ASCO 2009 Highlights in Gastrointestinal Malignancies

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					         ASCO 2009
Highlights in Gastrointestinal
        Malignancies


          Axel Grothey
      Professor of Oncology
      Mayo Clinic Rochester
Adjuvant Therapy of Colon Cancer

•   LBA 04   NSABP C-08        Wolmark
•   4000     Oncotype QUASAR   Kerr
•   4001     PETACC-3          Tejpar
•   4002     PETACC-3          Roth
•   4010     Elderly pts       McCleary
 History of adjuvant therapy of colon cancer
                                                               • 5-FU/LV superior to 5-
• 5-FU/lev superior                                                 FU/lev
  to surgery alone                                             • 6- and 12-month
                                                                    treatment cycles
                                                                    equivalent             • LV5FU2 and
                                                                                            monthly bolus
                                                               • Lev unnecessary            equivalent
                            • 5-FU/LV superior
                                to surgery alone               • High-dose and low-
                                                                    dose LV equivalent
                                                               • Monthly and weekly
                                                                    treatment equivalent



 1990                              1994                              1998                   2002
Moertel et al. Ann Intern Med. 1995;122:321.
Francini et al. Gastroenterol. 1994;106:899.
Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. Abstract
O’Connell et al. J Clin Oncol. 1998;16:295.
Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982.
Andre et al. Proc Am Soc Clin Oncol. 2002. Abstract 529.
Beyond 5-FU in the adjuvant setting
Completed studies:
• Oxaliplatin (MOSAIC, NSABP C-07)
• Irinotecan (CALGB 89803, ACCORD-2, PETACC-3)
• Capecitabine (X-ACT)
• Bevacizumab (NSABP C-08)
Ongoing studies:
• CAPOX (XELOXA)
• Bevacizumab (AVANT, E5202)
• Cetuximab in KRAS wt CC (N0147, PETACC-8)
                        MOSAIC: Study Design

                   n=2246
                                                        (n=1123)
Enrollment:
Oct 1998–Jan 2001 (146 centres;
                                                                          FOLFOX4
                                                                          (LV5FU2 + oxaliplatin 85 mg/m²)
20 countries)
• Completely resected colon cancer
• Stage II, 40%; Stage III, 60%                       R
• Age 18–75 years
• KPS ≥60
                                                                          LV5FU2
                                                         (n=1123)
• No prior chemotherapy


Primary end-point: disease-free survival
Secondary end-points: safety, overall survival
LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv
over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m 2 iv over 2 hours on Day 1
      MOSAIC: Disease-free Survival -
              Final Update
                            5-year DFS %
                                                     HR
Data cut-off: June 2006
                           FOLFOX4     LV5FU2      [95% CI]     p-value
ITT                          73.3          67.4      0.80       0.003
                                                  [0.68–0.93]
Stage III                    66.4          58.9      0.78       0.005
                                    Δ7.5          [0.65–0.93]
Stage II                     83.7          79.9      0.84       0.258
                                                  [0.62–1.14]
      High-risk stage II     82.1          74.9      0.74         —
                 n=576              Δ7.2          [0.52–1.06]
      Low-risk stage II      86.3          89.1      1.22         —
                n=323                             [0.66–2.26]
―High-risk‖ Stage II Colon Cancer

• Clinico-pathological parameters (MOSAIC)
   • T4 tumors
   • Obstruction/perforation
   • Lymphatic or vascular invasion
   • Undifferentiated histology
   • Less than 10 (12) Ln examined
• Molecular parameters
   • LOH 18q
   • MSS
   • Other?
     MOSAIC: OS: Stage II and Stage III
                   1.0
                                                                 p=0.996
                   0.9

                   0.8                                           p=0.029                 0.1%
                   0.7
                                                                                         4.4%
     Probability




                   0.6

                   0.5

                   0.4

                   0.3                    HR [95% CI]              FOLFOX4 stage II
                                                                   LV5FU2 stage II
                   0.2       Stage II    1.00 [0.71–1.42]
                                                                   FOLFOX4 stage III
                             Stage III   0.80 [0.66–0.98]
                   0.1                                             LV5FU2 stage III

                    0
                         0    6   12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Data cut-off: January 2007                     Overall survival (months)              Andre JCO 2009
                             Long-term Safety

                             60                                 Evaluable
 Peripheral                                Grade 1
                                                                patients n=811
                                           Grade 2
 Sensory                     50
                                           Grade 3              Grade 0     84.3%
 Neuropathy                  40
                                                                Grade 1     12.0%
                             30                                 Grade 2     2.8%

                             20                                 Grade 3     0.7%

                             10

                              0
                                  During     6       1-year   2-year   3-year   4-year
                                   Tx      months



Data cut-off: January 2007                                                Andre JCO 2009
        Treatment of Colorectal Cancer in Elderly
              Patients: ACCENT Database
    • Median age of diagnosis of CRC in the United States is 71 years
    • Previous analyses have shown that elderly patients (≥70 years)
       with CRC benefit from treatment with IV fluoropyrimidines in
       both the adjuvant and metastatic settings
    • This analysis reviewed the efficacy of newer therapies in older
       patients
    • Patient population was derived the ACCENT database
        • 10,499 pts <70 years, 2,170 pts ≥70 years
        • 6 phase III trials compared IV FU to combinations with
            irinotecan, oxaliplatin, or oral FU (capecitabine and
            UFT/LV) in stage II/III colon cancer
          • Endpoints were overall survival (OS), disease free survival
            (DFS), and time to recurrence (TTR)


