Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content.

Select slides from the original presentation are omitted where Research

To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual

reference materials have been provided for your use in place of any omitted slides.

Non-Small Cell Lung CancerYear in Review 2012

Corey J Langer, MDDirector of Thoracic Oncology

Abramson Cancer Center

Professor of Medicine

University of Pennsylvania

Vice Chair, Radiation Therapy Oncology Group

Have you attempted to obtain a ROS1 mutational analysis for any of your patients with non-small cell lung cancer (NSCLC)?

Clinical Activity of Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring ROS1 Gene Rearrangement

Shaw AT et al.Proc ASCO 2012;Abstract 7508

ROS1

• New “driver” mutation: ROS1

• ROS1: 18/1,073 (1.7%) tumors

• Receptor Tyrosine Kinase

• ATP binding like ALK

– 77% identical

• Detected by Break-apart FISH

• Younger pts

• Never-smokers

• Adenocarcinoma

Bergethon JCO 30:863, 2012: Janne JCO 30:878; 2012

ROS1 — Crizotinib Activity

• ROS1 included in crizotinib dose escalation

• At 250 mg bid dosing

• Reported on 15 pts

• 7/15 had PR; 1 CR and only 1 with PD

• Very similar RR and toxicity as in ALK+ pts

Clinical tumor responses in ROS1+ NSCLC treated with crizotinib

• Restaging scans at 8 weeks demonstrated near complete resolution of multifocal lung tumor, which was subsequently confirmed at 12 weeks1

• 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib2

1. Bergethon et al. JCO 20122. Davies et al., accepted AACR 2012

Crizotinib 250 mg po BIDcontinuous daily dosing

Key eligibility criteria:

•ALK+ NSCLC by central laboratory

– Local test allowed on case-by-case basis per protocol amendment (January 2011)

•ECOG PS: 0–3

•≥1 prior line of chemotherapy

•Stable/controlled brain metastases allowed

Primary endpoints:

•ORR

•safety/tolerability

Secondary endpoints include:

•OS

•PFS

•Duration of response

•Time to response

•PRO/HRQOL

Treatment

Phase II, single-arm, multicenter study; ~1100 patients (enrollment ongoing)

Study Design

Riely G et al. Chicago IASLC/ASTRO 2012;Abstract 3.

Patient CharacteristicsMature population

(n=261)Overall population

(n=901)

Median age, years (range) 52.0 (24.0–82.0) 53.0 (18–83.0)

Women, n (%) 142 (54.4) 514 (57.0)

Baseline ECOG PS, n (%) 0-1

23

216 (82.8) 42 (16.1)

3 (1.1)

736 (81.7)134 (14.9)

31 (3.4)

Adenocarcinoma histology, n (%) 245 (93.9) 826 (91.7)

Smoking status, n (%) Never smoker

Former/current smoker

176 (67.4) 85 (32.6)

592 (65.7)309 (34.3)

Prior therapies, n (%)012≥3

0 (0) 32 (12.3) 91 (34.9) 138 (52.8)

3 (<1.0)248 (27.5)299 (33.2)351 (39.0)

Riely G et al. Chicago IASLC/ASTRO 2012;Abstract 3.

Best Response of Indicator Lesions

100

80

60

40

20

0

–20

–40

–60

–80

–100

–120

Dec

reas

e o

r in

crea

se f

rom

b

asel

ine

(%)

*n=240 response-evaluable patients from the mature population, and excludes patients with early death, indeterminate response and non-measurable disease ^ Responses observed in untreated CNS mets+Per RECIST 1.1, percent change from baseline for subjects with best overall response of CR can be less than 100% when lymph nodes are included as target lesions

PD SD PR^ CR+

++

++

Mature population*

Status Response-evaluable patients n=259

Complete Response 4 (2%)

Partial Response 151 (58%)

Stable Disease 69 (27%)

Progressive Disease 19 (7%)

With permission from Riely G et al. Chicago IASLC/ASTRO 2012;Abstract 3.

ESMO 2012 – NSCLC

• PROFILE 1007: Phase III study of crizotinib vs pemetrexed or docetaxel chemotherapy in advanced ALK-positive NSCLC. Shaw AT et al. Abstract LBA1_PR.– Median PFS: 7.7 mo vs 3.0 mo (HR 0.49; P<0.0001)

– ORR: 65% vs 20% (P<0.0001)

– These findings establish crizotinib as the standard of care for pts with previously treated advanced ALK-positive NSCLC

A 60-year-old patient with adenocarcinoma of the lung, PS 0 and exon 19 EGFR mutation experiences a 1-year response to erlotinib but then develops slow, objective, asymptomatic disease progression. What is your likely approach?

