PANITUMUMABE Ricardo Caponero, Clínica de Oncologia Médica - São Paulo - SP - 2011 Ricardo Caponero.

PANITUMUMABE Ricardo Caponero, Clínica de Oncologia Médica - São Paulo - SP Ricardo Caponero

Declaração de Conflito de Interesses:
De acordo com a Resolução 1595/2000 do Conselho Federal de Medicina e RDC 102/2000 da ANVISA, declaro que: Participo de estudos clínicos patrocinados pelas empresas: Novartis; GlaxoSmithKline. Participo como palestrante de eventos das empresas: Aché; AstraZeneca; Bayer; GlaxoSmithKline; Helssin; Janssen-Cilag; MSD; Novartis; Pfizer; Sanofi-Aventis; Roche, Zodiac. Participo como membro do conselho consultivo das empresas: AstraZeneca; GlaxoSmithKline; Janssen-Cilag; Pfizer; Sanofi- Aventis; Merck; Novartis. Não possuo ações de quaisquer destas companhias farmacêuticas. Ricardo Caponero, 2011

OS ANTICORPOS MONOCLONAIS

Anticorpos Fisiologia
Produzidos por linfócitos (um dos tipos de glóbulos brancos do sangue) Contra antígenos específicos Produzindo a reação antígeno-anticorpo Imunidade humoral Parte da imunidade celular (Citotoxicidade dependente da apresentação de antígeno)

Anticorpos Pressuposto Células tumorais diferem das células normais
Genoma e fenótipo Produção insuficiente ou ausente de anticorpos contra esses antígenos É possível produzir anticorpos contra antígenos específicos Ex.: Soros antiofídicos

Anticorpos monoclonais
Problemas Produção em larga escala Imunogenicidade dos anticorpos de outras espécies Falta de um alvo específico

Prêmio Nobel de Medicina e Fisiologia 1984
Niels K. Jerne 1911 – 1994 Denmark Basel Institute for Immunology Basel, Switzerland Georges J.F. Köhler 1946 – 1995 Federal Republic of Germany César Milstein 1927 – Great Britain and Argentina MRC Laboratory of Molecular Biology Cambridge, Great Britain Ricardo Caponero

Evolução da tecnologia dos hibridomas
MURINO 100% de proteína do camundongo QUIMÉRICO 34% de proteína do camundongo (Cetuximabe) HUMANIZADO 10% de proteína do camundongo (Bevacizumabe) HUMANO 100% de proteína humana (Panitumumabe) Ricardo Caponero

Desenvolvimento de mAbs anti-EGFR
mAbs de camundongo mAbs recombinantes quiméricos Anticorpos enxertados mAbs trasfectados por fagos mAbs humanos derivados de camundongo transgênico 1975 1984 1986 1990 1994 11 anos 10 anos 11 anos 12 anos 12 anos 1986 1994 1997 2002 2006 Camundongo Humano Muronomabe (OKT3) Abciximabe Daclizumabe Adalimumabe Panitumumabe

Produção de anticorpos monoclonais humanos
Rato transgênico (ou outro bicho) Com os genes da imunoglobulina humana inserido em seu genoma Que não produza seus próprios anticorpos XenoMouse™ Ricardo Caponero

O Panitumumabe é o único anticorpo monoclonal totalmente humano aprovado para o tratamento do carcinoma colorretal 100% de proteína do camundongo Camundongo ~10% de proteína do camundongo Humanizado ~34% de proteína do camundongo Quimérico Humano 100% de proteína humana Cetuximabe Bevacizumabe Panitumumabe Cetuximabe† Bevacizumabe Panitumumabe† Pré medicação1 Anti-histamínico + corticosteróide (mandatório para a 1º, recomendado para infusões subsequentes) Nenhuma Reações infusionais Todos os graus Severa 20% 25%2 <3% <1%3,4 3% <1%1 Yang XD, et al. Crit Rev Oncol Hematol 2001;38:17– Erbitux®, MabThera®, Avastin®, Vectibix® European Public Assessment Reports as of May 2011; 2. Erbitux® US Package Insert as of May 2011, 3. Avastin® US Prescribing Information as of May 2011; 4. Kang and Saif. J Support Oncol 2007;5:451–7. † Monotherapy in mCRC. Data are not from comparative studies.