Folprecht. J Clin Oncol. 2008;26:1443-1451.
McCleary. ASCO 2009. Abstract 4010.
 Elderly Patients: Efficacy of FOLFOX
    Pooled Analysis C-07/MOSAIC
                           Endpoint*                        Deaths within
                         HR (95% CI)                           6 mos
Age            Experimental vs Control IV 5-FU/LV            Exp vs Ctrl
                 DFS           OS           TTP               % (p-value)

<70               0.77            0.81          0.76         0.81 v 0.81
n = 3,977     (0.68,0.86)     (0.71,0.93)   (0.67,0.86)         (p=1.0)

≥ 70              1.04            1.19          0.92         2.57 v 1.37
n = 703       (0.80,1.35)     (0.90,1.57)   (0.69,1.23)        (p=0.25)
Interaction
of age by
                  0.016         0.037           0.21
treatment
 p-value
  * Values < 1 favor experimental arm       McCleary, ASCO 2009, Abstract 4010
      Treatment of Colorectal Cancer in Elderly
            Patients: ACCENT Database

    • Limitations of study
        • ACCENT does not track:
           • Toxicity
           • Dose intensity
           • Co-morbidity
    • These data do not contradict earlier
      studies showing the benefit of adjuvant
      therapy with 5-FU/LV vs. surgery alone in
      elderly patients

McCleary. ASCO 2009. Abstract 4010.
Forest Plots of Hazard Ratios – DFS


      Oral




Oxaliplatin




Irinotecan



                                                          Age < 70
   Overall
                                                          Age >= 70



          0.2   0.4   0.6   0.8   1   1.2   1.4   1.6   1.8   2       2.2
                                  Hazard Ratio

                                                              McCleary, N. ASCO 2009
2009 Update of MOSAIC Trial




              No benefit in DFS with
              FOLFOX vs 5-FU/LV for
              patients > 65 yrs !



                              Andre JCO 2009
                         X-ACT: Cape vs Mayo - 5-year DFS
                            (median follow-up 6.8 years)
                         1.0                                                5-year
                                                                         n DFS (%)
 Estimated probability




                         0.8                                Capecitabine     1,004          60.8
                                                            5-FU/LV            983          56.7

                         0.6

                         0.4
                                                             HR=0.88 (95% CI: 0.77–1.01)
                         0.2                                       NI margin 1.20


                          0
                               0   6   12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102
                                                         Months
Test of non-inferiority p<0.0001                                                      ITT population
Test of superiority p=0.0682                                     Twelves C, et al. Eur J Cancer Suppl
ITT (intent-to-treat) population; NI = non-inferiority                       2007;5:1 (Abstract 1LB)
    XELOXA: phase III trial of CAPOX
        in the adjuvant setting
                     R
                     A   n=944                    CAPOX
                     N           Capecitabine 1,000mg/m2 b.i.d. days 1–15
                     D               Oxaliplatin 130mg/m2 day 1 q3w
      Chemo/         O
                     M
radiotherapy-naïve
                     I                 duration of therapy: 24 weeks
     stage III
                     S
   colon cancer      A
                     T                       Bolus 5-FU/LV
                     I                 Mayo Clinic or Roswell Park
                     O   n=942
  Trial open
                     N
 4/03 – 10/04
 Final data at       • Primary endpoint: disease-free survival
 ESMO 2009
                                     Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23
Adjuvant Trials in Colon Cancer with
   Cetuximab (KRAS wild-type!)
    PETACC 8
                       FOLFOX4 6m
    Stage III colon
   cancer (N=2400)
                      FOLFOX4 6m +
                      Cetuximab 6m


 Intergroup N0147
                      mFOLFOX6 6m
    Stage III colon
   cancer (N=3600)
                      mFOLFOX6 6m +
                       Cetuximab 6m
Adjuvant Trials in Colon Cancer with
           Bevacizumab
  AVANT                FOLFOX4 6m

Stage II/III colon     XELOX 6m +
cancer (N=3450)      Bevacizumab 12m

                      FOLFOX4 6m +
                     Bevacizumab 12m

NSABP C-08
                      mFOLFOX6 6m
Stage II/III colon
cancer (N=2710)                        Reported at
  25% Stage II                         ASCO2009
                     mFOLFOX6 6m +
                     Bevacizumab 12m
               NSABP C-08


                       mFOLFOX6 q2wk X 6 mo

R
                         BEV* q2wk X 1 yr




    N=2710 pts                    *5mg/kg
    25% stage II        Wolmark et al ASCO 2009
          NSABP C-08
           Accrual


                mFF6 mFF6+B
Randomized      1356           1354
Lost / Ineval    18                16
 Analysis       1338           1334

                       Wolmark et al ASCO 2009
            NSABP C-08
       Patient Characteristics

                  mFF6 mFF6+B
< 60 yr            58.3        58.2
Male               49.8        49.9
Stage II (0)       24.9        24.9
Stage III (1-3)    45.4        45.5
Stage III (4+)     29.7        29.6
                       Wolmark et al ASCO 2009
   NSABP C-08 Grade 3+ Toxicities
   Increased with Bevacizumab (%)

               mFF6   mFF6+B              P

Hypertension   1.8        12         <0.0001
    Pain       6.3      11.1         <0.0001
 Proteinuria   0.8       2.7          <0.001
Wound Comp     0.3       1.7          <0.001

