Whats on the Horizon?

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Whats on the Horizon?

• David Thomson,
• Lead Pharmacist,
• Yorkshire Cancer Network.

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Overview

• YCN Approach
• Breast Cancer
• Novel Cytotoxics
• ErbB Receptor Pathway
• Lung Cancer
• VEGF/R Pathway
• Colorectal Cancer
• Biological Combinations
• Renal Cell Carcinoma
• Sequence and combinations
• New agents targeting alternative pathways
• Best of the rest in other clinical areas

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YCN Horizon Scanning

• To provide advanced notice to organisations
  within the YCN of key new and emerging drugs
  around 1-3 years prior to launch in the UK.
• Designed to be informative rather than detailed
  and definitive.
• The reports outline
• What the drug is?
• Likely patient population?
• Available research evidence?
• Prediction of likely use and its potential
  financial impact in the YCN.

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YCN Chemotherapy Management Database
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Assumptions

• Evidence this is a summary only. Refer to the
  clinical data referenced.
• Dosing details indicates how the drug may be
  used i.e dosing regimen. Predicted length of
  course is presented as follows median values are
  taken from trial data assumptions are based on
  trial end-points such as PFS, TTP if no trial
  data available an estimate is used.
• Cost per patient assumes full courses and doses
  are given. Drug prices quoted are the acquisition
  costs (most recent BNF) of the drug in column 1
  only and make the following assumptions include
  VAT wastage where appropriate av. S.A. 1.75m2
  av. wt 75kg.
• Incidence these are estimated figures and are
  presented as either expected number of patients
  per 100,000 population or as the total estimated
  number of patients. 100 uptake assumed unless
  stated otherwise.
• Budget this assumes a full year effect i.e.
  that all eligible patients receive their full
  course of therapy within that financial year. The
  following assumptions apply YCN population
  2,600,000 HYCCN population 1,100,000.

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Horizon Scanning Report
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Disclaimer!

• The information used in producing these reports
  changes rapidly and the level of evidence
  presented and conclusions made about a drugs
  potential impact must be treated with caution.
• Reports are not intended to be a definitive
  statement on the safety, efficacy or
  effectiveness of the drug.
• It should also be noted that just as drugs that
  are included in reports may not be required in
  the YCN or eventually launched in the UK there
  may also be drugs not included in reports that
  are eventually launched in the UK and required
  within the YCN.

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The Challenge
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Predicted New Drug Approval Dates
13
Overview

• YCN Approach
• Breast Cancer
• Novel Cytotoxics
• ErbB Receptor Pathway
• Lung Cancer
• VEGF/R Pathway
• Colorectal Cancer
• Biological Combinations
• Renal Cell Carcinoma
• Sequence and combinations
• New agents targeting alternative pathways
• Best of the rest in other clinical areas

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Overview

• YCN Approach
• Breast Cancer
• Novel Cytotoxics
• ErbB Receptor Pathway
• Lung Cancer
• VEGF/R Pathway
• Colorectal Cancer
• Biological Combinations
• Renal Cell Carcinoma
• Sequence and combinations
• New agents targeting alternative pathways
• Best of the rest in other clinical areas

