Docstoc

17

Document Sample
17 Powered By Docstoc
					Neoplasie del Colon-retto
The therapeutic spectrum in adjuvant
 colon cancer and neoadjuvant rectal
            cancer: Chair‟s welcome
                         Alberto Sobrero
                     Ospedale San Martino
                              Genoa, Italy
              Adjuvant chemotherapy of
              colon cancer: steps ahead


5-FU/LEV                             6 months        Elderly    Stage II
                                                     as well




1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004




                  5-FU/LV                           FOLFOX        Xeloda
     Neoadjuvant chemoradiation:
  treating early to optimize outcomes



 Neoadjuvant chemoradiation improves1
  – downstaging
  – surgical resection
  – sphincter-sparing surgery




                         1Bosset   JF et al. J Clin Oncol 2005;23:5620–7
       New treatments, new hope


“It‟s time we pay more, not less, attention
to the concept of cure and give our
patients the benefit of the doubt”

                  De Vita, Nature Clin Pract, Feb 2006
Evolving choices in adjuvant
               colon cancer
                           Joe McKendrick
Box Hill Hospital, Box Hill, Victoria, Australia
Adjuvant chemotherapy
   for colon cancer


 Colon cancer
  – common
  – increasing
  – costly

 Adjuvant therapy
  reduces burden of disease
        Advances in the adjuvant
        treatment of stage III CRC

100            3-year overall survival (%)



80




60

                                             Surgery alone


40
 1980   1985       1990         1995         2000      2005
     Efficacy of adjuvant chemotherapy
      in colon cancer widely accepted
 1990 Intergroup study1
  – 5-FU/levamisole improves survival in surgically
    resected stage III colon cancer
  – 16% absolute reduction in risk of death
 Efficacy of adjuvant chemotherapy in stage III colon
  cancer widely accepted by early 1990s
 Adoption of adjuvant therapy slow and not universal

 Toxicity a significant issue

 Conflicting opinion about stage II disease
                                 1Moertel   CG et al. N Engl J Med 1990;322:352–8
   5-FU-based adjuvant chemotherapy:
  early modifications and improvements

 NSABP C-03,1 IMPACT,2 INT0089,3 NSABP C-04,4 QUASAR5

  – no advantage gained by adding levamisole to 5-FU/LV

  – low dose leucovorin (LV) is adequate

  – 6 months‟ therapy as good as 12 months‟ therapy

  – weekly therapy equivalent to monthly


    1Wolmark N et al. J Clin Oncol 1993;11:1879–87; 2IMPACT investigators. Lancet 1995;345:939–44
       3Haller DG et al. J Clin Oncol 2005;23:8671–8; 4Wolmark N et al. J Clin Oncol 1999;17:3553–9
                                           5QUASAR Collaborative Group. Lancet 2000;355:1588–96
     Roswell Park regimen: equivalent
    efficacy with distinct safety profiles

 No improvement in DFS or OS with Roswell Park
  versus Mayo Clinic regimen1

 For Mayo Clinic, major toxicity is myelosuppression2

 For Roswell Park, major toxicity is diarrhea3

 Need to improve safety of 5-FU-based therapy


                                    1Haller  DG et al. J Clin Oncol 2005;23:8671–8
                                         2Haydon   A. Intern Med J 2003;33:119–24
                     3Schmoll H-J et al. Eur J Cancer Suppl 2005;3:173 (Abst 617)
                     Similar efficacy with infused
                        5-FU/LV versus bolus
        Overall survival: stage III              Disease-free survival: stage III
Probability
  1.0
                                                                       Mayo (n=256)
                                                                       LV5FU2 (n=257)


  0.8



  0.6
            Hazard ratio = 1.27                        Hazard ratio = 1.025
            95% CI (0.87–1.86)                         95% CI (0.78–1.35)
            Log-rank p=0.21                            Log-rank p=0.86
  0.4
        0      0.5    1.0    1.5 2.0   2.5 2.8     0      0.5   1.0    1.5 2.0     2.5 2.8
                            Years                                     Years
                                                 André T et al. J Clin Oncol 2003;21:2896–903
                   Better toxicity profile with
                     LV5FU2 versus Mayo

                               Grade 3 / 4 adverse events
                                    (% of patients)
                             LV5FU2                 Bolus 5-FU/LV
                             (n=452)                   (n=453)
Neutropenia                     7                            16
Diarrhea                        4                              9
Mucositis                       2                              7
Nausea / vomiting*              1                              3
All toxicities                 11                            26


*Not significant                    André T et al. J Clin Oncol 2003;21:2896–903
  Issues with central venous catheters
 Additional costs

