Department of Thoracic/Head & Neck Medical Oncology 18 th Annual NOCR meeting Lung Cancer and Gender...

Department of Thoracic/Head & Neck Medical Oncology

18th Annual NOCR meeting

Lung Cancer and Gender

Anne S. Tsao, M.D.

Associate ProfessorFebruary 2012

The University of TexasMD ANDERSON CANCER CENTER

Director, Mesothelioma Program

Director, Thoracic Chemo-XRT Program

Gender Epidemiology

Female NSCLC incidence and trends

Outline

EtiologyBehavioralHormonalGenetic

Treatment differences

ChemotherapyTargeted Therapies

Hormone therapyFuture Studies

Siegal et al. CA Cancer, 2012 online

US

A 2

012

Jemal et al. CA Cancer, 61 (2): 69-90. Marhc/April 2011

Gender differences in Lung Cancer

• 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 never-smoking women than never-smoking men.• Different distribution rates of EGFR mutation, EML 4 ALK, KRAS

mutation between genders

• Treatment differences: women have better outcomes than men after surgery and chemotherapy.• 3E1594 Study Women (n=431) had median OS 9.2 months vs. Men

7.4 months (n= 726), p=0.004

1Siegfried 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

Gender Epidemiology


Outline





Behavioral – smoking practice• Overall smoking rates have declined by half since the mid-20th

century; but due to the increase in USA population, the overall number of smokers is the same. • Proportion of smoking women has increased from <25% to >40%; and 50%

of all new smokers are women.1

• ~25% US women currently smoke1

• 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• 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

• Exogenous and endogenous estrogen may impact on NSCLC development1,2

• 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 (ER) 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

1 Taioli E, et al. JNCI 84: 869-870, 1994; 2Siegfried J. Lancet Oncology, 2: 506-13, August 2001

Genetic Susceptibility

• 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

• EGFR mutation

• EML-4 ALK

EGFR mutations

• Found in 10% - 15% of all lung cancer patients and 85% who clinically respond to EGFR TKIs

• Found more commonly in never-smokers, adenocarcinomas, BAC, women, Asians

• Predominantly located in EGFR exons 19 - 21

• EGFR mutations are not the same. There are sensitive mutations and acquired resistance mutations (T790M).

• 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 lightex-smoker* withadenocarcinoma

histology

PS 0-2

Stage IIIB or IVchemotherapy-naïve

NSCLCN=1217

RANDOMIZE

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 tolerabilityExploratory: biomarkers – EGFR mutation, gene copy number, and protein expression

Mok. N Engl J Med. 2009;361:947.

*Never smoker=smoked <100 cigarettes in lifetime; light ex-smoker=stopped ≥15 years ago and smoked ≤10 pack-years.

0 4 8 12 16 20 240.0

0.2

0.4

0.6

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PFSGefitinibCarboplatin/paclitaxel

Months0 4 8 12 16 20 28

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OS*

Months

IPASS: Results in ITT Population

Gefitinib C/P

No. of Pts 609 608

Events 453 (74.4%) 497 (81.7%)

Median PFS5.7 mos 5.8 mos

HR=0.74; P<0.001

12-Mo PFS 25% 7%

Gefitinib C/P

Events 223 (36.6%) 227 (37.3%)

ORR 43.0% 32.2%

Median OS18.6 mos 17.3 mos

HR=0.91; P=NR

12-Mo OS 68% 64%

C/P=carboplatin/paclitaxel; ITT=intent to treat.Reproduced with permission from Mok. N Engl J Med. 2009;361:947.

*Follow-up ongoing.

GefitinibCarboplatin/paclitaxel

0 4 8 12 16 20 24Time From Randomization (Months)

0.0

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Gefitinib EGFR M+ (N=132)Gefitinib EGFR M– (N=91)Carboplatin/paclitaxel EGFR M+ (N=129)Carboplatin/paclitaxel EGFR M– (N=85)

HR <1 implies a lower risk of progression in the M+ group compared with the M– group.

IPASS: PFS by EGFR Mutation Status Within Treatment Arms

Gefitinib, HR=0.19; P<0.0001Carboplatin/paclitaxel, HR=0.78; P=0.1103

Adapted with permission from Mok. N Engl J Med. 2009;361:947; Mok. ESMO. 2008 (abstr LBA2).

M=mutation.

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

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.

EML4-ALK Fusion Gene

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

Crino et al. ASCO 2011 Abstract 7514

Phase II crizotinib in ALK-positive NSCLC

Crino et al. ASCO 2011 Abstract 7514

Best responseORR 51.1% SD 34%DCR week 6 85%

week 12 74%PD 7.5%

Tumor response

Crizotinib was FDA approved for usein pre-treated EML4 ALK patients.