Outras vantagens dos mAbs humanos
Evitam a formação de anticorpos antianticorpos Antimurinos (HAMAs) Antiquiméricos (HACAs) Reduzem o risco de: Reações anafiláticas Neutralização dos anticorpos terapêuticos Yang X-D, Jia X-C, Corvalan JRF, Wang P, Davis CG. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol. 2001;38:17-23 Yang X-D, Jia X-C, Corvalan JRF, Wang P, Davis CG. Crit Rev Oncol Hematol 2001; 38: 17-23 Ricardo Caponero

DENOMINAÇÃO COMUM BRASILEIRA

Denominação Comum Brasileira Radical geral: -mabe Sub-radicais Origem Sub-radical + Radical geral a Ratos amabe e Hamster emabe i Primatas imabe o Camundongos omabe u Humanos umabe xi Quiméricos ximabe zu Humanizados zumabe Ricardo Caponero

Denominação Comum Brasileira Sub-radicais relacionados a doenças ou classe dos alvos Sub-radicais Classe do alvo -ba(c)- Bacteriana -ci(r)- Cardiovascular -le(s)- Lesões infecciosas -li(m)- Imunomodulador -vi(r)- Viral - tu(m) - Tumores (vários) Ricardo Caponero

Denominação Comum Brasileira Sub-radicais relacionados ao local dos tumores Sub-radicais Local dos tumores -co(l)- Cólon -go(t)- Testículos -go(v)- Ovários -li(m)- Linfócitos -mar(r)- Mamas -me(l)- Melanoma -pr(o)- Próstata -tu(m)- Vários lugares Ricardo Caponero

Beva.ci.zu.mabe Pani.tu.mu.mabe Exemplos Monoclonal Humanizado
Cardiovascular Humanizado Monoclonal Pani.tu.mu.mabe Vários tumores Humano Monoclonal Ricardo Caponero

O EGFR

Vectibix™ - Panitumumabe
Novembro de 2009 Fortunato Ciardiello, Giampaolo Tortora. EGFR Antagonists in Cancer Treatment. N Engl J Med 2008; 358 (11): Figure 1. Signal Transduction Pathways Controlled by the Activation of EGFR. Three steps can be schematically defined in the activation of EGFR-dependent intracellular signaling.2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 First, the binding of a receptor-specific ligand occurs in the extracellular portion of the EGFR or of one of the EGFR-related receptors (HER2, HER3, or HER4). Second, the formation of a functionally active EGFR-EGFR dimer (homodimer) or of an EGFR-HER2, EGFR-HER3, or EGFR-HER4 dimer (heterodimer) causes the ATP-dependent phosphorylation of specific tyrosine residues in the EGFR intracellular domain. Third, this phosphorylation triggers a complex program of intracellular signals to the cytoplasm and then to the nucleus. The two major intracellular pathways activated by EGFR are the RAS–RAF–MEK–MAPK pathway, which controls gene transcription, cell-cycle progression from the G1 phase to the S phase, and cell proliferation, and the PI3K–Akt pathway, which activates a cascade of anti-apoptotic and prosurvival signals. bFGF denotes basic fibroblast growth factor, HB-EGF heparin-binding EGF, MAPK mitogen-activated protein kinase, P phosphate, PI3K phosphatidylinositol 3,4,5-kinase, TGF transforming growth factor , and VEGF vascular endothelial growth factor. Fortunato Ciardiello, Giampaolo Tortora. N Engl J Med 2008; 358 (11): Ricardo Caponero

Superfamília de receptores ERBB
Vectibix™ - Panitumumabe Novembro de 2009 Superfamília de receptores ERBB X AR HB-EGF ß cell TGFα EP NRG4 NRG2 NRG3 NRG1 ERBB1 EGFR ERBB2 HER2 ERBB3 HER3 ERBB4 HER4 TK Martin L, et al. J Clin Oncol 2007; 25: Ricardo Caponero

Ligação do EGF ao receptor
Vectibix™ - Panitumumabe Novembro de 2009 Ligação do EGF ao receptor Resultando em dimerização e autofosforilação TK EGF P Ativação de moléculas de sinalização intracelular Aumento da proliferação celular, inibição da apoptose, angiogênese neoplásica Martin L, et al. J Clin Oncol 2007; 25: Ricardo Caponero

Via de transdução do sinal do EGF
A ativação do EGFR desencadeia múltiplos processos Shc PI3K Grb2 AKT Sos-1 Ras mTOR Raf MEKK-1 MEK MKK-7 JNK ERK Fortunato Ciardiello, Giampaolo Tortora. N Engl J Med 2008; 358 (11):

Via de transdução do sinal do EGF
Metastases Angiogênese Shc PI3K Raf MEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1 TGFα Interleukin-8 bFGF VEGF Proliferação Inibição da Apoptose Transcrição

