Novel Targets in Colorectal Cancer by malj

VIEWS: 3 PAGES: 44

									New Drugs in Pancreatic Cancer
       Manuel Hidalgo, M.D., Ph.D.
          CIO “Clara Campal”
             Madrid, SPAIN
        Johns Hopkins University
          Baltimore, MD, USA
            Agenda

• Current situation.
• Promising new targets.
• Approaches to new drug
  development
• The “omis” of pancreatic cancer.
Significant Problem




              Jemal et al, Cancer Statistics 2007
      Pivotal Phase III Study of
   Gemcitabine in Pancreatic Cancer


                                   R   Gemcitabine
                                   A   (1000 mg/m2/wk)
• Advanced pancreatic cancer
                                   N
• No prior chemotherapy            D
• Pain, intensity scale > 20/100
                                   O
  (MPAC)
                                   M
• Adequate Karnofsky PS            I
                                   Z   5-Fluorouracil
                                       (600 mg/m2/wk)
                                   E


 Burris et al. JCO 1997
 Pivotal Phase III Study of Gemcitabine in
       Advanced Pancreatic Cancer

                                         5-FU Gemcitabine
        Parameter                        Arm     Arm                       P

        Clinical Benefit*                4.8%           23.8%           0.002
                                                                          2


        Response Rate                     0%             5.4%           0.077

        Sv (mo)                           4.4             5.6           0.002
    * Clinical benefit measured as an improvement in pain, performance status, or
         Survival
       weight gain with an algorithm using the Memorial Pain Assessment Card.
            Median                        4.41            5.65           0.002
            1-Year                        2%              18%              5
Burris et al. JCO 1997
Most Common Strategies to Develop
    Drug A in Pancreas Cancer

Phase I Trial (s) Single
                      R                 Gemcitabine
                      A




                           RANDOMIZED
                      N
  Phase I/II Trial in D
  Combination with O
    Gemcitabine       M
                      I
                                        Gemcitabine + A
                      Z
                      E
     Drug Tested that Failed
•   Taxanes.
•   Topo I inhibitors.
•   Platinum analogs.
•   FTIs.
•   VEGF antibodies.
•   MMP.
•   EGFR antibodies.
•   Antimetabolites.
                   Study Schema

                         R
                             Gemcitabine 1000 mg/m2 IV
Stratified by:
                         A                 +
- Center                 N   Erlotinib100/150 mg po daily
- PS (0/1 vs 2)          D
- Stage of disease       O
  (locally advanced vs
                         M
   distant metastases)       Gemcitabine 1000 mg/m2 IV
                         I
                                          +
                         Z   Placebo 100/150 mg po daily
                         E

                                Moore et al. JCO 2007
                           Supervivencia Global
              100
                                                                   RR = 0.81*
                                                                   95% CI (0.67, 0.97)
                                                                   P = 0.025
              80



              60
Percent age




                                                  Gemcitabina + Tarceva
                                                  Mediana = 6.37 meses
              40
                                                  Supervivencia 1 año=24%

                        Gemcitabina + Placebo
                        Mediana = 5.91 meses
              20
                        Supervivencia 1 año=17%



               0
                    0                  6                12                  18                   24
                                                  Time (Months)
                                                      Annals Oncol 2007; 18 (suppl 7): vii 14 (abs O-0010)
              Adverse Events
                     Erlotinib        Placebo
    Events           N = 282          N = 280
                  Any      Grade   Any      Grade
                             3,4              3,4
Rash              72%        6%    28%        1%
Diarrhea          51%        6%    36%        2%
Infection (any)   41%       16%    31%       14%
Stomatitis        23%      < 1%    14%         0
Fatigue           73%       17%    70%       16%
Nausea            61%        7%    58%        7%
Dehydration        7%        3%    10%        5%
         Serious Adverse Events
                                 Erlotinib                    Placebo
       Events
                                 N = 282                      N = 280


Infections Total                      16%                        13%
  - Pneumonia                         4%                          3%
  - Sepsis                            4%                          3%
ILD-like* Events           2.1% (6 patients)            0.4% (1 patient)
Nervous System                   5%                         < 1%
   Cerebral ischemia                  2%                           0


