Study of target therapy “Cetuximab”
 on the squamous cell carcinomas of
     the head and neck (SCCHN)

      Student ID :...
Outline
 Introduction
 Squamous cell carcinomas of the head and neck
    (SCCHN)
   EGFR’s role on SCCHN
   RT/CT’s in...
 Cancers arising in the upper aerodigestive tract,
 including the oral cavity, pharynx and larynx

 Tumors are further c...
 Squamous cell carcinomas are derived from:
   The epithelium lining the aerodigestive tract
   Account for approx. 90%...
 Stage of tumor is determined at diagnosis
 Staging helps assess prognosis and different treatment


 TNM system is oft...
Squamous cell carcinomas head& neck




                                        6
Prof J-L Lefebvre, personal communication
Factors contributing to the etiology of H&N cancers
researches Dep. collected the following data:

 Agent/factor         C...
ENT and Oral surgeons represent major
    patients source and treat trend
 70% patients are diagnosed by ENT and oral surg...
Cetuximab combined RT used in locally advanced H & N Ca,                              9
                                  ...
“Evidence for a
                       role for the EGFr
                        in the inhibition and
                   ...
EGFr is expressed in a variety
                                           of solid tumors
                Colorectal

    ...
 Cetuximab is an IgG1 MAb
                                      targeting the EGFr
                                     ...
Cetuximab: IgG1-Induced Antibody-Dependent
         Cell Cytotoxicity (ADCC)

                   IgG1
                (cet...
High EGFr expression in SCCHN is linked to lower
       survival and increased risk of locoregional relapse

             ...
Treatment modalities in SCCHN
                         locally adv
                                                       ...
Acute adverse effects: grade 3 or higher
                       34% with RT alone vs 77% with CRT (p<0.001)
              ...
9%
 21%          10%           9%    Early deaths due to treatment-related
                                  complications...
18
BONNER Study 2006



            Bonner,J .A., et al. 2006
                                        19
354:567-78, 2006




                   20
Cetuximab + RT in locally advanced
       SCCHN: phase III study design
Stratified by
 KPS (Karnofsky performance status)...
Phase III study: locoregional control
                             100
                                                   ...
Phase III study: overall survival
                         100
                                                           ...
RT         Cetuximab
Side effect                               (n=212)         + RT        p-valuea
Mucositis/stomatitis  ...
First line R /M SCCHN

      EXTREME Study
   Platinum-Based Chemotherapy
± Cetuximab in Head and Neck Cancer




Vermorke...
 Randomized phase III multicenter study

 Treatment: platinum (cisplatin or carboplatin) plus 5-
 FU, with or without ce...
Patients stratified according to:
                 Group A
    Cetuximab 400 mg/m2 initial dose          • KPS (<80 vs ≥80...
 Primary endpoint
     Overall survival time

 Secondary endpoints
     Duration of response
     Time to progression...
distribution of diseases are average
                                                Cetuximab +
                         ...
EXTREME: overall survival
                       1.0   |
                                 | ||
                           ...
1.0   |
                                                                  EXTREME:
                       0.9        | |||...
Cetuximab +
                        platinum/5-FU     Platinum/5-FU
                           (n=222)           (n=220)  ...
Most relevant grade 3/4 adverse events (%)




                                                                           ...
34
Cetuximab: summary of clinical studies
 in recurrent/metastatic SCCHN

Type of study        Disease                Treatme...
Grades (General Definitions)
     severity of side effects were divided into Grade0-5


 · 0 = No adverse event or within...
Overall survival by severity of skin rash
                    1.0                                                         ...
Phase III study: change of QoL* as a
  function of time
   Cetuximab + RT significantly improves locoregional control and...
Cetuximab ±CDDP or a variety of second-line
    treatments:clinical outcomes