 Median Duration of Bev = 11.5 months
                      Allegra et al JCO May 4, 2009
                                        Wolmark et al ASCO 2009

                   NSABP C-08 – DFS
100
80
60
40




                       Ev 3yDFS
            mFF6+B     291 77.4                 HR 0.89
20




            mFF6       312 75.5
                                                P  0.15
0




      0.0    0.5     1.0   1.5    2.0     2.5      3.0      3.5
                                       Wolmark et al ASCO 2009

                   NSABP C-08 – DFS
100
90
80




                      Ev 3yDFS
70




            mFF6+B    291 77.4                 HR 0.89
            mFF6      312 75.5
                                               P  0.15
60




      0.0    0.5     1.0   1.5   2.0     2.5      3.0      3.5
                        Wolmark et al ASCO 2009
  NSABP C-08 HR over Time

                         0.05       0.08
                 0.02
         0.004

0.0004
              DFS at 1 Yr                    Event-free at 1 Yr
100
90




                Time-Treatment Interaction
                        P = 0.001
80




                     Ev 1yDFS                   Ev
            mFF6+B    75  94.3 ∆ 3.6
            mFF6     122 90.7
                                           mFF6+B    216     HR 1.07
70




                                           mFF6      190
                                                             P 0.48
                           HR 0.60
                           P 0.0004                          NSABP C-08
60




      0.0            0.5         1.0 1.0       1.5     2.0     2.5           3.0
                                                             Wolmark et al ASCO 2009
                                         Wolmark et al ASCO 2009

                     NSABP C-08 – DFS
100
90
80




                   Scans?


                        Ev 3yDFS
70




            mFF6+B      291 77.4                 HR 0.89
            mFF6        312 75.5
                                                 P  0.15
60




      0.0    0.5       1.0   1.5   2.0     2.5      3.0      3.5
                                                                                      Wolmark et al ASCO 2009
100
                  DFS Stage II                                           DFS Stage III




                                                       100
80




                                                       80
60




                                                       60
                   Ev 3yDFS                                                      Ev 3yDFS
                        87.4 Δ 2.7                                               251 74.2 Δ 1.8

                                                       40
            mFF6+B 40                                              mFF6+B
40




             mFF6 47 84.7                                          mFF6          265 72.4

                  HR 0.82                                          HR 0.90
                                                       20
20




                  P 0.35                                           P 0.25                   NSABP C-08
                                                       0
0




      0.0   0.5    1.0   1.5   2.0   2.5   3.0   3.5         0.0   0.5    1.0   1.5   2.0    2.5    3.0    3.5
                NSABP C-08
       Status at 36 mo Med Follow-up
                     mFF6   mFF6+B           P
 Recurrence (N)      248      227           NS
    Death (N)        146      132           NS
 Second Ca (N)        46      47            NS
2yS Post Rec (%)      41      37            NS
Rec Mult Sites (%)    18      18            NS
   Sites of Rec       –        –            NS

                             Wolmark et al ASCO 2009
  Stage II and Stage III Colon
Cancers Are Different Diseases!
              ACCENT Database:
    Time from Recurrence to Death by Stage
          100
                                                    Stage II (N=1153)
               80                                   Stage III (N=4550)


                                                    Total   (N=5703)
     % Alive




               60

                                           Log Rank P-Value =
               40                               <0.0001

               20


               0
                    0   1    2   3       4      5      6      7      8
                                     Time (Years)
O’Connell, et al. JCO 2008
              PETACC 3: Stage-Specific
                 Molecular Markers
    • PETACC 3: 5-FU/LV + irinotecan vs 5-FU/LV in stage II/III CC
          • Translational study in 1404 pts with suitable biopsy material

                                        Stage II         Stage III
Molecular Marker (%)                                                  P Value
                                       (n = 420)         (n = 984)
p53 overexpression                         30                37          .01
SMAD4 loss                                 9                 13          .02
Thymidylate synthase                       43                29        .0001
Telomerase                                 40                48          .06
MSI-H                                      22                12        .0001
18q LoH                                    63                70          .04
KRAS                                       36                37          .67
BRAF                                       8                  8          .90
Roth AD, et al. GI Cancers Symposium 2009. Abstract 288; ASCO 2009.
   Defective MMR - Colon cancer

• Characterized by presence of MSI & loss of
 MLH1, MSH2, MSH6 or PMS2 expression
• ~15% of Sporadic CC, >90% loss of MLH1
• Clinical Correlations: Right sided, Female,
 Early stage, Better prognosis
• Tumors: Poorly differentiated, Signet-ring-
 cell, Lymphocytic infiltration, near diploid
• dMMR cells resistant to 5-FU1,2
                           1Carethers,   1999; 2Arnold 2003
             Defective MMR vs MSI

• Microsatellites (MS) = small DNA segments that consist of
  repetitive nucleotides of generally 100-200 base pairs
    • prone to replication errors which can change their length
• DNA mismatch repair (MMR) proteins consist of hMLH1, hMSH2,
  hMSH6, hPMS2, hMSH3, and hMLH3
• MMR proteins can be deficient due to
    • mutations of genes (e.g. HNPCC/Lynch) – 5% of CRC
    • methylation of promoter region – 15-20% of sporadic CRC
• Test method for dMMR phenptype:
    • Analysis of MS lengths using 5 specific DNA markers
        • MSI-H: MSI in at least 2 of 5 markers, MSI-L: MSI in only 1
         marker, MSS: no instability detected
    • IHC for MMR proteins: MLH1, MSH2 most important (>90%)
           Pooled data (N=1027)

