La terapia medica: La terapia medica: Novità

Transcription

Microcitoma
La terapia medica:
Novità
Sara Pilotto
Oncologia
g Medica, Scuola di Specializzazione
p
in Oncologia, Università di Verona
Direttore: Prof. G.P. Tortora
Policlinico‘G.B. Rossi’, Azienda Ospedaliera
Universitaria Integrata, Verona
Lucca, 27 Novembre 2013
‘aa Static
Static Landscape
Landscape’
Surgery
Radiotherapy
Nitrogen mustard
Combination > single agent
CAV or CEV
1970
1940
TNM staging
Novel agents
1990
1960
SCLC vs NSCLC
LD vs ED
Cyclophosphamide
2° line CT
PCI for LD‐SCLC
1980
EP
CT + RT for LD‐
SCLC
2000
IP
PCI for ED‐SCLC
Novel regimens
Focus on targeted agents and news from WCLC 2013
Focus on targeted agents and news from WCLC 2013
Chan & Coward, J Thorac Dis 2013
Clinical Relevance of the ‘O
‘Oncogene Addiction’
Addi i ’
• In patients with solid malignancies in which a dominant mutation or gene amplification drives tumor growth, targeted therapies are highly effective h
d h
h hl ff
but rarely curative…
–
–
–
–
cKit mutations in GIST
mutations in GIST
HER2 amplification in breast cancer
EGFR mutation in NSCLC
ALK translocation in NSCLC
GENETICS
DEPENDENCY
…Does that apply to SCLC?
PHARMACOLOGIC VULNERABILITY
Modified By Bria and Puglisi
SCLC [vs
SCLC [ s NSCLC]
Molecular Profile
Biologic Behavior
•
•
•
•
•
•
High cellular proliferation
High
cellular proliferation
Short cell cycle time
Rapid doubling time
Central presentation
Early metastasis
Ch
Chemo‐radiation sensitivity
di i
ii i
Peifer et al, Nature Genetics 2012 Genomic Analysis of SCLC
Genomic Analysis of SCLC
•
Hot spot mutations
– TP53, RB1, PIK3CA, CDKN2A, PTEN
TP53 RB1 PIK3CA CDKN2A PTEN
– RAS family regulators (RAB37, RASGRF1, RASGRF2)
– Chromatin modifiers (EP300, DMBX1, MLL2, MED12, etc.)
•
Hot spot mutations PLUS q
Hot spot mutations PLUS
q‐score
score
– RUNX1T1, CDYL, RIMS2
•
Gene families and pathways
– PI3K pathway, Notch and Hedgehog, glutamate receptor family,
p
y,
g
g, g
p
y,
DNA repair/checkpoint, SOX family
•
Focal amplifications
– MYC, SOX2, SOX4, KIT
•
Recurrent translocations and fusion genes
Circos plot whole genome SCLC
22 significantly mutated genes
22 significantly mutated genes
– Recurrent: RLF–MYCL1
– Kinase fusions
Peifer, M et al: Nature Genetics 44:1104‐1110, 2012
Rudin CM et al: Nature genetics 44:1111‐1116, 2012
Kelly, Oral Abstract Discussant IASLC 2013
‘the
the Old Glories
Old Glories’
Bevacizumab
Bevacizumab
Sunitinib
Pazopanib
I ili
Ipilimumab
b
 ..and many others
d
th
‘the
the Old Glories
Old Glories’
Bevacizumab
Bevacizumab
Sunitinib
Pazopanib
I ili
Ipilimumab
b
d
th
Bevacizumab [phase II]
[phase II]
Exp arm*
N
RR(%)
mPFS (ms)
‘Control arm’
mOS (ms)
‘Control arm’
P60E120B x 4
63
63.5
4.7
4.6#
10.9
10.2#
P30I65B 6
P30I65B x 6
72
75
7
4.1
4
1#
11 6
11.6
9.3
9
3#
1° line/M
P65 vs C5
E100B x 4
52
58
5.5
4.4
9.4
10.9
1° line/M
C4I60B x 6
51
84
9.1
6#
12.1
10#
2° line
T2.3B x 8
50
16
S:6.2/R:2.9
4.1#
7.4
6.5#
2° line
TXL90B
34
18
3.7
‐
7.5
‐
Setting
1° line/M
1° line
