Docstoc

HIGHLIGTHS IN LUNG CANCER.ppt

Document Sample
HIGHLIGTHS IN LUNG CANCER.ppt Powered By Docstoc
					HIGHLIGTHS IN LUNG
     CANCER
   G. Giaccone, MD PhD
  National Cancer Institute
      Bethesda, USA
                  NSCLC

•   Treatment of early disease
•   Treatment of advanced disease
•   Patient selection for EGFR TKIs
•   Angiogenesis inhibition
            Early NSCLC

• Adjuvant chemotherapy becoming
  standard for radically resected NSCLC
• Cisplatin-based (cisplatin and a vinca
  alkaloid)
Pre-operative chemotherapy in patients with
resectable non-small cell lung cancer: First results of
the MRC LU22 / NVALT 2 / EORTC 08012 multi-
centre randomized trial


Presented by Marianne Nicolson
on behalf of

David Gilligan, Ian Smith, Harry Groen, Christian Manegold,
Jan van Meerbeeck, Penelope Hopwood, Matthew Nankivell,
Cheryl Pugh, Richard Stephens and all the collaborators
Trial design

                                                     • Untreated NSCLC
              NSCLC Stage I, II, III                 • Any sex, age>18
                                                     • No distant
                                                       metastases
                                                     • Fit for
                            3 x cisplatin-based        chemotherapy
                          chemotherapy followed        and surgery
    Surgery
                                                     • WHO PS 0-2
                                     by
                                  surgery

          Clinician’s choice of chemotherapy regimen on a
          patient-by-patient basis, BEFORE randomisation

                  Mitomycin, ifosfamide, cisplatin (MIC)
                  Mitomycin, vinblastine, cisplatin (MVP)
                       Vinorelbine, cisplatin (NP)
Sample Size



  • To detect an absolute survival improvement of
    15% (from 40% with surgery alone, to 55% with
    neo-adjuvant chemotherapy) (5% significance
    level, 90% power)

  • Requires 233 events

  • Target 450 patients over 3 years


  • First patient entered July 1997
 Progression Free Survival
1.00




                                                                                              S     CT-S
                                                                     Events                   152   147
                                                             Log-rank p-value = 0.7415
0.75




                                                                     2-year PFS               52%   53%
0.50




                                            Events        Total
                                     S      152           261
0.25




                                     CT-S   147           258
                                                                                     HR 0.96
                                                                                     95% CI 0.77, 1.21
0.00




       At risk:
                                                                                     p= 0.74
          S       261   179          129             91                 48               31

       CT-S 258         183          125             89                 49               24


                  0     1              2           3                    4                5
                              Years from randomisation
       Overall Survival
1.00




                                                                                               S     CT-S
                                                                     Events
                                                              Log-rank p-value = 0.8600        122   122
0.75




                                                                     5-year OS                 45%   44%
0.50




                                               Events     Total
                                        S      122        261
0.25




                                        CT-S   122        258
                                                                                     HR 1.02
                                                                                     95% CI 0.80, 1.31
0.00




          At risk:
                                                                                     p= 0.86
             S       261   214          167             114              65               39

          CT-S 258         213          160             113              64               31


                     0     1              2           3                  4                5
                                 Years from randomisation
Summary


 In this trial, neo-adjuvant chemotherapy:
           Was feasible and acceptable (75% received 3 cycles)
           Gave good response rates (45% CR/PR)
           Caused down-staging in ~ 20%

And did not adversely affect:

           Quality of life
           Type of surgery
           Post-op complications
           Complete resection rates
           Planned timing of surgery (data not shown)
           Post-op nights in hospital (data not shown)
Summary



  However in this trial:

  There was no evidence that neo-adjuvant
  chemotherapy had an effect on:

           Progression-free survival

           Overall survival




  How does this trial add to the available evidence?
Updated systematic review

                     Number of patients
 Trial               CT + S       S                Hazard Ratio            HR (95% CI)