 Inconvenient for patients

 Need for invasive surgical procedure
  – possible complications include infections,
    bleeding, pneumothorax, deep-vein thrombosis
    and pulmonary embolism1,2
  – varying level of risk (7–20%) but base rate of
    complications unavoidable regardless of
    center/experience3
                                        1
                                        Kuter DJ. Oncologist 2004;9:207–16
                                2
                                 Verso M et al. J Clin Oncol 2003;21:3665–75
                        3
                         Sobrero A and Sciallero S. Ann Oncol 2005;16:521–2
Xeloda is established in MCRC and should
  simplify complex adjuvant treatments


  Xeloda is effective and well tolerated in MCRC
   – can replace 5-FU as monotherapy and in
     combination regimens
   – convenient home-based oral therapy

  Potential to translate these advantages into
   adjuvant setting
       Benefit of adjuvant therapy for
      stage II patients not always clear

 Relatively few stage II patients have been
  randomized

 Lower risk of recurrence

 Contradictory meta-analyses
  – IMPACT meta-analysis concluded no advantage
    in 1025 patients1
  – NSABP pooled data analysis showed improved
    event-free and overall survival in 1565 patients2
                                 1IMPACT.      J Clin Oncol 1999;17:1356–63
                          2Mamounas   E et al. J Clin Oncol 1999;17:1349–55
    QUASAR: adjuvant chemotherapy
significantly reduces recurrence in stage II
Relapse-free survival (%)
       100                                              Hazard ratio = 0.78
                                                        (95% CI: 0.67–0.91)
                                                             p=0.001
         80


         60


         40                    5-year
                               RFS (%)
         20       Chemotherapy 78.0
                  Observation   73.8

          0
              0   1    2    3   4      5       6       7      8       9      10
                                     Years
                                Gray RG et al. J Clin Oncol 2004;23:245s (Abst 3501)
  QUASAR: adjuvant chemotherapy
 improves overall survival in stage II
Survival (%)
  100                                                 Chemotherapy
                                                      Observation
                                                      p=0.04
   80


   60


   40


   20


     0
         0     1   2   3   4      5       6       7       8      9      10
                                Years
                           Gray RG et al. J Clin Oncol 2004;23:245s (Abst 3501)
        Dutch trial of 5-FU/LEV suggested
            improved OS for stage II
Overall survival (%)
       100
                                           5-FU/LEV (n=233)

        80

        60                                    Control (n=235)

        40

        20

         0
             0         1   2     3        4          5          6
                               Years
                                       Taal B et al. Br J Cancer 2001;85:1437–43
    Should high-risk stage II patients
   be offered adjuvant chemotherapy?

 Some high-risk patients may benefit from adjuvant
                 1
  chemotherapy
  – obstruction or perforation
  – venous or lymphatic invasion
  – perineural invasion
  – tumor adherence

 Better prognostic factors could aid in patient selection
  – Biomarker data collection incorporated in most
    ongoing studies

                        1NCCN   Clinical Practice Guidelines in Oncology v.2.2004
        Patients who could benefit are
         still denied adjuvant therapy

 Indication of benefit of adjuvant therapy in stage II1–5
   – small but significant benefit of chemotherapy

 High-risk stage II patients may benefit as much as
   some stage III patients

 Older patients and some minorities less likely to
   receive chemotherapy6,7
   – toxicity concerns
                                                   1Gray    RG et al. J Clin Oncol 2004;22:245s (Abst 3501)
                   2Taal   BG et al. Br J Cancer 2001;85:1437–43; 3IMPACT. J Clin Oncol 1999;17:1356–63
         4Gill S et al. J Clin Oncol 2004;22:1797–806; 5Figueredo A et al. J Clin Oncol 2004;22:3395–407
                                                           6Sargent DJ et al. N Engl J Med 2001;345:1091–7
                                         7Grothey A et al. Proc Am Soc Clin Oncol 2002;21:129a (Abst 512)
    Factors that may influence treatment
   decisions with adjuvant chemotherapy

             Preference      Patient      Biomarkers

                          characteristics
               Disease                        Comorbidities
                stage           Age      e.g. diabetes, impaired
                                            cardiac function


  Treatment
                                                             Healthcare
  outcomes                     Benefit to                    providers
Efficacy   Toxicity
                               risk ratio
                                                   Treatment costs   Resource
                                                                       use


                  Impact on
                   lifestyle     Patients
                                            Convenience
         Redefining adjuvant therapies

 Improve efficacy with new agents

 Reduce toxicity

 Prospective identification of high-risk stage II patients

 Tailor to ensure all patients can benefit
  – effective, well-tolerated, convenient therapy

 With Xeloda‟s approval, the need for an effective, well-
  tolerated, convenient and cost-effective therapy may be
  addressed
The next level in adjuvant treatment:
   new chemotherapy combinations
                           Alberto Sobrero
                       Ospedale San Martino
                                Genoa, Italy
                  Combinations in adjuvant
                chemotherapy: recent evidence

