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Disclaimer

•   The content and opinions presented in this activity are not meant to
    serve as a guideline for patient management and do not necessarily
    reflect the views of Sirtex Medical Limited.

•   Healthcare professionals are encouraged to critically appraise the
    information presented and are advised to consult appropriate
    resources for clinical information surrounding disease management
    and FDA-approved labeling for information about any product or
    device discussed in this activity.




                                                                                  2
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Agenda

            1. Colorectal Cancer Liver Metastases (mCRC): Overview
            2. Selective Internal Radiation Therapy (SIRT): Overview
            3. SIR-Spheres® microspheres: Clinical Data in mCRC
            4. Ongoing Level 1 RCT for mCRC in the liver




SIR-Spheres® is a registered trademark of Sirtex SIR-Spheres Pty Ltd.          3
                                                                        582-U-0712
Section I



Colorectal Cancer Liver Metastases
        (mCRC): Overview




                                            4
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Colorectal Cancer (CRC):
                          US Epidemiology
      • Third most common cancer diagnosed in the US 1
              – Estimated new cases in 2012 :1
                      – Colon: 103,170
                      – Rectal: 40,290
              – Age-adjusted incidence: 46.3 per 100,000 persons/yr2
      • Median age at diagnosis (2005-2009): 69 yrs2
      • Prevalence (2009):
              – ~ 1.1 million people were alive in the US with a history of CRC2
      • 20% of subjects present with metastatic disease2



1. American Cancer Society. 2012. Cancer Facts & Figures (page 4).                                         5
2. NCI Cancer Topics Colon and Rectal Cancer. http://seer.cancer.gov/statfacts/html/colorect.html
                                                                                                    582-U-0712
Colorectal Cancer:
                                     US Mortality

      • CRC is the second leading cause of all cancer deaths1
              – 51,690 Estimated deaths in 2012:2
      • CRC-related deaths have steadily declined over past 20
        yrs1
              – Due to improvements in screening, early detection, and
                treatment
              – 65% overall 5-yr relative survival3




1. American Cancer Society. 2011. Cancer Facts & Figures.
2. NCI Cancer Topics Colon and Rectal Cancer.
                                                                                6
3. SEER Stat Fact Sheets: Colon and Rectum.                              582-U-0712
Colorectal Cancer: Stage Distribution
and 5-year Relative Survival at Diagnosis
              (2001-2007)


                                                                        Stage         5-year
          Stage at
                                                    Definition       Distribution    Relative
         diagnosis
                                                                         (%)        Survival (%)
                                 Localized (confined to primary
    Stage I/IIA/B/C                                                      39            90.1
                                 site)
                                 Regional (spread to regional
    Stage IIIA/B/C                                                       37            69.2
                                 lymph nodes)
    Stage IV                     Distant (cancer has metastasized)       20            11.7
                                 Unknown (unstaged)                       5            33.3



1. SEER Stat Fact Sheets: Colon and Rectum, NCI PDQ Colon.                                           7
                                                                                              582-U-0712
mCRC liver metastases:
                             Treatment Options
       •     Surgery
              – Cytoreduction or Resection
                   • 5 year survival goes from <15% to >50% following successful
                      resection but only 15% of patients present with resectable disease
       •     Ablation
       •     Systemic Chemotherapy
              – Adjuvant, neoadjuvant, and palliative
       •     Targeted agents
              – EGFR inhibitors
              – VEGFR inhibitors
       •     Intra-arterial Therapies
              – Selective Internal Radiation Therapy (SIRT) with Y-90
              – Chemoembolization
       •     Clinical trials
1. NCCN. 2012. Clinical practice guidelines in oncology: colon cancer.                            8
                                                                                           582-U-0712
Bulk Reduce Tumors:
                           Improvement in Survival

      • Survival improvement has been shown in
        ovarian cancer, hepatocellular cancer (HCC),
        head-and-neck cancer (HNC) due to:1-4
      – Removal of poorly vascularized areas, thereby
        increasing chemotherapy exposure
      – Removal of chemoresistant cells
      – Reducing adverse metabolic consequences
      – Enhancement of immune function after tumor debulking


1. Covens AL. Gynecol Oncol. 2000;78:269-274. 2. Thigpen T. N Engl J Med. 2004;351:2544-2546.                                          9
3. Wyse G, et al. Neuroimaging Clin N Am. 2009;19:161-168. 4. Atwell TD, et al. Cardiovasc Intervent Radiol. 2005;28:409-421.
                                                                                                                                582-U-0712
FDA-Approved Agents for mCRC

                     Adjuvant                                          First-Line                 Refractory
       Levamisole                                        Leucovorin                        Irinotecan
       (+ 5FU)                                           (with 5FU)                        1996
       1990                                              1991                              Oxaliplatin
                                                         Irinotecan                        (+ 5FU/LV)
                                                         (+ 5FU/LV; FOLFIRI)               2002
                                                         2000                              Cetuximab*
                                                         Capecitabine                      2004
                                                         2001                              Panitumumab*
                                                         Oxaliplatin                       2006
                                                         (+ 5FU/LV; FOLFOX)                Aflibercept
                                                         2004                              2012
                                                         Oxaliplatin
                                                         (+ capecitabine; XELOX)
                                                         2004
                                                                                             Regorafenib currently
                                                         Bevacizumab
                                                         2004                                under Priority Review
                                                         Bevacizumab                         for refractory
                                                         (+ 5FU/LV, + FOLFIRI, + FOLFOX)     disease

                                                                                                                      10
* Benefit only demonstrated in KRAS wild type patients
                                                                                                                 582-U-0712
mCRC Systemic chemotherapy
               Treatment Pathways1,2

              First-line                                 FOLFIRI +                              FOLFOX +
                                                                                   or
              therapy                                  bevacizumab                             bevacizumab




              Second-line                                           Irinotecan +        Single-agent
                                             FOLFOX           or                                     or    FOLFIRI
              therapy                                                cetuximab           irinotecan


              Third-line                  Cetuximab +/-                                        Cetuximab +/-
                                                                         FOLFOX
              therapy                       irinotecan                                           irinotecan




1. Köhne C-H, Lenz H-J. Oncologist. 2009;14:5478-5488.                                                                    11
2. NCCN. 2011. Clinical practice guidelines in oncology: colon cancer.                                               582-U-0712
Survival Benefit of Systemic Chemotherapy
           and Biological Combinations




1. Source: Venook et al The Oncologist 2005;10:250–261        12
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Section II


Selective Internal Radiation Therapy
          (SIRT): Overview




                                            13
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SIRT: Design Concept

• Selectively targets liver tumor cells with lethal
  radiation dose
      while at the same time
• Minimizing radiation exposure to the normal
  liver parenchyma




                                                           14
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SIRT: Microsphere Delivery Concept

     • SIRT takes advantage of the hepatic dual blood supply
     • Normal liver parenchyma:
            – Majority of blood supply from portal vein (A)
     • Metastatic liver tumors:
            – Majority of blood supply from hepatic artery (B)




                                                                 B
                                                             A


1. Archer S, Gray BN. Br J Surg. 1989;76:545-548, LIV_MOA.                15
                                                                     582-U-0712
SIRT: Delivery Procedure

    Minimally invasive microcatheter therapy:
    Transfemoral access (A) to the hepatic artery (B)




                                                   B




A

                                                             16
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SIRT: Brachytherapy Implantation

     •    Liver tumor vessel diameter: 25μm -75μm with end arteriole
          diameter: 8μm
     •    Resin microspheres mean diameter: 32.5μm
     •    Microspheres are too large to pass through the capillary bed within
          the tumor, where they become permanently implanted




1. Source: Andrew S. Kennedy, MD, Wake Radiology Oncology, Cary, NC.                 17
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SIR-Spheres microspheres

                         Biocompatible resin
                         32.5μm average diameter
                         Yttrium90 permanently bound
                         Mean pure beta emission @
                          0.93MeV
                         Half life 64.1 hours
                         Penetration
                               – 2.5mm mean
                               – 11mm max




                                                        Scanning electron
                                                        micrograph




1. Data on file, Sirtex Medical Limited                                          18
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Section III



SIR-Spheres microspheres:
  Clinical Data in mCRC




                                 19
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The SIR-Spheres microspheres
             Patient

• Non-resectable, liver only or liver dominant metastatic
  colorectal cancer
• Progressed on first line chemotherapy
• Remaining chemotherapy / biological agent options
• Good performance status (PS <2)
• Adequate liver function (bilirubin <2 or stable)
• Expected survival >3 months




