Transcript Nexavar* A multi-kinase inhibitor

Nexavar™ Sorafenib
A Multikinase inhibitor
January 2009
Chloé DINGREVILLE Diane-Laurène SMAL Aurélie TELLIER
Initial target: Raf
Voie MAPK
Raf
EGF
EGFR
PDGFR
Ser/Thr
Kinase
VEGF
VEGFR
PDGF
2 major isoforms:
B-Raf
C-Raf or Raf1
Ras
MEK
ERK
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Raf:
Often hyper activated in human solid tumour:
1. caused by activation oncogenic mutations:
as b-raf V600E mutation
• Prevalent in melanomas 63%
• Papillary thyroid carcinoma 50%
2. Activation upstream of oncogenic ras mutants (Kras )
• 90% of pancreatic cancers
• 30% of Hepatocellular carcinoma HCC
• 35% of Non-Squamous-cell lung cancers
NSCLC
• 15% of melanoma
• 10% of kidney RCC
3. expression of upstream growth factor or/ and their
RTKs
• renal cell carcinoma (RCC) 50%
• hepatocellular carcinoma (HCC) 100%
Discovery and development of Sorafenib
• Sorafenib is a bi-aryl urea
• First oral kinase inhibitor, that targets RAF
Three Levels of Preclinical Evaluation
First level:
Kinase Inhibition
Biochemical
In vitro inhibitory profile of Sorafenib
Interaction between Sorafenib and kinases
Nexavar®
Raf kinase, PDGFR, VEGFR, cKit, RET, etc…
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In vitro inhibitory profile of Sorafenib
Sorafenib: Target cell proliferation
By inhibiting Raf which is:
•Central
•downstream of Ras
 Inhibit tumor growth
In vitro inhibitory profile of Sorafenib
Solid Tumors
Sorafenib: Target cell proliferation and angiogenesis
Sorafenib is a multi-kinase inhibitor
Which cancers should be targeted ?
« Because they attack multiple targets, it is hard to predict how
drugs like Nexavar sorafenib will perform against a specific
tumour type. »
Three Levels of Preclinical Evaluation
Kinase Inhibition
Biochemical
Determine the enter
in Clinical Evaluation
In vitro Inhibition
of cell proliferation
Tumor Xenograft
A balanced portfolio strategy
involves testing the drug both in:
• low-risk indications: highly likely to work given past successes
EX: Broad already approved indication in HCC and RCC
and geographical extension
• high-risk indications: less likely to work but the market would
be worthwhile
EX: Find new indications in other cancers
Nexavar clinical program
Cancer type
Nexavar treatment
Status
Liver cancer HCC
Post-transarterial chemoembolization
(TACE) (Japan)
1st line, docorubicin
TACE
Adjuvant
Combinations
Ph III
Adjuvant
Dose escalation
Combinations
Ph III
Ph II
Ph II
Kidney cancer RCC
Ph II
Planned Ph III
Planned Ph III
Planned Ph III
Non-small cell lung 1st line, carboplatin/paclitaxel
cancer (NSCLC)
1st line, gemcitabine/cisplatin
2nd/3rd line, single-agent
2nd line, Alimta pemetrexed
1st line, carboplatin/Alimta
2nd line, Tarceva erlotinib
Ph III *
Ph II
Ph II
Ph II
Ph I
Planned Ph II
Melanoma
Ph III
Ph II
1st line, carboplatin/paclitaxel
Multiple lines, temozolomide
Two already approved indications:
I. RCC: Renal Cell Carcinoma
II. HCC: Hepatocellular Carcinoma
Renal Cell Carcinoma
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• Nearly 3% of all cancers
• The most common kidney cancer
• Each year:
32,000 new cases diagnosed in the United States
40,000 diagnosed in the European Union
11,000 cases in Japan
• Maximum incidence on 6th decade
• Poor prognosis with a median survival of 10 to 12
months
• 5-year-survival rate is less than 10%
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Approved therapies before Nexavar®
Role of surgery:
- Nephrectomy
- Surgical metastasectomy
First line treatment:
First line systemic treatment
Good or intermediate prognosis
Age<60, good performance status
Bevacizumab + IFNα
High dose IL-2
high unmet medical need
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75% RCC tumor possessed alterations in the Von Hippel
Lindau (VHL) gene responsible for dysregulation of growth
factor signaling:
- TGF-α
- VEGF, PDGF-β, that play key roles in angiogenesis
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Sorafenib inhibits the growth of s.c. implanted human 786-O
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significant reduction in tumor vasculature within 3 days of sorafenib treatment
angiogenesis was assessed by measuring the level of CD31 endothelial marker
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The TARGET study
Treatment Approches in Renal cancer
Global Evaluation Trial