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Novel Paclitaxel Formulations
First Generation Second Generation Second Generation
Albumin-Bound Paclitaxel Paclitaxel Poliglumex Paclitaxel Injectable Emulsion
Active Drug Paclitaxel Conjugated Paclitaxel Paclitaxel
Carrier Human Serum Albumin Polyglutamate Vitamin E
Phase III II II
Albumin-bound Paclitaxel () (n229) Paclitaxel () (n225) P Value
ORR 33 19 0.001
Median TTP 23.0 wks 16.9 wks 0.005
Grade IV Neutropenia 9 22 lt0.001
Grade III Neuropathy 10 2 lt0.001
Gradisher WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor-oil based paclitaxel in women with breast cancer. J Clin Oncol 2005 23 7794 - 803 Gradisher WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor-oil based paclitaxel in women with breast cancer. J Clin Oncol 2005 23 7794 - 803 Gradisher WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor-oil based paclitaxel in women with breast cancer. J Clin Oncol 2005 23 7794 - 803 Gradisher WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor-oil based paclitaxel in women with breast cancer. J Clin Oncol 2005 23 7794 - 803
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Epothilone Analogues
Agent Epothilone Analogue Phase
Ixabepilone Aza-epothilone B III
Patupilone Epothilone B II
ZK-EPO Epothilone B (fully synthetic) II
Study No of pts Prior Chemotherapy Response rate
Low 37 Taxane 22
Denduluri 23 No taxane 43
Conte 49 Taxane 12
Bunnell 50 Anthracycline and taxane 30
Perez 62 Anthracycline, taxane, capecitabine 18
J Clin Oncol 2007 25 3389 J Clin Oncol 2007 25 3389 J Clin Oncol 2007 25 3389 J Clin Oncol 2007 25 3389
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Vinflunine
Number of Patients () (n60)
Overall Response Rate 18 (30)
Median PFS 3.7 mths (95 CI, 2.8-4.2 mths)
Median OS 14.3 mths (95 CI, 9.2-19.6 mths)
Campone M, Cortes-Funes H, Vorobiof D et al. Vinflunine a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy. Br J Cancer 2006 951161-65 Campone M, Cortes-Funes H, Vorobiof D et al. Vinflunine a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy. Br J Cancer 2006 951161-65
Novel cytotoxic agents Summary Good data in
breast cancer resistant to taxane
therapy. Combination with targeted therapies as
first-line therapy. Adjuvant therapy.
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Overview

• YCN Approach
• Breast Cancer
• Novel Cytotoxics
• ErbB Receptor Pathway
• ErbB Monoclonal Antibodies
• ErbB Tyrosine Kinase Inhibitors
• Lung Cancer
• VEGF/R Pathway
• VEGF Monoclonal Antibodies
• VEGFR Tyrosine Kinase Inhibitors
• Colorectal Cancer
• Combinations
• Renal Cell Carcinoma
• Sequence and combinations
• New agents targeting alternative pathways
• Best of the rest in other clinical areas

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ErbB Receptor Family

• Zhang H, Berezov A, Wang Q. ErbB receptors from
  oncogenes to targeted cancer therapies. J. Clin.
  Invest. 2007 117 2051-2058.

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HER2 MoAbs Pertuzumab
Number of Patients () (n33)
Overall Response Rate 6 (18)
Partial response 5 (15)
Complete response 1 (3)
Stable Disease ( 6 mths) 7 (21)
Clinical Benefit Rate 13 (39)
Baselga J, Cameron D, Miles D, et al. Objective response rate in a phase II multicenter trial of pertuzumab (P) a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T. J Clin Oncol 2007 25(suppl) 33s (abstract 1004) Baselga J, Cameron D, Miles D, et al. Objective response rate in a phase II multicenter trial of pertuzumab (P) a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T. J Clin Oncol 2007 25(suppl) 33s (abstract 1004)
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ErbB TKIs - Lapatinib
Lapatinib/ Capecitabine (n198) Capecitabine (n201) P Value
ORR 24 14 0.017
Median OS 15.6 mths 15.3 mths 0.177
Median TTP 6.2 mths 4.3mths 0.00013
CNS as Site of Progression 4 (2) 13 (6) 0. 045
Geyer CE, Martin A, Newstat B, et al. Lapatinib (L) plus capecitabine (C) in HER2 advanced breast cancer (ABC) genomic data. J Clin Oncol 2007 25 (Suppl) 40s (abstract 1035) Geyer CE, Martin A, Newstat B, et al. Lapatinib (L) plus capecitabine (C) in HER2 advanced breast cancer (ABC) genomic data. J Clin Oncol 2007 25 (Suppl) 40s (abstract 1035) Geyer CE, Martin A, Newstat B, et al. Lapatinib (L) plus capecitabine (C) in HER2 advanced breast cancer (ABC) genomic data. J Clin Oncol 2007 25 (Suppl) 40s (abstract 1035) Geyer CE, Martin A, Newstat B, et al. Lapatinib (L) plus capecitabine (C) in HER2 advanced breast cancer (ABC) genomic data. J Clin Oncol 2007 25 (Suppl) 40s (abstract 1035)

• Targets HER2 (ErbB2) and EGFR (ErbB1)
• Crosses blood brain barrier?

