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					Can clinical characteristics be
 used to select patients for
      Tarceva therapy?
           Romàn Pérez-Soler
        Montefiore Medical Center,
    Albert Einstein College of Medicine,
           Bronx, New York, USA
                    Introduction
 In BR.21, response rates for patients treated with
  Tarceva varied according to clinical and demographic
  characteristics

 Do these differences in response rate translate to the
  more important endpoint of patient survival?

 Importantly, clinical and demographic factors may
  have some prognostic value

  – outcomes in some subgroups may be better,
    regardless of the treatment administered
           Myth

Tarceva is only effective in
   female patients with
     adenocarcinoma
  Tumour response rates in BR.21 study
             (Tarceva arm)
                              Response rate
                                  (%)                      p value
Gender
   Male (n=281)                       6.0
                                                            0.006
   Female (n=146)                    14.4
Histology
   Adenocarcinoma (n=209)            13.9
                                                            <0.001
   Other (n=218)                      4.1

 In multiple logistic regression analyses, histology, but not
  gender, was significantly associated with response to
  Tarceva
                              Shepherd FA, et al. N Engl J Med 2005;353:123–32
      Case study: female, never smoker
            with adenocarcinoma
 78-year-old female, Caucasian, non-smoker; PS 2

 Stage T3N2M0 (IIIA)
  – poorly-differentiated adenocarcinoma
 First-line chemotherapy
  – 3 cycles of vinorelbine/carboplatin: no remission
 Unsuitable for second-line chemotherapy due to poor
  general physical condition
 Treatment with Tarceva 150mg/day initiated

Case kindly provided by:
Dr Wolfgang Schütte and Dr Sylke Nagel
Städtisches Krankenhaus Martha-Maria Halle Dölau, Germany
 Case study: outcome on Tarceva
Start of Tarceva   After 2 months’ Tarceva
      PS 2                 CR; PS 0




                                             Response
                                             maintained
                                             for 21
                                             months
                       BR.21: overall survival in females with
                          adenocarcinoma (second-line)
                                                                      Median OS
                       1.00                                            (months)
                                                 Tarceva (n=50)            11.8
Survival probability




                       0.75                      Placebo (n=26)            3.9

                                                                 HR=0.412
                       0.50                                      (95% CI: 0.234–0.724)


                                                                             RR=19.0%
                       0.25



                         0
                              0   6          12                 18                24
                                      Survival (months)
                                       OSI Pharmaceuticals and F. Hoffmann-La Roche; data on file
  Response alone is not a good indicator
      of survival benefit in NSCLC

 In BR.21, Tarceva produced a survival benefit in
  patients who did not obtain an objective response


              Tarceva           Placebo
              (n=367)           (n=204)

             Median OS        Median OS
                                                     HR            p value
              (months)         (months)
SD/PD           8.25                6.8              0.82           0.037




                        OSI Pharmaceuticals and F. Hoffmann-La Roche; data on file
                                        BR.21: overall survival according to
                                                       gender
                                                    Male: HR=0.8; p=0.01*
                                                    Female: HR=0.8; p=0.13*

                                              *Log-rank test                   0.5               HR              1

                                 1.00                                                     1.00
                                                          Female                                                      Male
Survival distribution function




                                                          RR=14.4%                                                   RR=6.0%

                                 0.75                                                     0.75

                                                        Tarceva (n=173)                                      Tarceva (n=315)
                                 0.50                                                     0.50


                                 0.25       Placebo (n=83)                                0.25

                                                                                                      Placebo (n=160)
                                   0                                                        0
                                        0       5        10     15        20         25          0       5      10     15   20   25   30
                                                       Time (months)                                             Time (months)

                                                                                     Shepherd FA, et al. N Engl J Med 2005;353:123–32
                                        BR.21: overall survival according to
                                                 tumour histology
      Adenocarcinoma: HR=0.7; p=0.008*
      Squamous-cell carcinoma: HR=0.67; p=0.0007*

      *Log-rank test                                                              0.5            HR                   1

                                 1.00               Adenocarcinoma                  1.00        Squamous-cell carcinoma
Survival distribution function




                                                       RR=13.9%                                             RR=3.8%

                                 0.75                                               0.75


                                 0.50                    Tarceva (n=246)            0.50
                                                                                                       Tarceva (n=144)

                                 0.25                                               0.25

                                            Placebo (n=119)                                Placebo (n=78)
                                   0                                                    0
                                        0       5      10    15    20    25      30       0      5        10     15     20      25
                                                       Time (months)                                   Time (months)
                                                            Shepherd FA, et al. N Engl J Med 2005;353:123–32; Tarceva Summary of
                                                                               Product Characteristics, F. Hoffmann-La Roche, 2007
              Myth

Tarceva is only effective in Asian
            patients
  Tumour response rates in BR.21 study
             (Tarceva arm)


                            RR (%)                      p value
Ethnicity
   Asian (n=53)               18.9
                                                          0.02
   Non-Asian (n=374)           7.5


 In multiple logistic regression analyses, ethnicity was
  not significantly associated with response to Tarceva