li
*
Cisplatin 60 mg/mq d1/etoposide 120 mg/mq d1‐3 + bevacizumab 15 mg/mq
Cisplatin 30 mg/mq d1,8/irinotecan
30 mg/mq d1 8/irinotecan 65 mg/mq d1,8 + bevacizumab
65 mg/mq d1 8 + bevacizumab 15 mg/mq
15 mg/mq
Cisplatin 65 mg/mq or carbo AUC5 d1/ d1/etoposide 100 mg/mq d1‐3 + bevacizumab/P 15 mg/mq
Carbo AUC4 d1,8,15/irinotecan 60 mg/mq d1,8,15 + bevacizumab 10 mg/mq d1,15
Oral topotecan 2.3 mg/mq d1‐5 + bevacizumab 15 mg/mq d1 Horn et al, JCO 2009 Spiegel et al, JCO 2009 ,
p g
,
Pacllitaxel 90 mg/mq d1,8,15 + bevacizumab
90 mg/mq d1 8 15 + bevacizumab 10 mg/mq d1,15
10 mg/mq d1 15
# historical controls
Ready et al, JCO 2011 Schmittel et al, AO 2011
Hanna et al, JCO 2006 Spiegel CLC 2013 Spiegel et al, JCO 2011 Jalal et al, JCO 2010
Bevacizumab
 None of these trials reached the mOS of 12.8 months obtained
for IP in Noda, NEJM 2002
 All regimes were feasible with few treatment‐related death
end no evidence of serious haemoptysis
 The addition of bevacizumab to standard chemotherapy might
implement the overall activity (in 1st line)
 But
B phase
h
II trial
i l often
f
overestimated
i
d the
h results
l
 Comparable of those observed in others malignancies  a
small
clinical benefit
 Phase III randomized trial comparing 1st chemotherapy +/‐
bevacizumab may be appropriate
Modified by Belani, IASLC 2013
Ongoing RCTs:
DDP VP 16 ± BEVACIZUMAB
DDP + VP‐16 ±
PI: A. Ardizzoni
• The objective of the study is voluntary pretentious (1‐
yr OS 40% → 58%) = 206 pts
yr OS 40% → 58%) 206 pts
• Interim analysis (for futility) ongoing (140/206 pts)
‘the
the Old Glories
Old Glories’
Bevacizumab
Bevacizumab
Sunitinib
Pazopanib
I ili
Ipilimumab
b
d
th
Sunitinib
Setting
Exp arm*
N
RR(%)
mPFS (ms)
‘Control arm’
OS
‘Control arm’
2° line
S
25
9
1.4
‐
5.6ms
‐
8.4(S)
( )
7.6(all)
( )
85%(1y)
( )
54%(1y)
( )
M
*

C4I60S
34(17)
( ) 59(CT)
( )
Sunitinib 50 mg/d for 4/6 weeks
Carbo AUC4 d1/irinotecan
AUC4 d1/irinotecan 60 mg/mq d1,8,15 60 mg/mq d1,8,15
 sunitinib 25 mg/d
Han et al, JCO 2011
Spigel et al, LC 2012
Ready, ASCO 2013
Modified by Ready, ASCO 2013
Sunitinib
 2nd line sunitinib (50 mg/d) does not seem to warrant further clinical
evaluation
 Low PFS (1.4 ms)
 Sunitinib was discontinued in half of patients due to toxicity
 IInteresting
t
ti results
lt deriving
d i i from
f
phase
h
II trials
t i l with
ith sunitinib
iti ib in
i
maintenance
 The ALLIANCE trial met its primary endpoint of PFS (although with a small
difference with respect to the expected HR), with an OS trend (despite 40%
crossover)
 Safety issues  in the ALLIANCE trial 46% of grade 3/4
/ toxicities
 But carefully consider plans for a randomized phase III trial
 REMEMBER TOPOTECAN [[Schiller JCO 2001],
], BEVACIZUMAB AND OTHER [[Rossi LC 2010]]
 Biomarker analysis of blood samples may be very challenging
Modified by Wakelee, ASCO 2013
‘the
the Old Glories
Old Glories’
Bevacizumab
Bevacizumab
Sunitinib
Pazopanib
I ili
Ipilimumab
b
d
th
Kotsakis A.1, Kentepozidis N.2, Karavasilis V.3, V th liti J.
