Transcript Diapositiva 1

LUNG CANCER
TRANSLATION INTO THE
ITALIAN CLINICAL
PRACTICE: OPPORTUNITY
AND LIMITS
Lucio Crinò
S.C. Oncologia Medica
Azienda Ospedaliera di Perugia
LUNG CANCER ASCO HIGHLIGHTS
•DIAGNOSIS
AND STAGING
•TREATMENT
OF EARLY STAGES
•MOLECULAR
MARKERS
•TARGETED
THERAPIES
•ADVANCED
DISEASE
ENDOSONOGRAPHY AND SURGICAL STAGING VS
SURGICAL MEDIASTINAL STAGING ALONE IN
NSCLC – An European randomised study


The Aster study abstr. 7000
Primary end point
N2-N3 detection
Secondary end point
Rate of futile
thoracothomy
complication
241 pts with PET
TBNA)
or CT scan stage
III NSCLC
and
ES + SS (EUSFNA and EBUS
SS alone (mediastinoscopy
mediastinotomy, VATS)
ENDOSONOGRAPHY AND SURGICAL STAGING VS
SURGICAL MEDIASTINAL STAGING ALONE IN
NSCLC – An European randomised study
RESULTS
ES + SS
p
SS Alone
Nodal metastasis
62 pts (50%)
+ 6 by SS
0.019
49 (35%)
Sensitivity for N
involvement
94%
Futile
thoracotomy
8 (7%)
Complications
6 pts
80%
0.009
21 (18%)
7 pts
(12/13 in SS)
ITALIAN EXPERIENCE



Limited experience with mediastinum surgical
staging
At the moment most of the diagnostic
approach to mediastinum staging is based on
endoscopy (TBNA) and CT scan ± PET
A very limited number of thoracic-oncology
departments have the opportunity and the
skills for systematic use of endosonography
EGFR TKIs GEFITINIB AS ADJUVANT TREATMENT
IN COMPLETELY RESECTED STAGE IB-IIIA
NSCLC – A NCIC randomised trial
Gefitinib 250 mg daily x 2
years
Sept 2002- Apr 2005
503 pts fully resected
R
Placebo
Results
Control
Gefitinib
M. follow-up 4.7 yrs
MDFS
reached
MDOS
4.2 yrs
5.1 yrs
HR 1.22
Not
NYR
EGFR mutations or amplification KRAS mutation are
not predictive neither prognostic
BR.19 – Disease Free Survival
EGFR TKIs GEFITINIB AS ADJUVANT TREATMENT
IN COMPLETELY RESECTED STAGE IB-IIIA
NSCLC – A NCIC randomised trial
COMMENTS
 No evidence of benefit for TKIs in adjuvant
setting
 Mutational status of EGFR or KRAS has
no prognostic value
 In adjuvant setting potential detrimental
effect in absence of overt disease
 Radiant trial with erlotinib in IHC selected
population has completed the accrual in
adjuvant setting
MOLECULAR EPIDEMIOLOGY OF KRAS
AND EGFR MUTATIONS IN NSCLC.
RESULTS OF TWO PROSPECTIVE STUDIES IN
OVER 1600 RESECTED EARLY STAGE NSCLC
(SWOG and MSKCC)





KRAS mutation was present in 19.3%, more frequent in
smokers 20% vs 9% and in adenocarcinoma
EGFR mutation was observed in 12.8%, significantly more
common in never smoker 45% vs 9% and in adenocarcinoma
EGFR and KRAS mutations are exclusive and smoking
history and histology but not gender were independent
variable
EGFR mutation shows a trend for better survival compared to
wild type
KRAS mutation has a less clear detrimental impact on
survival
MOLECULAR EPIDEMIOLOGY OF KRAS
AND EGFR MUTATIONS IN NSCLC.
RESULTS OF TWO PROSPECTIVE STUDIES IN
RESECTED EARLY STAGE NSCLC
COMMENTS



