Download Whats on the Horizon? - British Oncology Pharmacy Association

Whats on the Horizon?
David Thomson,
Lead Pharmacist,
Yorkshire Cancer Network.
Overview
1.
2.
YCN Approach
Breast Cancer
•
•
3.
Lung Cancer
•
4.
VEGF/R Pathway
Colorectal Cancer
•
5.
Biological Combinations
Renal Cell Carcinoma
•
•
6.
Novel Cytotoxics
ErbB Receptor Pathway
Sequence and combinations
New agents targeting alternative pathways
“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.
2.
YCN Approach
Breast Cancer
•
•
3.
Lung Cancer
•
4.
VEGF/R Pathway
Colorectal Cancer
•
5.
Biological Combinations
Renal Cell Carcinoma
•
•
6.
Novel Cytotoxics
ErbB Receptor Pathway
Sequence and combinations
New agents targeting alternative pathways
“Best of the rest” in other clinical areas
Overview
1.
2.
YCN Approach
Breast Cancer
•
•
3.
Lung Cancer
•
4.
VEGF/R Pathway
Colorectal Cancer
•
5.
Biological Combinations
Renal Cell Carcinoma
•
•
6.
Novel Cytotoxics
ErbB Receptor Pathway
Sequence and combinations
New agents targeting alternative pathways
“Best of the rest” in other clinical areas
Novel Paclitaxel Formulations
First Generation
Second Generation
Albumin-Bound
Paclitaxel
Paclitaxel
Poliglumex
Paclitaxel Injectable
Emulsion
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
33%
19%
0.001
23.0 wks
16.9 wks
0.005
Grade IV Neutropenia
9%
22%
<0.001
Grade III Neuropathy
10%
2%
<0.001
Active Drug
ORR
Median TTP
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
Agent
Epothilone Analogue
Phase
Ixabepilone
Aza-epothilone B
III
Patupilone
Epothilone B
II
Epothilone B
(fully synthetic)
II
ZK-EPO
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
Vinflunine
Number 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.
Overview
1.
2.
YCN Approach
Breast Cancer
•
•
Novel Cytotoxics
ErbB Receptor Pathway
•
•
3.
Lung Cancer
•
VEGF/R Pathway
•
•
4.
VEGF Monoclonal Antibodies
VEGFR Tyrosine Kinase Inhibitors
Colorectal Cancer
•
5.
Combinations
Renal Cell Carcinoma
•
•
6.
ErbB Monoclonal Antibodies
ErbB Tyrosine Kinase Inhibitors
Sequence and combinations
New agents targeting alternative pathways
“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
24%
14%
0.017
Median OS
15.6 mths
15.3 mths
0.177
Median TTP
6.2 mths
4.3mths
0.00013
4 (2%)
13 (6%)
0. 045
ORR
CNS as Site of
Progression
P Value
(n=201)
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 Trials
Study
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
II
NR
Inflammatory Breast Cancer
NCT00111787
Lapatinib + paclitaxel in neoadjuvant IBC
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’s
EGFR MoAb + EGFR TKI
Irreversible TKI’s
Adjuvant therapy
Overview
1.
2.
YCN Approach
Breast Cancer
•
•
3.
Lung Cancer
•
4.
VEGF/R Pathway
Colorectal Cancer
•
5.
Biological Combinations
Renal Cell Carcinoma
•
•
6.
Novel Cytotoxics
ErbB Receptor Pathway
Sequence and combinations
New agents targeting alternative pathways
“Best of the rest” in other clinical areas
Lung Cancer
Has chemotherapy in advanced
NSCLC done all it can?
Overview
1.
2.
YCN Approach
Breast Cancer
•
•
3.
Novel Cytotoxics
ErbB Receptor Pathway
Lung Cancer
•
VEGF/R Pathway
•
•
4.
Colorectal Cancer
•
5.
Biological Combinations
Renal Cell Carcinoma
•
•
6.
VEGF Monoclonal Antibodies
VEGFR Tyrosine Kinase Inhibitors
Sequence and combinations
New agents targeting alternative pathways
“Best of the rest” in other clinical areas
VEGF/R Pathway
Ongoing Bevacizumab Trials
Study
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
III
OS
Stage IB, II, IIIA NSCLC
NCT00324805
Adjuvant chemotherapy +/- bevacizumab
Available at: http://www.clinicaltrials.gov/ct. Accessed September 20, 2007.
Small-molecule TKI’s VS MoAb’s
TKI
MoAb
Selective
Specific
po
IV
Short
Long
Cross blood brain barrier
+
-
Interactions
+
+/-
ADCC
-
+
Receptor downregulation
+
-
Ability to target ligands
-
+
Conjugation
-
+
Tailoring effector functions
-
+
Target Specificity
Pharmokinetics
Bioavailability
Half-life
Mechanisms of Action
Potential for Engineering
VEGFR TKI’s for NSCLC –
ASCO 2007
Abstract No.
