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									Avances en terapia sistémica en cáncer
metastásico de colon y recto (mCRC)
Mauricio Lema Medina MD
Clínica de Oncología Astorga – Clínica SOMA – Medicáncer
Medellín, Colombia
Temario (107)

 Consideraciones iniciales: Vías de transducción de señales (EGFR), y angiogénesis en mCRC (15)
 Evolución histórica del tratamiento del mCRC -1: Citostáticos convencionales (12)
 Mecanismos de acción del Bevacizumab y los MOAs anti EGFR (10)
 Evolución histórica del tratamiento del mCRC -2: Terapia molecular dirigida (39)
  –   Bevacizumab en mCRC (31)
  –   Cetuximab en mCRC (8)
 Evolución histórica del tratamiento del mCRC -3: Terapia individualizada (29)
  –   Impacto de las alteraciones en las vías de transducción de señales del EGFR en la eficacia de Cetuximab (20)
  –   (Ausencia de) Impacto de las alteraciones en las vías de trasnducción de señales del EGFR en la eficacia de
      Bevacizumab (9)
 Conclusiones (2)
 Efectos adversos del Bevacizumab y de los MOAs anti EGFR (14)




Page  2
Consideraciones iniciales: Vías de transducción
de señales (EGFR), y angiogénesis en mCRC
Page  4
Page  5
 EGFR es una proteina transmembrana



           Dominio
           Extracelular
                                    Dominio
                                    Transmembrana




                          Dominio
                          intracelular




Page  6
                      La activación del EGFR
                      activa múltiples procesos




                     Shc
                           Grb2
             PI3-K                       Sos-1


                                   Ras
           AKT
                                             Raf
                           MEKK-1

                                             MEK
             mTOR          MKK-7

Page  7
                                          ERK
                      La activación del EGFR activa
                      múltiples procesos




                     Shc
                           Grb2
             PI3-K                       Sos-1


                                   Ras
           AKT
                                             Raf
                           MEKK-1

                                             MEK
             mTOR          MKK-7

Page  8
                                          ERK
  La activación del EGFR activa múltiples
  procesos

                                            Shc
                                                  Grb2
                          PI3-K                                 Sos-1


                                                          Ras
                        AKT
                                                                    Raf
                                                  MEKK-1

                                                                        MEK
                              mTOR                MKK-7

                                                                 ERK
                                                  JNK




Page  9   Apoptosis    Proliferation   Angiogenesis       Metastasis
           Resistance
Page  10
Page  11
Targeting the EGFR pathway:
K-Ras mutations

                                         EGFR overexpression:
                 TGF-α                   • CRC (27–77%)
                                         • Pancreatic cancer (30–50%)
                                         • Lung cancer (40–80%)
                                         • NSCLC (14–91%)




                                                 K-Ras*     K-Ras mutation:
                EGFR*                   Sos
                                                            • CRC (30–50%)
                                  Grb2                      • Pancreatic cancer (90%)
                                                  B-Raf*    • Papillary thyroid cancer (60%)
                                                            • NSCLC (30%)

                 EGFR mutation:
                 • NSCLC (10%)                     MEK
                 • Glioblastoma (20%)                       B-Raf mutation:
                                                            • CRC (10%)
                                                            • Melanoma (70%)
                                                  MAPK      • Papillary thyroid cancer (50%)




 *Mutated in human cancers
 NSCLC = non-small cell lung cancer
Page  12
 TGF = transforming growth factor                          Adapted from Roberts Der. Oncogene 2007
CRC: Adenoma-Carcinoma Sequence




     Normal         Hyperproliferative
                                                     Adenoma                 Carcinoma
     Colon             Epithelium


     APC          Methylation       APC          KRAS        18q        p53         Further
    hMSH2        abnormalities     hMSH2        mutation   deletion   deletion   accumulation
    hMLH1                          hMLH1                                          of genetic
 abnormalities                   inactivation                                    abnormalities
  (hereditary)

                                                  32% to 57%
                                                  KRAS mutant

Page  13
  Targeting the EGFR pathway

                               TGF-α
      extracellular
                           R        R


      intracellular                      Grb2
                                                Sos
                                                                         phosphorylation
                           K        K
                                         Shc
                                                Grb2    Sos
               mutation   PI3K                                                  Ras         mutation


            loss      PTEN                       Akt                            Raf        mutation



                   mTOR           FKHR          GSK–3          Bad            MEK1/2

                                   p27
                                                                               MAPK
                                 Cyclin D1, E

                   Cell cycle progression                     Survival      Proliferation
Page  14                                                                   Mendelsohn et al. JCO 2003
 VEGF: Un Mediador Clave de Angiogenesis




Aumento de los niveles de VEGF                     Factores ambientales
                                                   (hipoxia, pH)




                                                   Factores de
                                                   crecimiento, Hormonas
            Genes implicados                       (EGF, bFGF, PDGF,
            en tumorogénesis                       IGF-1, IL-1, IL-6,
            (p53, p73, src,                        estrogen)
            ras, vHL, bcr-abl)

  bFGF, basic fibroblast growth factors; EGF, epidermal growth factor; IGF, insulin-like growth factor; IL,
  interleukin; PDGF, platelet-derived growth factor; VEGFR, VEGF receptor.
  1. Dvorak HF. J Clin Oncol. 2002;20:4368-4380; 2. Ebos JM, et al. Mol Cancer Res. 2002;1:89-95; 3.
 Page  15 N, et al. Nat Med. 2003;9:669-676.
  Ferrara
VEGF: Un Mediador Clave de Angiogenesis




                                      Unión y activación
    VEGF                              del VEGFR


                           P    P
                           P    P

                                                   Activación de la
              PLC       PI3-K       FAK    Ras     célula
                                                   endotelial
            PKC   IP3    AKT    Paxillin   MAPK

            Surviva     Proliferation Migratio
            l                         n
Page  16   ANGIOGENESIS
VEGF es expresado durante toda la historia natural



                                                                  bFGF   bFGF                bFGF
                                                       bFGF      TGFb-1 TGFb-1              TGFb-1
                                          VEGF VEGF VEGF VEGF                              VEGF
                                                      TGFb-1      PIGF        PIGF    PIGF
                                                                            PD-ECGF PD-ECGF
                                                                                   Pleiotrophin




bFGF = basic fibroblast growth factor
                                                  Evolución tumoral
TGFb-1 = transforming growth factor b-1
PIGF = placenta growth factor
                                                            Adapted from Folkman. Cancer.
PD-ECGF = platelet-derived endothelial cell growth factor
                                                            Principles and practice of oncology 2005

Page  17   www.clinicaloptions.com
Evolución histórica del tratamiento mCRC – 1:
Citostáticos convencionales
Evolución histórica del manejo de mCRC
¿ Hacia una enfermedad crónica ?
    Terapia de               Oxaliplatino                  K-Ras mutado factor
    soporte                                                pronóstico adverso, y
                             Capecitabina                  predictivo de no respuesta
                             Irinotecán                    contra terapia dirigida con
                                                           EGFR




                                                                              Nuevas molécultas
  1985      1990          1998              2004              2009            están siendo
                                                                              evaluadas….




             Fluoruracilo inicia la          Bevacizumab
             terapia antineoplásica          Cetuximab




Page  19
Quimioterapia en mCRC
Citostáticos convencionales
     Inhibidores TS                     Inhibidores Topo-I       Alquilantes      Comentarios
  Fluoruracilo (IV)
  Capecitabina (PO)
                                         Irinotecán          Oxaliplatino      4
                                                                                Modulación con
                                                                                 folinato
                                                                                 incrementa
  Raltitrexed (IV)                                                              respuesta de
                                                                                 Fluoruracilo.
                                                                                Oxaliplatino es
                                                                                 inactivo como
                                                                                 monoagente




TS: Timidilato sintestasa; Topo-I: Topoisomerasa I

Page  20
La combinación de 3 agentes citotóxicos incrementa la
supervivencia mediana a 17-20 meses en mCRC
             Supervivencia mediana

                    BSC
        35
        30
        25                                    Aproximadamente 6 meses
        20
Meses




        15
        10
        5
        0
        1980                        1985        1990           1995     2000
Page  21
             BSC = mejor terapia de soporte
Fluoropirimidines en mCRC

  No cambio en la supervivencia mediana con diferentes esquemas
    – Supervivencia mediana: ~ 12 meses

  Regimen                                             Respuesta, %
  5-FU en bolo                                            7-15
  5-FU en infusión                                       20-30
  5-FU/LV
   Mayo, Roswell Park                                   12-35
   de Gramont (LV5-FU2)                                 28-33
   AIO (cada semana, 24-hour infusion)                  25-44
  Capecitabina                                           20-25



 Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.