                                                                 20
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SIR-Spheres microspheres in mCRC:

                                    First-Line Treatment
   Investigator               n       Treatment                                    ORR      TTP*/‡PFS    Survival

   Gray1                      74      SIR-Spheres† + HAC                           44%      15.9 mo*     39% at 2 yr
                                      HAC (FUDR)                                   18%       9.7 mo*     29% at 2 yr
                                                                                  P=0.01     P=0.001          P=0.06



   van Hazel2                 21      SIR-Spheres† + 5FU/LV                        91%      18.6 mo*     29.4 mo
                                      5FU/LV                                        0%       3.6 mo*     12.8 mo
                                                                                  P<0.001   P<0.0005    HR 0.33; P=0.025



   Sharma3                    20       SIR-Spheres† + FOLFOX4                      90%       9.2 mo‡     nr
                                                                                            14.2 mo‡L

 *TTP; ‡ PFS; ‡ LPFS in the liver; nr: not reported ,† SIR-Spheres microspheres




1. Gray, et al. Ann Oncol. 2001;12:1711–1720.
2. van Hazel, et al. J Surg Oncol. 2004;88:78–85.
                                                                                                                            21
3. Sharma, et al. J Clin Oncol. 2007;25:1099–1106.                                                                     582-U-0712
SIRT in First-Line Treatment of mCRC:
      Objective Response Rate and Time to Progression


                      Objective Response Rate                                                                   Time to Progression
               100%                                                                                20.0                                        18.6
                                                          91%                      90%
               90%                                                                                 18.0
                                                                                                                     15.9
               80%                                                                                 16.0
                                                                                                                                                                        13.8
               70%                                                                                 14.0
               60%                                                                                 12.0
                                                                                                          9.7                                                 9.3
               50%                   44%                                                           10.0
           %
           )
           (




               40%                                                                                  8.0
               30%                                                                                  6.0
                        18%                                                                                                         3.6
               20%                                                                                  4.0
                                                                                               m
                                                                                               o
                                                                                               h
                                                                                               n
                                                                                               P
                                                                                               e
                                                                                               T
                                                                                               g
                                                                                               s
                                                                                               r
                                                                                               t
                                                                                               )
                                                                                               (
                                                                                               i
       w




               10%                                                                                  2.0
       R
       o
       b
       p
       h
       n
       P
       C
       e
       T
       a
       E
       y
       S
       s
       t
       I
       i




                0%                                                                                   -
                          FUDR ±                 5FU/LV ±                 FOLFOX4 +                          FUDR ±                  5FU/LV ±                 FOLFOX4 +
                       SIR-Spheres†            SIR-Spheres†              SIR-Spheres†                     SIR-Spheres†             SIR-Spheres†              SIR-Spheres†
                      (Gray et al., 2001)   (van Hazel et al., 2004)   (Sharma et al., 2007)              (Gray et al., 2001)   (van Hazel et al., 2004)   (Sharma et al., 2007)
                            (n=74)                  (n=21)                    (n=20)                            (n=74)                  (n=21)                    (n=20)

†
    SIR-Spheres microspheres
1. Gray, et al. Ann Oncol. 2001;12:1711–1720.
2. van Hazel, et al. J Surg Oncol. 2004;88:78–85.
                                                                                                                                                                                   22
3. Sharma, et al. J Clin Oncol. 2007;25:1099–1106.                                                                                                                            582-U-0712
SIR-Spheres microspheres in First-Line
    Treatment : Cycles of Chemotherapy
                 received
                                                    Chemotherapy Cycles Administered
                                                                   P = 0.03
                                         9.0
                                                                                  8.1
                                         8.0

                                         7.0

                                         6.0

                                         5.0

                                         4.0             3.8

                                         3.0
                                 M
                                 m
                                 N
                                 o
                                 b
                                 u
                                 n
                                 e
                                 a
                                 r
                                 f




                                         2.0
                                     m
                                     A
                                     o
                                     h
                                     n
                                     d
                                     p
                                     C
                                     e
                                     a
                                     y
                                     c
                                     s
                                     r
                                     t
                                     i
                                     l




                                         1.0

                                         0.0
                                                        5FU/LV                 5FU/LV +
                                                                              SIR-Spheres
                                                                              Microspheres

1. van Hazel, et al. J Surg Oncol. 2004;88:78–85.                                                 23
                                                                                             582-U-0712
SIR-Spheres microspheres in mCRC:

                               Second-Line Treatment
                                      ORR: 33%                                              ORR: 48%
                               14.0   SD: 27%                                               SD: 39%
                                                                                               12.2
                               12.0

                               10.0                                        9.2

                                8.0
                                                           6.0
                                6.0         5.3
                        M
                        o
                        h
                        n
                        s
                        t




                                4.0

                                2.0

                                 -
                                           TTP             PFS          Liver PFS            Survival
                                        SIR-Spheres †                SIR-Spheres †
                                          + 5FU/LV                    + irinotecan
                                      Lim, et al. (n=30)         van Hazel, et al. (n=25)
†
    SIR-Spheres microspheres

1. Lim, et al. BMC Cancer. 2005;5:132.                                                                       24
2. van Hazel, et al. J Clin Oncol. 2009;27:4089–4095.                                                   582-U-0712
SIR-Spheres microspheres in mCRC:
         Salvage Therapy
       Investigator                n       Treatment                                   ORR           SD        TTP/PFS Survival

                                                                                                               ◊
       Hendlisz1                  4444 SIR-Spheres† + 5FU                              10%           76% 5.5 /4.5 mo         10.0 mo
                                       5FU > salvage with                               0%           35%    2.1 mo           7.3 mo
                                          SIR-Spheres at PD                                P=0.001          HR 0.38◊/0.51;
                                                                                                           P=0.003◊/P=0.03


       Seidensticker2             2929SIR-Spheres†                                     41%           17%       5.5 mo         8.3 mo
                                  29 best supportive care                              nr            nr        2.1 mo         3.5 mo
                                         (matched-pairs)                                                      HR 0.38;       HR 0.26;
                                                                                                              P<0.001        P<0.001


       Cosimelli3                  50      SIR-Spheres†                                24%           24%       4 mo          12.6 mo




◊
    time to liver progression (TTP); nr: not reported; † SIR-Spheres microspheres
1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–694.
2. Seidensticker et al Cardiovasc Intervent RadiolDOI 10.1007/s00270-011-0234-7 – E-Pub.                                                25
3. Cosimelli, et al. Br J Cancer. 2010;103:324–331.                                                                                582-U-0712
SIR-Spheres microspheres + 5FU
                Salvage Therapy: Study Design
  Eligible Patients                                              Stratify
  Liver-only mCRC,                                             •Institution
  PS 0–2, refractory to                                        •Interval to progression on chemotherapy
  chemotherapy
                                                                             Random Assignment

                                                                           Arm A:             Arm B:
                                                                                                 90
                                                                                                    Y resin microspheres
                                                                                               on Day 1 (D1) Cycle 1 (C1)
                                                                                                           +
                                                5FU protracted IV infusion (300              5FU protracted IV infusion (225
                                                     mg/m2 D1–14 q3w)                              mg/m2 D1–14 C1
                                                                                                and 300 mg/m2 D1–14
                                                                                                    q3w thereafter)

                                                        until progression                         until progression
  Eligible Patients
  Liver-dominant mCRC,                                 90
                                                            Y resin microspheres
  PS 0–2
1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694.                                                                             26
                                                                                                                            582-U-0712
SIR-Spheres microspheres + 5FU Salvage
                      Therapy:
              Time to Liver Progression




1. Adapted from: Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694.        27
                                                                     582-U-0712
SIR-Spheres microspheres
                          + 5FU Salvage Therapy:
                                TTP and OS
                                                 5FU Alone                      5FU +                      Hazard Ratio
                                                                             SIR-Spheres†                    (95% CI)
                                                       n = 23                   n = 21                        P value
        Median Time to                                                                                    0.38 (0.20–0.72)
        Liver Progression:                         2.1 months                    5.5 months                   P=0.003

        TTLP censored to                                                                                  0.35 (0.18–0.69)
        change of Tx plan:                         2.1 months                    5.6 months                   P=0.002

        Median Time to                                                                                     0.51 (0.28–0.94)
        Progression:                               2.1 months                    4.5 months                    P=0.03

        Median Overall                                                                                    0.92 (0.47–1.78)
        Survival:                                 7.3 months    *
                                                                                 10.0 months                   P=0.80

