Transcript Targeted Therapies Lung

18th Annual NOCR meeting
Lung Cancer and Gender
Anne S. Tsao, M.D.
Director, Mesothelioma Program
Director, Thoracic Chemo-XRT
Program
Associate Professor
February 2012
The University of Texas
MD ANDERSON
CANCER CENTER
Department of Thoracic/Head & Neck
Medical Oncology
Outline
Gender
Epidemiology
Female NSCLC incidence and trends
Etiology
Behavioral
Hormonal
Genetic
Treatment
differences
Chemotherapy
Targeted Therapies
Future
Studies
Hormone therapy
USA 2012
Siegal et al. CA Cancer, 2012 online
Jemal et al. CA Cancer, 61 (2): 69-90. Marhc/April 2011
Gender differences in Lung Cancer
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Women may have an increased susceptibility to tobacco
smoke - women with lung cancer have a lower overall
pack-year and duration exposure to tobacco1
Women are more likely to have adenocarcinoma, while
men have SCC2
Higher incidence of lung cancer development in neversmoking women than never-smoking men.
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Treatment differences: women have better outcomes
than men after surgery and chemotherapy.
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1Siegfried
Different distribution rates of EGFR mutation, EML 4 ALK, KRAS
mutation between genders
3E1594
Study Women (n=431) had median OS 9.2 months vs.
Men 7.4 months (n= 726), p=0.004
J. Lancet Oncology, 2: 506-13, August 2001; 2Ferguson M, et al. Ann Thorac Surg 69: 245-249, 2000; 3Wakelee H et al.
JTO 2006; 1:441-446
Outline
Gender
Epidemiology
Female NSCLC incidence and trends
Etiology
Behavioral
Hormonal
Genetic
Treatment
differences
Chemotherapy
Targeted Therapies
Future
Studies
Hormone therapy
Behavioral – smoking practice
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Overall smoking rates have declined by half since the mid20th century; but due to the increase in USA population, the
overall number of smokers is the same.
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Proportion of smoking women has increased from <25% to >40%;
and 50% of all new smokers are women.1
~25% US women currently smoke1
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35% of teenage girls have cigarette use (1 cigarette within 30 days)
Teenagers are more likely to be addicted to nicotine
Women are less likely to stop smoking
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Concerns for avoidance of weight gain
Cigarette use still occurs in 1 of every 4 pregnancies2
1Siegfried
J. Lancet Oncology, 2: 506-13, August 2001; 2DiFranza J, et al. J fam Prac 40: 385-394, 1995
Hormonal – Proposed theories
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1 Taioli
Exogenous and endogenous estrogen may impact on NSCLC
development1,2
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Early age at menopause (< 40 yrs) has a reduced risk of adenocarcinoma (OR 0.3)
Estrogen replacement therapy has a higher risk of adenocarcinoma (OR1.7)
Estrogen replacement + smoking has a higher risk of adenocarcinoma (OR 32.4)
Late menopause and shorter menstrual cycles are associated with increased risk
Estrogens can promote lung carcinogenesis via estrogen receptor
(ERa,b) present on tumor cells
Estrogen may be a direct carcinogen – can form DNA adducts
Estrogen may change metabolic activation of carcinogens from tobacco
Recent investigations suggest that the survival benefit seen in women is
predominantly in post-menopausal women
E, et al. JNCI 84: 869-870, 1994; 2Siegfried J. Lancet Oncology, 2: 506-13, August 2001
Genetic Susceptibility
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Higher frequency of p53 gene G->T transversion mutation and higher
accumulation of carcinogen adducts in female lung tumors despite less
tobacco exposure1
Decreased DNA repair capacity1,2
Increased expression of CYP1A1 isozyme (increases activation of
polycyclic hydrocarbons to carcinogenic intermediates).3
Higher gastrin-releasing peptide (GRP) receptor gene expression in
women (X-linked GRP receptor gene) – regulator of carcinogen
metabolism.4
Glutathione S-transferase (GST) – deactivate carcinogens and prevent
DNA adducts. Women are more likely to have null genotype GSTM1 which
signal a predisposition to lung cancer.5
Higher rate of symptomatic asthma in young smoking women than men.2
Potential effect of estrogen on development of adenocarcinoma2
1Kure
E, et al. Carcinogenesis 17: 2201-2205, 1996; 2Siegfried J. Lancet Oncology, 2: 506-13, August 2001; 3Mollerup et al. AACR
1998, 337; 4Shriver M, et al. JNCI 92: 24-33, 2000 , 5Tang D et al. Carcinogenesis. 19:1949-1953, 1998.