                                              DFS                                    OS
Oxaliplatin combinations                   hazard ratio          p value         hazard ratio           p value
MOSAIC1                                          0.77            <0.001                0.91                NR

NSABP C-07 2                                     0.79            <0.004                 NR                 NR

Irinotecan combinations
CALGB89803 3                                      NR               0.80                 NR                0.81

PETACC -34                                       0.89              0.091                NR                 NR

 ACCORD25                                        1.19              0.22                 NR                 NR

NR = not reported

                                                         1deGramont A et al. J Clin Oncol 2005;23:246s (Abst 3501)
2Wolmark   N et al. J Clin Oncol 2005;23:246s (Abst LBA3500); 3Saltz LB et al. J Clin Oncol 2004;22:245S (Abst 3500)
            4Van Cutsem E et al. J Clin Oncol 2005;23:3s (Abst LBA8); 5Ychou M et al. Proc ASCO 2005 (Abst 3502)
         MOSAIC: superior DFS with
      FOLFOX versus LV5FU2 in stage III
Estimated probability
       1.0                              Hazard ratio (95% CI)
                                          0.76 (0.62–0.92)
       0.8

       0.6

       0.4
                                       3-year DFS
                     FOLFOX4 (n=672)     72.2%
       0.2
                     LV5FU2 (n=675)      65.3%
       0.0
             0   6      12   18   24     30   36        42     48      54     60
                                       Months

                                          André T et al. N Engl J Med 2004;350:2343–51
             NSABP C-07: superior DFS with
             FLOX versus 5-FU/LV in stage III
Estimated probability                                                  3-year DFS
   1.0                                              FLOX (n=272)    76.5%
                                                    5-FU/LV (n=332) 71.6%
   0.9

   0.8

   0.7
               Hazard ratio (95% CI)
   0.6           0.79 (0.67–0.93)
                     p<0.004

   0.5
         0              1                2                   3                  4
                                       Years

                               Wolmark N et al. J Clin Oncol 2005;23:246s (Abst LBA3500)
        The strength of MOSAIC: clinically
      relevant absolute benefit is increasing

                     4-year DFS (%)1                  3-year DFS (%)2
II and III                      6.8*                           5.1*
III N1                           7.0                              –
III N2                           12                               –
III                             8.7*                           6.3*
II                               3.8                            2.7
High-risk stage II               5.4                            5.1


                     1de   Gramont A et al. J Clin Oncol 2005;23:246s (Abst 3501)
*p<0.05                          2André T et al. N Engl J Med 2004;350:2343–51
  FLOX vs FOLFOX: no difference in DFS



                 NSABP C-07   MOSAIC

3-year DFS (%)      76.5       78.2

Hazard ratio        0.79       0.77

Difference          4.9        5.1
                    FOLFOX versus LV5FU2:
                    grade 3/4 adverse events
  Patients (%)
      45
                              FOLFOX4 (n=1 108)
                *
        40                    LV5FU2 (n=1 111)

        15

        10

         5

                       †
         0



*12% grade 4
†Not reported                      André T et al. N Engl J Med 2004;350:2343–51
       Irinotecan has significant benefits
                    in MCRC


Regimen         N     PR    PFS   OS     Author

Douillard/AIO   338   23%   4.4   14.1   Douillard
 + Irinotecan         35%   6.7   17.4   Lancet 2000

FL (Saltz)      440   21%   4.3   12.6   Saltz
 + Irinotecan         39%   7.0   14.8   NEJM 2000

AIO             430   34%   6.4   16.9   Köhne
 + Irinotecan         62%   8.5   20.1   JCO 2005
        CALGB89803: DFS not improved
        with IFL in stage III colon cancer

Proportion disease free
       1.0

       0.8

       0.6

       0.4
                    5-FU/LV (Roswell Park regimen)
       0.2          IFL
                                                                           p=0.80
       0.0
             0        12              24             36              48              60
                                           Months
                           Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500)
        PETACC-3: DFS not significantly
       improved with FOLFIRI in stage III

Estimated probability                                                   3-year DFS
       1.0                                       FOLFIRI (n=1 044)           63.3
                                                 5-FU/LV (n=1 050)           60.3
       0.9

       0.8

       0.7

       0.6           Hazard ratio (95% CI)
                       0.89 (0.77–1.11)
       0.5                 p=0.091

       0.0
             0   3     6   9   12 15 18 21 24 27 30 33 36 39 42 45 48
                                         Months
                                  Van Cutsem E et al. J Clin Oncol 2005;23:3s (Abst LBA8)
      ACCORD2: DFS not improved with
      FOLFIRI in high-risk colon cancer

Estimated probability                                             3-year DFS
       1.0                                            LV5FU2         60%
                                                      FOLFIRI        51%
       0.8

