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									 Optimizing patient care – Xeloda         ®



(Capecitabine) for the treatment of
     metastatic breast cancer
             Dr Chris Twelves
     CRC Department of Medical Oncology
          Beatson Oncology Centre
                Glasgow, UK
  Treatment of metastatic breast cancer

 Range of chemotherapy and endocrine
 therapies available

 The need remains for
 – convenient, well tolerated treatments in
   resistant disease to improve QoL
 – more effective treatment to improve survival
   in patients with less advanced disease
 Phase II trial in paclitaxel-pretreated MBC
   Open-label, multicenter, phase II trial

   163* patients with stage IV breast cancer

   All patients were heavily pretreated
      – 100% had received prior paclitaxel
      – 91% had received prior anthracyclines
      – mean number of regimens per patient = 2.5
   Xeloda 1,250mg/m twice daily for 14 days,
                                        2



      followed by a 7-day rest period
*One patient withdrew prior to receiving treatment
                                                     Blum JL, et al. J Clin Oncol 1999;17:485–93
             Efficacy: phase II trial in
            paclitaxel-pretreated MBC

  20% objective tumor response
     – 29% tumor response in 42 patients refractory
       to both paclitaxel and anthracyclines
  43% stable disease

  Median duration of response = 7.9 months

  Median TTP* = 3.0 months

  Median survival = 12.6 months


*or death                     Blum JL, et al. J Clin Oncol 1999;17:485–93
                                       Survival: phase II trial in
                                      paclitaxel-pretreated MBC
                                                                         Responder
                        1.0
                                                                         Stable disease
                        0.9
                                                                         Progressive disease
Estimated probability




                        0.8
                        0.7
                        0.6
                        0.5
                        0.4
                        0.3
                        0.2
                        0.1
                        0.0
                              0   2      4   6     8    10     12      14       16
                                             Time (months)
                                                         Blum JL, et al. J Clin Oncol 1999;17:485–93
           Safety: phase II trial in
         paclitaxel-pretreated MBC

 Most frequent grade 3/4 treatment-related
  adverse events were diarrhea and hand-foot
  syndrome
 Only 4% experienced grade 4 adverse events
 Myelosuppression and alopecia were rare

 No treatment-related deaths


                          Blum JL, et al. J Clin Oncol 1999;17:485–93
       Summary of phase II trial in
        paclitaxel-pretreated MBC
 Xeloda is an effective agent for paclitaxel-
  pretreated MBC
 20% of patients had an objective response;
  an additional 43% had stable disease
 Median survival was 12.6 months

 Toxicities were manageable with dose
  interruption or, where necessary, dose
  adjustment without compromising efficacy
                          Blum JL, et al. J Clin Oncol 1999;17:485–93
  Efficacy of Xeloda in taxane-pretreated
                                       ®



               MBC: summary

                       Tumor            Response                               Median
                      response           duration            TTP               survival
Pretreated with          (%)            (months)           (months)           (months)

Paclitaxel1 (n=162)         20                7.9               3.0              12.6

Taxanes2 (n=74)             26                8.3               3.2              12.2
 Paclitaxel                 27
 Docetaxel                  20

Taxanes3 (n=100)            18                9.0               3.5               9.9


                                                1
                                                  Blum JL, et al. J Clin Oncol 1999;17:485–93
                                                            2
                                                             Blum JL, et al. Cancer (in press)
                       3
                           Reichardt P, et al. Breast Cancer Res Treat 2000;64:83 (Abst 331)
       Single-agent Xeloda in MBC
                               ®




 Effective, well tolerated treatment in
  taxane-pretreated patients

 Widely licensed and in clinical use in more
  than 40 countries across the world
           Xeloda plus docetaxel:
                    ®



          rationale in breast cancer


 Xeloda and docetaxel have considerable
  single-agent activity in breast cancer

 Xeloda and docetaxel have distinct mechanisms
  of action and no overlap of key toxicities

 Synergistic interaction between Xeloda and
  docetaxel mediated by further taxane-induced
  upregulation of thymidine phosphorylase (TP)
 TP upregulation in tumor xenografts
                     (mg/kg)
          Control
        Paclitaxel      100
       Docetaxel          15
      Vincristine        1.5
      Vinblastine          3
        Vindesine          5
     Mitomycin C           5
     Doxorubicin         7.5
         Cisplatin        10
          Control
     Methotrexate        50
Cyclophosphamide        200