  Dautzenberg 1990      13          13                                     1.03   [0.37,   2.93]
  Roth 1994             28          32                                     0.89   [0.42,   1.88]
  Rosell 1994           30          30                                     0.63   [0.32,   1.24]
  Depierre 2002       179         176                                      0.83   [0.64,   1.07]
  JCOG9209 2003         31          31                                     0.75   [0.43,   1.30]
  Sorensen 2005         44          46                                     0.89   [0.49,   1.63]
  SWOG9900 2005        168         167                                     0.84   [0.60,   1.18]
  Current trial       258         261                                      1.02 [0.80, 1.31]

  Total               751         756                                      0.88 [0.76, 1.01]

                                         0.1 0.2   0.5 1    2     5   10
                                          Favours CT+S Favours S




 Test for heterogeneity: Chi² = 3.04, df = 7 (P = 0.88), I² = 0%
 Test for overall effect: Z = 1.78 (P = 0.07)
    Locally advanced NSCLC

• Concomitant chemo-radiotherapy
 becoming standard also in Europe
   Role of consolidation docetaxel (SWOG)?
• Timing and choice of drugs still not settled
Phase III trial of cisplatin plus etoposide plus concurrent
chest radiation with or without consolidation docetaxel in
  patients with inoperable stage III non-small cell lung
                           cancer:
              HOG LUN 01-24/USO 02-033



           Nasser Hanna, Marcus Neubauer, Rafat Ansari,
          Ramaswamy Govindan, Daniel Bruetman, William
            Fisher, Naveed Chowhan, Sreenivasa Nattam,
             Constantin Yiannoutsos, Lawrence Einhorn
                SWOG 9504
           Gandara et al JCO 2003;21:2004-10

            Concurrent Chemoradiation
       PE: Cisplatin 50 mg/m2 IV d 1, 8, 29, 36
           Etoposide 50 mg/m2 IV d 1-5, 29-33
       RT: 45 Gy (1.8 Gy/fraction)
           16 Gy boost (2 Gy/fraction)




         Consolidation Docetaxel X 3 cycles



Median Survival Time 26 months
          HOG LUN 01-24/USO 02-033
                                       ChemoRT
                           Cisplatin 50 mg/m2 IV d 1,8,29,36
                          Etoposide 50 mg/m2 IV d 1-5 & 29-33
                           Concurrent RT 59.4 Gy (1.8 Gy/fr)



    Stratification Variables:
            PS 0-1 vs 2
            IIIA vs IIIB             Randomize
         CR vs. non-CR




Docetaxel 75 mg/m2 q 3 wk  3                           Observation
Grade 3/4 Hematological Toxicities
 Toxicity              PE/XRT   Docetaxel

 Neutropenia           32.0%    24.7%

 Febrile neutropenia   9.9%     10.9%

 Anemia                5.9%      1.3%

 Thrombocytopenia      10.8%     0.0%
  Grade 3/4 Non-Hematological Toxicities

  Toxicity            PE/XRT         Docetaxel       OBS       *p-value
  Esophagitis         17.2%          -------------   -------   -----------
  Infections           8.9%          11.0%           0.0%       0.003
  Pneumonitis         ------------    9.6%**         1.4%      <0.001
  Rx-related death     1.5%           5.5%           0.0%       0.058

*p-value corresponds to comparison of Docetaxel vs. Observation groups
**Includes 1 patient death
        Hospitalizations and Transfusions
  Variable           PE/XRT Docetaxel         OBS      p-value*

  Hospitalized       36.5%      28.8%         8.1%     <0.001
  RBC transfused     10.3%      5.5%          1.4%      0.209

*p-value corresponds to comparison of Docetaxel vs. Observation groups
                                         Progression-Free Survival (ITT)
                                          Randomized Patients (n=147)
                                                              Observation: Median: 12.9 months (8.3-17.1)
Percent of patient without progression

                                         100%
                                                              Docetaxel:      Median: 12.3 months (9.4-16.9)
                                                              P-value: 0.941
                                         80%



                                         60%



                                         40%



                                         20%
                                                    Observation
                                                    Docetaxel consolidation
                                          0%
                                                0      12              24           36          48             60