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Current Lapatinib Trials
Study Study Treatment Phase Primary Endpoints
Refractory metastatic breast cancer patients Refractory metastatic breast cancer patients Refractory metastatic breast cancer patients Refractory metastatic breast cancer patients Refractory metastatic breast cancer patients
NCT00320385 Trastuzumab Lapatinib vs Lapatinib Trastuzumab Lapatinib vs Lapatinib III PFS, RR
NCT00098605 Lapatinib in brain metastases Lapatinib in brain metastases II RR in CNS
First-line advanced breast cancer patients First-line advanced breast cancer patients First-line advanced breast cancer patients First-line advanced breast cancer patients First-line advanced breast cancer patients
NCT00075270 Paclitaxel Lapatinib vs Paclitaxel Placebo Paclitaxel Lapatinib vs Paclitaxel Placebo III TTP, OS, RR
NCT00073528 Letrozole Lapatinib vs Letrozole Placebo Letrozole Lapatinib vs Letrozole Placebo III TTP, OS, RR
NCT00272987 Paclitaxel Trastuzumab Lapatinib vs Paclitaxel Trastuzuab Placebo Paclitaxel Trastuzumab Lapatinib vs Paclitaxel Trastuzuab Placebo III TTP, OS, RR
Inflammatory Breast Cancer Inflammatory Breast Cancer Inflammatory Breast Cancer Inflammatory Breast Cancer Inflammatory Breast Cancer
NCT00111787 Lapatinib paclitaxel in neoadjuvant IBC Lapatinib paclitaxel in neoadjuvant IBC II NR
Adjuvant Breast Cancer Adjuvant Breast Cancer Adjuvant Breast Cancer Adjuvant Breast Cancer Adjuvant Breast Cancer
NCT00490139 (ALTTO) Trastuzumab vs Lapatinib vs Trastuzumab Lapatinib vs Trastuzumab - Lapatinib Trastuzumab vs Lapatinib vs Trastuzumab Lapatinib vs Trastuzumab - Lapatinib III OS, TTP, RR
NCT00374322 Lapatinib vs placebo Lapatinib vs placebo III DFS,OS, CNS recurr.
Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007.
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Second Generation ErbB TKIs
Target Type of binding Phase
HKI-272 EGFR (ErbB1) HER2 (ErbB2) Irreversible II
CI-1033 EGFR (ErbB1) HER2 (ErbB2) ErbB4 Irreversible II
EKB-569 EGFR (ErbB1) Irreversible I

• New strategies
• Covalent irreversible binding to target
• Broadening the affected targets

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ErbB Target - Summary
Combinations with/without chemotherapy EGFR
MoAbs VEGF MoAbs EGFR VEGFR TKIs EGFR MoAb
EGFR TKI Irreversible TKIs Adjuvant therapy
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Overview

• YCN Approach
• Breast Cancer
• Novel Cytotoxics
• ErbB Receptor Pathway
• Lung Cancer
• VEGF/R Pathway
• Colorectal Cancer
• Biological Combinations
• Renal Cell Carcinoma
• Sequence and combinations
• New agents targeting alternative pathways
• Best of the rest in other clinical areas

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Lung Cancer
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Has chemotherapy in advanced NSCLC done all it
can?
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Overview

• YCN Approach
• Breast Cancer
• Novel Cytotoxics
• ErbB Receptor Pathway
• Lung Cancer
• VEGF/R Pathway
• VEGF Monoclonal Antibodies
• VEGFR Tyrosine Kinase Inhibitors
• Colorectal Cancer
• Biological Combinations
• Renal Cell Carcinoma
• Sequence and combinations
• New agents targeting alternative pathways
• Best of the rest in other clinical areas