In a recent Phase III study, afatinib was shown to be superior to __________ as first-line treatment for patients with advanced EGFR mutation-positive NSCLC.

Erlotinib versus Standard Chemotherapy as First-Line Treatment for European Patients with Advanced EGFR Mutation-Positive Non-Small-Cell Lung Cancer (EURTAC): A Multicentre, Open-Label, Randomised Phase 3 TrialRosell R et al.

Lancet Oncology 2012;13(3):239-46.

EURTAC Study Design

Primary endpoint• Progression-free survival (PFS)

– interim analysis planned at 88 events

Secondary endpoints• Objective response rate• Overall survival (OS)• Location of progression• Safety• EGFR mutation analysis in serum• Quality of life

ECOG = Eastern Cooperative Oncology Group; PS = performance status; PD = progressive disease*Cisplatin 75mg/m2 d1 / docetaxel 75mg/m2 d1; cisplatin 75mg/m2 d1 / gemcitabine 1250mg/m2 d1,8;carboplatin AUC6 d1 / docetaxel 75mg/m2 d1; carboplatin AUC5 d1 / gemcitabine 1000mg/m2 d1,8

• Chemonaїve

• Stage IIIB/IV NSCLC

• EGFR exon 19 deletion or exon 21 L858R mutation

• ECOG PS 0–2

(n = 174)

R

Platinum-based doublet chemotherapy q3wks

x 4 cycles*PD

Erlotinib 150mg/day PD

Stratification

• Mutation type

• ECOG PS (0 vs 1 vs 2)

PFS in ITT Population

PFS:

• Erlotinib (n = 86), 9.7 months

• Chemotherapy (n = 87), 5.2 months

– HR = 0.37 (0.25-0.54)

– Log-rank p<0.0001 (data cut-off 1-26-11)

OS HR 1.04, NS; MST 19.3mo-E vs 19.5mo-C

Rosell R et al. Lancet Oncology 2012;13(3):239-46.

EGFR TKI vs Platinum-Based TherapyTrial Comparison ORR PFS (HR) OS

IPASS*(n = 261)

Gefitinib vs.Carbo/paclitaxel

71.2% vs. 47.3% P < .001

0.48, P < .0019.5 vs. 6.3 mos

HR 1.00, P = .990MST 21.6 vs. 21.9 mos

NEJSG(n = 200)

Gefitinib vs.Carbo/paclitaxel

73.7% vs. 30.7% P < .001

0.30, P < .00110.8 vs. 5.4 mos

MST 30.5 vs. 23.6 mos P = .31

WJTOG(n = 172)

Gefitinib vs.Cisp/doc

62.1% vs. 32.2% P < .0001

0.49, P < .00019.2 vs. 6.3 mos

Not available

CTONG(n = 165)

Erlotinib vs. Carb/gem

83.0% vs. 36% P < .0001

0.16, P < .00113.1 vs. 4.6 mos

Not available

1st-signal*(n = 42)

Gefitinib vs.Cisp/gem

84.6% vs. 37.5% P = .002

0.61, P = .0848.4 vs. 6.7 mos

HR = 0.823, P = .64830.6 vs. 26.5 mos

EURTAC(n = 174)

Erlotinib vs.Platinum doublet

58% vs. 15% 0.37, P < .00019.7 vs. 5.2 mos

HR = 1.04, P = .8719.3 vs. 19.5 mos

Mok et al. NEJM 2009; Fukuoka et al. JCO 2011; Maemondo et al. NEJM 2010; Mitsudomi et al. Lancet Oncology 2010; Zhou et al. Lancet Oncology 2011; Lee 13th WLC 2009, Rosell et al. Lancet Oncology 2012

* Numbers represent EGFR mutation positive subsets

LUX-Lung 3: A Randomized, Open-Label, Phase III Study of Afatinib vs Cisplatin/Pemetrexed as 1st-Line Treatment for Patients with Advanced Adenocarcinoma of the Lung Harboring EGFR-Activating Mutations

Yang JCH et al.

Proc ASCO 2012;Abstract LBA7500.

LUX LUNG3 Study Design

Randomization 2:1 Stratified by:

EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian)

Afatinib 40 mg/day†

Cisplatin + Pemetrexed 75 mg/m2 + 500 mg/m2

i.v. q21 days, up to 6 cycles

Primary endpoint: PFS (RECIST 1.1, independent review)Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, PRO, safety, PK

Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6)

EGFR mutation in tumor(central lab testing; Therascreen EGFR29 RGQ PCR)

Yang JC et al. Proc ASCO 2012;Abstract LBA7500.

