26 ส งหาคม 2553; น.

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1 26 ส งหาคม 2553; น. Asia Pacific Oncology Pharmacy Society T h a i l a n d Lunch Symposium: Industry Satellite symposium on Erbitux ห วหน าสาขามะเร งว ทยา และ ห วหน าศ นย องค รวมเพ อการศ กษาและบ าบ ดโรคมะเร ง (HOCC-PSU) ภาคว ชาอาย รศาสตร มหาว ทยาล ยสงขลานคร นทร

2 ERBITUX: A New Era for Cancer Treatment Patrapim Sunpaweravong, MD Holistic Center for Cancer Study and Care (HOCC-PSU) Division of Medical Oncology Prince of Songkla University 26 Aug 2010

3 In Europe Erbitux (Cetuximab): Indications Erbitux is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)- expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan. Erbitux is indicated for the treatment of patients with squamous cell cancer of the head and neck (SCCHN): in combination with radiation therapy for locally advanced disease or in combination with platinum-based chemotherapy for recurrent and/or metastatic disease

4 In Thailand, Erbitux: Indications NOW APPROVED from 1 st line mcrc Erbitux is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)- expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan Erbitux in combination with radiation therapy is indicated for the treatment of patients with locally advanced squamous cell cancer of the head and neck.

5 EGFR signaling The EGFR is activated by growth factors (e.g. epidermal growth factor (EGF) and transforming growth factor- (TGF- )). EGFR-activation leads to the building of either receptor homo- or heterodimers. Receptor dimerization initiates an intracellular signaling cascade, gene activation and the stimulation of cell cycle progression. * Baselga 2001

6 EGFR expression in human tumors Head and neck Type of tumor Tumors with EGFR expression Head and neck % Colon 75 89% Pancreas Up to 95% Colorectal Breast Up to 91% Renal Up to 90% NSCLC Up to 80% Lung (NSCLC) Ovary Up to 77% Bladder Up to 72% Glioma Up to 63% EGFR expression is also linked to reduced response, a poorer outcome, and/or increased resistance to chemotherapy and RT

7 Erbitux (cetuximab) Erbitux (cetuximab) is an IgG1 MAb targeting the EGFR Binding blocks EGFR signaling and inhibits proliferation angio-genesis metastasis stimulates apoptosis and differentiation

8 ERBITUX may elicit ADCC ERBITUX binding to a tumor cell can trigger a host immune response, resulting in destruction of the tumor cell In mediating the ADCC response cytotoxic host immune cells recognize the Fc (constant) region of bound ERBITUX The tumor cell is lyzed and undergoes apoptosis ADCC: antibody-dependent cellular cytotoxicity

9 Erbitux in mcrc: Personalized Therapy to Improve outcomes in mcrc with KRAS

10 KRAS 1st Molecular Marker for EGFR inhibitors in Colorectal Cancer (CRC) When KRAS gene is mutated, KRAS protein (p21 ras) is active regardless of EGFR activation ERBITUX KRAS mutations are an early event occur in 40 45% of CRC patients Hot spot point mutation within codon 12 or 13 of the KRAS gene 1. Lièvre A, et al. Cancer Res 2006;66: ; 2. van Engeland M, et al. Oncogene 2002;21: ; 3. Jen J, et al. Cancer Res 1994;54: ; 4. Esteller M, et al. J Clin Oncol 2001;19:

11 Evolution of Treatment in mcrc Irinotecan Oxaliplatin Targeted therapy 5-FU/LV -> UFT, Capecitabine VEGF inhibitors: Bevacizumab EGFR inhibitors: Erbitux

12 Pre-treated Erbitux Targeted EGFR in mcrc 3rd line and beyond NCIC C0.17 BOND 2nd line EPIC BOND after irinotecan Nonpre-treated after oxaliplatin 1st line CRYSTAL + FOLFIRI Phase III Adjuvant PETACC 8 OPUS + FOLFOX Phase II NCCTG NO147

13 CRYSTAL: Study design Cetuximab + FOLFIRI EGFR-expressing mcrc R Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly + irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus mg/m2 as 46-hr continuous infusion) + FA every 2 weeks Stratification by: Regions ECOG PS Populations: Randomized patients (n=1217) FOLFIRI Irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus mg/m2 as 46-h continuous infusion) + FA every 2 weeks Safety population (n=1202) ITT population (n=1198) Van Cutsem E, et al. NEJM 2009

