Transcript Diapositiva 1

ONCOLOGY
OFONCOLOGY
TORINO––DEPARTMENT
UNIVERSITY
UNIVERSITYOFOFTORINO
DEPARTMENTOF
State-of-the-art of the
management of advanced stage
adenocarcinoma
Giorgio V. Scagliotti
University of Torino
Department of Oncology
[email protected]
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
First-line therapy for metastatic NSCLC
in 2012
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
First-line therapy for metastatic NSCLC
in 2012
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Disease segmentation based
on oncogenic events
From an organ-based disease to
a molecular classifications
of rare diseases
« Druggable » genomic alterations
4
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
2002-2012 – Changes in the therapeutic
landscape of stage IV lung cancer
HER2
EGFR mutants
ALK
ROS/RET
b-raf
K-ras
K-ras
Adeno
LCC/NOS
SCC
SCLC
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Chipping away at the lung cancer
genome
Lung Adenocarcinoma
Squamous Cell Carcinoma of the lung
Pao W. Nat. Med. 2012 ;
Sos M. and Thomas R. Oncogene 2012
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
EGFR-TKIs and EGFR Mutation -Directed
Front - Line Studies
Study
Entry Criteria
HR for PFS
(EGFR mut +)
HR for OS
(EGFR mut +)
IPASS
Mok
NEJM 2009
Asiatic, never- & light –
smokers, adenocarcinoma
(EGFR mut + 59.7%)
0.48
(0.36-0.66)
0.91 *
(0.76-1.10)
*overall population
First – SIGNAL
Proc. IASLC
2009
Adenocarcinoma, Neversmokers
(EGFR mut + 44%)
0.61
(0.30-1.22)
0.82
(0.35-1.92)
NEJ002
NEJM 2010
Proc. ASCO 2011
EGFR Mutation + (all)
0.35
(0.25-0.50)
0.887
(0.634-1.241)
WJTOG3405
Lancet Onc. 2010
EGFR Mutation + (all)
0.520
(0.378-0.715)
1.185
(0.767-1.829)
EURTAC (EU)
EGFR Mutation + (all)
0.42 (0.27-0.64)
?
OPTIMAL (China)
EGFR Mutation + (all)
0.16 (0.10-0.26)
1.04 (0.69–1.58)
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Clinical characteristics do not completely predict
EGFR mutation status
Spanish Lung Cancer Group trial in advanced NSCLC patients
with EGFR mutations (n=350)1
Patients
100%
Female
Never
smoker
80%
60%
40%
20%
Adenocarcinoma
Significant segment of EGFR M+ population
fall outside
typical subgroups
30
Male
26
Former
smoker
0%
Gender
BAC, bronchioloalveolar carcinoma
Smoking
status
9
Non-adeno /
BAC
Histology
1Rosell
et al 2009
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
EGFR Targeted Therapeutics in NSCLC
Matuzumab
Cetuximab
Panitumumab
Necitumumab
(IMC-11F8)
K
EGFR
K TKI
EGFR
Gefitinib
Erlotinib
Lapatinib
Afatinib
Dacomitinib
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
EGFR-TKIs and EGFR Mutation -Directed
Front - Line Studies
Study
Entry Criteria
HR for PFS
(EGFR mut +)
HR for OS
(EGFR mut +)
IPASS
Mok
NEJM 2009
Asiatic, never- & light –
smokers, adenocarcinoma
(EGFR mut + 59.7%)
0.48
(0.36-0.66)
0.91 *
(0.76-1.10)
*overall population
First – SIGNAL
Proc. IASLC
2009
Adenocarcinoma, Neversmokers
(EGFR mut + 44%)
0.61
(0.30-1.22)
0.82
(0.35-1.92)
NEJ002
NEJM 2010
Proc. ASCO 2011
EGFR Mutation + (all)
0.35
(0.25-0.50)
0.887
(0.634-1.241)
WJTOG3405
Lancet Onc. 2010
EGFR Mutation + (all)
0.520
(0.378-0.715)
1.185
(0.767-1.829)
EURTAC (EU)
EGFR Mutation + (all)
0.42 (0.27-0.64)
?
OPTIMAL (China)
EGFR Mutation + (all)
0.16 (0.10-0.26)
1.04 (0.69–1.58)
LUX-LUNG 3
EGFR Mutation + (all)
0.58 (0.43–0.78)
?