A randomized double-blind international phase III trial of the
effects of sorafenib on overall survival (OS) in people
with RCC
Objective:
Primary endpoint: Overall survival (OS)
Secondary endpoint: Progression-free-survival (PFS)
• Tumor response
• Clinical benefit rate
• Toxic effects
• Time to self-reported health status deterioration
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Patients eligibility:
• Disease progression after they received at least one systemic
treatment for mRCC
• Low/intermediate risk as prognostic score
Method:
903 patients
randomized
451
Sorafenib
452
Placebo
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Results: Progression free survival Kaplan-Meier analysis in phase III
RCC trial
Twofold increased median PFS compared with placebo (24
vs 12 weeks; p <0.000001)
This PFS benefit was independent of gender, age and prior
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therapy
Overall survival Kaplan-Meier analysis in phase III RCC trial
Median OS was 19, 3 months for patients in the sorafenib group and 15,9
months for patients in the placebo group (hazard ratio, 0,77; 95% CI, 0,63 to
0,95; P=0,02)
No statistical significance
Second line treatment:
Second line systemic treatment
Prior cytokine therapy
Sunitinib
Sorafenib
Prior tyrosine kinase inhibitor
Other antiVEGF
Temsirolimus
Bevacizumab +
IFNα
•Approved by the FDA in December 2005
•Approved by the EMEA in July 2006
•Indication and usage:
Treatment of patients with advanced renal cell carcinoma (RCC), a type of kidney
cancer
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Low-risk extension of indication
Sorafenib Dose Escalation in RCC
A non-randomized, open-label and multi-centre phase II trial to study the impact
of dose escalation of sorafenib as first line treatment in mRCC
Objective: recording Tumor Response Rates
And then:
- Safety and tolerability
- Pharmacokinetics
- Progression free survival
- Time to progression
Method:
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•
•
•
•
One arm
Treatment cycle of 28 days
Initial dose of sorafenib will be 400mg bid administered orally
Day 29-56 600mg bid
Day 57 onwards 800mg bid
Results due
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HepatoCellular
Carcinoma
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HCC: Unresectable hepatocellular carcinoma
• Primary malignant cancer of the liver (80 to 90%)
• 5th most frequent form of cancer worldwide
• 1 million news cases each year
• Third leading cause of cancer related mortality
• More than 600 000 deaths per year
• Fatal disease: Die within 1 year after the diagnosis
• Poor prognosis: fast spreading! and hard to treat
• Etiology: viral hepatitis B and C, alcohol, cirrhosis
Urgent need of new therapy for this aggressive
disease !!!
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• Important role in the development of HCC :
- Frequent mutation of k-ras
- overexpression of Raf-1kinase in a high number of HCC
- Angiogenesis
Preclinical Overview of Sorafenib,p 3130
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 Sorafenib strongly inhibits the growth of PLC/PRF/5 HCC
tumors in a xenograft mouse model
Preclinical Overview of Sorafenib,p 3135
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• Sorafenib significantly inhibits CD34 in PLC/PRF/5 HCC
tumors in mice. CD34 and microvessel density were plotted
CD34-Positive Area (%)
0,8
0,6
0,4
0,2
0
vehicle
Preclinical Overview of Sorafenib,p 3135
30mg/kg 100mg/kg
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The unresectable HepatoCellular Carcinoma
HCC
The SHARP study
Sorafenib HCC Assessement Randomized Protocol
• Pivotal study in Phase III
• International, multicenter (America, Australia, New-Zealand, Europe),
double-blind, placebo-controlled trial, randomized
• 602 patients with advanced HCC
Outcomes:
• Firstly :
-
Overall survival (OS)
Time to progression (TTP)
• Secondly :
-
Time to radiologic progression
Safety
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Patients eligibility: for inclusion in the SHARP trial :
–
–
–
–
–
Histologically proven HCC
Advanced HCC
Measurable untreated lesions
Child pugh class A
No prior systemic treatment
Methods:
602 patients
randomized
303
Placebo
299
Sorafenib
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Results:
OS =10,7 months Sorafenib / 7,9 months Placebo
  44% of the overall survival !