14 CRYSTAL: PFS & Response KRAS wild-type Median PFS [95% CI] FOLFIRI ERBITUX + FOLFIRI (n=350) 8.4 months [ ] (n=316) 9.9 months [ ] HR [95% Cl] Odd Ratio [ ] p<0.0001a (log rank) Response rate (%) p-value 57.3 Progression-free survival 50 Erbitux + FOLFIRI FOLFIRI yr PFS 25% vs 43% Months acochran Mantel Haenszel test FOLFIRI (n=350) ERBITUX + FOLFIRI (n=316) Van Cutsem E, et al. ASCO GI 2010 (Abstract No. 281)

15 OS in patients with KRAS wt tumors 1.0 FOLFIRI ERBITUX + FOLFIRI Median OS (n=350) 20.0 months (n=316) months 0.8 [95% CI] [ ] [ ] HR [95% Cl] OS estimate [ ] p-value (log rank) Median follow-up was 46 months ERBITUX + FOLFIRI FOLFIRI Time (months) Van Cutsem E, et al. ASCO GI 2010 (Abstract No. 281)

16 CRYSTAL: Conclusions The addition of Erbitux to FOLFIRI in the 1st-line treatment of mcrc resulted in a significant improvement in median OS to 23.5 months in patients with KRAS wild-type tumors (p=0.0094) 20% reduction in risk of death (p=0.0093) 30% reduction in risk of progression (p=0.0012) Doubling in likelihood of tumor response (OR , p<0.0001) Van Cutsem E, et al. ECCO/ESMO Congress 2009; Abstract No: 6077

17 OPUS: Study design Cetuximab + FOLFOX mg/m2 initial IV infusion (day 1) then 250 mg/m2 weekly + oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeks EGFR-expressing mcrc R FOLFOX-4 Stratification by: ECOG PS 0-1, 2 Oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeks Treatment until progression, symptomatic deterioration, or unacceptable toxicity Bokemeyer C, et al. J Clin Oncol 2008

18 OPUS: PFS & response KRAS wild-type Median PFS FOLFOX4 ERBITUX + FOLFOX4 (n=97) 7.2 months (n=82) 8.3 months HR [95% Cl] [ ] p-value (log rank) Cetuximab + FOLFOX FOLFOX Response rate (%) 1.0 Progression-free survival Odd Ratio p=0.0027a astratified Months Cochran Mantel Haenszel test FOLFOX4 (n=97) ERBITUX + FOLFOX4 (n=82) Bokemeyer C, et al. ASCO GI 2010 (Abstract No. 428)

19 OS in patients with KRAS wt tumors 1.0 No. of events 0.9 Median OS [95% CI] FOLFOX4 (n=97) ERBITUX + FOLFOX4 (n=82) [ ] 22.8 [ ] OS estimate 0.8 HR [95% CI]: [ ] p-value= (log rank) ERBITUX + FOLFOX4 FOLFOX Time (months) Bokemeyer C, et al. ASCO GI 2010 (Abstract No. 428)

20 OPUS: Conclusions The addition of Erbitux to FOLFOX in the 1st-line treatment of mcrc resulted in an improvement in median OS of 4.3 months in patients with KRAS wild-type 43% reduction in risk of progression (p=0.0064) More than doubling of likelihood of tumor response (OR 2.551, p=0.0027) Bokemeyer C, et al. ECCO/ESMO Congress 2009; Abstract No: 6079

21 CRYSTAL + OPUS: Meta-analysis CRYSTAL: number of patients assessable for KRAS mutation status increased from 45% (n=540) to 89% (n=1063) ERBITUX ± FOLFIRI CRYSTAL OPUS ERBITUX ± FOLFOX4 Pooled raw data (OS, PFS, ORR) ERBITUX + CT vs CT alone Van Cutsem E, et al. ECCO-ESMO Abstract No. 6077

22 Meta-analysis results: Significantly improved OS in KRAS wt population Van Cutsem E, et al. ECCO-ESMO Abstract No. 6077

23 Conclusions Personalized treatment via the use of biomarkers is the way forward KRAS is currently the only clinically relevant validated biomarker for ERBITUX treatment in 1st-line mcrc KRAS status should be determined at diagnosis to ensure optimal treatment selection ERBITUX is the first targeted therapy to show a significant OS benefit for mcrc in a phase III study when combined with a current standard chemotherapy (FOLFIRI) ERBITUX significantly increases PFS, response rate, and tumor shrinkage ERBITUX in combination with chemotherapy is a new 1st-line standard in mcrc for patients with KRAS wt tumors