Trial       Treatment    N     % Stage II   % dMMR

784852      5FU/LEV     117      30%           14%
INT 0035    5FU/LEV     215      50%           18%
874651       5FU/LV     66       19%           12%
GIVIO        5FU/LV     183      52%           16%
FFCD         5FU/LV     154      66%           19%
NCIC         5FU/LV     292      61%           15%
Total                   1027     52%           16%

                                            Sargent ASCO 2008
 DFS/OS in Stage II dMMR Patients
             (N=102)
         5-yr DFS                N = 47               5-yr OS
                                 N = 55




Untreated 87%   HR: 2.80 (0.98-8.97)      Untreated   93%   HR: 3.15 (1.07-9.29)
Treated 72%           p=0.05              Treated     75%         p=0.03




                                                            Sargent ASCO 2008
             PETACC 3: Stage-Specific
                Prognostic Values
                         Stage II (n=420)            Stage III (n=984)
Marker
                           HR             P           HR                P
MSI (Hi vs Stable)         0.3          0.004         0.7             0.06
18qLOH                     2.1          0.03           1              0.91
SMAD4 (any loss)           1.4          0.21          1.6           <0.0001
hTERT (High)               1.4          0.32          1.5             0.01
p53 (High)                 1.0          0.98          1.3             0.03
TS (High)                  0.5          0.03          0.7             0.02
KRAS (Mutated)             1.1          0.84          1.0             0.72
BRAF(Mutated)              0.9          0.90          1.2             0.28

P values from the Wald test in a univariate Cox regression
HR = hazard ratio
                                                             Roth AD, et al. ASCO 2009.
PETACC 3: Multivariate Analysis
           Stage II

    Markers      HR [95% CI]             P value

T4 v. T3       2.58 [1.56 - 4.28]       0.00024

MSI-H v. MSS   0.28 [0.10 - 0.72]        0.0089

18qLOH         1.37 [0.67 - 2.77]          0.38




                                    Roth AD, et al. ASCO 2009.
                                            5-Year Relative Survival
                                                By AJCC Stage
                               100     93
  Percentage of Patients (%)




                                90             85                 83                    p < .001
                                80                      72
                                70                                         64
                                60
                                50                                                 44
                                40
                                30
                                20
                                                                                               8
                                10
                                 0
                                     Stage I  Stage    Stage     Stage    Stage    Stage Stage IV
                                               IIA      IIB       IIIA     IIIB     IIIC
                                     (T1–2N0) (T3N0)    (T4N0)   (T1–2N1) (T3–4N1) (TanyN2) (M1)
O’Connell et al., 2004.
 PETACC 3: Detailed Analysis of MSI

                                    Frequency Analysis
                      Stage II           Stage III             Stage IV

MSI-H                   22%               12%                   3.5% *

                     (86/395)           (104/859)



• MSI as a suppressor of lymph node and
  distant metastasis?

*Br J Cancer. 2009 100(2):266-73.

                                             Tejpar, et al. ASCO 2009. (abstract 4001)
                 Results: Prognostic impact of MSI

HR MSI H                     5FU                  5FU/iri                 Both arms
(95% CI)                   (n= 625)              (n= 608)

Stage II        RFS   0.228 (0.05-0.955)    0.296 (0.091-0.968)       0.265(0.107- 0.661)
(n= 391)                   P= 0.043              P=0.044                  P= 0.0044


                OS     0.18 (0.02-1.34)      0.143 (0.02-1.06)        0.159( 0.039- 0.659)
                          P= 0.095               P=0.057                    P=0.011


Stage III       RFS   0.596 (0.344-1.03)    0.815 (0.478-1.39)         0.693 (0.473-1.02)
(n= 842)                   P=0.064               P=0.45                     P= 0.06


                OS    0.515 (0.261-1.02)    0.939 (0.515-1.71)        0.699 (0.446- 1.09 )
                           P=0.055               P=0.84                     P= 0.12

Both stages     RFS   0.501 (0.300-0.837)   0.642 (0.394-1.05)       0.569 ( 0.400 -0.811)
* P are stage              P=0.0083              P=0.076                  P=0.0018
corrected
                OS    0.437(0.229-0.833)    0.676 (0.380-1.20)        0.548 (0.357-0.842)
                           P= 0.012              P= 0.18                   P=0.006



                                                   Tejpar, et al. ASCO 2009. (abstract 4001)
    Development and Validation of an 18-Gene RT-
             PCR Colon Cancer Assay

                                        Colon Cancer Technical Feasibility



      761 genes                Development Studies              Development Studies
                                  Surgery Alone                  Surgery + 5FU/LV
                                  NSABP C-01/C-02 (n=270)           NSABP C-04 (n=308)
      375 genes                         CCF (n = 765)               NSABP C-06 (n=508)




      18 genes                        Selection of Final Gene List & Algorithm


                                          Validation of Analytical Methods

                               Clinical Validation Study – Stage II Colon Cancer
  ASCO 2009
                                                        QUASAR (n>1200)
                                        Test prognostic, but not predictive!
Kerr et al., ASCO 2009, abstr. 4000
                           QUASAR: OS in patients with ―no clear
                           indication for chemo‖ (mostly stage II)
                                  5-FU/LV vs surgery alone
                     100
                                                                         Observation (n=1622)
                                                                         Chemotherapy (n=1617)
                      80
     % of Patients




