CLORIDRATO DE ERLOTINIBE NO TRATAMENTO EM 1ª LINHA DE CPNPC

1. CLORIDRATO DE ERLOTINIBE NO TRATAMENTO EM 1ª LINHA DE CPNPC DR NELSON AQUINO DE CARVALHO IPC 31/03/2011

2. CASO CLÍNICO PACIENTE C.H.A. - 59 ANOS - BRANCO - CASADO QUEIXA PRINCIPAL: DOR EM COLUNA CERVICAL Início: Dor progressiva em coluna cervical irradiando para mãos. CT Coluna Cervical: TU Corpo Vertebral C2 com componentes de partes moles, infiltrando e Comprimindo canal medular.

3. CASO CLÍNICO 09/12/2010 : Laminectomia + Artrodese + Ressecção Parcial de Tumor Cervical • LAP: • HE: Metástases de Adenocarcinoma no Tecido Ósseo • IHC: Sítio primário: Pulmão • EGFR: (NOVOCASTRA/COD. EGFR.25) POSITIVO • ++/+++ 70% de células

4. CASO CLÍNICO • TRATAMENTO: • Radioterapia em Coluna Cervical • Quimioterapia com TARCEVA • Estadiamento com PET-CT

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18. Efficacy results from the randomised phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM), in Chinese advanced non-small-cell lung cancer (NSCLC) patients (pts) with EGFR activating mutations Caicun Zhou,1 Yi-long Wu,2 Gongyan Chen,3 Jifeng Feng,4 Xiaoqing Liu,5 Changli Wang,6 Shucai Zhang,7 Jie Wang,8 Songwen Zhou,1Shengxiang Ren,1 on behalf of the OPTIMAL investigators 1Shanghai Pulmonary Hospital, Tongji University, Shanghai; 2Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou; 3The Cancer Hospital of Harbin Medical University, Harbin; 4Jiangsu Province Cancer Hospital, Nanjing; 5307 Hospital of the Academy of Military Medical Sciences, Cancer Center, Beijing; 6Tianjin Cancer Hospital, Tianjin; 7Beijing Chest Hospital, Beijing; 8Peking University School of Oncology, Beijing Cancer Hospital, Beijing; China

19. Rationale for the OPTIMAL study • Erlotinib, an EGFR tyrosine-kinase inhibitor (TKI) provides a significant survival benefit in unselected patients with relapsed or refractory advanced NSCLC1 • Tumours with activating EGFR mutations are particularly sensitive to EGFR TKI therapy • potential for first-line erlotinib in patients whose tumours are confirmed to have these mutations • Clinical selection to enrich study populations for activating EGFR mutations is inadequate • 40–60% mutation rate achieved when selecting Asian patients on the basis of clinical characteristics2–4 1. Shepherd FA, et al. N Engl J Med 2005;353:123–32; 2. Mok T, et al. N Engl J Med 2009;361:947–573. Lee JS, et al. WCLC 2009; 4. Janne PA, et al. ASCO 2010

20. Primary endpoint Progression-free survival (PFS) Secondary endpoints Overall survival (OS), objective response rate (ORR), time to disease progression, duration of response, safety, HRQoL (FACT-L, LCSS), exploratory biomarker analyses OPTIMAL study design Erlotinib 150mg/day • Chemonaїve • Stage IIIB/IV NSCLC • EGFR Act Mut+ (exon 19 deletion or exon 21 L858R mutation) • ECOG PS 0–2 • (n=165) R 1:1 Gemcitabine (1,000 mg/m2 d1,8) Carboplatin (AUC5 d1) q3w, up to 4 cycles Stratification factors • Mutation type • Histology • Smoking status Efficacy assessment • Every 6 weeks Act Mut+ = activating mutations; ECOG = Eastern Cooperative Oncology Group; PS = performance status HRQoL = health-related quality of life; FACT-L = Functional Assessment of Cancer Therapy-Lung; LCSS = lung cancer symptom scale

21. Inclusion criteria Age ≥18 years old with informed consent Histologically confirmed advanced or recurrent stage IIIB or IV NSCLC EGFR exon 19 deletions or exon 21 L858R mutation detected via polymerase chain reaction (PCR)-based direct sequencing (central laboratory) Measurable disease, according to RECIST ECOG PS 0–2 Adequate haematological, biochemical and organ function Exclusion criteria Prior systemic anticancer therapy (adjuvant or neoadjuvant allowed where relapse occurred ≥6 months after final treatment) Uncontrolled brain metastases Key inclusion/exclusion criteria RECIST = Response Evaluation Criteria in Solid Tumors