Page  22   www.clinicaloptions.com
IFL vs FOLFOX vs IROX (N9741)



                           diseño

                             IFL
                           (n=264)

                           FOLFOX                            Bolo (IFL) vs infusión
    R
                           (n=267)                                 (FOLFOX)
n=795
                            IROX
                           (n=264)




                                     Primary endpoint: PFS

Goldberg et al, JCO 2004

Page  23
   FOLFOX4: ciclo de 14-días




                                       5-FU 400mg/m2




                                                                                   5-FU 400mg/m2
                      OX 85mg/m2




                                          iv bolus




                                                                                      iv bolus
                         iv 2 h                        5-FU 600mg/m2                               5-FU 600mg/m2
                    LV 200mg/m2                            iv 22 h   LV 200mg/m2                       iv 22 h
                        iv 2 h                                           iv 2 h

                 d1                                                d2                                          d3

     IFL
                                  5-FU 500mg/m2




                  Iri 125mg/m2
                                     iv bolus




                      iv 1.5 h
                    LV 20mg/m2
                       iv 2 h

                1             8                        15        22


Page  24
            5-FU = 5-fluorouracilo; LV = leucovorin (Folinato de calcio); OX = oxaliplatino; Iri = Irinotecán
Page  25   N9741: Sanoff HK. J Clin Oncol 26:5721-5727.
                                             N9741
                                         Resultados

                           IFL   FOLFOX      IROX
                  n        264     267        264
            RR (%)         31      45         35
            PFS (m)        6.9    8.7         6.5
            OS (m)         15     19.5       17.4
                  p              0.0001
Goldberg et al, JCO 2004

Page  26
Efficacy: Sequence FOLFIRI/FOLFOX



                                         Arm A                          Arm B
  Results                      FOLFIRI  FOLFOX                   FOLFOX  FOLFIRI
  Patients, n                   109                 81            111           69
  Confirmed RR, %                56                 15            54            4
  TTP, mos                      8.5                 4.2           8.0           2.5
  Survival, mos                           21.5                          20.6


                 No statistically significant differences in first- or
                     second-line therapy RR or TTP and OS




Page  27   Tournigand C, et al. J Clin Oncol. 2004;22:229-237.
XELOX y FOLFOX4


XELOX: 21-day cycle

                 OX 130mg/m2
                     iv 2 h
                                                                                                   Rest

             d1                                  OralCapecitabina (Xeloda) 1000mg/m2 bid
                                       d2                                             d15                 d21


FOLFOX4 + Avastin/placebo: 14-day cycle
                              5-FU 400mg/m2




                                                                          5-FU 400mg/m2
                 OX 85mg/m2
                                 iv bolus




                                                                             iv bolus
                    iv 2 h                    5-FU 600mg/m2                               5-FU 600mg/m2
             LV 200mg/m2                          iv 22 h   LV 200mg/m2                       iv 22 h
                 iv 2 h                                         iv 2 h

            d1                                            d2                                          d3
                    5-FU = 5-fluorouracil; LV = leucovorin; OX = oxaliplatin; PL = placebo
Page  28
CapeOx Noninferior to FOLFOX



  Median follow-up: 17.7 mos
  HR for PFS: 1.04 (97.5% CI: 0.93-1.16)
    – Upper limit of 97.5% CI: < 1.23 (noninferiority margin)



                                          CapeOx/                      FOLFOX-4/
                                     CapeOx + Placebo/             FOLFOX-4 + Placebo/
  PFS
                                   CapeOx + Bevacizumab          FOLFOX-4 + Bevacizumab
                                         (n = 1017)                    (n = 1017)
   Events, n                                   813                        826
   Median (ITT), mos                            8                         8.5




Page  29   Cassidy J, et al. J Clin Oncol. 2008;26:2006-2012.
Plateau de la eficacia de la quimioterapia
convencional en mCRC

 La supervivencia mediana con los citostáticos convencionales
  alcanza unos 17-20 meses


  Combinación                                          Agentes activos                Supervivencia
                                                                                     mediana (meses)
  5-FU/LV                                                    1 droga                      11-12
  Irinotecan/5-FU                                           2 drogas                      14-15
  Oxaliplatino/5-FU ± irinotecan                            3 drogas                      17-20




 Meta-analysis Group in Cancer. J Clin Oncol. 1998;16:301-308. Saltz LB, et al. N
 Engl J Med 2000;343:905-914. de Gramont A, et al. J Clin Oncol. 2000;18:2938-
 2947. Goldberg RM, et al. J Clin Oncol. 2002;20:4591-4596. Tournigand C, et al. J
 Clin Oncol. 2004;22:229-237.

Page  30   www.clinicaloptions.com
Quimioterapia en mCRC
La combinación de citostáticos incrementa la supervivencia


                                                                                 Comentarios
            Inhibidores TS                             Inhibidores TS               4
                                                                            La supervivencia
                                                                             mediana con la
        Fluoruracilo (IV)                            Fluoruracilo (IV)     exposición a los 3
        Capecitabina (PO)                            Capecitabina (PO)     agentes es de
                                                                             aproximadamente 20
                                                                             meses.
        Inhibidores Topo-I                               Alquilantes
                                                                            Grothey A, et al J Clin
         Irinotecán                                  Oxaliplatino          Oncol. 2005;23:9441-
                                                                             9442.




TS: Timidilato sintestasa; Topo-I: Topoisomerasa I

Page  31
Mecanismos de acción del
Bevacizumab y los MOAs anti EGFR
VEGF (Bevacizumab)
Bevacizumab



                                                                         Mab Recombinante
                                                                          humanizedo anti VEGF
                                                                         Neutraliza todas las isoformas
                                                                          de VEGF A
                                                                         T1/2 17-21 días




Page  34TM
Avastin       (bevacizumab) [package insert]. San Francisco, Calif: Genentech, Inc; 2004.
Bevacizumab (Avastin®): Mecanismo de Acción



                                      Bevacizumab
        VEGF




                     P   P
                     P   P




Page  35
  Bevacizumab (Avastin®): Mecanismo de Acción




                             Bevacizumab
                VEGF




                         P     P
                         P     P




  BLOQUEO de la activación del VEGFR
Page  36
EGFR (Cetuximab, Panitumumab)
Cetuximab


             IgG1 (anticuerpo quimérico)
             Anti EGFR (y sus heterodímeros)
             Aprobado en 2004 en mCRC




Page  38                            Courtesy of: Paulo Hoff
 MAb Anti-EGFR



            Extracelular




            Intracelular
                                     Shc
                                       Grb2
                             PI3-K               Sos-1


                                           Ras
                           AKT
                                                    Raf
                                     MEKK-1
Page  39
 MOAs Anti-EGFR



             Extracelular




              Intracelular
                                              Shc
                                                Grb2
                                      PI3-K                Sos-1


                                                       mK-Ras
                                  AKT
                                                                Raf
                                               MEKK-1

                                                                MEK
Page  40   www.clinicaloptions.com   mTOR     MKK-7
  Targeting the EGFR pathway

                               TGF-α
      extracellular
                           R        R


      intracellular                      Grb2
                                                Sos
                                                                         phosphorylation
                           K        K
                                         Shc
                                                Grb2    Sos
               mutation   PI3K                                                  Ras         mutation


            loss      PTEN                       Akt                            Raf        mutation



                   mTOR           FKHR          GSK–3          Bad            MEK1/2

                                   p27
                                                                               MAPK
                                 Cyclin D1, E

                   Cell cycle progression                     Survival      Proliferation
Page  41                                                                   Mendelsohn et al. JCO 2003
Evolución histórica del tratamiento mCRC – 2:
Terapia molecular dirigida
Bevacizumab en mCRC – Primera
línea
Phase III Trial With Bevacizumab
Therapy in First-Line MCRC


                           R
                           A   Bolus IFL + placebo
                                    (n = 412)
                           N
                           D
               Untreated   O     Bolus IFL + BV
                MCRC                (n = 403)
                           M
                           I
                           Z       5-FU/LV + BV
                                     (n = 110):
                           E   Closed due to lack of
                                      efficacy

Hurwitz. NEJM, 2004

Page  44                                              Courtesy of: Paulo Hoff
                   Phase III Trial of Bevacizumab
                   in First-Line mCRC




                                          IFL +            IFL +
                                         Placebo        Bevacizumab
                                         (n=411)          (n=402)       P Value
   ORR (%)                                       35         45           0.0036

            CR                                   2.2        3.7

            PR                                   32.5      41.2



Hurwitz H et al. N Engl J Med 2004;350:2235–42
Page  45                                                             Courtesy of: Paulo Hoff
Phase III Trial : PFS


                                                               Median PFS (months)
  Probability of being progression-free




                                          1.0                  IFL + placebo: 6.2 (95% CI: 5.6–7.7)
                                                               IFL + bevacizumab: 10.6 (95% CI: 9.0–1.0)
                                          0.8                  HR=0.54 (95% CI: 0.45–0.66) p<0.001


                                          0.6
                                                                                        IFL + bevacizumab
                                          0.4                                           IFL + placebo

                                          0.2

                                                    6.2        10.6
                                           0
                                                0         10                   20                      30
                                                                PFS (months)
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Page  46                                                                                      Courtesy of: Paulo Hoff
Phase III Trial: Survival

                                                  Median survival (months)
                            1.0
                                                  IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs
                                                  IFL + bevacizumab: 20.3 (95% CI: 18.5–24.2)
                            0.8                   HR=0.66 (95% CI: 0.54–0.81) p<0.001
  Probability of survival




                            0.6
                                                                           IFL + bevacizumab
                                                                           IFL + placebo
                            0.4


                            0.2

                                           15.6           20.3
                             0
                                  0   10            20                30                40
                                             Survival (months)
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Page  47                                                                        Courtesy of: Paulo Hoff
Trial of Bevacizumab plus
FOLFIRI/mIFL (BICC-C): design


                           Initial design                        Amended design

                             FOLFIRI                             FOLFIRI+Bev.
                             (n=144)                                (n=60)
                                mIFL                               mIFL+Bev.
    R                                              R
                              (n=141)                                (n=57)
 n=430                                           n=117
                              XELIRI                           May 2004 – Dec 2004
                              (n=145)

                        Feb 2003 – April 2004                  Protocol amended due
                                                                   to approval of
                                                                    bevacizumab
                                       Primary endpoint: PFS

     * Celecoxib data not shown
Fuchs et al, JCO 2008
Page  48                                                              Courtesy of: Paulo Hoff
Overall Survival


                                                                              Median OS
                                                                 Regimen       (months)   1 Year     P Value

                            1                                  FOLFIRI+ BEV        28      87%           --
                           0.9                                  mIFL + BEV         19.2    61%         0.01
  Proportion of Subjects




