Download Advances in Clinical Research in Lung Cancer

Chemotherapy for Lung
Cancer
Giorgio V. Scagliotti
University of Torino
Dept. Clinical & Biological Sciences
[email protected]
www.oncologiapolmonare.it
Therapeutic Research in Lung Cancer
Non-Small Cell Lung Cancer
Small Cell Lung Cancer
SCLC: Treatment Options
Overview
• Limited-Stage Disease
•
•
•
•
•
surgery
platinum-based combination chemotherapy
thoracic irradiation
prophylactic cranial irradiation (PCI) [for responders]
New Agents (taxanes, topoisomerase I inhibitors,
pemetrexed)
• Extensive-Stage Disease
• combination chemotherapy
• radiotherapy + combination chemotherapy or vice versa
• prophylactic cranial irradiation (PCI) [for responders]
Treatment of NSCLC in 2007
Stage
I
II
IIIA
T1-2N0
T1-2N1
T3N0
T3N1
T1-3N2
Treatment
Surgery (± CT)
Surgery (+CT)
Surgery (+CT)
Surgery (+CT)
Chemo/Surgery
Chemo/RT
IIIB
T1-4N3
T4 effusion
Chemo/RT
Chemo
IV
M1
Chemo
Supportive Care
Survival
60-70%
40-55%
25%
10-25%
10-20%
<10%
<5%
Established Key Points in 2007
• Chemotherapy prolongs survival
• Platinum-based doublets with 3rd generation
cytotoxics (Gemcitabine, Taxane, Irinotecan
and Vinorelbine) are the standard
• Elderly patients may benefit from
chemotherapy but patients with poor KPS
may not
• Cisplatin has slight advantage over
carboplatin in terms of survival but more
disadvantageous in terms of toxicity
NSCLC Meta-Analysis: Results with
First-Line Cisplatin-Based CT
Treatments
Hazard ratio
(95% CI)
P
value
Reduction
risk of
death (%)
Surgery vs
Surgery + CT
0.87
(0.74–1.20)
0.08
Surgery + RT vs
Surgery + RT + CT
0.94
(0.79–1.11)
RT vs
RT + CT
BSC vs
BSC + CT
Absolute benefit (%)
2 years
5 years
13
3
5
0.46
6
2
2
0.87
(0.79–0.96)
<0.01
13
4
2
0.73
(0.63–0.96)
<0.001
27
10
(1 year)
MST
>1.5 months
BSC: best supportive care; CT: chemotherapy; MST: median survival
time; RT: radiotherapy.
NSCLC Collaborative Group BMJ 1995.
“Efficacy Plateau” of Cytotoxic
Chemotherapy in NSCLC
Drugs
# Pts
%,
St. IV
%,
ORR
MST
%,
1-YS
Kelly,2001
SWOG 9503
Vnr/Cis
Tax225/Cb
202
208
88
89
28
25
8
8
33
36
Schiller,2002
ECOG 1594
Tax135/Cis
Gem/Cis
Txt/Cis
Tax225/Cb
292
288
293
290
89
86
86
86
21.3
21
17.3
15.3
8.1
8.1
7.4
8.3
31
36
31
35
Scagliotti,2002
ILCP
Vnr/Cis
Gem/Cis
Tax225/Cb
201
205
201
81
81
82
30
30
32
9.5
9.8
9.9
37
37
43
Vnr/Cis
Txt/Cis
TxT/Cb
404
408
402
67
67
67
25
32
24
10.1
11.3
9.4
41
46
38
Study
Belani,2002
TAX 326
Response and Survival with Doublet vs
Single-Agents; Triplets vs Doublets
Delbaldo C. et al., JAMA 2004; 292:470
New Cytotoxics in Lung Cancer
• Platinum Analogs
• New Antimetabolites (Pemetrexed,
Raltitrexed)
• Second Generation Taxanes
• Epothilons
• Hypoxic Cytotoxins
• Oral Agents (Vinorelbine, Taxanes,
Camptothecins)
• Cell Cycle Inhibitors
Phase II Studies of Pemetrexed as Single Agent or