                                                                    8.8 months
        *
          Note: 10 patients in the 5FU arm received SIR-Spheres microspheres as salvage therapy after disease progression which potentially
              compromised the overall survival data
        †
          SIR-Spheres microspheres

                                                                                                                                          28
1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694.
                                                                                                                                     582-U-0712
SIR-Spheres microspheres + 5FU Salvage
                      Therapy:
                   Adverse Events
       Parameter                                              5FU Alone            5FU + SIR-Spheres microspheres
                                                                n = 23                       n = 21

                                                  Grades 1–2          Grades 3–4   Grades 1–2      Grade 3–4
       Gastrointestinal
       Stomatitis                                        1                     1        2              -
       Nausea                                            -                     -        5              -
       Constipation                                      3                     -        -              -
       Anorexia                                          6                     1        5              -
       Pain
       Abdominal pain                                    3                     -        4              -
       Myalgia                                           1                     -        2              -
       Constitutional
       Fatigue                                           6                     5       8               -
       Dermatological/Skin                               2                     -       -               -
       Hand-foot syndrome                                2                     -       -               1
       Pulmonary                                         1                     2       -               -
       Other Toxicity                                    1†                    -       2‡              -
       †
           ascites; ‡ 1 with thrombocytopenia, 1 with stomach ulcer, ascites
1. Hendlisz A, et al. J Clin Oncol. 2010;28:3687–3694.                                                              29
                                                                                                               582-U-0712
Matched Pair SIRT in Chemotherapy
           Refractory Liver-Dominant mCRC: Study
                            Design
             Matched mCRC
              pairs by prior                                                                SIR-Spheres† + BSC
            treatment history
                   and
             tumor burden +
           liver involvement;
               metastases;
             ALP; CEA level                                                                 BSC
             (N=29 per arm)

        • 1° end point: OS
        • 2° end points: PFS, ORR, safety and tolerability
     ALP=alkaline phosphatase; BSC=best supportive care; CEA= carcinoembryonic antigen.
 *
     Per investigator’s discretion starting at cycle 4 (treatment arm) or cycle 1 (control arm)
 †
     SIR-Spheres microspheres

1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print].              30
                                                                                                                 582-U-0712
Matched Pair SIRT in Chemotherapy
                  Refractory Liver-Dominant mCRC:
                           Overall Survival




1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print].        31
                                                                                                           582-U-0712
Matched Pair SIRT in Chemotherapy
                 Refractory Liver-Dominant mCRC:
                         Study Conclusions

        • Addition of radioembolization improved OS in
          chemotherapy refractory liver-dominant mCRC patients
                – Median 8.3 months vs. 3.5 months, (P <.001)


        • Improved PFS in patients receiving radioembolization
                – Median 5.5 months vs. 2.1 months
                – Progression was defined as a clinically significant change in:
                   • Symptoms
                OR • CEA levels
                   • Confirmed by radiological imaging


1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print].        32
                                                                                                           582-U-0712
Matched Pair SIRT in Chemotherapy
               Refractory Liver-Dominant mCRC:
                             Safety

       • Adverse events following SIRT were predominately transient
         and self-limiting, including:
              – grade 1–2 fatigue (69%)
              – grade 1 abdominal pain/nausea (48%)
              – 3 patients developed grade 2 gastrointestinal ulcer, which were
                managed medically
              – 3 cases of grade 3 radiation-induced liver disease (RILD) were
                medically managed and not life-threatening




1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; (Epub ahead of print)        33
                                                                                                          582-U-0712
SIR-Spheres microspheres in mCRC:
                Retrospective Data
       Investigator                   n      Treatment                                     ORR             SD TTP*/‡ PFS             Survival


       Kennedy1                     176      SIR-Spheres microspheres                      35.5%**         55%             7.2 mo*   10.5 mo
                                             responders
                                     31      non-responders/controls                       na              na             na          4.5 mo
                                                                                                                       HR 0.38;      HR 0.26;
                                                                                                                       P<0.001       P<0.001



       Bester2                      224¥     SIR-Spheres microspheres                      nr              nr             nr         11.9 mo
                                     29      best supportive care                          nr              nr             nr          6.6 mo

                                                                                                                                      HR 0.50;
                                                                                                                                      P=0.001




        ‡
            PFS; *TTP; ‡L PFS in the liver; **L OS in the liver; nr: not reported, ¥: CRC cohort


1. Kennedy, et al. Int J Radiat Oncol Biol Phys. 2006;65:412–425. 2. Bester et al. J Vasc Inter Rad, 2011;23: 96-10.                             34
                                                                                                                                            582-U-0712
Multi-center Retrospective Responder
             Analysis (Kennedy): Overall Survival

                                                                        N   Median Survival (95% CI)
                                                 Responders (PET) :   176   10.5 months
                                                                                                       P=0.0001
                                               Non-responders:         31    4.5 months




1. Kennedy, et al. Int J Radiat Oncol Biol Phys. 2006;65:412–425                                            35
                                                                                                       582-U-0712
Comparative Retrospective Study (Bester):
                  Overall Survival

                                                                           N   Median Survival (95% CI)
                                                  SIR-Spheres microspheres :   224 11.9 months (10.1 –
                                                                                                           P=0.001
                                                14.9)
                                                Standard Care:            29    6.6 months

                                                        Hazard Ratio:          0.50 (0.30 – 0.77)
75


           50


                          25


                                          0


                                                              0.3       0.4    0.5      0.6    0.7   0.8
 Overall Survival (                                                            Hazard Ratio




             0         6         12            18         24       30        36
     Time from receiving or potentially eligible for SIR-Spheres microspheres (months)

 1. Bester et al. J Vasc Inter Rad, 2011;23: 96-105                                                             36
                                                                                                           582-U-0712
Adjuvant Care Parallel
for Non-resectable mCRC Liver Tumors




                Similar
                 Level
                  of
               Evidence




                                       37
                                  582-U-0712
Section IV



Ongoing Level 1 RCT for mCRC
          in the liver




                                    38
                               582-U-0712
SIRFLOX: Study Design

            mCRC patients                                       SIR-Spheres† (day 3-4/cycle 1) +
             WHO PS 0-1                                         FOLFOX6m ± Bevacizumab*
           All patients have
                no prior
            chemotherapy
           unresectable liver
              metastases
                                                                FOLFOX6m ± Bevacizumab*
                (N=450)

       •    1° end point: PFS
       •    2° end points: OS, TRR, recurrence rate, HR-QoL, liver resection
            rate

*
    Per investigator’s discretion starting at cycle 4 (treatment arm) or cycle 1 (control arm)
†
    SIR-Spheres microspheres
1. Source: www.clinicaltrials.gov. NCT00724503.                                                       39
                                                                                                 582-U-0712
SIRFLOX 120 Patient Safety Data:
     Constitutional adverse events

                    Oxaliplatin package insert   SIRFLOX Study Patient Group
                           safety data
                                                            (n =122)
  Constitutional
                            (n = 259)
Treatment related
 Adverse Events     Grade            Grade          Grade              Grade
                     1-4              3-4            1-4                3-4
                      %                %              %                  %
Nausea                 71               6             59                 2
Vomiting               41               4             31                 3
Diarrhea               69               12            47                 7
Constipation           32               4             22                 0
Abdominal pain         29               8             18                 3

 * Nausea and vomiting reported as a single event in this study
                                                                                    40
                                                                               582-U-0712
SIRFLOX 120 Patient Safety Data:
Other Treatment related Adverse Events


                    Oxaliplatin package insert   SIRFLOX Study Patient Group
                           safety data
 Other Treatment
                             (n = 259)                      (n = 122)
 Related Adverse
     Events          Grade           Grade          Grade               Grade
                      1-4             3-4            1-4                 3-4
                       %               %              %                   %
 Fatigue               70                7            63                  7
 Neuropathy            77                19           87                  6
 Anorexia              35                2            26                  2
 Stomatitis /          38                0            38                  5
 Mucositis
 Alopecia              38                0            11                  0
  * Nausea and vomiting reported as a single event in this study
                                                                                     41
                                                                                582-U-0712
Questions?