22. Statistical analyses • Objective:to demonstrate superiority of erlotinib over chemotherapy based on PFS • Sample size set as 152 patients (103 events) based on following assumptions • PFS: erlotinib 11 months, chemotherapy 6 months • 10% dropout rate • 80% power to detect HR 0.54; α=0.025 • 12-month enrolment period and 12-month follow-up • Primary PFS data cut-off: 16 July 2010 • Updated PFS data cut-off: 16 August 2010 • median follow-up: 15.6 months HR = hazard ratio

23. Study profile (16 August 2010) 165 patients randomized 83 assignedto receive erlotinib 82 assignedto receive gem/carbo 10 excluded – 9 withdrew consent – 1 did not start treatment 1 excluded – no target lesion 82 received erlotinib 72 received gem/carbo 51 discontinued study – 49 PD or death – 1 withdrew consent – 1 lost to follow-up 71 discontinued study – 63 PD or death – 4 protocol violation* – 4 lost to follow-up 31 remain in study 1 remains in study 116 remain in OS follow-up§ *Received erlotinib (3) or gefitinib (1) after chemotherapy, but before PD§112 events had occurred by 16 August 2010; PD = progressive disease

24. Baseline characteristics Current = smoked >100 cigarettes in lifetime and either currently smoking or quit <1 year ago; Former = smoked >100 cigarettes in lifetime and quit ≥1 year ago; Never = smoked ≤100 cigarettes in lifetime or never smoked

25. Erlotinib (n=82) Gem/carbo (n=72) OPTIMAL PFS: primary analysis (ITT) 1.0 0.8 0.6 0.4 0.2 0 HR=0.16 (0.10–0.26) Log-rank p<0.0001 PFS probability 0 5 10 15 20 Time (months) Patients at risk Erlotinib 82 70 51 15 2 Gem/carbo 72 26 4 0 0

26. Erlotinib (n=82) Gem/carbo (n=72) OPTIMAL PFS: updated analysis (ITT) 1.0 0.8 0.6 0.4 0.2 0 HR=0.16 (0.10–0.26) Log-rank p<0.0001 PFS probability 4.6 13.1 0 5 10 15 20 Time (months) Patients at risk Erlotinib 82 70 51 20 2 Gem/carbo 72 26 4 0 0

27. Subgroup analysis of PFS Overall Stage IV Stage IIIB Female Male Age ≥65 Age <65 PS 0–1 PS 2 Never smoker Current/former smoker Adenocarcinoma Non-adenocarcinoma HR (95% Cl) n 0.16 (0.10–0.26) 154 0.18 (0.11–0.28) 138 0.27 (0.06–1.16) 16 0.13 (0.07–0.24) 91 0.26 (0.14–0.50) 63 0.17 (0.07–0.43) 38 0.19 (0.11–0.31) 116 0.16 (0.10–0.26) 144 0.21 (0.04–1.28) 10 0.14 (0.08–0.25) 109 0.21 (0.09–0.49) 45 0.17 (0.11–0.28) 134 0.22 (0.06–0.73) 20 0 0.5 1.0 1.5 HR Favours erlotinib Favours gem/carbo

28. Best tumour response* *in evaluable patients; CR = complete response; PR = partial response; SD = stable disease; DCR = disease control rate (CR + PR + SD)

29. Response according to clinical characteristics Response rate (%)

30. Summary of safety data *increased alanine aminotransferase (ALT); rash; total bilirubin elevation; stomatitis **1 patient, due to spleen cyst; ¶2 pts, increased ALT

31. Treatment-related haematological toxicity 100 80 60 40 20 0 Patients (%) Anaemia Infection Neutropenia Thrombocytopenicpurpura Thrombocytopenia Febrile neutropenia

32. Treatment-related non-haematological toxicity 100 80 60 40 20 0 Patients (%) Rash Fatigue Dry skin Diarrhoea Stomatitis Paronychia Constipation ALT elevation ILD-like events Skin exfoliation Nausea/vomiting Renal dysfunction

33. Summary • OPTIMAL is the first prospective head-to-head study comparing first-line erlotinib with platinum doublet chemotherapy in EGFR Act Mut+ NSCLC • Erlotinib is highly potent in this setting • median PFS of 13.1 months and HR of 0.16 vs chemotherapy • Consistent benefit observed regardless of histology, smoking history, age, gender and disease stage • Erlotinib had less severe toxicity than chemotherapy, except for rash (mostly mild or moderate in severity)

34. CONSIDERAÇÕES FINAIS • Dúvidas: • É seguro optar o TARCEVA como tratamento de 1ª linha • nos pacientes de CPNPC com EGFR+? • Existe indicação de ressecção de nódulo pulmonar • Existe indicação de Bifosfonato EV?