Varthalitis
J 4, Peroukidis
P
kidi S.
S 5, Ziras
Zi N.
N 6, Res H.
R H 7, Mavroudis D.1, Georgoulias V.1, Agelaki S.1
1
Department of Medical Oncology, University General Hospital of Heraklion, Crete, Greece , 2 Department of
Medical Oncology, 251 Air Force General Hospital, Athens, Greece, 3 Department of Medical Oncology,
"Papageorgiou" General Hospital, Thessaloniki, Greece, 4 Department of Medical Oncology, General Hospital of
Chania, Crete, Greece, 5 Division of Oncology, Department of Medicine, University Hospital of Rio, Patras, Greece, 6
2ndd Department off Medical
d l Oncology,
l
Metaxa Anticancer Hospital,l Piraeus, Greece, 7 Third
h d Department off Medical
d l
Oncology, "Agioi Anargiri" Anticancer Hospital, Athens, Greece
Kentepozidis, IASLC 2013
Study design: aa two‐cohort, non‐randomized, two‐stage Phase
two cohort non randomized two stage Phase II study II study
Patients with sensitive (cohort A) and resistant/refractory (cohort B) are enrolled onto the study (sensitive: relapse in > 60 days; resistant: ≤ 60 days from the 1st line chemo)
Objectives:
Primary endpoint: Progression‐free rate as determined by radiological assessment using standard RECIST 1.1 criteria at Week 8.
standard RECIST 1.1 criteria at Week 8.
Primary endpoints: Overall response rate, Overall survival (OS) and progression‐free survival (PFS), toxicity.
Statistical consideration:
Using the Simon's Minimax 2‐Stage Design, in stage 1, 19 subjects will be enrolled into each cohort. If 7 or more subjects in cohort A or B have no PD at Week 8, further 20 subjects will be enrolled. The null hypothesis will be rejected in favor of the alternative hypothesis if 17 or more subjects out of the total of 39 subjects in cohort A or B have no PD at Week 8.
Treatment plan:
Treatment plan:
Pazopanib will be given at a dose of 800mg/day, orally
•
•
•
•
Median follow up: 9.6 months (1.0 Median
follow up: 9 6 months (1 0 – 22.6)
22 6)
Deaths: 7/19 patients
1‐year OS (Kaplan‐Meier estimate): 57.3% Median PFS: 3.6 months (0.8‐ 17.7)
Overall Response Rate
O
ll
Response
n (%)
CR
‐
PR
4 (21)
SD
8 (42)
8 (42)
Overall DCR (CR+PR+SD)
12 (63)
95% C.I.
41.5 ‐ 84.85
PD
7 (37)
Leukopenia
Neutropenia
Anemia
Nausea
Vomiting
Diarrhoea
Mucositis
E i t i / Bl di
Epistaxis/ Bleeding
Rash
Fatigue
Elevated tranasaminases
Proteinouria
Hypertension
Hair discoloration
All Grades
n
%
8
42
3
7
3
2
8
3
6
4
8
3
16
37
16
10
42
16
32
21
42
16
6
7
8
32
37
42
Leukopenia
≥ GrIII
n
%
1
5
Neutropenia
Nausea
Diarrhoea
Epistaxis/ Bleeding
Epistaxis/ Bleeding
Fatigue
Hypertension
1
1
1
1
2
1
5
5
5
5
10
5
Pazopanib
 2nd line pazopanib in patients with ‘sensitive’ relapse SCLC showed
interesting activity (4/19 PR)
 Strengths:
Strengths
 Multi‐site prospective phase II trial
 Pazopanib was well tolerated with manageable toxicity
 Biomarker analysis ongoing
 Weaknesses:




The primary endpoint was 8 weeks PFS
No data about ‘resistant’ cohort
Pazopanib 800 mg/d
Another p
phase II trial [[Gandi ASCO 2013]] of p
pazopanib
p
in relapsed/refractory
p /
y SCLC failed to
demonstrate any activity
 No relevant results with others anti‐angiogenic agents
vandetanib,
d
ib sorafenib,..]