in Combination With Platinums in NSCLC
Author
Platinum
No. of
patients
ORR
(%)
Median
OS (mo)
Grade 3-4
neutropenia
Rusthoven, 1999*
None
33
23
9.2
39%
Clarke, 2002*
None
59
16
7.2
42%
Manegold, 2000*
Cisplatin
36
39
10.9
21%
Shepherd, 2001*
Cisplatin
29
45
8.9
11%
Scagliotti, 2005**
Carboplatin
(AUC6)
39
32
10.3
26%
Scagliotti, 2005**
Oxaliplatin
(120 mg/m2)
41
27
10.3
7.3%
Zinner, 2005**
Carboplatin
(AUC6)
50
24
13.5
26%
*All studies conducted without vitamin supplementation. ** All studies conducted with vitamin
supplementation
A Randomized Phase III Trial of Cis/Pem
vs Cis/ Gem in Patients with Advanced
NSCLC
 Stage IIIB/IV
NSCLC
 PS 0 - 1
 No prior chemo
 Randomization:
gender, PS,
stage, histo vs
cyto dx, brain
mets
Pemetrexed 500 mg/m2 +
Cisplatin 75 mg/m2 day 1
Primary objective: Overall Survival
R
15% Non-inferiority margin (HR 1.17)
N = 1700 Patients (final analysis when 1190
deaths have occurrred; Power 80%)
Gemcitabine 1250 mg/m2 +
Cisplatin 75 mg/m2 day 1;
Gemcitabine 1250 mg/m2 day 8
B12, folate, and dexamethasone given in both arms
Clinical Efficacy and Safety Results

Overall survival: Cisplatin/Pemetrexed non-inferior to
Cisplatin/Gemcitabine
– 10.3 vs 10.3 mo [HR 0.94, 95% CI: 0.841.05]

PFS and ORR: Cisplatin/Pemetrexed non-inferior to
Cisplatin/Gemcitabine
–
–


PFS: 4.8 vs 5.1 mo [HR 1.04, 95% CI: 0.941.15]
ORR: 31% vs 28%
Cisplatin/Pemetrexed appears to have better efficacy in
adenocarcinoma and large cell carcinoma than in
squamous cell carcinoma
Cisplatin/Pemetrexed showed a significantly better
safety profile than Cisplatin/Gemcitabine
Scagliotti G. et al. Proc. JTO 2007
Thymidilate Synthase Expression in
Normal Lung Tissue & Lung Cancer
Snap Frozen Tissues
TS mRNA levels
FFPE Tissues
Significantly Higher in Lung
Cancer than in normal lung
tissue
Significantly Higher in
Squamous Cell Carcinoma
of the Lung
Ceppi P. et al. Cancer 2006
Is Platinum Necessary?
Platinum- vs. Non-Platinum Based CT
in NSCLC : A metaanalysis
•
•
N=6.504
•
No increase when platinum
therapies were compared to
3° generation-based
combination therapies
(OR 1.11, P=.17)
1-yr survival increased of 5%
(34% vs. 29%) with platinum
(OR 1.21, P=.0003)
D’Addario G et al. J. Clin. Oncol. 2005
A New Platform for Clinical
Research in Lung Cancer
• Implementation of pharmacogenomic
research (study of genome-derived data,
including human genetic variation, RNA
and protein expression differences, to
predict drug response in individual
patients or groups of patients)
• Integration of molecularly targeted
therapies
What’s the Clinical Promise?
• Focused treatment by pre-identifying
genetic backgrounds likely to respond.
• Reduce adverse events by predicting who is
at risk
• In other words TO INCREASE THE
THERAPEUTIC MARGINS
• Way to save drugs in the pipeline that are
very effective only in subpopulations.
