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  • The EGFR pathway is very complex pathway. Inhibitors to EGFR have proven antitumor activity in colorectal cancer.
  • 2 2 Simplified diagram of the EGFR pathway consisting of the EGFR signal transduction cascade, and cellular effects of stimulation through the EGFR. 5 The ligand binding site serves as the receptor for ligands such as EGF and TGF-  Upon ligand binding, subsequent receptor signaling, including autophosphorylation of the receptor and phosphorylation of target proteins, occurs downstream in the signal transduction cascade. 2 • EGFR is expressed in a significant percentage of human tumors. Expression has been correlated with poor prognosis, decreased survival, and/or increased metastases. 2 • EGFR plays a critical role in cellular growth, repair, and survival and has been demonstrated to function as a key pathway for the regulation of growth in many tumor types. 2 • Current therapies have significant therapeutic and safety limitations in the management of solid tumors. The use of EGFR targeted therapy is a potentially important addition to standard anticancer therapy. 2 • It has been postulated that EGFR inhibitors may synergize with radiation and certain chemotherapeutic agents, possibly through apoptotic, antiangiogenic, and/or cell cycle effects. 2
  • 2 2 Simplified diagram of the EGFR pathway consisting of the EGFR signal transduction cascade, and cellular effects of stimulation through the EGFR. 5 The ligand binding site serves as the receptor for ligands such as EGF and TGF-  Upon ligand binding, subsequent receptor signaling, including autophosphorylation of the receptor and phosphorylation of target proteins, occurs downstream in the signal transduction cascade. 2 • EGFR is expressed in a significant percentage of human tumors. Expression has been correlated with poor prognosis, decreased survival, and/or increased metastases. 2 • EGFR plays a critical role in cellular growth, repair, and survival and has been demonstrated to function as a key pathway for the regulation of growth in many tumor types. 2 • Current therapies have significant therapeutic and safety limitations in the management of solid tumors. The use of EGFR targeted therapy is a potentially important addition to standard anticancer therapy. 2 • It has been postulated that EGFR inhibitors may synergize with radiation and certain chemotherapeutic agents, possibly through apoptotic, antiangiogenic, and/or cell cycle effects. 2
  • EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. Clinical data suggest that several factors are of potential use in predicting the activity of EGFR inhibitors. These include skin rash, EGFR status, and EGFR activation.
  • EGFR, epidermal growth factor receptor. Skin rash appears early in treatment with EGFR inhibitors; more than 80% of patients treated with cetuximab or panitumumab develop a rash that eventually improves. Longer treatment durations are associated with other skin toxicity, such as fissures or paronychia, which are more difficult to treat.
  • CRC, colorectal cancer; SCCHN, squamous cell carcinoma of the head and neck. Multiple clinical trials in multiple indications, including retrospective studies, have shown a correlation between the severity of rash and the activity of cetuximab and panitumumab. Increasing rash severity has been correlated with longer survival time across these analyses.
  • ES, extension study; PD, progressive disease; q2w, every 2 weeks; q3m, every 3 months; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization. This slide shows a pooled analysis of 5 different clinical trials that evaluated panitumumab-associated skin toxicity in patients with chemorefractory colorectal cancer. In these trials, panitumumab was administered as a single agent.
  • CI, confidence interval; OS, overall survival; PFS, progression-free survival. This analysis shows that, across these 5 studies, patients with a grade 2-4 rash had longer progression‑free survival and longer overall survival than patients with no rash or with a grade 1 rash.
  • FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; PFS, progression-free survival. The Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial evaluated FOLFIRI with and without cetuximab as first-line treatment for patients with metastatic colorectal cancer. Results showed a correlation between progression-free survival and rash. The upper line shows that patients with grade 3 rash had the longest progression-free survival time whereas the lower line shows that patients without rash or with grade 1 rash had the shortest survival without progression. For more information on this study, go online to: clinicalcareoptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202007/Tracks/Gastrointestinal%20Cancer/Capsules/4000.aspx
  • q2w, every 2 weeks. The data on the correlation between rash and activity led to the question of whether the dose of an EGFR inhibitor could be adjusted according to presence and severity of rash. The phase II EVEREST study evaluated the activity of escalating doses of cetuximab in irinotecan-refractory colorectal cancer patients with no rash or with only a slight rash. Patients were evaluated on Day 22 of treatment with cetuximab and irinotecan. Those patients with a severe rash (ie, ≥ grade 2) or other toxicity received the classic standard dose of cetuximab plus irinotecan. Patients with no rash or grade 1 rash and no other toxicity were randomized to either the standard regimen of cetuximab plus irinotecan or to irinotecan plus gradually escalating doses of cetuximab.
  • AE, adverse event. Results from EVEREST show slightly more toxicity in the dose-escalation arm, although the toxicity was acceptable. Toxicity included slightly more diarrhea and slightly more skin rash.
  • CI, confidence interval; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. Among the interesting findings from EVEREST was a 30% response rate in the dose-escalation arm, which received up to a double dose of cetuximab. By contrast, patients with no rash or grade 1 rash receiving the standard dose of cetuximab plus irinotecan had a response rate of 16%. Median progression-free survival times were 3.9 months with standard cetuximab dosing vs 4.8 months in the dose-escalation arm; however, overlapping confidence intervals and the sample size of the study did not allow a formal statistical comparison. Despite the lack of statistical power, this study produced valuable hypothesis-generating data.
  • EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. Regarding molecular markers that can help predict the effect of EGFR inhibitors, the initial trials with cetuximab and panitumumab were based in part on the idea that EGFR receptor status, as determined by immunohistochemistry, could help enrich or predict for activity. However, as I will show, that turned out not to be the case.
  • EGFR, epidermal growth factor receptor. The BOND study showed no correlation between EGFR receptor status and clinical response, as determined by immunohistochemistry. For instance, the data showed that patients given irinotecan plus cetuximab had a consistent response rate of 20% to 25%, regardless of whether they had a low or high percentage of EGFR-expressing cells or a low or strong EGFR staining intensity. In other words, EGFR receptor expression did not help to distinguish and predict for higher or lower toxicity. Other published data also suggest that patients not expressing the EGFR receptor, at least by immunohistochemistry, can respond as well as patients that have a high expression of the receptor.
  • EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; OS, overall survival. Similarly, in the pivotal study of panitumumab vs best supportive care, there was no difference in activity for panitumumab based on EGFR staining intensity. However, further analysis evaluated whether other factors might predict efficacy.
  • EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization. Moroni and colleagues published interesting data on the possible role of EGFR gene copy number in the treatment of metastatic colorectal cancer. Indeed, this study and later studies demonstrated a correlation between EGFR copy number and activity of anti-EGFR agents.
  • EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; mCRC, metastatic colorectal cancer; OS, overall survival; TTP, time to progression. There were clear methodologic issues in studies evaluating the use of FISH to determine EGFR expression, and there is no consensus on the use of the FISH test to help select patients. Therefore, it is not currently of use in clinical practice. Various groups that conducted different, relatively small, studies are now working together to combine these data to generate clear consensus recommendations on the use of FISH in colorectal cancer treatment.
  • CR, complete response; EGFR, epidermal growth factor receptor; PD, progressive disease; PR, partial response; SD, stable disease. Sartore‑Bianchi and colleagues conducted a retrospective study in which they looked at the EGFR copy number and outcomes with panitumumab therapy. They came to the same conclusions as the previously discussed studies: Patients with a high EGFR copy number have longer progression-free and overall survival times when treated with panitumumab. This was demonstrated both by looking directly at EGFR copy number and by evaluating chromosome 7 polysomy/amplification, another marker of EGFR level.
  • CRC, colorectal cancer; EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer. Among patients with non-small-cell lung cancer, a subset of patients has been identified that exhibit EGFR gene mutations. The presence of these mutations is associated with the efficacy of EGFR-targeting therapies . Although these EGFR gene mutations also have been identified in colorectal cancer, they are rare, and their predictive role in this setting is as-yet unclear.
  • EGFR, epidermal growth factor receptor. Few data exist regarding EGFR phosphorylation. This slide shows data from a very small study that suggested that EGFR phosphorylation might be of predictive value in the future. However, further studies are needed.
  • CRC, colorectal cancer; EGFR, epidermal growth factor receptor. Another parameter becoming validated as a prognostic factor is KRAS mutation status. Data on KRAS mutations have been collected from more than 800 patients with chemorefractory colorectal cancer. KRAS is important in the EGFR pathway potentially in part because when the KRAS gene is mutated, the KRAS protein is active regardless of EGFR activation. On the other hand, KRAS mutations are an early event and are found in only approximately 40% of colorectal cancer patients.
  • mCRC, metastatic colorectal cancer; OS, overall survival. Lievre and colleagues conducted one of the first studies of KRAS mutations in colorectal cancer. This was a small retrospective study, with only 30 patients, all of whom were refractory and treated with cetuximab plus irinotecan. In this study, approximately 40% of the patients had a KRAS mutation. Strikingly, patients with wild-type KRAS had much longer survival than patients with mutated KRAS .
  • CRC, colorectal cancer. A more recent study by Khambata-Ford and colleagues evaluated the importance of KRAS mutations in a series of chemorefractory patients with colorectal cancer. The majority of patients in this study who achieved disease control following treatment with cetuximab monotherapy had wild-type KRAS .
  • Cmab, cetuximab; CT, chemotherapy; EGFR, epidermal growth factor receptor; MT, mutated type; WT, wild type. Five other recently published studies looked at patients treated with EGFR inhibitors. This slide shows that across all 5 studies, almost no responses were seen in patients with a KRAS mutation. Conversely, response rates were substantial in patients with wild-type KRAS . Although these are relatively small, retrospective studies, the results as a whole suggest that responses seen after treatment with cetuximab or panitumumab are essentially confined to patients with wild-type KRAS .
  • Cmab, cetuximab; CI, confidence interval; Iri, irinotecan; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival. Liévre and colleagues conducted a retrospective study of cetuximab in irinotecan-refractory patients that demonstrated striking differences in progression-free and overall survival times for patients with wild-type tumor vs KRAS -mutated tumor.
  • Cmab, cetuximab; CRC, colorectal cancer; Iri, irinotecan; OS, overall survival. Similar to other studies of cetuximab, the investigators also reported a correlation between skin toxicity and outcome.