24 Current KRAS Laboratories in Thailand Hospital Method Price as of TAT Aug Ramathibodi Hospital Direct Sequencing 6,600/6,800 Bahts 10 days 2. Siriraj Hospital Test Kit (DxS) 6,600/7,200 Bahts 7 days 3. Chulalongkorn Hospital Pyro-sequencing 6,500 Bahts 7-10 days 4. Chulabhorn Hospital Direct Sequencing 4,500 Bahts 3 weeks 5. Bangkok Hospital Test Kit (DxS) 10,000 Bahts 7 days 6. Maharajnakorn Chiangmai Hospital Direct Sequencing 6,500 Bahts 3 weeks 7. Songklanagarind Hospital Direct Sequencing N/A 3 weeks

25 New paradigm shift to treat liver limited disease mcrc: give hope for a cure?

26 Resection rate is significantly associated with response rate in mcrc Liver metastases only 0.6 Resection rate All patients Response rate Folprecht G, et al. Ann Oncol 2005;16:

27 ERBITUX significantly increases response rate resulting in high resection rate R0 resection rate CRYSTAL Liver-limited disease cohort in ITT population ITT p= ITT 4.5 Patients (%) Patients (%) 8 OPUS FOLFIRI ERBITUX + FOLFIRI FOLFIRI ERBITUX + FOLFIRI FOLFOX4 ERBITUX + FOLFOX4 Van Cutsem E, et al. ASCO GI 2010 (Abstract No. 281); Van Cutsem E, et al. Ann Oncol 2008;19(Suppl. 8):viii4 [update to 710]; Van Cutsem E, et al. Eur J Cancer Suppl. 2007;5:235 (Abstract No. 3001) (updated information presented); Bokemeyer C, et al. J Clin Oncol 2009;27:

28 Standardizing resectability: The CELIM study Patients with technically unresectable / 5 liver metastases of CRC without extrahepatic metastases Biopsy EGFR screening Primary endpoint: Response Randomization FOLFOX6 + ERBITUX Blinded surgical review FOLFIRI + ERBITUX Therapy: 8 cycles (~4 months) Evaluation of resectability Technically unresectable Technically resectable 4 further treatment cycles Resection Therapy continuation for 6 cycles (~3 months) Folprecht G, et al. ASCO Gastrointestinal Cancers Symposium 2009, Abstract No. 296 (updated information presented)

29 CELIM: High response and liver resection rates achieved with ERBITUX in patients with KRAS wt tumors Response rate Patients (%) Patients (%) Patients (%) R0/R1/RFA resection rate R0 resection rate RFA=radio frequency ablation Bechstein WO, et al. J Clin Oncol 2009;27(Suppl. 15): Abstract No. 4091

30 CELIM: Resectability according to blinded assessment by 7 surgeons Before ERBITUX + CT After ERBITUX + CT % % 0% Non-resectable Chemo preferred Resectable Exploration 50% resectable 0% Resectable - 100% non - resectable Non-resectable 100% 50% 100% 100% Patient Patient 32% 60% ERBITUX + CT increases resectability in patients with liver metastases (p<0.01) 28% Bechstein W, et al. ASCO 2009

31 ERBITUX (cetuximab) In head and neck cancer

32 Optimizing the treatment in locally advanced SCCHN

33 Current treatment standards in locally advanced SCCHN Erbitux + Radiotherapy Radiotherapy only Chemotherapy + Radiotherapy

34 Erbitux + RT in locally advanced SCCHN

35 Erbitux in locally advanced SCCHN: Bonner Phase III study RT (n=213) Stage III and IV non-metastatic SCCHN N=424 R Erbitux + RT (n=211) Erbitux initial dose (400 mg/m2) Erbitux (250 mg/m2) + RT (wks 2 8) Primary endpoint: duration of locoregional control Secondary endpoints: OS, PFS, RR, QoL, and safety Bonner et al. NEJM 2006

36 Erbitux in locally advanced SCCHN: Significant benefit in locoregional control Erbitux + RT significantly increases median duration of locoregional control vs RT alone by 10 months Locoregional control (%) 100 HR=0.68 [95% CI: ] p= RT Erbitux + RT 3-year control rate 60 47% 24.4 months 14.9 months % Months Bonner et al. NEJM 2006

37 Erbitux in locally advanced SCCHN: 5-year survival update RT Erbitux + RT year survival rate Overall survival (%) 90 HR=0.73 [95% CI: ] p= months 46% months % Months Bonner et al. Lancet Oncol 2010

