Afinitor (Everolimus) 針對 ER+/HER2- 晚期乳癌經荷爾蒙治療失效病人之第三期臨床試驗

AGINITOR 標竿臨床試驗 1

RANDOMISATION (2:1) Afinitor (Everolimus) 針對 ER+/HER2- 晚期乳癌經荷爾蒙治療失效病人之第三期臨床試驗 BOLERO-2 Phase III: Everolimus + Exemestane in abc Eligibility Criteria (N = 724) Postmenopausal ER+ Unresectable locally advanced or MBC Recurrence or progression after LET or ANA EVE 10 mg PO daily + EXE 25 mg PO daily (n=485) Placebo PO daily + EXE 25 mg PO daily (n=239) PFS OS ORR Time to ECOG PS deterioration Safety QoL Stratification by Sensitivity to prior hormone therapy Visceral metastases Treatment until disease progression or unacceptable toxicity PO = orally; ECOG PS = Eastern Cooperative Oncology Group performance status; LET = letrozole; ANA = anastrozole; EVE = everolimus; EXE = exemestane Baselga et al. N Engl J Med. 2012 Feb 9;366(6):520-9.

BOLERO-2: Baseline Characteristics Were Generally Balanced Between Arms Characteristic Everolimus + Exemestane (N = 485), % Placebo + Exemestane (N = 239), % Median age (range), years 62 (34, 93) 61 (28, 90) Race 即使內臟轉移, 只 Caucasian 要症狀不嚴重, 也 74 78 有機會從口服 Asian mtor 的治療組合 20 19 Performance status 0 中受益 60 59 Liver involvement 33 30 Lung involvement 29 33 Measurable disease a 70 68 a All other patients had 1 bone lesion. Adapted from: Baselga J, et al. N Engl J Med. 2012;366(6):520-529. 3

Probability (%) of Event 研究結果證實 Afinitor (Everolimus) 可顯著延緩乳癌腫瘤惡化達 11 個月 BOLERO-2: Primary Endpoint, PFS (Central Assessment) 100 80 HR = 0.38 (95% CI = 0.31, 0.48) Log-rank P <.0001 Everolimus + Exemestane: 11.0 mo (E/N = 188/485) 60 Placebo + Exemestane: 4.1 mo (E/N = 132/239) 40 20 Number of patients still at risk Everolimus 485 Placebo 239 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 Time, wk 427 179 359 114 292 76 239 56 211 39 166 31 140 27 108 16 77 13 62 9 48 6 32 4 21 1 18 0 11 0 10 0 5 0 0 0 CI, confidence interval; E/N, patients with events/total patients; HR, hazard ratio; PFS, progression-free survival. Piccart-Gebhart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

Afinitor (Everolimus) 可幫助 腫瘤縮小 & 穩定病情 BOLERO-2: Clinical Benefit Rate (Local Assessment) CBR, clinical benefit rate Piccart-Gebhart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

Afinitor (Everolimus) 對患者 整體存活率有延長的趨勢 BOLERO-2: Overall Survival Was Numerically Better With Everolimus (Between-Group Differences Through 18 Months Median Follow-up) Interim Analysis (7-mo follow-up) 1 Updated Analysis (12.5-mo follow-up) 2 Final PFS Analysis (18-mo follow-up) 3 Cutoff date 11 Feb 2011 8 Jul 2011 15 Dec 2011 OS events (everolimus vs placebo) 83 (10.7% vs 13.0%) 137 (17.3% vs 22.7%) 200 (25.4% vs 32.2%) Δ OS events 2.3% 5.4% 6.8% Abbreviations: OS, overall survival; PFS, progression-free survival. 1. Baselga J, et al. N Engl J Med. 2012;366(6):520-529; 2. Hortobagyi G, et al. SABCS 2011, abstract S3-7; 3. Piccart M, et al. ASCO 2012, abstract 559. 6

Probability of Event, % Afinitor (Everolimus) 可顯著延緩 患者生活品質惡化 BOLERO-2: Quality of Life 100 90 80 70 60 50 40 30 20 10 Censoring times Everolimus + Exemestane (E/N = 254/485) Placebo + Exemestane (E/N = 113/239) P value =.0084 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time to Deterioration in QoL, wk Patients still at risk, n 485 427 305 245 198 176 145 119 99 71 52 43 29 18 13 9 8 Eve+ Exe 239 201 116 83 62 49 36 27 19 16 7 6 3 1 0 0 0 Placebo + Exe EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire; E/N, patients with events/total patients; MID, minimal important difference; QoL, quality of life. Beck JT, et al. J Clin Oncol. 2012;30(suppl; abstr 539)(poster).