  • Cmab, cetuximab; CRC, colorectal cancer; Iri, irinotecan; OS, overall survival. When Liévre and colleagues looked at skin rash and KRAS status, patients with wild-type KRAS and grade 2/3 rash had superior survival times vs patients with poor prognostic factors (ie, mutated KRAS or less severe rash).
  • CI, confidence interval; CR, complete response; HR, hazard ratio; mCRC, metastatic colorectal cancer; PD, progressive disease; PR, partial response; SD, stable disease. Our recently published study from Leuven included 113 chemorefractory colorectal cancer patients treated with cetuximab. In our study, as well as in other studies, a response rate of 30% to 35% was seen in patients with wild-type KRAS following treatment with cetuximab plus irinotecan.
  • BSC, best supportive care; ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; q2w, every 2 weeks. In this analysis of the pivotal trial of panitumumab, the KRAS status of more than 400 patients with chemorefractory colorectal cancer was determined.
  • BSC, best supportive care; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; Pmab, panitumumab. This slide shows progression-free survival results by KRAS status in this study. Overall, patients with colorectal cancer had superior progression-free survival times when treated with panitumumab vs best supportive care alone (hazard ratio: 0.59). However, with a hazard ratio of 0.45 and a median difference of 5 weeks between populations, panitumumab was clearly more effective in those patients with wild-type KRAS . In fact, panitumumab-treated patients with mutated KRAS had very similar progression-free survival times to patients who received best supportive care alone.
  • BSC, best supportive care; CR, complete response; PD, progressive disease; Pmab, panitumumab; PR, partial response; SD, stable disease. The response rate to panitumumab across all evaluable patients was 10%. Patients with mutated KRAS experienced no objective responses to panitumumab whereas those with wild-type KRAS had an objective response rate of 17%. An analysis of the same data with waterfall plots showed that virtually no patients with mutated KRAS had tumor regression vs a considerable number of patients with wild-type KRAS. Clearly, at least in chemorefractory patients with colorectal cancer, the activity of EGFR inhibitors appears confined to those with wild-type KRAS . This also suggests that KRAS mutations are a marker for resistance. However, KRAS is not the only potential predictive factor, although data on other markers are limited.
  • CRC, colorectal cancer; TTP, time to progression. BRAF is another candidate biomarker for resistance in colorectal cancer, although BRAF mutations occur in far fewer patients than KRAS mutations. A recent study by Benvenuti and colleagues suggested that BRAF status could help distinguish some patients who are more likely to benefit from treatment.
  • AREG, amphiregulin; EGFR, epidermal growth factor receptor; EREG, epiregulin; PFS, progression-free survival. Khambata-Ford and colleagues published a study looking at the EGFR ligands epiregulin and amphiregulin, which showed that patients with high expression of these ligands have better progression-free survival outcomes. More data are emerging on the possible predictive role of EGFR ligands.
  • OS, overall survival; PFS, progression-free survival. The EVEREST study evaluated many possible predictive markers in colorectal cancer patients. These data confirm the results from Khambata-Ford and colleagues by showing that patients with a high vs low epiregulin expression have superior progression-free survival rates.
  • ADCC, antibody-dependent cell-mediated cytotoxicity; PFS, progression-free survival. Results from a small study by Zhang and colleagues suggested a positive association between progression-free survival and FC polymorphism in colorectal cancer patients receiving cetuximab, but it is too early to use FC status in clinical practice today.
  • CRC, colorectal cancer; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; mCRC, metastatic colorectal cancer; PFS, progression-free survival; RR, response rate. This presentation discussed potential predictors of clinical activity of cetuximab and panitumumab in metastatic colorectal cancers, including the correlation between skin rash and outcome. It is clear that EGFR status by immunohistochemistry is not useful in selecting patients and that there appears to be no role of somatic EGFR gene mutations. However, an increased EGFR gene copy number, as assessed by FISH, correlates with response rates and progression-free survival. These data comprise retrospective evidence from different studies in chemorefractory patients and major methodologic issues need to be addressed before implementing this knowledge in clinical practice. There is strong evidence from different studies for an association between KRAS mutation and lack of activity in chemorefractory patients. However, more data from first-line trials will be needed to definitively ascertain the validity of these results. Finally, EGFR ligand expression is emerging as a predictive marker for treatment with cetuximab or panitumumab.

Abordaje del ca colorectal...dr almenarez Presentation Transcript

  • 1. ABORDAJE TERAPEUTICO DEL CANCER COLORECTAL DR. JOSE ALFREDO ALMENAREZ GOMEZ ONCOLOGIA CLINICA I.P.S. UNIVERSITARIA – U. DE ANTIOQUIA CENTRO ONCOLOGICO DE ANTIOQUIA MEDELLIN - ANTIOQUIA
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  • 18. ESTADIO T N M DUKES MAC 0 is 0 0 - - I 1 2 0 0 0 0 A A A B1 IIA 3 0 0 B B2 IIB 4a 0 0 B B2 IIC 4b 0 0 B B3 IIIA 1 - 2 1 1 - 1c 2a 0 0 C C C1 C1 IIIB 3 - 4a 2 - 3 1 - 2 1 - 1c 2a 2b 0 0 0 C C C C2 C1 - C2 C1 IIIC 4a 3 - 4a 4b 2a 2b 1 - 2 0 0 0 C C C C2 C2 C3 IVA ANY ANY 1a - - IVB ANY ANY 1b - -
  • 19. ESTADIO 0 - I
    • CIRUGIA OPTIMA.