38 Compliance with Erbitux or CT when administered with RT CRT arms of different studies comparing CRT vs RT alone Weekly doses (median 8 doses) Erbitux cycles at weeks 1 and 5 Cisplatin2 2nd cycle 71 3 cycles at weeks 1, 4, and 7 Carboplatin/5-FU3 3rd cycle 51 3 cycles at weeks 1, 3, and 6 Cisplatin/5-FU/FA4 3rd cycle Patients receiving all planned doses (%) 1 Bonner et al. NEJM 2006; 2Huguenin et al. JCO 2004; 3Calais et al. J Natl Cancer Inst 1999; 4Semrau et al. IJROBP 2006; 5Budach et al. JCO 2005

39 Erbitux in locally advanced SCCHN Adding Erbitux to RT has proven to significantly Prolong survival Control disease for longer Increase response rate Erbitux + RT offers the highest therapeutic benefit Favorable safety profile Better compliance

40 Recurrent and/or metastatic SCCHN

41 EXTREME: Study design Randomized Group A Either cisplatin (100 mg/m2 IV, d1) or carboplatin (AUC 5, d1) + 5-FU (1000 mg/m2 IV, d1 4): 3-week cycles + Cetuximab 400 mg/m2 initial dose then 250 mg/m2 weekly Group B Either cisplatin (100 mg/m2 IV, d1) or carboplatin (AUC 5, d1) + 5-FU (1000 mg/m2 IV, d1 4): 3-week cycles 6 chemotherapy cycles maximum Cetuximab No treatment Progressive disease or unacceptable toxicity Vermorken JB et al. N Engl J Med 2008;359:

42 EXTREME: Overall survival Survival probability 0.8 Chemotherapy only Chemotherapy + Cetuximab 0.7 HR [95%CI]: 0.80 [ ] p= months months Survival time (months) Vermorken JB et al. N Engl J Med 2008;359:

43 EXTREME: Progression-free survival Progression free (%) Chemotherapy only Chemotherapy + Cetuximab HR [95%CI]: 0.54 [ ] 0.6 P< months months PFS time (months) 12 Vermorken JB et al. N Engl J Med 2008;359:

44 Objective response rate (%) EXTREME: Response rate CR = 0.9 CR = CT alone CT + Cetuximab Odds ratio (95% CI): 2.33 ( ); p<0.001 Vermorken JB et al. N Engl J Med 2008;359:

45 Cetuximab plus platinum-based chemotherapy in 1st-line R/M SCCHN Adding Cetuximab to platinum-based chemotherapy: significantly improves overall survival significantly increases PFS almost doubles the response rate is feasible with an acceptable side-effect profile First regimen in 30 years to show a survival benefit Cetuximab + platinum-based CT is a new standard in the treatment of R/M SCCHN

46

47 The new ERBITUX 5 mg/ml formulation Same benefits, more convenience ERBITUX 5 mg/ml is a sterile, colorless liquid for intravenous administration (syringe pump, infusion pump or gravity drip) ERBITUX 5 mg/ml comes in one vial size 20 ml (contains 100 mg of ERBITUX)

48 Key advantages ERBITUX 5 mg/ml offers comparable efficacy with the 2 mg/ml formulation it replaces PLUS the following advantages Preparation: FAST Less liquid means less handling FLEXIBLE Ready for use, or dilute if preferred* (sterile 0.9 % NaCl) Stable for up to 48 hrs** when stored < + 25 C in the recommended infusion containers Administration: SIMPLE No in-line filtration required * Data on file; ** ERBITUX Summary of Product Characteristics

49 Flexible preparation ERBITUX 5 mg/ml comes ready to use, but can if preferred, be diluted with a sterile 0.9 % sodium chloride solution The maximum tested dilution is 1 part ERBITUX + 10 parts NaCl solution* (e.g. 50 ml ERBITUX ml NaCl solution) * Data on file

50 Infusion rate For the ready to use solution, the maximum infusion rate is 10 mg/minute which is equal to 2 ml/minute. For example: After dilution of 1 part ERBITUX ready to use solution in 4 parts sterile NaCl solution (1:5 dilution), the rate of 10 mg/minute is equal to 10 ml/minute.* Storage of ERBITUX 5 mg/ml vials ERBITUX 5 mg/ml vials should be stored under refrigeration at 2 C to 8 C and not frozen. * ERBITUX Summary of Product Characteristics