Afinitor (Everolimus) 再創乳癌標靶治療之新篇章! Monotherapy Combination chemotherapy Trastuzumab + chemotherapy HER2+ MBC Everolimus + exemestane (BOLERO-2) HR+/HER2- MBC Docetaxel Chan 1999 Doxorubicin Chan 1999 Paclitaxel Seidman 2004 Vinorelbine Muñoz 2006 Doxorubicin + paclitaxel Jassem 2001 Xeloda + docetaxel O Shaughnessy 2002 Gemcitabine + paclitaxel Albain 2004 FEC Zielinski 2005 Epirubicin + docetaxel Pacilio 2006 Trastuzumab + docetaxel Marty 2005 Docetaxel Marty 2005 Everolimus + exemestane BOLERO-2 2012 exemestane BOLERO-2 2012 4.1 4.1 5.3 5.2 6.0 6.1 6.1 6.5 Median PFS / TTP 8.3 9.0 9.0 11.7 11.0 0 2 4 6 8 10 12 14 Time (months)

用法, 用量及副作用處理 9

劑型 用法用量及注意事項 劑型 癌伏妥 錠 5 毫克 衛署藥輸字第 025165 號 用法用量 建議用量為 10 毫克 應於每天同一時間服用一次, 與食物或不與食物併服都可以 需以整杯水吞服整顆藥錠, 不可咀嚼或咬碎錠劑 用法用量 ( 續 ) 對無法吞服錠劑的患者, 應將 AFINITOR 錠劑以輕輕攪拌的方式完全溶散於一杯水 ( 約 30 毫升 ) 中, 並立即喝下 再於杯中倒入等量的水滌洗, 然後將滌洗液全部喝掉, 以確保服下完整的劑量 10

劑型 用法用量及注意事項 ( 續 ) 用法用量 ( 續 ) 應告知病患若忘記服用一劑 AFINITOR 時, 距離正常服藥時間 6 小時內仍可立即服一劑, 若超過 6 小時, 則應跳過這次劑量, 第二天再於正常服藥時間服用 AFINITOR 應警告病患不可服用二劑來補償忘記服用的劑量 11 劑量調整 出現嚴重和 / 或不耐受的不良反應 具肝功能不全患者 併用中效 CYP3A4 或 P-gP 抑制劑, 以及併用強效 CYP3A4 誘導劑時應適當調整劑量 禁忌 對於主成分 rapamycin 衍生物或任何賦形劑過敏者

特殊族群 腎功能不全的患者 Everolimus 大約有 5% 排泄至尿液中 在針對 170 名末期癌症受試者所進行的族群藥物動力學研究中, 未偵測到 everolimus 的 CL/F 對於肌酸酐廓清率 (25 至 178 毫升 / 分鐘 ) 有顯著影響 肝功能不全的患者 對於重度肝功能不全之荷爾蒙接受器呈陽性晚期乳癌患者, 若期望的益處超過風險時, 可降低 AFINITOR 的劑量使用 對於輕至中度肝功能不全患者, 建議調降劑量 12

特殊族群 ( 續 ) 年齡與性別的影響 在癌症受試者中進行的族群藥動學評估, 並未偵測到年紀或性別對 everolimus 的口服廓清率有顯著關聯性 疫苗接種 應告知病人避免接受活性疫苗注射或與接種活性疫苗的人進行緊密接觸 懷孕 懷孕分級 :D 應告知育齡婦女 AFINITOR 可能對胎兒造成傷害, 服用 AFINITOR 治療期間應採取有效之避孕措施並應持續至療程結束後 8 週 13

