Modeling Protease Inhibitors by suchenfz

VIEWS: 5 PAGES: 76

									Keeping Pace with Targeted Therapies in Lung Cancer
   Highlights from the ASCO 2006 Annual Meeting




                                                      1
Introduction




               2
Overview of Targeted Therapies
  and Focus on Monoclonals
            Karen Kelly, MD
          Professor of Medicine
     Department of Medical Oncology
     University of Colorado at Denver
            Aurora, Colorado

                                        3
                 FDA-Approved Agents Being
            Investigated for Lung Cancer Treatment
  Agent                                           Class                              Targets                               Indications

  Bevacizumab                               Monoclonal (IV)                           VEGF                                     CRC
  (Avastin®; Genentech)
  Cetuximab                                                                           EGFR                         Head & neck cancer, CRC
  (Erbitux®; ImClone)
  Erlotinib                              Reversible TKI (oral)                    HER1/EGFR                                  NSCLC
  (Tarceva®; Genentech)
  Gefitinib                                                                       HER1/EGFR                                  NSCLC
  (Iressa®; AstraZeneca)
  Sunitinib                                                             VEGFR-1, -2, -3; PDGFR-α, -β;                      RCC, GIST
  (Sutent®; Pfizer)                                                           KIT; RET; FLT3
  Sorafenib                                                               VEGFR-2, -3; cRAF; bRAF;                             RCC
  (Nexavar®; Bayer)                                                         PDGFR-β; FLT3; KIT
  Bortezomib                             Proteasome inhibitor                      Proteasome                          Multiple myeloma
  (Velcade®, Millennium)                         (IV)

  Bexarotene                                 Retinoid (oral)                  RXRα, RXRβ, RXRγ                    Cutaneous T-cell lymphoma
  (Targretin®; Ligand)

VEGF = vascular endothelial growth factor; CRC = colorectal cancer; EGFR = epidermal growth factor receptor; TK = tyrosine kinase; NSCLC = non–
small-cell lung cancer; PDGFR = platelet-derived growth factor receptor; RCC = renal cell carcinoma; GIST = gastrointestinal stromal tumor;
RXR = retinoid X receptor.
                                                                                                                                                  4
     Examples of Novel Targeted Agents Being
      Investigated for Lung Cancer Treatment
 Biologic Target                    Class                     Molecular Targets                                 Agent
 Tumorigenesis                    Monoclonal                       EGFR                                     Panitumumab
                                     (IV)                                                                      (Amgen)
 Angiogenesis                     Reversible                    VEGFR-1, -2, -3;                              Vatalanib
                                   TKI (oral)                     PDGFR-β                               (Novartis/Schering AG)
                                                               VEGFR-1, -2, -3;                             AMG706 (Amgen)
                                                                PDGFR; RET
                                                                 VEGFR-2                               AZD2171 (AstraZeneca)
 Angiogenesis +                       Dual                    VEGFR-2, -3; RET;                          ZD6474 (Zactima;
 tumorigenesis                  reversible TKI                    EGFR                                     AstraZeneca)
                                      (oral)
 Tumor                              Vaccine    TGF-β antisense gene TGFβAS Vaccine (Lucanix;
                                 (intradermal)  modified allogeneic       NovaRx)
                                                 tumor cell vaccine
EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor; PDGFR = platelet-derived
growth factor receptor; TGF = transforming growth factor.
                                                                                                                                                5
                                        ASCO 2006 Update
                                          Bevacizumab in NSCLC


         Paclitaxel + carboplatin ± bevacizumab (updated
         results from randomized phase III trial E4599)
            Sandler AB, et al.1
            Brahmer JR, et al.2
            Dowlati A, et al.3




1. Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4. 2. Brahmer JR, et al. 42nd ASCO;
June 2-6, 2006. Abstract 7036. 3. Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.       6
              Paclitaxel/Carboplatin ± Bevacizumab
                         Previously Reported ECOG 4599 Results
                                                         PC                PCB
                                                      (n = 427)          (n = 420)           P-Value
   Response rate, %*                                        10              27.2             < .0001
   Median PFS, mo                                          4.5               6.4              < .0001
   6-mo PFS, %                                            32.6              55.0
   1-y PFS, %                                              6.4              14.6
   Median OS, mo                                          10.2              12.5                .007
   12-mo OS, %                                            43.7              51.9
   24-mo OS, %                                            16.9              22.1
  *As percent of patients with measurable disease, n = 350 for the PC arm and n = 357 for PCB arm.
  ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab;
  PFS = progression-free survival; OS = overall survival.
Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4.
                                                                                                        7
                Paclitaxel/Carboplatin ± Bevacizumab
                     Possible Gender Differences in Overall Survival

        Unplanned subgroup analysis of ECOG 4599
        Key finding: compared with males, females did not appear to gain
         same overall survival benefit from addition of bevacizumab

                                                               PC             PCB                  P-Value
    Overall survival, mo                                       10.3           12.3                  .003
    Overall survival males, mo                                 8.7            11.7                  .001
    Overall survival females, mo                               13.1           13.3                   .87
    ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab.




Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.
                                                                                                             8
                Paclitaxel/Carboplatin ± Bevacizumab
                       No Gender Differences in Overall Survival

         Females on PCB arm had higher response rate and progression-
          free survival compared with females in the PC arm

                                                      Males                             Females
                                       PC              PCB                PC       PCB
                                    (n = 230)        (n = 191) P-Value (n = 162) (n = 190) P-Value
     Overall response                   15.7           28.8      .001    14.2      41.1    < .0001
     rate (CR + PR), %
     Progression-free                   4.3              6.3   < .0001        5.3           6.2         .002
     survival, mo
     P = paclitaxel; C = carboplatin; B = bevacizumab; CR = complete response; PR = partial response.




Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.
                                                                                                               9
              Paclitaxel/Carboplatin ± Bevacizumab
                    Perspective on Unplanned Analysis by Gender
          Treatments at time of disease progression were not different, except that in
           the PCB arm, females were slightly less likely than males to get
           chemotherapy as 2nd-line therapy
          Reasons for observed differences in overall survival are unclear, possibilities
           include
             – Random chance
             – Pitfalls of unplanned subgroup analysis
          These results contrast with results in CRC trials where no gender differences
           reported in overall survival
          PCB remains ECOG reference treatment in NSCLC
     PCB = paclitaxel/carboplatin/bevacizumab; CRC = colorectal cancer; ECOG = Eastern Cooperative Oncology
     Group; NSCLC = non–small-cell lung cancer.

Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.
Laskin JJ. 42nd ASCO; June 2-6, 2006. Lung Cancer I Poster Discussion. Discussant.
Hurwitz H, et al. N Engl J Med. 2004;350:2335.
Genentech data on file                                                                                        10
              Prospective Correlative Assessment of
                  Biomarkers from ECOG 4599
         Biomarkers studied
          Endothelial leukocyte adhesion molecule-1 (E-selectin)
             – Expressed only on endothelial cell after activation by
                 inflammatory cytokines
             – Elevated E-selectin seen in disorders characterized by endothelial
                 cell apoptosis and malignancies
          Intercellular adhesion molecule-1 (ICAM-1; CD54)
             – Expressed on endothelial, epithelial, lymphocytes, monocytes,
                 hepatocytes, and hemapoietic cells
             – Elevated levels seen in many malignancies and alterations seen
                 with vascular targeting and antiangiogenic agents
          Vascular endothelial growth factor (VEGF) and basic-fibroblast growth
            factor (b-FGF)
             – Well-known angiogenic factors
Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.
                                                                                    11
             Prospective Correlative Assessment of
             Biomarkers From ECOG 4599—Results
      Baseline plasma ICAM may be
                                                                                             Survival by Baseline ICAM
       prognostic for response and survival                                        1.0 -

       in advanced NSCLC                                                           0.8 -
                                                                                                       <260.5 (62 deaths/75 cases)
                                                                                                       >260.5 (70 deaths/75 cases)
           – This might be useful stratification




                                                                     Probability
                                                                                   0.6 -               P = .000050

             factor in future trials                                                                          1 y 60%
                                                                                   0.4 -

           – Low levels indicate a 2-fold                                          0.2 -
             increase in likelihood of response                                            1 y 25%
             to chemotherapy (unclear if this is
                                                                                   0.0 -

                                                                                       0          10         20         30           40

             prognostic or predictive)                                                                    Months


      Future trials are needed to determine
       if these will be better markers for
       clinical outcome than conventional
       radiographic response assessment

Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027. Reprinted with permission from Dr. Dowlati.
Hirsch F. 42nd ASCO; June 2-6, 2006. Lung Cancer III. Discussant.                                                                         12
     Risk Factors for Pulmonary Hemorrhage (PH)
           in Bevacizumab-Treated Patients

         Retrospective study of ECOG 4599 data examining association
         between baseline clinical factors and incidence of early onset
         (< 150 d from initial treatment) PH
          Grade  3 PH occurred in 2.3% of patients
          Of 10 cases identified, 6 met criteria for early onset PH related
            to bevacizumab
          Pretreatment cavitation may be associated with increased risk
            of PH
          Hemoptysis was predicative of possible future PH



Sandler AB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7068.
                                                                               13
                                    ASCO 2006 Update on
                                    Cetuximab in NSCLC


               SWOG 0342 phase II trial of chemotherapy +
                cetuximab vs chemotherapy followed by
                cetuximab1
               FLEX phase III trial of cisplatin/vinorelbine ±
                cetuximab2



1. Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.
2. Von Pawl, J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.
                                                                   14
        Preliminary Results of SWOG 0342 Phase II
        Trial of Paclitaxel/Carboplatin + Cetuximab
     Primary objectives
      Compare response rate and toxicity of concurrent vs sequential
        platinum-based chemotherapy + cetuximab regimens as 1st-line
        treatment for advanced NSCLC
      Select regimen for future trials based on overall survival

                                                        Paclitaxel/
                                                       carboplatin +                             Cetuximab
                                                        cetuximab                                weekly × 1
                                                        × 4 cycles                                  year
                Randomize                                (n = 106)
                stage IIIB/IV
                  NSCLC
                                                        Paclitaxel/                              Cetuximab
                                                        carboplatin                              weekly × 1
                                                        × 4 cycles                                  year
                                                         (n = 119)

Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly.
                                                                                                              15
                             Phase II Trial of
                   Paclitaxel/Carboplatin + Cetuximab
                                       Preliminary Efficacy Results
                                                            Chemo                     Chemo +
                                                            Cetuximab                 Cetuximab
                                                            (n = 119)*                (n = 106)*
   Complete response                                             0                         0
   Partial response, % (95% CI)                             25 (17–36)                37 (26–49)
   Stable disease, % (95% CI)                               44 (33–55)                38 (27–50)
   Disease stabilization, %                                 69 (58–78)                75 (63–84)
     (95% CI)
   Progression-free survival, mo                                4                            4
   Median overall survival, mo                                  9                           10
   1-year overall survival, %                                  43                           49
   *Patients evaluable for response: 71 in the chemo + cetuximab arm and 87 in the chemo-only arm.
Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.
                                                                                                     16
                                                        SWOG 0342—Phase II Trial of
                                                      Paclitaxel/Carboplatin + Cetuximab
                                                                            Preliminary Safety Results
                                             Adverse Events (grade 3/4)
                                      80 -
                                                       67
            % of Evaluable Patients




                                      70 -

                                      60 -     55
                                      50 -
                                                                                                       Grade 3/4 AE (>5%) on Chemo (+/-C)
                                              N=101 N=94
                                      40 -                                       Sequential

                                                                     27          Concurrent
                                      30 -                                                       Adverse       Chemo + C   Chemo       C
                                                               20
                                      20 -                                                       Event           N = 94       N = 94       P-Value
                                                              N=20 N=22
                                      10 -                                                       Dyspnea          6.4           4            NS
                                       0-
                                              Chemo +/- C    Post-Chemo C
                                                                                                 Fatigue          8.5           9            NS

                                                                                                 Leukocytes       16           18.8          NS

                                                      Rash (grade 3/4)                           Joint pain       6.4           3            NS

                                                                                                 Nausea           6.4           2            NS
                                      14 -
                                                       12                                        Neuropathy       15            5.9          .04
            % of Evaluable Patients




                                      12 -
                                                               10
                                      10 -                                                       Neutrophils     41.4          36.6          NS
                                                      N=94
                                       8-
                                                              N=20 N=22
                                       6-                                        Sequential
                                                                    No new       Concurrent
                                       4-                           cases
                                       2-       1                   concurrent
                                              N=101                 ann
                                       0-
                                              Chemo +/- C    Post-Chemo C
                                                                                              Chemo = paclitaxel/carboplatin; C = cetuximab.
Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly.
                                                                                                                                                     17
                             Phase II Trial of
                   Paclitaxel/Carboplatin + Cetuximab
                                           Preliminary Conclusions
              Concurrent cetuximab + chemotherapy arm met
               predetermined 10-month minimal median survival
               requirement
              Trend toward higher response rate in concurrent arm
              Rash only significant additional toxicity seen with
               concurrent administration of cetuximab + chemotherapy
              Biomarker correlative studies ongoing
              New trials with this concurrent regimen + bevacizumab
               planned

Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.
                                                                       18
                             Phase III Trial of
                    Cisplatin/Vinorelbine ± Cetuximab
                                         Preliminary Safety Report
             Stage IIIB with documented malignant pleural effusion or stage
              IV previously untreated NSCLC
             Epidermal growth factor receptor expression by
              immunohistochemistry
             Patients recruited from 166 centers in 29 countries in Europe,
              Asia, Australia, and South America
             Primary objective: overall survival
             Preplanned analysis by Data Safety Monitoring Board (DSMB) of
              baseline and safety data from 365 patients
             Results
               – Recruitment completed in February 2006
               – 1125 patients randomized
               – Trial continues
Von Pawl J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.
                                                                               19
     SWOG S0339—Phase II Trial of Bortezomib +
            Gemcitabine/Carboplatin
              Design
                – Primary endpoint: OS (goal 10 month median OS to rule
                    out null hypothesis)
                – Stage IIIB (with pleural effusion) or IV NSCLC,
                    chemotherapy-naive
                – PS = 0 or 1
              Results
                – N = 121 accrued (116 eligible)
                – Median age: 64 years (range, 28–78)
                – 11% stage IIIB, 86% stage IV
                – Median follow-up: >15 months
                – Median number of cycles: 3.6
       SWOG = Southwest Oncology Group; OS = overall survival; PS = performance status.

Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.                               20
                                Phase II Trial of Bortezomib
                                + Gemcitabine/ Carboplatin
                                          Efficacy and Safety Results
                                         No. (%)              Grade 3/4 Toxicity in          No. (%)
         Response                       (n = 114)             > 10% of Patients             (n = 114)
         ORR                              24 (21)             Neutropenia                    59 (52)
          CR                                2 (2)
                                                              Thrombocytopenia               72 (63)
          PR                              22 (19)
                                                              Anemia                         15 (13)
         SD                               51 (45)
                                                              Fatigue                        15 (13)
         PD                               21 (18)
                                                              AST/ALT                        14 (12)
         Not evaluable                    18 (16)

             Overall survival 11 months (95% CI 8.2–13 months)
             1-year survival 47%; 2-year survival 14%
             Results above predetermined statistical endpoint to proceed to a phase III trial
       ORR = overall response rate; CR = complete response; PR = partial response; SD = stable disease;
       PD = progressive disease; AST = aspartate aminotransferase; ALT = alanine aminotransferase.

Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.
                                                                                                          21
                       Summary

   Clarification with regards to carboplatin/paclitaxel ±
    bevacizumab phase III trial ECOG 4599
     – Bevacizumab does have some differential gender effect
         on overall survival, but not clinically meaningful
     – Potential predictive or prognostic biomarkers
     – Risk factors for bevacizumab-associated pulmonary
         hemorrhage
   Promising results from phase II trials
     – Cetuximab + carboplatin/paclitaxel
     – Cetuximab + cisplatin/vinorelbine
     – Bortezomib + gemcitabine/carboplatin
   Data from phase III trials needed for cetuximab and bortezomib
                                                                     22
Focus on Small Molecules and
   Investigational Agents
        Roy S. Herbst, MD, PhD
          Professor of Medicine
      Department of Thoracic/Head
       and Neck Medical Oncology
           University of Texas
      M.D. Anderson Cancer Center
             Houston, Texas

                                    23
            Update on Small Molecule
            and Investigational Agents

   Tyrosine kinase inhibitors      Investigational agents
    with FDA approvals                – Vatalanib
                                      – ZD6474
     – Sunitinib                      – ABI-007
     – Sorafenib                      – AMG706/panitumumab
     – Erlotinib                    Biomarkers
                                      – Osteopontin
     – Gefitinib
                                      – EGF, Her2, p-Akt
                                      – RXR-beta, pPARy




                                                              24
Tyrosine Kinase Inhibitors Target Both the Tumor and Endothelial Cells
             Growth Factor Receptor
                                             VEGFR/PDGFR
             EGFR
             RAS-RAF
             VEGFR
             NRP1                                     VEGFR 1,2,3
                                                      PDGFR
              Nucleus                                               Nucleus




            Tumor Cell                              Endothelial Cell
                                      VEGF
                                                                              PDGF




              Endothelial Cell                   Pericytes
                                                                                     25
                 Similarities and Differences in Targets for TKIs
                                and Monoclonals

               Inhibitor                           Erlotinib                              Bevacizumab
               Mechanism             Inhibits tumor cell growth                    Inhibits endothelial cells from
                                     and blocks synthesis of                       responding to the angiogenic
                                     angiogenetic proteins                         protein VEGF
                                     (eg, bFGF, VEGF, TGF-
                                     by tumor cells



                                                        bFGF
                                                        VEGF
                                                        TGF-




                Tumor                                                        Endothelial cells

Herbst RS, et al. J Clin Oncol. 2005;23:2544. Reprinted with permission from the
American Society of Clinical Oncology.
                                                                                                                     26
      Sunitinib Phase II Trial in Previously Treated
                   Advanced NSCLC
           Open-label, single-arm, 2-stage multicenter trial
           Patients had recurrent stage IIIB/IV NSCLC that had failed 1 or more
            chemotherapy regimens (with/out EGFR inhibitor)
           Sunitinib given at 50 mg/d for 4 wk followed by 2 wk off treatment
            before next 6-week cycle
           Primary endpoint: overall confirmed objective response rate (ORR)
           Enrollment
             – 63 patients
             – 64% had adenocarcinoma, 90% had stage IV disease
             – 43% had 1 prior regimen, 44% had 2 prior regimens, 13% had 3
                 or more prior regimens
             – 33% had received prior EGFR inhibitor
Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.
                                                                                   27
                      Sunitinib Phase II Trial in
                Previously Treated Advanced NSCLC
                                                   Safety Results

   Severe Events Occurring in  10% of Patients                        % of Patients
   Adverse Event                                                    Grade 3   Grade 4
   Fatigue/asthenia                                                   22         5
   Pain/myalgia                                                       14         3
   Nausea/vomiting                                                    10         0
   Dyspnea                                                            13         0

        Most toxicities were grade 1 or 2
        3 hemorrhage-related deaths on study: 2 (a pulmonary hemorrhage and
         a cerebral hemorrhage) were considered study-drug related
Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.
                                                                                        28
                                 Sunitinib Phase II Trial in
                           Previously Treated Advanced NSCLC
                                                     Efficacy Results

                                  No. (%)                                                       Best Response for
                                  (n = 63)                                                   Target Lesions by Patient
  Response                                                                            100


  ORR                          6 (9.5)                                                 80
                                                                                                 Partial Responses by RECIST

                           95% CI (3.6–19.6)                                           60




                                                           Change from Baseline (%)
                                                                                                 Stable Disease/Progressive Disease
                                                                                       40

  PR                               6 (9.5)                                             20


  SD                             27 (42.9)
                                                                                        0

                                                                                       -20


  PD                             14 (22.2)                                             -40

                                                                                       -60

  Not evaluable                  16 (25.4)                                             -80

                                                                                      -100


  Median duration of response: 12.2 weeks (range, 4.3–30.1+ weeks)
  Median PFS: 11.3 weeks (95% CI 10.0–15.7)
  Median OS: 23.9 weeks (95% CI 17.0–28.3)
 ORR = overall response rate; PR = partial response; SD = stable disease; PD = progressive disease;
 RECIST = response evaluation criteria in solid tumors.
Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001. Reprinted with permission from Dr. Socinski.
                                                                                                                                      29
   Phase II Trial of Sorafenib in Advanced NSCLC
             Primary objective: tumor response by RECIST of sorafenib 400 mg BID in
              previously treated pts
             Eligibility
               – 1–2 prior treatments
               – No prior gefitinib
               – Asymptomatic brain metastases permitted
             Enrollment
               – 52 patients
               – Median age 62 years (range, 26–85)
               – 85% ECOG PS = 1
               – 54% adenocarcinoma, 31% squamous cell carcinoma
               – 94% stage IV
               – 67% 1 prior chemotherapy; 29% 2 prior chemotherapy