                           0.8
      Who Survived




                           0.7
                           0.6
                           0.5
                           0.4
                           0.3
                                     FOLFIRI + Bevacizumab
                           0.2
                           0.1       mIFL + Bevacizumab

                            0
                                 0      10                20                  30               40

                                              Survival Time (months)
Fuchs et al. JCO 2008
Page  49                                                                                   Courtesy of: Paulo Hoff
  Phase III Trial of Bevacizumab With
  Oxaliplatin-Based Therapy in CRC

                                      + Bevacizumab
                                     (7.5 mg/kg, q3w)
                           XELOX

                                        + Placebo             Primary
         Previously                                          end point:
      untreated MCRC                                            TTP
                                     + Bevacizumab
                                     (5 mg/kg, q2w)
                           FOLFOX4

                                        + Placebo

Saltz L, et al. JCO 2008
  Page  50                                             Courtesy of: Paulo Hoff
Progression-free Survival


                 1.0
                                                HR = 0.83 [97.5% CI 0.72–0.95] (ITT)
                 0.8                            p = 0.0023
  PFS estimate




                 0.6

                 0.4

                 0.2
                                          8.0     9.4
                  0
                    0                     5              10          15              20
                  25                                    Months
                        FOLFOX+placebo/XELOX+placebo         N=701; 547 events
                        FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events
Saltz L, et al. JCO 2008
Page  51                                                                        Courtesy of: Paulo Hoff
                 Efficacy

                           XELOX/FOLFOX   XELOX/FOLFOX + bev   P-value
                               N=701           N=699


 Response rate (%)             49%              47%               0.99


 PFS (mos)                     8.0               9.4           0.0023


 OS (mos)                      19.9             21.3             0.076




Saltz L, et al. JCO 2008
Page  52                                                      Courtesy of: Paulo Hoff
Patients should remain ‘on treatment’* to achieve
optimal clinical benefit with bevacizumab

                          1.0       6 months                FOLFOX4/XELOX + bevacizumab
                                                            FOLFOX4/XELOX + placebo
  Estimated probability




                          0.8

                                                          On treatment: HR=0.63
                          0.6
                                                          (PFS 10.4 vs 7.9 months, p<0.0001)
                                                           General: HR=0.83
                          0.4                              (PFS 9.4 vs 8.0 months, p=0.0023)

                          0.2

                           0
                                0          5       10          15             20
                                           PFS (months)
 *Prespecified secondary analysis
Page  53
                                                                    Saltz, et al. ASCO 2007 (poster)
  Phase III Trial of Bevacizumab + Panitumumab-CT
  With Bev-CT in CRC (PACCE)

                                     Bev + Pan


                            Ox-CT

                                       Bev        Primary
         Previously                              end point:
      untreated MCRC                                PFS
                                     Bev + Pan


                            Iri-CT

                                       Bev

Hecht JR, et al. JCO 2008
  Page  54
  Phase III Trial of Bevacizumab + Panitumumab-CT
  With Bev-CT in CRC (PACCE)

                                     Bev + Pan


                            Ox-CT

                                       Bev        Primary
         Previously                              end point:
      untreated MCRC                                PFS
                                     Bev + Pan


                            Iri-CT

                                       Bev

Hecht JR, et al. JCO 2008
  Page  55
  Phase III Trial of Bevacizumab + Panitumumab-CT
  With Bev-CT in CRC (PACCE)




Hecht JR, et al. JCO 2008
  Page  56
  Phase III Trial of Bevacizumab + Panitumumab-CT
  With Bev-CT in CRC (PACCE)




Hecht JR, et al. JCO 2008
  Page  57
Phase IV BRiTE
Therapy in First-Line MCRC



            E
            N
            R
Untreated                             Bev + CT
 MCRC       O
            L
            L




Page  58       Grothey, et al. JCO 2008
Phase IV BRiTE
Therapy in First-Line MCRC

                                           PFS FOLFOX + Bev: 10 m (n=1092)


            E
            N
            R
Untreated                             Bev + CT
 MCRC       O
            L
            L

                                           PFS FOLFIRI + Bev: 10.4 m (n=280)




Page  59       Grothey, et al. JCO 2008
BRiTE:* continuation of bevacizumab post-first progression significantly
   increases OS (time from initiation of first-line treatment to death)
                                                                           Post-progression therapy
                             1.0
                                                                                Bevacizumab post-PD (n=642)
                                                                                No bevacizumab post-PD (n=531)
                                                                                No treatment (n=253)
     Estimated probability




                             0.8


                             0.6


                             0.4 Post-progression bevacizumab
                                       HR=0.48 (95% CI: 0.41–0.57)
                                       p<0.001
                             0.2
                                                         12.6            19.9                      31.8
                                   0          5         10           15     20         25          30          35
                              0                                      OS (months)
                                                                                    Grothey, et al. ASCO 2007 (poster)
 Page  60                    *Non-randomised, observational trial                            Grothey, et al. JCO 2008
BRiTE:* continuation of bevacizumab post-first progression significantly
increases survival beyond progression, irrespective of subgroup factors

  Subgroup                                         HR      95% CI
  Age at disease progression                                              Favours bevacizumab       Favours
       <65 years                                   0.47   0.37–0.60                                 CTx
       ≥65 years                                   0.51   0.40–0.65
  Race
       White                                       0.51   0.42–0.62
       Black                                       0.32   0.18–0.57
       Other                                       0.48   0.21–1.08
  Baseline ECOG PS
       0                                           0.53   0.40–0.71
       1                                           0.45   0.35–0.59
       ≥2                                          0.37   0.18–0.65
  Site of primary tumour
       Colon                                       0.49   0.40–0.59
       Rectum                                      0.49   0.32–0.75
  First-line chemotherapy regimen
       FOLFOX                                      0.47   0.37–0.59
       FOLFIRI                                     0.38   0.24–0.59
       Other                                       0.62   0.46–0.85
  Exposed to EGFR inhibitors
       No                                          0.52   0.41–0.66
       Yes                                         0.42   0.32–0.54
  Exposed to all three active chemotherapy
  agents                                           0.51   0.39–0.68
       No                                          0.42   0.33–0.52
       Yes
  Time to first progression
       <6 months                                   0.48   0.37–0.62
       ≥ 6 months                                  0.52   0.41–0.65
  Best first-line response
       Complete response/partial response          0.44   0.33–0.59
       SD/PD                                       0.50   0.41–0.63
  All patients                                     0.49   0.41–0.58

Page  61                                                             0         0.5                1
            *Non-randomised, observational trial                                       Grothey, et al. JCO 2008
 PFS benefits of bevacizumab with irinotecan-
 based therapy confirmed in daily practice
                                                                                                                10 months
                                            FOLFIRI alone1       (n=109)                           8.5

                           Bevacizumab + FOLFIRI (BICC-C)2       (n=209)                                       11.2
    clinical trials
    Phase II–IV




                           Bevacizumab + FOLFIRI (PACCE)3        (n=115)                                            11.7

                            Bevacizumab + FOLFIRI (AVIRI)4       (n=209)                                      11.1

                      Bevacizumab + FOLFIRI (MD Anderson)5       (n=43)                                                12.5

                          Bevacizumab + XELIRI (AIO 0604)6       (n=120)                                             12.1
    practice*




                            Bevacizumab + FOLFIRI (BRiTE)7       (n=280)                                     10.9
     Daily




                            Bevacizumab + FOLFIRI (BEAT)8        (n=503)                                        11.6

                                                             0            2      4       6       8       10                12    14
                                                                                     Median PFS (months)
                                                1. Tournigand, et al. JCO 2004; 2. Fuchs, et al. JCO 2007; 3. Hecht, et al. JCO 2009
*Large prospective, observational trials
                                           4. Ackland, et al. ASCO GI 2008; 5. Kopetz, et al. ASCO 2007; 6. Reinacher-Schick, et al.
 Page  62
                                                         ASCO 2008; 7. Grothey, et al. JCO 2008; 8. Van Cutsem, et al. ESMO 2008
PFS benefits of bevacizumab with oxaliplatin-
based therapy confirmed in daily practice
                     XELOX/FOLFOX4 alone (NO16966)1            (n=699)                            8.0                  10 months

                       Bevacizumab + XELOX/FOLFOX4
                                                               (n=699)                                    9.4
  clinical trials
   Phase II/III




                                              (NO16966)1
                       Bevacizumab + XELOX/FOLFOX4
                                                               (n=699)                                          10.4
                              ‘on treatment’* (NO16966)1

                     Bevacizumab + oxaliplatin (PACCE)2        (n=410)                                               11.1

                     Bevacizumab + XELOX (AIO 0604)3           (n=127)                                          10.4

                      Bevacizumab + FOLFOX (BRiTE)4            (n=1,092)                                     10.0
         practice‡




                       Bevacizumab + FOLFOX (BEAT)5            (n=552)                                               11.3
          Daily




                        Bevacizumab + XELOX (BRiTE)4           (n=94)                                                11.2

                        Bevacizumab + XELOX (BEAT)5            (n=346)                                              10.8

                                                           0             2     4         6       8                  10        12
                                                                             Median PFS (months)
  *Secondary endpoint                                                        1. Saltz, et al. JCO 2008; 2. Hecht, et al. JCO 2009
  ‡Large prospective, observational trials
                                                    3. Reinacher-Schick, et al. ASCO 2008 (poster); 4. Grothey, et al. JCO 2008
Page  63
                                                                                       5. Van Cutsem, et al. ESMO 2008 (poster)
MACRO: Maintenance Bev vs Continued Bev +
XELOX in Patients With mCRC