                                                                 Months since registration
                                      Overall Survival (ITT)
                                   Randomized Patients (n=147)
                                100%                           Observation: Median: 24.1 months (18.0-34.2)
                                                                            3 year survival rate: 27.6%
                                                               Docetaxel:   Median: 21.5 months (17.-34.8)
Percent of patients surviving




                                75%                                         3 year survival rate: 27.2%
                                                               P-value: 0.940

                                50%




                                25%

                                           Observation
                                           Docetaxel Consolidation
                                 0%
                                       0    10          20           30         40      50         60

                                                       Months since registration
             Advanced disease
• Platinum-based chemotherapy for PS 0-1
   Single agent for worse PS
• Chemotherapy has reached a plateau
   Several doublets shown to have similar efficacy in first-
    line treatment
• Brain metastases respond to chemotherapy
• Duration of therapy:
   4 cycles, may be longer if continuous response and
    therapy well tolerated (max 6 cycles)
• Introduction of targeted agents
   Bevacizumab with carboplatin-paclitaxel approved by
    FDA
         Phase III Trial of Bevacizumab
     in Non-Squamous NSCLC: ECOG 4599
                                 N=855 (eligible)
                                                 (PC)
                                                                   No crossover to
                                         Paclitaxel 200 mg/m2      Bevacizumab
                                         Carboplatin AUC = 6       permitted
                                        (q 3 weeks) x 6 cycles
Eligibility:
• Non-squamous NSCLC
• No Hx of hemoptysis
                                               (PCB)
• No CNS metastases
                                           PC x 6 cycles
Stratification Variables:                         +
•RT vs no RT                                Bevacizumab
•Stage IIIB or IV vs recurrent         (15mg/kg q 3 wks) to PD
•Wt loss <5% vs >5%
•Measurable vs non-measurable
                                                  Sandler, et al. NEJM, Dec 2006
      Response Rate:

        N = 769 patients
      (Measurable Disease)

PC        PCB                P value
15%       35%                <0.001
                                      E4599: Overall Survival
                            1.0
     Proportion surviving

                                                                              12 mo 24 mo
                                                                    PC        44.4% 15.4%
                            0.8
                                                                    BV/PC 51.0% 22.0%
                            0.6                                     HR: 0.80, P = 0.003


                            0.4                             Medians: 10.3, 12.3

                            0.2


                            0.0
                                  0     6     12       18      24        30    36     42      48
Patients at risk
                            PC 444      318   190     104      36        9      5         1   0

     BV/PC 434                          340   216     127      54        25     8         3   0
                                                    Survival (months)
Progression-Free Survival



       Medians: 4.5, 6.2 months
  Grade 3 – 5 Non-Hematologic Toxicity
                     CP         BvCP        P
                  (N = 441)   (N = 427)   Value
Hemorrhage           1.1         4.7      0.001
 Hemoptysis         0.5%        2.1%
 CNS                0.2%        0.7%
 GI                 0.5%        1.2%
 Other†             0.2%        1.2%
Hypertension        0.7%        7.7%      <0.001
Proteinuria          ---        3.1%      <0.001
Venous thromb       3.2%        5.6%
Arterial thromb     1.6%        2.8%
      Treatment Related Deaths
                                                  PC            PCB
                                                  427           420
  Hemorrhage
      Hemoptysis                                    0            5
      GI bleed                                      1            2
  Neutropenic fever                                 1            5
  Cerebrovascular                                   0            2
  Pulmonary Embolus                                 0            1

  Total                                             2            15




* Two deaths due to cardiac ischemia not felt to be treatment related
AVAiL: first-line phase III trial of
Avastin plus chemotherapy in NSCLC
                                                                        No Avastin
                                     CG  6 + placebo              PD   after progression

        Previously
    untreated, stage
                                 CG  6 + Avastin 7.5mg/kg         PD
  IIIB, IV or recurrent
                                      every 3 weeks
     non-squamous
          NSCLC
         (n=1,050)              CG  6 + Avastin 15mg/kg
                                                                   PD
                                     every 3 weeks

 Cisplatin 80mg/m2 i.v. every 3 weeks; gemcitabine i.v. 1,250mg/m2 on days 1 and 8
  of each 3-week cycle
 Primary endpoint: progression-free survival
 Secondary endpoints: overall survival, time to treatment failure, response rate
 Stratification factors: disease stage, ECOG PS, region, gender