• Better understanding of drug interactions
Pharmacogenomics
Human Genetics
• SNPs
• Haplotypes
• Sequencing
Expression Profiling
• Specific transcript
levels
• Total RNA profiling
Phenotype
• Drug response
Proteomics
• Specific biochemical
markers
• Protein profiling
• Disease
Prediction
Reported Predictive Molecular Markers in Tumor
for Response to Chemotherapy in NSCLC
Gene
Abnormality
Drug
p53
Mutation
Multiple
K-ras
Mutation
Platinum
-tubulin
Increased isotype 3
Taxanes
RRM1
Increased expression Gemcitabine
ERCC1
Increased expression
Platinum
TS
Increased expression
Antifolates
EGFR mutation
Present
Platinum
Response
Gene Expression and Lung Cancer
• ERCC1,RRM1, BRCA1, TS
• Mainly retrospective studies, few
prospective
• Not fully validated techniques, frozen
vs. paraffin-embedded tissues,
different house-keeping genes,
different cut-off values
• Predictive vs. prognostic information
ERCC1-based Customization of
Chemotherapy in NSCLC
R
A
N
D 1:2
O
M
I
Z
E
Docetaxel/
cisplatin
Control arm
Patient accrual:
Aug. 2001 – Oct. 2005
low ERCC1 mRNA
Genotypic arm
ERCC1 levels
Docetaxel/
cisplatin
high ERCC1 mRNA
Docetaxel/
gemcitabine
• ERCC1 mRNA expression predicts response but not survival to
docetaxel/cisplatin
– Docetaxel inadequate partner for cisplatin in patients with low ERCC1 levels
– Second-line treatment significantly influenced overall survival
• Basis for planned second randomized trial of customized chemotherapy based on
BRCA1
– mRNA expression by quartiles, instead of high/low dichotomy, could further improve
customization
Cobo M, et al. J Clin Oncol. 2007;25:2747-2754.
ITACA Adjuvant Trial
Pharmacogenomic :Yes or No
Taxanes
High
Profile 4
Control
TS
High
ERCC1
Low
Pem
Low
Profile 3
High
Profile 2
Control
Cis/Gem
Control
TS
Cis/Pem
Low
Profile 1
Control
Control = Investigators’ choice; Primary end-point =overall survival;
Sample size =700 patients
Challenges for Tomorrow
• Inherited component of response to drugs is often
polygenic
• Two strategies : SNP maps to perform genome- wide
searches or candidate gene approach
• Both with values and limitations
• Gene-expression profiling and proteomic studies
are evolving fields
• Need for well characterized patients who have been
uniformly treated and systematically evaluated
• Pharmacogenomic relation validated for each
therapeutic indication and in different racial and
etnic groups.
Acquired Capabilities of Cancer
Self-sufficiency in
growth signals
Evading
apoptosis
Insensitivity to antigrowth signals
Sustained
angiogenesis
Tissue invasion
and metastasis
Limitless replicative
potential
Adapted from Hanahan and Weinberg. Cell. 2000;100:57.
Targeted Therapies are Drugs to
Treat :
• Biologically homogenous cancer patient
population
• Tumor specific molecular abnormality
• Tumor specific molecular profile
• Expression of a specific receptor or antigen
• Different cancers likely to require different
therapies
• Patient population likely to be small
Most Attractive Targets for
Molecular-Targeted Strategies
•
•
•
•
•
Receptor & non-receptor tyrosine kinases
Ras/raf/MAPK pathway
PI3K/Akt/PTEN pathway
Proteosome inhibition
Gene expression modification with
antisense oligonucleotide and RNAi
• Endothelial cell & angiogenesis-associated
factors (i.e., VEGF)
• Modulation of Apoptosis
Most Attractive Targets for
Molecular-Targeted Strategies
•
•
•
•
•
Receptor & non-receptor tyrosine kinases