                  42
             582-U-0712
Appendix




                43
           582-U-0712
SIRT Treatment Algorithm

                                                    Patient Selection
                                                    Patient Selection
1-2 weeks




                            Tumor Mapping
                            Tumor Mapping                Labs
                                                         Labs


                                                                                    Lung Shunt
                                                                                    Lung Shunt
                            Vessel
                            Vessel            Vessel
                                              Vessel               CT/Hepatic
                                                                    CT/Hepatic     Breakthrough
                                                                                   Breakthrough
                           Mapping
                           Mapping          Embolization
                                            Embolization           Angiogram **
                                                                   Angiogram           Scan
                                                                                       Scan
1-2 weeks




                        Review
                        Review        Treatment Plan
                                      Treatment Plan             Dosimetry
                                                                 Dosimetry         Ordering
                                                                                   Ordering




                                     SIR-Spheres
                                      SIR-Spheres                                 Post Treatment
                                                             Bremsstrahlung
                                                             Bremsstrahlung       Post Treatment
                  Labs
                  Labs               microspheres
                                     microspheres                                      Care
                                                                 Scan **
                                                                 Scan                   Care
                                       Delivery
                                        Delivery


            *optional
                                                       Follow Up
                                                       Follow Up
                                                                                                        44
                                                                                                   582-U-0712
Pre-treatment Planning and Microsphere Implant:
           2012 Medicare APC Reimbursement
           Procedure                     CPT                  Quantity                         APC Natl Pymt
                                                    1 - pretreatment                            $7,358.35 (2) =
Transcatheter embolization w S&I     37204/ 75894
                                                    1 - day of treatment                          $14,716.70
                                        36247       Operator determined (pre-
Selective catheter 2-3rd order                                                       Packaged
                                      36248 x ___   treatment & day of treatment)
Diagnostic angiogram (Visceral)          75726      1 – pretreatment                 $2,086.63
Diagnostic selective – addl vessel                  Operator determined (pre-
                                         75774                                       Packaged
beyond basic                                        treatment & day of treatment)
                                                    1 - pretreatment                             $75.48 (2) =
F/U angiogram post Embo                  75898
                                                    1 - day of treatment                           $150.96
Basic dosimetry                          77300      1                                $107.56
Triple phase CT                          74170      1                                $334.09
Lung shunt imaging                       78205      1                                $293.36
Post treatment imaging               78201 or 78205 1                                $293.36
Radiopharma by intra-arterial
                                         79445      1 – day of treatment             $230.32
administration
                                                                                                  $15,716.28
Microspheres                            C2616       1 – day of treatment                 (- $15,000 dose acquisition cost)
                                                                                                    $716.28
                                                                                    45
                                                                           Total               $18,929.26
Level of Evidence Example

                                               SIRT                          # of Patients   Level of
                                               Study & Year                                  Evidence

ABLATION                 # of       Level of   Gray et al, 2001 10           74              I
Study & Year             Patients   Evidence
                                               Hendlisz et al, 2010 11       46              I
Hur et al, 2009 1        25         II-2

Solbiati et al, 2001 2   117        II-2       Seidensticker et al, 201112   58              II-1


Giliams & Lees,          309        II-2       Bester et al, 2012 13         339             II-1
2008 3
Elias et all, 2002 4     29         II-2       Cosimelli et al, 2010 14      50              II-2


Oshowo et al, 2003       25         II-2       Kennedy et al , 2006 15       208             II-2
5


Machi et al, 2006 6      100        II-2       van Hazel et al, 2004 16      21              II-1


Vogel et al, 2004 7      603        II-2       Sharma et al, 2007 17         20              II-1


Sorenson et al,          100        II-2       Evans et al, 2010 18          140             II-2
2007 8
Sofocleous et al,        56         II-2
2011 9