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
FLEX : HRs for death in pre-specified
subgroup analysis of the ITT population
Pirker R. et al. Lancet 2009; 373:1525-31
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Clinical Profile of ALK-positive NSCLC
• Gene fusions involving the ALK gene within chromosome 2 have been
identified in 0.6‒11.6% of NSCLC tumors1,2
– Incidence rates are influenced by sample size, screening methods and
enrichment prior to pre-selection
• ALK is associated with adenocarcinoma histology
– Incidence of 2.4–5.6%3–5
– In squamous cell patients incidence of ALK <1%1
• Trend for ALK patients to be non/light smokers2–4
• ALK mutations appear to occur in the absence of EGFR/KRAS mutations2,3,7
• Possible correlation between signet ring carcinoma and ALK status3
1Boland
et al. Human Pathol 2009;40:1152–8; 2Zhang et al. Mol Cancer 2010;9:188
et al. Clin Cancer Res 2009;15:5216–23; 4Wong et al. Cancer 2009;115:1723–33
5Takahashi et al. Ann Surg Oncol 2010;17:889–97
6Horn and Pao J Clin Oncol 2009;27:4232‒35; 7Shaw et al. J Clin Oncol 2009;27:4247–53
3Rodig
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Erlotinib in EGFR mutant NSCLC
Vemurafenib in BRAF mutant melanomas
Crizotinib in ALK rearranged NSCLC
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
ROS1 Rearrangement in NSCLC
• 18/1073 tumors (1.7%) rearranged by FISH.
• ROS1 re-arranged pts significantly younger
and more likely to be never smokers (p
<0.001)
• All adenocarcinoma, higher grade
• ROS1+ vs. ROS1 – no difference in survival
• Sensitive to crizotinib
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
RET gene fusion in lung adenocarcinoma
• 11,294,741-bp pericentric inversion on chromosome 10 generating a new
gene fusion joining exons 1-15 of KIF5B to exons 12-20 of RET
• Mutually exclusive with EGFR, HER2, KRAS, BRAF mutations and with ALK
or ROS1 translocation
• Exclusively identified in adenocarcinomas, never or light smokers
Lipson et al. Nature Med. 2012
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Kinase oncogene dependence and
principles of drug resistance
Wagle N. et al. J. Clin. Oncol. 2011;
29:3085
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Genotypic Evolution of Lung Cancer Acquiring
Resistance to EGFR and ALK Inhibitors
ALK
ALK
EGFR
KRAS
ALK
ALK
ALK
Sequist L. et al. Sci. Transl. Med. 2011; 3 (75) 75ra26
Doebele R. et al. Proc. ASCO 2012
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
How to improve results in EGFR mutants ?
EGFR TKI + HD 2nd-gen EGFR TKI
EGFR TKI + BCL-2i
Chemo-naïve
advanced
NSCLC
EGFR TKI + IGF-1Ri
EGFR mutant
EGFR TKI + METi
EGFR TKI + HCQ
EGFR TKI (diff dosing schedules)
EGFR TKI + chemo
Potent 2nd-gen EGFR TKI
EGFR mutant NSCLC
with acquired resistance*
2nd-gen EGFR TKI + cetuximab
Chemo  EGFR TKI
2nd-gen EGFR TKI + METi
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
K-ras mutation & NSCLC
• Is k-ras mutation prognostic or predictive ?
• Is there any evidence for excluding k-ras mutants
from receiving chemo?
K-ras
K-ras
K-ras mutation not predictive or prognostic in resected early stage NSCLC treated
with adjuvant chemotherapy (Shepherd F. et al. Proc. ASCO 2012)
Meta-Analysis of 881 Cases - Stages I-IV - RR of 2.35 (1.6-3.2) at 2 years
k-ras mutation may be associated with shortened survival but need to be
confirmed in well designed multivariate analyses addjusted for known prognostic
factors (Huncharek M et al., Carcinogenesis 1999)
K-RAS mutational status does not predict benefit from the anti-EGFR monoclonal
antibody cetuximab (O’ Byrne Lancet Oncology 2011)
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
First-line therapy for metastatic NSCLC
in 2012
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Cis/Pem vs. Cis/Gem in Advanced NSCLC
Scagliotti GV et al. J. Clin. Oncol 2008; 26:3543
p<0.0001
Adenocarcinoma
Relative expre. levels
Relative expre. levels