                         No. of             ...
Conclusions:
       platinum-refractory second-line

 Cetuximab is also active in second-line setting in
 patients with p...
National Comprehensive Cancer Network

   only proposal of the target treatment on 2008 NCCN guideline




   Cetuximab as...
Thanks
for your attention



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SCCH&N cancer report

  1. 1. Study of target therapy “Cetuximab” on the squamous cell carcinomas of the head and neck (SCCHN) Student ID : Student : H Date :2009 1
  2. 2. Outline  Introduction  Squamous cell carcinomas of the head and neck (SCCHN)  EGFR’s role on SCCHN  RT/CT’s influence on SCCHN  Cetuximab was used on the locally advanced SCCHN  Cetuximab was used on the first line recur/meta SCCHN  Cetuximab was used on the 2nd line recur/meta SCCHN  Conclusions 2
  3. 3.  Cancers arising in the upper aerodigestive tract, including the oral cavity, pharynx and larynx  Tumors are further classified by Histological type (Adenocarcinomas, Squamous cell carcinomas )  Brain tumors are excluded as they behave, and are treated, very differently 3
  4. 4.  Squamous cell carcinomas are derived from:  The epithelium lining the aerodigestive tract  Account for approx. 90% of primary head and neck cancers  SCCHN occur in a range of different sites resulting in:  Distinct clinical presentations and outcomes.  Are treated differently than other head and neck cancers 4
  5. 5.  Stage of tumor is determined at diagnosis  Staging helps assess prognosis and different treatment  TNM system is often used in all solid tumors:  T – size of primary tumor  N – involvement of lymph nodes  M – presence of metastases  T definitions are specific to the site of each primary tumor  N and M definitions in SCCHN are as same as for other tumors 5 American joint committee on cancer staging (AJCC),
  6. 6. Squamous cell carcinomas head& neck 6 Prof J-L Lefebvre, personal communication
  7. 7. Factors contributing to the etiology of H&N cancers researches Dep. collected the following data: Agent/factor Cancer site Agent/factor Cancer site Tobacco Oral, larynx Occupational Exposure: Alcohol Oral, larynx Textile industry Oral, pharyngeal Areca nuts Oral Printing trade Oral, pharyngeal Asbestos Larynx Wood Nasal (Larynx) Oral snuff Oral Nickel Nasal Infectious agents: Mustard gas Larynx Sulfuric acid Larynx HPV Oral HSV Oral EBV Nasopharynx Radiation Salivary gland 7 Cancer of the larynx, www.FIRSTConsult.com, Elsevier, (07.11.09).
  8. 8. ENT and Oral surgeons represent major patients source and treat trend 70% patients are diagnosed by ENT and oral surgeons Some successful experience in penetrating radiation oncologist and ENT surgeon segments Treatment strategy generally follow protocol in multidisciplinary team Radiation RT & CT oncologist ENT / Oral Patient (Surgeon) Diagnosis & surgery CT Oncologist 8 Data source: 2007 Oct 20 1st wave survey by APR
  9. 9. Cetuximab combined RT used in locally advanced H & N Ca, 9 http://www.fda.gov/ Cetuximab monotherapy used in the Recur / meta H & N after platinum failure
  10. 10. “Evidence for a role for the EGFr in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor.”* EGFr message transmission result in cancer cells---- 10 Bernier J. and Schneider D.(2006)
  11. 11. EGFr is expressed in a variety of solid tumors Colorectal Head & neck 90 – 100% cancer Lung Lung cancer 40 – 91% (NSCLC) (NSCLC) Colorectal cancer 72 – 84% Breast cancer 14 – 91% Head & Neck (SCC) Ovarian cancer 35 – 70% Renal cell cancer 50 – 90% Cunningham et al. 2004; Grandis et al.1996; Salomon et al. 1995; Walker & Dearing.1999; Folprecht et al.2004 11