O KRAS

KRAS E BRAF em Carcinoma Colorretal
Vectibix™ - Panitumumabe Novembro de 2009 KRAS E BRAF em Carcinoma Colorretal Mutações constitutivas do KRAS predizem resistência aos MoAbs anti-EGFR em CCR Contexto refratário1 Contexto 1ª-linha2–3 Base para aprovação regulatória (EMEA) e diretrizes nacionais EUA (NCCN) O papel das mutações em outras proteínas transdutoras de sinal está sendo investivado i.e. BRAF: Contexto refratário4 EGFR RAS RAF PI3K MEK Taken from: ASCO 2008 presentation - Tabernero MAPK Akt Sobrevida Proliferação 1. Lièvre. Cancer Res 2006 2. Van Cutsem, et al. NEJM 2009 3. Bokemeyer, et al. JCO 2009 4. Di Nicolantonio, et al. JCO 2008 Ricardo Caponero

Novembro de 2009 Relações potenciais entre o status do KRAS e a resposta ao MoAb anti-EGFR, isolado ou em combinação com irinotecano em pacientes quimiorrefratários Não-respondedores mutação BRAF: 10% Resposta com a dose convencional 22% Não-respondedores: Perda do PTEN Ou mutação PI3K % ignorada KRAS Selvagem Resposta com o incremento da dose ~5% Não-respondedores: Razão ignorada % ignorada KRAS Mutado Não-respondedores: KRAS mutado: 40% Wong and Cunningham. J Clin Oncol 2008; 26 (35): Ricardo Caponero

BLOQUEIO DA VIA EGFR

Terapias disponíveis, dirigidas ao EGFR
Vectibix™ - Panitumumabe Novembro de 2009 Terapias disponíveis, dirigidas ao EGFR Pequenas moléculas inibidoras de tirosinoquinases Gefitinibe Erlotinibe Anticorpos monoclonais Cetuximabe Panitumumabe TK, tyrosine kinase. Manuel Hidalgo, 2009 Ricardo Caponero

Novembro de 2009 Figure 2. Mechanisms of Action of Anti-EGFR Drugs in Cancer Cells. Anti-EGFR monoclonal antibodies bind to the extracellular domain of EGFR and block ligand binding and receptor activation. Small-molecule EGFR tyrosine kinase inhibitors (TKIs) compete with ATP to bind to the intracellular EGFR tyrosine kinase catalytic domain and thus block EGFR autophosphorylation and downstream signaling. As a consequence of treatment with these drugs, key EGFR-dependent intracellular signals in cancer cells are affected. There is inhibition of cancer-cell proliferation (blockade of cell-cycle progression and G1 arrest through an increase in the p27kip1 inhibitor of cyclin-dependent kinases); inhibition of tumor-induced angiogenesis by blockade of cancer-cell production of angiogenic factors, including transforming growth factor , vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor; inhibition of cancer-cell invasion and metastasis; and potentiation of antitumor activity of cytotoxic drugs and radiotherapy Fortunato Ciardiello, Giampaolo Tortora. EGFR Antagonists in Cancer Treatment. N Engl J Med (11): Cancer cells may acquire the capacity for autonomous and dysregulated proliferation through the uncontrolled production of specific molecules that promote cell growth (growth factors) or through abnormal, enhanced expression of specific proteins (growth factor receptors) on the cell membranes to which growth factors selectively bind. Both processes trigger a series of intracellular signals that ultimately lead to the proliferation of cancer cells, induction of angiogenesis, and metastasis.1 The majority of human epithelial cancers are marked by functional activation of growth factors and receptors of the epidermal growth factor receptor (EGFR) family. Given this phenomenon, EGFR was the first growth factor receptor to be proposed as a target for cancer therapy. After 20 years of drug development, four EGFR antagonists are currently available for the treatment of four metastatic epithelial cancers: non–small-cell lung cancer, squamous-cell carcinoma of the head and neck, colorectal cancer, and pancreatic cancer. Less information is available about the use of EGFR antagonists in the treatment of earlier stages of cancer. This article summarizes the mechanisms of action of EGFR inhibitors, presents the clinical evidence of their anticancer activity, and considers the current, and controversial, clinical issues with respect to their optimal use in the treatment of patients with cancer. Fortunato Ciardiello, Giampaolo Tortora. N Engl J Med (11): Ricardo Caponero

Anticorpos monoclonais Anti-EGFR
Vectibix™ - Panitumumabe Novembro de 2009 Anticorpos monoclonais Anti-EGFR Shc PI3-K Raf MEKK-1 Ras Grb2 AKT Sos-1 Extracelular Intracelular Ricardo Caponero