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Squamous cell carcinoma of the lung compared with other histotypes shows
higher messenger RNA and protein levels for thymidylate synthase
P<0.001
Squamous
P<0.001
Ceppi et al. Cancer 2006
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Summary of the Effect of Pemetrexed in Patients with
Advanced NSCLC by ALK Status
• Reports from three small, retrospective analyses suggest pemetrexed given as a
single agent or in combination with chemotherapy may be effective in ALK-positive
NSCLC1–3
Report
Camidge et al2
Lee et al3
Altavilla et al1
Treatment
Pemetrexed single
agent or combination
therapy, any line
Second-line or later
single-agent
pemetrexed
Pemtrexed + cisplatin
TTP, time to progression
Study populations and
comparator populations
N
ORR
(%)
Time to event, months
(95% CI)
ALK-positive NSCLC
19
42
PFS, 9.0
(95% CI: 3–12)
ALK/EGFR/KRAS-triple
negative NSCLC
37
14
PFS, 4.0
(95% CI: 3–5)
ALK-positive NSCLC
15
47
TTP, 9.2
(95% CI: 4.7–13.7)
EGFR wild-type NSCLC
37
ALK-positive NSCLC,
adenocarcinoma
8
25
TTP, 9.0
ALK-negative NSCLC
32
–
TTP, 6.2
TTP, 2.9
1. Altavilla G, Santarpia M, Arrigo C, et al. J Clin Oncol 2010;28 (Abstract 7610)
2. Camidge DR, Kono SA, Lu X, et al. J Thorac Oncol 2011;6:774–780
3. Lee JO, Kim TM, Lee SH, et al. J Thorac Oncol 2011;6:1474–1480
TS Expression
N
Median
ALK+ Patients
63
2.02
1.60-2.11 0.55-19.44
3.32
3.15-3.45 0.36-53.51
ALK- Patients 1698
95% CI
Range
p Value
<0.0001
60
20
50
15
10
All ALK-neg TS2
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
TS Expression in ALK+ versus ALK- NSCLC
40
30
20
5
10
0
0
TS in patients with ALK+ cancers
TS in patients with ALK- cancers
Gandara D. et al. Proc. ASCO 2012
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Agents Targeting the VEGF Pathway
Anti-VEGF
Antibodies
Soluble VEGFRs
(bevacizumab)
(VEGF-Trap)
VEGF
Anti-VEGFR
Antibodies
(IMC-1121b)
P
P
P
P
P
P
VEGFR-1
P
P
VEGFR-2
Endothelial Cell
Small-molecule VEGFR
inhibitors:
•
•
•
•
•
Vatalanib (PTK 787)
Sunitinib (SU11248)
Sorafenib (Bay 43-9006)
Vandetanib (ZD6474)
AZD 2171
Podar K, Anderson KC. Blood 2005;105:1383–1395
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Targeting angiogenesis in NSCLC
the rationale
Need to improve outcomes
for patients with NSCLC:
late diagnosis and poor
prognosis1,2
Angiogenic factors, including
growth factor overexpression, are found in more
than 46% of NSCLC tumours3,4
Why inhibit angiogenesis
in NSCLC?
The growth of new blood
vessels and the presence of
angiogenic growth factors are
associated with poor
prognosis in NSCLC5
1Yang
Anti-angiogenic therapy in
NSCLC may slow or reverse
tumour growth and prevent
metastases5
P, et al. Chest 2005; 128:452–462; 2Cancer Research UK 2010 3Shou Y, et al. Br J Cancer 2001:85:1706–1712;
4O’Byrne KJ, et al. Br J Cancer 2000;82:1427–1432; 5Bremnes RM, et al. Lung Cancer 2006;51:143–158.
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Phase III studies of VEGF antibody
inhibition in NSCLC
Trial
Treatment line
Treatment arms
Primary endpoint
Trial outcome
ECOG 45991
First line
Paclitaxel/carboplatin
+ bevacizumab
OS
12.3 months*
Positive
Paclitaxel/carboplatin
10.3 months
Cisplatin/gemcitabine
+ bevacizumab
PFS
High dose: 6.5 months*
Low dose: 6.7 months*
Cisplatin/gemcitabine
+ placebo
6.1 months
Bevacizumab + erlotinib
OS
9.3 months
Erlotinib + placebo
9.2 months
Bevacizumab + erlotinib
PFS
4.8 months*
Bevacizumab + placebo
3.7 months
AVAiL2
BETA3
ATLAS4,5
First line
Second line
First line
maintenance
Positive for
primary
endpoint
Negative
Positive for
primary
endpoint
*Significantly different from comparator.
1Sandler
A, et al. N Engl J Med 2006;355:2542–550; 2Reck M, et al. J Clin Oncol 2009;27:1227–1234;
3Hainsworth J, et al. J Thor Oncol 2008;3:S302; 4Miller VA, et al. J Clin Oncol 2009;27(suppl 1):Abstract LBA8002 and
presentation; 5Kabbinavar FF, et al. J Clin Oncol 2010;28:7526.