                      60
                                   5-yr OS difference: 2.9%
                      40


                      20       P = .02
                               5-year OS, Observation = 77.4% vs Chemotherapy = 80.3%
                               Relative risk = 0.83 (95% CI, 0.71-0.97)
                      0
                           0      1      2    3     4     5     6    7      8     9     10
                                                        Years
QUASAR group, Lancet 2007
        QUASAR: Evaluable Stage II Colon Cancer
                      Patients
                          Parent QUASAR study
                                 n=3,239


                      Patients with collected blocks
                              n=2,197 (68%)

                                                       707 cases stage III and
                                                            rectal cancer


                            Confirmed stage II
                              n=1,490 (69%)
                                                        54 excluded (3.6%):
                                                       29 synchronous tumors
                                                          8 insufficient tissue
                                                           7 identifier queries
                                                         6 RNA quality/quantity
                        Final evaluable population        4 ineligible histology

                                  n=1,436

Kerr et al., ASCO 2009, abstr. 4000
        QUASAR: Pre-Specified Primary Endpoint:
                  Recurrence Risk
                                      RECURRENCE SCORE
       Is there a significant         Calculated from Tumor
  relationship between the risk         Gene Expression
    of recurrence and the pre-        STROMAL    CELL CYCLE
       specified continuous             FAP         Ki-67
                                       INHBA       C-MYC
  Recurrence Score in stage II          BGN        MYBL2

      colon cancer patients
                                            GADD45B
 randomized to surgery alone?
                                           REFERENCE
                                             ATP5E
                                              GPX1
                                              PGK1
                                              UBB
                                             VDAC2


Kerr et al., ASCO 2009, abstr. 4000
       QUASAR Results: Recurrence Risk in
   Pre-specified Recurrence Risk Groups (n=711)
                                                               1.0



Recurrence     Range   Proportion of                           0.8
Risk Group     of RS   patients

Low             <30       43.7%




                                       Proportion Event Free
                                                               0.6
Intermediate   30-40      30.7%

High            ≥41       25.6%                                0.4

                                                                                               Kaplan-Meier Estimates (95% CI)
                                                                                                of Recurrence Risk at 3 years
                                                                         Recurrence Risk Group
                                                               0.2
                                                                                         Low        12%       ( 9% -16%)
                                                                                  Intermediate
Comparison of High vs. Low                                                                          18%       (13%-24%)
                                                                                          Hig       22%       (16%-29%)
 Recurrence Risk Groups                                        0.0                         h

using Cox Model: HR = 1.47                                           0       1             2              3                4     5
                                                                                                   Years
        (p=0.046)
                                                                                 Kerr et al., ASCO 2009, abstr. 4000
 QUASAR Results: Prediction of Differential
   5FU/LV Benefit for Treatment Score
• Continuous Treatment Score and Treatment Benefit
  with 5FU/LV
   – Treatment Score by Treatment Interaction for RFI:
     interaction p = 0.19

• Selected Secondary Analyses
   – Treatment Score by Treatment Interaction not
     significant when adjusted for prognostic covariates
   – Treatment Score by Treatment Interaction not
     significant for DFS (interaction p=0.12) or OS
     (interaction p=0.15)


                               Kerr et al., ASCO 2009, abstr. 4000
QUASAR RESULTS: Recurrence Score, T Stage, and MMR
Deficiency are Key Independent Predictors of Recurrence
                in Stage II Colon Cancer




                                      Multivariate Analysis
Kerr et al., ASCO 2009, abstr. 4000
QUASAR Results: Recurrence Score, T Stage, and
 MMR Deficiency are Key Independent Predictors
    of Recurrence in Stage II Colon Cancer
                                45%
Risk of recurrence at 3 years




                                40%                                                    T4 stage (13%)

                                35%
                                30%
                                25%                                                     T3 and MMR
                                                                                       proficient (76%)
                                20%
                                15%
                                10%                                                     T3 and MMR
                                                                                       deficient (11%)
                                5%
                                0%
                                      0   10     20    30    40     50     60     70
                                               Recurrence Score
                                                                  Kerr et al., ASCO 2009, abstr. 4000
      Decision Algorithm in Adjuvant Therapy
                                  Resected Colon Ca


                     Stage II                               Stage III


                    T4 and/or     yes
                                         High-Risk
                     <12 LNs
                          no                                                 *
              yes
 Low-Risk            dMMR                                  FOLFOX
                        no
                    Intermed.
                       Risk                     *         5-FU/LV or
No therapy!
                                                         Capecitabine
                    Oncotype
                        ?
                     Colon ?
                                *pts not considered candidates for oxaliplatin
  Neo-Adjuvant Therapy of Rectal
             Cancer


• 4007   ACCORD-2       Gerard
• 4008   STAR           Aschele
• 4014   AIO            Hofheinz
               Addition of Oxaliplatin
      to Fluoropyrimidine-based Neoadjuvant
               Radio-Chemotherapy
   • Locally advanced rectal cancer
       • High rates of distant metastases (30-35%)
       • Positive circumferential resection margin in 10-
            30% of ―resectable‖ tumors
   • Oxaliplatin
      • Improves the efficacy of FU-based
            chemotherapy
        •   Radiosensitizing properties in experimental
            models
        •   Promising activity with preoperative
            radiotherapy and fluorouracil