                                                                                                          46
                                                                                                    427-U-1111

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  • 2. Disclaimer • The content and opinions presented in this activity are not meant to serve as a guideline for patient management and do not necessarily reflect the views of Sirtex Medical Limited. • Healthcare professionals are encouraged to critically appraise the information presented and are advised to consult appropriate resources for clinical information surrounding disease management and FDA-approved labeling for information about any product or device discussed in this activity. 2 582-U-0712
  • 3. Agenda 1. Colorectal Cancer Liver Metastases (mCRC): Overview 2. Selective Internal Radiation Therapy (SIRT): Overview 3. SIR-Spheres® microspheres: Clinical Data in mCRC 4. Ongoing Level 1 RCT for mCRC in the liver SIR-Spheres® is a registered trademark of Sirtex SIR-Spheres Pty Ltd. 3 582-U-0712
  • 4. Section I Colorectal Cancer Liver Metastases (mCRC): Overview 4 582-U-0712
  • 5. Colorectal Cancer (CRC): US Epidemiology • Third most common cancer diagnosed in the US 1 – Estimated new cases in 2012 :1 – Colon: 103,170 – Rectal: 40,290 – Age-adjusted incidence: 46.3 per 100,000 persons/yr2 • Median age at diagnosis (2005-2009): 69 yrs2 • Prevalence (2009): – ~ 1.1 million people were alive in the US with a history of CRC2 • 20% of subjects present with metastatic disease2 1. American Cancer Society. 2012. Cancer Facts & Figures (page 4). 5 2. NCI Cancer Topics Colon and Rectal Cancer. http://seer.cancer.gov/statfacts/html/colorect.html 582-U-0712
  • 6. Colorectal Cancer: US Mortality • CRC is the second leading cause of all cancer deaths1 – 51,690 Estimated deaths in 2012:2 • CRC-related deaths have steadily declined over past 20 yrs1 – Due to improvements in screening, early detection, and treatment – 65% overall 5-yr relative survival3 1. American Cancer Society. 2011. Cancer Facts & Figures. 2. NCI Cancer Topics Colon and Rectal Cancer. 6 3. SEER Stat Fact Sheets: Colon and Rectum. 582-U-0712
  • 7. Colorectal Cancer: Stage Distribution and 5-year Relative Survival at Diagnosis (2001-2007) Stage 5-year Stage at Definition Distribution Relative diagnosis (%) Survival (%) Localized (confined to primary Stage I/IIA/B/C 39 90.1 site) Regional (spread to regional Stage IIIA/B/C 37 69.2 lymph nodes) Stage IV Distant (cancer has metastasized) 20 11.7 Unknown (unstaged) 5 33.3 1. SEER Stat Fact Sheets: Colon and Rectum, NCI PDQ Colon. 7 582-U-0712
  • 8. mCRC liver metastases: Treatment Options • Surgery – Cytoreduction or Resection • 5 year survival goes from <15% to >50% following successful resection but only 15% of patients present with resectable disease • Ablation • Systemic Chemotherapy – Adjuvant, neoadjuvant, and palliative • Targeted agents – EGFR inhibitors – VEGFR inhibitors • Intra-arterial Therapies – Selective Internal Radiation Therapy (SIRT) with Y-90 – Chemoembolization • Clinical trials 1. NCCN. 2012. Clinical practice guidelines in oncology: colon cancer. 8 582-U-0712
  • 9. Bulk Reduce Tumors: Improvement in Survival • Survival improvement has been shown in ovarian cancer, hepatocellular cancer (HCC), head-and-neck cancer (HNC) due to:1-4 – Removal of poorly vascularized areas, thereby increasing chemotherapy exposure – Removal of chemoresistant cells – Reducing adverse metabolic consequences – Enhancement of immune function after tumor debulking 1. Covens AL. Gynecol Oncol. 2000;78:269-274. 2. Thigpen T. N Engl J Med. 2004;351:2544-2546. 9 3. Wyse G, et al. Neuroimaging Clin N Am. 2009;19:161-168. 4. Atwell TD, et al. Cardiovasc Intervent Radiol. 2005;28:409-421. 582-U-0712
  • 10. FDA-Approved Agents for mCRC Adjuvant First-Line Refractory Levamisole Leucovorin Irinotecan (+ 5FU) (with 5FU) 1996 1990 1991 Oxaliplatin Irinotecan (+ 5FU/LV) (+ 5FU/LV; FOLFIRI) 2002 2000 Cetuximab* Capecitabine 2004 2001 Panitumumab* Oxaliplatin 2006 (+ 5FU/LV; FOLFOX) Aflibercept 2004 2012 Oxaliplatin (+ capecitabine; XELOX) 2004 Regorafenib currently Bevacizumab 2004 under Priority Review Bevacizumab for refractory (+ 5FU/LV, + FOLFIRI, + FOLFOX) disease 10 * Benefit only demonstrated in KRAS wild type patients 582-U-0712
  • 11. mCRC Systemic chemotherapy Treatment Pathways1,2 First-line FOLFIRI + FOLFOX + or therapy bevacizumab bevacizumab Second-line Irinotecan + Single-agent FOLFOX or or FOLFIRI therapy cetuximab irinotecan Third-line Cetuximab +/- Cetuximab +/- FOLFOX therapy irinotecan irinotecan 1. Köhne C-H, Lenz H-J. Oncologist. 2009;14:5478-5488. 11 2. NCCN. 2011. Clinical practice guidelines in oncology: colon cancer. 582-U-0712
  • 12. Survival Benefit of Systemic Chemotherapy and Biological Combinations 1. Source: Venook et al The Oncologist 2005;10:250–261 12 582-U-0712
  • 13. Section II Selective Internal Radiation Therapy (SIRT): Overview 13 582-U-0712
  • 14. SIRT: Design Concept • Selectively targets liver tumor cells with lethal radiation dose while at the same time • Minimizing radiation exposure to the normal liver parenchyma 14 582-U-0712
  • 15. SIRT: Microsphere Delivery Concept • SIRT takes advantage of the hepatic dual blood supply • Normal liver parenchyma: – Majority of blood supply from portal vein (A) • Metastatic liver tumors: – Majority of blood supply from hepatic artery (B) B A 1. Archer S, Gray BN. Br J Surg. 1989;76:545-548, LIV_MOA. 15 582-U-0712
  • 16. SIRT: Delivery Procedure Minimally invasive microcatheter therapy: Transfemoral access (A) to the hepatic artery (B) B A 16 582-U-0712
  • 17. SIRT: Brachytherapy Implantation • Liver tumor vessel diameter: 25μm -75μm with end arteriole diameter: 8μm • Resin microspheres mean diameter: 32.5μm • Microspheres are too large to pass through the capillary bed within the tumor, where they become permanently implanted 1. Source: Andrew S. Kennedy, MD, Wake Radiology Oncology, Cary, NC. 17 582-U-0712
  • 18. SIR-Spheres microspheres  Biocompatible resin  32.5μm average diameter  Yttrium90 permanently bound  Mean pure beta emission @ 0.93MeV  Half life 64.1 hours  Penetration – 2.5mm mean – 11mm max Scanning electron micrograph 1. Data on file, Sirtex Medical Limited 18 582-U-0712
  • 19. Section III SIR-Spheres microspheres: Clinical Data in mCRC 19 582-U-0712
  • 20. The SIR-Spheres microspheres Patient • Non-resectable, liver only or liver dominant metastatic colorectal cancer • Progressed on first line chemotherapy • Remaining chemotherapy / biological agent options • Good performance status (PS <2) • Adequate liver function (bilirubin <2 or stable) • Expected survival >3 months 20 582-U-0712
  • 21. SIR-Spheres microspheres in mCRC: First-Line Treatment Investigator n Treatment ORR TTP*/‡PFS Survival Gray1 74 SIR-Spheres† + HAC 44% 15.9 mo* 39% at 2 yr HAC (FUDR) 18% 9.7 mo* 29% at 2 yr P=0.01 P=0.001 P=0.06 van Hazel2 21 SIR-Spheres† + 5FU/LV 91% 18.6 mo* 29.4 mo 5FU/LV 0% 3.6 mo* 12.8 mo P<0.001 P<0.0005 HR 0.33; P=0.025 Sharma3 20 SIR-Spheres† + FOLFOX4 90% 9.2 mo‡ nr 14.2 mo‡L *TTP; ‡ PFS; ‡ LPFS in the liver; nr: not reported ,† SIR-Spheres microspheres 1. Gray, et al. Ann Oncol. 2001;12:1711–1720. 2. van Hazel, et al. J Surg Oncol. 2004;88:78–85. 21 3. Sharma, et al. J Clin Oncol. 2007;25:1099–1106. 582-U-0712
  • 22. SIRT in First-Line Treatment of mCRC: Objective Response Rate and Time to Progression Objective Response Rate Time to Progression 100% 20.0 18.6 91% 90% 90% 18.0 15.9 80% 16.0 13.8 70% 14.0 60% 12.0 9.7 9.3 50% 44% 10.0 % ) ( 40% 8.0 30% 6.0 18% 3.6 20% 4.0 m o h n P e T g s r t ) ( i w 10% 2.0 R o b p h n P C e T a E y S s t I i 0% - FUDR ± 5FU/LV ± FOLFOX4 + FUDR ± 5FU/LV ± FOLFOX4 + SIR-Spheres† SIR-Spheres† SIR-Spheres† SIR-Spheres† SIR-Spheres† SIR-Spheres† (Gray et al., 2001) (van Hazel et al., 2004) (Sharma et al., 2007) (Gray et al., 2001) (van Hazel et al., 2004) (Sharma et al., 2007) (n=74) (n=21) (n=20) (n=74) (n=21) (n=20) † SIR-Spheres microspheres 1. Gray, et al. Ann Oncol. 2001;12:1711–1720. 2. van Hazel, et al. J Surg Oncol. 2004;88:78–85. 22 3. Sharma, et al. J Clin Oncol. 2007;25:1099–1106. 582-U-0712
  • 23. SIR-Spheres microspheres in First-Line Treatment : Cycles of Chemotherapy received Chemotherapy Cycles Administered P = 0.03 9.0 8.1 8.0 7.0 6.0 5.0 4.0 3.8 3.0 M m N o b u n e a r f 2.0 m A o h n d p C e a y c s r t i l 1.0 0.0 5FU/LV 5FU/LV + SIR-Spheres Microspheres 1. van Hazel, et al. J Surg Oncol. 2004;88:78–85. 23 582-U-0712
  • 24. SIR-Spheres microspheres in mCRC: Second-Line Treatment ORR: 33% ORR: 48% 14.0 SD: 27% SD: 39% 12.2 12.0 10.0 9.2 8.0 6.0 6.0 5.3 M o h n s t 4.0 2.0 - TTP PFS Liver PFS Survival SIR-Spheres † SIR-Spheres † + 5FU/LV + irinotecan Lim, et al. (n=30) van Hazel, et al. (n=25) † SIR-Spheres microspheres 1. Lim, et al. BMC Cancer. 2005;5:132. 24 2. van Hazel, et al. J Clin Oncol. 2009;27:4089–4095. 582-U-0712
  • 25. SIR-Spheres microspheres in mCRC: Salvage Therapy Investigator n Treatment ORR SD TTP/PFS Survival ◊ Hendlisz1 4444 SIR-Spheres† + 5FU 10% 76% 5.5 /4.5 mo 10.0 mo 5FU > salvage with 0% 35% 2.1 mo 7.3 mo SIR-Spheres at PD P=0.001 HR 0.38◊/0.51; P=0.003◊/P=0.03 Seidensticker2 2929SIR-Spheres† 41% 17% 5.5 mo 8.3 mo 29 best supportive care nr nr 2.1 mo 3.5 mo (matched-pairs) HR 0.38; HR 0.26; P<0.001 P<0.001 Cosimelli3 50 SIR-Spheres† 24% 24% 4 mo 12.6 mo ◊ time to liver progression (TTP); nr: not reported; † SIR-Spheres microspheres 1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–694. 2. Seidensticker et al Cardiovasc Intervent RadiolDOI 10.1007/s00270-011-0234-7 – E-Pub. 25 3. Cosimelli, et al. Br J Cancer. 2010;103:324–331. 582-U-0712