Outline

Gender Epidemiology


EtiologyBehavioral

GeneticHormonal




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

(PCB)PC x 6 cycles+ Bevacizumab (15mg/kg q 3 wks) to PD

Eligibility:• Non-squamous NSCLC• No Hx of hemoptysis• No CNS metastases

No crossover to Bevacizumab permitted

Stratification Variables:•RT vs no RT•Stage IIIB or IV vs recurrent•Wt loss <5% vs >5%•Measurable vs non-measurable

Brahmer et al., Abstract 7036 ASCO 2006

ECOG 4599 Response RatesMale Female

StatusPC

(n=230)PCB

(n=191)P-value

PC (n=162)

PCB (n=190)

P-value

CR 0 1 (0.5%)1

(0.6%)3

(1.6%)

PR36

(15.7%)54

(28.3%)22

(13.6%)75

(39.5%)

ORR36

(15.7%)55

(28.8%)0.001

23 (14.2%)

78 (41.1%)

<0.0001

Stable

(≥ 39 days)96

(41.7%)79

(41.4%)77

(47.5%)61

(32.1%)


Both men and women have improvement in response rates with bevacizumab

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


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

ECOG 4599 OS by gender

Analysis of Gender Differences• 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

PCB

n=417

Type Male Female Male Female

Non-Chemo 51 (12%) 26 (6%) 29 (7%) 31 (7%)

Chemotherapy 116 (27%) 89 (20%) 100 (24%) 85 (20%)

Not specified 0 0 1(<1%) 0

Nothing reported

86 (20%) 65 (15%) 80 (19%) 91 (22%)


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

• Women < age 60 appear to derive benefit with the addition of bevacizumab to chemotherapy.

• Men of all ages had treatment benefit with bevacizumab-chemotherapy.

Median OS

Women Age Carbo-paclitaxel-bevacizumab

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

Wakelee et al., Abstract 131 IASCL 2008; JTO 3 (11) S4: S282

ASCO Abstract 7039: Gender Differences in 2 randomized phase III trials

Ross et al., Abstract 7039 ASCO 2006

RANDOMIZE

Carboplatin AUC 6 Paclitaxel 225 mg/m2

Q3wks

Eligibility Criteria:•Chemo-naïve•Advanced NSCLC•PS 2Stratified by:•Stage•gender•brain mets•geography

STELLAR 3N=400

STELLAR 4N=381

RANDOMIZE

PPX 175 mg/m2 Q3wks

Gemcitabine 1000 mg/m2 days 1,8,15 every 4 wks orvinorelbine 30 mg/m2 days 1, 8, 15 every 3 wks

Eligibility Criteria:•Chemo-naïve•Advanced NSCLC•PS 2Stratified by:•Stage•gender•brain mets•geography

Carboplatin AUC 6 PPX 210 mg/m2 Q3wks

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

PPX or Poly-(L-Glutamic Acid) – Paclitaxel

Paclitaxel Covalently linked

Poly L-glutamate


Gender Differences in OS

Women treated with PPX have a survival benefitHR = 0.70, p=0.03.

Women > 55yrsWomen < 55yrs


Subgroup Analysis by Age

Women < 55 yrs who received PPX HR 0.51, p=0.03

Women > 55 yrs who received PPX HR 0.75, p=0.134


Median OSHR P-value

1-yr survival

PPX Control 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%

Subgroup Analysis by Menopause

Pre-menopausal women had improved survival when treated with PPX over control HR=0.54, p=0.039


Survival in Pre-Menopausal Women

Conclusions for Abstract 7039Findings

• 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)

Erlotinib150 mg daily

Placebo150 mg daily

RANDOM I ZE*

SD=stable disease; PD=progressive disease;* 2:1 randomization.

2

1

•Primary endpoint: Improvement in overall survival of 33%

•Secondary endpoints include PFS, ORR, duration of response, QOL, and safety

Shepherd et al. NEJM 353: 123-132, 2005

BR.21: Survival by Gender

BR.21 study report; on file.

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Females Males

Erlotinib (n=173)RR=14.4%

HR=0.80 (95% CI, 0.59-1.07)

0 5 10 15 20 25

Months Months

0 5 10 15 20 25 30

Erlotinib (n=315)RR= 6%

HR=0.76 (95% CI, 0.62-0.94)

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TARCEVAPlacebo*Retrospective Analysis

Shepherd et al. NEJM 353: 123-132, 2005

Outline

Gender Epidemiology






Pilot trial of gefitinib + fulvestrant in post-menopausal women with NSCLC

NSCLCPost-

menopausal female

IIIB/IV

ECOG PS 0-1

> 2 lines prior therapy

N=22

Gefitinib 250 mg po dailyFulvestrant 250 mg IM monthly*

Primary endpoint: safety/tolerability in post-menopausal womenSecondary endpoint: RR, PFS, OSCorrelative assays: tumor IHC, EGFR mutation, EGFR amplification (FISH)

Fulvestrant is a pure ER antagonist that blocks ER and ER

*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.

Traynor et al. Lung Cancer 64: 51-59, 2009

Patient characteristicsDemographic Number (N)

Patients 22

Median Age (range) 66 (56-81)

PS 012

1093

Lines of prior therapy 01

> 2

868

HistologyAdenocarcinomaNSCLC – NOS

SCCBAC

8644

Smoking historyNeverFormerCurrent

7132


Results

• 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 ER IHC expression led to a longer median OS 65.5 weeks versus 21 weeks (p=0.52)

Outcomes Patient number or %

ORRCRPRSDPD

15% 03

116

PFS 12 weeks

OS 38.5 weeks


Future studies

• Phase II erlotinib +/- fulvestrant (UCLA/TPRI network)

• Dose escalation trial of vandetanib + fulvestrant• 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)

NSCLC Gender

•Gender differences exist in NSCLC.

•Women may be susceptible to the effects of tobacco smoke and/or may be more likely to develop NSCLC as evidenced by the higher rate of never-smoking 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.

Tsao Conclusions

Department of Thoracic/Head & Neck Medical Oncology 18 th Annual NOCR meeting Lung Cancer and Gender...

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