Ras/raf/MAPK pathway
PI3K/Akt/PTEN pathway
Proteosome inhibition
Gene expression modification with
antisense oligonucleotide and RNAi
• Endothelial cell & angiogenesis-associated
factors (i.e., VEGF)
• Modulation of Apoptosis
Doublets & Targeted Therapies
Trial
OS [m]
1-Y [%]
RR [%]
INTACT 1 364 x 3
9.9-10.9
41-44%
47-51%
INTACT 2 406 x 3
8.7-9.9
37-42%
29-30%
TALENT 586 x 2
9.9-10.1
TRIBUTE 529 x 2
10.6-10.8
19-22%
Affinitak ? x 2
10.0-10.4
29-35%
Affinitak 300 x 2
9.7-10.0
SPIRIT 1 311 x 2
8.7-9.9
SPIRIT 2 306 x 2
8.5-9.2
E4599 427 x 2
10.2
12.5
41-42%
36-37%
44
10
52%
27%
Median Survival (mo)
4
2
0
6
Tax 320
N=248
Gridelli
N=220
Camps
N=254
Tax 317
N=104
8
JMEI
N=571
BSC
Erlotinib 150 mg q d
Alimta 500 mg/m2 q 21d
Doc 75 mg/m2
BSC
Doc 75 mg/m2
Doc 36m w
Doc 75 m q 21d
Doc 33.3m w
Doc 75 m q 21d
Nav/Ifos
Doc 75 mg/m2
Survival Results in Randomized
Studies in 2nd-Line NSCLC
10
BR21
N=731
Determinants of Sensitivity/
Resistance to EGFR-TKIs
• Clinical: gender, histology, ethnicity,
smoking status
• Molecular: EGFR mutations, gene copy
number, baseline AKT/MAPK, K-Ras
mutations
• Post-therapy: skin rash
Prospective Trials Correlating
Response with EGFR
Mutations in Exons 19 and 21
N
Agent
Response
Rate
Ex 19
Ex 21
Inoue
JCO 2006
16
Gefitinib
75%
67%
86%
Cappuzzo
JCO 2007
17
Gefitinib
76%
77%
75%
Paz-Ares
ASCO 2006
38
Erlotinib
82%
95%
67%
Kris
ASCO 2006
13
Gefitinib
85%
86%
80%
Phase III Trial of Second-line Gefitinib 250 mg vs
Docetaxel in NSCLC (INTEREST): OS
Overall
1.0
High EGFR Gene Copy Number
1.0
Docetaxel (n = 710)
Docetaxel (n = 89)
0.8
Median OS: 8.0 vs 7.6 mo
HR (95% CI): 1.02 (0.91-1.15)
1-year survival: 34 vs 32%
0.6
0.4
0.2
0.0
Gefitinib (n = 85)
Probability of Survival
Probability of Survival
Gefitinib (n = 723)
0.8
Median OS: 7.5 vs 8.4 mo
HR (95% CI): 1.09 (0.78-1.51)
1-year survival: 35 vs 32%
0.6
0.4
0.2
0.0
0
8
16
24
32
40
0
8
16
24
32
40
Months
Months
Conclude noninferiority
in the overall population
Conclude no statistical superiority
in EGFR FISH+ patients
N0723: Predictive Marker Study Design
Initial
Registration
2nd-line
NSCLC
with
specimen
4 years’ accrual
1,196 patients
FISH
Testing
Strata
Randomize
EGFR FISH+
(~30%)
Erlotinib
EGFR FISH−
(~70%)
Pemetrexed
Erlotinib
Pemetrexed
Outcome
1° PFS
2° OS, ORR
1-2 years’
minimum
additional
follow-up
957 patients
• PFS endpoint (less influenced by treatment crossover)
• Power
– 90% to detect 50% PFS improvement favoring erlotinib in FISH+
– 90% to detect 30% PFS improvement favoring pemetrexed in FISH−
– >90% to detect interaction
Will the INTEREST results affect this trial??
VEGF: A Key Mediator of
Angiogenesis
Increased VEGF levels
Genes implicated
in tumorigenesis
(p53, p73, src, ras,
vHL, bcr-abl)
Environmental factors
(hypoxia, pH)
Growth factors,
hormones
(EGF, bFGF, PDGF,
IGF-1, IL-1, IL-6,
estrogen)
bFGF, basic fibroblast growth factors; EGF, epidermal growth factor; IGF, insulin-like growth
factor; IL, interleukin; PDGF, platelet-derived growth factor; VEGFR, VEGF receptor.
1. Dvorak HF. J Clin Oncol. 2002;20:4368-4380; 2. Ebos JM, et al. Mol Cancer Res. 2002;1:89-95;
3. Ferrara N, et al. Nat Med. 2003;9:669-676.
Agents Targeting the VEGF
Pathway
Anti-VEGF
antibodies
VEGF
Soluble
VEGF
receptors
Anti-VEGFR
antibodies
P
P
P
P
VEGFR-1
P
P
P
P
VEGFR-2
Ribozymes
Endothelial Cell
Small-molecule
VEGFR inhibitors
(TKIs)
Bevacizumab in Advanced NSCLC
Study
Regimen
N.