      RECIST = response evaluation criteria in solid tumors; ECOG = eastern cooperative oncology group;
      PS = performance status.
Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.
                                                                                                          30
                 Phase II Trial of Sorafenib in Advanced NSCLC
                                                    Efficacy Results

                                                                   Maximum Percentage Reduction of
                                                                    Target Lesion by Patient (N = 48)†
  Response                      No. (%)                    60


                                (n = 51)
                                                                                                   SD Patients   PD Patients
                                                           40



  SD                             30 (59)                   20




  PD                             18 (35)
                                                            0


                                                          -20

  Not evaluated*                  3 (6)                   -40


                                                          -60


      Tumor cavitation in 4 patients
      Median PFS: 2.7 mo; median OS: 6.7 mo
      SD patients: median PFS 5.5 mo
      2 patients treated for > 2 years with ongoing treatment
  SD = stable disease; PD = progressive disease; PFS = progression-free survival; OS = overall survival.
*Patients died prior to tumor assessment. †48 patients with postbaseline tumor measurements available.
Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier.
                                                                                                                               31
       Phase II Trial of Sorafenib in Advanced NSCLC
                              Safety and Biomarker Analysis Results
     Safety                                                                          Biomarker analysis
       – No grade 4 events                                                                – Plasma biomarkers evaluated
       – Grade 3 events: hand-foot skin                                                       by ELISA
           reactions (20%), hypertension                                                  – High VEGF at baseline
           (4%), diarrhea (2%), fatigue (2%),                                                 correlated with shorter survival
           headache (2%)                                                                      (P < .05)
       – 4 patients had sorafenib-related
           bleeding events (3 epistaxis, 1 fatal


                                                               Survival Fraction
                                                                                   1.0                             Low VEGF
           pulmonary hemorrhage 30 days
                                                                                                                   High VEGF
           after stopping sorafenib)
                                                                                   0.5


                                                                                   0.0
                                                                                         0   100 200 300 400 500 600 700
                                                                                                  Time to Death (Days)
   ELISA = enzyme-linked immunosorbent assay; VEGF = vascular endothelial growth factor.
Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier.
                                                                                                                                 32
   Phase II Trial of Sorafenib in Advanced NSCLC
                                                     Conclusions


           Sorafenib has some activity in NSCLC
           Historical comparisons show that 59% stable disease is in
            same range as other targeted agents in NSCLC
           Agent generally well tolerated, with low incidence of bleeding
           Deterioration of quality of life not seen
           Shorter median overall survival correlated with high baseline
            VEGF and greater decreases in plasma VEGF during sorafenib
            treatment
           Phase III study of carboplatin/paclitaxel ± sorafenib is currently
            accruing patients

Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.
                                                                                 33
    Randomized Phase II Trial of Chemotherapy ±
      Bevacizumab vs Erlotinib + Bevacizumab

         Phase II, multicenter 3-arm randomized trial
           – Arm 1: chemotherapy (docetaxel or pemetrexed) + placebo
           – Arm 2: chemotherapy (docetaxel or pemetrexed) + bevacizumab
           – Arm 3: erlotinib + bevacizumab
         Arms 1 and 2 were double-blinded
         Patients stratified by ECOG performance status and smoking history
         Eligibility: recurrent unresectable NSCLC
         Primary endpoint: safety and preliminary efficacy



Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062.
                                                                               34
                Phase II Chemotherapy ± Bevacizumab vs
                         Erlotinib + Bevacizumab
                                                            Efficacy
                                                                          Chemotherapy +                    Erlotinib +
                                               Chemotherapy                Bevacizumab                     Bevacizumab
                                                   (n = 41)                  (n = 40)                         (n = 39)
  Progression-free survival
    Median, mo                                        3.0                         4.8                               4.4
    6-mo rate                                       21.5%                        30.5%                         33.6%
    Adjusted HR* (95% CI)                             NA                   0.66 (0.38, 1.16)              0.72 (0.42,1.23)

    Unadjusted HR (95% CI)                            NA                   0.78 (0.47, 1.30)              0.76 (0.45, 1.28)
  Overall survival
    6-mo rate                                       62.4%                        72.1%                         78.3%
  Response rate
    CR/PR                                           12.2%                        12.5%                         17.9%
    CR/PR/SD                                        39.0%                        52.5%                         51.3%

   *Adjusted by randomization stratification factors (ECOG PS, smoking history).
   HR = hazard ratio; NA = not applicable; CR = complete response; PR = partial response; SD = stable disease.
Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher.
                                                                                                                              35
                      Phase II Chemotherapy ± Bevacizumab vs
                               Erlotinib + Bevacizumab
                                                            Safety
                                                                               Percent of Patients
                                                                                Chemotherapy +              Erlotinib +
                                                      Chemotherapy               Bevacizumab               Bevacizumab
                                                         (n = 41)                  (n = 40)                   (n = 39)
    Toxicities
    Most common overall
      Fatigue                                                 66                        70                          56
      Nausea                                                  48                        42                          41
      Diarrhea                                                17                        40                          69
      Rash/dermatitis/acneform                                29                        20                          82
      Anemia                                                  22                        32                          10
      Neutropenia                                             24                        30                          10
    Most common grade 3/4
      Fatigue                                                 12                        12                          7
      Neutropenia                                             17                        20                          5
    Drug-related deaths                                       2                          3                          1

Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher.         36
                        Phase II Trial of Erlotinib vs
                      Carboplatin/Paclitaxel in NSCLC

           Primary endpoint: PFS (treatment worthy of further evaluation if PFS  3.5
            months)
           Study design
             – Eligibility: stage IIIB or IV no prior chemotherapy
             – Performance status 2
             – No prior treatment with any EGFR inhibitor; no uncontrolled brain
                  metastases
             – Optional cross-over to erlotinib
           Enrollment: 103 patients
           Arms well balanced in demographics and baseline characteristics



      PFS = progression-free survival; EGFR = epidermal growth factor receptor.

Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.
                                                                                         37
                                Phase II Trial of Erlotinib vs Carboplatin/
                                        Paclitaxel (CP) in NSCLC
                                                           Efficacy Results
                             Progression-Free Survival (PFS)
                                                                                                        No. of Pts (%)
                     1.0 -

                     0.9 -
                                         Group     N Median(M) 95% Cl             Response          Erlotinib      CP
                                                                                                    (n = 52)     (n = 51)
                                         Erlotinib 52  1.91   (1.28, 2.69)
                     0.8 -
                                         PC        51  3.52   (1.48, 4.87)

                     0.7 -                                                        PR                   1 (2)      6 (12)
                     0.6 -
   PFS Probability




                                                                                  SD                  19 (37)     21 (41)
                     0.5 -

                     0.4 -
                                                                                  PD                  23 (44)     10 (20)
                     0.3 -                                                        Unable to           8 (15)      13 (25)
                     0.2 -
                                                                                  determine/not
                     0.1 -
                                                                                  evaluated
                     0.0 -                                                        Still on active      1 (2)       1 (2)
                         0        6      12         18          24           36   therapy
                                         PFS (Months)




Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022. Reprinted with permission from Dr. Lilenbaum.
                                                                                                                            38
                             Phase II Trial of Erlotinib vs
                           Carboplatin/Paclitaxel in NSCLC
                                                     Conclusions
             Single-agent erlotinib treatment did not meet progression-free
              survival endpoint to warrant further evaluation
             Results in erlotinib-treated patients who developed grade 2+
              rash were “in closer range to chemotherapy”
             Sample size too small to make significant correlation between
              biomarkers analyzed and outcome
             Quality of life parameters similar between 2 treatment arms
             Development of erlotinib in 1st-line NSCLC centers on
               – Molecular selection of patients
               – Combination with other targeted agents
               – Dosing optimization

Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.
                                                                               39
                Molecular Predictors of Outcome with Erlotinib in
                   Bronchioloalveolar Cell Carcinoma (BAC)

             Results of a prospective phase II trial
             Objective: compare clinical, pathologic, and molecular characteristics of tumor
              specimens associated with response, PFS, and OS
             Marker analysis: EGFR (mutations, amplification, polysomy, chromogenic in situ
              hybridization [CISH]), KRAS (mutations)


         Outcome of Patients Treated with Erlotinib                           Molecular Characteristics and Outcome

                                                                                                              Median PFS      Median OS
                             n Median PFS Median OS                                       n    RR(%)    P        (mo)    P      (mo)    P
                                  (mo)      (mo)                             EGFR mut +   18    83     <.01       13   <.01      23   .65
                                                                             EGFR wt      64     7                2              17
           All              102       4           17
                                                                             CISH ≥ 4     24    43     <.01       9    <.01      25   .38
           CR+PR            22       15           24                         CISH < 4     53    13                2              16
           Stable disease   38        6           29                         IHC ≥ 1      25    20     .99        4    .76       19   .60
                                                          P < .01            IHC 0        39    21                4              16
           Progression      36        1            8                         KRAS mut +   19     0     <.01       4    .25       13   .24
           Not evaluable     6        1            1                         KRAS wt      62    32                5              21



Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003. Adapted with permission from Dr. Miller.
                                                                                                                                            40
                      Molecular Predictors of Outcome
                           with Erlotinib in BAC
                                                       Conclusions
             Erlotinib resulted in 23% overall response rate (ORR) and 17 mo
              median overall survival (OS) in BAC
             Presence of EGFR mutation associated with an 83% ORR,
              13 mo progression-free survival (PFS) and 22 mo OS
             EGFR amplification in BAC rare
             EGFR polysomy predictive of improvement in PFS
             KRAS exon 2 mutation associated with no responses and poorer OS
             Patients with EGFR mutation + CISH  4 had ORR 90%,
              PFS 15 mo, OS 35 mo
             Patients with wild type EGFR + CISH < 4 had ORR 4%, PFS 2 mo,
              OS 15 mo

Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003.                     41
                      Phase II Trial 1st-Line Erlotinib in Patients
                         with NSCLC and EGFR Mutations
                                  Primary endpoint: time to progression
                                  Eligibility
                                    – Stage IIIB/IV NSCLC + mutated EGFR
                                    – No prior chemotherapy
                                    – No prior EGFR targeted agents

           Response, % (95% CI)                 All (n = 38)   Exon 19 (n = 20)   Exon 21 (n = 18)
           ORR                                      82               95                 67
                                                  (66–92)         (75–100)            (41–87)
           CR                                       13.2             20                 5.5
           PR                                       68.4             75                61.1
           SD                                       13.2              5                22.2
           PD                                        5.3              0                 11.1
Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020.
                                                                                                     42
                     Phase II Trial 1st-Line Erlotinib in NSCLC
                               with EGFR Mutations
                                                                              Results
                           Response Predictors                                           TTP According to Mutational Status
                          ORR       P-value                         ORR        P-value                      Log Rank P =.06
     EGFR Mutation                   .038     PS                                .662                        Breslow P =.06
               Exon 19   19 (95%)                             0     8 (73%)
                                                              1    18 (86%)
               Exon 21   12 (67%)
                                                              2     5 (83%)
     Smoking                         .038     Histology                         .754
                Never    24 (90%)                         Adeno    23 (79%)
               Former     7 (70%)                           BAC     4 (100%)
               Current    0 (0%)                           Other    4 (80%)
     Gender                          .203     Stage                              1.0
               Female    22 (88%)                           IIIB   4 (100%)
                 Male     9 (69%)                             IV   27 (79%)               TTP According to Smoking Habits
                                                                                                             Log Rank P =.12
                                                                                                             Breslow P =.02
  Conclusions
     Most benefit: Exon 19 deletions, patients who never
      smoked, visceral site other than lung
     Phase III trial planned (erlotinib vs platinum-based
      chemotherapy in EGFR-mutated NSCLC)
Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020. Reprinted with permission from Dr. Paz-Ares.
                                                                                                                               43
                                    Randomized Phase II Trial of ZD6474 vs
                                        Gefitinib in Advanced NSCLC
                                                                          Part A Results
                                Primary Endpoint in Part A:                                                 Individual Changes in Size of Target
                                Progression-Free Survival                                                      Lesions from Baseline: Part A




                                                                                   Best Confirmed Change from Baseline
                                                                                                                                                                           ZD6474
     Probability of Remaining




                                                     Hazard ratio = 0.69




                                                                                         in Target Lesion Size (%)
                                                     95% Cl = 0.50 to 0.96
        Progression-Free




                                                     Two-sided P-value = .025

                                                          Median PFS
                                                          ZD6474 = 11.0
                                                          Gefitinib = 8.1 weeks                                                                                           Gefitinib




                                                                                                                                                           Final data cut-off, July 2005
                                  Progression-free survival in Part A (months)



             Secondary Efficacy Endpoint in Part A                                                                                 No. of Patients (%)

                                                                                   ZD6474 (n = 83)                                              Gefitinib (n = 85)
             Objective response                                                                                           7 (8)                          1 (1)
             Disease control > 8 wk                                                                                      37 (45)                     29 (34)

Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.
                                                                                                                                                                                           44
                   Randomized Phase II Trial of ZD6474 vs
                       Gefitinib in Advanced NSCLC
                                                                         Part B Results


                                                                 Secondary Endpoint:
                                                                   Overall Survival
                         Probability of Remaining Alive




                                                                                    Median PFS
                                                                                    ZD6474 then gefitinib = 6.1 months
                                                                                    Gefitinib then ZD6474 = 7.4 months




                                                          Hazard ratio = 1.19
                                                          (95% Cl = 0.84 to 1.68)
                                                          Two-sided P-value = .34


                                                                              Time to Death (months)
                                                                                                            Final data cut-off, July 2005




Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.
                                                                                                                                            45
             Randomized Phase II Trial of ZD6474 vs Gefitinib in
                   Advanced NSCLC: Adverse Events
                    Event*                                  ZD6474 (n = 83)              Gefitinib (n = 85)
                    Diarrhea                                      58%                            41%
                       Grade 3/4, no.                              4/2                           1/0
                    Rash                                          46%                            49%
                       Grade 3, no.                                 4                             1
                    Nausea/vomiting                               28%                            34%
                       Grade 3, no.                                 1                             1
                    Headache                                      18%                            13%
                       Grade 3, no.                                 2                             0
                    Dizziness                                     14%                            9%
                    Hypertension                                  12%                            1%
                       Grade 3, no.                                 3                             0
                    QT-related events                             21%                            5%


*AEs are all CTC grade 1 or 2 except where noted.
Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.
                                                                                                              46
                  Randomized Phase II Trial of ZD6474 vs
                      Gefitinib in Advanced NSCLC
                                                      Conclusions

         Part A met primary endpoint of prolonging progression-free
          survival (PFS)
           – ZD6474 prolonged PFS by 45% compared with gefitinib
         PFS prolongation did not result in overall survival
          advantage in Part B
           – Why? Not clear, maybe optional switchover confounded
             survival assessment
         Adverse events (AEs) for both agents mostly mild
         Slight differences in AE profiles

Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000.            47
                    Novel Targeted Agents Under
               Investigation for Lung Cancer Treatment
                                     Highlights of ASCO 2006
 Agent                    Study                                         Results
 AMG706              Blumenschein      Ongoing phase Ib trial in advanced NSCLC of AMG706 + CP, AMG706 +
                     Abstract 7119     panitumumab ± CP
 TGFβAS               Nemunaitis       75 patients, safety of optimal dose determined, results suggest greater
 Vaccine             Abstract 7018     survival compared with historical controls
 Vatalanib              Jahan          Tolerated in mesothelioma
                     Abstract 7081     Activity: 8.5% PR, 68.1% SD
                                       But 3-mo PFS (53.3%) did not met protocol-specified level of 75%
 ZD6474                 Natale         As shown in previous slides, ZD6474 produced longer PFS compared with
                     Abstract 7000     gefitinib in refractory NSCLC
                       Heymach         ZD6474 + docetaxel is being tested in ongoing double-blind, randomized
                     Abstract 7016     phase II trial in 2nd-line NSCLC
 ABI-007                 Rizvi         Phase I/II trial, 1st-line in advanced NSCLC, MTD reached; ORR 30% and
                     Abstract 7105     10.9 mo OS; grade 3 sensory neuropathy and fatigue, minimal
                                       myelosuppresion
 AZD2171                Laurie         Phase I trial in advanced NSCLC of AZD2171 + CP; manageable toxicities
                     Abstract 3054     including hypertension; evidence of activity
CP = carboplatin/paclitaxel.                                                                                     48
                      Other Searches for Useful
                  Biomarkers in NSCLC—ASCO 2006
         Mack PC, et al1                                        Toschi L, et al2
           Elevated osteopontin plasma                            FISH or IHC analysis of samples
            levels may have prognostic                              from 190 consecutive patients
            value in advanced NSCLC                                 treated for advanced NSCLC
           Osteopontin is a secreted                              EGFR, HEr2, and p-Akt status
            glycoprotein involved in                                are not predictors of sensitivity
            induction of urokinase (uPA)                            to chemotherapy
            and increased cell migration                           EGFR FISH + and/or HER2
                                                                    FISH+ patients seemed to
                                                                    benefit more from nonplatinum
                                                                    vs platinum-based combinations
                                                                    (but N small)
                                                                   In EGFR FISH+ patients, RR
                                                                    and TTP after EGFR-TKI used
                                                                    as 2nd-line treatment were at
                                                                    least equal to 1st-line
                                                                    chemotherapy
1. Mack PC, et al. 42nd ASCO, June 2-6, 2006. Abstract 7198.
2. Toschi L, et al. 42nd ASCO, June 2-6, 2006. Abstract 7111.                                           49
                          Summary

   First-generation TKIs (gefitinib, erlotinib) the search continues for
      – Molecular markers for patient selection
      – Optimal combinations
      – Improved dosing
   Multitargeted TKIs currently on the market (sorafenib, sunitinib)
      – Some promising, but not yet conclusive results
   Investigational multitargeted TKIs (vatalanib, ZD6474, AMG706, AZ2171)
      – Need data from randomized trials
      – Some differences in adverse event profiles
   General areas of need
      – Surrogate markers for evaluation of agents
      – Biomarkers for patient selection
      – Optimization of clinical trial design

                                                                             50
Toxicity Management of Targeted
   Therapies: Implications for
  Nursing and Managed Care
     Michelle Purdom, RN, BSN
   Manager, Clinical Trials Operations
          Phase I Program
         University of Texas
    M.D. Anderson Cancer Center
           Houston, Texas

                                         51
                     Overview

   Management of side effects associated with
    targeted therapies
   Pharmacoeconomics of cancer management
    and role/implications of targeted therapies in
    managed care setting




                                                     52
            Targeted Therapies and Approval Dates


                                                                                                 QuickTime™ and a
                                                                                            TI FF (LZ W) decompressor
                                                                                         are needed to see thi s pi ct ure.




         May 2, 2003*                February 12, 2004      November 19, 2004           January 26, 2006




2003                                2004                               2005              2006
           May 13, 2003                 February 26, 2004                       December 20, 2005




* Iressa was approved with contingencies on May 2, 2003.
                                                                                                                              53
                           Most Common Side Effects Associated
                           with FDA-Approved Targeted Therapies
Side Effect          Bevacizumab*      Sunitinib    Bortezomib      Sorafenib    Cetuximab**    Erlotinib† Gefitinib‡
Abdominal pain                                                                                   
Acne and/or rash                                                                                         
Alopecia                                                                            
Altered taste                              
Anemia                                                                               
Anorexia and/or
 weight loss                                                                                     
Appetite decrease/
 taste disorder                                          
Arthralgia/myalgia                                                                                
Asthenia                                                                            
Bleeding                                   
Constipation                                                                                    
Cough                                                                                              
Dehydration                                                                           
Diarrhea                                                                                                     
Dizziness                                               
Dry and/or
 discolored skin                                                                                                 
Dysesthesia and/or
 paresthesia                                              
Dyspepsia                                 
Dyspnea                                                                                         

Includes: *+IFL, +5-FU/LV, +FOLFOX4, and monotherapy; **+radiation, +irinotecan, and monotherapy; †+gemcitabine
and monotherapy; ‡250 mg/d and 500 mg/d.
                                                                                                                        54
                         Most Common Side Effects Associated
                     with FDA-Approved Targeted Therapies (cont’d)
Side Effect             Bevacizumab*   Sunitinib    Bortezomib      Sorafenib    Cetuximab**    Erlotinib†   Gefitinib‡
Edema                                                                                              
Epistaxis                    
Fatigue                                                                                           
Fever                                                                                            
GI hemorrhage                
Hand-foot skin reaction                                                  
Headache                                                                           
Hypertension                              
Insomnia                                                 
Leukopenia and/or
  neutropenia and/or
  thrombocytopenia                                                                   
Mucositis/stomatits                                                                              
Nausea and/or
  vomiting                                                                                     
Pain                                                                                             
Peripheral neuropathy                                    
Pharyngitis                                                                           
Proteinuria                  
Pruritis                                                                              
Upper respiratory
  infection                  
Xerostomia                                                                            