       0.6

       0.4
                 Hazard ratio (95% CI)
       0.2         1.19 (0.90–1.59)
                        p=0.22
       0.0
             0          1      2           3           4            5             6
                                         Years
                                     Ychou M et al. J Clin Oncol 2005;23 (Abst 3502)
    Xeloda has the potential to replace
      5-FU in adjuvant combinations

 Xeloda is at least as effective as 5-FU/LV with
  – significantly superior relapse-free survival
  – trends to improved disease-free and overall
    survival
  – consistent benefits in all efficacy endpoints

 XELOX has similar high efficacy and favorable safety
  profile compared with FOLFOX in metastatic CRC

 Xeloda is the optimal fluoropyrimidine partner to
  simplify complex combination regimens
         XELOXA: adjuvant Xeloda +
      oxaliplatin (XELOX) versus 5-FU/LV

                                               XELOX
                                               24 weeks
       Chemotherapy-naïve,
            stage III
          colon cancer
             n=1 886
                                          Bolus 5-FU/LV
                                            Mayo Clinic
                                                 or
                                            Roswell Park
                                           24 or 32 weeks

 1º endpoint: DFS – XELOX >5-FU/LV
  – minimal absolute difference targeted: 6%
 2º endpoints: survival, tolerability, convenience, pharmacoeconomics
 Recruitment completed: September 2004
           XELOX is an ideal combination
              in the adjuvant setting
                        1
                  XELOXA
Grade 3/4
toxicities     XELOX 5-FU/LV

Diarrhea        19      20
Stomatitis      <1      8
Nausea           5      4
Vomiting         6      3
Neurosensory    11      0
HFS              5      <1
Neutropenia      8      15
Febrile         <1      4
neutropenia


                               Schmoll H-J et al. Proc ASCO GI 2006 (Abst 278)
                               1
           XELOX is an ideal combination
              in the adjuvant setting
                               1                       2                           3
                     XELOXA                   MOSAIC               NSABP C-07
Grade 3/4
toxicities               5-FU/LV
                      XELOX                   FOLFOX                    FLOX

Diarrhea                 19   20                 12                       36
Stomatitis               <1    8                  3                       NR
Nausea                   5     4                  5                       15
Vomiting                 6     3                  6                       12
Neurosensory             11    0                 12                        8
HFS                      5    <1                  2                       NR
Neutropenia              8    15                 41                        5
Febrile                  <1    4                  2                       NR
neutropenia
                                          1
                                           Schmoll H-J et al. Proc ASCO GI 2006 (Abst 278)
                                              2
                                               André T et al. N Engl J Med 2004;350:2343–51
              3
               Smith R et al. Proc Am Soc Clin Oncol 2003;22:294 (Abst 1181; poster update)
        UK QUASAR2: adjuvant Xeloda
                ± Avastin

                                              Xeloda
                                         8 cycles (24 weeks)
        Stage II/III
       colon cancer
         n=3510
                                              Xeloda
                                         8 cycles (24 weeks)
                                              Avastin
                                             7.5mg/kg
                                        16 cycles (48 weeks)
 1º endpoint: DFS
  – minimal absolute difference targeted: 6%
 2º endpoints: 5-year overall survival, safety, health economics
 Recruitment opened 2005
         AVANT: adjuvant FOLFOX
           vs XELOX ± Avastin
                                        XELOX
                                         plus
                                        Avastin
Chemotherapy-naïve,
     stage II/III
   colon cancer                        FOLFOX
      n=3450

                                       FOLFOX
                                         plus
                                       Avastin
   1º endpoint: DFS
    – minimal absolute difference targeted: 5.3%
   2º endpoints include: overall survival and tolerability
   Started Q4 2004
    Xeloda provides added advantages
    in adjuvant combination regimens

 Xeloda should be preferred to i.v. 5-FU/LV
  – consistent efficacy benefits in stage III colon cancer
  – more convenient for patient and physician
  – reduces hospitalizations for adverse events
  – cost-saving for most healthcare systems

 Adjuvant XELOX has a favorable safety profile with
  less neutropenia than FOLFOX

 Xeloda is an ideal backbone for future development
              Landmark trials: adjuvant
             Xeloda-based combinations

                           AVANT survival follow-up

                   QUASAR2 last follow-up planned

                     AVANT 1° efficacy

                 XELOXA survival follow-up

            XELOXA 1° efficacy

       XELOXA final safety


2004      2005      2006        2007     2008         2009   2010   2011
          ®
Avastin therapy: the essential basis
     of first-line treatment regimens
                                        Bruce Giantonio
    Abramson Cancer Center, The University of Pennsylvania,
                                         Philadelphia, USA
     Mode of action suggests Avastin can
 be combined with all first-line chemotherapy