72% Asian, 65% women, 68% NS49% del19, 40% L858R, 11% other

Primary Endpoint: PFS Independent review — all randomized patients

Pro

gre

ssio

n-f

ree

surv

ival

(p

rob

abil

ity)

1.0

0.8

0.6

0.4

0.2

0.0

Progression-free survival (months)0 3 6 9 12 15 18 21 24 27

Afatinib

n = 230

Cis/pem n = 115

PFS event, n (%) 152 (66) 69 (60)

Median PFS (months) 11.1 6.9

Hazard ratio(95% confidence interval)

0.58 (0.43–0.78)p = 0.0004

47%

22%

HR 0.47 if “other”excluded

With permission from Yang JC et al. Proc ASCO 2012;Abstract LBA7500.

Most Frequent Related Adverse Events>20% difference between treatment arms

Afatinib (n = 229)

Cis/pem (n = 111)

All Gr† (%) Gr 3 (%) Gr 4 (%) All Gr† (%) Gr 3 (%) Gr 4 (%)

Diarrhea 218 (95.2) 33 (14.4) 0 17 (15.3) 0 0

Rash/acne* 204 (89.1) 37 (16.2) 0 7 (6.3) 0 0

Stomatitis/mucositis* 165 (72.1) 19 (8.3) 1 (0.4) 17 (15.3) 1 (0.9) 0

Paronychia 130 (56.8) 26 (11.4) 0 0 0 0

Dry skin 67 (29.3) 1 (0.4) 0 2 (1.8) 0 0

Nausea 41 (17.9) 2 (0.9) 0 73 (65.8) 4 (3.6) 0

Decreased appetite 47 (20.5) 7 (3.1) 0 59 (53.2) 3 (2.7) 0

Fatigue* 40 (17.5) 3 (1.3) 0 52 (46.8) 14 (12.6) 0

Vomiting 39 (17.0) 7 (3.1) 0 47 (42.3) 3 (2.7) 0

Neutropenia 2 (0.9) 1 (0.4) 0 35 (31.5) 17 (15.3) 3 (2.7)

Anemia 7 (3.1) 1 (0.4) 0 31 (27.9) 5 (4.5) 2 (1.8)

* Grouped term. † No grade 5 events for the presented AEs.

Yang JC et al. Proc ASCO 2012;Abstract LBA7500.

SELECT: A Multicenter Phase II Trial of Adjuvant Erlotinib in Resected EGFR Mutation Positive NSCLCJoel Neal1, Nathan Pennell2, Ramaswamy Govindan3, Rebecca Heist4, Alice Shaw4, Alona Muzikansky4, Pasi Jänne5, Thomas Lynch6, Jerry Azzoli4,7, Lecia Sequist4

Proc ASCO 2012;Abstract 70101 Stanford Cancer Institute, Stanford, CA ; 2 Cleveland Clinic, Cleveland, OH; 3 Washington University, St. Louis, MO; 4 Massachusetts General Hospital, Boston, MA; 5 Dana-Farber Cancer Institute, Boston, MA; 6 Yale Cancer Center, New Haven, CT; 7 Memorial Sloan-Kettering Cancer Center, New York, NY

SELECT: Study Design

2 years duration

CT surveillance: - Every 6 mo x 3 years - Annually years 4 and 5

ObservationErlotinib

150 mg PO daily

Primary Endpoint: •Disease Free Survival:

Goal: 2-year >86%Secondary Endpoints:•Safety and Tolerability•Overall Survival

• Single arm Phase II study • Adjuvant erlotinib following surgery and “standard” therapy

• Stage IA-IIIA NSCLC

• Surgically resected

• EGFR mutation positive

• Completed routine adjuvant chemotherapy and/or XRT

Total N = 100This report on 36 pts

With permission from Neal J et al. Proc Chicago Multidisciplinary Symposium in Thoracic Oncology 2012;Abstract 16.

SELECT: Disease Free Survival

Patients at Risk 36 35 34 34 33 19 7 3 1 0

Time from initiating adjuvant erlotinib (Years)

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Surv

ival

Pro

babi

lity

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Median follow-up time: 2.7 years

Censored observation

What is your usual front-line and maintenance strategy for patients with EGFR wild-type tumors without contraindications to bevacizumab?