f ib ] in this setting
[sunitinib,
Modified by Millward, IASLC 2013
‘the
the Old Glories
Old Glories’
Bevacizumab
Bevacizumab
Sunitinib
Pazopanib
I ili
Ipilimumab
b
d
th
 Design
 130 untreated patients with ED‐SCLC randomized 1:1:1 to receive
paclitaxel 175mg/mq/carboplatin AUC6 + placebo or ipilimumab 10
mg/kg in 2 regimens:
 CONCURRENT: I + TXL/C  P + TXL/C
 PHASED:
PHASED P + TXL/C  I + TXL/C
Every 3 ws for a maximum of 18 ws (induction) followed by
maintenance ipilimumab or placebo every 12 ws
 Endpoint was PFS, irPFS, BORR, irBORR, OS and safety
 IMMUNE‐RELATED [IR] response criteria
Reck et al, AO 2013
 Results
 Phased ipilimumab improved irPFS vs control [HR 0.64, p=0.03]




No improvement in PFS [HR 0.93, p=0.37] or OS [HR 0.75, p=0.13]
Median irPFS: 6.4 ms for phased I, 5.7 ms for concurrent I, 5.3 ms for control arm
Median OS: 12,9 ms for phased I, 9,1 ms for concurrent I, 9,9 ms for control arm
Grade 3/4 Aes was 17% for phased I, 21% for concurrent I, 9% for control
Reck et al, AO 2013
Ipilimumab
 Reliable existence of an immune response against SCLC tumors
[although often suppressed]
 LEMS and
d others
th paraneoplastic
l ti syndromes
d
 Phased ipilimumab improved irPFS when added to standard 1st line
chemotherapy in SCLC
 A not significant trend towards OS prolongation [12.9 ms vs 9.9 ms, HR 0.75]
 PHASED somministration > concurrent
1. Reduction of tumor burden
2. Release of tumor antigens
3. Infiltration of cytolytic
y y T cells and diminishingg of tumor‐associated immunosuppression
pp
 Combination with chemotherapy/radiotherapy to achieve efficacy
 Immune response
p
require
q
time
 irRC has not yet been validated  only hypothesis generating results
‘the
the Old Glories
Old Glories’
Bevacizumab
Bevacizumab
Sunitinib
Pazopanib
I ili
Ipilimumab
b
d
th
……..the others
the others
AGENT
SETTING
TREATMENT
RESULT
NOTES
G fiti ib
Gefitinib
relapse
l
alone
l
negative
ti
some results in EGFR mutant SCLC
(3‐4%, combined with adeno?)
Imatinib
1st line
relapse
maintenance
+ IC
alone
negative
no correlation with c‐kit mutation
Vandetanib
chemosensitive
alone
negative
gastrointestinal toxicity and rash
Sorafenib
relapse
alone
interesting
comparable with
comparable
with historical 2
historical 2nd line
major toxicity (18/89 discontinuation) Everolimus
relapse
alone
negative
limited activity in unselected SCLC
Cediranib
relapse
alone
negative
Thalidomide
chemosensitive
alone
negative
trend towards longer OS in poor PS Lu et al, Oncology Letters 2013
EGFR, IG1‐R, MET, KIT, RAS, PKC, …
PKC, … MATRIX METALLOPROTEINASE INHIBITORS
P53, Bcl‐2, p16
VACCINES
ONCOLYTIC VIRUS
Modified by Adjei, IASLC 2013
‘the
the New Hopes
New Hopes’
ABT‐263
OSI 906
OSI‐906
G it
Ganitumab/Rilotumumab
b/Ril t
b
Alisertib
‘the
the New Hopes
New Hopes’
ABT‐263
OSI 906
OSI‐906
G it
b/Ril t
b
Alisertib
ABT 263
ABT‐263
ABT 263
ABT‐263
 Limited efficacy in heavy pre‐treated SCLC
 DCR 27%, PFS 1.6 ms, OS 3.2 ms
 Relevant toxicityy
 Serious AEs 11/39, dose reduction 6/39
 Diarrhoea [43%], back pain [43%], thrombocytopenia [29%]
 Might potentially implement CT cytotoxic effect
 First line study comparing ABT‐263
ABT 263 with CE is in progress
‘the
the New Hopes
New Hopes’
ABT‐263
OSI 906
OSI‐906
G it
b/Ril t
b
Alisertib
Modified by Kelly, IASLC 2013
OSI 906
OSI‐906
 Response rate and
d efficacy
ff
outcome suggest drug
d
inactivity
 DCR 1%, PFS 1.4 ms, OS 3.6 ms
 No Relevant toxicity
 A Data Safety Monitoring Board is evaluating about
the p
pursuance or not of this studyy
‘the
the New Hopes
New Hopes’
ABT‐263
OSI 906
OSI‐906
G it
b/Ril t
b
Alisertib
Glisson et al, IASLC 2013
Ganitumab/Rilotumumab
 Phase II multi‐site study of two experimental agents in frontline SCLC
 The study did not met its primary OS endpoint
 Not significant signal of activity/efficacy with the addiction of ganitumab or
rilotumumab to PE
 No
N relevant
l
t toxicity
t i it
 Open questions:
 Is the target ‘oncologically
oncologically relevant
relevant’ for SCLC survival?