Genetic mutations in Never-smokers
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EGFR mutation
EML-4 ALK
EGFR mutations
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Found in 10% - 15% of all lung cancer patients and 85%
who clinically respond to EGFR TKIs
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Found more commonly in never-smokers,
adenocarcinomas, BAC, women, Asians
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Predominantly located in EGFR exons 19 - 21
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EGFR mutations are not the same. There are sensitive
mutations and acquired resistance mutations (T790M).
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85% of EGFR mutations are either deletion exon 19 or
L858 mutation.
Pao, Miller. J Clin Oncol. 2005;23:2556-2568; Wu et al. J Thorac Oncol. 2007;2:430-439.
IPASS: Phase III Trial of Gefitinib vs Carboplatin/Paclitaxel in
Selected Patients
With Advanced NSCLC
Never or light
ex-smoker* with
adenocarcinoma
histology
PS 0-2
Stage IIIB or IV
chemotherapy-naïve
NSCLC
N=1217
R
A
N
D
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M
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Gefitinib (250 mg/day)
Offered carboplatin/paclitaxel
on progression
Carboplatin (AUC 5 or 6) +
Paclitaxel (200 mg/m2)
3 times weekly up to 6 cycles
Primary endpoint: PFS (noninferiority)
Secondary endpoints: ORR, OS, QOL, disease-related symptoms, safety, and tolerability
Exploratory: biomarkers – EGFR mutation, gene copy number, and protein expression
*Never smoker=smoked <100 cigarettes in lifetime; light ex-smoker=stopped ≥15
years ago and smoked ≤10 pack-years.
Mok. N Engl J Med. 2009;361:947.
IPASS: Results in ITT Population
PFS
Gefitinib
Carboplatin/paclitaxel
0.8
OS*
1.0
0.6
0.4
0.2
Probability of Survival
Probability of PFS
1.0
0.0
Gefitinib
Carboplatin/paclitaxel
0.8
0.6
0.4
0.2
0.0
0
4
8
12
16
20
24
0
4
8
Months
No. of Pts
Events
Median PFS
12-Mo PFS
16
20
24
Months
Gefitinib
C/P
609
608
453 (74.4%)
497 (81.7%)
5.7 mos
5.8 mos
Events
ORR
Median OS
HR=0.74; P<0.001
25%
12
7%
12-Mo OS
*Follow-up ongoing.
C/P=carboplatin/paclitaxel; ITT=intent to treat.
Reproduced with permission from Mok. N Engl J Med. 2009;361:947.
Gefitinib
C/P
223 (36.6%)
227 (37.3%)
43.0%
32.2%
18.6 mos
17.3 mos
HR=0.91; P=NR
68%
64%
28
IPASS: PFS by EGFR Mutation Status
Within Treatment Arms
1.0
Gefitinib EGFR M+ (N=132)
Gefitinib EGFR M– (N=91)
Carboplatin/paclitaxel EGFR M+ (N=129)
Carboplatin/paclitaxel EGFR M– (N=85)
Probability of PFS
0.8
Gefitinib, HR=0.19; P<0.0001
Carboplatin/paclitaxel, HR=0.78; P=0.1103
0.6
0.4
0.2
0.0
0
4
8
12
16
Time From Randomization (Months)
20
24
HR <1 implies a lower risk of progression in the M+ group
compared with the M– group.
M=mutation.
Adapted with permission from Mok. N Engl J Med. 2009;361:947; Mok. ESMO. 2008 (abstr LBA2).