  • 26. SIR-Spheres microspheres + 5FU Salvage Therapy: Study Design Eligible Patients Stratify Liver-only mCRC, •Institution PS 0–2, refractory to •Interval to progression on chemotherapy chemotherapy Random Assignment Arm A: Arm B: 90 Y resin microspheres on Day 1 (D1) Cycle 1 (C1) + 5FU protracted IV infusion (300 5FU protracted IV infusion (225 mg/m2 D1–14 q3w) mg/m2 D1–14 C1 and 300 mg/m2 D1–14 q3w thereafter) until progression until progression Eligible Patients Liver-dominant mCRC, 90 Y resin microspheres PS 0–2 1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694. 26 582-U-0712
  • 27. SIR-Spheres microspheres + 5FU Salvage Therapy: Time to Liver Progression 1. Adapted from: Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694. 27 582-U-0712
  • 28. SIR-Spheres microspheres + 5FU Salvage Therapy: TTP and OS 5FU Alone 5FU + Hazard Ratio SIR-Spheres† (95% CI) n = 23 n = 21 P value Median Time to 0.38 (0.20–0.72) Liver Progression: 2.1 months 5.5 months P=0.003 TTLP censored to 0.35 (0.18–0.69) change of Tx plan: 2.1 months 5.6 months P=0.002 Median Time to 0.51 (0.28–0.94) Progression: 2.1 months 4.5 months P=0.03 Median Overall 0.92 (0.47–1.78) Survival: 7.3 months * 10.0 months P=0.80 8.8 months * Note: 10 patients in the 5FU arm received SIR-Spheres microspheres as salvage therapy after disease progression which potentially compromised the overall survival data † SIR-Spheres microspheres 28 1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694. 582-U-0712
  • 29. SIR-Spheres microspheres + 5FU Salvage Therapy: Adverse Events Parameter 5FU Alone 5FU + SIR-Spheres microspheres n = 23 n = 21 Grades 1–2 Grades 3–4 Grades 1–2 Grade 3–4 Gastrointestinal Stomatitis 1 1 2 - Nausea - - 5 - Constipation 3 - - - Anorexia 6 1 5 - Pain Abdominal pain 3 - 4 - Myalgia 1 - 2 - Constitutional Fatigue 6 5 8 - Dermatological/Skin 2 - - - Hand-foot syndrome 2 - - 1 Pulmonary 1 2 - - Other Toxicity 1† - 2‡ - † ascites; ‡ 1 with thrombocytopenia, 1 with stomach ulcer, ascites 1. Hendlisz A, et al. J Clin Oncol. 2010;28:3687–3694. 29 582-U-0712
  • 30. Matched Pair SIRT in Chemotherapy Refractory Liver-Dominant mCRC: Study Design Matched mCRC pairs by prior SIR-Spheres† + BSC treatment history and tumor burden + liver involvement; metastases; ALP; CEA level BSC (N=29 per arm) • 1° end point: OS • 2° end points: PFS, ORR, safety and tolerability ALP=alkaline phosphatase; BSC=best supportive care; CEA= carcinoembryonic antigen. * Per investigator’s discretion starting at cycle 4 (treatment arm) or cycle 1 (control arm) † SIR-Spheres microspheres 1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print]. 30 582-U-0712
  • 31. Matched Pair SIRT in Chemotherapy Refractory Liver-Dominant mCRC: Overall Survival 1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print]. 31 582-U-0712
  • 32. Matched Pair SIRT in Chemotherapy Refractory Liver-Dominant mCRC: Study Conclusions • Addition of radioembolization improved OS in chemotherapy refractory liver-dominant mCRC patients – Median 8.3 months vs. 3.5 months, (P <.001) • Improved PFS in patients receiving radioembolization – Median 5.5 months vs. 2.1 months – Progression was defined as a clinically significant change in: • Symptoms OR • CEA levels • Confirmed by radiological imaging 1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print]. 32 582-U-0712
  • 33. Matched Pair SIRT in Chemotherapy Refractory Liver-Dominant mCRC: Safety • Adverse events following SIRT were predominately transient and self-limiting, including: – grade 1–2 fatigue (69%) – grade 1 abdominal pain/nausea (48%) – 3 patients developed grade 2 gastrointestinal ulcer, which were managed medically – 3 cases of grade 3 radiation-induced liver disease (RILD) were medically managed and not life-threatening 1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; (Epub ahead of print) 33 582-U-0712
  • 34. SIR-Spheres microspheres in mCRC: Retrospective Data Investigator n Treatment ORR SD TTP*/‡ PFS Survival Kennedy1 176 SIR-Spheres microspheres 35.5%** 55% 7.2 mo* 10.5 mo responders 31 non-responders/controls na na na 4.5 mo HR 0.38; HR 0.26; P<0.001 P<0.001 Bester2 224¥ SIR-Spheres microspheres nr nr nr 11.9 mo 29 best supportive care nr nr nr 6.6 mo HR 0.50; P=0.001 ‡ PFS; *TTP; ‡L PFS in the liver; **L OS in the liver; nr: not reported, ¥: CRC cohort 1. Kennedy, et al. Int J Radiat Oncol Biol Phys. 2006;65:412–425. 2. Bester et al. J Vasc Inter Rad, 2011;23: 96-10. 34 582-U-0712
  • 35. Multi-center Retrospective Responder Analysis (Kennedy): Overall Survival N Median Survival (95% CI) Responders (PET) : 176 10.5 months P=0.0001 Non-responders: 31 4.5 months 1. Kennedy, et al. Int J Radiat Oncol Biol Phys. 2006;65:412–425 35 582-U-0712
  • 36. Comparative Retrospective Study (Bester): Overall Survival N Median Survival (95% CI) SIR-Spheres microspheres : 224 11.9 months (10.1 – P=0.001 14.9) Standard Care: 29 6.6 months Hazard Ratio: 0.50 (0.30 – 0.77) 75 50 25 0 0.3 0.4 0.5 0.6 0.7 0.8 Overall Survival ( Hazard Ratio 0 6 12 18 24 30 36 Time from receiving or potentially eligible for SIR-Spheres microspheres (months) 1. Bester et al. J Vasc Inter Rad, 2011;23: 96-105 36 582-U-0712
  • 37. Adjuvant Care Parallel for Non-resectable mCRC Liver Tumors Similar Level of Evidence 37 582-U-0712
  • 38. Section IV Ongoing Level 1 RCT for mCRC in the liver 38 582-U-0712
  • 39. SIRFLOX: Study Design mCRC patients SIR-Spheres† (day 3-4/cycle 1) + WHO PS 0-1 FOLFOX6m ± Bevacizumab* All patients have no prior chemotherapy unresectable liver metastases FOLFOX6m ± Bevacizumab* (N=450) • 1° end point: PFS • 2° end points: OS, TRR, recurrence rate, HR-QoL, liver resection rate * Per investigator’s discretion starting at cycle 4 (treatment arm) or cycle 1 (control arm) † SIR-Spheres microspheres 1. Source: www.clinicaltrials.gov. NCT00724503. 39 582-U-0712
  • 40. SIRFLOX 120 Patient Safety Data: Constitutional adverse events Oxaliplatin package insert SIRFLOX Study Patient Group safety data (n =122) Constitutional (n = 259) Treatment related Adverse Events Grade Grade Grade Grade 1-4 3-4 1-4 3-4 % % % % Nausea 71 6 59 2 Vomiting 41 4 31 3 Diarrhea 69 12 47 7 Constipation 32 4 22 0 Abdominal pain 29 8 18 3 * Nausea and vomiting reported as a single event in this study 40 582-U-0712
  • 41. SIRFLOX 120 Patient Safety Data: Other Treatment related Adverse Events Oxaliplatin package insert SIRFLOX Study Patient Group safety data Other Treatment (n = 259) (n = 122) Related Adverse Events Grade Grade Grade Grade 1-4 3-4 1-4 3-4 % % % % Fatigue 70 7 63 7 Neuropathy 77 19 87 6 Anorexia 35 2 26 2 Stomatitis / 38 0 38 5 Mucositis Alopecia 38 0 11 0 * Nausea and vomiting reported as a single event in this study 41 582-U-0712
  • 42. Questions? 42 582-U-0712
  • 43. Appendix 43 582-U-0712
  • 44. SIRT Treatment Algorithm Patient Selection Patient Selection 1-2 weeks Tumor Mapping Tumor Mapping Labs Labs Lung Shunt Lung Shunt Vessel Vessel Vessel Vessel CT/Hepatic CT/Hepatic Breakthrough Breakthrough Mapping Mapping Embolization Embolization Angiogram ** Angiogram Scan Scan 1-2 weeks Review Review Treatment Plan Treatment Plan Dosimetry Dosimetry Ordering Ordering SIR-Spheres SIR-Spheres Post Treatment Bremsstrahlung Bremsstrahlung Post Treatment Labs Labs microspheres microspheres Care Scan ** Scan Care Delivery Delivery *optional Follow Up Follow Up 44 582-U-0712
  • 45. Pre-treatment Planning and Microsphere Implant: 2012 Medicare APC Reimbursement Procedure CPT Quantity APC Natl Pymt 1 - pretreatment $7,358.35 (2) = Transcatheter embolization w S&I 37204/ 75894 1 - day of treatment $14,716.70 36247 Operator determined (pre- Selective catheter 2-3rd order Packaged 36248 x ___ treatment & day of treatment) Diagnostic angiogram (Visceral) 75726 1 – pretreatment $2,086.63 Diagnostic selective – addl vessel Operator determined (pre- 75774 Packaged beyond basic treatment & day of treatment) 1 - pretreatment $75.48 (2) = F/U angiogram post Embo 75898 1 - day of treatment $150.96 Basic dosimetry 77300 1 $107.56 Triple phase CT 74170 1 $334.09 Lung shunt imaging 78205 1 $293.36 Post treatment imaging 78201 or 78205 1 $293.36 Radiopharma by intra-arterial 79445 1 – day of treatment $230.32 administration $15,716.28 Microspheres C2616 1 – day of treatment (- $15,000 dose acquisition cost) $716.28 45 Total $18,929.26
  • 46. Level of Evidence Example SIRT # of Patients Level of Study & Year Evidence ABLATION # of Level of Gray et al, 2001 10 74 I Study & Year Patients Evidence Hendlisz et al, 2010 11 46 I Hur et al, 2009 1 25 II-2 Solbiati et al, 2001 2 117 II-2 Seidensticker et al, 201112 58 II-1 Giliams & Lees, 309 II-2 Bester et al, 2012 13 339 II-1 2008 3 Elias et all, 2002 4 29 II-2 Cosimelli et al, 2010 14 50 II-2 Oshowo et al, 2003 25 II-2 Kennedy et al , 2006 15 208 II-2 5 Machi et al, 2006 6 100 II-2 van Hazel et al, 2004 16 21 II-1 Vogel et al, 2004 7 603 II-2 Sharma et al, 2007 17 20 II-1 Sorenson et al, 100 II-2 Evans et al, 2010 18 140 II-2 2007 8 Sofocleous et al, 56 II-2 2011 9 46 427-U-1111