* Pneumonitis, pulmonary infiltrate
                                             Moore MJ et al. J Clin Oncol 2007;25:1960–6
            Laboratory Abnormalities
   Worst Grade per Patient On Study
                    Erlotinib                        Placebo
Parameters             N = 282                        N = 280
               Grade 1,2 Grade 3,4 Grade 1,2 Grade 3,4


WBC              51%             19%           49%              18%
ANC              31%             25%           28%              26%
Platelets        64%             10%           66%              12%
Hb               85%             12%           84%              12%
ALT              64%             14%           64%              9%
Bilirubin        37%             12%           25%              12%
                                  Moore MJ et al. J Clin Oncol 2007;25:1960–6
 PA.3: Riesgo relativo en supervivencia con
  características basales (100mg cohorte)

      Factores                         n      HR      95% CI

      Tarceva: placebo*               521     0.81    0.7–1.0
      PS 0–1                          432     0.87    0.7–1.1
      PS 2                             89     0.70    0.5–1.1
      Localmente advanzado            124     0.93    0.6–1.3
      Metástasis a distancia          397     0.80    0.7–1.0
      Intensidad del dolor 20        238     0.72    0.6–0.9
      Intensidad del dolor >20        268     1.00    0.8–1.3
      HER1/EGFR positivo               70     0.82    0.5–1.3
      HER1/EGFR negativo               66     0.75    0.5–1.2
      HER1/EGFR no analizado          385     0.86    0.7–1.1
      Hombre                          273     0.74    0.6–0.9
      Mujer                           240     1.00    0.8–1.3
      Edad <65 años                   274     0.78    0.6–1.0
      Edad 65 años                   247     0.94    0.7–1.2




*Estratificación por PS y extensión de la enfermedad               0    0.50   1.00        1.50   2.00   2.50
**no permitida quimioterapia previa, excepto radiosensibilizante                      HR



                                                                   Moore MJ et al. J Clin Oncol 2007;25:1960–6
                     PA.3: Supervivencia global en pacientes
                      con Cáncer de Páncreas metastásico*
                                1.00
Probabilidad de supervivencia




                                0.75           RR=0.80 (0.66–0.98); p=0.029
                                                25% mejora en SG
                                                20% reducción del riesgo de muerte
                                0.50



                                0.25                                Gemcitabine + Tarceva
                                                                    Gemcitabine + placebo


                                  0
                                       0   6     12        18           24           30           36
                                                      Tiempo (meses)

*Cohorte 100mg
                                                             Annals Oncol 2007; 18 (suppl 7): vii 14 (abs O-0010)
         PA.3 Rash vs Supervivencia
                          100

                                                         Riesgo relativo = 0.71
                          80                             p<0.0001

                                                       Grado 2
                          60
            Percent age




                          40                         Grado 1
                                    Grado 0
                          20



                           0
                                0         5                  10                  15                   20
                                                       Time (Months)