Anticorpos monoclonais Anti-EGFR
Vectibix™ - Panitumumabe Novembro de 2009 Anticorpos monoclonais Anti-EGFR L1 L1 CR1 CR1 EGF EGF L2 L2 EGF, TGF-a Inibição por ligação alostérica EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; TGF-α, transforming growth factor alpha L1 L1 X Bloqueio do ligante CR1 CR1 L2 L2 CR2 CR2 Johns TG, et al. J Biol Chem 2004; 279: Ricardo Caponero

Novembro de 2009 Figure 3. Mechanisms of Action of Anti-EGFR Monoclonal Antibodies in Cancer Cells. The mechanisms of action and pharmacologic effects of anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors do not completely overlap, and some of the differences between them may be clinically relevant (see Table 1). In particular, the anti-EGFR monoclonal antibody cetuximab, which is an IgG1 immunoglobulin, could elicit host antitumor immune responses, including antibody-dependent, cell mediated cytotoxicity (Panel A). Furthermore, anti-EGFR monoclonal antibodies can induce EGFR cellular internalization and down-regulation, thereby enhancing receptor degradation (Panel B). These two mechanisms could make an important contribution to antitumor activity. Fortunato Ciardiello, Giampaolo Tortora. EGFR Antagonists in Cancer Treatment. N Engl J Med (11): Cancer cells may acquire the capacity for autonomous and dysregulated proliferation through the uncontrolled production of specific molecules that promote cell growth (growth factors) or through abnormal, enhanced expression of specific proteins (growth factor receptors) on the cell membranes to which growth factors selectively bind. Both processes trigger a series of intracellular signals that ultimately lead to the proliferation of cancer cells, induction of angiogenesis, and metastasis.1 The majority of human epithelial cancers are marked by functional activation of growth factors and receptors of the epidermal growth factor receptor (EGFR) family. Given this phenomenon, EGFR was the first growth factor receptor to be proposed as a target for cancer therapy. After 20 years of drug development, four EGFR antagonists are currently available for the treatment of four metastatic epithelial cancers: non–small-cell lung cancer, squamous-cell carcinoma of the head and neck, colorectal cancer, and pancreatic cancer. Less information is available about the use of EGFR antagonists in the treatment of earlier stages of cancer. This article summarizes the mechanisms of action of EGFR inhibitors, presents the clinical evidence of their anticancer activity, and considers the current, and controversial, clinical issues with respect to their optimal use in the treatment of patients with cancer. Fortunato Ciardiello, Giampaolo Tortora. N Engl J Med (11): Ricardo Caponero

O PANITUMUMABE

Panitumumabe: Anti EGFR
Vectibix™ - Panitumumabe Novembro de 2009 Panitumumabe: Anti EGFR Anticorpo monoclonal IgG2 contra o EGFRR, totalmente humano. Alta afinidade, KD = 5 x M Inibe a fosforilação da tirosino quinase induzida por ligante 100% proteína humana Manuel Hidalgo, 2009 Ricardo Caponero

Resposta tumoral (CCR M1)
Vectibix™ - Panitumumabe Novembro de 2009 Resposta tumoral (CCR M1) Estudo fase I de Panitumumabe Basal 6ª semana Melhor resposta CRC, colorectal cancer Data on file Ricardo Caponero

Estudo fase III vs. MCS Vectibix™ - Panitumumabe Novembro de 2009 Ricardo Caponero