                            Shepherd FA, et al. N Engl J Med 2005;353:123–32
                                                        BR.21: overall survival
                                                        according to ethnicity
                                                        Non-Asian: HR=0.8
                                                        Asian: HR=0.6

                                                                        0.2        0.4           0.6        0.8    1       1.2
                                                                                                       HR

                                 1.00                                               1.00
                                                      Non-Asian                                                    Asian
Survival distribution function




                                                        RR=7.5%                                                   RR=18.9%

                                 0.75                                               0.75
                                                                                                                        Tarceva (n=63)


                                 0.50               Tarceva (n=425)                 0.50

                                                                                                       Placebo (n=28)
                                 0.25                                               0.25

                                            Placebo (n=215)
                                   0                                                     0
                                        0       5     10   15     20   25     30             0            105      15       20
                                                    Time (months)                                   Time (months)
                                                                              Shepherd FA, et al. N Engl J Med 2005;353:123–32
Smoking history
   Tumour response rates in BR.21 study
              (Tarceva arm)
                                                    RR (%)             p value
Smoking history
    Current/former smoker (n=311)                      3.9
    Never smoked* (n=93)                               24.7           <0.001
    Unknown (n=23)                                     13.0
*Less than 100 cigarettes in lifetime


 In multiple logistic regression analyses, smoking status
   was significantly associated with response to Tarceva


                                        Shepherd FA, et al. N Engl J Med 2005;353:123–32
      BR.21: overall survival according to
               smoking status


 Never smokers: HR 0.4; p<0.001*
 Current/ex-smokers: HR 0.9; p=0.14*

 *Log-rank test
                                       0.2    0.4      0.6        0.8    1      1.2
                                                             HR




 Benefit cannot be ruled out in current/ex-smokers




                                       Shepherd FA, et al. N Engl J Med 2005;353:123–32
       Pharmacokinetics of Tarceva in smokers
       versus non-smokers (healthy volunteers)
 Single dose of Tarceva 150mg
                                                                        AUC0–∞ non-smoker (18,726ng•h/mL)
                      1,000                                             AUC0–∞ smoker (6,718ng•h/mL)
                                       Non-smokers (n=16)
                                                                        p<0.0001
Mean ± SEM Tarceva




                                       Smokers (n=16)
 in pllasma (ng/mL)




                                                                        Exposure in smokers versus
                       750
                                                                        non-smokers = 35.9%
                                                                        Cmax non-smoker (1,056ng/mL)
                       500                                              Cmax smoker (689ng/mL)
                                                                        p=0.310
                       250                                              Maximum exposure in smokers
                                                                        versus non-smokers = 65.2%

                         0
                              0   12    24    36    48      60     72
                                         Time (hours)

 Likely explanation: cigarette smoke induces CYP enzymes that are
             responsible for metabolism of Tarceva

                                          Hamilton M, et al. Proc Am Assoc Cancer Res 2005;46:1451 (Abs. 6165)
                                                               Hamilton M, et al. Clin Cancer Res 2006;12:2166–71
           Smoking history: caveats

 In BR.21, smoking history data were collected
  retrospectively

 Cut-off for never-smoker status is arbitrary and
  requires validation

 Outcomes of current smokers should be considered
  separately from those of former smokers

 Dose escalation may be required in current smokers
  – trials are ongoing to investigate this possibility
                                 BR.21: overall survival in male current/former
                                   smokers with squamous-cell carcinoma
                                 1.00                                                  Median OS
                                                                                        (months)
Survival distribution function




                                                            Tarceva (n=100)                 5.5
                                 0.75
                                                            Placebo (n=57)                  3.4

                                 0.50
                                                                        HR=0.66
                                                                        (95% CI: 0.47– 0.92)
                                 0.25

                                                                                        RR=6.8%
                                   0
                                        0   2.5   5.0   7.5  10.0 12.5      15.0     17.5    20.0
                                                         Time (months)
                                                                Clark GM, et al. Clin Lung Cancer 2006;7:389–94
            Myth

Tarceva should be reserved for
    patients with poor PS
                                              BR.21: overall survival
                                 1.00                                                Tarceva      Placebo
                                                                                     (n=488)      (n=243)

                                                       Median survival (months)         6.7          4.7
Survival distribution function




                                 0.75                  1-year survival (%)              31           21
                                                       HR=0.73, P<0.001

                                                       PS 0-1                           8.3          6.8
                                 0.50                  PS 2-3                           3.6          3.2



                                 0.25
                                            Tarceva
                                            Placebo
                                   0
                                        0     5       10         15       20           25         30
                                                      Survival time (months)

                                                        OSI Pharmaceuticals and F. Hoffmann-La Roche, data on file
                    Conclusions

 In BR.21, response rates to Tarceva were higher in
  certain patient subgroups

 However, almost all patient subgroups derived a
  survival benefit from Tarceva
  – including those who have low response rate

 There is no scientific rationale for excluding patients
  to receive Tarceva based on patient demographics or
  clinical factors
                 Final comments

 Certain groups may derive more benefit from Tarceva
  than others
  – potentially defined by tumour sensitivity, or
    differences in drug pharmacokinetics/metabolism

 Tumour molecular analyses may be more precise than
  gross clinical characteristics in identifying which
  patients benefit most

				
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