Pts
ORR,%
PFS,
months
MST,
months
ECOG 4599, CbT+Placebo
NEJM 2006 CbT+ Bev 15
444
434
15
35
P=.001
4.5
6.2
HR=.66
10.3
12.3
HR=.79
AVAiL, Proc. CG+Placebo
ASCO 2007 CG+ Bev 7.5
347
345
351
6.1
6.7
HR=.75
6.5
HR=.82
NR
NR
CG + Bev 15
20
34
P=.0001
30
P=.0017
NR
Anti-VEGF Class Toxicities
•
•
•
•
•
•
Hypertension
Fatigue
Increased clotting
events
Bleeding (epistaxis,
pulmonary
hemorrhage, tumor
associated)
Headache
Neurologic events
•
•
•
•
Increased LFTs
Pain at tumor sites
Proteinuria
Hypothyroidism?
Bevacizumab and/or Erlotinib in NSCLC
Overall Survival1
100
100
80
80
% of Patients
% of Patients
Progression-free Survival1
60
40
20
60
40
20
Median = 7.0 months
Median = 12.6 months
0
0
0
5
10
15
0
20
Months
5
10
Months
Erlotinib (BR.21)2
Bev/Erlotinib1
ORR, %
8.9
20.0
Median OS, month
6.7
12.6
1-year survival, %
31
54.2
1. Herbst RS, et al. J Clin Oncol. 2005;23:2544-2555.
2. Shepherd FA, et al. N Engl J Med. 2005;353:123-132.
15
20
Bevacizumab with Erlotinib in NSCLC:
On-going Phase III Trials
ATLAS Trial
•Previous chemotherapy
1:1
N = 1,150
-Carboplatin/paclitaxel
Randomization
-Carboplatin/gemcitabine
-Carboplatin/docetaxel
(patients w/o PD
•Bevacizumab ( 4 cycles)
or sign. toxicity)
•Squamous + nonsquamous
Arm 1
Bev. + PBO
to PD
Arm 2
Bev. + Erlotinib
to PD
Erlotinib
Off-study
therapy
• Primary endpoint: Progression-free survival
• Secondary endpoint: Overall surviva; RR; safety
BETA Lung Trial
• Previously treated locally
advanced or metastatic
NSCLC
• Stratified by ECOG,
smoking history and sex
• Tumor assessments by
RECIST criteria every 6
weeks
N = 650
1:1
Randomization
Arm 1
150 mg/d Erlotinib
+
PBO
Arm 2
150 mg/d Erlotinib
+
15 mg/kg q3w Bev.
• Primary endpoint: Overall survival
• Secondary endpoint: Progression-free survival, safety, EGFR markers for outcomes
Tumor Angiogenesis: Bevacizumab and
Multitargeted Agents
Angiogenic growth factors
PDGF
Pericyte
O2
Tumor cell
Endothelial
cell
Paracrine factors
Rationale for Multitargeted
Therapy
• Agents acting on single molecular targets may have
limited long-term effectiveness
– acquired resistance occurs in many tumors1
• Agents or combinations acting on multiple targets
have the potential to overcome this problem
• Additive toxicities may limit the potential for
combining single-target therapies
• An alternative strategy is the use of multitargeted
agents such as sunitinib or sorafenib in advanced
NSCLC2–4
1. Haber DA, et al. Cold Spring Harb Symp Quant Biol 2005;70:419–26. 2. Gatzemeier U, et al. J Clin
Oncol 2006;24(June 20 Suppl.):18s(abstract 7002). 3. Liu B, et al. J Clin Oncol 2006;24(June 20
Suppl.):18s(abstract 17119). 4. Socinski MA, et al. J Clin Oncol 2006;24(June 20 Suppl.):18s(abstract
7001).
Characteristics of VEGFR TKIs
Drug
Half-life (h)
IC50 (nM)**
VEGFR-1
Other
VEGFR-2
VEGFR-3
PDGFR
KIT
9
17
8
10
RET
B-Raf, RET
Sunitinib
44
Sorafenib
~27
-
90
20
68
AZD2171
13-35
5
<1
<3
2
AMG 706
5-7
2
3
6
ZD6474
~120
1600
40
110
AG13736
2-5
1.2
0.25
0.29
Vatalinib
3-6
54
39
195
567
21
21
13
59
BIBF1120
8
84
RET
EGFR, RET
364
FGFR-1/3
*Biochemical IC50 values were determined using slightly different methods between the studies and
are not directly comparable.