 Avastin‟s unique mechanism of action is potentially
  exploited best when used with chemotherapy, but
  – it shouldn‟t be dependent upon any particular
    chemotherapy regimen

 Efficacy data indicate that the magnitude of benefit
  achieved with Avastin is greatest when used with first-line
  chemotherapy

 Clinically and statistically significant survival benefit is
  seen despite modest improvements in response rates
               Treatment of metastatic CRC

                                               Metastatic CRC



First-line               IFL/FOLFIRI/         5-FU or Xeloda           FOLFOX or XELOX
                            XELIRI



Second-line Irinotecan + FOLFOX                 BSC/FOLFOX/             FOLFIRI       5-FU/LV
             cetuximab                            FOLFIRI




CRC = colorectal cancer; IFL = irinotecan, 5-fluorouracil (5-FU)/leucovorin (LV);
FOLFIRI = 5-FU/LV + irinotecan; XELIRI = Xeloda® + irinotecan; FOLFOX = 5-FU/LV + oxaliplatin;
XELOX = Xeloda + oxaliplatin; BSC = best supportive care
                                    Phase III trial of IFL ± Avastin
                                       (AVF2107g): survival
                          1.0                           Median survival
                                                        IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs
                                                        IFL + Avastin: 20.3 (95% CI: 18.5–24.2)
Probability of survival




                          0.8                           HR=0.66 (95% CI: 0.54–0.81)
                                                        p<0.001
                          0.6
                                                                                  IFL + Avastin
                                                                                  IFL + placebo
                          0.4


                          0.2

                                               15.6          20.3
                           0
                                0         10                20               30                  40
                                                      Time (months)

CI = confidence interval; HR = hazard ratio                 Hurwitz H, et al. N Engl J Med 2004;350:2335–42
                                 Phase III trial of IFL ± Avastin:
                                   progression-free survival
                       1.0                           Median progression-free survival
                                                     IFL + placebo: 6.2 (95% CI: 5.6–7.7)
                                                     IFL + Avastin: 10.6 (95% CI: 9.0–11.0)
                       0.8
Probability of being




                                                     HR=0.54 (95% CI: 0.45–0.66)
 progression-free




                                                     p<0.001
                       0.6
                                                                                      IFL + Avastin
                       0.4                                                            IFL + placebo

                       0.2

                                      6.2            10.6
                        0
                             0                   10                    20                           30
                                            Progression-free survival (months)
                                                            Hurwitz H, et al. N Engl J Med 2004;350:2335–42
             Use of Avastin with
            FOLFIRI-based therapy


 Avastin has proven efficacy in combination with IFL

 Studies of IFL and FOLFIRI regimens suggest
  improved safety and comparable, if not superior,
  efficacy of FOLFIRI

 Based on what we know, it is expected that Avastin
  will enhance efficacy when combined with FOLFIRI
     Phase II trial of Avastin plus FOLFIRI:
     preliminary efficacy and safety results
 Avastin plus FOLFIRI appears to be well tolerated with
  comparable efficacy1
 It is expected that progression-free survival will
  surpass the 8.5 month median progression-free
  survival reported for FOLFIRI alone2 and be at least
  equivalent to the 10.6 months reported for IFL plus
  Avastin3
 Incidence of adverse events is lower than that
  reported with IFL plus Avastin
  – no grade 3/4 diarrhoea versus 32%1
  1HoffPM, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006;
  San Francisco, Ca. Abstract 252. Available at http://www.asco.org. Accessed 28 February 2006
                                               2Tournigand C, et al. J Clin Oncol 2004;22:229–37
                                                3Hurwitz H, et al. N Engl J Med 2004;350:2335–42
     Phase IV trial of Avastin plus
   irinotecan (AVIRI): study design


   Patients with
    previously
                                  Avastin 5mg/kg every
    untreated
                                   2 weeks + FOLFIRI
  metastatic CRC
     (n=202)


 Primary endpoint: progression-free survival

 Secondary endpoints: overall survival, overall response
  rate, duration of response and safety
 Data available: 2006
         Planned trial of Avastin plus
     FOLFIRI/ XELIRI: ACCORD 13 (MEXICO)
                                Avastin         Avastin
                              5mg/kg every     7.5mg/kg
                                                                  PD
                               2 weeks +         every
   Patients with                FOLFIRI        3 weeks
    untreated
  metastatic CRC
     (n=140)                      Avastin        Avastin
                              7.5mg/kg every    7.5mg/kg
                                                                  PD
                                 3 weeks +        every
                                   XELIRI       3 weeks

Duration of treatment           24 weeks

 Primary endpoint: progression-free survival
 Secondary endpoints: overall survival, overall response rate,
    duration of response and safety
PD = progression of disease
          Avastin can be combined with
        IFL/FOLFIRI/XELIRI-based therapy