CG = cisplatin/gemcitabine
                          Progression-free survival: primary analysis
                          (intent-to-treat) of bevacizumab 7.5mg/kg
                                     versus pooled placebo
                          1.0
                                                                                       Placebo    Bev 7.5
                                                                                        + CG       + CG
     Possibility of PFS




                          0.8
                                                                                       n = 347    n = 345
                                                                         HR             ---          0.75
                          0.6                                       [95% CI]                     [0.62, 0.91]
                                                                        p-value         ---       0.0026

                          0.4
                                    Placebo + CG
                                    Bev 7.5mg/kg + CG
                          0.2


                          0.0
                                0     3            6            9                 12             15             18
No. at risk                                             Time (months)
 Placebo + CG 347                    228          122          36                 12              3             0
  Bv 7.5 + CG 345                    251          150          52                 18              3             0
                          Progression-free survival: primary analysis (intent-to-treat) of
                                  bevacizumab 15mg/kg versus pooled placebo
                            1.0

                                                                                        Placebo     Bev 15
     Possibility of PFS




                            0.8
                                                                                         + CG        + CG
                                                                                        n = 347     n = 351
                            0.6                                               HR         ---          0.82
                                                                         [95% CI]                 [0.68, 0.98]
                            0.4                                              p-value     ---       0.0301
                                        Placebo + CG
                            0.2         Bev 15mg/kg + CG



                            0.0
                                  0       3             6            9             12             15             18
                                                             Time (months)
No. at risk
Placebo + CG                      347    228           122          36             12              3             0
 Bev 15 + CG                      351    238           148          46             16              5             0
     Safety: Severe (Gr 3) adverse events
               of special interest
                                                Bevacizumab   Bevacizumab
                                      Placebo    7.5mg/kg +    15mg/kg +
                                       + CG          CG           CG
                                      n = 327      n = 330      n = 329
Bleeding                                2%          4%            4%

Hypertension                            2%          6%            9%

Proteinuria                             –          0.3%           1%

Gastrointestinal perforation           0.6%         –            0.3%

Ischaemic events (includes arterial     5%          2%            3%
thromboembolic events)

Venous thromboembolic events            6%          7%            7%
     Safety: Pulmonary haemorrhage events
                                              Placebo           Bevacizumab        Bevacizumab
                                               + CG            7.5mg/kg + CG      15mg/kg + CG
                                              n = 327             n = 330            n = 329

Pulmonary haemorrhage
(all grades)                                    17 (4.9%)            23 (7.0%)     32 (9.7%)

Pulmonary haemorrhage
(Gr  3)                                          2 (0.6%)             5 (1.5%)     3 (0.9%)

Fatal pulmonary
haemorrhage                                       1 (0.3%)             4 (1.2%)     3 (0.9%)

Of note:
• 38% of patients had central lesions
    –   4/10 patients with severe pulmonary haemorrhage had central lesions
•   9% of patients had therapeutic anticoagulation
    –   but none of them had a severe pulmonary haemorrhage
 Treatment of advanced NSCLC
   after first-line chemotherapy
• Docetaxel registered in second-line, based
  on an increase of survival of 2 m over BSC
• Pemetrexed registered based on an
  equivalence study with docetaxel, less
  toxic
• Erlotinib registered in second- and third-
  line based on increase in survival of 2 m
  over BSC
    BR.21: erlotinib phase III study in
      advanced, relapsed NSCLC
                 stage IIIB/IV, relapsed NSCLC; PS 0–3;
                    failed one or two prior regimens
                            2:1 randomization




       Daily oral erlotinib                      Daily oral placebo
           150mg/day

• n=731 patients
•   Primary objective: overall survival
•   Secondary objectives: response rate, stable-disease rate, duration of
    response, time to disease progression, and QoL

Shepherd et al. NEJM 2005
                                                Overall Survival
                                                   All Patients
                                 1.00