                                                           XELOX + Bevacizumab
                                                                (n = 239)
  Patients with                   Induction                                        Disease
   previously                      Therapy                                       progression,
untreated mCRC                   XELOX +                                            severe
                                Bevacizumab                                       toxicity, or
    (N = 480)                      6 cycles                                        consent
                                                                Bevacizumab       withdrawal
                                                                  (n = 241)



  Maintenance cycles administered q3w:
  Oxaliplatin 130 mg/m2 IV on Day 1
  Capecitabine 1000 mg/m2 BID PO on Days 1-14
  Bevacizumab 7.5 mg/kg IV on Day 1

Page  64       Tabernero J, et al. ASCO 2010. Abstract 3501.
MACRO: Duration of PFS Comparable Between Bev vs
XELOX + Bev


  No significant difference between treatment arms in any efficacy outcome
  Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be confirmed
    – The median PFS HR 95% CI (0.89-1.37) beyond the planned noninferiority limit of 1.32


  Outcome                  Bevacizumab              XELOX/          HR             OR
                             (n = 241)           Bevacizumab     (95% CI)       (95% CI)
                                                   (n = 239)
  Median PFS,* mos               9.7                  10.4          1.11            --
                                                                (0.89-1.37)
  Median OS,* mos                21.7                 23.4          1.04            --
                                                                (0.81-1.32)
  Confirmed objective             49                    46           --            0.89
  response, %                                                                  (0.62-1.27)
  *Median follow-up: 20.4-21.1 mos.
Page  65    Tabernero J, et al. ASCO 2010. Abstract 3501.
MACRO: Conclusions


 After bevacizumab + XELOX induction therapy for patients with mCRC,
  maintenance bevacizumab comparable to continued bevacizumab +
  XELOX
  – No significant difference in any efficacy outcome between arms
 Single-agent bevacizumab may be a feasible option for patients receiving
  bevacizumab + XELOX as induction therapy




Page  66   Tabernero J, et al. ASCO 2010. Abstract 3501.
Bevacizumab: only biological proven to extend
both PFS and OS in first- and second-line
                           1.0                                                                             1.0
                                                First-line1                                                                       Second-line2
   Estimated probability




                                                                                  Estimated probability
                           0.8                           IFL + bevacizumab
                                                                                                           0.8                             FOLFOX + bevacizumab
                                                                                                                                           FOLFOX
                                                         IFL + placebo
                           0.6                                                                             0.6

                           0.4                                                                             0.4

                           0.2                                                                             0.2
                                     6.2          10.6                                                               4.7          7.3
                            0                                                                                0
                                 0              10         20                30                                  0                 10           20
                           1.0                   PFS (months)                                             1.0                      PFS (months)


                                                                                  Estimated probability
   Estimated probability




                           0.8                              IFL + bevacizumab                             0.8                             FOLFOX4 + bevacizumab
                                                            IFL + placebo                                                                 FOLFOX4
                           0.6                              HR=0.66 (p<0.001)                             0.6                             HR=0.75 (p=0.0011)

                           0.4                                                                            0.4

                           0.2                                                                            0.2
                                            15.6          20.3                                                             10.8         12.9
                             0                                                                              0
                                 0         10        20      30              40                                  0                12         24              36
                                                 OS (months)                                                                        OS (months)
Page  67
                                                                                                          1. Hurwitz, et al. NEJM 2004; 2. Giantonio, et al. JCO 2007
                         Bevacizumab + FU in 1st Line mCRC


   mCRC with at
    least one of:                                               FU/LV (Weekly)
                                                                   (n=105)
     65≤ age, or
       PS 1-2,
  3.5≤Albumin, or                      R
      Previous
  abdominopelvic                                       FU/LV + Bevacizumab (5 mg/kg/q2w)
         RT                                                         (n=104)

                     Main end point:
                     OS
                     Secondary end points
                     PFS
                     RR
                     QoL

Page  68   Kabbinavar FF. J Clin Oncol 23:3697-3705
Page  69   Kabbinavar FF. J Clin Oncol 23:3697-3705
Page  70   Kabbinavar FF. J Clin Oncol 23:3697-3705
Bevacizumab improves survival without impacting on
health-related QoL
   First comparisons of QoL with the addition of bevacizumab to
    chemotherapy
     – study 2107
            • IFL + placebo (n=411)
            • IFL + bevacizumab (n=402)
     – study 2192
            • 5-FU/LV + placebo (n=105)
            • 5-FU/LV + bevacizumab (n=104)

   Assessed CCS score, TOI-C, FACT-C

                 Addition of bevacizumab does not add to the
                      treatment burden of chemotherapy
Page  71
            CCS = colorectal cancer subscale      Kabbinavar, et al. Oncologist 2008
Role of Bevacizumab in curable mCRC


 Phase II trial: XELOX + bevacizumab
  – 54 patients with potentially resectable liver metastases
  – 6 cycles of neoadjuvant therapy (1 week on, 1 week off)
  – Clinical response: 74%
  – pCR: 11%




Gruenberger B, et al. ASCO 2007. Abstract 4060.

Page  72
 Bevacizumab in ‘borderline’ resectable mCRC: OS in
 resected patients

                            1.0                                                  100%
                                                                         94.4%

                            0.8
    Estimated probability




                            0.6                         63.6%


                            0.4
                                   Response                                       n (%)
                                       Complete pathological response             5 (9)
                            0.2
                                       Partial response                          36 (64)
                                       Stable disease                            12 (21)
                             0


                               0                                    20
                              40              OS (months)
                                                        Gruenberger, et al. ASCO 2008 (poster)
Page  73
 Chemotherapy-induced sinusoidal injury reduced with
 addition of bevacizumab in mCRC

                              100                                    p=0.002

                                                           p=0.001
                              80
                                             p=0.212
      sinusoidal injury (%)




                              60
          Incidence of




                              40

                              20
                                                                                 p=0.086

                                0
                                                                               4/78
                                         36/79     22/38                                4/24
                                                                               (6%)
                                         (46%)     (58%)                               (17%)

                                    1–8 cycles   ≥9 cycles              1–8 cycles    ≥9 cycles
                                            FOLFOX                    FOLFOX + bevacizumab
                                                                                   Zorzi, et al. ASCO GI 2009
Page  74
Impact of bevacizumab on OS in mCRC:
a population-based study

            Patients with mCRC (n=1,417): 2003–2004 (pre-bevacizumab)
                           versus 2006 (post-bevacizumab)


                          Proportion of patients receiving


                                                                Bevacizumab
       Irinotecan or                Anti-EGFR
                                                                   therapy:
         oxaliplatin                 therapy:
                                                                 increased
         and 5-FU:                  no change
                                                               5.9% vs 30.6%
    no change (p=0.68)               (p=0.63)
                                                                  (p<0.001)

                 Addition of bevacizumab to systemic chemotherapy
                              significantly improved OS:
                            23.6 vs 18.6 months (p<0.001)
Page  75
                                                             Renouf, et al. ASCO GI 2009
Impact of bevacizumab in mCRC: significantly
improved OS
                                    1.0


                                    0.8
            Estimated probability




                                                                    Bevacizumab era (2006)
                                                                       30.6% received
                                    0.6
                                                                        bevacizumab

                                    0.4 Pre-bevacizumab (2003–2004)
                                              5.9% received bevacizumab                p<0.001

                                    0.2           Bevacizumab + standard chemotherapy
                                                        significantly improved OS:
                                                      23.6 vs 18.6 months (p<0.001)
                                     0
                                          0          6        12       18        24             30
                                                              OS (months)
                       Bevacizumab era (2006), n=448
Page  76
                       Pre-bevacizumab (2003–2004), n=969                       Renouf, et al. ASCO GI 2009
Cetuximab en mCRC
Cetuximab versus BSC




                                     R   Cetuximab
          Metastatic                 A     + BSC
      colorectal cancer              N      (287)
       with prior 5-FU,              D
       irinotecan and                O
          oxaliplatin                M
           (572 pts)
                                     I
                                           BSC
                                     Z
                                           (285)
                                     E



Jonker et al. NEJM 2007; 357: 2040
Page  78                                          Courtesy of: Paulo Hoff
                   Cetuximab versus BSC



                                      BSC       Cetuximab     P value
                                     (285)        (287)


             RR                        0%          8%        P<0.001


            PFS                  1.8 months     1.9 months   HR = 0.68
                                                             P<0.001

             OS                  4.6 months     6.1 months   P=0.005



Page  79   Jonker et al NEJM 2007; 357: 2040                    Courtesy of: Paulo Hoff
   EPIC: Cetuximab + Irinotecan after Fluoropyrimidine +
   Oxaliplatin failure

                                                            Cetuximab 400 mg/m2 initial dose
                                                            cycle 1, wk 1, 250 mg/m2 weekly
      mCRC with                                             Irinotecan 350 mg/m2
                                                             (n=648)
 progression after 1st
line fluoropyirimidine
    and Oxaliplatin
                                               R
       (n=1298)                                             Irinotecan
                                                            (n=650)

        Primary endpoint:
        Overall survival




Page  80   Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC


                                     Cet + Iri                  Iri      P value
                                     (n=648)                 (n=650)


              RR                      16.4%                   4.2%       P<0.05


             PFS                    4 months                2.6 months   P<0.005


              OS                      10.7 m                  10 m       P=0.71



Page  81   Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
                   CRYSTAL: Cetuximab in First Line mCRC

                                             Cetuximab 400 mg/m2 initial dose
                                             cycle 1, wk 1, 250 mg/m2 weekly
                                             Irinotecan 180 mg/m2
                                             5-FU mg/m2 bolus +2400 mg/m2 CI
                                             LV every 2 weeks
EGFR-expressing
    mCRC                             R
                                             Irinotecan 180 mg/m2
                                             5-FU mg/m2 bolus + 2400 mg/m2 40-h
                                             CI
                                             LV every 2 weeks