                               0      5          10       15            20
                                   TP activity (unit/mg protein)
Gemcitabine and vinorelbine also upregulate TP
                                      Ishitsuka H. Invest New Drugs 2000;18:343–54
                                                  TP upregulation
                                Dose- and time-dependent upregulation of TP in human
                                               colon cancer xenografts
                                     Paclitaxel                                                           Docetaxel
                       20                             *                                    20
                                                  *           *
TP (unit/mg protein)




                                                                    TP (unit/mg protein)
                                                                                                                      *
                                                                                                                              *   *
                       15                                                                  15

                       10                                                                  10
                                                          *                                                 *
                                              *
                        5                *                                                  5
                                                                                                                          *

                        0                                                                   0
                            0    2     4     6     8     10                                     0    2    4      6     8     10
                                Days after administration                                           Days after administration
                            No treatment                                                        No treatment
                            Vehicle                                                             Vehicle
                            Paclitaxel 15mg/kg                                                  Docetaxel 3.75mg/kg
                            Paclitaxel 100mg/kg                                                 Docetaxel 15mg/kg

*p<0.05                                                           Sawada N, et al. Clin Cancer Res 1998;4:1013–19
     Exploring the potential of Xeloda       ®



         as a combination partner

Ongoing phase I/II trials are evaluating Xeloda as
a combination partner for several agents, including
 Docetaxel

 Paclitaxel

 Vinorelbine

 Epirubicin/docetaxel (TEX)
 Epirubicin/cyclophosphamide (CEX)
Activity of docetaxel in anthracycline-
          pretreated patients

 Docetaxel is regarded as one of the most
  effective treatments for anthracycline-
  pretreated breast cancer
  – response rates of 29–54%
  – median TTP of approximately 4–7 months
  – median overall survival of approximately
    11 months

             Bonneterre J, et al. Proc Am Soc Clin Oncol 1997;16 (Abstract 564)
                                Nabholtz JM, et al. J Clin Oncol 1999;17:1413–24
                               Sjöström J, et al. Eur J Cancer 1999;35:1194–200
  Single-agent, first-line chemotherapy
         in MBC: response rates


Drug                            Overall response rate (%)
Docetaxel (75–100mg/m )2
                                              48–68
Paclitaxel (175–250mg/m )  2
                                              29–63
Vinorelbine                                   30–41
Gemcitabine                                   18–40
Doxorubicin                                   43–54




                               Trudeau ME. Semin Oncol 1999;3(Suppl. 8):21–6
          Xeloda plus docetaxel:
                   ®



          phase I study summary


 Two dose regimens were shown to be feasible
 – 75mg/m docetaxel + 1,250mg/m Xeloda
           2                                2



   twice daily
 – 100mg/m docetaxel + 825mg/m Xeloda
               2                        2



   twice daily
 No evidence of a pharmacokinetic interaction
 between docetaxel and Xeloda

                           Pronk L, et al. Br J Cancer 2000;83:22–9
        Xeloda plus docetaxel:
                     ®



         phase III study design

                                                             2
                               Xeloda 1,250mg/m
                               twice daily, days 1–14
 Randomization                 docetaxel 75mg/m , day 1      2


(3-weekly cycles)
                                                                 2
                               Docetaxel 100mg/m , day 1

 Patients responding or with stable disease after
  6 weeks of treatment continued until disease
  progression or unacceptable toxicity


             O’Shaughnessy J, et al. Breast Can Res Treat 2000;64 (Abstract 381)
                 Xeloda plus docetaxel:
                        ®



                    study objectives
             Primary
             – time to disease progression*
             Secondary
             – objective response rate
             – overall survival
             – safety profile
             – quality of life (EORTC QLQ-C30
               and QLQ-BR23)
             – medical care utilization
*or death
              Xeloda plus docetaxel:
                     ®



              overall tumor response

                          Xeloda/
                         docetaxel   Docetaxel
                          (n=255)     (n=256)
PR + CR (%)                 42          30       p=0.006
 95% CI                   35– 48      24– 36
Stable disease (%)          38          44
 95% CI                   32– 44      38– 51
                                  Xeloda plus docetaxel :
                                               ®



                                   duration of response
                        1.0
                                                                           Median (months)
                                                          Xeloda/docetaxel       7.2
                        0.8
Estimated probability




                                                          Docetaxel              6.9


                        0.6


                        0.4


                        0.2

                                        6.9   7.2
                         0
                              0     5               10         15          20         25
                                                    Time (months)
                                     Xeloda plus docetaxel:
                                                   ®