Aschele. ASCO 2009. Abstract CRA4008.
     Oxaliplatin in Neoadjuvant Radio-
     Chemotherapy for Rectal Cancer
                                                         Grade 3- Pathological
   Author       N         Chemo               RT
                                                         4 toxicity CR rate
                                           50.4 Gy in
              379    5-FU 225 mg/m2/d
                                          28 fractions     8%        16%
   Aschele
                     5-FU 225 mg/m2/d
   (STAR)                                 50.4 Gy in
              368    Oxaliplatin 60       28 fractions    24%        15%
                     mg/m2/w x 6
                      Capecitabine 800    45 Gy in 25
              295
                      mg/m2 bid           fractions       11%        14%
   Gerard            Capecitabine 800
                     mg/m2 bid 5 of 7 d   50 Gy in 25
 (ACCORD)     292
                                          fractions       25%        19%
                     Oxaliplatin 50
                     mg/m2/w


Aschele. ASCO 2009. Abstract CRA4008. Gerard. ASCO 2009; Abstract LBA4007.
      AIO Study – Rtx + Cape or 5-FU:
           Disease free survival
                          Preliminary data
                                             50.4 Gy +   N Pts
                                                          197
                                                          195




                    Log-rank:
                     p=0.303
                                      Median follow-up: 1.6 years



Hofheinz. ASCO 2009. Abstract 4014.
    Neoadjuvant Therapy of Rectal
        Cancer – ASCO 2009
• Capecitabine had activity similar to 5-FU
• Addition of oxaliplatin did not improve response
   • Increased toxicity
   • Oxaliplatin does not appear to be a
      radiosensitizer in these studies
• Implications for ongoing NSABP R-04?
    • Cape vs ci 5-FU +/- oxaliplatin plus Rtx
    • Primary EP: local disease control
    • Accrual: 1260/1600 pts
           Other GI Malignancies



•   4503     GemCis Biliary   Valle
•   4505     ESPAC-3          Neoptolemos
•   4506     LMWH in PC       Riess
•   4509     ToGA             Van Cutsem
    Trastuzumab plus Chemotherapy in
  Advanced HER2+ Gastric Cancer: ToGA
Rationale: A subpopulation of gastric cancers overexpress HER2

                                                           5-FU or Capecitabine
                                                         (investigator discretion)
                                                        + Cisplatin + Trastuzumab
Screen 3807                                                       (n=294)
                    HER2+ GC
GC patients
 for HER2
                     (n = 810,      R
                       22%)                                5-FU or Capecitabine
expression
                                  (n = 584)              (investigator discretion)
                                                                + Cisplatin
        Stratification by                                         (n=290)
        •Gastric vs GEJ
   •Advanced vs metastatic
     •5-FU vs capecitabine           5-FU 800 mg/m2/d infusional d1-5 q3w X 6
                                    Capecitabine 1000 mg/m2 bid d1-14 q3w X 6
                                            Cisplatin 80 mg/m2 q3w X 6
                                 Trastuzumab 6 mg/kg q3w to PD (8 mg/kg loading)
 Primary endpoint: OS
                                   Van Cutsem et al. J Clin Oncol 2009; 27(suppl):798s (LBA4509)
                                    Bang et al. J Clin Oncol 2009; 27(suppl): 215s (abstract 4556)
ToGA: Main patient selection criteria

Inclusion criteria
• Adenocarcinoma of stomach or GEJ
• Inoperable locally advanced and/or metastatic disease
• Measurable (RECIST), or non-measurable evaluable disease
• HER2-positive tumor (centrally assessed)
    – IHC 3+ and/or FISH+
• Adequate organ function and ECOG performance status ≤2
• Written informed consent
Exclusion criteria
• Previous adjuvant chemotherapy within 6 months
• Chemotherapy for advanced disease
• Congestive heart failure or baseline LVEF <50%
• Creatinine clearance <60 mL/min
IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LVEF, left ventricular ejection fraction

                                                                             Van Cutsem et al. ASCO 2009 (LBA4509)
      Patient demographics and baseline
                characteristics
      Characteristic                                F+C              F+C + trastuzumab
                                                   n=290                  n=294
      Sex, %
         Male / Female                             75 / 25                  77 / 23
      Age, median (range) years                 59.0 (21-82)             61.0 (23-83)
      Weight, median (range) kg                 60.3 (28-105)           61.5 (35-110)
      Region, n (%)
          Asia                                    166 (56)                 158 (53)
          C/S America                              26 (9)                   27 (9)
          Europe                                   95 (32)                 99 (33)
          Other                                     9 (3)                   14 (5)
      Type of GC (central assessment)
          Intestinal                                74.2a                    76.8b
          Diffuse                                    8.7a                    8.9b
          Mixed                                     17.1a                    14.3b
      Prior gastrectomy                             21.4                     24.1
Highest recruitment was from Korea, Japan, China and Russia
       F, fluoropyrimidine; C, cisplatin an=287; bn=293         Van Cutsem et al. ASCO 2009 (LBA4509)
        ToGA: Primary end point: OS

 Event 1.0                                                      Median
                                                          Events OS    HR               95% CI       p value
       0.9
       0.8                                FC + T           167       13.8      0.74 0.60, 0.91       0.0046
       0.7                                FC               182       11.1
       0.6
       0.5
       0.4
       0.3
       0.2
       0.1                   11.1             13.8
       0.0
             0   2   4   6   8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
                                                                                Time (months)