Sunitinib
7542
Sorafenib
7547
Vandetinib
(ZD6474)
7544
7654
AZD2171
(RecentinTM)
7649
Vatalinib
7541
Author
Phase
Study
Brahmer
II
Continuous suntinib in previously
treated
Adjei
II
First line
Heymach
II
First line – randomised study of Van vs
Carbo/Pac vs Van/Carbo/Pac
De Boer
I
Van + Pemetrexed in previously
treated
Goss
I
AZD2171/Gem/Cis in advanced
NSCLC
Gauler
II
Second line monotherapy
Is potency important?
Drug
t1/2 (hrs)
IC50 (Nm)
Other
VEGFR-1
VEGFR-2
VEGFR-3
PDGFR
KIt
2
9
17
2
22
RET
90
20
68
B-Raf, RET
EGFR,RET
Sunitinib
44
Sorafenib
~27
Vandetinib
(ZD6474)
~120
1600
40
110
1100
>20000
Recentin
(AZD2171)
13-35
5
<1
<3
5
2
AMG706
5-7
2
3
6
8
84
Axitinib
(AGO13736)
2-5
1.2
0.25
0.29
0.25
0.2
Vatalinib
3-6
77
37
660
580
730
RET
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
VEGFR3
PDGFR
KIt
2
9
17
2
22
RET
90
20
68
B-Raf,
RET
EGFR,RE
T
Sunitinib
44
Sorafenib
~27
Vandetinib
(ZD6474)
~120
1600
40
110
1100
>20000
Recentin
(AZD2171)
13-35
5
<1
<3
5
2
AMG706
5-7
2
3
6
8
84
Axitinib
(AGO13736)
2-5
1.2
0.25
0.29
0.25
0.2
Vatalinib
3-6
77
37
660
580
730
RET
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
Bevacizumab
High risk patients
Combination therapy (with chemo+/-biologics)
Earlier stage disease
Novel TKI’s
TKI’s versus MoAbs?
Is potency important?
Dual kinase vs single kinase inhibitors?
Overview
1.
2.
YCN Approach
Breast Cancer
•
•
3.
Lung Cancer
•
4.
VEGF/R Pathway
Colorectal Cancer
•
5.
Combinations
Renal Cell Carcinoma
•
•
6.
Novel Cytotoxics
ErbB Receptor Pathway
Sequence and combinations
New agents targeting alternative pathways
“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 proangiogenic 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?
Ongoing Studies
Study
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.
2.
YCN Approach
Breast Cancer
•
•
3.
Lung Cancer
•
4.
VEGF/R Pathway
Colorectal Cancer
•
5.
Biological Combinations
Renal Cell Carcinoma
•
•
6.
Novel Cytotoxics
ErbB Receptor Pathway
Sequence and combinations
New agents targeting alternative pathways
“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
Temsorilumus
Interferon
(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 2007
Abstract No.
Sequence
Sequence
Sequence
5038
5106
5032
Sorafenib
Combinations
5100
Sunitinib
Combinations
Combination
5099
5101
ECOG
(2804): BEST
Trial
Author
Phase
Study
Sequential sorafenib – sunitinib vs
sunitinib - sorafenib
Sablin
Dham
II
Sequential sorafenib – sunitinib vs
sunitinib - sorafenib
Rini
II
Sequential sorefenib - axitinib
I/II
II
II
Sorafenib + Bevacizumab
Sorafenib + Evorilimus (RAD-001)
Sorafenib + IFN-α
Sorafenib + HD – IL2
Feldman
Kondagun
ta
I
I
I
Sunitinib + Everolimus (RAD-001)
Suntinib + Bevacizumab
Sunitinib + IFN
-
II
Bevacizumab vs Bevacizumab +
Sorafenib vs Bevacizumab +
Temsorilimus vs Sorafenib +
Temsorilimus in the front line setting
Bracarda
-
New agents in mRCC – ASCO
2007?
Abstract
No.
Axitinib
Author
Phase
Rini
II
Sequential in patients refractory to
sorafenib – estimated PFS > 7.1mths
Jac
II
No more than 1 prior therapy –
prolonged TTP = 3mths
Hutson
II
In patients who had failed one
bevacizumab or cytokine containing
regimen – PR rate at wk 12 of 40%
Yazji
II
Anti-integrin antibody – Median TTP
4mths. Median OS not reached after
22mths. OS at 12mths 68%.
5032
Everolimus
(RAD 001)
5107
Pazopanib
5031
Voliciximab
5094
Study
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 TKI’s
Sequence of different therapies
Adjuvant therapy
Overview
1.
2.
YCN Approach
Breast Cancer
•
•
3.
Lung Cancer
•
4.
VEGF/R Pathway
Colorectal Cancer
•
5.
Biological Combinations
Renal Cell Carcinoma
•
•
6.
Novel Cytotoxics
ErbB Receptor Pathway
Sequence and combinations
New agents targeting alternative pathways
“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