Carbo/pemetrexed/bev

bev/pemetrexed

Carbo/pemetrexed/bev

pemetrexed

Carbo/pemetrexed/bev bev

Carbo/paclitaxel/bev

pemetrexed/bev

Carbo/paclitaxel/bev pemetrexed

Carbo/paclitaxel/bev bev

A Randomized, Open-Label, Phase III, Superiority Study of Pemetrexed (Pem) + Carboplatin (Cb) + Bevacizumab (Bev) Followed by Maintenance Pem + Bev versus Paclitaxel (Pac) + Cb + Bev Followed by Maintenance Bev in Patients with Stage IIIB or IV Non-Squamous Non-Small Cell Lung Cancer (NS-NSCLC)

Patel JD et al.2012 Chicago Multidisciplinary Symposium in Thoracic Oncology;Abstract LBPL1.

Inclusion:- No prior systemic

therapy for lung cancer

- PS 0/1

- Stage IIIB-IV NS-NSCLC

- Stable tx’t brain mets

Exclusion:- Peripheral neuropathy

≥ Gr 1

- Uncontrolled pleural effusions

PointBreak: Study Design

Induction Phaseq21d, 4 cycles

Maintenance Phase q21d until PD

Pemetrexed (folic acid & vitamin B12)

+ Carboplatin + Bevacizumab

Paclitaxel + Carboplatin + Bevacizumab

R1:1

Stratified for:

PS (0 vs 1); sex (M vs F); disease stage (IIIB vs IV); measurable vs nonmeasurable disease

Note Randomization BEFORE initiation of therapy

• Randomized, open-label, Phase III superiority study conducted in US • Pemetrexed 500 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg• Paclitaxel 200 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg

Pemetrexed (folic acid & vitamin B12)

+ Bevacizumab

Bevacizumab

450 patients each

Two POINT-BREAK Questions:• Would it POINT the way to a new treatment paradigm?• If Pemetrexed/Bevacizumab became a new standard

during induction and maintenance, would the combination BREAK the bank?

0 3 6 9 12 15 18 21 24 27 30 33 36 39

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time from Induction (Months)

Su

rviv

al

Pro

ba

bil

ity

PointBreak: Kaplan-Meier (KM) OS from Randomization (ITT)

Pem+Cb+Bev Pac+Cb+Bev

OS median (mo) 12.6 13.4

HR (95% CI); P value 1.0 (0.86, 1.16); P=0.949

Censoring (%) 27.8 27.2

Survival rate (%)

1-year 52.7 54.1

2-year 24.4 21.2

With permission from Patel J et al. Chicago IASLC/ASTRO 2012;Abstract LBPL1.

Carboplatin-Based, Bevacizumab-Based Trials in Advanced NSCLC

Study China1 E45992 Patel3 Penn4 POINT-BREAK5

No 151 140 417 51 43 472 467

Bev 7.5 15 15 15 15 15 15

CbPac +++ +++ +++ +++

CbGem +++ +++

CbPem +++ +++ +++

Maint B B B BP B BP B

OR % 37 46.4 35 55 47 34 33

PFS mo 6.8 6.7 6.2 7.8 7.1 6.0 5.6

OS mo 13.4 13.7 12.2 14.1 17.1 12.6 13.4

1Mok et al, ESMO 20112Sandler et al, NEJM 20063Patel et al, JCO 20094Stevenson, Cancer 20115Patel et al, Chicago IASLC/ASTRO, 2012

Carboplatin-Based, Bevacizumab-Based Trials in Advanced NSCLC

Study China1 E45992 Patel3 Penn4 POINT-BREAK5

No 151 140 417 51 43 472 467

Bev 7.5 15 15 15 15 15 15

CbPac +++ +++ +++ +++

CbGem +++ +++

CbPem +++ +++ +++

Maint B B B BP B BP B

OR % 37 46.4 35 55 47 34 33

PFS mo 6.8 6.7 6.2 7.8 7.1 6.0 5.6

OS mo 13.4 13.7 12.2 14.1 17.1 12.6 13.4

1Mok et al, ESMO 20112Sandler et al, NEJM 20063Patel et al, JCO 20094Stevenson, Cancer 20115Patel et al, Chicago IASLC/ASTRO, 2012

0 3 6 9 12 15 18 21 24 27 30 33 36

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time from Induction (Months)

Su

rviv

al

Pro

ba

bil

ity

PointBreak: KM PFS from Randomization (ITT)

Pem + Cb + Bev

Pac + Cb + Bev

PFS median (mo) 6.0 5.6

HR (95% CI); p-value 0.83 (0.71, 0.96); p = 0.012

ORR (%) 34.1 33.0

Exploratory analysisCensoring rate for Pem + Cb + Bev was 26.9%; for Pac + Cb + Bev was 23.3%

OS median (mo) 12.6 13.4

HR (95% CI); p-value 1.00 (0.86, 1.16); p = 0.949 Survival rate (%)

1-year 52.7 54.1

2-year 24.4 21.2

With permission from Patel JD et al. 2012 Chicago Multidisciplinary Symp in Thoracic Oncol;Abstract LBPL1.

