Whats on the Horizon?
description
Transcript of Whats on the Horizon?
Whats on the Horizon?
David Thomson,
Lead Pharmacist,
Yorkshire Cancer Network.
Overview
1. YCN Approach2. Breast Cancer
• Novel Cytotoxics• ErbB Receptor Pathway
3. Lung Cancer• VEGF/R Pathway
4. Colorectal Cancer• Biological Combinations
5. Renal Cell Carcinoma• Sequence and combinations• New agents targeting alternative pathways
6. “Best of the rest” in other clinical areas
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.
YCN Chemotherapy Management Database
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.
Horizon Scanning Report
Disclaimer!
• The information used in producing these reports changes rapidly and the level of evidence presented and conclusions made about a drug’s 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.
The Challenge
Predicted New Drug Approval Dates
Overview
1. YCN Approach2. Breast Cancer
• Novel Cytotoxics• ErbB Receptor Pathway
3. Lung Cancer• VEGF/R Pathway
4. Colorectal Cancer• Biological Combinations
5. Renal Cell Carcinoma• Sequence and combinations• New agents targeting alternative pathways
6. “Best of the rest” in other clinical areas
Overview
1. YCN Approach2. Breast Cancer
• Novel Cytotoxics• ErbB Receptor Pathway
3. Lung Cancer• VEGF/R Pathway
4. Colorectal Cancer• Biological Combinations
5. Renal Cell Carcinoma• Sequence and combinations• New agents targeting alternative pathways
6. “Best of the rest” in other clinical areas
Novel Paclitaxel FormulationsFirst 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 (%)
(n=229)
Paclitaxel (%)
(n=225)
P Value
ORR 33% 19% 0.001
Median TTP 23.0 wks 16.9 wks 0.005
Grade IV Neutropenia 9% 22% <0.001
Grade III Neuropathy 10% 2% <0.001
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
Epothilone Analogues
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
Agent Epothilone Analogue Phase
Ixabepilone Aza-epothilone B III
Patupilone Epothilone B II
ZK-EPO Epothilone B
(fully synthetic)
II
VinflunineNumber of Patients (%)
(n=60)
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; 95:1161-65
Novel cytotoxic agents – Summary
Good data in breast cancer resistant to taxane therapy.
Combination with targeted therapies as first-line therapy.
Adjuvant therapy.
Overview1. YCN Approach2. Breast Cancer
• Novel Cytotoxics• ErbB Receptor Pathway
• ErbB Monoclonal Antibodies• ErbB Tyrosine Kinase Inhibitors
3. Lung Cancer• VEGF/R Pathway
• VEGF Monoclonal Antibodies• VEGFR Tyrosine Kinase Inhibitors
4. Colorectal Cancer• Combinations
5. Renal Cell Carcinoma• Sequence and combinations• New agents targeting alternative pathways
6. “Best of the rest” in other clinical areas
ErbB Receptor Family
Zhang H, Berezov A, Wang Q. ErbB receptors: from oncogenes to targeted cancer therapies. J. Clin. Invest. 2007; 117: 2051-2058.
HER2 MoAbs – Pertuzumab
Number of Patients (%)
(n=33)
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)
ErbB TKI’s - Lapatinib
Lapatinib/
Capecitabine
(n=198)
Capecitabine
(n=201)
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)
• Targets HER2 (ErbB2) and EGFR (ErbB1)• Crosses blood brain barrier?
Current Lapatinib TrialsStudy Treatment Phase Primary Endpoints
Refractory metastatic breast cancer patients
NCT00320385 Trastuzumab + Lapatinib vs Lapatinib III PFS, RR
NCT00098605 Lapatinib in brain metastases II RR in CNS
First-line advanced breast cancer patients
NCT00075270 Paclitaxel + Lapatinib vs Paclitaxel + Placebo
III TTP, OS, RR
NCT00073528 Letrozole + Lapatinib vs Letrozole + Placebo
III TTP, OS, RR
NCT00272987 Paclitaxel + Trastuzumab + Lapatinib vs Paclitaxel + Trastuzuab + Placebo
III TTP, OS, RR
Inflammatory Breast Cancer
NCT00111787 Lapatinib + paclitaxel in neoadjuvant IBC II NR
Adjuvant Breast Cancer
NCT00490139
(ALTTO)
Trastuzumab vs Lapatinib vs Trastuzumab + Lapatinib vs Trastuzumab - Lapatinib
III OS, TTP, RR
NCT00374322 Lapatinib vs placebo III DFS,OS, CNS recurr.
Available at: http://www.clinicaltrials.gov/ct. Accessed September 20, 2007.
Second Generation ErbB TKI’s
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
ErbB Target - Summary
Combinations with/without chemotherapy:EGFR MoAbs + VEGF MoAbs
EGFR + VEGFR TKI’sEGFR MoAb + EGFR TKI
Irreversible TKI’s
Adjuvant therapy
Overview
1. YCN Approach2. Breast Cancer
• Novel Cytotoxics• ErbB Receptor Pathway
3. Lung Cancer• VEGF/R Pathway
4. Colorectal Cancer• Biological Combinations
5. Renal Cell Carcinoma• Sequence and combinations• New agents targeting alternative pathways
6. “Best of the rest” in other clinical areas
Lung Cancer
Has chemotherapy in advanced NSCLC done all it can?