    • NO REALIZAR TTO. ADYUVANTE.
    • SEGUIMIENTO PERIODICO:
      • Cada 3-6 meses x 2 a ñ os y luego cada 6 meses hasta los 5 a ñ os.
      • Realizar CEA o ACE cada 3-6 meses
      • TAC toraco-abdominal contrastado anualmente.
      • EXAMEN FISICO
  • 20. ESTADIO T N M DUKES MAC 0 is 0 0 - - I 1 2 0 0 0 0 A A A B1 IIA 3 0 0 B B2 IIB 4a 0 0 B B2 IIC 4b 0 0 B B3 IIIA 1 - 2 1 1 - 1c 2a 0 0 C C C1 C1 IIIB 3 - 4a 2 - 3 1 - 2 1 - 1c 2a 2b 0 0 0 C C C C2 C1 - C2 C1 IIIC 4a 3 - 4a 4b 2a 2b 1 - 2 0 0 0 C C C C2 C2 C3 IVA ANY ANY 1a - - IVB ANY ANY 1b - -
  • 21. ESTADIO IIA, IIB, IIC
    • CON BAJO RIESGO DE RECAIDA:
      • SEGUIMIENTO PERIODICO
    • CON ALTO RIESGO DE RECAIDA:
      • Invasi ó n linfo-vascular grado 3-4
      • Obstrucci ó n col ó nica.
      • < 12 ganglios linf á ticos extra í dos.(RESECCION/ESTADIAJE SUBOPTIMO)
      • T4N0M0
      • T3N0M0 con perforaci ó n col ó nica
      • Con margen quir ú rgico positivo o indeterminado o estrecho.
      • Celularidad en anillo de sello.
      • QUIMIOTERAPIA ADYUVANTE CON FOLFOX, FLOX, 5-FU/LEUCOVORIN, CAPECITABINA, UFT, X 6 MESES.
  • 22. ESTADIO T N M DUKES MAC 0 is 0 0 - - I 1 2 0 0 0 0 A A A B1 IIA 3 0 0 B B2 IIB 4a 0 0 B B2 IIC 4b 0 0 B B3 IIIA 1 - 2 1 1 - 1c 2a 0 0 C C C1 C1 IIIB 3 - 4a 2 - 3 1 - 2 1 - 1c 2a 2b 0 0 0 C C C C2 C1 - C2 C1 IIIC 4a 3 - 4a 4b 2a 2b 1 - 2 0 0 0 C C C C2 C2 C3 IVA ANY ANY 1a - - IVB ANY ANY 1b - -
  • 23. ESTADIO III
    • QUIMIOTERAPIA ADYUVANTE:
      • FOLFOX6 cada 15 dias por 6 meses (12 aplicaciones en total)
      • FOLFOX4 cada 15 dias por 6 meses (12 aplicaciones en total)
      • FLOX X 3 MESES
  • 24. ESTADIO T N M DUKES MAC 0 is 0 0 - - I 1 2 0 0 0 0 A A A B1 IIA 3 0 0 B B2 IIB 4a 0 0 B B2 IIC 4b 0 0 B B3 IIIA 1 - 2 1 1 - 1c 2a 0 0 C C C1 C1 IIIB 3 - 4a 2 - 3 1 - 2 1 - 1c 2a 2b 0 0 0 C C C C2 C1 - C2 C1 IIIC 4a 3 - 4a 4b 2a 2b 1 - 2 0 0 0 C C C C2 C2 C3 IVA ANY ANY 1a - - IVB ANY ANY 1b - -
  • 25. ESTADIO IV
    • Factores a tener en cuenta:
      • La resecabilidad de las met á stasis.
      • Estado de actividad f í sica (ECOG o KARNOFSKY).
      • La presencia de comorbilidades.
      • La edad cronol ó gica.
      • Estado del gen K-ras.
        • Hay dos formas el K-ras natural o salvaje y el K-ras mutado.
        • Se expresa mutado en el 40% de los tumores de colon.
        • Asociado a resistencia a los inhibidores de EGFR (cetuximab y panitumumab).
    J Clin Oncology 26:374. 2008
  • 26. Importancia del K-RAS Y DEL BRAF
    • BRAF: una serine treonine kinase es una de las dianas del Kras.
    • Está ocasionalmente mutado en algunos canceres de colon.
    • Sobretodo en KRAS wt.
    • Como biomarcador indica mal pronostico.
    • KRAS mutado produce resistencia al anti EGFR.
  • 27. The Epidermal Growth Factor Receptor Pathway Proliferation Metastasis Angiogenesis Apoptosis Resistance Shc PI3-K Raf MEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1
  • 28. The Angiogenic Switch and Antiangiogenic Therapy Somatic mutation Small avascular tumor Tumor secretion of angiogenic factors stimulates angiogenesis Rapid tumor growth, invasion and metastasis Angiogenic inhibitors may reverse this vascularization Carmeliet and Jain. Nature. 2000;407:249 .
  • 29.  