Panitumumabe em pacientes com CCR (20020408)
G U I M N T O Panitumumabe 6,0 mg/kg q2s + MCS (n = 231) PD CCR Metastático (n=463) R 1:1 Melhor Cuidado de Suporte (MCS) (n = 232) Estudo opcional de cruzamento p/ panitumumabe (n = 176) PD 76% dos pacientes com apenas MCS entraram no estudo de cruzamento This large, randomised, phase 3 trial included patients with EGFR-expressing metastatic colorectal tumours with documented evidence of disease progression after failure of fluoropyrimidines and prespecified exposure to oxaliplatin and irinotecan. An open-label design was used in this study, as blinding was not feasible because of expected skin-related toxicities in patients receiving panitumumab. Patients were randomised between panitumumab 6 mg/kg every 2 weeks plus best supportive care (BSC) and BSC alone. Panitumumab was administered by intravenous (IV) infusion at a dose of 6 mg/kg given once every 2 weeks until disease progression, inability to tolerate the investigational product or other reason for discontinuation. Patients who progressed in the BSC alone group had the option of receiving panitumumab 6 mg/kg once every 2 weeks in a separate open-label extension study. Stratification was done for performance status and geographical region; this study was conducted in Europe, Australia, Canada and New Zealand. Patients determined to have progressive disease by the investigator were discontinued from the treatment phase of the study. Patients were evaluated for tumour response according to the modified Response Evaluation Criteria in Solid tumours (RECIST) at 1- to 2-month intervals during the first year (i.e. at weeks 8, 12, 16, 24, 32, 40, and 48) and every 3 months thereafter until disease progression. All patients were followed for survival approximately every 3 months for up to 2 years after their randomization into the study. Best supportive care could include psychotherapy, counselling, antibiotics, analgesics, growth factors, palliative surgery or nutritional support. References Peeters M, et al. A phase 3, multicentre, randomised controlled trial of panitumumab plus best supportive care (BSC) vs BSC alone in patients with metastatic colorectal cancer. Proc Am Assoc Cancer Res. 2006;47:A CP-1. Peeters M. presented at: 97th Annual Meeting of the American Association for Cancer Research (AACR) meeting; 4/3/2006; Washington DC. Presentation available at Accessed 7/25/06 Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13): Principais critérios de inclusão: Progressão de doença na avaliação tomográfica após fluoropirimidina, irinotecano e oxaliplatina Positividade padrão membrana na coloração para o EGFR em ≥1% das células tumorais Estratificação: Escore ECOG: 0 – 1 vs. 2 Região geográfica Van Cutsem E, et al. J Clin Oncol 2007; 25: ClinicalTrials.gov identifier: NCT ; protocol ID:

Novembro de 2009 Recrutados N = 1.040 Falhas na inclusão N = 577 Randomizados N = 463 Panitumumabe + MCS N = 231 Eric Van Cutsem, Marc Peeters, Salvatore Siena, Yves Humblet, Alain Hendlisz, Bart Neyns, Jean-Luc Canon, Jean-Luc Van Laethem, Joan Maurel, Gary Richardson, Michael Wolf, Rafael G. Amado. Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer. Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp Purpose Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR). We compared the activity of panitumumab plus best supportive care (BSC) to that of BSC alone in patients with metastatic colorectal cancer who had progressed after standard chemotherapy. Patients and Methods We randomly assigned 463 patients with 1% or more EGFR tumor cell membrane staining, measurable disease, and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC (n = 231) or BSC alone (n = 232). Tumor assessments by blinded central review were scheduled from week 8 until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included objective response, overall survival (OS), and safety. BSC patients who progressed could receive panitumumab in a cross-over study. Results Panitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66, [P < .0001]). Median PFS time was 8 weeks (95% CI, 7.9 to 8.4) for panitumumab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. Mean (standard error) PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC. Objective response rates also favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), which was confounded by similar activity of panitumumab after 76% of BSC patients entered the cross-over study. Panitumumab was well tolerated. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed. No patients had grade 3/4 infusion reactions. Conclusion Panitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer. Melhor Cuidado de Suporte N = 232 Panitumumabe após cruzamento N = 176 Eric van Cutsen, et al. J Clin Oncol 2007; 25 (13): Ricardo Caponero

Novembro de 2009 Fig 2. Progression-free survival (all randomly assigned analysis set). BSC, best supportive care. Efficacy Progression-free survival. A statistically significant improvement in PFS was observed favoring the panitumumab group compared with the BSC group (P < .0001, stratified log-rank test, all randomly assigned analysis set; Fig 2). Patients receiving panitumumab had a 46% decrease in the relative progression rate compared with patients receiving BSC (HR, 0.54; 95% CI, 0.44 to 0.66). At week 8, the PFS rates were 49% for panitumumab and 30% for BSC, and a 95% CI for the difference in PFS rates favored panitumumab at all scheduled assessments from weeks 8 to 32. Median PFS time was 8 (95% CI, 7.9 to 8.4) weeks for panitumumab and 7.3 (95% CI, 7.1 to 7.7) weeks for BSC. Mean (standard error) PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC. Consistent with the primary analysis, PFS favored panitumumab in all sensitivity analyses (HR range, 0.41 to 0.63; Table A1, online only). These included an interval-censored analysis to compensate for time ascertainment bias. In this analysis, which imputed radiologic disease progression to the nearest scheduled assessment time point, the HR for PFS continued to favor panitumumab (HR, 0.61). Eric Van Cutsem, Marc Peeters, Salvatore Siena, Yves Humblet, Alain Hendlisz, Bart Neyns, Jean-Luc Canon, Jean-Luc Van Laethem, Joan Maurel, Gary Richardson, Michael Wolf, Rafael G. Amado. Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer. Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp Eric van Cutsen, et al. J Clin Oncol 2007; 25 (13): Ricardo Caponero