EML4-ALK Fusion Gene
ALK – anaplastic lymphoma kinase
EML 4 – echinoderm microtubule associated protein like 4
• Found Primarily in adenocarcinoma patients who are never- or light former
smokers, EGFR and KRAS WT, and younger
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All adenocarcinomas: 9% EML4-ALK
If EGFR WT, Caucasian never-smoker, adenocarcinoma: ~10-20%
EML4-ALK
•EML4-ALK-positive tumors are a distinct entity among lung
adenocarcinomas and usually do not respond to EGFR TKIs.
•EML 4 ALK is a negative prognostic factor
 ALK (+) NSCLC treated with 2nd/3rd line crizotinib have longer OS than
those who are not treated with crizotinib.
Koivunen et al. CCR 14 (13): 2008; Shaw et al. ASCO 2011 Abstract 7507; Kris et al. on behalf of
LCMC investigators, ASCO June 2011 Abstract #CRA7506
Phase II crizotinib in ALK-positive
NSCLC
Crino et al. ASCO 2011 Abstract 7514
Tumor response
Best response
ORR
SD
DCR week 6
week 12
PD
51.1%
34%
85%
74%
7.5%
Crizotinib was FDA approved for use
in pre-treated EML4 ALK patients.
Crino et al. ASCO 2011 Abstract 7514
Outline
Gender
Epidemiology
Female NSCLC incidence and trends
Etiology
Behavioral
Genetic
Hormonal
Treatment
differences
Chemotherapy
Targeted Therapies
Future
Studies
Hormone therapy
ASCO Abstract 7036: ECOG 4599 subset
analysis of survival by gender
(PC)
Paclitaxel 200 mg/m2
Carboplatin AUC = 6
(q 3 weeks) x 6 cycles
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
No crossover to
Bevacizumab
permitted
(PCB)
PC x 6 cycles
+
Bevacizumab
(15mg/kg q 3 wks) to PD
Brahmer et al., Abstract 7036 ASCO 2006
ECOG 4599 Response Rates
Male
Female
Status
PC
(n=230)
PCB
PC
PCB
P-value
(n=191)
(n=162) (n=190)
CR
0
1 (0.5%)
1
(0.6%)
PR
36
(15.7%)
54
(28.3%)
22
75
(13.6%) (39.5%)
ORR
36
(15.7%)
55
(28.8%)
Stable
(≥ 39 days)
96
(41.7%)
79
(41.4%)
0.001
P-value
3
(1.6%)
23
78
(14.2%) (41.1%)
<0.0001
77
61
(47.5%) (32.1%)
Both men and women have improvement in
response rates with bevacizumab
Brahmer et al., Abstract 7036 ASCO 2006
ECOG 4599 PFS by gender
Group
PCB/PC
Hazard Ratio
95% Conf
Interval
P-value
Overall
0.66
(0.57, 0.77)
<0.0001
Males
0.64
(0.53, 0.78)
<0.0001
Females
0.71
(0.57, 0.88)
0.002
ECOG 4599 OS by gender
PC
PCB
P-value
Overall
10.3 mo.
12.3 mo.
0.003
Males
8.7 mo.
11.7 mo.
0.001
Females
13.1 mo.
13.3 mo.
0.87
Brahmer et al., Abstract 7036 ASCO 2006
Analysis of Gender Differences
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Women in PCB arm were more likely to have liver
involvement and prior weight loss
Women in the PCB arm were less likely to receive
chemotherapy after treatment progression on
ECOG4599
PC
n=433
Type
Non-Chemo
Chemotherapy
Not specified
Nothing
reported
Male
PCB
n=417
Female
Male
Female
51 (12%)
26 (6%)
29 (7%)
31 (7%)
116 (27%)
89 (20%)
100 (24%)
85 (20%)
0
0
1(<1%)
0
86 (20%)
65 (15%)
80 (19%)
91 (22%)
Brahmer et al., Abstract 7036 ASCO 2006
Conclusions ASCO Abstract 7036
Findings
• Subset analysis shows that women do not have overall
survival benefit from PCB
• Potentially related to women in the PCB arm having more
liver involvement and that they were less likely to receive
chemotherapy after progressing on ECOG 4599
• Unclear etiology - ? Menopausal status
Conclusion
• Preliminary analysis of unclear significance and would
continue treating eligible women with ECOG 4599 regimen.