                                  time to disease progression
                        1.0

                                                             Xeloda/docetaxel
                        0.8
Estimated probability




                                                             Docetaxel

                        0.6                                                Hazard ratio = 0.643

                                                                                 Log-rank
                        0.4                                                      p=0.0001


                        0.2

                                   4.2       6.1
                         0
                              0          5             10        15         20           25
                                                       Time (months)
                                  Xeloda plus docetaxel:
                                         ®



                                      overall survival
                        1.0
                                                                      Median (CI)
                                                   Xeloda/docetaxel 13.7 (12.3–16.1)
                        0.8
Estimated probability




                                                   Docetaxel        11.1 (9.8–12.4)

                                                                   Hazard ratio = 0.753
                        0.6
                                                                      (0.603–0.940)

                        0.4                                             Log-rank
                                                                        p=0.0119

                        0.2

                                       11.1       13.7
                         0
                              0   5     10         15         20      25         30
                                              Time (months)
                      ®
 Xeloda plus docetaxel: most common treatment-
    related clinical adverse events (all grades)
                 70                      Xeloda/docetaxel (n=251)
                 60                      Docetaxel (n=255)
                 50
  Patients (%)




                 40
                 30
                 20
                 10
                 0




HFS = hand-foot syndrome; NF = neutropenic fever
                           ®
     Xeloda plus docetaxel: most common (>5%)
         grade 3/4 treatment-related toxicities
                      30       Xeloda/docetaxel (n=251)   Grade 3
                                                          Grade 4
                      25              Docetaxel (n=255)   Grade 3
                                                          Grade 4
       Patients (%)




                      20

                      15

                      10

                      5

                      0



*Grade 4 not applicable
                                   ®
     Xeloda plus docetaxel: grade 3/4
treatment-related adverse events over time

                     100
                                                                Xeloda/docetaxel
                      80
Adverse events (%)




                                                                Docetaxel

                      60


                      40


                      20


                       0
                           0   6       12   18    24     30     36     42    48    54
                                                 Time (weeks)
                 ®
    Xeloda plus docetaxel: most common grade
           3/4* laboratory abnormalities
                                                       Xeloda/
                                                     docetaxel (%) Docetaxel (%)
                                                       (n=251)       (n=255)
Hematology
 Hemoglobin (<8.0g/dL)                                         9.6      5.9
 Neutrophils (0.5–1.0 x 109/L)                                19.4     10.2
 Neutrophils (<0.5 x 109/L)                                   44.0     62.0
 Platelets (<50 x 109/L)                                       2.8      2.8
Chemistry
 ASAT (SGOT) (>5.0 x ULN)                                      2.8      3.5
 Alkaline phosphatase (>5.0 x ULN)                             0.8      1.8
 Total bilirubin (>1.5–3 x ULN)                                6.8      1.6
 Total bilirubin (>3 x ULN)                                    2.0      1.6

*NCIC common toxicity criteria; ULN = upper limit of normal
           Xeloda plus docetaxel:
                    ®



             summary of safety
 Treatment with Xeloda plus docetaxel compared
  with docetaxel alone leads to
  – fewer grade 4 adverse events (25% vs 30% with
    docetaxel)
  – more gastrointestinal side effects and
    hand-foot syndrome
  – less myalgia, arthralgia and grade 4
    neutropenia with associated complications
  – dose reduction in combination arm in 65% of
    patients compared to 36% with monotherapy
          Xeloda plus docetaxel:
                   ®



         summary of safety (cont’d)


 Similar incidence of treatment-related
  hospitalizations with the combination versus
  docetaxel alone (96 vs 91, respectively)

 Quality of life (measured using the EORTC
  QLQ-C30 global health status) showed a trend
  in favor of the combination arm
          Xeloda plus docetaxel:
                   ®



               conclusions
 The addition of oral Xeloda to docetaxel leads to
  – superior response rates (42% vs 30%)
  – superior progression-free survival (36% risk
    reduction)
  – superior overall survival with a minimum
    follow-up of 15 months (23% risk reduction)
 Manageable safety profile

 Xeloda plus docetaxel is the first cytotoxic
  combination to improve survival over docetaxel
  alone in anthracycline-pretreated patients
    Ongoing Xeloda combination trials
                         ®




Additional trials are investigating Xeloda plus
 Weekly paclitaxel/docetaxel
 Vinorelbine (three studies exploring different
    schedules)
   Docetaxel/epirubicin in untreated advanced breast
    cancer
   Cyclophosphamide/epirubicin as neo-adjuvant
    therapy (EORTC)
   Idarubicin
                           all-oral regimens
   Cyclophosphamide

								
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