                                  Metastatic CRC



First-line        IFL/FOLFIRI/    5-FU or Xeloda   FOLFOX or XELOX
                     XELIRI



Second-line Irinotecan + FOLFOX    BSC/FOLFOX/      FOLFIRI   5-FU/LV
             cetuximab               FOLFIRI
                  Combined analysis of Avastin plus
                5-FU-based regimens: overall survival

               100                    Median survival: 14.6 vs 17.9 months
                                      HR=0.74, p=0.0081
               80
Survival (%)




               60                                         5-FU/LV/Avastin 5mg/kg
                                                          5-FU/LV or IFL
               40

               20
                               14.6      17.9
                0
                     0    10                20                  30                  40
                                      Time (months)


                                         Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12
                                          Combined analysis of Avastin
                                           plus 5-FU-based regimens:
                                            progression-free survival

                                                   Median progression-free survival:
Progression-free survival (%)




                                100                5.6 vs 8.8 months
                                                   HR=0.63, p=0.0001
                                80
                                                                  5-FU/LV/Avastin 5mg/kg
                                60
                                                                  5-FU/LV or IFL
                                40

                                20
                                           5.6    8.8
                                 0
                                      0           10                       20                         30
                                                        Time (months)

                                                           Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12
   Xeloda in metastatic CRC: significantly
 superior response rate versus bolus 5-FU/LV

                                                Bolus
                                Xeloda         5-FU/LV
                                (n=603)        (n=604)          p value
Response rate (%)                   26              17         <0.0002
Time to progression (months)       4.6             4.7           0.9535
Overall survival (months)          12.9           12.8           0.48


  The efficacy of Xeloda versus bolus 5-FU/LV was similar
   to infusional 5-FU/LV versus bolus 5-FU/LV


                               Van Cutsem E, et al. Br J Cancer 2004;90:1190–7
                              Preclinical evidence for the use of
                              Avastin with Xeloda-based therapy
 Combining Avastin and Xeloda resulted in a greater duration of tumour
                  inhibition than with either agent alone
                            2,000
                                                                                         Control
 Mean tumour volume (mm3)




                            1,750
                                                                                         Avastin*
                            1,500
                            1,250                                                        Xeloda*

                            1,000                                                        Avastin* +
                                                                                         Xeloda*
                             750
                             500
                             250
                               0
                                    0   7   14   21   28      35   42    49      56     63
                                                           Day
                                                                   Shen BQ, et al. Proc Am Assoc Cancer
*Sub-maximum effective doses                                                 Res 2004;45 (Abstract 2203)
     Ongoing/planned trials of Xeloda
  plus Avastin in first-line metastatic CRC
 MAX (ML18513); randomised phase II/III trial (n=333)
  – patients with previously untreated metastatic CRC will be
    randomised to receive one of three regimens until disease
    progression
    • Xeloda
    • Avastin 7.5mg/kg every 3 weeks plus Xeloda
    • Avastin 7.5mg/kg every 3 weeks plus Xeloda plus mitomycin C

 Several other trials of Avastin plus Xeloda are planned, including
  – ML18524, open label study comparing the effect of three
    chemotherapy regimens (n=300)
  – ML18799, phase II trial (n=80)
  – ML19823, phase II trial in elderly patients (n=60)
          Avastin can be combined with
        5-FU/LV- or Xeloda-based therapy

                                  Metastatic CRC



First-line        IFL/FOLFIRI/    5-FU or Xeloda   FOLFOX or XELOX
                     XELIRI



Second-line Irinotecan + FOLFOX    BSC/FOLFOX/      FOLFIRI   5-FU/LV
             cetuximab               FOLFIRI
                           Phase III trial of Avastin plus FOLFOX
                          in second line (E3200): overall survival
                          1.0
                                                                                   HR=0.76
                          0.8                                                      A vs B: p=0.0018
                                                                                   B vs C: p=0.95
Probability of survival




                          0.6


                          0.4


                          0.2
                                               10.8

                                               10.2         12.9
                           0
                                0   3     6      9     12     15    18  21        24     27     30    33     36
                                                              Time (months)
                                                                         Total    Dead    Alive      Median
                                    A: FOLFOX4 + Avastin                 289       246     43         12.9
                                    B: FOLFOX4                           290       257     33         10.8
                                    C: Avastin                           243       216     27         10.2
                                             Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)
      Phase III trial of Avastin plus FOLFOX in
   second line (E3200): progression-free survival
                       1.0
                                                                               HR=0.64
                       0.8                                                     A vs B: p<0.0001
Probability of being