KRAS and EGFR mutations represents molecular
signature of different diseases in adenocarcinoma
in NSCLC
Future prospective studies will definitively assess
their prognostic value
In our country all the early stages resected
patients should be evaluated for the presence of
EGFR and KRAS mutation prospectively
MOLECULAR TARGETED THERAPIES

Trials designed to define the spectrum of
activity of EGFR TKIs

Trials designed to overcome TKIs
resistance

Trials designed on new molecular targets
(IGFR1-ELM4-ALK)
MOLECULAR TARGETED THERAPIES
COMMENTS (I)


Clear indications in two randomised trial for selective
use of TKIs. A positive CALGB study in 188 never or
light smokers adenocarcinomas of erlotinib alone vs
ECP: validation of IPASS results, with equivalent
activity better outcome in EGFR mutated pts. A
negative Italian trial of erlotinib vs CDDP Gem in
unselected patients
Negative prospective trial in pts unfit for
chemotherapy of erlotinib vs BSC. Better outcome in
female adenocarcinoma subgroups.
Clinical Activity of the Oral ALK Inhibitor,
Crizotinib (PF-02341066), in Patients with
ALK-positive Non-small Cell Lung Cancer
Bang Y,1 Kwak EL,2 Shaw A,2 Camidge
DR,3 Iafrate AJ,2 Maki RG,4
Solomon B,5 Ou SI,6 Salgia R,7 Clark J2
1Seoul
National University, Seoul, Korea; 2Massachusetts General Hospital,
Boston, MA, USA; 3University of Colorado Cancer Center, Aurora, CO, USA;
4Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 5Peter
MacCallum Cancer Centre, East Melbourne, Australia;
6University of California at Irvine, Irvine, CA, USA; 7University of Chicago
Cancer Center, Chicago, IL, USA
Abstract 3
ASCO Annual Meeting 2010
Potential Oncogenic “Drivers” in
Non-small Cell Lung Cancer (NSCLC)
Adenocarcinoma
K-ras
EGFR
B-raf
Her2
PIK3CA
Other
ALK
MET
Other
ALK (~5%)
ALK = anaplastic lymphoma kinase; EGFR = epidermal
growth factor receptor; Her2 = human epidermal
growth factor receptor 2; PIK3CA = phosphoinositide-3kinase, catalytic, alpha polypeptide
Massachusetts General Hospital, data on file.
[AT Shaw, personal communication]
FISH Assay for ALK Rearrangement*
p25.2
p25.2
p24.3
p24.1
p23.2
p22.3
p22.1
p16.3
ALK 29.3
p24.3
p24.1
p23.2
p22.3
p22.1
EML4 42.3
Telomere
2p23 region
p16.3
p16.1
p16.1
p14
p13.2
p14
p13.2
p12
p12
q12.1
q12.3
q12.1
q12.3
q14.1
q14.1
q14.3
q21.2
q14.3
q21.2
q22.1
q22.2
q23.2
q22.1
q22.2
q23.2
q24.1
q24.1
q24.3
q24.3
q31.3
q31.3
q32.1
q32.1
q32.3
q32.3
q33.2
q33.2
q34
q34
q36.1
q36.3
q37.2
q36.1
q36.3
q37.2
3’
5’
~250 kb
Centromere
t(2;5) ALK gene
breakpoint region
~300 kb
Break-apart FISH assay
for ALK-fusion genes1
Split
signal
Non-split
signal
ALK break-apart FISH assay
[Courtesy John Iafrate, Massachusetts General Hospital]
*Assay is positive if rearrangements can be detected in ≥15% of cells
FISH = fluorescence in situ hybridization
1Shaw
AT et al. J Clin Oncol
2009;27:4247–4253
Clinical and Demographic Features of
Patients with ALK-positive NSCLC
Mean (range) age, years
Gender, male/female
N=82
51 (25–78)
43/39
Performance
status,* n (%)
0
1
2
3
24 (29)
Race, n (%)
Caucasian
Asian
46 (56)
29 (35)
Smoking
history, n (%)
Never smoker
Former smoker
Current smoker
62 (76)
19 (23)
1 (1)
Histology, n (%)
Adenocarcinoma
Squamous
Other
79 (96)
1 (1)
2 (2)
Prior treatment
regimens, n (%)
0
1
2
5 (6)
27 (33)
15 (18)
34 (41)
1 (1)
≥3
Not reported
44 (54)
13 (16)
1 (1)
*Performance status = Eastern Cooperative Oncology Group
Tumor Responses to Crizotinib for
Patients with ALK-positive NSCLC
Maximum change in tumor size (%)
60
Progressive disease
Stable disease
40
Confirmed partial response
Confirmed complete response
20
0
–20
–30%
–40
–60
–80
–100
*
*Partial response patients with 100% change have non-target disease present
77% of Patients with ALK-positive NSCLC
Remain on Crizotinib Treatment
Individual patients
• Duration of treatment
(median: 5.7 months)
0–3 mo
13 pts
>3–6 mo
29 pts
>6–9 mo
24 pts
>9–12 mo
9 pts
>12–18 mo
4 pts
>18 mo
3 pts
0
3
6
9
12
15
Treatment duration (months)
N=82; red bars represent discontinued patients
18
• Reasons for discontinuation
– Related AEs
1
– Non-related AEs
1
– Unrelated death
2
– Other
2
– Progression
13
21
Summary