        Stratification:
        • Regions
        • ECOG PS
        Randomized patients: 1217
Page  82   Van Cutsem E, et al. NEJM 2009                          Courtesy of: Paulo Hoff
CRYSTAL Trial: Primary Endpoint PFS

                   1.0
                                                                       Cetuximab + FOLFIRI, n=599
                   0.9
                                                                       FOLFIRI, n=599
                   0.8                                        HR = 0.851; 95% CI = [0.726-0.998]
                   0.7
                                                             Stratified log-rank p-value = 0.0479
    PFS estimate




                   0.6

                   0.5
                                                      8.9 mo
                                                                                    1-year PFS rate
                                      8.0 mo                                          23% vs 34%
                   0.4

                   0.3

                   0.2

                   0.1

                   0.0
                         0   2   4      6       8      10      12     14       16      18         20
                                     Progression-free survival time (months)

Page  83                                                                                   Courtesy of: Paulo Hoff
 Van Cutsem E, et al. NEJM 2009
                    Correlation of Skin Toxicity and Efficacy with
                    Cetuximab in the CRYSTAL Study (1st Line)

                             CRYSTAL combination arm: Cetuximab + FOLFIRI (n=599)
                    1.00
                                                                         Skin reaction grade 3*, n=112 (18.7%)
                                                                         Skin reaction grade 2, n=243 (41%)
                                                                         Skin reaction grade 0 or 1, n=244 (41%)
                    0.75
                                                                         *There were no grade 4 skin reactions
     PFS estimate




                                     5.4 mo           9.4 mo              11.3 mo
                    0.50




                    0.25




                    0.00
                           0.0     2.5          5.0    7.5        10.0       12.5      15.0      17.5          20.0

Page  84=
 *PFS               progression-free survival                Time (months)                    Courtesy of: J Tabernero
 Van Cutsem et al. Proc ASCO 2007
Evolución histórica del tratamiento mCRC – 3:
Terapia individualizada
Impacto de las alteraciones en las vías de
trasnducción de señales del EGFR en la eficacia
de Cetuximab
                               OPUS: FOLFOX4 + Erbitux

                                                          Cetuximab 400 mg/m2 initial dose
                                                          cycle 1, wk 1, 250 mg/m2 weekly
                                                          Oxaliplatin 85 mg/m2
                                                          5-FU/FA every 2 weeks

EGFR-detectable
    mCRC                           R      Skin rash 0/1
                                                      FOLFOX4
                                                      Oxaliplatin 85 mg/m2
                                                      5-FU/FA every 2 weeks
        Primary endpoint:
        Overall response rate
        Stratification:
        • ECOG PS 0/1, 2
        Randomized patients: 337



Page  87   Bokemeyer, et al. ASCO 2008                                        Courtesy of: Paulo Hoff
                            Relating KRAS Status to Efficacy
                            PFS & Response – KRAS Wild-type

                                 KRAS wild-type: HR=0.57; p=0.016
                                        mPFS Cetuximab + FOLFOX: 7.7 months
                                                                                                                       p=0.011
                                             mPFS FOLFOX: 7.2 months
                                                                                                                   Odds ratio=2.544
                                                                                                            70   (95% CI: 1.238–5.227)
                                                    Cetuximab + FOLFOX        FOLFOX
                             1.0                                                                            60
                             0.9
Progression-free survival




                             0.8                                                                            50                       61




                                                                                        Response rate (%)
                             0.7
                                                                                                            40
                             0.6
                             0.5                                                                            30
                             0.4                                                                                   37
                             0.3                                                                            20
                             0.2
                                                                                                            10
                             0.1
                             0.0
                                                                                                             0
                                   0        2        4        6     8     10       12                            FOLFOX       Cetuximab +
                                                           Months                                                              FOLFOX
                            Page  88                                                                                   Courtesy of: Paulo Hoff
                            Bokemeyer C, et al. J Clin Oncol 2008
 MOAs Anti-EGFR



             Extracelular




              Intracelular
                                              Shc
                                                Grb2
                                      PI3-K                Sos-1


                                                       mK-Ras
                                  AKT
                                                                Raf
                                               MEKK-1

                                                                MEK
Page  89   www.clinicaloptions.com   mTOR     MKK-7
CRYSTAL: Summary of Efficacy Data in KRAS wt


                       Pre-2009 ESMO                Post-2009 ESMO
                            KRAS wt                       KRAS wt
                    FOLFIRI           Cetuximab   FOLFIRI            Cetuximab
                                      +FOLFIRI                       +FOLFIRI
KRAS Analysis (%)           540 (45%)                     1063 (89%)
ORR (%)               43                 59        39.7                57.3
p-value                       0.0025                        < 0.0001


mPFS (Months)         8.7                9.9        8.4                 9.9
HR                             0.68                           0.70
p-value                       0.017                         0.0012


OS (Months)          21.0               24.9       20.0                23.5
P-value                        0.22                         0.0094
Page  90
                                                                 Courtesy of: Paulo Hoff
NCIC CTG C0.17: Overall Survival in
K-ras Wild-Type Patients
                               1
                                                                            Study arm          MS (months)           95% CI
                                                                         Cetuximab + BSC           9.5              7.7 – 10.3
                             0.8                                           BSC alone               4.8              4.2 – 5.5
        Proportion Alive




                             0.6
                                                                                       HR 0.55 95% CI (0.41,0.74)
                                                                                       Log rank p-value: <0.0001
                             0.4



                             0.2
                                         Cetuximab
                                         BSC
                               0
                                   0       2        4        6      8     10      12     14        16         18
                                                           Time from Randomization (Months)
   Cetuximab 117                        108       95        81      52     34     20       9        6           2
   BSC       113                         92       69        36      24     17     12       5        3           3
Page  91                                                                                                Courtesy of: Paulo Hoff
                           Karapetis C et al, New Engl J Med 2008
Phase III MRC COIN



                        R   XELOX/OxMdG
                        A     (n = 815)

                        N
                        D   XELOX/OxMdG +
            Untreated
                              Cetuximab
             MCRC       O      (n = 815)
                        M
                        I   XELOX/OxMdG +
                        Z     Cetuximab
                               (n = 815)
                        E     Intermitent



Page  92
                                            ESMO, 2009
                                     COIN: K-ras WT OS

              Survival probability                      Arm A (XELOX/FOLFOX)
            1.00                                        Arm B (XELOX/FOLFOX + cetuximab)
                                                                   Arm A      Arm B       Diff.
                                                    Median OS,      17.9       17.0       –0.92
            0.75                                    months
                                                    2-year          36.1       34.4       -1.66
                                                    survival, %
            0.50
                                                                  HR point estimate = 1.038
                                                                     95% CI 0.90–1.20
            0.25                                                           p=0.68


               0
                   0     6     12      18     24   30      36      42
                                        Time (months)
    No. at risk
    Arm A       367    316     250    154    83    44      19       1
    Arm B       362    306     238    149    80    42      17       3
Page  93
    ITT analysis                                         Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
                                   COIN: K-ras WT PFS

               Survival probability                    Arm A (XELOX/FOLFOX)
             1.00                                      Arm B (XELOX/FOLFOX + cetuximab)

                                                                    Arm A     Arm B         Diff.
             0.75                                  Median PFS,       8.6        8.6        +0.07
                                                   months


             0.50
                                                                    HR point estimate = 0.959
                                                                       95% CI 0.84–1.09
                                                                             p=0.60
             0.25


                   0
                       0      6    12    18   24      30       36      42

    No. at risk
    Arm A              367   245    92   41   18     11        6      1
    Arm B              361   249   103   42   22      9        6      0
Page  94
    ITT analysis                                           Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
COIN: No Significant Difference in OS, PFS
Between Treatment Arms, Pt Subsets

  Survival Outcome,             Cetuximab +        Chemotherapy     HR (95% CI)       P Value
  Mos                          Chemotherapy
  Wild-type KRAS
   Median OS                        17.0                  17.9   1.038 (0.90-1.20)     .68
   Median PFS                        8.6                  8.6    0.959 (0.84-1.09)     .60
  All wild-type patients
   Median OS                        19.9                  20.1   1.019 (0.86-1.20)     .86
   Median PFS                        9.2                  8.8    0.922 (0.80-1.07)     .36
  Patients with mutated
  KRAS, NRAS, or BRAF
   Median OS                        12.7                  14.4   1.004 (0.87-1.15)     .96
   Median PFS                        6.3                  6.6    1.079 (0.95-1.23)     .33



Page  95   Maughan TS, et al. ASCO 2010. Abstract 3502.
     ITT Survival: WT K-Ras (n=729)


                        XELOX/OxMdG   XELOX/OxMdG +      HR
                                        Cetuximab     (p value)


               OS          17,9           17,0        1,038
             (months)                                 (0,68)
            2y OS (%)      36,1           34,4

              PFS           8,6            8,6         0,95
             (months)                                 (0,60)



Page  96
                                                                  ESMO, 2009
            COIN: K-RAS and Response

                          All patients           K-ras WT                  K-ras MT


                                Cetuximab          Cetuximab          Cetuximab
                       FOLFOX/            FOLFOX/            FOLFOX/
                                + FOLFOX/          + FOLFOX/          + FOLFOX/
                        XELOX              XELOX              XELOX
                                  XELOX              XELOX              XELOX
                        (n=815)            (n=367)            (n=268)
                                  (n=815)            (n=362)            (n=297)

        Best overall
        response         51         53      57              64        46              43
        (%)

