Department of Thoracic/Head & Neck Medical Oncology 18 th Annual NOCR meeting Lung Cancer and Gender Anne S. Tsao, M.D. Associate Professor February 2012 The University of Texas MD ANDERSON CANCER CENTER Director, Mesothelioma Program Director, Thoracic Chemo-XRT Program

Gender Epidemiology Female NSCLC incidence and trends Outline Etiology Behavioral Hormonal Genetic Treatment differences Chemotherapy Targeted Therapies Hormone therapy Future Studies

Siegal et al. CA Cancer, 2012 online USA 2012

Jemal et al. CA Cancer, 61 (2): 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 tobacco 1 Women are more likely to have adenocarcinoma, while men have SCC 2 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. 3 E1594 Study Women (n=431) had median OS 9.2 months vs. Men 7.4 months (n= 726), p= Siegfried J. Lancet Oncology, 2: , August 2001; 2 Ferguson M, et al. Ann Thorac Surg 69: , 2000; 3 Wakelee H et al. JTO 2006; 1:

Gender Epidemiology Female NSCLC incidence and trends Outline Etiology Behavioral Hormonal Genetic Treatment differences Chemotherapy Targeted Therapies Hormone therapy Future Studies

Behavioral – smoking practice Overall smoking rates have declined by half since the mid- 20 th century; but due to the increase in USA population, the overall number of smokers is the same. Proportion of smoking women has increased from 40%; and 50% of all new smokers are women. 1 ~25% US women currently smoke 1 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 pregnancies 2 1 Siegfried J. Lancet Oncology, 2: , August 2001; 2 DiFranza J, et al. J fam Prac 40: , 1995

Hormonal – Proposed theories Exogenous and endogenous estrogen may impact on NSCLC development 1,2 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: , 1994; 2 Siegfried J. Lancet Oncology, 2: , 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 exposure 1 Decreased DNA repair capacity 1,2 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 adenocarcinoma 2 1 Kure E, et al. Carcinogenesis 17: , 1996; 2 Siegfried J. Lancet Oncology, 2: , August 2001; 3 Mollerup et al. AACR 1998, 337; 4 Shriver M, et al. JNCI 92: 24-33, 2000, 5 Tang D et al. Carcinogenesis. 19: , 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 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: ; Wu et al. J Thorac Oncol. 2007;2:

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 RANDOMIZERANDOMIZE Gefitinib (250 mg/day) Offered carboplatin/paclitaxel on progression Carboplatin (AUC 5 or 6) + Paclitaxel (200 mg/m 2 ) 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 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.

Probability of PFS PFS Gefitinib Carboplatin/paclitaxel Months Probability of Survival 24 OS* Months IPASS: Results in ITT Population GefitinibC/P No. of Pts Events453 (74.4%)497 (81.7%) Median PFS 5.7 mos5.8 mos HR=0.74; P< Mo PFS25%7% GefitinibC/P Events223 (36.6%)227 (37.3%) ORR43.0%32.2% Median OS 18.6 mos17.3 mos HR=0.91; P=NR 12-Mo OS68%64% C/P=carboplatin/paclitaxel; ITT=intent to treat. Reproduced with permission from Mok. N Engl J Med. 2009;361:947. *Follow-up ongoing. Gefitinib Carboplatin/paclitaxel

Time From Randomization (Months) Probability of PFS 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< Carboplatin/paclitaxel, HR=0.78; P= Adapted with permission from Mok. N Engl J Med. 2009;361:947; Mok. ESMO (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 2 nd /3 rd 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 response ORR 51.1% SD 34% DCR week 6 85% week 12 74% PD7.5% Tumor response Crizotinib was FDA approved for use in pre-treated EML4 ALK patients.