51 Handling of ERBITUX 5 mg/ml As ERBITUX 5 mg/ml does not contain any antimicrobial preservative or bacteriostatic agent, the infusion is to be given immediately The in-use storage time of ERBITUX 5 mg/ml in the infusion bag or syringes is the responsibility of the user As guidance, in-use storage of ERBITUX 5 mg/ml should not exceed 24 hours at 2 C to 8 C, unless preparation has taken place under controlled and validated aseptic conditions ERBITUX 5 mg/ml prepared in this manner and stored in the recommended infusion containers is chemically and physically stable for up to 48 hours* at controlled room temperatures up to 25 C Any unused portion of the vial should be discarded. * ERBITUX Summary of Product Characteristics

52 Summary New formulation Concentration Old formulation Erbitux 5mg/ml Erbitux 2mg/ml Sterile, colourless liquid Sterile, colourless liquid Vial cap is grey Vial cap is red 20ml = 100mg of Erbitux 50ml = 100mg of Erbitux Description Vial sizes Ready to use in empty bag, or Should not be diluted Preparation During administration Maximum infusion rate Dilute if preferred with sterile 0.9% NaCl solution No in-line filtration needed In-line filtration required 10mg/min 10mg/min

53 Hypersensitivity reactions management กรณ ม อาการในระด บ grade 1 หร อ 2 (อาการ ม ไข หนาวส น เว ยนศ รษะ ม ผ น หร อหายใจต ด) ปร บลด infusion rate ให ช าลง และ ควรให ยาใน infusion rate ระด บต าท กคร งส าหร บ การให ยาคร งต อไป กรณ ม อาการในระด บ grade 3 หร อ 4 (ระบบทางเด นหายใจอ ดต นอย างรวดเร ว ผ นลมพ ษ และ/หร อ ภาวะความด นต า ) ต องหย ดยาท นท และหย ดการร กษาอย างถาวร และ อาจม ความจ าเป นต องให การร กษาแบบภาวะฉ กเฉ น

54 Skin reactions related to EGFR inhibitor therapy อาการท พบบ อยค อผ นล กษณะคล ายส ว (acne-like rash) ผ วแห ง และ/หร อ เล บ ผ ดปกต (ซ งพบได น อยกว า) เช น เน อเย อรอบเล บม ออ กเสบ (paronychia) ส วนใหญ พบในระหว างส ปดาห แรกของการร กษา จากน นจะบรรเทาลงโดยไม ม การต ดเช อ DefinitionNCI-CTC skin reactions (rash/desquamation) Grade 1 Macular or papular eruption or erythema without associated symptoms Grade 2 Macular or papular eruption or erythema with pruritus or other associated symptoms; or localised desquamation or other lesions covering < 50% of BSA Grade 3 Symptomatic generalized erythroderma or macular, papular or vesicular eruption or desquamation covering 50% of BSA

55 การบรรเทาอาการ ใช bath oil /shower oil แทน ประเภทเจล (shower gel) หร อสบ ใช emollient cream ป องก นผ วแห ง ใช sun protection ป องก นการเก ด hyperpigmentation อาจปร กษาแพทย ผ วหน งเม อจ าเป น

56 Treatment adjustment scheme for Erbitux เม อพบผ ป วยม ความร นแรงในอาการปฏ ก ร ยาต อผ วหน งระด บ grade 3 หย ดการให EBITUX จนอาการลดความร นแรงลงมาท grade 2 จ งจะให ยาคร งต อไป และถ าเก ดปฏ ก ร ยาน เป นคร งแรก ของการร กษา อาจไม ต องปร บเปล ยนขนาดยาท ให กรณ ท เก ดอาการข นเป นคร งท 2และคร งท 3 ต องม การหย ดร กษาด วย ERBITUX เช นก น โดยถ าท ง 2 กรณ สามารถลดความร นแรงลงมาท grade 2 ได ควรปร บขนาดยาจากเด มลงมาคราวละ 50mg/m2 : หล งการเก ดปฏ ก ร ยาในคร งท 2 อาจปร บขนาดยาลดลงเป น 200 mg/m2 ส าหร บการเก ดปฏ ก ร ยาในคร งท 3 ปร บเป น 150 mg/m2 ถ าม อาการในระด บร นแรงเก ดข นอ กเป นคร งท 4 หร อไม สามารถลด ระด บความร นแรงของอาการลงมาท grade 2 ในระหว างท หย ดการ ร กษา จ าเป นต องหย ดการร กษาด วย ERBITUX อย างถาวร