Includes: *+IFL, +5-FU/LV, +FOLFOX4, and monotherapy; **+radiation, +irinotecan, and monotherapy; †+gemcitabine
and monotherapy; ‡250 mg/d and 500 mg/d.
                                                                                                                          55
                  Management of Bevacizumab-Associated
                              Side Effects
 Side Effect                                 Scope                                   Symptoms and Management
 Hypertension            Incidence Gr 3/4: B + C 12% vs C 2%               Standard oral antihypertensives
                         Not infusion related; usually observed            If severe, temporarily suspend treatment
                         during course of treatment                        If hypertensive crisis, discontinue treatment
                                                                           Monitor BP at least every 2–3 weeks
 AT events               Incidence B + C 4.4% vs C 1.9%                    Permanently discontinue treatment
 GI perforation          Incidence: B + C 2–4% vs C 0.3%                   Symptoms: abdominal pain, constipation, vomiting


 Wound healing or        Incidence: among patients requiring surgery       Wait for complete healing of surgical incision and
 bleeding                within 60 d of B + C 15% vs C 4%                  at least 28 d after surgery before starting
 complications                                                             B therapy

 Hemorrhage              Incidence Gr 3–5 bleeding: B + C 5.2% vs B        Epistaxis usually mild, use standard first aid
                         3.8% vs C 0.7%                                    techniques
                         Incidence epistaxis (nosebleeds): B + C           Patients with recent hemoptysis should not
                         35% vs C 10%                                      receive B therapy
 AT = arterial thromboembolic; B = bevacizumab; C = chemotherapy.

Sources: www.avastin.com/avastin/nurseFaqPro4.m
Avastin (bevacizumab) prescribing information. Available at:
http//www.gene.com/gene/products/information/oncology/avastin/insert.jsp                                                    56
                                Blood Pressure Diary




Courtesy of Michelle Purdom, RN, BSN                   57
                   Management of Bortezomib-Associated
                              Side Effects
Side Effect                       Scope                               Symptoms and Management
Peripheral          Incidence of new cases: 36%     Monitor patients for symptoms: burning sensation, hyperesthesia,
neuropathy          Gr 3, 7%                        hypoesthesia, paresthesia, discomfort, neuropathic pain
                                                    New and worsening neuropathy: depending on severity consider
                                                    recommended changes in dose and schedule
                                                    Before initiating therapy, carefully consider risk/benefits of
                                                    bortezomib treatment for patients with pre-existing neuropathy
Asthenia            Incidence: bortezomib 61% (Gr   Educate patients about caution in operating cars and other
(fatigue,           3/4, 12%) vs dexamethasone      machinery because of potential for fatigue, dizziness, syncope,
malaise,            45% (Gr 3/4, 6%)                hypotension, diplopia, blurred vision
weakness)                                           Educate patients about avoiding dehydration and seeking medical
                                                    advice if experience dizziness, light-headedness, or fainting spells


GI toxicities       Incidence Gr 3 bortezomib 18% Most common GI toxicities: nausea, diarrhea, constipation,
                    vs dexamethasone 6% (Gr 4     vomiting, and anorexia
                    rare in both groups)
Hypotension         Incidence: bortezomib 11% vs    May need to adjust doses of antihypertensive medications
                    dexamethasone 2%

Velcade (bortezomib) prescribing information.                                                                          58
                     Management of Cetuximab-Associated
                                Side Effects
Side Effect                   Scope                                 Symptoms and Management
Infusion reactions   Incidence of severe        Symptoms of severe (potentially fatal) reactions: rapid onset of airway
                     reactions: 2%–4%           obstruction (bronchospasm, stridor, hoarseness), urticaria,
                     Incidence of Gr 1–2        hypertension, and/or cardiac arrest
                     reactions: 16%–19%         Symptoms of Gr 1–2 reactions: chills, fever, dyspnea on 1st day of
                                                initial dosing
                                                Severe reactions: immediate and permanent cetuximab treatment
                                                discontinuation
                                                Mild/moderate reactions: slow infusion rate, use antihistamines (eg,
                                                diphenhydramine) in subsequent doses
Cardiopulmonary      Incidence of arrest        Use with caution in patients with coronary heart disease, congestive
arrest               and/or sudden death:       heart failure, and arrhythmias
                     cetuximab + radiation      Closely monitor serum electrolytes (including magnesium, potassium,
                     therapy 2% vs 0% for       calcium) during and after cetuximab therapy
                     radiation therapy
Dermatologic         Incidence in CRC: 89%      Signs: acneform rash, skin drying and fissuring
toxicity             of all treated patients,   Monitor for development of inflammatory and infectious sequelae;
                     severe in 11%              consider topical and/or oral antibiotics
                                                Severe acneform rash: institute dose modifications
                                                Topical corticosteroids not recommended

www.erbitux.com                                                                                                     59
               Management of Erlotinib-Associated
                        Side Effects
Side Effect                       Scope                            Symptoms and Management
Rash               Overall incidence of rash: erlotinib  Take erlotinib at the same time each day between
                   75% vs placebo 17%                    meals (one hour before or two hours after eating).
                   Incidence of Gr 3 rash with erlotinib:Pts with severe skin reactions may need dose
                   8%                                    reductions or interruptions
Diarrhea           Incidence of severe diarrhea: 6%      Educate patients to seek prompt medical attention
                                                         for severe or persistent diarrhea
                                                         Usually managed with loperamide
                                                         Use dose reductions or interruptions in patients
                                                         who are dehydrated or have unresponsive severe
                                                         diarrhea
Interstitial       Overall incidence of ILD-like events: Interrupt treatment for acute onset or progression
lung disease       0.7%                                  of unexplained pulmonary symptoms
(ILD)              Most cases in lung cancer patients If ILD confirmed, discontinue treatment
                   associated with confounding factors Educate patients to seek prompt medical attention
                                                         for onset or worsening of unexplained shortness of
                                                         breath or cough

www.tarceva.com.                                                                                         60
                 Management of Gefitinib-Associated
                          Side Effects
   Side Effect                       Scope                     Symptoms and Management
   Interstitial lung   Overall incidence: 1% of      Symptoms: acute onset of dyspnea, sometimes
   disease (ILD)                                     with cough or low-grade fever, often quickly
                       gefitinib-treated patients (1/3
                       of these cases were fatal)    worsening and requiring hospitalization
                                                     Interrupt treatment in patients with acute onset
                                                     or worsening of pulmonary symptoms (dyspnea,
                                                     cough, fever)
                                                     Discontinue gefitinib treatment if ILD confirmed
   Eye toxicity        Low incidence of eye pain and Consider therapy interruption until symptoms
                       corneal erosion/ulcer,        resolved and removal of aberrant eyelash (if
                       sometimes with aberrant       present)
                       eyelash growth

 Most common gefitinib-associated adverse events: diarrhea, rash, acne, dry skin, nausea, vomiting




www.iressa.com                                                                                          61
       Example of
         Typical
     Rash Induced by
     EGFR Inhibitors