  • 30. EGFR & Cancer
    • Tumor Type % Expressing
            • EGFR
    • Colon 25-75%
    • RCC 50-90%
    • Breast 15-90%
    • Ovarian 35-70%
    • Glioma 40-50%
    • Pancreas 30-50%
    • H & N 80-100%
    • NSCLC 40-80%
    • Vejiga 30-50%
  • 31.  
  • 32. VEGF and Angiogenesis
  • 33. EGF Signalling Pathway
  • 34.  
  • 35. VEGF and Angiogenesis
  • 36.  
  • 37. EGF Signalling Pathway
  • 38. Predicting the Effect of EGFR Inhibitors
    • Skin rash
    • Measuring EGFR status
      • EGFR — IHC
      • FISH expression
  • 39. Mutations
      • Gene levels
    • Measuring EGFR activation
      • KRAS
      • EGFR ligands
      • EGFR phosphorylation
  • 40.
    • 1 2 3 4 5 6 7 8 9
    EGFR Inhibitor – Induced Skin Reactions Description of severe cases Post inflammatory effects Acne-like rash Paronychia Dry skin Topical antiacne creams (drying effect) ± tetracyclines ± antihistamines Pruritus
        • Pulse dye laser
        • Emollients
        • Hydrocolloid dressing or propylene glycol ± acetylsalicyl
        • Antiseptic soaks, silver nitrate (pyogenic granuloma)
    Fissura Segaert S, Van Cutsem E, et al. Ann Oncol. 2005;16:1425-1433. Therapy Suggestions
  • 41. Correlation of Rash and Survival After Treatment With Cetuximab 1. Saltz L, et al. Proc ASCO. 2001. 2. Saltz L, et al. J Clin Oncol. 2004;22:1201-1208. 3. Cunningham D, et al. N Engl J Med. 2004;351:337-345. 4. Van Cutsem E, et al. EORTC/NCI Geneva. 2004. 5. Xiong H, et al. J Clin Oncol. 2004;22:2610-2616. 6. Kies MS, et al. Proc ASCO. 2002. 0 No reaction Grade 2 Grade 1 Grade 3 Survival (Months) 16 12 8 4 CRC 9923 Saltz (2001) [1] CRC 0141 Saltz (2004) [2] CRC BOND Cunningham [3] CRC Van Cutsem (2004) [4] Pancreatic Xiong (2004) [5] SCCHN Kies (2002) [6]
  • 42. Pooled Analysis: Predictive Value of Skin Toxicity With Panitumumab *Berlin study is interim. † Patients who developed progressive disease while receiving best supportive care in the phase III study were allowed to cross over to this extension study to receive panitumumab until disease progression or drug intolerability. Michelini T, et al. ASHP 2007. Abstract P141D. Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664. Berlin J, et al. ASCO 2006. Abstract 3548. Mitchell EP, et al. ASCO 2007. Abstract 4082. Hecht JR, et al. Cancer. 2007;110:980-988. Van Cutsem, et al. 2007 Berlin, et al. 2006* Mitchell, et al. 2007 Hecht, et al. 2007 Phase III Panitumumab Crossover Phase III III (ES † ) II II II Patients enrolled, n 231 177 93 160 150 Patients included in current analysis, n 218 166 52 145 146 Dose schedule 6 mg/kg q2w 6 mg/kg q2w 6 mg/kg q2w 6 mg/kg q2w 2.5 mg/kg qw Response assessment RECIST central review RECIST local review WHO central review WHO central review RECIST central review Assessment schedule Wks 8-48 and q3m after until PD q8w ~ q8w for Wks 8-48 and q3m after until PD ~ q8w for Wks 8-48 and q3m after until PD q9w
  • 43. Severity of Skin Toxicity Throughout Treatment Is Associated With PFS Michelini T, et al. ASHP 2007. Abstract P141D. 2.6 8.4 1.8 5.4 0 2 4 6 8 10 12 PFS OS Median Survival (months) Grade 2-4 Grade 0-1 Hazard ratio (grade 2-4:0-1): 0.66 (95% Cl: 0.56-0.78); P < .0001 Hazard ratio (grade 2-4:0-1): 0.62 (95% Cl: 0.5-0.74); P < .0001 Skin Toxicity
  • 44. CRYSTAL: PFS by On-Study Skin Reactions: Cetuximab + FOLFIRI *There were no grade 4 skin reactions. Van Cutsem E, et al. ASCO 2007. Abstract 4000. Skin reaction grade 0 or 1 (n = 244) 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 PFS Time (Months) 1.00 0.75 0.50 0.25 0.00 PFS Estimate Skin reaction grade 2 (n = 243) Skin reaction grade 3* (n = 112) 11.3 months 5.4 months 9.4 months
  • 45. EVEREST: Study Design Day 22 Not eligible for randomization All patients continued to receive irinotecan Treatment until disease progression, unacceptable toxicity or withdrawal of consent. Skin and tumor biopsy at baseline, Week 3 and, in Arm B, at maximum cetuximab dose. Van Cutsem E, et al. WCGIC 2007. Abstract 0-034. Arm C Standard Cetuximab regimen (250 mg/m 2 /wk) Cetuximab 400 mg/m 2 initial dose then 250 mg/m 2 /wk + Irinotecan (180 mg/m 2 q2w) Arm A Standard cetuximab regimen (250 mg/m 2 /wk) Arm B Cetuximab dose escalation (dose increases of 50 mg/m 2 q2w up to maximum 500 mg/m 2 /wk) Screening