Potential Class Effects of mtor Inhibition Stomatitis Noninfectious pneumonitis Infections All Grades, % EVE + EXE (BOLERO-2)1 n=482 Hyperglycemia and hyperlipidemia Rash EVE + TAM (TAMRAD)2 n=54 TEM (Phase 3, RCC)3 n=208 Stomatitis 67a 56 20 Rash 39 44 47 Noninfectious 19b 17 29 d pneumonitis Infections 50c 35 27 Hyperglycemia 14 NR 26 Hyperlipidemia NR NR 27 a Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. b Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. c Includes all preferred terms within the infections and infestations system organ class. d Maroto JP, et al. J Clin Oncol. 2011;29(13):1750-1756. Retrospective analysis of 178 pts on TEM. 1. Afinitor (everolimus) [US prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012; 2. Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724; 3. Hudes G, et al. N Engl J Med. 2007;356(22):2271-2281. Images are not actual patients. 4

Stomatitis: Clinical Presentation mtor inhibitor-associated stomatitis 1,2 Distinct from chemotherapyinduced stomatitis Aphthous-like ulcers characterized by discrete, ovoid, superficial, well-demarcated ulcerations with a grayish-white pseudomembrane Ulcers typically develop acutely in the first cycle of therapy Severity usually peaks within the first 2 weeks of therapy Image reprinted from Porta C, et al. Eur J Cancer. 2011;47(9):1287-1298. 1. de Oliveira MA, et al. Oral Oncol. 2011;47(10):998-1003; 2. Wojtaszek C. Clin J Oncol Nurs. 2000;4(6):263-270. Images are not actual patients. 9

Stomatitis: Clinical Management Strategy Grade Symptoms Treatment and Management Everolimus Dose Modification 1 Minimal; can maintain normal diet 2 Symptomatic but can eat and swallow modified diet 3 Symptomatic and unable to adequately aliment or hydrate orally 4 Associated with life-threatening consequences Nonalcoholic or 0.9% salt water mouthwash several times daily Topical analgesic mouth treatments with or without topical corticosteroids Avoid agents containing hydrogen peroxide, iodine, and thyme derivatives Topical analgesic mouth treatments with or without topical corticosteroids Avoid agents containing hydrogen peroxide, iodine, and thyme derivatives Treat with appropriate medical therapy No change Temporarily interrupt dose until recovery to grade 1, then restart at same dose If stomatitis recurs at grade 2, then temporarily interrupt dose until recovery to grade 1, and restart at reduced dose Temporarily interrupt dose until recovery to grade 1, then restart at reduced dose Discontinue treatment Afinitor (everolimus) [US prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. Images are not actual patients. 12

Stomatitis: Patient Education Patient awareness and early intervention are important 1,2 Consider evaluation for herpesvirus or fungal infection 1 Oral hygiene: Educate patients about good oral hygiene 1,2 Rinse with nonalcoholic mouthwash Floss after each meal Use mild toothpaste and soft-bristled toothbrush Avoid agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives Note: Preventive treatment with sodium bicarbonate-based mouthwash has been shown to be ineffective 3 Advise patients to avoid foods that are spicy/acidic/salty 4 Prompt reporting: Advise patients to promptly report any signs or symptoms 1 >3 lesions Lesions lasting >3 days Lesions interfering with eating and drinking 17 1. Porta C, et al. Eur J Cancer. 2011;47(9):1287-1298; 2. Pilotte AP, et al. Clin J Oncol Nurs. 2011;15(5):E83-E89; 3. Ferte C, et al. Eur J Cancer. 2011;47(15):2249-2255; 4. Eisen T, et al. J Natl Cancer Inst. 2012;104(2):93-113.