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VEGF/R Pathway
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Ongoing Bevacizumab Trials
Study Treatment Phase Primary Endpoints
Second-line advanced NSCLC Second-line advanced NSCLC Second-line advanced NSCLC Second-line advanced NSCLC
NCT00130728 Bevacizumab erlotinib vs placebo erlotinib III 0S
First-line advanced NSCLC First-line advanced NSCLC First-line advanced NSCLC First-line advanced NSCLC
NCT00257608 Chemotherapy followed by bevacizumab erlotinib vs bevacizumab placebo IIIb PFS
NCT00531960 Chemotherapy bevacizumab vs erlotinib bevacizumab II PFS
Locally advanced NSCLC with previously treated CNS metastases Locally advanced NSCLC with previously treated CNS metastases Locally advanced NSCLC with previously treated CNS metastases Locally advanced NSCLC with previously treated CNS metastases
NCT00312728 Bevacizumab in combination with 1st or 2nd line chemotherapy II Assess rate of grade 2 CNS hemorrhage
Stage IB, II, IIIA NSCLC Stage IB, II, IIIA NSCLC Stage IB, II, IIIA NSCLC Stage IB, II, IIIA NSCLC
NCT00324805 Adjuvant chemotherapy /- bevacizumab III OS
Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007.
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Small-molecule TKIs VS MoAbs
TKI MoAb
Target Specificity Selective Specific
Pharmokinetics
Bioavailability po IV
Half-life Short Long
Cross blood brain barrier -
Interactions /-
Mechanisms of Action
ADCC -
Receptor downregulation -
Ability to target ligands -
Potential for Engineering
Conjugation -
Tailoring effector functions -
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VEGFR TKIs for NSCLC ASCO 2007
Abstract No. Author Phase Study
Sunitinib 7542 Brahmer II Continuous suntinib in previously treated
Sorafenib 7547 Adjei II First line
Vandetinib (ZD6474) 7544 Heymach II First line randomised study of Van vs Carbo/Pac vs Van/Carbo/Pac
Vandetinib (ZD6474) 7654 De Boer I Van Pemetrexed in previously treated
AZD2171 (RecentinTM) 7649 Goss I AZD2171/Gem/Cis in advanced NSCLC
Vatalinib 7541 Gauler II Second line monotherapy
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Is potency important?
Drug t1/2 (hrs) IC50 (Nm) IC50 (Nm) IC50 (Nm) IC50 (Nm) IC50 (Nm) Other
VEGFR-1 VEGFR-2 VEGFR-3 PDGFR KIt
Sunitinib 44 2 9 17 2 22 RET
Sorafenib 27 90 20 68 B-Raf, RET
Vandetinib (ZD6474) 120 1600 40 110 1100 gt20000 EGFR,RET
Recentin (AZD2171) 13-35 5 lt 1 lt 3 5 2
AMG706 5-7 2 3 6 8 84 RET
Axitinib (AGO13736) 2-5 1.2 0.25 0.29 0.25 0.2
Vatalinib 3-6 77 37 660 580 730
Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764
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Or are other factors?
Drug t1/2 (hrs) IC50 (Nm) IC50 (Nm) IC50 (Nm) IC50 (Nm) IC50 (Nm) Other
VEGFR-1 VEGFR-2 VEGFR-3 PDGFR KIt
Sunitinib 44 2 9 17 2 22 RET
Sorafenib 27 90 20 68 B-Raf, RET
Vandetinib (ZD6474) 120 1600 40 110 1100 gt20000 EGFR,RET
Recentin (AZD2171) 13-35 5 lt 1 lt 3 5 2
AMG706 5-7 2 3 6 8 84 RET
Axitinib (AGO13736) 2-5 1.2 0.25 0.29 0.25 0.2
Vatalinib 3-6 77 37 660 580 730
Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764 Adapted from Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials Current status and future directions. Oncologist 2006 11 753-764
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Dual Kinase Inhibition - Vandetinib
Docetaxel (n41) Vandetinib 100mg Docetaxel (n42) Vandetinib 300mg Docetaxel (n44)
Median PFS 12 wks 18.7 wks p0.037 17.0 wks p 0.231
Median OS NS NS NS
Heymach JV, Johnson BE, Prager D. Randomized, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel in Previously Treated NonSmall-Cell Lung Cancer. J Clin Oncol 2007 25 4270-4277 Heymach JV, Johnson BE, Prager D. Randomized, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel in Previously Treated NonSmall-Cell Lung Cancer. J Clin Oncol 2007 25 4270-4277 Heymach JV, Johnson BE, Prager D. Randomized, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel in Previously Treated NonSmall-Cell Lung Cancer. J Clin Oncol 2007 25 4270-4277 Heymach JV, Johnson BE, Prager D. Randomized, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel in Previously Treated NonSmall-Cell Lung Cancer. J Clin Oncol 2007 25 4270-4277
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VEGF/R Target - Summary
Bevacizumab High risk patients Combination
therapy (with chemo/-biologics) Earlier stage
disease Novel TKIs TKIs versus MoAbs? Is
potency important? Dual kinase vs single kinase
inhibitors?
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Overview