                                         Grado 0         Grado 1        Grado >2
                                          N= 79          N= 108          N= 103
Mediana de supervivencia                      5.29         5.75           10.51
Supervivencia al 1 año                        16%          11%             43%
                                                               Annals Oncol 2007; 18 (suppl 7): vii 14 (abs O-0010)
          Expresión K-ras y EGFR como factor
                      predictivo*
                                   Gemcitabina +             Gemcitabina +               RR           p
                                        Tarceva                Placebo
    Supervivencia                       Meses                     Meses
     K-ras mutado                          6.0                       7.4                1.07        0.78
     K-ras salvaje                         6.1                       4.5                0.66        0.34
     EGFR FISH +                           5.2                       5.2                0.90        0.73
     EGFR FISH -                           8.4                       6.7                0.60        0.08
    SLP                                 Meses                     Meses
     K-ras mutado                          3.8                       4.0                0.93        0.74
     K-ras salvaje                         3.6                       4.0                1.30        0.57
     EGFR FISH +                           3.6                       2.0                0.97        0.91
     EGFR FISH -                           5.6                       4.0                0.74        0.30
*RR ajustados por supervivencia
Interacción entre tratamiento y mutación del K-ras = 1.71 (0.64 -4.63 ; p=0.29)
Interacción entre tratamiento y expresión de EGFR = 1.41 (0.60 –3.32 ; p=0.43)
•RR ajustado por SLP
Interacción entre tratamiento y mutación del K-ras = 0.60 (0.22,- 1.62;p=0.31)
Interacción entre tratamiento y expresión de EGFR = 1.18 (0.52-2.6; p=0.69 )
                                             Moore M, et al. JCO, 2007 ASCO Annual Meeting Proceedings Part I. Vol
                                                                       25, No. 18S (June 20 Supplement), 2007: 4521
      Punch line of Erlotinib in
        Pancreatic Cancer
• Another drug for docs and patients to use.
• Data is weak but still best data.
• Need to continue exploring erlotinib in
  pancreas cancer:
  –   Adjuvant and neoadjuvant settings.
  –   Continue to explore biomarkers of activity.
  –   Exploit rash as a predictor of efficacy.
  –   Incorporate into other combinations
Factors that may be implicated
      in high failure rate
• Few single agent studies.
  – Most studies have been done in
    combination with gemcitabine.
• Poor understanding of mechanism of
  action.
  – MMPs
  – Ras inhibitors.
• Lack of solid phase II data.
  – Cetuximab.
   Known Genetic Profile of Pancreatic
               Cancer
          Gene             Rate of genetic alteration
■ p16                                 98
■ K-ras(90%) (+ 5% BRAF)              95
■ p53                                 70
■ DPC4                                55
■ BRCA2 (FANC C and G)                7-10
■ Mismatch repair genes                4
■ STK11 (Peutz-Jeghers)                5
FA Complex Genes Physiology




                     Genes and Develop, 2003
Mitomycin C - Sensitivity




              Am J Pathol. 2004 Aug;165(2):651-7
MMC Prospective Trial in BRCA2 mut Patients

                                 Standard
                    BRCA2         therapy
                   wild type

 Patient
   with
             Test for
pancreatic   BRCA2
  cancer

                   BRCA2       Mitomycin C C
                                Mitomycin-
                   mutant
Poly (ADP-Ribose) Polymerase Pathway




                        Ratnam et al, CCR 2007
PARP Inhibitors




             Ratnam et al, CCR 2007
 Some Recently Discovered Potential
    Targets in Pancreatic Cancer
     Target        Therapeutic Intervention
  PSCA Antigen       Monoclonal Antibodies
Hedgehog Pathway       Small molecules
                     Monoclonal Antibodies
   Mesothelin        Monoclonal Antibodies
                      Vaccine strategies
                        Immunotoxins
      TrkB             Small Molecules
       Src             Small Molecules
      PLK1             Small Molecules
 Death receptors     TRAIL and Antibodies
    Role of the Sonic Hedgehog Pathway in
                 Tumorigenesis




                     Hh ligand                              SHH mutation
               Smo                   Smo      Cyclopamine


Ptch                   Ptch         Fu
                                 Cos2 SuFu

     Fu
 Cos2
      SuFu

       Processing             Stabilization

 Repress Gli             Activates Gli



                                    Ptch
                                    Gli1




Pathway Off            Pathway On
Targeting Hedgehog Pathway in
       Pancreatic Cancer
Targeting Hedgehog Pathway in
       Pancreatic Cancer
   Newer Approaches for Drug
Development in Pancreatic Cancer
 • Better understanding of what are the
   key targets.
 • Drug development oriented
   preclinical models.
 • More effective clinical trials design.
   Gene
Genetic Mouse Models of
   Pancreas Cancer




                   Hruban, et al. Can Res, 2007
        Design and dynamics
     Pancreas xenograft model: methodology



F0                             Patient Phase



F1                             Engraftment Phase


F2                             Expansion Phase


                               Treatment Phase
F3
                               Biologic studies
                               Biomarker discovery

Fn                             Perpetual bank




                                       Rubio et al, CCR 2007
                                           Example of a prospective patient


                                                                       Diagnosis   Gemcitabine   Mitomycin C

                                   120
Growth (% normalized to control)




                                   100

                                    80

                                    60

                                    40

                                    20

                                     0
                                         Control   Gemcitabine   MMC
    The Complexity of Cancer Genome




• Average of 90 mutated genes
  per case.

• Average of 11 thought to be
  relevant for the neoplastic
  process.


