EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITORS by HC11112504915

VIEWS: 120 PAGES: 22

									EPIDERMAL GROWTH
FACTOR RECEPTOR
      (EGFR)
    INHIBITORS
                The HER Family




                                   (NRG1)
                                   HRG
       Ligand
      binding


Transmembrane



     Tyrosine
       kinase    erb-b1   neu          Erb-b3   Erb-b4
                 EGFR     Erb-b2       HER3     HER4
                 HER1     HER2
  Effects of HER1/EGFR activation
                                                  Extracellular


     Intracellular                                       Transactivation



   Src    PLCg        GAP    Grb2    Shc   Nck     Vav     Grb7    Crk

          PKC               Ras
                                                 JNK               Abl
                     PI3K   Akt     MAPK


Migration, proliferation, adhesion, invasion, angiogenesis,
                 and inhibition of apoptosis
            Human tumors with
        high HER1/EGFR expression
                                                          HER1/EGFR
                    Tumor                                expression (%)
                    HNSCC                                       70–100
                    NSCLC                                       50–90
                    Prostate                                    40–70
                    Glioma                                      10–50
                    Gastric                                     30–60
                    Breast                                      35–70
                    Colorectal                                  45–80
                    Pancreatic                                  30–50
                    Ovarian                                     35–60
Ciardiello F, Tortora G. Expert Opin Investig Drugs 2002;11:755–68
Salomon DS, et al. Crit Rev Oncol Hematol 1995;19:183–232
Clinical consequences of HER1/EGFR
   dysregulation in cancer patients

  • Metastasis
    – due to increased tumor-cell motility and
      adhesion

  • Chemotherapy and radiotherapy resistance

  • Resistance to hormonal therapy

  • Poor prognosis

  • Reduced survival
                        HER1/EGFR-Targeted
                           Approaches
                                                               Tyrosine
                                                                Kinase
                                                              inhibitors
                                                                                                     TOXIN
                                                                            TOXIN
                                                                                        TOXIN




                                                 Antiligand
                                                  blocking                  Ligand-     P
                                 Anti-HER        antibodies                  toxin
                                 blocking                                                Antibody-
           HER dimerization                                                conjugates      toxin
              inhibitors        antibodies                                                           P
                                                                                        conjugates


Adapted from Noonberg and Benz. Drugs. 2000;59:753.
   Selected HER1/EGFR-Targeted
       Monoclonal Antibodies
Agent       Specificity   Selected Tumor Types         Phase

C225        ECD           Colorectal, HNSCC, NSCLC,      Apr.
                          pancreatic


ABX-EGF     ECD           NSCLC, colorectal, renal,        II
                          prostate

EMD 72000   ECD           NSCLC, colorectal                II



h-R3        ECD           HNSCC                           I/II


MAb 806     vIII          Glioma                      Preclinical
            Selected HER Tyrosine
               Kinase Inhibitors
Agent        Molecule/binding Specificity Selected tumor types             Phas
                                                                            e
Erlotinib    Anilinoquinazoline   HER1-TK     NSCLC, pancreatic, H&N,      Appr
             Reversible                       breast, ovarian, prostate,   oved
                                              colorectal, glioma            in
                                                                           USA.
Gefitinib    Anilinoquinazoline   HER1-TK     NSCLC, H&N, breast,          Appr
             Reversible                       ovarian, prostate,           oved
                                              pancreatic, colorectal,       in
                                              glioma                       USA.


EKB-569      3-cyanoquinoline     HER1/2-TK   NSCLC, breast, other HER-     I/II
             Irreversible                     dysregulated solid tumors
CI-1033      Anilinoquinazoline   HER1-4 TK   NSCLC, breast, other HER-     I/II
             Irreversible                     dysregulated solid tumors
GW572016     6-                   HER1/2-TK   HER-dysregulated solid        III
             thiazolylquinazoline             tumors
             Reversible
Small molecule inhibitors of the tyrosine-kinase
  activity (TKI): mode of antitumor activity




                             
                                          Tyrosine Kinase Inhibitors

   Proliferation                                   Apoptosis

        Invasion                                Sensitivity to
                                                chemotherapy
           Metastasis                     Adhesion
                          Angiogenesis
Erlotinib (erlotinib HCl) properties



                                   HN
                               O

     
                           O            N
               Erlotinib                    HCI
                           O       N
                               O



   • Small-molecule inhibitor of
     HER1/EGFR TK
   • Chemical class: quinazoline
   • Orally available
Erlotinib: mode of antitumor activity



                                      Erlotinib

 Proliferation                                      Apoptosis

      Invasion                                Sensitivity to
                                              chemotherapy
         Metastasis                      Adhesion
                        Angiogenesis





Preclinical Data
                                       Inhibition of purified
                                    HER1/EGFR TK by Erlotinib
                                                                            Target      IC50 (nM)
                              100                                           HER1/EGFR          2
Phosphorylation (% control)




                                                                            HER2            350
                              80                                            VEGFR           600
                                                                            IR          >10,000
                              60                                            IGF-1R      >10,000
                                                                            CSF-1R      >10,000
                              40                                            Met         >10,000
                                                                            src            1,300
                              20                                            Abl            1,500
                                                                            lck         >10,000
                               0
                               0.01   0.1      1      10    100     1,000
                                      Tarceva™ concentration (nM)

 Adapted from Moyer J, et al. Cancer Res 1997;57:4838–48
      Antitumor activity of Erlotinib in a head and
         neck cancer xenograft model (HN5)
                                   HN5 carcinoma xenograft growth in athymic mice
                       2,500
                                                 Vehicle control
                                                 1.6mg/kg/day p.o.
                       2,000
  Tumor volume (mm3)




                                                 12.5mg/kg/day p.o.
                                                 50mg/kg/day p.o.
                       1,500                     100mg/kg/day p.o.