• YCN Approach
• Breast Cancer
• Novel Cytotoxics
• ErbB Receptor Pathway
• Lung Cancer
• VEGF/R Pathway
• Colorectal Cancer
• Combinations
• Renal Cell Carcinoma
• Sequence and combinations
• New agents targeting alternative pathways
• Best of the rest in other clinical areas

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Current Treatments

• Irinotecan, oxaliplatin, capecitabine,
  bevacizumab, cetuximab.
• Optimal combinations
• Optimal sequences maintenance vs holidays
• Duration of therapy

FOLFIRI Cetuximab (n599) FOLFIRI (n599) P Value
Median PFS 8.9 mths 8.0 mths 0.0479
Median PFS (liver mets only) 11.4 mths 9.2 mths 0.023
Van Cutsem E, Nowacki M, Lang I et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC) The CRYSTAL trial. J Clin Oncol 2007 25(suppl) 18s (abstract 4000) Van Cutsem E, Nowacki M, Lang I et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC) The CRYSTAL trial. J Clin Oncol 2007 25(suppl) 18s (abstract 4000) Van Cutsem E, Nowacki M, Lang I et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC) The CRYSTAL trial. J Clin Oncol 2007 25(suppl) 18s (abstract 4000) Van Cutsem E, Nowacki M, Lang I et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC) The CRYSTAL trial. J Clin Oncol 2007 25(suppl) 18s (abstract 4000)
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Bevacizumab vs Cetuximab Combinations
Combination n RR PFS Duration of therapy
CRYSTAL FOLFIRI /- Cetuximab 1198 8.2 8.9 vs 8.0 mths 5.6 vs 5.9 mths
NO16966 FOLFOX/XELOX /- Bevacizumab 1400 NR 9.4 vs 8.0 mths 6.0 vs 6.0 mths
AVF2107 IFL /- Bevacizumab 813 10 10.6 vs 6.2 mths 8.0 vs 5.2 mths
PFS Improvements limited. CRYSTAL/NO16966 stopped all therapy upon progression. Is there higher level of benefit from continuing treatment beyond progression?
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Why target both VEGF and ErbB?

• EGFR inhibitors known to exert angiogenic effects
  by reducing expression of VEGF and other
  pro-angiogenic factors by tumour cells
• EGFR may be induced on tumour epithelium and
  contribute to tumour angiogenesis
• Acquired resistance to EGFR blockade is
  associated with increased VEGF expression

Combinations - Summary Combined VEGF/EGFR
inhibition may therefore provide a more potent
antiangiogenic effect in addition to direct
effects on EGFR tumour cells Is maintenance
therapy of benefit?
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Ongoing Studies
Study Treatment Phase Primary Endpoints
Bevacizumab adjuvant CRC Bevacizumab adjuvant CRC Bevacizumab adjuvant CRC Bevacizumab adjuvant CRC
NCT00217737 5FU/Leucovorin/Oxaliplatin /- bevacizumab III DFS at 3yrs
Cetuximab/ Bevacizumab combinations in mCRC Cetuximab/ Bevacizumab combinations in mCRC Cetuximab/ Bevacizumab combinations in mCRC Cetuximab/ Bevacizumab combinations in mCRC
NCT00265850 Combination chemotherapy cetuximab /- bevacizumab III OS
NCT00499369 Chemotherapy cetuximab /- bevacizumab III OS
Novel VEGFR TKIs Novel VEGFR TKIs Novel VEGFR TKIs Novel VEGFR TKIs
NCT00457691 FOLFIRI /- sunitinib III PFS
NCT00460603 Axitinib/FOLFOX/Bevacizumab vs Axitinib/ FOLFOX vs FOLFOX/Bevacizumab II ORR
NCT00387389 FOLFOX6 or CapeOx /- pazopanib I Safety
Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007. Available at http//www.clinicaltrials.gov/ct. Accessed September 20, 2007.
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Overview