  • 46. EVEREST: Most Common Treatment-Related Grade 3/4 AEs *Safety population includes 9 additional patients in Arm C who were not randomized because they discontinued study medication before day 22. † All grade 2 and 3 skin reactions in Arms A and B started after randomization. Van Cutsem E, et al. WCGIC 2007. Abstract 0-034. Adverse Event, % Randomized Nonrandomized Arm A standard (n = 45) Arm B escalation (n = 44) Arm C (n = 77*) Diarrhea 11 23 23 Fatigue 7 9 5 Hypomagnesemia 2 9 3 Neutropenia 16 2 21 Leucopenia 2 2 8
    • Skin reaction
    • Any
    • Grade 1 (at any time)
    • Grade 1 (onset after randomization)
    • Grade 2 †
    • Grade 3 †
    91 56 38 36 -- 98 41 34 45 11 91 23 -- 53 14
  • 47. EVEREST: Efficacy Outcomes Van Cutsem E, et al. WCGIC 2007. Abstract 0-034. Randomized Nonrandomized Response Outcomes Arm A standard (n = 45) Arm B escalation (n = 44) Arm C (n = 68)
    • Best confirmed response, %
    • PR
    • SD
    • PD
    • Not evaluable
    16 42 29 13 30 41 27 2 25 37 34 4 Confirmed response rate, % (95% CI) 16 (7-30) 30 (17-45) 25 (15-37) Disease control rate, % (95% CI) 58 (42-72) 71 (55-83) 62 (49-73) Median PFS, months (95% CI) 3.9 (2.8-5.3) 4.8 (3.8-6.7) 4.7 (2.8-6.2) Median OS, months (95% CI) 10.0 (6.0-12.1) 8.6 (7.3-12.5) 8.7 (6.4-12.6)
  • 48. Predicting the Effect of EGFR Inhibitors
    • Skin rash
    • Measuring EGFR status
      • EGFR — IHC
      • FISH expression
      • Mutations
      • Gene levels
    • Measuring EGFR activation
      • KRAS
      • EGFR ligands
      • EGFR phosphorylation
  • 49. 0 10 20 30 40 50 22.9 20.0 22.2 24.2 20.8 24.7 22.7 7.1 31.3 0 9.4 4.8 12.7 11.8  10 > 10 -  20 > 35 Faint Weak/ moderate Strong Irinotecan/cetuximab Cetuximab > 20 -  35 0 10 20 30 40 50 Percentage Percentage EGFR-expressing Cells (%) EGFR-staining Intensity Clinical Response Rate Clinical Response Rate Correlation of Response Rate and EGFR Expression (IHC): BOND Data Cunningham D…Van Cutsem D, et al. N Eng J Med. 2004; 351:337-345. P for trend = .87 P for trend = .64
  • 50. OS for Panitumumab by EGFR Tumor Membrane Staining Categories (IHC) 0.0 0.2 0.4 0.6 0.8 1.0 Months From Randomization 0 2 4 6 8 10 12 14 16 18 20 22 24 Survival Probability Van Cutsem E, et al. WCGIC 2005. Abstract O-027. EGFR Tumor Membrane Staining Category (IHC) > 35% (n = 76) 10% - 35% (n = 63) 1% - < 10% (n = 43)
  • 51. Correlation Between EGFR Gene Copy Number and Clinical Response
    • Metastatic colorectal cancer patients treated with cetuximab or panitumumab (N = 31) screened for EGFR copy number and mutation profile
      • Objective response (n = 10)
      • Stable or progressive disease (n = 21)
    Moroni M, et al. Lancet Oncol. 2005;6:279-286. 89.9 4.8 0 20 40 60 80 100 Objective responders Nonresponders Increased EGFR Copy Number by FISH (%) P < .0001
  • 52. EGFR Inhibitors: EGFR Expression by FISH
    • Retrospective analyses suggest a correlation between anti-EGFR therapy and EGFR gene copy numbers by FISH [2,3]
    • Methodology issues for translation into clinical practice [4]
    Cetuximab Treatment of mCRC (n = 85) [1] 1. Cappuzzo F, et al. Ann Oncol. 2007;Epub. 2. Moroni M, et al. Lancet 2005;6:279-286. 3. Sartore-Bianchi A, et al. J Clin Oncol. 2007;25:3238-3245. 4. Personeni N, et al. J Clin Oncol. 2007;25:18S. Abstract 10569. 6.6 11.3 3.5 8.5 0 4 8 12 16 TTP OS Months EGFR FISH+ EGFR FISH- P = .02 P = .8
  • 53.
    • Survival, response outcomes on panitumumab associated with EGFR gene copy number
    100 70 30 0 20 40 60 80 100 < 2.47 ≥ 2.47 CR + PR PD + SD 100 32 0 20 40 60 80 100 < 43% ≥ 43% 68 P = .0009 P = .0007 Patients (%) Patients (%) EGFR gene copy number Chromosome 7 polysomy or amplification EGFR Gene Copy Number and Outcome After Panitumumab Sartore-Bianchi A, et al. J Clin Oncol. 2007;25:3238-3245.
  • 54.