Rash: Clinical Presentation Drug-induced acneiform dermatitis 1 Can occur with mtor inhibitors and several other types of drugs (eg, corticosteroids, EGFR inhibitors, cyclosporine, anticonvulsants, anabolic steroids, azathioprine, and testosterone) Usually starts as an inflammatory lesion (papule or pustule); comedones (blackheads) may appear thereafter 1,2 Wide and unusual distribution typically found in acne-free areas (eg, upper extremities, trunk, neck) 1-4 Treatment includes topical treatments (with products containing corticosteroids, benzoyl peroxide, and antibiotics), systemic, antibiotics, and dose adjustments per PI. Images courtesy of Carmen Jacobs, RN, OCN; MD Anderson Cancer Center, Houston, TX. 1. Momin SB, et al. J Drugs Dermatol. 2010;9(6):627-636; 2. Mahe E, et al. Transplantation. 2005;79(4):476-482; 3. Plewig G, et al. Dermatology. 1998;196(1):102-107; 4. Mahe E, et al. J Am Acad Dermatol. 2006;55(1):139-142. Images are not actual patients. 23

Rash: Clinical Management Strategy Grade Symptoms Treatment and Management 1 Macular or papular eruption or erythema without associated symptoms 2 Macular or papular eruption or erythema with pruritus or other associated symptoms; localized desquamation or other lesions covering <50% of body surface area 3 Severe, generalized erythroderma or macular, papular, or vesicular eruption; desquamation covering 50% of body surface area 4 Generalized exfoliative, ulcerative, or bulbus dermatitis Mild lesions may resolve spontaneously; no specific therapy Topical treatment with corticosteroids and products containing benzoyl peroxide and antibiotic initially Some patients with acne before starting everolimus benefit from topical as well as oral antibiotic therapy (i.e., tetracycline; avoid strong CYP3A4 inhibitors such as clarithromycin) Avoid retinoids as they may disrupt skin integrity and introduce risk for infection Everolimus Dose Modification No change If patient is able to tolerate the toxicity, maintain same dose If patient is unable to tolerate the toxicity, hold dose until recovery to grade 1, then restart at same dose If toxicity returns to grade 2, hold dose until recovery to grade 1, then restart at lower dose level Interrupt dose until recovery to grade 1, then restart at lower dose level Discontinue everolimus 1. Agricola K, et al. AANN 2011; Abstract P56 (poster); 2. Afinitor (everolimus) [US prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012; 3. Moldawer NP, et al. Kidney Cancer J. 2010;8(2):51-59. Images are not actual patients. 12

Rash: Patient Education Inform patients that rash is a potential adverse event with everolimus use Advise patients not to use cosmetics containing retinoids Emphasize importance of prompt reporting of signs and symptoms 20

Hyperglycemia: Guidance for Practical Management Monitor fasting serum glucose levels before initiating everolimus therapy and periodically thereafter 1,2 Achieve optimal glycemic control before starting everolimus 1,2 Manage according to standard consensus guidelines 3 Grade Lab Values Treatment and Management 1 Glucose: >ULN-160 mg/dl (>ULN-8.9 mmol/l) 2 Glucose: >160-250 mg/dl (8.9-13.9 mmol/l) 3 Glucose: >250-500 mg/dl (13.9-27.7 mmol/l) 4 Glucose: >500 mg/dl (>27.7 mmol/l) Everolimus Dose Modification None No change Manage with appropriate medical therapy according to American Diabetes Association and European Association for the Study of Diabetes standard guidelines and monitor No dose adjustment required Temporary dose interruption until recovery to grade 1 Restart at a lower dose Discontinue everolimus 1. Afinitor Summary of Product Characteristics. West Sussex, UK: Novartis Europharm Ltd.; 2012; 2. Eisen T, et al. J Natl Cancer Inst. 2012;104(2):93-113; 3. Nathan DM, et al. Diabetes Care. 2009;32(1):193-203. 12

Inhibition of PI3K/AKT/mTOR Signaling Affects Glucose Homeostasis and Fat Metabolism mtor is downstream effector of insulin signaling and subsequent gluconeogenesis, glycogen synthesis, and lipogenesis As a consequence, mtor inhibition can disrupt these physiologic processes to varying degrees Hyperglycemia and hyperlipidemia are both known AEs that can occur with everolimus use 22

How to address the diagnosis of noninfectious pneumonitis? Baseline imaging (chest x-ray) before starting everolimus is key Consider the patient s risk for infection or malignancy in the chest Attend to new or worsening respiratory symptoms Differential diagnosis and a multidisciplinary approach is important (pulmonologist, infectious disease specialist) 23