Novembro de 2009 Fig 3. Subset analyses of progression-free survival (PFS). Hazard ratios (HR) for PFS and the 95% CIs for HRs are shown and represented by the diamond and horizontal line, respectively. The HR for the all randomly assigned analysis was adjusted for randomization factors, as described. All other HRs were unadjusted. Consistent with the primary analysis, PFS favored panitumumab in all sensitivity analyses (HR range, 0.41 to 0.63; Table A1, online only). These included an interval-censored analysis to compensate for time ascertainment bias. In this analysis, which imputed radiologic disease progression to the nearest scheduled assessment time point, the HR for PFS continued to favor panitumumab (HR, 0.61). Across all variables examined, the treatment effect on PFS was consistent with that of the primary analysis (Fig 3). By EGFR membrane–staining categories, PFS favored panitumumab (HR range, 0.47 to 0.62), and objective response rates were similar to those in the primary analyses (5% to 10%). Eric Van Cutsem, Marc Peeters, Salvatore Siena, Yves Humblet, Alain Hendlisz, Bart Neyns, Jean-Luc Canon, Jean-Luc Van Laethem, Joan Maurel, Gary Richardson, Michael Wolf, Rafael G. Amado. Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer. Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp Eric van Cutsen, et al. J Clin Oncol 2007; 25 (13): Ricardo Caponero

Panitumumab vs BSC: SVLP
K-ras natural (selvagem) 100 90 Panitumumabe + MCS (n = 124) MCS (n = 119) 80 70 60 12,3 Livres de Progressão (%) 50 HR: 0,45 (IC95%: 0,34 - 0,59) P < 0,0001 7,3 Amado R, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol 2008;26: Reprinted with permission from the American Society of Clinical Oncology. BSC, best supportive care; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. 40 30 20 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Semanas Rafael G. Amado, et al. J Clin Oncol 2008; 26 (10):

Panitumumab vs BSC: SVLP
K-ras mutado 100 90 Panitumumabe + MCS (n = 84) MCS Apenas (n = 100) 80 70 60 Livres de Progressão (%) 7,4 50 HR: 0,99 (IC95%: 0,73 - 1,36) 7,3 Amado R, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol 2008;26: Reprinted with permission from the American Society of Clinical Oncology. BSC, best supportive care; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. 40 30 20 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Semanas Rafael G. Amado, et al. J Clin Oncol 2008; 26 (10):

Novembro de 2009 Fig 4. (A) Overall survival (OS)—primary analysis (all randomly assigned analysis set). (B) OS by worst severity of skin-related toxicity. Hazard ratio (grade 2-4 relative to grade 1) was adjusted for randomization factors as described. Overall Survival In the primary analysis of OS, a total of 380 (82%) had died (186 [81%] patients in the panitumumab group and 194 [84%] patients in the BSC group). The minimum follow-up time was 52 weeks, with a median follow-up time of 72 weeks for all patients (range, 52 to 113 weeks). No significant difference was observed between groups (HR, 1.00; 95% CI, 0.82 to 1.22; P = .81, stratified log-rank test; Fig 4A). Subset Analyses Among patients in the panitumumab group, PFS appeared to favor patients with a worst severity of grade 2 to 4 versus grade 1 skin toxicity (HR, 0.62; 95% CI, 0.44 to 0.88). Nineteen (86%) of 22 responders had a maximum skin toxicity severity of either grade 2 or 3, and the remaining three (14%) responders had a maximum skin-toxicity severity of grade 1. Additionally, OS favored patients with a skin toxicity of grade 2 to 4 versus grade 1 (Fig 4B). Eric Van Cutsem, Marc Peeters, Salvatore Siena, Yves Humblet, Alain Hendlisz, Bart Neyns, Jean-Luc Canon, Jean-Luc Van Laethem, Joan Maurel, Gary Richardson, Michael Wolf, Rafael G. Amado. Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer. Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp Eric van Cutsen, et al. J Clin Oncol 2007; 25 (13): Ricardo Caponero