Editor's Notes

  1. Make own comments as you like
  2. This section provides an overview on Colorectal Cancer Liver Metastases (mCRC).
  3. CRC is the 3 rd most commonly diagnosed US cancer behind prostate (240k) and breast (232k) cancers References: American Cancer Society. 2012. Cancer Facts &amp; Figures. Page 4 http://seer.cancer.gov/statfacts/html/colorect.html
  4. CRC is second leading cause of all US cancer deaths behind lung cancer (156k) References: American Cancer Society. 2011. Cancer Facts &amp; Figures. http://www.cancer.gov/cancertopics/types/colon-and-rectal SEER Stat Fact Sheets: Colon and Rectum.
  5. The overall 5-year relative survival for 2001-2007 from 17 SEER geographic areas was 64.3%. Five-year relative survival by race and sex was: 65.5% for white men; 64.5% for white women; 55.0% for black men; 56.9% for black women. Reference: SEER Stat Fact Sheets: Colon and Rectum. http://www.cancer.gov/cancertopics/pdq/treatment/colon/HealthProfessional/page6
  6. Surgery is the only potentially curative therapy for mCRC to the liver (laparoscopy and open surgical resection are both still practiced) Some non-surgical treatment options can be used neoadjuvantly and/or adjuvantly to complement surgical outcomes Reference: NCCN. 2011. Clinical practice guidelines in oncology: colon cancer.
  7. Use of non-surgical treatment options for other for types of cancers has shown survival improvement by reducing tumor burden neoadjuvant to surgery Applying the same treatment theory to mCRC liver tumors is an attractive concept that is effective when selecting the correct patients References: 1. Covens AL. Gynecol Oncol. 2000;78:269-274. 2. Thigpen T. N Engl J Med 2004;351:2544-2546. 3. Wyse G, et al. Neuroimaging Clin N Am. 2009;19:161-168. 4. Atwell TD, et al. Cardiovasc Intervent Radiol 2005;28:409-421.
  8. There is a wide range of approved systemic agents, and combination of agents for mCRC to the liver. No new agents approved since 2006 Aflibercept approved 2012 Regorafeniblikely to be approved in 2012 Reference: www.fda.gov
  9. The number of treatment options for patients with mCRC has grown rapidly during the past few decades leading to improvements in median overall survival (OS). Current data supports the role of combined therapy in significantly improving the OS time of patients with mCRC. Current clinical practice guidelines suggest treatment pathways for patients with mCRC. 1,2 References: 1 . Köhne C-H, Lenz H-J. Oncologist. 2009;14:5478-5488. 2. NCCN. 2011. Clinical practice guidelines in oncology: colon cancer.
  10. Widely accepted and referenced chart on the survival improvement resulting from an evolving combination of systemic therapies. While from a 2005 publication in The Oncologist, the projection of 24+ months of survival with the newest combinations of agents listed on the far left side of graph has resulted in this realized median survival in recent years. New agents are being researched all the time, but the concept of a combination of systemic agents PLUS liver directed therapies, and surgery where possible, is very interesting and a main driver of this discussion today.
  11. This section will provide an overview on Selective Internal Radiation Therapy (SIRT).
  12. Radiation is very effective at killing tumor cells in virtually all types of cancer, and its no different for mCRC liver tumors. The problem has been that the healthy liver parenchyma doesn’t do well with passing enough radiation through it, from outside the body, to kill the tumors. Selective Internal Radiation Therapy is an elegant solution of providing the tumoricidal benefits of radiation to tumors within the liver
  13. The delivery of SIRT takes advantage of the differences in blood supply between normal liver and metastatic tissue. Tumors receive over 80% of their blood supply from the hepatic artery. Reference: Archer S, Gray BN. Br J Surg . 1989;76:545-548.
  14. SIRT is an outpatient minimally invasive therapy in which a transfemoral microcatheter is used to access to the hepatic artery supplying the liver. Patients typically go home within 4-6 hours following the procedure and have relatively fewer side effects compared to other therapies for treatment of liver tumors
  15. Microsphere brachytherapy exploits the anatomical and physiological characteristics of vasculature and tolerance: Reference: Source: Andrew S. Kennedy, MD, Wake Radiology Oncology, Cary, NC.
  16. The physical characteristics of radioactive microspheres
  17. This section will review clinical data in mCRC for SIR-Spheres ® microspheres.
  18. Consider borderline unresectable, chemo holiday, patients on dose reduction
  19. Gray and colleagues demonstrated that the addition of a single administration of SIR-Spheres more than doubles the TRR and significantly increases the TTP. 1 (prospective randomized trial) van Hazel and colleagues demonstrated s ignificant improvement in ORR, PFS, and survival. 2 (prospective randomized trial) Sharma and colleagues demonstrated the combined modality of SIR-Spheres and FOLFOX4 is generally well-tolerated in this patient population. 3 (prospective trial) While these are small studies, these data show outcomes favorable to the newest systemic treatment regimens, despite the use of Y90 in combination with earlier systemic agents. This has encouraged the start of a large level 1 RCT that we will speak to in more detail a little later in the presentation References: 1. Gray, et al. Ann Oncol. 2001;12:1711–1720. 2. van Hazel, et al. J Surg Oncol. 2004;88:78–85. 3. Sharma, et al. J Clin Oncol. 2007;25:1099–1106 .
  20. Here’s a look at the same data in a graphical format to illustrate the potential advantage of Y90 in the first line setting
  21. van Hazel’s data indicated that patients who received 5FU/LV (a common first line combination outside the US) in combination with SIR-Spheres microspheres received more than double the number of cycles of chemotherapy than those who received 5Fu/LV alone did. This results from the improved response rate and the patients improved ability to benefit from additional cycles of chemo post Y90 therapy Reference: van Hazel, et al. J Surg Oncol. 2004;88:78–85
  22. We also see similar benefits of adding Y90 to second line therapy. Here ’ s a couple of examples: Lim and colleagues demonstrated promising results in the pre-treated population with a number of partial responses seen in previously failed oxali/irino treatments. 1 van Hazel and colleagues demonstrated acceptable safety profile in 5FU failures as well as promising efficacy. 2 References: Lim, et al. BMC Cancer. 2005;5:132. van Hazel, et al. J Clin Oncol. 2009;27:4089–4095.
  23. The majority of the Y90 evidence today exists in the salvage setting. There is LEVEL 1 evidence for 3 rd line mCRC patients. Allows for a chemo break – resensitizes some patients to oxali / irinotecan Hendlisz demonstrated SIGNIFICANTLY improved overall survival in patients receiving SIR-Spheres – It should be noted that patients in the control arm who received 5FU alone were able to receive SIR-Spheres as salvage therapy on disease progression – this may have compromised the overall survival data . 1 Seidensticker and colleagues demonstrated significant improvement in PFS and overall survival. Patients in this prospective phase II study had failed all chemotherapy options, and were matched with a contemporary pair by tumor burden, prior chemotherapy received, synchronous vs. metachronous metastases, ALP increase and CEA &gt;200 U/mL. 2 Cosimelli and colleagues demonstrated the efficacy and safety of SIR-Spheres in the SITILO study where 76% of patients had failed 4 th or 5 th -line chemotherapy. 3 QOL studies were positive here too References: 1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694 . 2. Seidensticker et al Cardiovasc Intervent RadiolDOI 10.1007/s00270-011-0234-7 3. Cosimelli, et al. Br J Cancer. 2010;103:324–331 .
  24. Let’s look at the Hendlisz study recently published in JCO in a little more detail, here is the study design Reference: Hendlisz A, et al. J Clin Oncol. 2010;28:3687–3694.