Noninfectious Pneumonitis: Clinical Management Strategy Grade Symptoms Treatment and Management Everolimus Dose Modification 1 Asymptomatic No specific therapy Initiate appropriate monitoring 2 Symptomatic, not interfering with ADL Depending on severity of symptoms: Consider consulting a pulmonologist Consider diagnostics to exclude infectious causes Consider corticosteroids No change required Consider dose interruption until recovery to grade 1, restart at a lower dose Discontinue treatment if failure to recover within 4 weeks 3 Symptomatic, interfering with ADL, O2 required 4 Life threatening, ventilatory support indicated Consult a pulmonologist Perform diagnostics to exclude infectious causes If infectious cause excluded, consider use of corticosteroids In presence of impending respiratory distress: consider use of concomitant corticosteroids and antibiotics Dose interruption until recovery to grade 1, consider restarting everolimus at a lower dose If toxicity recurs at grade 3, consider discontinuation Discontinue everolimus 1. Adapted from Porta C, et al. Eur J Cancer. 2011;47(9):1287-1298; 2. Moldawer NP, et al. Kidney Cancer J. 2010;8(2):51-59; 3. Eisen T, et al. J Natl Cancer Inst. 2012;104(2):93-113; 4. Afinitor (everolimus) [US prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. 12

Noninfectious Pneumonitis: Patient Education Advise patients to promptly report any new or worsening respiratory symptoms Shortness of breath Cough Fever 25

Hepatitis B Virus Reactivation: Clinical Management Strategy PI3K/mTOR pathway activation has been associated with suppressed HBV viral replication; thus, mtor inhibition may trigger HBV replication and the process of viral reactivation 1 Baseline Results Reactivation Definition Management Resolution Positive HBV DNA OR Positive HBsAg Negative HBV DNA and HBsAg AND Positive HBsAb (with no history of vaccination against HBV) OR Positive HBcAb Increase of 1 log in HBV DNA relative to baseline HBV DNA value OR New appearance of measurable HBV DNA New appearance of measurable HBV DNA Start a second antiviral AND Interrupt everolimus administration until resolution ( baseline HBV DNA levels) Start first antiviral medication AND Interrupt everolimus administration until resolution (negative HBV DNA levels) 28 days: restart everolimus at one dose lower If patient is already receiving the lowest dose, restart at the same dose after resolution >28 days, discontinue everolimus Continue antiviral therapy at least 4 weeks after last dose of everolimus 1. Guo H, et al. J Virol. 2007;81(18):10072-11080. 12

GENERAL GUIDANCE ON EVEROLIMUS DOSE MODIFICATIONS 27

Everolimus Dose Modifications for AEs Management of AEs may require temporary dose reduction and/or interruption Grade Everolimus Dose Modification 1 Mild Treat according to best clinical practice No specific dose modifications are needed 2 Moderate a Interrupt everolimus until recovery to grade 1 Restart everolimus at the same dose 3 Severe a Interrupt everolimus until recovery to grade 1 Restart everolimus at the next lower dose level 4 Debilitating b Discontinue everolimus a For stomatitis, pneumonitis, and other toxicities. b For stomatitis and pneumonitis. Afinitor (everolimus) [US prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. 12

Everolimus Dose Modifications for Hepatic Impairment Dose reductions are recommended for patients with hepatic impairment Child-Pugh Class Everolimus Dose Modification 1 Mild Suggested dose is 7.5 mg/day Dose can be further reduced to 5 mg/day if not well tolerated 2 Moderate Suggested dose is 5 mg/day Dose can be further reduced to 2.5 mg/day if not well tolerated 3 Severe If desired benefit outweighs the risk, suggested dose is 2.5 mg/day This dose should not be exceeded Afinitor (everolimus) [US prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. 12

Everolimus Dose Modifications for Drug-Drug Interactions Avoid use of strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) Be cautious when using moderate CYP3A4 and/or P- glycoprotein inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) If coadministration is necessary, reduce dose to 2.5 mg/day Avoid use of strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) If coadministration is necessary, increase dose to 20 mg/day 30

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