        Odds ratio       1.08 (p=0.428)    OR=1.35 (p=0.049)        OR=0.88 (p=0.449)




Page  97
                                                       Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
                 NORDIC VII: Cetuximab in First Line mCRC
                                      Nordic FLOX (FU 500 mg/m2 + LV
                                      60 mg/m2, d1,2 Q2W)

            mCRC
                                  R   Nordic FLOX + Cetuximab


                                      Nordic FLOX stop & go + Cetuximab




        Endpoint:
        • PFS
        Randomized patients: 571

Page  98   Tveit KM, ESMO 2010
                  NORDIC VII: Cetuximab in First Line mCRC
                                         Nordic FLOX (FU 500 mg/m2 + LV
                                         60 mg/m2, d1,2 Q2W)

            mCRC
                                   R     Nordic FLOX + Cetuximab


                                         Nordic FLOX stop & go + Cetuximab

             Outcome              FLOX    F+Cet        Stop&Go-Cet
             PFS                  7.9     8.3          7.3
             RR                   41%     49%          47%
             OS                   20.4    19.7         20.3
        Endpoint:
        • PFS
        Randomized patients: 571

Page  99   Tveit KM, ESMO 2010
                  TRIALS IN mCRC 1st Line treatment
                  K-Ras status WT

TRIAL        PH                PFS                                  OS
                               FOLFIRI+                          FOLFIRI +
                   FOLFIRI                    P      FOLFIRI                    P
                              CETUXIMAB                         CETUXIMAB
CRYSTAL      3
                     8.4         9.9        0.0017     20          23.5       0.0094
                               FOLFOX +                          FOLFOX +
                   FOLFOX                     P      FOLFOX                     P
  OPUS       2                CETUXIMAB                         CETUXIMAB

                     7.2         8.3        0.006     18.5         22.8       0.3854
                   XELOX/    XELOX/FOLFOX            XELOX/    XELOX/FOLFOX
                                              P                                 P
                   FOLFOX    +CETUXIMAB              FOLFOX     + CETUXIMAB
  COIN       3
                     8.6         8.6         0.6      17.9          17         0.68

                                FLOX +                            FLOX +
                    FLOX                      P       FLOX                      P
                              CETUXIMAB                         CETUXIMAB
 NORDIC      3

                     7.9         8.3         0.3      20.4         19.7        0.30




Page  100
                NCCTG0147: Adjuvant FOLFOX +/- Cetuximab
                                                 mFOLFOX6 q2w x12



   CRC stage III                      R
Endpoint:                                        mFOLFOX6 q2w x12 + Cetuximab
• DFS@3y
Randomized patients: 2581


                                      FOLFOX       FOLFOX-Cet       Total
              Wt KRAS                     909          955          1864
              Mt KRAS                     374          343          717
              Total                       1283        1298          2581


Page  101   Goldberg RM, ASCO 2010
                NCCTG0147: Adjuvant FOLFOX +/- Cetuximab
                                              mFOLFOX6 q2w x12



   CRC stage III                      R
Endpoint:                                     mFOLFOX6 q2w x12 + Cetuximab
• DFS@3y
Randomized patients: 2581


      Outcome               FOLFOX –      FOLFOX+Cet   FOLFOX –   FOLFOX+Cet
                             wt-KRAS       – wt-KRAS   mut-KRAS    mut-KRAS
       DFS@3y                   76%          72%         67%         64%
             OS                 88%          84%         88%         80%


Page  102   Goldberg RM, ASCO 2010
  Targeting the EGFR pathway

                             TGF-α
      extracellular
                         R        R


     intracellular                     Grb2
                                              Sos
                                                                       phosphorylation
                         K        K
                                       Shc
                                              Grb2    Sos
             mutation   PI3K                                                  Ras         mutation


        loss        PTEN                       Akt                            Raf        mutation



               mTOR             FKHR          GSK–3          Bad            MEK1/2

                                 p27
                                                                             MAPK
                               Cyclin D1, E

                 Cell cycle progression                     Survival      Proliferation
Page  103                                                                Mendelsohn et al. JCO 2003
                   Incidence of genetic alterations in CRC




      Molecular finding                        % of Incidence
      K-RAS mutation                                  30 – 50%
      Loss of PTEN                                         19%
      Epiregulin                                               ?
      BRAF mutation                                    3 – 10%
      PI3K                                                 13%
      EGFR non-amplified                              11 – 25%



                                                  Loupakis F et al. J Clin Oncol. 2009 Jun 1;27(16):2622-9
                                  Laurent-Puig P, et al. J Clin Oncol 2009 doi: 10.1200/ JCO.2009.22.4295
                                                          Perrone F, et al. Ann Oncol. 2009 Jan;20(1):84-90
Page  104                                                  Goldstein NS, et al. Cancer 2001;92:1331-1346
 CRYSTAL: BRAF mutations and PFS
          for cetuximab



PFS according to
BRAF status in
retrospective
CRYSTAL substudy




 Page  105
                         Köhne et al. ASCO 09. Abstract 4068
         BRAF mutations and response to
          cetuximab in K-RAS wild type




Page  106
                        Laurent-Puig P, et al. J Clin Oncol 2009 doi: 10.1200/ JCO.2009.22.4295
COIN: Prognostic Effect of Mutational Status



   Strong OS prognostic effect of                           12   Chemotherapy         Chemotherapy +




                                                Median PFS
    KRAS, NRAS, and BRAF                                                                 Cetuximab




                                                  (Mos)
    mutation status evident                                   6
    regardless of cetuximab use
                                                              0
         – Patients with wild-type
                                                             18
           KRAS have better


                                                Median OS
           prognosis vs mutated                              12



                                                  (Mos)
           KRAS                                               6

         – Patients with mutated                              0
                                                         n=       57 268 367            45 297 362
           BRAF have the poorest                                    340 815 289           366 815 292
           prognosis
                                                Mutation Status
 Maughan TS, et al. ASCO 2010. Abstract 3502.          BRAF mutation        All patients
                                                       Any mutation         KRAS wild type
Page  107                                                                  All wild type
                                                       KRAS mutation
Many patients will not respond to treatment with
EGFR inhibitors due to KRAS and BRAF
mutations
             mCRC patients treated with panitumumab or cetuximab (n=114)

                  KRAS mutational status (evaluable patients n=113)

                                         Mutant KRAS           Wild-type KRAS
                                         34/113 (30%)           79/113 (70%)
  Responders                               2/34 (6)*              22/79 (28)*
  Non-responders                          32/34 (94)*             57/79 (72)*


               BRAF mutational status on wild-type KRAS tumours (n=79)

                                         Mutant BRAF           Wild-type BRAF
                                          11/79 (14%)           68/79 (86%)
  Responders                               0/11 (0)‡              22/68 (32)‡
  Non-responders                          11/11 (100)‡            46/68 (68)‡
  *p<0.05 (p=0.011); ‡p<0.05 (p=0.029)
Page  108
                                                         Di Nicolantionio, et al. JCO 2008
   Loss of PTEN and response to cetuximab
              in K-RAS wild type




Page  109
                       Laurent-Puig P, et al. J Clin Oncol 2009 doi: 10.1200/ JCO.2009.22.4295
         Loss of PTEN and response to
                  cetuximab

                                                              1.0                         PTEN+ median PFS = 4.7 months
                                                                                          PTEN– median PFS = 3.3 months




                                      Estimated probability
                                                              0.8

                 PTEN+     PTEN–                              0.6                        Log-rank test: p=0.005
                 (n=33)    (n=22)                                                    HR=0.49; 95% CI: 0.20–0.75

Responders                                                    0.4
(CR+PR+SD) (%)   12 (36)    1 (5)
Non-responders                                                0.2
                 21 (64)   21 (95)
(%)
                                                               0
                                                                    0   2.5   5.0   7.5    10.0 12.5 15.0
                                                                               PFS (months)
    Fisher’s Exact Test: p=0.008
    Concordance primary tumour sample/metastasis: 27/45 (60%)

Page  110
                                                                                                   Loupakis, et al. JCO 2009
KRAS status and EGFR monoclonal antibodies in
chemorefractory patients

  Non-responder:
  BRAF mutation 10%
                                         Responds to
                                         standard dose
                                         22%
                                                             KRAS
  Non-responder:                                             wild-type
  loss of PTEN
  or PI3K mutation
                                            Responds to
  percentage
                                            increased
  unknown
                                            dose ~5%

  Non-responder:
                        Non-responder:                       KRAS
  reason unknown
                       KRAS mutant 40%                       mutant
  percentage unknown



Page  111
                                             Wong, Cunningham. JCO 2008
(Ausencia de) Impacto de las alteraciones en las
vías de trasnducción de señales del EGFR en la
eficacia de Bevacizumab
 AVF2107: OS by K-ras Status

                                        Group: Mutant (N=78)                                                            Group: Wild-Type (N=152)
                                           HR=0.69; P=0.26                                                                   HR=0.58; P=0.04
                        1.0                                                Median                           1.0                                                 Median
                                                                           OS (mo)                                                                              OS (mo)
                                                           IFL + Placebo    13.6                                                                IFL + Placebo    17.6
                        0.8                                                                                 0.8
                                                           IFL + Avastin    19.9                                                                IFL + Avastin    27.7




                                                                                     Proportion Surviving
 Proportion Surviving




                        0.6                                                                                 0.6



                        0.4                                                                                 0.4



                        0.2                                                                                 0.2



                        0.0                                                                                 0.0
                              0        5      10      15       20     25       30                                 0     5     10    15     20       25     30
                                    Duration of Survival (months)                                                     Duration of Survival (months)


Page  113                        Ince et al. J Natl Cancer Inst. 2005;97:981.
                                  Hurwitz et al. GI World Congress. Abstract O-035 and poster.
AVF2107: PFS by K-ras Status