Panitumumabe: Resultados
Vectibix™ - Panitumumabe Novembro de 2009 Panitumumabe: Resultados Estudo randomizado, fase III, em carcinoma colorretal M1 Panitumumabe + MCS MCS Valor p SVLP em 24 sem, % 18 5 SVLP em 36 sem, % 10 4 Taxa de RO, % 8 Duração mediana da RO, semanas 17 -- SV, meses 6,4 0,6065* PFS, progression free survival; ORR, overall response rate; OS, overall survival; BSC, best supportive care; mCRC, metastatic colorectal cancer *A alta taxa de cruzamento (75%) compromete a habilidade em demonstrar efeito do tratamento na sobrevida global Análise atuarial (Kaplan-Meier) SVLE HR: 0,54 (IC95%: 0,44-0,66) Teste log-rank estratificado, p = 0, Peeters M. AACR Abstract CP-1. Ricardo Caponero

Status do KRAS e resposta ao panitumumabe
Vectibix™ - Panitumumabe Novembro de 2009 Status do KRAS e resposta ao panitumumabe n = 463 Ca. colorretal Metastático EGFR positivo ≥ 2 QTs prévias R A N D O M Panitumumabe 6 mg/kg cada 2 semanas + melhor cuidado de suporte (n = 231) Melhor cuidado de suporte (n = 232) Estratificação PS ECOG Região geográfica 75% Panit. MCS Valor p SVLP 24s (%) 18 5 HR: 054 IC95%: 0,44-0,66 p=0, SVLP 36s (%) 10 4 Taxa de respostas (%) 8 Duração de resposta (sem) 17 -- SV (meses) 6,4 0,6065 Peeters M. AACR Abstract CP-1 Amado RG, et al. GI Cancers Symposium Abstract 278 Ricardo Caponero

Status do KRAS e resposta ao panitumumabe
Vectibix™ - Panitumumabe Novembro de 2009 Status do KRAS e resposta ao panitumumabe SV mais curta em pacientes com mutações do KRAS, independentemente do tratamento recebido (HR: 0,67; IC95%: 0,55-0,82) Progressão de doença após o panitumumabe duas vezes maior em pacientes com KRAS mutado (Mutado: 70% vs. Selvagem: 36%) Panitumumabe efetivo apenas em pacientes com KRAS selvagem Situação mutacional do KRAS não influencia a SVLP após cuidado de suporte Genotipagem do KRAS recomendada Amado RG, et al. GI Cancers Symposium Abstract 278 Ricardo Caponero

EVENTOS ADVERSOS

CCR – Estudos com Panitumumabe em monoterapia
todos os graus de toxicidade graus 3 ou 4 de toxicidade Peeters M, et al. ASCO 2007

Toxicidade dermatológica do Panitumumabe
Hiperpigmentação Alterações capilares Telangiectasia Paroníquia Pele seca, fissuras Dermatite acneiforme Semanas Fases das possíveis reações cutâneas Van Cutsem E. Oncologist 2006; 11:

PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) Vectibix™ - Panitumumabe Novembro de 2009 Ricardo Caponero

PRIME Vectibix™ - Panitumumabe Novembro de 2009 Ricardo Caponero

Jean-Yves Douillard, Salvatore Siena, James Cassidy, Josep Tabernero, Ronald Burkes, Mario Barugel, Yves Humblet, György Bodoky, David Cunningham, Jacek Jassem, Fernando Rivera, Ilona Kocákova, Paul Ruff, Maria Błasińska-Morawiec, Martin Šmakal, Jean-Luc Canon, Mark Rother, Kelly S. Oliner, Michael Wolf, Jennifer Gansert. Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study. J Clin Oncol November 1, 2010 vol. 28 no Purpose Panitumumab, a fully human anti–epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. Patients and Methods In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. Results KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. Conclusion This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC. Ricardo Caponero

K-ras selvagem K-ras mutado
Progression-free survival in patients with (A) wild-type (WT) KRAS and (B) mutant (MT) KRAS. Overall survival in patients with (C) WT KRAS and (D) MT KRAS. FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin; Panit., panitumumab; HR, hazard ratio. Jean-Yves Douillard, Salvatore Siena, James Cassidy, Josep Tabernero, Ronald Burkes, Mario Barugel, Yves Humblet, György Bodoky, David Cunningham, Jacek Jassem, Fernando Rivera, Ilona Kocákova, Paul Ruff, Maria Błasińska-Morawiec, Martin Šmakal, Jean-Luc Canon, Mark Rother, Kelly S. Oliner, Michael Wolf, Jennifer Gansert. Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study. J Clin Oncol November 1, 2010 vol. 28 no Purpose Panitumumab, a fully human anti–epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. Patients and Methods In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. Results KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. Conclusion This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC. Jean-Yves Douillard, et al. J Clin Oncol Nov 1st 2010; 28 (31): Ricardo Caponero