    • In contrast to a subset of NSCLC patients, somatic EGFR gene mutations appear to be rare in CRC patients
    • However, EGFR inhibitors seem to be effective in cancer cells regardless of wild-type or mutated EGFR gene status
    EGFR Mutations Khambata-Ford S, et al. J Clin Oncol. 2007;25:3230 - 3237. Tsuchihashi Z, et al. N Engl J Med. 2005;353:208 - 209.
  • 55. EGFR Phosphorylation
    • Measuring EGFR phosphorylation by immunohistochemistry may predict higher response rates
    • Major methodological issues for translation into clinical practice
    pEGFR ≥ 7 (n = 7) pEGFR < 7 (n = 13) 0 20 40 60 80 100 Disease Control Rate (%) 100 54 P = .05 Level of EGFR Phosphorylation Personeni N, et al. Semin Oncol. 2005;32:S59 - S62.
  • 56. EGFR Pathway and KRAS
    • EGFR pathway is the entry way to multiple intracellular signaling cascades.
    • When KRAS gene is mutated, KRAS protein (p21 ras) is active regardless of EGFR activation .
    • KRAS gene mutations are an early event and are found in 40% to 45% of CRC patients.
    Mendelsohn J, et al. Oncogene. 2000;19:6550-6565. Khambata-Ford S, et al. J Clin Oncol. 2007;25:3230 - 3237 .
  • 57. OS With Cetuximab Is Significantly Reduced With Mutant KRAS
    • 30 mCRC patients treated with cetuximab
      • 43% with KRAS mutation
    • KRAS mutation observed in
      • 0% of 11 responders
      • 68% of 19 nonresponders
        • P = .0003
    • OS in patients without KRAS mutation was significantly better than patients with mutation
    Lievre A, et al. Cancer Res. 2006;66:3992-3995. 6.3 16.9 0 5 10 15 20 Median Survival (months) Mutated KRAS Wild type KRAS P = .016
  • 58. Predictive Role of KRAS in CRC Patients Treated With Cetuximab Khambata-Ford S, et al. J Clin Oncol. 2007;25:3230 - 3237. P = .003 11 51 89 46 0 20 40 60 80 100 Disease Control Group Patients (%) Mutant at KRAS codon 12 or 13 Wild-type KRAS Nonresponders
  • 59. Single-Arm Studies: KRAS as a Biomarker for EGFR Inhibitors Treatment (Panitumumab or Cetuximab) No. of Patients (WT:MT) Objective Response n (%) MT WT Li é vre, et al (AACR Proceedings 2007) Cmab ± CT 76 (49:27) 0 (0) 24 (49) Benvenuti, et al (Cancer Res, 2007) Pmab or cmab or cmab + CT 48 (32:16) 1 (6) 10 (31) De Roock, et al (Ann Oncol. 2007;Epub) Cmab or cmab + irinotecan 113 (67:46) 0 (0) 27 (40) Capuzzo, et al (Ann Oncol. 2007;Epub) Cmab ± CT 81 (49:32) 2 (6) 13 (26) Di Fiore, et al (Br J Cancer. 2007) Cmab + CT 59 (43:16) 0 (0) 12 (28) Khambata-Ford, et al (J Clin Oncol. 2007) Cmab 80 (50:30) 0 (0) 5 (10)
  • 60. Outcome & KRAS Status in Iri-Refractory mCRC Treated With Cmab Lièvre A, et al. J Clin Oncol. 2008;26:374-379. KRAS status Median PFS (95% CI), n = 88 Median OS (95% CI), n = 88 KRAS mutation 10.1 weeks (8-16) 10.1 months (5.1-13) Wild type 31.4 weeks (19.4-36) 14.3 months (9.4-20) P Value .0001 .026
  • 61. Survival & Skin Toxicity in Iri-Refractory CRC Treated With Cmab N = 113 Lièvre A, et al. J Clin Oncol. 2008;26:374-379. Skin toxicity 2-3 Skin toxicity 0-1 P = .029 13.9 8.2 0 5 10 15 20 Median Survival (months) Median OS
  • 62. OS in Iri-Refractory CRC Treated With Cmab: KRAS and Skin Toxicity Lièvre A, et al. J Clin Oncol. 2008;26:374-379. P = .0008 5.6 10.7 15.6 0 5 10 15 20 Median OS Median Survival (months) 0 good prognostic factors (KRAS mutation and grade 0-1 skin toxicity) 1 good prognostic factors (wild type or grade 2-3 skin toxicity) 2 good prognostic factors (wild type and grade 2-3 skin toxicity)
  • 63. KRAS in Irinotecan-Refractory mCRC Treated With Cetuximab and Irinotecan P = .020; HR: 0.620 (95% CI: 0.41-0.92) De Roock W…Van Cutsem E, et al. Ann Oncol. 2007;Epub. 43.0 10.7 0 10 20 30 40 50 Median Survival (weeks) KRAS wild type KRAS mutant 17 26 42 74 39 2 0 20 40 60 80 100 Wild type KRAS Mutant KRAS CR PR SD PD Best Response (%)
  • 64.
