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER 2 -positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann–La Roche/Genentech; Clinical. Trials. gov number, NCT 00567190)

Unbling list_SNUH

CASE (1) • F/58 • Breast cancer, Lt, IDC, stage IV c. T 4 N 3 (SCN+) M 1 Inflammatory breast cancer M/lung, multiple, LN ER/PR/HER-2: -/-/3+ HER-2 FISH: Positive

CASE(1) • 2009. 3. 31 CLEOPATRA ICF 동의함 • s/p Docetaxel + herceptin + pertuzumab #61 (2009. 4. 9 - ) ->PR • omit docetaxel since #22

CASE(2) • F/42 • Breast ca. stage IIIB, IDC c. T 4 : 10. 5 x 9. 1 x 9. 4 cm, skin ulceration c. N 2 : fixed • ER- PR- HER 2(3+) • HER 2 FISH+

CASE(2) • s/p neoadj. DA #3 ( 2005. 9. 20 - 11. 3 ) : good PR Lt. MRM on 2005. 11. 23 p. T 1 N 0 adj. DA #3(#6) ( 2005. 12. 5 - 2006. 1. 27 ) RTx ( 2006. 2. 23 - 2006. 4. 7 ) • s/p adj. herceptin #18 ( 2006. 4. 11 - 2007. 5. 10 ) • RFS 2 Y 8 M> • 2008. 7. Pelvic bone meta (rt. iliac wing) 로 recur

CASE(2) • 2008. 7. 23 CLEOPATRA ICF 동의함 • s/p Docetaxel + Herceptin - pertuzumab #66 (2008. 8. 5 - ) --> SD • Pertuzumab 상담 후 투여 안함.

CASE(3) • F/52 • Breast cancer, Lt M/Liver IDC, E/P/H (-/-/3+) • HER 2 FISH +

CASE(3) • 2009. 3. 10 CLEOPATRA ICF 동의함. • s/p Docetaxel+herceptin - Pertuzumab Since 2009 -03 -25 -> PR (-65. 5%) -> #9 ->CR (+Metabolic CR) ->#12 ->CR ->#59 • Pertuzumab 상담 후 투여 안함.