  12. 12.  Cetuximab is an IgG1 MAb targeting the EGFr  Binding blocks EGFr signaling, the message transmission and inhibits proliferation, angiogenesis ,metastasis, stimulates apoptosis and differentiation  combined chemotherapy or radiation , can enhance the anti-tumor effect  Fc region may induce antibody-dependent cell- mediated cytotoxicity (ADCC) (immune response) 12 Bernier J. and Schneider D.(2006)
  13. 13. Cetuximab: IgG1-Induced Antibody-Dependent Cell Cytotoxicity (ADCC) IgG1 (cetuximab) cetuximab) Attachment Lysis of antibody-coated cell EGFR MEDIATED IgG1 MEDIATED Anti-tumour Activity ADCC IgG1 attachment surface antigen ,trigger NK identify ca.cell by antibody MAXIMIZE ANTI-TUMOUR ACTIVITY Fan Z, et al. Cancer Res.1993;53:4322-8 Res.1993;53:4322- 13
  14. 14. High EGFr expression in SCCHN is linked to lower survival and increased risk of locoregional relapse Overall survival Locoregional relapse 100 100 p=0.0006 p=0.003 75 75 EGFr>median Failed (%) Alive (%) EGFrmedian 50 50 EGFrmedian 25 25 EGFr>median n=155 n=155 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years from randomization Years from randomization inhibit EGFr pathway extened tumor progression Ang K. K, et al. 2002 14
  15. 15. Treatment modalities in SCCHN locally adv rec/met SCCHN refractory Surgery RT Alone RT + CT CT Palliation • Early disease is treated with surgery or radiotherapy alone • Locally advanced SCCHN • Radiotherapy for patients at intermediate risk • Chemoradiotherapy for high-riska disease • Recurrent and/or metastatic disease • Chemotherapy is main treatment • Combination therapies are associated with increased toxicities – eg mucositis and swallowing dysfunction aStage 15 III–IV disease, excluding T1–2 N1 and T3 N0
  16. 16. Acute adverse effects: grade 3 or higher 34% with RT alone vs 77% with CRT (p<0.001) 80 RT alone (n=231) 60 Combined RT + cisplatin (n=228) Subjects (%) 40 20 0 us ting ract kin io n ia) ic ct ia c ne i a a g i I t S c t om l og tra nem log r ph vom r G e Inf eros t eu ro na ry A to mb eso e ri a e nd p (x N ou m m He us x an sea d a Up nd la nit o uc ary n au yg Ge M N ar Ph liv Sa 16 Cooper ,J.S., et al. 2004
  17. 17. 9% 21% 10% 9% Early deaths due to treatment-related complications 6% Late deaths due to treatment-related complications 45% 15% of patient died for the SE of CT/RT not for cancer. Cause of death Time of occurrence, years median (range) Disease progression 1.5 years (0.3–8.6) Comorbidities 1.9 years (0.07–8.8) Treatment-related 0.3 years (0.03–3.4) Second primary tumors 3.5 years (1.5–10.1) Unknown 5.1 years (1.1–9.5) 17 Argiris ,A., et al. 2004
  18. 18. 18
  19. 19. BONNER Study 2006 Bonner,J .A., et al. 2006 19
  20. 20. 354:567-78, 2006 20
  21. 21. Cetuximab + RT in locally advanced SCCHN: phase III study design Stratified by  KPS (Karnofsky performance status)  Nodal involvement  Tumor stage  RT fractionationa RT (n=213) Stage III and IV non metastatic Cetuximab + RT (n=211) SCCHN R Cetuximab initial dose (400 (n=424) mg/m2) 1 week before RT Cetuximab (250 mg/m2) + RT (weeks 2–8)b • Primary endpoint: duration of locoregional control • Secondary endpoints: OS, PFS, RR, and safety 21 Bonner,J .A., et al. 2006
  22. 22. Phase III study: locoregional control 100 Cetuximab + RT p-value Locoregional control (%) RT 80 Locoregional 47% 34% <0.01 control rate 3-year 60 Cetuximab + RT (n=211) 40 20 14.9 24.4 RT (n=213) 0 0 10 20 30 40 50 60 70 Months Hazard ratio = 0.68 (95% CI: 0.52–0.89) Log-rank p=0.005 22 Bonner,J .A., et al. 2006