                                               Group: Mutant (N=78)                                                                Group: Wild-Type (N=152)
                                                HR=0.41; P=0.0008                                                                       HR=0.44; P<0.0001
                                   1.0                                                                                 1.0
                                                                          Median                                                                                      Median
                                                                         PFS (mo)                                                                                    PFS (mo)




                                                                                         Proportion progression-free
     Proportion progression-free




                                   0.8                                                                                 0.8
                                                             IFL + Placebo    5.5                                                                    IFL + Placebo      7.4
                                                             IFL + Avastin    9.3                                                                    IFL + Avastin     13.5

                                   0.6                                                                                 0.6



                                   0.4                                                                                 0.4



                                   0.2                                                                                 0.2



                                   0.0                                                                                 0.0
                                         0      5       10       15      20         25                                       0      5       10     15      20         25
                                             Duration of Survival (months)                                                       Duration of Survival (months)

   Page  J
Ince et al.114Natl Cancer Inst. 2005;97:981.
Hurwitz et al. GI World Congress. Abstract O-035 and poster.                                                                                                 Core Slide
AVF2107g: Response according to
K-Ras status

                            70
                                                          IFL + Avastin
                                   60
                            60                            IFL + placebo
        Response rate (%)




                            50                     43
                                                                  41
                                           37
                            40

                            30

                            20

                            10

                             0   K-Ras wild-type   K-Ras mutant
                                    p=0.006             p=0.8
                                                        Hurwitz HI, et al. Oncologist 2009;14:22-8
Page  115
Bevacizumab improves patient outcome independent
of KRAS or BRAF status
                                   Placebo + IFL      Bev + IFL
                                         Median          Median
  Biomarker                  N     n    (months)    n   (months)   HR      (95% CI)            HR
  All subjects              267   120     17.45    147    26.35    0.57   (0.39–0.85)
  KRAS mutation status
      Mutant                 78    34    13.60      44   19.91     0.69   (0.37–1.31)
      Wild-type             152    67    17.64      85   27.70     0.58   (0.34–0.99)
  BRAF mutation status
      Mutant                 10     3     7.95       7   15.93     0.11   (0.01–1.06)
      Wild-type             217    97    17.45     120   26.35     0.53   (0.34–0.82)
  KRAS and BRAF mutation
  status
      Mutant                 88    37    13.60      51   19.91     0.67   (0.37–1.20)
      Wild-type             125    57    21.72      68   27.70     0.57   (0.34–0.82)
  p53 mutation status
     Mutant                 139    63    21.72      76   27.70     0.54   (0.30–0.95)
     Wild-type               66    31    16.36      35    NR       0.67   (0.32–1.42)
  p53 overexpression
     Positive               191    92    17.45      99   26.35     0.70   (0.45–1.10)
     Negative                75    28    16.26      47   25.07     0.32   (0.15–0.70)

                                                                                        0.2   0.5    1     2       5
                Survival benefit also independent of p53, VEGF (plasma and tissue) and TSP-2
                                                                       Jubb, et al. JCO 2006; Ince, et al. JNCI 2005
Page  116
  Bev = bevacizumab                         Holden, et al. ASCO 2005 (Abstract 3555); Hurwitz, et al. Oncologist 2009
Avastin in K-RAS mutant patients

             IFL
             IFL + Avastin

             Folfiri
             Folfiri + Cetuximab

             Folfox
             Folfox + Cetuximab



             Xelox + Avastin



             Folfiri + Avastin



                                 Progression Free Survival

Page  117
Avastin in K-RAS wild-type

             IFL
             IFL + Avastin

             Folfiri
             Folfiri + Cetuximab

             Folfox
             Folfox + Cetuximab



             Xelox + Avastin



             Folfiri + Avastin



                                 Progression Free Survival

Page  118
    Incidences of bevacizumab-associated adverse events
        were comparable for the two K-RAS subgroups




Page  119
                                          Hurwitz HI, et al. Oncologist 2009;14:22-8
                  TRIALS IN mCRC 1st Line treatment
                  K-Ras status WT

TRIAL        PH                PFS                                  OS
                               FOLFIRI+                          FOLFIRI +
                   FOLFIRI                    P      FOLFIRI                    P
                              CETUXIMAB                         CETUXIMAB
CRYSTAL      3
                     8.4         9.9        0.0017     20          23.5       0.0094
                               FOLFOX +                          FOLFOX +
                   FOLFOX                     P      FOLFOX                     P
  OPUS       2                CETUXIMAB                         CETUXIMAB

                     7.2         8.3        0.006     18.5         22.8       0.3854
                   XELOX/    XELOX/FOLFOX            XELOX/    XELOX/FOLFOX
                                              P                                 P
                   FOLFOX    +CETUXIMAB              FOLFOX     + CETUXIMAB
  COIN       3
                     8.6         8.6         0.6      17.9          17         0.68

                               FOLFOX +                          FOLFOX +
                   FOLFOX                     P      FOLFOX                     P
                             PANITUMUMAB                       PANITUMUMAB
  PRIME      3

                     8           9.6        0.023     19.7         23.9       0.072

                                 IFL +                             IFL +
                     IFL                      P        IFL                      P
                             BEVACIZUMAB                       BEVACIZUMAB
AVF2107g     3

                     7.4         13.5       0.0001    17.6         27.7        0.04
Page  120
                         Conclusiones
La adición de Bevacizumab a Quimioterapia en mCRC en primera
 línea mejora los desenlaces relevantes en forma CONSISTENTE
  – Quimioterapias basadas en oxaliplatino
  – Quimioterapias basadas en irinotecán
  – Quimioterapias basadas en fluoruracilo
  – En pacientes con mutaciones del K-RAS, y sin ellas
  – En pacientes con otras mutaciones de la cascada del EGFR
  – Se ratifican en estudios observacionales prospectivos
  – Se ratifican en estudios poblacionales
  – Se debe continuar hasta progresión
  – Hay evidencia no aleatorizada, pero impactante, del beneficio de continuarlo
    más allá de progresión
  – Exhibe buenas tasas de respuesta en pacientes marginalmente resecables
  – Parece mitigar el daño sinusoidal asociado a oxaliplatino


Page  121
                   Conclusiones
La toxicidad adicional asociada al Bevacizumab es manejable
Los MOAs anti EGFR no son eficaces en pacientes con mutación
 del KRAS, y su uso en estos pacientes debe ser excluido de la
 práctica diaria.
Los MOAs anti EGFR exhiben respuestas INCONSISTENTES en
 pacientes con KRAS nativo (en primera línea)
Los MOAs anti EGFR son ineficaces en una fracción no
 determinable – y no despreciable - de pacientes con mCRC por
 razones biológicas (Mutaciones de BRAF, PTEN, etc)
Los MOAs anti EGFR tienen un papel en pacientes en última línea
 de tratamiento (con KRAS nativo)
El Bevacizumab y los MOAs anti EGFR no deben ser combinados



Page  122
              Bev o Cet en 1ª Línea- mCRC
 Estudio (año pub)          Tipo Línea     Brazo (n)                        PFS (m) OS (m)
                                                                       RR (%)                                     Comentarios
N9741 (2008)                F3   1ª    FOLFOX / IFL                        8.7 / 6.9 19.5 /
                                                                      45 / 31                         FOLFOX mejor que IFL
                                                                                        14.5
Hurwitz (2004)        F3      1ª      Bev IFL / IFL         45 /35         10/6         20 / 16       Registro Bev en 1ª línea
Kabbinavar (2005)     RF2 1ª          Bev FULV / FULV 21/18                             17 / 13       Pacientes no candidatos a I u O
Ackland (2008)        D       1ª      FOLFIRI + Bev         50                          22
Giantonio (2005)      RF2 2ª          Fox / Bev + Fox                                   7.2 / 12.9 Registro Bev en 2ª línea
NO16966 (2007)        F3      1ª      Fox / Bev + Fox       47 / 49        8 / 9.4 19.9 /             Bev sólo durante Negativo.
                                                                                        21.3
PACCE (2009)          F3      1ª      Bev+Fox/PBev+Fo 48 / 46              11.4 /       24.5 /        RR KRAS nativo Bev+Fox: 56%
                                      x                                    10           19.4
PACCE (2009)          F3      1ª      Bev+Fir/PBev+FIr 40 / 43             11.7/10. 20.5/20.7
                                                                           1
BICC-C (2007)         F3      1ª      Bev+Fir/Bev+mIFL 58 / 56             11.2/8.3 >23/19.2
First BEAT            OCS 1ª          Bev + QT                             10.2         22.7          – No US
BRiTE                 OCS 1ª          Bev + QT (>Fox)                      10           25            1953 pts – US
BRiTE                 OCS 1ª          BBP / No-BBP                                      31.8/
                                                                                        19.9
Cochrane              MA 1ª           Bev + QT / QT                        9.7/7.1 20.5/17.7 HR 0.61 para PFS, 0.81 para OS
CRYSTAL (2009)        F3      1ª      Cet + FIr / FIr       47 / 39        8.9/8        19.9/18.6 No discriminados por KRAS
CRYSTAL (2009)        AS 1ª           Cet + FIr / FIr       59 / 43        9.9/8.7 24.9/21 KRAS nativo
                      F3      1ª                   FOx      51/53          8.6/8.6 17/17.9 KRAS nativo F: predictivo
COIN (2009) RR: Tasa de respuestas (PRCet + Fox /Supervivencia libre de progresión; OS: Supervivencia global; m: meses;no Fase; RF: Fase
   Abreviaturas:                      + CR); PFS:
  aleatorizado; D: Descriptivo; OCS: Estudio de observación de cohorte, prospectivo; Fox: Fluoropirimidina + Oxaliplatino; Bev: Bevacizumab; PBev:
  Panitumumab – Bevacizumab; FIr: Folfiri; Cet: Cetuximab; QT: Quimioterapia; US: Estados Unidos; BBP: Bevacizumab luego de progresión –
  Bevacizumab beyond progression; HR: Hazard ratio; MA: Meta-análisis; AS: Análisis de subgrupo retrospectivo.