  25. The median time to liver progression (TTLP) was 2.1 months in the control arm (5FU only) and 5.5 months in 5FU + SIR-Spheres microspheres arm 62% reduction in the risk of progressing for those receiving SIR-Spheres. Reference: Hendlisz A, et al. J Clin Oncol. 2010;28:3687–3694.
  26. The primary endpoint in the Hendlisz et al study was time to progression. SIR-Spheres when added to 5FU significantly improved median time to progression either in the liver or any organ. Reference: Hendlisz A, et al. J Clin Oncol. 2010;28:3687–3694.
  27. Treatment with 5FU + 90Y resin microsphere was well tolerated, without serious or life-threatening events. Grade 3–4 events were reported in 6 patients receiving 5FU only compared to 1 patient receiving radioembolization + 5FU (p=0.10). Those additional grade 3–4 toxicities in Arm A were probably unrelated to chemotherapy side effects, but rather due to rapidly progressive disease. Reference: Hendlisz A, et al. J Clin Oncol. 2010;28:3687–3694.
  28. Study Design for Matched Pair Radioembolization in Chemotherapy Refractory Liver-Dominant mCRC Analysis. This is a matched-pair comparison of patients who received radioembolization plus best supportive care (BSC) or BSC alone for chemotherapy-refractory, liver-dominant colorectal metastases in the salvage setting. Patients treated prospectively with radioembolization were retrospectively paired with controls who received BSC only. The clinical records of more than 500 patients from 3 centers were evaluated. Matching pairs were identified in two stages: 1) initially matching for prior treatment history and tumor burden and 2) by four matching criteria: liver involvement (±20% absolute difference); synchronous versus metachronous metastases; alkaline phosphatase (ALP) increase versus no increase; and carcinoembryonic antigen (CEA) C200 ng/ml versus \\200 ng/ml. The first 29 consecutive matching patients identified were analyzed to receive either: Treatment Arm A: Best supportive care Treatment Arm B: A single injection of SIR-Spheres microspheres (or two injections during the same procedure if lobar treatment with SIRT is used) into the liver, plus best supportive care Reference: Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print] .
  29. The median overall survival of patients treated with radioembolization (after a median of three lines of chemotherapy) was highly significant at 8.3 months (95% CI, 0.15 to 0.48; P &lt; .001). Reference: Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print] .
  30. The authors concluded that radioembolization using SIR-Spheres significantly prolonged overall survival compared with BSC alone in a well-matched cohort of patients with extensive, liver-dominant refractory disease for whom there are limited treatment options. The authors noted that the evidence suggests that radioembolization should be considered as a treatment option for patients with liver-only or liver-dominant CRC-metastases who have failed or are intolerant of chemotherapy. Reference: Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print] .
  31. Again, the safety information that can be extracted from this study show an acceptable adverse events profile
  32. Kennedy and colleagues, in addition to failing chemotherapy (all had failed 1 st -line; 93% had failed &gt; 2 lines of chemotherapy; and 87% had failed &gt; 3 lines of chemotherapy), 46% had also previously received local-regional therapies (resection, RFA, TACE, etc.). 1 References: 1. Kennedy, et al. Int J Radiat Oncol Biol Phys. 2006;65:412–425.
  33. 208 patients received SIR-Spheres. Responders (as measured by PET) had median survival of 10.5 months, non-responders just 4.5 months (p=0.0001).
  34. Bester retrospectively compared patients who received SIR-Spheres with those receiving just best supportive care. A significant survival advantage was conferred on those receiving SIR-Spheres p=0.001
  35. Both RFA/ablation and SIRT are used extensively with standard chemotherapy regimens for CLM as adjuvant care. While RFA is typically used for singular and small lesion mCRC disease, SIRT is suitable for multifocal or large tumors where ablation isn’t technically feasible. Lets look at the level of clinical evidence between the two types of adjuvant therapy
  36. This section will review the study design for the SIRFLOX clinical trial.
  37. SIRFLOX: Phase 3 study of efficacy and safety of adding SIR-Spheres microspheres to FOLFOX6m as first-line in mCRC This is a multi-center randomized controlled study that will assess the effect of adding targeted radiation, in the form of SIR-Spheres microspheres, to a standard chemotherapy regimen of FOLFOX6m as first-line therapy in patients with non-resectable liver metastases from primary colorectal carcinoma. At the investigator&apos;s discretion, patients will be allowed to receive bevacizumab in addition to the FOLFOX6m chemotherapy regimen. A total of 450 eligible patients with non-resectable liver metastases from a primary colorectal carcinoma, either with or without evidence of extra-hepatic metastases and who have not received prior chemotherapy for advanced disease, will be randomized to receive either: Treatment Arm A: Systemic chemotherapy consisting of oxaliplatin + leucovorin + 5-fluorouracil (FOLFOX6m) Treatment Arm B: A single injection of SIR-Spheres microspheres (or two injections during the same procedure if lobar treatment with SIRT is used) into the liver, plus systemic chemotherapy consisting of oxaliplatin + leucovorin + 5-fluorouracil (FOLFOX6m). Approx 300 pts have been enrolled to date, anticipate complete enrollment late 2012 Reference: www.clinicaltrials.gov. NCT00766220
  38. There was no interim efficacy analysis. No increased adverse events in the SIR-Spheres microspheres group many of whom received bevacizumab.
  39. There was no interim efficacy analysis. No increased adverse events in the SIR-Spheres microspheres group many of whom received bevacizumab.
  40. This is an example of a “base case” in OPPS for the technical charges and only includes the CPT codes that are billed for the Y-90 procedure. Excludes E/M codes and other Interventional services. The Y-90 dose is reimbursed under PPPS (prospective payment) and is paid separate from the interventional services.
  41. While comparison of the clinical endpoints such as PFS or OS is not realistic due to different patient types (including resectable vs unsectable patients, early in chemo treatment lines vs chemo refractory patients, etc..) it’s important to note that credibility is given to the RFA/Ablation body of clinical evidence. The same credibility is warranted for SIRT looking at the SIRT body of clinical evidence. 1) Hur H, Ko YT, Min BS, et al., Am J Surg 2009; 197:728–736. 2) Solbiati L, Livraghi T, Goldberg SN, et al. Radiology 2001; 221:159–166 3) Gillams AR, Lees WR, Radiol 2008; 19:712–717. 4) Elias D, De Baere T, Smayra T, Ouellet JF, Roche A, Lasser P., Br J Surg 2002; 89:752–756. 5) Oshowo A, Gillams A, Harrison E, Lees WR, Taylor I., Br J Surg 2003; 90:1240–1243. 6) Machi J, Oishi AJ, Sumida K, et al., Cancer J 2006; 12:318–326. 7) Vogl TJ, Straub R, Eichler K, Sollner O, Mack MG., Radiology 2004; 230:450–458. 8) Sørensen SM, Mortensen FV, Nielsen DT, Acta Radiol 2007; 48: 253–258. 9) Sofocleous CT, Petre EN, Gonen M, et al, J Vasc Interv Radiol 2011; 22:755–761. 10) Gray B, Van Hazel G, Hope M, et al., Ann Oncol 2001; 12:1711–1720. 11) Hendlisz A, Van den Eynde M, Peeters M, et al., J Clin Oncol 2010; 28:3687–3694. 12) Seidensticker R., Denecke t., Kraus P., et al., Cardiovasc. Intervent Radiol, Jul 2011 13) Bester L, Meteling B., Pocock N., Pavlakis N., Chua t., Saxena A, Morris D., J Vasc Interv Radiol 2012; 23:96–105 14) Cosimelli M et al. BR J Cancer 2010; 15) Kennedy AS, Coldwell D, Nutting C, et al., Int J Radiat Oncol Biol Phys 2006; 65:412–425. 16) Van Hazel G, Blackwell A, Anderson J, et al, J Surg Oncol 2004; 88:78–85. 17) Sharma RA, Van Hazel GA, Morgan B, et al., J Clin Oncol 2007; 25:1099–1106. 18) Evans KA, Richardson MG, Pavlakis N, Morris DL, Liauw W, Bester L., J Vasc Interv Radiol 2010; 21:1521–1526.