IASLC Abstract 131: Menopausal
status and E4599
Median OS
Women Age
Carbo-paclitaxelbevacizumab
Carbo-paclitaxel
P-value
<60 years
15.5 months
11 months
0.12
<45 years (n=19)
16.8 months
5.8 months
0.07
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Women < age 60 appear to derive benefit with the addition of
bevacizumab to chemotherapy.
Men of all ages had treatment benefit with bevacizumabchemotherapy.
Wakelee et al., Abstract 131 IASCL 2008; JTO 3 (11) S4: S282
ASCO Abstract 7039: Gender Differences in 2
randomized phase III trials
STELLAR 3
N=400
STELLAR 4
N=381
Eligibility Criteria:
•Chemo-naïve
•Advanced NSCLC
•PS 2
Stratified by:
•Stage
•gender
•brain mets
•geography
Eligibility Criteria:
•Chemo-naïve
•Advanced NSCLC
•PS 2
Stratified by:
•Stage
•gender
•brain mets
•geography
Ross et al., Abstract 7039 ASCO 2006
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Carboplatin AUC 6
PPX 210 mg/m2 Q3wks
Carboplatin AUC 6
Paclitaxel 225 mg/m2
Q3wks
PPX 175 mg/m2 Q3wks
Gemcitabine 1000 mg/m2
days 1,8,15 every 4 wks
or
vinorelbine 30 mg/m2 days
1, 8, 15 every 3 wks
PPX or Poly-(L-Glutamic Acid) – Paclitaxel
Paclitaxel
Covalently linked
Poly L-glutamate
Preclinical studies: Estrogen and PPX interaction
Cathepsin B is an estrogen-regulated lysosomal enzyme
that is the major metabolizing enzyme of PPX backbone
thereby controlling release of paclitaxel
Gender Differences in OS
Women treated with PPX have a survival benefit
HR = 0.70, p=0.03.
Ross et al., Abstract 7039 ASCO 2006
Subgroup Analysis by Age
Women < 55yrs
Women > 55yrs
Women < 55 yrs who received PPX HR 0.51, p=0.03
Women > 55 yrs who received PPX HR 0.75, p=0.134
Ross et al., Abstract 7039 ASCO 2006
Subgroup Analysis by Menopause
Median OS
PPX
Control
HR
P-value
1-yr survival
PPX
control
Pre-menopausal
STELLAR 3
239
167
0.66
0.011
38%
22%
STELLAR 4
NE
188
0.38
0.146
51%
16%
Composite
309
181
0.56
0.008
43%
19%
Post-menopausal
STELLAR 3
NE
347
0.71
0.523
50%
36%
STELLAR 4
320
163
0.47
0.312
40%
17%
Composite
320
23
0.62
0.256
47%
30%
Pre-menopausal women had improved survival when
treated with PPX over control HR=0.54, p=0.039
Ross et al., Abstract 7039 ASCO 2006
Survival in Pre-Menopausal Women
Ross et al., Abstract 7039 ASCO 2006
Conclusions for Abstract 7039
Findings
• Exploratory analysis in 2 phase III trials (STELLAR 3 and
4) showed that pre-menopausal women had a survival
benefit when treated with PPX (HR 0.54, p=0.039)
Limitations
• Limited by retrospective analysis
Conclusion
• Provocative hypothesis requiring prospective validation
• PIONEER is a phase III trial randomizing patients to
paclitaxel or PPX and will stratify chemo-naïve women by
menopausal status
BR.21 Treatment Schema
Stratified by:
• Center
• Performance status (0/1 vs
2/3)
• Response to prior Rx
(CR/PR:SD:PD)
• Prior regimens (1 vs 2)
• Prior platinum (Yes vs no)
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N
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*
2
Erlotinib
150 mg daily
1
Placebo
150 mg daily
•Primary endpoint: Improvement in overall survival of 33%
•Secondary endpoints include PFS, ORR, duration of response,
QOL, and safety
SD=stable disease; PD=progressive disease;* 2:1 randomization.