 Page  123
Efectos adversos de Bevacizumab y
MOAs anti EGFR
Toxicidad de clase de los Anti-VEGF (Bevacizumab)



 Hipertensión arterial    Incremento de los LFT
 Fatiga                   Dolor en el sitio del tumor
 Coágulos                 Proteinuria
 Sangrado (Epistaxis,     Hipotiroidismo?
  hemoptisis, tumoral)     Perforación intestinal
 Cefalea
 Eventos neurológicos



Page  125
Hypertension and Bevacizumab


 Meta-analysis of 7 trials: 1850 patients
 Bevacizumab was associated with hypertension in a dose dependent
  manner:
  – Low doses (3-7.5 mg/Kg): RR 3.0 (95% CI 2.2-4.2)
  – High doses (10-15 mg/Kg): RR 7.5 (95% CI 4.2-13.4)
 Incidence:
  – Low doses: all grades 2.7%-32%; grade 3: 8.7%
  – High doses: all grades 17.6-36%; grade 3: 16%
  – Placebo: grade 3: 1.7%




 Zhu X, et al. Am J Kidney Dis 2007; 49: 186-193
Page  126                                                Courtesy of: J Tabernero
   ATEs and Bevacizumab:
   Pooled Analysis of Five Randomized Trials


                                                                Chemotherapy         Bevacizumab +
                                                                    alone            chemotherapy
                                                                   (n=782)              (n=963)
  ATEs, n (%)                                                          13 (1.7)           37 (3.8)
  Person-years of observation                                           419                673
  Rate/100 person-years (95% CI)                                    3.1 (1.7–5.3)     5.5* (3.9–7.6)
  Hazard ratio (95% CI)                                                    1.99** (1.05–3.75)
  *p=0.076; **p=0.03
  CI = confidence interval
  ATE = arterial thromboembolic event

                      Higher risk observed in patients with history of ATEs and
                       aged ≥65 years, hypertension and proteinuria



                  JR, et al. Proc ASCO 2005; 23: 3019
Page  127 Skillings                                                                      Courtesy of: J Tabernero
          Scappaticci FA et al. J Natl Cancer Inst 2007;99:1232-9
 ATEs Incidence with Bevacizumab
 by Risk Factor and Aspirin Use

                                   Aspirin at baseline                    No aspirin at baseline
                            Control %            Bevacizumab        %   Control %      Bevacizumab           %
Risk factor                   (n/N)                  (n/N)                (n/N)           (n/N)


All patients                 2.0 (1/49)              7.6 (6/79)         1.6 (12/733)   3.5 (31/884)
Age <65 years and
no history of ATEs            0 (0/11)                5 (1/20)           1 (5/479)     1.7 (10/582)
History of ATEs              5.3 (1/19)             10.7 (3/28)          2.5 (1/40)     18 (11/61)
Age 65 years                 0 (0/32)               9.1 (5/55)         2.8 (7/247)    6.7 (19/284)
Age 65 years and
history of ATEs               0 (0/13)              12.5 (3/24)           3 (1/33)       21 (9/43)
  N = total number; n = subgroup

 Aspirin did not increase bleeding risk of any grade
    Grade 3/4 bleeding with and without aspirin: 3.6 versus 5.6%
 Page  128 HambletonJ, et al. Proc ASCO 2005; 23: 3554                                Courtesy of: J Tabernero
          Scappaticci FA et al. J Natl Cancer Inst 2007;99:1232-9
Proteinuria and Bevacizumab


 Meta-analysis of 7 trials: 1850 patients
 Bevacizumab was associated with proteinuria in a dose dependent
  manner:
  – Low doses (3-7.5 mg/Kg): RR 1.4 (95% CI 1.1-1.7)
  – High doses (10-15 mg/Kg): RR 2.2 (95% CI 1.6-2.9)
 Incidence:
  – Low doses: all grades 21-41%; grade 3: 1.0%
  – High doses: all grades 22-63%; grade 3: 1.8%
  – Placebo: grade 3: 0.1%
  – Renal cell carcinoma patients: grade 3: 7.7%




Page  129                                                 Courtesy of: J Tabernero
 Zhu X, et al. Am J Kidney Dis 2007; 49: 186-193
Gastrointestinal perforations


  Bevacizumab:
   Metaanalysis: 12,294 patients, 17 RCTs
   Gastrointestinal perforation rate: 0.9% (95% CI 0.7-1.2)
   RR 2.14, p=.011, 95% CI 1.19-3.85
   Relative risks:
     – Dose 5 vs 2.5 mg/Kg/week:
         RR 2.67 (95% CI 1.14-6.26) vs 1.61 (95% CI 0.76-3.38)
     – Tumor type:
         CRC RR 3.1 (95% CI 1.26-7.63)
         RCC RR 5.67 (95% CI 0.66-48.42)
   No robust data for VEGFR inhibitors and aflibercept

Page  130
                                                           Hapani et al; Lancet Oncol 2009
Toxicidad de clase de los Anti-EGFR (Cetuximab)



 Exantema acneiforme (89%)  Cefalea (26%),
 Astenia (48%)                Diarrea (25%),
 Náuseas leves (29%)          Cambios en las uñas y
 Constipación leve (26%)       tejidos vecinos (14%)

 Dolor abdominal leve(26%)    Hipomagnesemia




Page  131
Skin Toxicity: Pathophysiology


 EGFR inhibitors1:
  – EGFR-inhibition driven:
  – Similar in all EGFR-inhibitors.
  – Cutaneous effects: dose-dependent: cetuximab (EVEREST), panitumumab,
    erlotinib
  – Polymorphisms in EGFR gene, intron 1
  – EGFR null skin mice: similar lesions
  – Unique combination: itchy acneiform eruption, xerosis, paronychia, hair
    changes, telangiectasia
  – Mechanism unknown




Page  132                                                           Courtesy of: J Tabernero
 Segaert S, et al. Ann Oncol 2006
  Cutaneous and Nail Toxicities
  Associated with Cetuximab
Intensity          Acne-like Rash
                                                         Only 14% of patients experience
                                                         Grade 3 Acne-like rash



                             3                     6
 Week          1       2               4    5            7     8       9       10        11       12


                                                         Dry skin            Fissures              Nail bed




                          Grade 3                                     Images kindly provided by Prof. Segaert
                    Acne-like rash

                                                THERAPY SUGGESTIONS

                   Topical antiacne
                              -                                Emollients    Hydrocolloid          Antiseptic
                   creams (drying effect)                                    dressing/’glue’       soaks or
                                                                                                   Silver nitrate
                   +/- tetracyclines
  Page  133
                   +/- antihistamines                                                     Courtesy of: J Tabernero
         Correlation of Skin Toxicity and Efficacy with
         Cetuximab in the BOND Study (Refractory)

       BOND combination arm: Cetuximab + Irinotecan (n=218)

    Maximum grade of                Number of             Response    mTTP*       mOS**
      skin reaction                  patients                (%)     (months)    (months)

                0                   32 (14.7%)              6.3        1.4            3.0

                1                   58 (26.6%)              8.6        1.5            6.5

                2                   99 (45.4%)              27.3       4.2           10.3

                3                   29 (13.3%)              55.2       8.2           13.7


    Skin reactions appear to be predictive for efficacy

*mTTP = median time to progression ; **mOS = median overall survival
Page  134                                                                      Courtesy of: J Tabernero
Cunningham D et al. N Engl J Med 2004; 351(4): 337-345.
                    Correlation of Skin Toxicity and Efficacy with
                    Cetuximab in the CRYSTAL Study (1st Line)

                             CRYSTAL combination arm: Cetuximab + FOLFIRI (n=599)
                    1.00
                                                                         Skin reaction grade 3*, n=112 (18.7%)
                                                                         Skin reaction grade 2, n=243 (41%)
                                                                         Skin reaction grade 0 or 1, n=244 (41%)
                    0.75
                                                                         *There were no grade 4 skin reactions
     PFS estimate




                                     5.4 mo           9.4 mo              11.3 mo
                    0.50




                    0.25




                    0.00
                           0.0     2.5          5.0    7.5        10.0       12.5      15.0      17.5          20.0

 *PFS =
Page  135          progression-free survival                Time (months)                    Courtesy of: J Tabernero
 Van Cutsem et al. Proc ASCO 2007
Hypomagnesaemia


   Hypomagnesaemia                                     Total                            Grade 3-4
        Panitumumab1                                   36%                                    3%
        Cetuximab2                                     53%                                   15%

 Related to duration of treatment3:
   – Grade 3-4: 6% <3 m, 23% 3-6 m, 47% >6 m
 Treatment4:
   – Related symptoms: asthenia, irritability
   – Be cautious in case of: cardiomyopathy, renal failure, treatment with
     platin
   – Grade 1-2: oral or iv replacement
   – Grade 3-4: discontinuation and iv replacement, stop and go?
                                                                                                Courtesy of: J Tabernero

Page  136 1VanCutsem et al. J Clin Oncol 2007;25:1658-1664 2Jonker DJ et al. N Engl J Med 2007;357:2040–8
          3Fakih MG et al. Clin Colorectal Cancer 2006;6:152–6 4Izzedine H et al. Crit Rev Oncol/Hematol 2009 (Epub)

								
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