Overview1. YCN Approach2. Breast Cancer
• Novel Cytotoxics• ErbB Receptor Pathway
3. Lung Cancer• VEGF/R Pathway
• VEGF Monoclonal Antibodies• VEGFR Tyrosine Kinase Inhibitors
4. Colorectal Cancer• Biological Combinations
5. Renal Cell Carcinoma• Sequence and combinations• New agents targeting alternative pathways
6. “Best of the rest” in other clinical areas
VEGF/R Pathway
Ongoing Bevacizumab TrialsStudy Treatment Phase Primary Endpoints
Second-line advanced NSCLC
NCT00130728 Bevacizumab + erlotinib vs placebo + erlotinib
III 0S
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
NCT00312728 Bevacizumab in combination with 1st or 2nd line chemotherapy
II Assess rate of grade ≥2 CNS hemorrhage
Stage IB, II, IIIA NSCLC
NCT00324805 Adjuvant chemotherapy +/- bevacizumab III OS
Available at: http://www.clinicaltrials.gov/ct. Accessed September 20, 2007.
Small-molecule TKI’s VS MoAb’s
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 - +
VEGFR TKI’s for NSCLC – ASCO 2007
Abstract No. Author Phase Study
Sunitinib7542
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
7654De 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
Is potency important?Drug t1/2 (hrs) 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 >20000 EGFR,RET
Recentin (AZD2171)
13-35 5 < 1 < 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
Or are other factors?Drug t1/2 (hrs) 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 >20000 EGFR,RET
Recentin (AZD2171)
13-35 5 < 1 < 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
Dual Kinase Inhibition - Vandetinib
Docetaxel
(n=41)
Vandetinib 100mg + Docetaxel
(n=42)
Vandetinib 300mg + Docetaxel
(n=44)
Median PFS 12 wks 18.7 wks
p=0.037
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 Non–Small-Cell Lung Cancer. J Clin Oncol 2007; 25: 4270-4277
VEGF/R Target - Summary
BevacizumabHigh risk patients
Combination therapy (with chemo+/-biologics)Earlier stage disease
Novel TKI’sTKI’s versus MoAbs?Is potency important?
Dual kinase vs single kinase inhibitors?
Overview
1. YCN Approach2. Breast Cancer
• Novel Cytotoxics• ErbB Receptor Pathway
3. Lung Cancer• VEGF/R Pathway
4. Colorectal Cancer• Combinations
5. Renal Cell Carcinoma• Sequence and combinations• New agents targeting alternative pathways
6. “Best of the rest” in other clinical areas
Current Treatments
• Irinotecan, oxaliplatin, capecitabine, bevacizumab, cetuximab.– Optimal combinations– Optimal sequences : maintenance vs holidays– Duration of therapy
FOLFIRI + Cetuximab
(n=599)
FOLFIRI
(n=599)
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)
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?
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 - SummaryCombined 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?
Ongoing StudiesStudy Treatment Phase Primary
Endpoints
Bevacizumab adjuvant CRC
NCT00217737 5FU/Leucovorin/Oxaliplatin +/- bevacizumab III DFS at 3yrs
Cetuximab/ Bevacizumab combinations in mCRC
NCT00265850 Combination chemotherapy + cetuximab +/- bevacizumab
III OS
NCT00499369 Chemotherapy + cetuximab +/- bevacizumab III OS
Novel VEGFR TKI’s
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.
Overview
1. YCN Approach2. Breast Cancer
• Novel Cytotoxics• ErbB Receptor Pathway
3. Lung Cancer• VEGF/R Pathway
4. Colorectal Cancer• Biological Combinations
5. Renal Cell Carcinoma• Sequence and combinations• New agents targeting alternative pathways
6. “Best of the rest” in other clinical areas
mTOR Pathway - Temsirolimus
Rini B, Kar S, Kirkpatrick P. Temsirolimus. Nature Reviews Drug Discovery 2007; 6: 599-600
TemsorilumusInterferon
(n=207)
Temsirolimus
(n=209)
Interferon + Temsirolimus
(n=210)
Median OS 7.3 mths 10.9 mths
p=0.008
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
Sequence and Combination in mRCC – ASCO 2007Abstract No. Author Phase Study
Sequence5038
Sablin Sequential sorafenib – sunitinib vs sunitinib - sorafenib
Sequence5106
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-α
Sorafenib + HD – IL2
Sunitinib Combinations
5099
5101
-
Feldman
Kondagunta
I
I
I
Sunitinib + Everolimus (RAD-001)
Suntinib + Bevacizumab
Sunitinib + IFN
CombinationECOG
(2804): BEST Trial
- II Bevacizumab vs Bevacizumab + Sorafenib vs Bevacizumab + Temsorilimus vs Sorafenib + Temsorilimus in the front line setting
New agents in mRCC – ASCO 2007?
Abstract No.
Author Phase Study
Axitinib5032
Rini II Sequential in patients refractory to sorafenib – estimated PFS > 7.1mths
Everolimus (RAD 001) 5107
Jac II No more than 1 prior therapy – prolonged TTP = 3mths
Pazopanib5031
Hutson II In patients who had failed one bevacizumab or cytokine containing regimen – PR rate at wk 12 of 40%
Voliciximab5094
Yazji II Anti-integrin antibody – Median TTP 4mths. Median OS not reached after 22mths. OS at 12mths 68%.
Novel Agents and Strategies - Summary
New agents with targets other than ErbB orVEGF/R
Which combination(s) is best?
Which sequence of agents is best?Sequence of TKI’s
Sequence of different therapies
Adjuvant therapy
Overview
1. YCN Approach2. Breast Cancer
• Novel Cytotoxics• ErbB Receptor Pathway
3. Lung Cancer• VEGF/R Pathway
4. Colorectal Cancer• Biological Combinations
5. Renal Cell Carcinoma• Sequence and combinations• New agents targeting alternative pathways
6. “Best of the rest” in other clinical areas
Haematology –MDS
Haematology – AML
Haematology – Chronic Leukaemias
Haematology – Multiple Myeloma
Haematology - General
Prostate Cancer
Head and Neck Cancer
Pancreatic Cancer
Skin Cancer
Upper GI Cancer