                                                                    HR = 0.72, p = 0.001
                                 0.75                      Erlotinib Median = 6.7 mo (n=488)
                                                           Placebo Median = 4.7 mo (n=243)
Survival Distribution Function




                                 0.50

                                                                                1-yr Survival = 31%
                                                                                1-yr Survival = 21%
                                 0.25




                                 0.00
                                        0   5     10               15           20        25          30
                                                       Survival Time (Months)
Tumor Response in Selected
        Subsets
Subset               RR     p-value
Females             14.4%
                            0.0065
Males                6.0%


Adenocarcinoma      13.9%
Squamous Cell Ca     3.8%   0.0020
Other Histologies    4.5%


Never smoked        24.7%
Current/Ex-smoker    3.9%   <0.0001
    Patient selection for EGFR
               TKIs
• Positive selection
   Patient characteristics
     • never-smoking, female, adenocarcinoma, East Asian
   EGFR mutations
   EGFR FISH
   EGFR overexpression

• Negative selection
   K-ras mutations
   Resistant EGFR mutations (e.g. T790M)
   C-Met amplification
Predictivity of response to EGFR
TKIs – prospective studies
   Mutations : 75 -100%
   FISH + : ~ 50 - 70%
   IHC + : ?
   FISH + / IHC + : ?
   Never smokers : 40 – 50%
 EGFR mutations and response
to EGFR-TKI in advanced NSCLC

• Mutation frequency approximately 12% in
  Caucasians
• More frequent in never-smokers, women,
  adenocarcinoma, BAC and Asians
• Rare or absent in other tumor types
• Presence of a mutation predicts response to
  small molecules EGFR inhibitors
• Presence of EGFR mutations confers distint
  survival advantage (20 m vs 8 m) upon treatment
  with EGFR TKIs
• Early event in lung carcinogenesis
      Phase II study of Iressa monotherapy
  for NSCLC patients with EGFR gene mutation


                                           N=28
                                                               Primary
NSCLC                              IRESSA 250 mg/day           endpoint
  N=120                      +          until PD
                                                               Response
Stage IIIB/IV    EGFR                                           (>50%?)
PS 0-2          mutation
20-75 yr                                                       RR%=75%
                Exon 18,
 Less than 1
 prior
                 19, 21       -     Study off
 chemo                              Standard chemotherapy



   Okamoto I et al. Poster discussion, Monday June 5, 2-6 PM
                  WJTOG3405
                                              Stratification by
                                              •Adjuvant CTx Yes or No
                                              •Institution
                                          R   •DFS<1y or >1y
                                          a
                                          n     Gefitinib
                                          d
                                    Yes   o     250mg/day
                 EGFR mutation            m
  NSCLC                                   i
                 Exon 19 deletion
                                          z      CDDP+DOC
  Postop rec     L858R (exon 21)          e
                                    No        80mg/sqm+60mg/sqm, q3w
   Resected specimen                          X 3-6 courses
                                    Off study
Primary endpoint: Progression free survival
Sample size: Mutation +ve 200 cases
Activated on March 20, 2006
      SLCG Phase III Trial in EGFR-mutated NSCLC




                     R
                     A
Eligibility:         N
                         Erlotinib 150 mg/day PO
• No prior Rx        D                             Cross-
• Stage IIIB or IV   O                             over at
                                                     PD
• Mutated EGFR       M   Platinum-based Chemo
• ECOG PS 0-2        I
                     Z
                     E
     CALGB 30406 Randomized Phase II
          Study: Trial Design
          Chemotherapy naive patients with stage III/IV
 adenocarcinoma or BAC who are never or “light” former smokers*
                        ECOG PS 0-1



                                                          Daily oral erlotinib +
          Daily oral erlotinib
                                                     6 cycles carboplatin/paclitaxel



          Daily oral erlotinib                                Daily oral erlotinib

    • Patients can continue therapy until evidence of disease progression or
      toxicity ; present accrual : 20
*never smoker:  100 cigarettes/lifetime; “light” former smoker: quit  1 year ago and  10 pack years
Comparison of MALDI-TOF MS test with clinical
predictors of EGFR TKI sensitivity

 Covariate                       Hazard Ratio [95% CI] P-value
 Sex (female)                    1.08 [0.84 – 1.38]             0.53

 Histology                       1.156 [0.94 – 1.44]            0.17
 (adenocarcinoma vs. others)
 Smoking Hx (never)              0.60 [0.44 – 0.81]             0.0006

 MALDI-TOF MS test (good)        0.59 [0.49 – 0.73]             <0.0001




 Cox regression analysis for overall survival using the covariates sex,
 smoking status, histology, and MALDI-ToF MS test result ( n = 206
 NSCLC patients treated with gefitinib).