 No.         294 277 246 209 173 147 113 90    71    56    43   30   21   13   12   6   4   1    0
  at         290 266 223 185 143 117 90 64     47    32    24   16   14   7     6   5   0   0    0
 risk

T, trastuzumab                                                            Van Cutsem et al. ASCO 2009 (LBA4509)
ToGA: Secondary end point: PFS

Event      1.0                                                     Median
                                                             Events PFS HR                  95% CI       p value
           0.9
           0.8                                     FC + T     226         6.7      0.71 0.59, 0.85       0.0002
           0.7                                     FC         235         5.5
           0.6
           0.5
           0.4
           0.3
           0.2
           0.1           5.5       6.7
           0.0
                 0   2   4     6   8 10 12 14 16 18 20 22 24 26 28 30 32 34
                                                                                       Time (months)

  No.            294 258 201 141 95      60   41   28   21   13   9   8     6      6    6   4   2    0
 at risk         290 238 182 99 62       33   17    7    5    3   3   2     2      1    1   0   0    0


                                                                                Van Cutsem et al. ASCO 2009 (LBA4509)
 ToGA: Efficacy: OS by HER2 status

Subgroup                                                              N       Median OS       Hazard 95% CI
                                                                               (months)        ratio


All                                                                   584      11.1 vs 13.8    0.74   0.60, 0.91

        Pre-planned analysis
  IHC0/FISH+                                                          61       7.2 vs 10.6     0.92   0.48, 1.76
 IHC1+/FISH+                                                          70       10.2 vs 8.7     1.24   0.70, 2.20
 IHC2+/FISH+                                                          159      10.8 vs 12.3    0.75   0.51, 1.11
 IHC3+/FISH+                                                          256      12.3 vs 17.9    0.58   0.41, 0.81
  IHC3+/FISH-                                                         15       17.7 vs 17.5    0.83   0.20, 3.38

            Exploratory analysis
   IHC0 or 1+/FISH+                                                   131      8.7 vs 10.0     1.07   0.70, 1.62
 IHC2+/FISH+ or IHC3+                                                 446      11.8 vs 16.0    0.65   0.51, 0.83




                0.2        0.4   0.6       1        2   3   4 5
                Favors T               Risk ratio       Favors no T
                                                                            Van Cutsem et al. ASCO 2009 (LBA4509)
       ToGA: OS in IHC2+/FISH+ or
         IHC3+ (exploratory analysis)
Event 1.0                                                       Median
                                                          Events OS    HR             95% CI
      0.9
      0.8                                     FC + T       120      16.0      0.65 0.51, 0.83
      0.7                                     FC           136      11.8
      0.6
      0.5
      0.4
      0.3
      0.2
      0.1                     11.8                16.0
      0.0
            0   2   4   6   8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
                                                                         Time (months)

No.         228 218 196 170 142 122 100 84   65   51 39    28    20 12   11   5   4   1   0
 at         218 198 170 141 112 96 75 53     39   28 20    13    11 4    3    3   0   0   0
risk

                                                                    Van Cutsem et al. ASCO 2009 (LBA4509)
               ToGA: Efficacy Outcome
          Fluoropyrimidine
                             Fluoropyrimidine
            + Cisplatin +
                                + Cisplatin      HR [95% CI]          P Value
            Trastuzumab
                                 (n = 290)
              (n = 294)
OS           13.8 months       11.1 months      0.74 [0.60-0.91]        .0046
PFS          6.7 months         5.5 months      0.71 [0.59-0.85]        .0002
ORR             47%               34.5%                                 .0017
   CR            5%                2%                                   .0599
   PR           42%                32%                                  .0145

• Preplanned subgroup analysis indicated improved OS benefit with
  increasing HER2 expression by IHC

• Exploratory analysis of IHC2+/FISH+ and IHC3+ cohort demonstrated a
  4 month increase in OS with trastuzumab (HR [95% CI], 0.65 [0.51-0.83])

                                                  Van Cutsem et al. ASCO 2009 (LBA4509)
      ToGA: Select Grade 3/4 Toxicities*
                          Fluoropyrimidine +
                                               Fluoropyrimidine +
                              Cisplatin +
                                                    Cisplatin
                             Trastuzumab
                                                    (n = 290)
                               (n = 294)
Hematologic
      Neutropenia                27%                     30%
        Anemia                   12%                     10%
Nonhematologic
        Diarrhea                 9%                       4%
        Nausea                   7%                       7%
Asymptomatic LVEF drops
                                 6%                       1%
       (< 50%)


          *2 deaths due to cardiac events in each arm

                                               Van Cutsem et al. ASCO 2009 (LBA4509)
   Gemcitabine ± Cisplatin in Advanced Biliary
     Tract Cancer: Phase III UK ABC-02 Trial

    Eligibility criteria:                       Cisplatin 25 mg/m2
                                R
  •No prior systemic                        + Gemcitabine 1000 mg/m2
                                A
  therapy                                     d 1, 8 q21d for 8 cycles
                                N
  •Adequate biliary                                   (n=204)
                                D
  drainage
                                O
                                M
      Stratification by                     Gemcitabine 1000 mg/m2 d
                                I
  •Site of primary                           1, 8, 15 q28d for 6 cycles
                                Z
  •LA vs metastatic                                    (n=206)
                                E
  •Prior therapy
                             (n = 410)