Estudo STEPP Vectibix™ - Panitumumabe Novembro de 2009 Ricardo Caponero

STEPP: Desenho do estudo
Vectibix™ - Panitumumabe Novembro de 2009 STEPP: Desenho do estudo Skin Toxicity Evaluation Protocol with Panitumumab (n=95) CCR M1 Pós 2ª-linha Idade mediana 60 anos; PS ECOG 0-1 FOLFIRI + Panitumumabe 6 mg/kg a cada 2 semanas Tratamento cutâneo profilático (n = 48) Ou Irinotecano + Panitumumabe 9 mg/kg a cada 3 semanas Tratamento cutâneo reativo (n = 47) ECOG PS, Eastern Cooperative Oncology Group Performance Score; FOLFIRI, 5-fluorouracil/leucovorin/irinotecan; mCRC, metastatic colorectal cancer; STEPP, Skin Toxicity Evaluation Protocol with Panitumumab Lacouture ME, et al. GI Cancers Symposium Abstract 291 56 Ricardo Caponero

STEPP: Tratamento cutâneo
Vectibix™ - Panitumumabe Novembro de 2009 STEPP: Tratamento cutâneo Profilático Semanas 1 a 6 da QT Creme hidratante a cada manhã, na face, mãos, pés, pescoço, dorso e tórax FPS ≥ 15 na pele exposta ao sol Creme de Hidrocortisona 1% a cada noite na face, mãos, pés pescoço, costas e tórax Doxiciclina 100mg VO 2x/dia Reativo A critério do médico, com base na toxicidade cutânea a qualquer tempo entre as semanas 1 a 6. PABA, para-amino benzoic acid; SPF, sun protection factor; STEPP, Skin Toxicity Evaluation Protocol with Panitumumab Lacouture ME, et al. GI Cancers Symposium Abstract 291 57 Ricardo Caponero

STEPP: Toxicidade cutânea e respostas
Vectibix™ - Panitumumabe Novembro de 2009 STEPP: Toxicidade cutânea e respostas Desfecho Profilático (n = 48) Reativo (n = 47) Comentário Toxicidade cutânea grau ≥ 2, % 29 62 OR: 0,3 (IC95%: 0,1-0,6) Tempo mediano para início da toxicidade cutânea de grau ≥ 2, semanas > 6,0 2,1 Mediana não atingida para o braço profilático Resposta à quimioterapia (RC + RP), % 15 11 Taxas de resposta à terapia similares Controle de doença (RC + RP + DE), % 65 64 Progressão de doença, % 19 21 CR, complete response; OR, odds ratio; PR, partial response; SD, stable disease; STEPP, Skin Toxicity Evaluation Protocol with Panitumumab O tratamento cutâneo profilático leva a menos atrasos na dose de panitumumabe e menos toxicidades não cutâneas. Lacouture ME, et al. GI Cancers Symposium Abstract 291 58 Ricardo Caponero

INDICAÇÕES

Panitumumabe (Vectibix®)
Vectibix™ - Panitumumabe Novembro de 2009 Panitumumabe (Vectibix®) Indicação Vectibix® é indicado como monoterapia para o tratamento de pacientes com expressão de EGFR Carcinoma colorretal metastático, com KRAS não mutado (natural ou selvagem “wild-type”) Após falha a regimes contendo fluoropirimidina, oxaliplatina, e irinotecano Vectibix® Resumo das características do produto Ricardo Caponero

Panitumumabe (Vectibix®)
Vectibix™ - Panitumumabe Novembro de 2009 Panitumumabe (Vectibix®) Posologia A dose recomendada é de 6mg/Kg de massa corpórea. Por via endovenosa. Administrada a cada duas semanas. Vectibix® Resumo das características do produto Ricardo Caponero

Contra Indicações Histórico de reações de hipersensibilidade graves ou potencialmente fatais à substância ativa ou a qualquer um dos excipientes. Pneumonite intersticial ou fibrose pulmonar. Menores de 18 anos (insuficiência de dados de segurança e eficácia).

CONCLUSÕES

Conclusões O Panitumumabe é o primeiro e único anticorpo monoclonal totalmente humano com efetividade e segurança estabelecidas em todas as linhas de tratamento do carcinoma colorretal metastático. O Panitumumabe é o único anticorpo anti-EGFR com resultados positivos em estudos de fase III baseados em dados prospectivos do KRAS.

Clínica de Oncologia Médica
Ricardo Caponero Clínica de Oncologia Médica

PANITUMUMABE Ricardo Caponero, Clínica de Oncologia Médica - São Paulo - SP - 2011 Ricardo Caponero.

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