    • Hypothesis: clinical benefit of panitumumab would be confined to colorectal cancer patients with wild-type KRAS
    Randomized by ECOG score 0-1 vs 2 and geographic region (Western EU vs Central and Eastern EU vs rest of world) Panitumumab vs Best Supportive Care in Colorectal Cancer: KRAS Analysis Van Cutsem E, et al. J Clin Onc. 2007;25:1658-1664. Panitumumab 6.0 mg/kg q2w + BSC (n = 231) PD Follow-up BSC (n = 232) Optional Panitumumab crossover study PD Follow-up
  • 65. Progression-Free Survival: Final Analysis Amado R...Van Cutsem E, et al. ECCO 2007. Abstract 0007. KRAS Evaluable Group PFS Pmab + BSC BSC Alone HR (95% CI) Events/N (%) 191/208 (92) 209/219 (95) 0.59 (0.48-0.72) Median, wks 8.0 7.3 Mean, wks 15.4 9.6 Wild-Type KRAS Group PFS Pmab + BSC BSC Alone HR (95% CI) Events/N (%) 115/124 (93) 114/119 (96) 0.45 (0.34-0.59); P < .0001 Median, wks 12.3 7.3 Mean, wks 19.0 9.3 Mutant KRAS Group PFS Pmab + BSC BSC Alone HR (95% CI) Events/N (%) 76/84 (90) 95/100 (95) 0.99 (0.73-1.36) Median, wks 7.4 7.3 Mean, wks 9.9 10.2
  • 66. Objective Tumor Response and Progression-Free Survival Amado R...Van Cutsem E, et al. ECCO 2007. Abstract 0007. KRAS All Evaluable Mutant Wild Type Response, n (%) Pmab + BSC (n = 208) BSC (n = 219) Pmab + BSC (n = 84) BSC (n = 100) Pmab + BSC (n = 124) BSC (n = 119) CR 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) PR 21 (10) 0 (0) 0 (0) 0 (0) 21 (17) 0 (0) SD 52 (25) 22 (10) 10 (12) 8 (8) 42 (34) 14 (12) PD 104 (50) 149 (68) 59 (70) 60 (60) 45 (36) 89 (75) CR, PR, SD 73 (35) 22 (10) 10 (12) 8 (8) 63 (51) 14 (12)
  • 67. BRAF and KRAS Mutations in CRC
    • BRAF mutations in colorectal cancer present only in tumors that do not carry KRAS mutations [1]
      • BRAF linked to the ability of tumors to repair mismatched DNA bases in DNA
      • Results suggest that BRAF and KRAS mutations exert equivalent effects in tumorigenesis
    • Time to progression [2]
      • Shorter TTP with mutated KRAS vs wild type ( P = .0443)
      • Equivalent TTP for mutated vs wild type BRAF ( P = .5369)
      • Shorter TTP with KRAS or BRAF mutation vs wild type of both ( P = .0259)
    1. Rajagopalan H, et al. Nature. 2002;418:934. 2. Benvenuti S, et al. Cancer Res. 2007;67:2643-2648.
  • 68. EGFR Ligand Expression: A Predictor for Increased PFS? EGFR Ligand Expression High Low 0 20 40 60 80 100 120 140 Median PFS (Days) 103.5 days 115.5 days 57 days 57 days EREG (P = .0002) AREG (P = .0002) Single study data, further validation required in prospective studies n = 110, cetuximab monotherapy. Khambata-Ford S, et al. J Clin Oncol 2007;25:3230 - 3237.
  • 69. EVEREST Study: Analysis of Epiregulin Expression Association of PFS and OS with the baseline expression level of epiregulin (EREG) Van Cutsem E, et al. WCGIC 2007. Abstract 0 – 034. PFS Survival High Low 1.0 0.8 0.6 0.4 0.2 0.0 0 100 200 300 400 500 0 200 400 600 800 High Low Refseq NM_001432 (EREG), 205767_at P = .013 Refseq NM_001432 (EREG), 205767_at P = .00033 Time (Days) Time (Days) Proof of PFS Proof of OS 1.0 0.8 0.6 0.4 0.2 0.0
  • 70. Polymorphism of the FC Receptors
    • Positive association between FC  2A H151H and FC  3A F158F genotype in 39 patients
    • These polymorphisms may indicate a role of ADCC
    Zhang W, Lenz H, et al. J Clin Oncol. 2007;25:3712-3718. Log-rank P = .004 FCGR2A H/H or H/R and FCGR3A F/F or F/V (n = 22) FCGR2A R/R or FCGR3A V/V (n = 13) PFS for patients with metastatic colorectal cancer receiving cetuximab by fragment c  receptor (FCGR) polymorphisms. 3.7 1.1 0 2 4 6 8 10 Median PFS Median PFS (months)
  • 71. Potential Predictors of Clinical Activity of Cetuximab, Panitumumab in mCRC
    • Skin reactions ( “ rash ” ) correlate with outcome
    • No role of IHC selection in CRC
    • No role of somatic EGFR gene mutations in CRC
    • Increased EGFR gene copy numbers assessed by FISH correlate with higher RR and PFS
      • Retrospective evidence from different studies, mainly in chemotherapy refractory patients; major methodology issues for clinical practice
    • High evidence for a role of KRAS gene mutations and lack of activity
      • Strong evidence from different studies, in chemotherapy-refractory patients treated with cetuximab ( ± irinotecan) and panitumumab
    • Other markers with emerging role: ligands
    • Need for data from first-line therapy randomized trials