                       1,000           Treatment period


                        500


                          0
                               0         10      20        30         40     50    60   70
                                                  Time after implantation (days)
Pollack V, et al. J Pharmacol Exp Ther 1999;291:739–48
             Antitumor activity of Erlotinib in
             a NSCLC xenograft model (A549)
                          800         Vehicle
Mean tumor volume (mm )




                                      Erlotinib 100mg/kg
3




                          600         Erlotinib 25mg/kg



                          400


                          200


                           0
                            26   28    30   32     34 36 38 40 42 44            46   48   50
                                                 Days post-tumor cell implant

Desai B, et al. Eur J Cancer 2002;38:63 (Abs. 203)
                                      Inhibition of mutant
                                     EGFRvIII by Erlotinib
                                    HN5 overexpresses wild-type HER1/EGFR
                                    HC2 overexpresses EGFRvIII mutant
                                    70

                                    60
           cell proliferation (%)
           Inhibition of tumor




                                    50

                                    40

                                    30

                                    20                                       HN5

                                    10                                       HC2 (low passage)

                                     0
                                     0.001   0.01     0.1     1      10     100
                                             Erlotinib concentration (µM)
Iwata K, et al. Proc ASCO 2002;21:21a (Abs. 79)
               Erlotinib in combination with
                chemotherapeutic agents
             • Significant tumor-growth inhibition
               in xenograft models with
               Tarceva™ plus
                                 1,2
                 –   cisplatin
                                       3
                 –   doxorubicin
                                  3
                 –   paclitaxel
                                       2,3
                 –   gemcitabine
                                           4
                 –   capecitabine
                 –   no interaction with 5-fluorouracil and vinorelbine tartrate
                                              3
                     (head and neck model)

             • No increase in toxicity
1
 Pollack V, et al. J Pharmacol Exp Ther 1999;291:739–48
2
 Higgins B, et al. Proc ASCO 2003;22:226 (Abs. 907)
3
 Data on file, OSI Pharmaceuticals Inc. 1997
4
 Tanaka Y, et al. Proc AACR 2003 (Abs. 4678)
Erlotinib: additive antitumor response in
        combination with cisplatin
                                        HN5 carcinoma xenograft growth in athymic mice
                                        80                                      Erlotinib + cisplatin
          Tumor-growth inhibition (%)




                                        70                                      Cisplatin 10mg/kg

                                        60                                      Erlotinib 9mg/kg b.i.d.

                                        50
                                        40
                                        30
                                        20
                                        10
                                         0
                                             0   4      7 10 12 14 17 19 21 24
                                                     Time after implantation (days)
 Adapted from Pollack V. J Pharmacol Exp Ther 1999;291:739–48
                         Enhanced radiation response
                                with Erlotinib
                   250                                                  100
                           Figure 1                                               Figure 2           Control
                   225                                                                               Erlotinib
Caspase activity




                   200
 (% of control)




                                                                        10




                                                         Survival (%)
                   175

                   150
                                                                         1
                   125

                   100

                    0                                                   0.1
                         Control Tarceva™ XRT Tarceva™                        0      3       6         9         12
                                                 XRT                                     Dose (Gy)

 Tarceva™ enhances radiosensitivity of NSCLC cells grown in culture

Chinnaiyan P, et al. Proc AACR 2003 (Abs. R3790)
Phase I monotherapy
  studies in cancer
      patients
        Erlotinib phase I monotherapy
                  studies: PK
       • Dose-proportional Cmax and AUC
       • Repeated daily dosing does not result in
         drug accumulation
       • High plasma exposure at 150mg/day p.o.
                      TarcevaTM    IressaTM   IressaTM    IressaTM
                    (150mg/day) (225mg/day) (525mg/day) (700mg/day)
Cmax (ng/mL)              2,120                  307     903     2,146
AUC0–24
(ng·hour/L)              38,420              5,041     14,727   36,077
t1/2 (hours)                  18                 47       56       65

Hidalgo M, et al. J Clin Oncol 2001;19:3267–79
Ranson M, et al. J Clin Oncol 2002;20:2240–50
Erlotinib phase I monotherapy studies:
   antitumor activity and tolerability
 Antitumor activity
 • Daily dosing regimen (n=40)
   – eight patients with SD for >5 months
 • Weekly dosing regimen (n=27)
   – four patients with SD for >6 months
 Tolerability
 • Acneiform rash (grade 1/2) localized above the waist and diarrhea
   – both dose related
   – diarrhea dose limiting at 200mg/day (daily dosing)
   – MTD not reached in weekly dosing study (>1,600mg)
 • Other less common side effects
   – headache, nausea, and vomiting
 The MTD, 150mg/day continuous dosing, was selected for phase II studies
Hidalgo M, et al. J Clin Oncol 2001;19:3267–79
Karp D, et al. Proc ASCO 1999;18:388a (Abs. 1499)

								
To top