   Taguchi F et al, JNCI 99, 838, 2007
                                   2. Independent Blinded Validation
                               (n = 67 Italian patients treated with gefitinib)

                                                          Survival
                           P-diff = 0.15                                                             P-diff = 0.10
                                                     Good                           100
                     100                             Bad                                                                   Good
                                                     Undefined                                                             Bad




                                                                 Percent survival
                                                                                    75
  Percent survival




                     75
                                       p = 0.007                                                       p = 0.0097
                     50                                                             50


                     25                                                             25


                      0                                                              0
                           0     250   500   750   1000   1250                            0    250   500   750      1000   1250
                                         Days
                               Survival (days)                                                         (days)
                                                                                              Survival Days

HR 0.49 [0.22-0.79]                                                                 HR 0.52 [0.25-0.83]
MS: 73 vs. 192 days (bad v. good)                                                   MS: 92 vs. 207 days (bad v. good)

  (8 undefined)                                                  (1 undefined)
  Concordance of Results between Colorado
      and Vanderbilt (n = 206 spectra)
                                                    Colorado
P-diff = 0.15                                Good      Bad     Undefined


                  Vanderbilt
                                   Good      117        0         12
89% concordance
                                   Bad        0        57          2

                                 Undefined    8         0         10

                                                    Colorado
P-diff = 0.10                                Good      Bad     Undefined
                    Vanderbilt




97% concordance                    Good       139       1          0

                                    Bad        2        59         0

                                 Undefined     3        0          2
Effect of MALDI-ToF MS test in
        smokers ( n = 159)
        Hazard Ratio: 0.40 [0.18-0.44]
        Logrank p < 0.0001




         Survival (days)
 Effect of MALDI-ToF MS test in
patients with squamous histology
             (n=37)




               Hazard Ratio: 0.23 [0.06-0.35]
                      Logrank p < 0.0001
                               Proposed Trial Schema




                                                              Erlotinib*
IIIB/IV
NSCLC                            Favor
                  Serum
No Prior          MALDI
Tx                                                            Chemo*
                 analysis
PS 0/1
                                   Unfav                         Standard of
                                                                 care




PrImary Endpoint: PFS (< 4 m with erlotinib    Designed with 95% power at the one-
would be considered inferior)                  sided significance level of 0.05 to reject
Estimated sample size: 665 pts                 the null hypothesis of inferiority of
Projected # with favorable profile: 466        erlotinib (estimating a hazard ratio
Non-inferiority design                         (chemo/erlotinib) < 0.80) if the true
                                               hazard ratio (chemo/erlotinib) is 1.1 or
                                               more.
* + Bevacizumab in Bev eligible patients
Acquired EGFR mutations confer resistance to
    gefitinib, but not all EGFR inhibitors




             Kobayashi et al. NEJM, 352, 786-792, 2005
       EGFR Inhibitors:
  Active in EGFR Resistance
    TKI              TKI         Antibody
(reversible)   (irreversible)
  Gefitinib       EKB-569        Cetuximab
 Erlotinib       CI-1033        Panitumumab
 Lapatinib       HKI-272         EMD 7200
  ZD6474         HKI-357
               CL-387.785
                BIBW 2992
Activity of irreversible EGFR inhibitors in
        H1975 cells (L858R/T790M)



                                                   Cellular proliferation assay




                                                   Autophosphorylation assay




       Carter et al. PNAS 102, 11011-11016, 2005
       EKB-569 irreversible EGFR inhibitor
 Phase I in Japan
 2 minor responses seen in gefitinib resistant patients
    (del19; L858R)