Statistically signifiant advantage for Sorafenib
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TTP =5,5 months Sorafenib / 2,8 months Placebo
So convincing  stop of trial (interim analysis) : significant
survival advantage
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NEXAVAR ®
•
•
Approved by the FDA in November 2007
Approved by EMEA in autumn 2007
Treatment of patients with Unresectable Hepatocellular
Carcinoma (HCC), a type of liver cancer
No other substance with this label
Considered as new, first, and only standard of care in patients with
advanced HCC
constitutively active upstream oncogenic ras mutants (K-ras ) : 30% of HCC
overexpression of upstream growth factor or/ and their RTKs : 100% of HCC
Geographical extension of
Nexavar indication in HCC
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Geographical extension of Nexavar
indication in HCC
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Extend of SHARP study
• SHARP trial is not able to address the relevance of Sorafenib for the Asian
population:
 Parallel trial in an Asia-Pacific population
 Efficacy and safety of Sorafenib
Multinational phase II, randomised, doubled-blind, placebo controlled-trial
Method:
226 patients
randomized
76
placebo
150
Sorafenib
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Outcomes:
- Overall Survival : 6,5 vs 4,2 months
www.thelancet.com/oncology Vol 10, January 2009
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- TTP :2,8 vs 1,4 months
www.thelancet.com/oncology Vol 10, January 2009
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High-risk indication:
NSCLC: No Squamous Cell Lung
Carcinoma
1. Sorafenib and NSCLC:
 proliferation signalling of the Ras/Raf/MEK/ ERK pathway is
increased in NSCLC due to K-Ras mutations
 sorafenib inhibited the growth of two NSCLC xenograft models
(A549 and NCI-H460)
2. Epidemiology:
•
1,2 million new cases worldwide every year
•
the third most common cancer after prostate and breast cancer
•
the incidence of lung cancer had been rising in women, and still high in
men
Age: median age is 70 years
Geography: North America and Eastern Europe population
Survival:
•
•
The overall 5-year survival rate for lung cancer is 15%
median survival is 4 months for untreated patient
A commercial opportunity and a great patient need!
3. Standard treatment:
 Surgery for patients with early- stage NSCLS
 Adjuvant treatment: Radiation and Chemotherapy:
•
•
chemotherapy-naïve:
bevacizumab (Avastin®)- chemotherapy
chemotherapy-refractory:
erlotinib (Tarceva®)
 tumour control and symptom palliation
Promising signals in two non-randomized Phase II
NSCLC combination trials with Nexavar
+ Commercial Opportunity
+ great patient need
=international, randomized, 900 patients ESCAPE study:
•
Ph III trial without a randomized Ph II study
•
No possibility to predict how a multi-target agent such as Nexavar
will perform against a given tumor type
ESCAPE: Phase III Trial Comparing CarboplatinPaclitaxel +/- Sorafenib in NSCLC
Stratification:
geographical region
ECOG PS 0 vs1
Squamous cell vs NonSquamous Cell
Stage IIIb vs Stage IV
n=900
R
A
N
D
O
M
i
S
A
T
I
O
N
Carboplatin+
Paclitaxel+
Sorafenib
(CPS)
Sorafenib
400mg bid
Carboplatin+
Paclitaxel+
Placebo
(CPP)
Placebo
Phase III ESCAPE study of Nexavar in combination with
carboplatin/paclitaxel
The trial would not meet its Primary endpoint:
 improved Overall survival
In the subset of patients with squamous cell carcinoma of the
lung, higher mortality was seen when Nexavar was given in
combination with carboplatin/paclitaxel than chemotherapy only
Why did it fail?
Main reasons:
• Limits of the xenograft: only 1 cell type tumor implanted
• Heterogeneous with multiple mutations
Melanoma
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PREVALENCE
•
•
•
Less than 10% of skin cancer cases
Large majority of skin cancer deaths: responsible for nearly three times the
number of deaths by nonmelanoma skin cancers (approximately 7,910 vs 2,800)
The incidence of melanoma has increased steadily since 1930 and continues to
rise at a rate that has exceeded all other cancer types
AGE
Average age of development: 55 years
LIFE EXPECTANCY
Patients with advanced metastatic melanoma (stage IV) have a 5-year survival rate of
only 2%
 Failure of chemotherapy (dacarbazine) or immunotherapy regimens (IL-2, TNF-α)
The MAPK signaling pathway is activated in majority of melanomas
Activating mutations of the B-RAF gene for 60% (B-raf V 600 E)
Constitutively active RAS oncogenes for 15%
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Sorafenib inhibits growth
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The 11715 Study
A double-blind randomized and multicenter phase II study of
the combination of sorafenib and dacarbazine in patients with
advanced melanoma
• 2 arms:
placebo plus dacarbazine
sorafenib plus dacarbazine
• evaluate the efficacy and safety of sorafenib plus dacarbazine
Patients eligibility:
• chemotherapy-naïve patients
• unresectable stage III or stage IV melanoma
Method:
101 patients randomized: 50 with placebo and 51 with sorafenib
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Results:
Median PFS in the sorafenib arm was 21.1 weeks vs 11.7
weeks in the placebo arm (hazard ratio [HR], 0.665; P .068)
Results were statistically significant
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No difference in OS was observed (median, 51.3 v 45.6 weeks
in the placebo and sorafenib arms, respectively; HR, 1.022)
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CONCLUSION
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Thank you for your attention
Chloé DINGREVILLE Diane-Laurène SMAL Aurélie TELLIER
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