Treatment with crizotinib resulted in impressive
clinical activity in patients with ALK-positive
advanced NSCLC
–
ORR: 57%
–
DCR at 8 weeks: 87%
–
PFS probability at 6 months: 72%
Crizotinib was well tolerated
–
The most frequent adverse events were mild and
moderate gastrointestinal events and mild visual
disturbances
MOLECULAR TARGETED THERAPIES
COMMENTS (II)




C-Met inhibitors seem to be very active in combination
with erlotinib vs erlotinib alone. Potential interest in EGFR
wild type and KRAS mutation
Identification of a new activating mutation in
adenocarcinoma, EML4-ALK translocation present in 4%
of pts. High activity of a specific TKIs at the moment
evaluated in selected pts in Europe and USA in phase IIIII trials
Anti IGFR1 monoclonal antibody failed in combination
with chemotherapy in phase III trial
In a whole, constant better results for small molecules
TKIs versus monoclonal antibody in NSCLC
RANDOMISED PHASE III STUDY IN ELDERLY PATIENT
(75-89 YEARS) OF SINGLE AGENT STANDARDS
CHEMOTHERAPY VERSUS PLATINUM DOUBLET


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Benefit in OS for doublet 10, 5 months vs 6.2 months
Benefit in PFS for doublet 6.3 months vs 3.2 months
Flu hematological toxicity worse in doublet arm (Grade 3-4
54% vs 17.9)
COMMENTS
Large age interval 75-89 years
Large proportion >30% of PS 2 patients
Unacceptable mortality rate 23.7%, 16.6% in both arm
respectively
Data to evaluate in the contest of SER USA results showing
a significant benefit with platinum containing chemotherapy
in elderly JCO 2010
Chemotherapy and survival benefit
in elderly patients with advanced NSCLC
Edelman DM et al, JCO 2010
• Any
chemotherapy was associated with HR
reduction (0.558, CI 0.547-0.569) and with increase
of 1 year survival from 11,6% to 27%
• Platinum doublet increases one year survival
over single agent regimens from 19,4% to 30,1%
CONCLUSIONS
• Most elderly patient with advanced NSCLC do
not receive chemotherapy, yet there are clear
survival benefits, even with controls for age,
comorbidity and PS
•The benefit of chemotherapy is greater for
platinum-based doublet regimens, than for single
agent chemotherapy