 Preclinical data
 Are the experimental drugs really inactive?
 Are the experimental agents only active in a selected population?
 Biomarker analysis [low IGFBP‐2 levels associated with increased response to ganitumab]
‘the
the New Hopes
New Hopes’
ABT‐263
OSI 906
OSI‐906
G it
b/Ril t
b
Alisertib
Havel et al, IASLC 2013
Alisertib
 The study met its primary ORR endpoint
 Antitumor activity was seen in both sensitive and refractory disease
 Modest response rate when compared to others 2nd line agents
 Particularly in chemosensitive patients [19% vs 44% amrubicin and 15% topotecan]
 Hematological toxicity was modest
 grade 3 neutropenia 30% with alisertib [41% with amrubicin and 53% with
topotecan]
 Convenient oral dosing and schedule
 Interesting candidate predictive biomarker profile identified
 Continued evaluation of alisertib is warranted
‘the
the New Hopes
New Hopes’
ABT‐263
OSI 906
OSI‐906
G it
b/Ril t
b
Alisertib
……..the others
the others
AGENT
TARGET
SETTING
RESULT
NOTES
Bec2/BCG
GD3 ganglioside
phase III adj
phase
III adj
responding LD‐SCLC
negative
trend towards longer OS for those trend
towards longer OS for those
developing a humoral response
Marimastat
MMP
responding SCLC
negative
BY‐129566
MMP
responding SCLC
Negative
Obatoclax
Bcl‐2
1st line + CT
Interesting
trend towards longer OS Panobinostat
HDI
relapse
Negative
limited activity in unselected
Cixutumab
Vismodegib
IGF1‐R
Hedgehog
1st line/M + CT
Negative
Modified by Murray, IASLC 2013
‘something
something completely different
different’
Pravastatin
Picornavirus
 Rationale
 Anti‐tumor effects of statins




Inhibition of tumor cell growth [stabilization cell cycle kinase, inhibition RAS]
Inhibition of angiogenesis [inhibition capillary formation, decreased VEGF]
Induction of apoptosis
p p
[decrease in Bcl‐2, caspase
p
activation]
Repression of tumor metastasis [decrease MMP and EGF]
 Results
 No advantage in the primary endpoint OS
 Negative study expending considerable resources
Seckl et al, IASLC
 Rationale
 The replication‐competent virus might replicate in cancer cells
resulting in cell death
 Results
R l
 The maintenance therapy with NTX‐010 did not improve PFS
 OS was adversely affected in patients with viral titers at 7 and 14 d
Molina et al, IASLC
Conclusions
 No clinical practice changing data
 A growing attention towards the deeper
characterization for refining the SCLC molecular
background
 To better drive target therapy strategy
 Strengthen the preclinical rationale of new agents
in SCLC models
 Redesigning early phase clinical trials
 Availability of biological material [biobanking of tumor tissue,
tissue
blood samples, re‐biopsies at progression, biomarker analysis]

La terapia medica: La terapia medica: Novità

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