  23. 23. Phase III study: overall survival 100 Cetuximab + RT RT p-value 80 Survival rate 55% 45% 0.05 Overall survival (%) 3-year 60 Cetuximab + RT (n=211) 40 RT (n=213) 20 29.3 49.0 0 0 10 20 30 40 50 60 70 Months Hazard ratio = 0.74 (95% CI: 0.57–0.97) Log-rank p=0.03 23 Bonner,J .A., et al. 2006
  24. 24. RT Cetuximab Side effect (n=212) + RT p-valuea Mucositis/stomatitis 52% 56% 0.44 Dysphagia 30% 26% 0.45 Radiation dermatitis 18% 23% 0.27 Xerostomia 3% 5% 0.32 Fatigue/malaise 5% 4% 0.64 Acne-like rash 1% 17% <0.001 Infusion-related reactionsb 0% 3% 0.01 will not increase the incidence of RT side effects 24 Bonner,J .A., et al. 2006
  25. 25. First line R /M SCCHN EXTREME Study Platinum-Based Chemotherapy ± Cetuximab in Head and Neck Cancer Vermorken,J .B., et al. N Engl J Med 2008 25
  26. 26.  Randomized phase III multicenter study  Treatment: platinum (cisplatin or carboplatin) plus 5- FU, with or without cetuximab  80 sites in 17 European countries  No prior EGFr testing was required for study entry  Patients were stratified according to:  Prior chemotherapy  KPS (< 80 vs ≥ 80) 26 Vermorken,J .B., et al. 2006
  27. 27. Patients stratified according to: Group A Cetuximab 400 mg/m2 initial dose • KPS (<80 vs ≥80) then 250 mg/m2 weekly + • Prior chemotherapy (yes vs no) R EITHER carboplatin (AUC 5, d1) A Cetuximab OR cisplatin (100 mg/m2 IV, d1) N + 5-FU (1000 mg/m2/day IV, d1-4): D 3-week cycles O (6 cycles maximum) Progressive M disease or unacceptable I toxicity Z Group B E EITHER carboplatin (AUC 5, d1) D OR cisplatin (100 mg/m2 IV, d1) No treatment + 5-FU (1000 mg/m2/day IV, d1–4): 3-week cycles (6 cycles maximum) Vermorken,J .B., et al. 2006 27
  28. 28.  Primary endpoint  Overall survival time  Secondary endpoints  Duration of response  Time to progression  Response rate  Assessment of quality of life (QoL)  Safety Vermorken,J .B., et al. 200628
  29. 29. distribution of diseases are average Cetuximab + platinum / 5-FU Platinum / 5-FU (n=222) (n=220) Median age (range) 56 years (37–80) 57 years (33–78) Men / women 89% / 11% 92% / 8% Recurrence/metastasis Locoregional recurrence 54% 54% Metastasisa 46% 46% Primary metastatic disease 8% 7% aIncluding also distant metastasis and locoregional recurrence 29 Vermorken,J .B., et al. 2006
  30. 30. EXTREME: overall survival 1.0 | | || | First time R/M SCCHN over 10M in survival. 0.9 | | || 0.8 || Cetuximab + CTX | CTX only 0.7 Survival probability | 0.6 HR (95% CI): 0.797 (0.644; 0.986) 0.5 | Strat. log-rank test: 0.0362 0.4 | | | | 0.3 |||| || | | 7.4 10.1 | || |||| | || || || || months months || | | 0.2 || || | || || ||| | | | | | ||| | | | | || | | | | |||| | | || 0.1 0.0 0 3 6 9 12 15 18 21 24 Patients at risk Survival time (months) 222 184 153 118 82 57 30 15 3 220 173 127 83 65 47 19 8 1 30 Vermorken,J .B., et al. 2006
  31. 31. 1.0 | EXTREME: 0.9 | ||||| Progression-free survival (PFS) | | | ||| Cetuximab + CTX 0.8 | | | CTX only | | 0.7 || Progression free (%) | HR (95%CI): 0.538 (0.431, 0.672) | | 0.6 | | Strat. log-rank test: <0.0001 | || 0.5 | 5.6 months | 3.3 months | ||| | 0.4 | || | 0.3 | | || | 0.2 | | | | 0.1 | 0.0 0 3 6 9 12 15 Patients at risk PFS time (months) 222 138 72 29 12 7 220 103 29 8 3 1 31 Vermorken,J .B., et al. 2006
