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







Overview







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


• ErbB Monoclonal Antibodies• ErbB Tyrosine Kinase Inhibitors


• VEGF Monoclonal Antibodies• VEGFR Tyrosine Kinase Inhibitors

4. Colorectal Cancer• Combinations



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.

http://www.clinicaltrials.gov/ct



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







Lung Cancer

Has chemotherapy in advanced NSCLC done all it can?

Overview1. YCN Approach2. Breast Cancer



• VEGF Monoclonal Antibodies• VEGFR Tyrosine Kinase Inhibitors




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



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




4. Colorectal Cancer• Combinations



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





Overview







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







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

Documents

Whats on the Horizon?