Yoshimura et al. Lung
Cancer 51, 363-368, 2006
          HKI-272 Phase I Trial:
           Preliminary Efficacy
                  Breast      NSCLC
                  N = 29      N = 16
Evaluable           23             12
Confirmed PR        7              0
SD ≥ 24 wk          1              5




Wong: ASCO 2006
      HKI-272 in Advanced NSCLC:
            A Phase 2 study

                                         Yes   A: EGFR mutation (n=46)
                  Yes   EGFR mutation?
Prior EGFR TKI?                          No
                                                B: EGFR wt (n=46)
                  No
                         C: Adenocarcinoma
                           <10 pack-years
                        (mutant EGFR ~30%)
                               (n=46)
      cMET is amplified in
     gefitinib resistant cells




Engelman et al. Science 2007
MET siRNA inhibits pEGFR and ErbB3
 signaling in gefitinib resistant cells




Engelman et al. Science 2007
Non-inferiority for survival study design
                                    Gefitinib
                                   250 mg/day                      Post-
 Randomization                                                    study        Overall
                                                                treatment      survival
                             Docetaxel 60 mg/m2
                               every 3 weeks

Stratification factors                                        Change to opposite
• Sex, PS (0-1 vs 2), tumor type                              treatment only at
  (adenocarcinoma vs others)                                  patient request
• Study sites
Main inclusion criteria
• Advanced/metastatic (Stage IIIB/IV) or recurrent NSCLC
• One or two chemotherapy regimens (at least one containing platinum)
• Aged  20 years
• PS 0-2
  PS, performance status; NSCLC, non-small-cell lung cancer      Niho et al. ASCO 2007
                         Overall survival (ITT)
                                                                                           Gefitinib Docetaxel
Probability 1.00                                             N                                  245            244
of survival
                                                             Events                             156            150

                                                                 HR (95.24% CI) = 1.12 (0.89, 1.40) p=0.330
            0.75

                                                             Median (months)                    11.5           14.0
                                                             1-year survival (%)                48             54
            0.50                                             Supportive Cox analysis with covariates
                                                                      HR (95% CI) = 1.01 (0.80, 1.27) p=0.914


            0.25




           0.00
                   0 2   4   6    8   10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months
        At Risk :
        Gefitinib 245 226 197 169 148 127 98 77    63   47       35    29   25   18   9     5    4     1   0
        Docetaxel 244 233 214 189 173 140 105 87   69   44       35    25   18   14   10    7    6     3   0
                   Progression-free survival
                   (evaluable for response)
Probability 1.00                                                                Gefitinib    Docetaxel
of
progression                                          N                                200        187
-free                                                Events                           180        158
survival    0.75
                                                              HR (95% CI) = 0.90 (0.72, 1.12) p=0.335
                                                     Median (months)                  2.0         2.0
                                                     6 months PFS (%)                 22          20
            0.50
                                                     Supportive Cox analysis with covariates
                                                              HR (95% CI) = 0.81 (0.65, 1.02) p=0.077

            0.25




            0.00
                   0   2    4    6    8    10   12       14     16   18    20    22    24   26 Months
      At Risk :
      Gefitinib 200    95   55   39   26   20   13       9       5    4     4     2     1    0
      Docetaxel 187    86   45   25   13    3   1        0       0    0     0     0     0    0

       Consistent results were observed in a sensitivity analysis for the ITT population
       PFS, Progression-free survival
      Objective tumor response (RECIST)
                                                                  Gefitinib (n=200)
Patients 50                                                       Docetaxel (n=187)
     (%)
                                                                  p=0.735
        40


        30                     p=0.009


        20
                                                           34.0         33.2

        10              22.5
                                    12.8
         0
                   Objective response rate              Disease control rate
                          (CR+PR)                     (CR+PR+SD > 12 weeks)

              The vertical bars on the plot represent the 95% CIs
              p-values are derived from logistic regression analysis
                      Quality of life and
                    symptom improvement
Patients 50                                                           Gefitinib
     (%)                                                              Docetaxel
         40
                     p=0.023                                        p=0.562
                                            p=0.002
         30