                                Sjoblom, et al. Science, 2006
    The “omics” of pancreatic

• Gene mutations.
• Gene deletions and amplifications:
    – CGH, MLPA, SNP analysis.
•   Expression arrays.
•   microRNAs.
•   Methylation.
•   Proteomics.
•   More to come.
MLPA Assessment of Gene Changes
      in the EGFR Pathway
         P198    P410   P286   P140   P163   P287   P253   P194   P265   P215

 HER1        2    2      0      0      2      2      0      0      2      2

 HER2        1    0      0      2      0      1      1      0      2      2

 HER4        0    0      0      2      2      2      2      0      0      2

 NRAS        2    2      1      0      2      0      1      0      1      0

 BRAF        2    2      2      2      2      2      2      2      2      0

 AKT1        2    2      0      2      2      0      0      0      0      2

PIK3CA       2    2      1      0      2      0      2      2      2      0

PIK3CB       0    0      2      2      0      0      2      0      0      0


 Gain
 No change
 Loss
         KEGG Active Pathways in
           Pancreatic Cancers

140 HSA00252 Alanine and aspartate metabolism

159 HSA00980 Metabolism of xenobiotics by cytochrome P450

163 HSA05130 Pathogenic Escherichia coli infection - EHEC

185 HSA04020 Calcium signaling pathway

194 HSA05130 Pathogenic Escherichia coli infection - EHEC

198 HSA01430 Ribosome

215 HSA04020 Calcium signaling pathway

219 HSA03010 DNA polymerase
 In Vivo Activity of Erlotinib, Cetuximab
      and the Combination in Direct
    Xenografts from Pancreas Cancer
160


140


120


100

                                                                  Control
 80
                                                                  Erlotinib
                                                                  Cetuximab
 60
                                                                  Erlotinib+cetuximab

 40


 20


  0
      198   410   286   140   163   287   253   194   265   215
-20
       Baseline IHC Profile

Case   EGFR   pEGFR   pMAPK   pAkt   PTEN
198     ++      +      ++      +     +++

410     ++      +      ++      +      +

286     ++      -      ++      -      ++

140     -       -       +      -      +

163     +       -       -      -      ++

253     +       -       +      -      ++

194     -       -       +      -      +

287     +       -       +      -      +

265     ++      -      ++      +     +++

215     +       -      ++      -      ++
Baseline Mutation and Gene Amplification


                                    EGFR   HER2
      EGFR   KRAS   BRAF   PIK3CA   FISH   FISH
198    wt    mut     wt      wt      1      1
410    wt     wt     wt     mut      5      5
286    wt    mut     wt      wt      2      2
140    wt    mut     wt      wt      5      6
163    wt    mut     wt      wt      4      4
253    wt    mut     wt      wt      4      4
194    wt    mut     wt      wt      4      2
287    wt     wt     wt      wt      5      5
265    wt    mut     wt      wt      2      4
215    wt    mut     wt      wt      5      4
GSEA of EGFR Sensitive Tumors
Figure 3C.   Figure 3D.
          Potentially useful trials
• Proof of mechanism studies.
• Single agent phase II studies.
    – Window of opportunity
    – Second line
•   Randomized phase II studies.
•   Biomarker driven trials
•   Randomized discontinuation studies.
•   Novel exploratory endpoints
    – CA199
    – PET
     Incorporating Biomarkers in Phase II Studies

 • Determine the clinical activity of PLK-1 inhibitor based
   on cyclin B1 ex vivo assay.


              Does not meet       END
              efficacy criteria
                                                   17 ex vivo positive
                                  Ex vivo              subjects:
19 patients
                                  predicts        Compare with cohort 1
                                                    Analyze globally
               Meets efficacy
                  criteria
                                   Ex vivo           17 unselected
                                  does not             subjects:
                                   predict          Analyze globally
              Conclusions
• Pancreatic cancer remains hard to beat.
• Erlotinib is the only drug to demonstrate
  survival improvement in pancreatic cancer.
• Significant number of new targets and new
  drugs.
  – Which are important?
  – How to develop them fast?
• Better understanding and “big picture” of
  pancreas cancer starts to emerge.
• Individualized treatment is the next step.

								
To top