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
ECOG 4599: Survival by Histology Subtype
Baseline
Characteristics
PC
(n = 444)
PCB
(n = 434)
Median
N Months
Median
N Months
878
444
10.3
434
- Adenocarcinoma
602
302
10.3
- Large Cell
48
30
8.7
- Squamous
3
2
- BAC
23
- NSCLC,NOS
- Other
All patients
Total
N
Hazard
Ratio
95% CI
12.3
0.80
0.69-0.93
300
14.2
0.69
0.58-0.83
18
10.0
1.15
0.60-2.24
12.3
1 22.4
0.00
0.00-
11
17.7
12 10.0
1.48
0.57-3.69
165
86
10.0
79
9.5
1.16
0.84-1.61
34
11
12.6
23
8.4
0.92
0.43-1.98
Histologic type
Sandler A. et al. J Thorac Oncol. 2008;3(11 Suppl 4): Abstract 133.
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Progress in the treatment of
metastatic lung cancer
Pao W. et al. Nat. Rev. Cancer 2010; 10;760
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Bevacizumab biomarker trial in NSCLC
ABIGAIL (BO21015): phase II biomarker trial
Previously untreated stage
IIIB/IV non-squamous NSCLC
(n=300)
Bevacizumab 7.5mg/kg +
carboplatin/gemcitabine or
carboplatin/paclitaxel
Bevacizumab
q3w until
progression
PD
Bevacizumab 15mg/kg +
carboplatin/gemcitabine or
carboplatin/paclitaxel
Bevacizumab
q3w until
progression
PD
• Primary endpoint: correlation of biomarkers with response rate
• Conclusion
– After adjustment for multiple testing, none of the candidate
biomarkers correlated with overall response rate according to baseline
plasma level
Mok, et al. ESMO 2011
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Targeting alternative pathways to VEGF:
FGF and PDGFR
FGF, PDGFR
& others
• After blockade of VEGF pathway, there is compensatory up-regulation of
FGF, PDGFR, EGFR, others
• Additional blockade of FGF, PDGFR suppresses angiogenesis
FGF(R)=fibroblast growth factor (receptor); PDGF(R)=platelet-derived growth factor (receptor); VEGF(R)=vascular growth factor (receptor).
Casanovas O, et al. Cancer Cell 2005;8:299–309.
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Many multi-targeted anti-angiogenic agents are
already failed Phase III development in NSCLC
Agent
Description
Target
NSCLC
Sunitinib1
Small-molecule TKI
VEGFR-1,-2, 3; PDGFRβ; c-kit; Flt-3
Phase III (terminated)
Sorafenib2
Small-molecule TKI
b-Raf; VEGFR-2, -3; PDGFRβ; Flt-3;
c-kit
Phase III (terminated)
Cediranib3
Small-molecule TKI
VEGFR-1, -2, -3; PDGFR; FGFR-1; ckit
Phase III (terminated)
Vandetanib4
Small-molecule TKI
VEGFR-2, -3; EGFR
Phase III (terminated)
Aflibercept5
VEGF-trap
Fusion protein that binds to binds
to VEGFR-1 and VEGFR-2
Phase III (terminated)
Vadimezan
(ASA 404)6
Vascular disrupting
agent
Motesanib7
Small-molecule TKI
VEGFR-1, -2, -3; PDFGR; c-kit
BIBF 11208
Small-molecule TKI
VEGFR-1, -2, -3; PDGFRα, -β; FGFRPhase III (terminated)
1,-2, -3
1Christensen
Phase III (terminated)
Phase III (terminated)
JG, et al. Ann Oncol 2007;Suppl 10; 2Wilhelm SM, et al. Cancer Res 2004;64:7099–7109; 3Wedge SR, et al.
Cancer Res 2005;65:4389–4400; 4Ryan AJ, et al. Br J Cancer 2005;92(Suppl 1):S6–S13; 5Hsu JY, Wakelee HA. BioDrugs
2009;23:289–304; 6Baguley BC, et al. Future Oncol 2010;6:1537–1543; 7Rosen LS, et al. J Clin Oncol 2007;25:2369–2376;
8Hilberg F, et al. Cancer Res 2008;68:4774–4782.
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Summary
• EGFR Mut+ lung cancer should be treated with and EGFR TKI
and ALK translocated tumors with crizotinib.
• Therapeutic choices based on histology are the current
standard of care for the majority of our patients
• In non-squamous histology cisplatin plus pemetrexed or
platinum-doublet chemotherapy plus bevacizumab are
effective treatment choices. The efficacy/toxicity ratio favors
cisplatin and pemetrexed.
• The definition of homogeneous genetic subgroups of tumours
and the search for individualised approaches is the way to
substantially increase survival expectancy in this disease
1. NCCN NSCLC guidelines 2012