• Primary endpoint: OS
• Secondary endpoints including: PFS, toxicity


                                                     Valle et al. ASCO 2009 (abstract 4503)
UK ABC-02 Trial: Select Grade 3/4 Adverse
                 Events
                           Gem + Cis          Gem
                            (n = 159)       (n = 165)
  Hematologic
       Neutropenia         36 (23%)         29 (18%)
       Leukopenia          24 (15%)         18 (11%)
  Nonhematologic
           Any             102 (64%)      108 (65.5%)
     Elevated Bilirubin     17 (11%)        21 (13%)
       Elevated ALT        15 (10%)         28 (18%)
      Elevated AST          12 (8%)         17 (11%)
          Fatigue          29 (19%)         27 (17%)


          No significant differences between arms

                                          Valle et al. ASCO 2009 (abstract 4503)
             UK ABC-02 Trial: Efficacy
                    Gemcitabine +
                                    Gemcitabine             P Value
                      Cisplatin
                                     (n = 132)            (HR [95%CI])
                      (n = 148)
ORR                   38 (26%)       21 (16%)                    NR
       CR             1 (< 1%)        1 (< 1%)                   NR
       PR             37 (25%)       20 (15%)                    NR
SD                    79 (53%)       73 (55%)                    NR
CBR (CR + PR +SD)     117 (79%)      94 (71%)                    .256
                      (n = 204)      (n = 206)
                                                              .003
PFS                  8.4 months     6.5 months
                                                       (0.72 [0.57-0.90])
                                                              .002
OS                   11.7 months    8.3 months
                                                       (0.70 [0.54-0.89])



                                                 Valle et al. ASCO 2009 (abstract 4503)
      ABC-02 Results:
Progression-free survival (ITT)

                 Treatment arm                  Gem          Gem + Cis
                 Number of patients            n=206              n=204
                 PFS events n(%)             155 (75.2)      135 (66.2)
                 Median PFS (mo)                6.5                8.4
                 Log rank p value                         0.003
                 Hazard ratio (95% CI)            0.72 (0.57, 0.90)




                                      Valle et al. ASCO 2009 (abstract 4503)
 ABC-02 - Results:
Overall Survival (ITT)

            Treatment arm                Gem           Gem + Cis
            Number of patients           n=206           n=204
            Deaths n(%)                141 (68.5)      122 (59.8)
            Median survival (mo)          8.3               11.7
            Log rank p value                        0.002
            Hazard ratio (95% CI)            0.70 (0.54, 0.89)




                                 Valle et al. ASCO 2009 (abstract 4503)
ABC-02 - Overall Survival
 Exploratory sub-group
        analysis




                   Valle et al. ASCO 2009 (abstract 4503)
          CONKO-001 Gemcitabine as
        Adjuvant Therapy in Resected PC
      R
      a                           Ultrasound                Ultrasound                  CT Scan
                                  after week 8              after week 16              after week 32
      n
      d
      o
      m          Gem         Gem           Gem          Gem           Gem         Gem
                                                                                                     Follow up
      i                                                                                               every 8
      z           Obs        Obs           Obs          Obs           Obs         Obs                 weeks
      a
      t           4 weeks     4 weeks       4 weeks     4 weeks        4 weeks     4 weeks
      i     CA 19-9     CA 19-9       CA 19-9     CA 19-9        CA 19-9     CA 19-9       CA 19-9

      o
      n
                                                      Gem      Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks

                                                      Obs      Observation: d1; q 4 weeks
Oettle et al., JAMA 2007
                CONKO-001 ASCO 2008 Update
         100%
                                 Gemcitabine
                               mOS: 22.8 mos
                               (95% CI, 18.5-27.2)              OS Rate (%)
          75%
                                 Observation
                                                                   Obs    GEM
                               mOS: 20.2 mos
          50%                  (95% CI, 17.7-22.8)        1yr      72.5   72.0

                                                          3yrs     19.5   36.5
          25%

                                                          5yrs     9.0    21.0
                    P = 0.005
           0%
                0    12   24   36    48   60   72    84


                months

Neuhaus et al., ASCO 2008
ESPAC-3: Adjuvant bolus 5-FU/LV vs
 Gemcitabine in Pancreatic Cancer




                      Neoptolemos et al. ASCO 2009 (abstract 4505)
ESPAC-3: Adjuvant bolus 5-FU/LV vs
 Gemcitabine in Pancreatic Cancer




                      Neoptolemos et al. ASCO 2009 (abstract 4505)
ESPAC-3: Adjuvant bolus 5-FU/LV vs
 Gemcitabine in Pancreatic Cancer




                      Neoptolemos et al. ASCO 2009 (abstract 4505)
CONKO-4: LMWH vs Observation in
         metastatic PC




                       Riess et al. ASCO 2009 (abstract 4506)
CONKO-4: LMWH vs Observation in
         metastatic PC




                       Riess et al. ASCO 2009 (abstract 4506)
CONKO-4: LMWH vs Observation in
         metastatic PC




                       Riess et al. ASCO 2009 (abstract 4506)
CONKO-4: LMWH vs Observation in
         metastatic PC




                       Riess et al. ASCO 2009 (abstract 4506)
               CONKO-4: LMWH vs Obs. in mPC




Riess et al. ASCO 2009 (abstract 4506)