         20
                    23.4                                         22.7
                                          20.5                            20.4
         10
                           13.9
                                                      8.7
           0
               n=   185     173           185         173         225      211
                     FACT-L                     TOI          Symptom by LCS
  •p-values are derived from logistic regression analysis
  •FACT-L, Functional Assessment of Cancer Therapy – Lung; TOI, Trial Outcome Index; LCS, Lung
  Cancer Subscale
  •FACT-L: Japanese version 4-A including 2 extra Japan-specific questions in subscale of
  social/family well-being
                   Conclusions
   Non-inferiority in overall survival between gefitinib
    and docetaxel was not achieved (HR 1.12; 95.24%
    CI 0.89, 1.40) according to the predefined criteria
    (upper CI for HR <1.25)
   No statistical evidence of a difference in overall
    survival (p=0.330) between gefitinib and docetaxel
                     SCLC

• State of the art
• Highlights:
   PCI in extensive disease
   Role of topoisomerase I inhibitors in first-line
    treatment of extensive disease
       SCLC : state of the art
• Limited Disease
   Concomitant early radiotherapy for limited disease
    SCLC
   Cisplatin-etoposide best tested
   PCI for complete responders
   Surgery rarely used
• Extensive Disease
   Platinum-based chemotherapy
   Second-line therapy with topotecan
    A Randomized Phase III Trial of
      Irinotecan plus Carboplatin
         versus Etoposide plus
      Carboplatin in Patients With
     Extensive Disease Small Cell
       Lung Cancer – IRIS Study

     A Hermes, B Bergman, R Bremnes, L Ek, S Fluge,
 C Sederholm, S Sundstrøm, L Thaning, J Vilsvik, U Aasebø
  and S Sörenson for the Norwegian Lung Cancer Group
(NLCG) and the Swedish Lung Cancer Study Group (SLCSG)
   Introduction




Noda et al. NEJM 2000
            Introduction




Hanna et al. 2006          ASCO 2007, Chicago, IL
                     Study Design
                          carboplatin (Chatelut AUC4)
                          and irinotecan (175 mg/m²)
                          iv day 1 q21 (IC, n=105)
    ED SCLC
   Stratification:
•PS 0-1,2, 3-4
•age 18-70 or >70
•institution
                          carboplatin (Chatelut AUC4)
                          and etoposide (120 mg/m²)
                          orally d 1-5 q21 (EC, n=104)
          Statistical Considerations


the  study hypothesis was that median survival would be
prolonged from 0.75 to 1.1 years by use of irinotecan instead
of etoposide
with one-sided test, the study population was calculated to
200 patients with a power of 80% and a significance level of
0.05




                                                   ASCO 2007, Chicago, IL
                       Results

                       IC    EC
Median survival        8.5   7.1   p=0.02, log rank
(months)                                test
Complete response      18     7        p=0.02
(number of patients)
1-year survival        34%   24%




                                              ASCO 2007, Chicago, IL
                     Overall Survival
                1
                                   IC
                                   EC
                ,8
                           HR 1.41 (95% CI 1.06;1.87)
Cum. Survival



                ,6


                ,4


                ,2


                0
                     0    12                  24        36
                               Time, months




                                                         ASCO 2007, Chicago, IL
                    Toxicity

Toxicity CTC 3-4°      IC         EC       p-value
                     (n=104     (n=102)
Leucopenia           34 (33%)   35 (34%)     NS
Anemia                5 (5%)     8 (8%)      NS
Thrombocytopenia     11 (11%)   27 (26%)    0.05
Diarrhea             11 (11%)    1 (1%)    0.003




                                               ASCO 2007, Chicago, IL
               Conclusions III

   Treatment with irinotecan and carboplatin yields
    a significantly longer median survival than
    etoposide and carboplatin without
    compromising life quality

   Our study supports the use of carboplatin plus
    irinotecan as standard chemotherapy regimen
    in Extensive Disease Small Cell Lung Cancer



                                         ASCO 2007, Chicago, IL

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:69
posted:5/16/2012
language:English
pages:74
wangnuanzg wangnuanzg http://
About