Adapted from Lee and Heymach, Clin Lung Ca 2006
Wedge SR, Cancer Res 62:4645-55, 2002; Mendel DB, Clin Cancer Res 9:327-37, 2003; Wilhelm SM, Cancer Res 64:7099109, 2004; Hess-Stumpp ChemBioChem 2005
Potential Limits of Targeted
Therapies
• Role of molecular pathways may have a different
role in different stages of the disease (to be
shown)
• Quite unlikely that blocking a couple of targets
(WITHOUT TOXICITY!!!) we will be able to take
control of a SMART cell as the neoplastic cell
• Many target inhibitions not successful because of
redundancies and overlapping of complex signal
transduction pathways
• Aberration is present in cancer cells but it doesn’t
drive tumor behaviour (genetic instability in
tumors).
Probable Scenario in the
Coming Years
• Cytotoxic chemotherapy will remain the backbone
of treatment
• Its use will be revisited through pharmacogenomic
markers.
• Development of rationale combinations of targeted
agents, based on their mechanism of action and
potentiation.
• Identification of subsets of patients.
• It will be harder to assess targets when combinations will be used.
• Control of MRD or prevention of the recurrence will
be a therapeutic goal
Most Important “Targeted
Therapy” for Lung Cancer
Phase III Trial of Bevacizumab
in Non-Squamous NSCLC: ECOG 4599
N=855 (eligible)
Eligibility:
• Non-squamous
NSCLC
• No Hx of hemoptysis
• No CNS metastases
Stratification Variables:
•RT vs no RT
•Stage IIIB or IV vs recurrent
•Wt loss <5% vs >5%
•Measurable vs non-measurable
(PC)
Paclitaxel 200 mg/m2
Carboplatin AUC = 6
(q 3 weeks) x 6 cycles
No crossover
to
Bevacizumab
permitted
(PCB)
PC x 6 cycles
+
Bevacizumab
(15mg/kg q 3 wks) to PD
Sandler, et al. NEJM, Dec 2006
AVAiL
Study Design
Previously
untreated, stage
IIIb, IV or recurrent
NSCLC
(n=1,150)
CG x 6 + placebo
PD
CG x 6 + bevacizumab
7.5mg/kg Q 3 weeks
PD
CG x 6 + bevacizumab
15mg/kg Q 3 weeks
PD
No bevacizumab
after progression
• Cisplatin 80mg/m2 i.v. every 3 weeks; gemcitabine 1,250mg/m2 on
days 1 and 8 of each 3-week cycle
• Primary endpoint: progression-free survival
• Secondary endpoint: overall survival and response rate
CG = cisplatin/gemcitabine
Manegold et al., ASCO 2007, Abstract LBA7514
Adverse Events According to Treatment
Sandler A. et al, NEJM 2006; 355:2542
Antiangiogenic Therapy and
Vascular Normalization
Rakesh Jain Nat Medicine 7:987, 2001
Angiogenesis
• Angiogenesis is the formation of new blood
vessels from pre-existing vasculature
• Angiogenesis is highly dependent on the VEGF
signaling pathway
•
VEGFR-2 is the most important VEGF signaling pathway for angiogenesis
• VEGF is frequently overexpressed in cancer
and is associated with poor prognosis
• Without a blood supply, tumors do not grow
larger than 1–2mm
• As tumors grow they become hypoxic, which
leads to the up-regulation of angiogenic
factors such as VEGF
•
Stimulates the production of new vasculature
Phase II Activity of EGFR TKIs
In Unselected NSCLC
Result
Erlotinib
Gefitinib
IDEAL 1
Gefitinib
IDEAL 2
250mg 500mg 250mg 500mg
Number
57
104
106
102
114
Response Rate
12.3%
18%
19%
12%
9%
Median Survival
8.4 m
7.6 m
8.0 m
7.0 m
6.0 m
1-Yr Survival
40%
35%
29%
27%
24%