  32. 32. Cetuximab + platinum/5-FU Platinum/5-FU (n=222) (n=220) p-valuea ORR [CR + PR], % 35.6 19.5 0.0001 [95% CI] [29.3–42.3] [14.5–25.4] DCR [CR + PR + SD], % 81.1 60.0 <0.0001 [95% CI] [75.3–86.0] [53.2–66.5] Vermorken,J .B., et al. 2006 32
  33. 33. Most relevant grade 3/4 adverse events (%) 10 15 20 25 0 5 An em ia N eu t ro Th pe ro ni a m bo cy to pe n ia N au se a Vo m itin g Platinum / 5-FU (n=215) D ia rr h ea St om at itis D ys pn ea Pn eu m on Ac ia ne - li ke In ra fu sh Cetuximab + platinum / 5-FU (n=214) si on re ac tio n Vermorken,J .B., et al. 2006 33
  34. 34. 34
  35. 35. Cetuximab: summary of clinical studies in recurrent/metastatic SCCHN Type of study Disease Treatment Reference Phase I Mixed CDDP + cetuximab Shin 2001 Phase I/II/III Pt-sensitive Pt-based CT ± Burtness 2005 cetuximab Bourhis 2006 Vermorken 2007 Paclitaxel + cetuximab Hitt 2007 Phase II Pt-refractory Cetuximab alone Vermorken 2007 Platinum + cetuximab Baselga 2005 Herbst 2005 three clinical trials confirm the efficacy, refractory of patients 35 the side effects and efficacy hard to balance.
  36. 36. Grades (General Definitions) severity of side effects were divided into Grade0-5  · 0 = No adverse event or within normal limits  · 1 = Mild adverse event  · 2 = Moderate adverse event  · 3 = Severe and undesirable adverse event  · 4 = Life-threatening or disabling adverse event  · 5 = Death related to adverse event Cetuximab side effects of most below the Grade 3, side effects and survival appear positively related . 36
  37. 37. Overall survival by severity of skin rash 1.0 Grade 0 Grade 1 Grade 2/3 No. of events 27 (96%) 24 (100%) 25 (93%) 0.9 Median survival 2.2 months 5.4 months 7.1 months 0.8 [95% CI] [1.9–4.3] [2.7–6.7] [4.1–11.1] 0.7 Proportion 0.6 0.5 0.4 0.3 0.2 Grade 2/3 0.1 Grade 0 Grade 1 0 0 3 6 9 12 15 18 21 24 27 Time (months) Grade 0 28 12 6 3 1 1 Grade 1 24 16 11 5 3 1 1 Grade 2/3 27 22 15 9 7 4 1 1 1 37 balance the side effects and efficacy, SE can tolerance, handle, encouraged treat Herbst ,R.S., et al. 2005
  38. 38. Phase III study: change of QoL* as a function of time  Cetuximab + RT significantly improves locoregional control and overall survival without adversely affecting QoL, maintain quality of life. 100 Global health status / QoL score Radiotherapy 80 Radiotherapy / ERBITUX 60 40 20 0 -20 Baseline Week 4 Month 4 Month 8 Month 12 Visit 38 *Postbaseline scores for the QLQ-C30 Curran ,D., et al. 2007
  39. 39. Cetuximab ±CDDP or a variety of second-line treatments:clinical outcomes No. of TTP Treatment patients RR DCR MS (median) Cetuximab1 103 13% 46% 5.9 months 2.3 months Cetuximab + platinum2 96 10% 53% 6.2 months 2.8 months Cetuximab + CDDP3 79 10% 56% 5.2 months 2.2 months Retrospective study4 All patients 151 3% 15% 3.4 months N/A CT only 43 0% 9% 3.6 months N/A 1. Vermorken JB, et al. 2007; 2. Baselga J, et al. 2005;23:5568–557 3. Herbst RS, et al. 2005; 4. Vermorken JB, et al. 2005; 39
  40. 40. Conclusions: platinum-refractory second-line  Cetuximab is also active in second-line setting in patients with platinum-refractory SCCHN  In second-line setting Cetuximab + platinum showed similar results to Cetuximab monotherapy Vermorken JB, et al. 2007; Baselga J, et al. 2005;Herbst RS, et al. 2005; Vermorken JB, et al. 2005; 40
  41. 41. National Comprehensive Cancer Network only proposal of the target treatment on 2008 NCCN guideline Cetuximab as the most effective treatment for different stages of SCCHN, 41 either LA,RT,R/M +cisplain+5Fu and monotherapy.
  42. 42. Thanks for your attention 42

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