Outline Gender Epidemiology Female NSCLC incidence and trends Etiology Behavioral Genetic Hormonal Treatment differences Chemotherapy Targeted Therapies Hormone therapy Future Studies

ASCO Abstract 7036: ECOG 4599 subset analysis of survival by gender (PC) Paclitaxel 200 mg/m 2 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% Measurable vs non-measurable Brahmer et al., Abstract 7036 ASCO 2006

ECOG 4599 Response Rates MaleFemale Status PC (n=230) PCB (n=191) P-value PC (n=162) PCB (n=190) P-value CR01 (0.5%) 1 (0.6%) 3 (1.6%) PR 36 (15.7%) 54 (28.3%) 22 (13.6%) 75 (39.5%) ORR 36 (15.7%) 55 (28.8%) (14.2%) 78 (41.1%) < Stable (≥ 39 days) 96 (41.7%) 79 (41.4%) 77 (47.5%) 61 (32.1%) Brahmer et al., Abstract 7036 ASCO 2006 Both men and women have improvement in response rates with bevacizumab

ECOG 4599 PFS by gender GroupPCB/PC Hazard Ratio 95% Conf Interval P-value Overall0.66(0.57, 0.77)< Males0.64(0.53, 0.78)< Females0.71(0.57, 0.88)0.002 Brahmer et al., Abstract 7036 ASCO 2006 PCPCBP-value Overall10.3 mo.12.3 mo Males8.7 mo.11.7 mo Females13.1 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 TypeMaleFemaleMaleFemale Non-Chemo51 (12%)26 (6%)29 (7%)31 (7%) Chemotherapy116 (27%)89 (20%)100 (24%)85 (20%) Not specified001(<1%)0 Nothing reported 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 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 AgeCarbo-paclitaxel- bevacizumab Carbo-paclitaxelP-value <60 years15.5 months11 months0.12 <45 years (n=19)16.8 months5.8 months0.07 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 RANDOMIZE Carboplatin AUC 6 Paclitaxel 225 mg/m 2 Q3wks Eligibility Criteria: Chemo-naïve Advanced NSCLC PS 2 Stratified by: Stage gender brain mets geography STELLAR 3 N=400 STELLAR 4 N=381 RANDOMIZE RANDOMIZE PPX 175 mg/m 2 Q3wks Gemcitabine 1000 mg/m2 days 1,8,15 every 4 wks or vinorelbine 30 mg/m 2 days 1, 8, 15 every 3 wks Eligibility Criteria: Chemo-naïve Advanced NSCLC PS 2 Stratified by: Stage gender brain mets geography Carboplatin AUC 6 PPX 210 mg/m 2 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

Ross et al., Abstract 7039 ASCO 2006 Gender Differences in OS Women treated with PPX have a survival benefit HR = 0.70, p=0.03.

Women > 55yrsWomen < 55yrs Ross et al., Abstract 7039 ASCO 2006 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

Ross et al., Abstract 7039 ASCO 2006 Median OS HRP-value 1-yr survival PPXControlPPXcontrol Pre-menopausal STELLAR %22% STELLAR 4NE %16% Composite %19% Post-menopausal STELLAR 3NE %36% STELLAR %17% Composite %30% Subgroup Analysis by Menopause 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

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) Erlotinib 150 mg daily Placebo 150 mg daily R A N D O M I Z E * 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: , 2005

BR.21: Survival by Gender BR.21 study report; on file. Survival distribution function FemalesMales Erlotinib (n=173) RR=14.4% HR=0.80 (95% CI, ) Months Erlotinib (n=315) RR= 6% HR=0.76 (95% CI, ) Survival distribution function TARCEVA Placebo *Retrospective Analysis Shepherd et al. NEJM 353: , 2005

Outline Gender Epidemiology Female NSCLC incidence and trends Etiology Behavioral Hormonal Genetic Treatment differences Chemotherapy Targeted Therapies Hormone therapy Future Studies

Pilot trial of gefitinib + fulvestrant in post- menopausal women with NSCLC NSCLC Post- menopausal female IIIB/IV ECOG PS 0-1 > 2 lines prior therapy N=22 Gefitinib 250 mg po daily Fulvestrant 250 mg IM monthly* Primary endpoint: safety/tolerability in post-menopausal women Secondary endpoint: RR, PFS, OS Correlative 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 characteristics DemographicNumber (N) Patients22 Median Age (range)66 (56-81) PS Lines of prior therapy 0 1 > Histology Adenocarcinoma NSCLC – NOS SCC BAC Smoking history Never Former Current Traynor et al. Lung Cancer 64: 51-59, 2009

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) OutcomesPatient number or % ORR CR PR SD PD 15% PFS12 weeks OS38.5 weeks Traynor et al. Lung Cancer 64: 51-59, 2009

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