Shepherd et al. NEJM 353: 123-132, 2005
BR.21: Survival by Gender
1.00
Males
HR=0.80 (95% CI, 0.59-1.07)
Survival distribution function
Survival distribution function
Females
Erlotinib (n=173)
RR=14.4%
0.75
0.50
0.25
1.00
HR=0.76 (95% CI, 0.62-0.94)
Erlotinib (n=315)
RR= 6%
0.75
0.50
0.25
0
0
0
5
10
15
Months
*Retrospective Analysis
BR.21 study report; on file.
20
25
TARCEVA
Placebo
0
5
10
15 20
Months
25
30
Shepherd et al. NEJM 353: 123-132, 2005
Outline
Gender
Epidemiology
Female NSCLC incidence and trends
Etiology
Behavioral
Hormonal
Genetic
Treatment
differences
Chemotherapy
Targeted Therapies
Future
Studies
Hormone therapy
Pilot trial of gefitinib + fulvestrant in postmenopausal women with NSCLC
NSCLC
Postmenopausal
female
IIIB/IV
ECOG PS 0-1
> 2 lines prior
therapy
Gefitinib 250 mg po daily
Fulvestrant 250 mg IM monthly*
Fulvestrant is a pure ER antagonist that blocks ERa and ERb
*Initial 18 pts received 250 mg fulvestrant IM monthly, the last 4 pts received
fulvestrant 500 mg IM loading dose day 1, then 250 mg IM days 15 and 29, then 250
mg IM every 28 days thereafter. 1 cycle = 28 days.
N=22
Primary endpoint: safety/tolerability in post-menopausal women
Secondary endpoint: RR, PFS, OS
Correlative assays: tumor IHC, EGFR mutation, EGFR amplification (FISH)
Traynor et al. Lung Cancer 64: 51-59, 2009
Patient characteristics
Demographic
Number (N)
Patients
22
Median Age (range)
66 (56-81)
PS
0
1
2
10
9
3
Lines of prior therapy
0
1
>2
8
6
8
Histology
Adenocarcinoma
NSCLC – NOS
SCC
BAC
8
6
4
4
Smoking history
Never
Former
Current
7
13
2
Traynor et al. Lung Cancer 64: 51-59, 2009
Results
Outcomes
ORR
Patient number or %
15%
CR
PR
SD
PD
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0
3
11
6
PFS
12 weeks
OS
38.5 weeks
All 3 responders were never-smokers – 2 of the 3 were
treatment naïve.
No statistically significant difference in outcomes by
correlatives seen.
However,although not statistically significant, more
intense ERb IHC expression led to a longer median OS
65.5 weeks versus 21 weeks (p=0.52)
Traynor et al. Lung Cancer 64: 51-59, 2009
Future studies
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Phase II erlotinib +/- fulvestrant (UCLA/TPRI network)
Dose escalation trial of vandetanib + fulvestrant
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Both studies intend to enroll pre- and post-menopausal women and men to
evaluate the role of estrogen blockade in NSCLC.
Phase II maintenance bevacizumab +/- fulvestrant and
anastrazole in post-menopausal women (University of
Pittsburgh)
Tsao Conclusions
•Gender differences exist in NSCLC.
•Women may be susceptible to the
NSCLC
Gender
effects of tobacco smoke and/or may be
more likely to develop NSCLC as
evidenced by the higher rate of neversmoking females.
•Women usually have improved survival
when compared to men with NSCLC, but
distinct treatment differences are found
with the new targeted therapies. This
has not been clarified yet, but is
consistently observed.
•Hormonal status may be important. And
targeted therapy and hormonal studies
are underway.