                                                                               B vs C: p<0.0001
 progression-free




                       0.6


                       0.4


                       0.2

                                 2.7    4.8             7.2
                        0
                             0    2       4      6     8     10     12     14    16              18      20
                                              Progression-free survival (months)
                                                                     Total     Fail   Cens       Median
                                 A: FOLFOX4 + Avastin                273       228     45         7.2
                                 B: FOLFOX4                          273       241     32          4.8
                                 C: Avastin                          229       215     14          2.7
                                         Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)
          Phase II trial of Avastin with oxaliplatin/
         fluoropyrimidine (TREE-2): study design
                                                        mFOLFOX6 + Avastin
                                                        5mg/kg every 2 weeks                          PD
                                                               (n=75)


                                                          bFOL + Avastin
       First-line metastatic
                                                        5mg/kg every 2 weeks                          PD
           CRC (n=223)
                                                               (n=74)

                                                          XELOX + Avastin
                                                       7.5mg/kg every 3 weeks                         PD
                                                               (n=74)
 Primary endpoint: grade 3/4 toxicity
 Secondary endpoints include overall response rate, time to
    progression and overall survival
                                     Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium;
mFOLFOX = modified FOLFOX                      26–28 January 2006; San Francisco, Ca. Abstract 244. Available at
bFOL = bolus 5-FU/LV + oxaliplatin                               http://www.asco.org. Accessed 28 February 2006
                         Phase II trial of Avastin with oxaliplatin/
                         fluoropyrimidine: overall response rate
                    60                                                                            TREE-1
                                                                                                  (without Avastin)1
                    50            52.1
Response rate (%)




                           46.9                                                                   TREE-2
                                                                                     45.8
                    40                                                                            (with Avastin)2
                                                                             37.5
                    30                                    34.3
                                                32.0

                    20

                    10

                    0
                           mFOLFOX6              bFOL                          XELOX
                                               Regimen*

                                         1Hochster   HS, et al. J Clin Oncol 2005;23(June 1 Suppl.):249s (Abstract 3515)
                                         2Hochster   HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium;
*Avastin is added to each                                          26–28 January 2006; San Francisco, Ca. Abstract 244.
of the regimens in TREE-2                                  Available at http://www.asco.org. Accessed 28 February 2006
                Phase II trial of Avastin with oxaliplatin/
             fluoropyrimidine: time to tumour progression
                       1.0
                                                                          XELOX + Avastin
                                                                          FOLFOX + Avastin
                       0.8
Probability of being




                                                                          bFOL + Avastin
 progression-free




                       0.6


                       0.4


                       0.2


                        0
                             0   5            10                   15                20
                                         Time (months)
  Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006;
     San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006
                                                     Phase II trial of Avastin with
                                                 oxaliplatin/fluoropyrimidine: toxicity
                                            40
Overall incidence of grade 3/4 toxicities




                                                                                                             mFOLFOX6 + Avastin
                                                                                                             bFOL + Avastin
                                                                                                             XELOX + Avastin
                                            30



                                            20



                                            10



                                             0
                                                 Neutropenia Febrile    Vomiting Dehydration Diarrhoea   Grade 3     Bleeding   Thrombo-
                                                            neutropenia                                neurotoxicity             embolic
                                                                                                                                  event
   Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco,
                                      Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006
          Phase II trial of Avastin with three
 oxaliplatin/ fluoropyrimidine regimens: conclusion




       Avastin given in combination with each of three
      oxaliplatin-fluoropyrimidine regimens is effective
                       and well tolerated




Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006;
   San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006
        Phase II trial of XELOX plus
      Avastin (XELOX-A): study design

   Previously                   Xeloda 1,000mg/m2 b.i.d. days 1–5
   untreated                      and days 8–12, every 2 weeks
                                                                                     PD
 metastatic CRC                 oxaliplatin 85mg/m2 every 2 weeks
     (n=50)                      Avastin 10mg/kg every 2 weeks


 Primary endpoint: response rate

 Secondary endpoints: safety and tolerability, time to
  progression, disease-free and overall survival
 Exclusion criteria include: unstable or poorly controlled
  hypertension, arterial or venous thrombosis within the last
  3 months, coagulopathy and anticoagulation therapy

                  Fernando N, et al. J Clin Oncol 2005;23(June 1 Suppl.):260s (Abstract 3556)
           Phase II trial of XELOX plus
         Avastin (XELOX-A): response rate

Response (RECIST criteria)                                              n=30 (%)
Complete response                                                         1 (3)
Partial response                                                          16 (53)
Stable disease                                                            11 (37)
PD                                                                         2 (7)
Overall response rate*                                                 17/30 (57)
Time to progression (months)                                          11.9 (9.8–∞)
*Overall response rate = complete response plus partial response
RECIST = Response Evaluation Criteria in Solid Tumors