• YCN Approach
• Breast Cancer
• Novel Cytotoxics
• ErbB Receptor Pathway
• Lung Cancer
• VEGF/R Pathway
• Colorectal Cancer
• Biological Combinations
• Renal Cell Carcinoma
• Sequence and combinations
• New agents targeting alternative pathways
• Best of the rest in other clinical areas

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mTOR Pathway - Temsirolimus

• Rini B, Kar S, Kirkpatrick P. Temsirolimus.
  Nature Reviews Drug Discovery 2007 6 599-600

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Temsorilumus
Interferon (n207) Temsirolimus (n209) Interferon Temsirolimus (n210)
Median OS 7.3 mths 10.9 mths p0.008 8.4 mths p 0.7
Median PFS 1.9 mths 3.8 mths 3.7 mths
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. N Engl J Med 2007 356 pg. 2271 Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. N Engl J Med 2007 356 pg. 2271 Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. N Engl J Med 2007 356 pg. 2271 Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. N Engl J Med 2007 356 pg. 2271
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Sequence and Combination in mRCC ASCO 2007
Abstract No. Author Phase Study
Sequence 5038 Sablin Sequential sorafenib sunitinib vs sunitinib - sorafenib
Sequence 5106 Dham II Sequential sorafenib sunitinib vs sunitinib - sorafenib
Sequence 5032 Rini II Sequential sorefenib - axitinib
Sorafenib Combinations 5100 - - Bracarda - I/II II II Sorafenib Bevacizumab Sorafenib Evorilimus (RAD-001) Sorafenib IFN-a Sorafenib HD IL2
Sunitinib Combinations 5099 5101 - Feldman Kondagunta I I I Sunitinib Everolimus (RAD-001) Suntinib Bevacizumab Sunitinib IFN
Combination ECOG (2804) BEST Trial - II Bevacizumab vs Bevacizumab Sorafenib vs Bevacizumab Temsorilimus vs Sorafenib Temsorilimus in the front line setting
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New agents in mRCC ASCO 2007?
Abstract No. Author Phase Study
Axitinib 5032 Rini II Sequential in patients refractory to sorafenib estimated PFS gt 7.1mths
Everolimus (RAD 001) 5107 Jac II No more than 1 prior therapy prolonged TTP 3mths
Pazopanib 5031 Hutson II In patients who had failed one bevacizumab or cytokine containing regimen PR rate at wk 12 of 40
Voliciximab 5094 Yazji II Anti-integrin antibody Median TTP 4mths. Median OS not reached after 22mths. OS at 12mths 68.
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Novel Agents and Strategies - Summary
New agents with targets other than ErbB
or VEGF/R Which combination(s) is best? Which
sequence of agents is best? Sequence of
TKIs Sequence of different therapies Adjuvant
therapy
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Overview

• YCN Approach
• Breast Cancer
• Novel Cytotoxics
• ErbB Receptor Pathway
• Lung Cancer
• VEGF/R Pathway
• Colorectal Cancer
• Biological Combinations
• Renal Cell Carcinoma
• Sequence and combinations
• New agents targeting alternative pathways
• Best of the rest in other clinical areas

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Haematology MDS
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Haematology AML
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Haematology Chronic Leukaemias
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Haematology Multiple Myeloma
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Haematology - General
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Prostate Cancer
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Head and Neck Cancer
60
Pancreatic Cancer
61
Skin Cancer
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Upper GI Cancer