Courtesy of Michelle Purdom, RN, BSN   62
                                       EGFR Rash




Courtesy of Michelle Purdom, RN, BSN               63
                     Management of Sunitinib-Associated
                              Side Effects
Side Effect                           Scope                                          Symptoms and Management

GI events          Most common: diarrhea, nausea,                 Supportive care with antiemetic or antidiarrhea medications
                   stomatitis, dyspepsia, vomiting

Left ventricular   Incidence: sunitinib 11% vs placebo 3%         Some patients recovered without intervention
dysfunction                                                       Possible interventions: dose reduction, use of antihypertensive or
                                                                  diuretic
                                                                  Carefully monitor patients for signs and symptoms of congestive
                                                                  heart failure
Hemorrhage         Incidence of bleeding: sunitinib 18% vs        Epistaxis most common hemorrhagic adverse event
                   placebo 17%
                   Fatal pulmonary hemorrhage occurred in 2
                   patients in a sunitinib NSCLC clinical trial
Hypertension       Incidence: sunitinib 15% (Gr 3, 4%) vs         Monitor and treat with standard hypertensive
                   placebo 11% (Gr 3, 0)                          If severe, suspend sunitinib treatment until hypertension is
                   No Gr 4                                        controlled

Skin toxicity      Skin discoloration: occurs in 1/3 of pts       Advise patients of potential occurrence
                   Attributed to yellow drug color                Other possible dermatologic effects: dryness, thickness or cracking
                                                                  of skin, blister or rash on palms of hand and soles of feet



www.sutent.com                                                                                                                         64
              Management of Sorafenib-Associated
                        Side Effects
Side Effect                    Scope                        Symptoms and Management
Dermatologic       Hand-foot skin reaction (35%)   Topical therapies for symptomatic relief
                   and rash (38%) most common      Temporary treatment interruption or dose
                   adverse event                   modifications
                   Usually Gr 1-2, appear during   Severe or persistent cases may require treatment
                   1st 6 weeks of treatment        discontinuation
Hypertension       Incidence: sorafenib 16.9% vs   BP should be monitored weekly for 1st 6 weeks of
                   placebo 1.8%                    sorafenib therapy
                   Usually mild to moderate and    Manage with standard antihypertensive therapy
                   occurs early in treatment       Temporary treatment interruption or dose
                                                   modifications
                                                   Treatment discontinuation rare
Hemorrhage        Incidence: sorafenib 15.3%       If bleeding necessitates medical intervention,
                  (Gr 3, 2%; no Gr 4) vs placebo   consider permanently discontinuing sorafenib
                  8.2% (Gr 3, 1.3%; Gr 4 0.2%)
Cardiac ischemia Incidence: sorafenib 2.9% vs      Consider temporary or permanent treatment
and/or infarction placebo 0.4%                     discontinuation

www. nexavar.com
                                                                                                  65
                Pharmacoeconomics of Cancer
              Management and Role/Implications of
                    Targeted Therapies in
                    Managed Care Setting




Cohen M, et al. Am J Manag Care. 2006;12:524.       66
             Targeted Therapies and Managed Care


              New therapies need evidence of effectiveness
               and safety
              Impact on quality of life
              Net impact on total cost of care
              Concept of value differs among patients,
               providers, health plans, and employers


Cohen M, et al. Am J Manag Care. 2006;12:524.
                                                              67
                                   Biotechnology Pipeline
                                       Condition                        Number of Agents
                        AIDS/HIV infections/related conditions             17
                                       Autoimmune disorders                 26
                                               Blood disorders         2
                                    Cancer/related conditions                                           154
                                      Cardiovascular disease               19
                                                Eye conditions          5
                                  Diabetes/related conditions           10
                                          Digestive disorders            11
                                             Genetic disorders          9
                                              Growth disorder          3
                                            Infectious disease                   43
                                         Neurologic disorders              16
                           Other conditions not specified here              17
                                        Respiratory disorders              14
                                                Skin disorders         7
                                               Transplantation         3



2004 Survey. Medicines in Development: Biotechnology. Available at: http://www.phrma.org/files/Biotech%20survey.pdf.
Accessed February 15, 2006.                                                                                            68
                      Growth Drivers for Biologics

            Key contributors from managed care perspective include
             Increased availability of targets for biologic agents
             Increased use of approved drugs
             Increased approval of biotechnology drugs for more
              common conditions
             Expanded indications for approved drugs




Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.
                                                                               69
       Reasons for Off-Label Use of Biologics

            Small population size and/or assessed cost of clinical trials may
             discourage marketers from seeking formal FDA approval
            Potential of newer therapies for better efficacy and outcomes
            Proven safety and efficacy in other disease states
            Potential for increased quality of life
            Thought leader advocacy/patient demand
            Better understanding of disease pathways, particularly immune-
             modulating diseases



Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.     70
               Managed Care’s Concerns Regarding
                   Off-Label Use of Biologics

                                Safety/efficacy questions
                                Differing dosing and administration
                                Potential for inappropriate care
                                Potential for cost increase
                                Paucity of data
                                Lack of uniform guidelines/best
                                 practices
                                Legal/ethical issues


Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.
                                                                               71
                     Recommendations for Managing
                         Expanded Indications
            Scan the pipeline to become aware of impending drug
             launches
            Increase education for P&T committees
            Define a process and clear criteria
            Develop and/or augment treatment guidelines for
             expanded indications
            Increase case management/disease management
            Strive for innovative management strategies that
             contain cost and maintain access

Cohen M, et al. Am J Manag Care. 2006;12:524.
                                                                   72
                           Continued Challenges for
                          Managed Care Organizations
         Expanding indications for FDA-approved drugs present unique
          challenges for MCOs.
           – This translates into added expenditures for MCOs because of increased
                frequency of administration and/or longer duration of therapy
           – For patients, may result in higher copays and more restrictive access
                management strategies, particularly the use of prior authorization
         Maintain focus on potential of agents for reduction in disease progression and
          disability rather than solely on patient copays and aggressive management
          strategies
           – Shift focus on cost to clinical decision making through evidence-based
                medicine
         Adequately plan for agents with multiple indications
           – Need more definitive criteria for evaluating expanded indications and
                potential for cost savings
Cohen M, et al. Am J Manag Care. 2006;12:524.
                                                                                           73
          Nursing Implications

 The nurse should help the patient understand
  importance of prior insurance authorization due
  to the high cost of biopharmaceuticals
 The nurse should assist the patient as a liaison
  with the hospital business office/MCO by
  initiating the process early and often
 Emotional support



                                                     74
                          Summary

   Expanding indications and off-label applications of FDA-approved
    targeted therapies present unique challenges
     – MCOs face added expenses
     – Patients face higher co-pays and more restrictive access
     – Clinicians need to expand their knowledge base and skill sets
   Nurses have an important role in providing
     – Professional care
     – Toxicity management and side effect education
     – Assistance in navigating the preauthorization process
     – Emotional support



                                                                       75
Keeping Pace with Targeted Therapies in Lung Cancer
   Highlights from the ASCO 2006 Annual Meeting




                                                      76

								
To top