                      Fernando N, et al. J Clin Oncol 2005;23(June 1 Suppl.):260s (Abstract 3556)
      Ongoing phase III trial: XELOX ± Avastin
      versus FOLFOX4 ± Avastin (NO16966C)
 2 x 2 factorial, randomised phase III trial
                                                  Avastin 5mg/kg
                                                       every
                                 FOLFOX4
                                                  2 weeks (n=330)
        Previously                (n=300)
        untreated                                  Placebo (n=330)
       patients with
      metastatic CRC
                                                  Avastin 7.5mg/kg
        (n=1,920)
                                  XELOX                 every
                                  (n=300)         3 weeks (n=330)

                                                   Placebo (n=330)
 Primary objectives
  – at least equivalent time to progression with XELOX (± Avastin) versus
    FOLFOX4 (± Avastin)
  – superior time to progression with Avastin + XELOX/FOLFOX4 versus
    XELOX/FOLFOX4
                                  DREAM study
                                  mFOLFOX7 x6                             mFOLFOX7 x6
                                                            Avastin

                                  mFOLFOX7 x6                             mFOLFOX7 x6
    Previously
    untreated                          Avastin            Avastin +             Avastin
   patients with                                          Tarceva®
  metastatic CRC
                                    XELOX4 x6                                XELOX4 x6
     (n=640)
                                                            Avastin

                                    XELOX4 x6                                XELOX4 x6
                                       Avastin             Avastin +            Avastin
                                                            Tarceva
 Primary endpoint: progression-free survival
 Secondary endpoints include: overall survival, response rate, duration of disease control,
  tolerance and quality of life
 mFOLFOX7 or XELOX4: Avastin 5mg/kg every 2 weeks ± Tarceva 100mg/day
 During chemotherapy pause: Avastin 7.5mg/kg every 3 weeks ± Tarceva 150mg/day
       Ongoing phase IV optimisation trial
     (CONcePT) in first-line metastatic CRC

 2x2 randomised, multicentre study


                         mFOLFOX7 + Avastin
                           INTERMITTENT
  Patients with              oxaliplatin             ±
 metastatic CRC                                 intravenous
    (n=532)              mFOLFOX7 + Avastin        Ca/Mg
                            CONTINUOUS
                              oxaliplatin
                           „treat-to-failure‟


 Primary endpoint: time to treatment failure
          CONcePT: intermittent oxaliplatin
    Stage 1
      Avastin 5mg/kg
                            x8 cycles, months 1–4
      CI 5-FU/LV            Oxaliplatin 680mg/m2*
      Oxaliplatin 85mg/m2

    Stage 2
      Avastin 5mg/kg        x8 cycles, months 5–8
      CI 5-FU/LV

    Stage 3
      Avastin 5mg/kg        x8 cycles, months 9–12
      CI 5-FU/LV            Oxaliplatin 1,360mg/m2*
      Oxaliplatin 85mg/m2
CI = continuous infusion
*Cumulative dose
         Avastin therapy: the essential
      basis of first-line treatment regimens


                                  Metastatic CRC



First-line         Avastin +         Avastin +        Avastin +
                 IFL/FOLFIRI/     5-FU or Xeloda   FOLFOX or XELOX
                    XELIRI



Second-line Irinotecan + FOLFOX    BSC/FOLFOX/      FOLFIRI   5-FU/LV
             cetuximab               FOLFIRI
                                  Large observational study of Avastin
                                    plus first-line chemotherapy for
                                        metastatic CRC (BRiTE)
 Median progression-free survival is at least as good as that reported in
   trial conditions despite the fact that this is a clinical practice population
   treated with many different chemotherapy regimens
                                  1.0
    without disease progression
       Proportion of patients




                                  0.8


                                  0.6


                                  0.4


                                  0.2

                                                                 11.3
                                   0
                                        0   2   4   6   8     10   12   14   16   18   20
                                                        Time (months)
  Kozloff M, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006;
  San Francisco, Ca. Abstract 247. Available at http://www.asco.org. Accessed 28 February 2006
        Ongoing and planned trials of
              Avastin in CRC
 Data from ongoing and planned trials are expected to
  support and investigate
  – optimisation of Avastin use with chemotherapy
  – optimisation of chemotherapy use with Avastin
  – incorporation of targeted agents with Avastin
  – activity of Avastin across multiple lines of therapy
    • first-line use is currently recommended to
      maximise benefit

 Studies are ongoing to examine continued efficacy
  after progression
             Avastin in first-line treatment
                  of metastatic CRC
  Avastin has shown consistent efficacy improvements in
     metastatic CRC, regardless of the regimen with which it is
     combined

                                    Metastatic CRC



First-line            Avastin +        Avastin +      Avastin + FOLFOX
                    IFL/FOLFIRI/    5-FU or Xeloda        or XELOX
                       XELIRI

Second-line Irinotecan +   FOLFOX    BSC/FOLFOX/     FOLFIRI      5-FU/LV
             cetuximab                 FOLFIRI

				
DOCUMENT INFO