0 3 6 9 12 15 18 21 24 27 30 33 36 39

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time from Induction (Months)

Su

rviv

al P

rob

ab

ilit

y

PointBreak: Pre-specified Exploratory Analysis of KM OS from Randomization: Maintenance Group

Pem + Cb + Bev

(n = 292)Pac + Cb + Bev

(n = 298)

OS median (mo) 17.7 15.7

Pre-specified exploratory non-comparative subgroup analysesCensoring rate for Pem + Cb + Bev was 36.0%; for Pac + Cb + Bev was 30.2%

With permission from Patel JD et al. 2012 Chicago Multidisciplinary Symp in Thoracic Oncol;Abstract LBPL1.

Bevacizumab

Bevacizumab + Pemetrexed

Pemetrexed

ECOG-E5508: Phase III Study of Maintenance Bevacizumab, Pemetrexed

or the Combination in NSCLC

R

Target Accrual: 1,282 Study Start Date: August 2010

Eligibility• Stage IIIB/IV• Nonsquamous• NSCLC• No brain mets• ≥ stable or response

after carbo/paclitaxel + bevacizumab

Primary Endpoint: Overall survival

www.clinicaltrials.gov, October 2012

Multidisciplinary Symposium in Thoracic Oncology 2012 (ASCO) 06-08 September 2012

Hirsch V et al. Weekly nab-Paclitaxel in Combination with Carboplatin as First-Line Therapy in Patients (pts) with Advanced Non-Small Cell Lung Cancer(NSCLC): Analysis of Patient-Reported Neuropathy and Taxane-Associated Symptoms. Abstract 108; Thoracic Oncology 2012

Socinski MA et al. Weekly nab-Paclitaxel In Combination With Carboplatin As First-line Therapy In Elderly Patients (pts) With Advanced Non-small Cell Lung Cancer (NSCLC). Abstract 109; Thoracic Oncology 2012.

Renschler MF et al. Safety and Efficacy by Histology of Weekly nab-Paclitaxel in Combination with Carboplatin as First-line Therapy in Patients (pts) with Advanced Non-Small Cell Lung Cancer (NSCLC). Abstract 110; Thoracic Oncology 2012

October 15, 2012

• The FDA has approved nab-paclitaxel plus carboplatin for patients with untreated locally advanced or metastatic non-small cell lung cancer (NSCLC) who are not candidates for surgery or radiation

• The approval was based on results from the phase III CA031 trial, which showed that weekly nab-paclitaxel combined with carboplatin significantly improved overall response rate (ORR), when compared with solvent-based (sb) paclitaxel plus carboplatin

Source: FDA Press Release

What is your usual first-line chemotherapy regimen for patients with metastatic squamous cell NSCLC?

Carboplatin/nanoparticle albumin-bound (nab) paclitaxel

Other

Carboplatin/pemetrexed

Carboplatin/gemcitabine

Carboplatin/paclitaxel

Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients with Advanced Non-Small-Cell Lung Cancer

J.R. Brahmer,1 L. Horn,2 S.J. Antonia,3

D. Spigel,4 L. Gandhi,5 L.V. Sequist,6 J.M. Wigginton,7 D. McDonald,7 G. Kollia,7 A. Gupta,7 S. Gettinger8

1Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD; 2Vanderbilt-Ingram Cancer Center, Nashville, TN; 3H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 4Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; 5Dana-Farber Cancer Institute, Boston, MA; 6Massachusetts General Hospital Cancer Center, Boston, MA; 7Bristol-Myers Squibb, Princeton, NJ; 8Yale University School of Medicine, New Haven, CT

Proc ASCO 2012;Abstract 7509.

Response of Metastatic NSCLC (BMS-936558, 10 mg/kg)

• Initial progression in pulmonary lesions of a NSCLC patient with non-squamous histology was followed by regression

• Dx ‘04, EGFR mutation+; Rx gem/carbo, erlotinib, erlotinib + LBH589 (trial for T790 mutation), and lastly pemetrexed

With permission from Brahmer JR et al. Proc ASCO 2012;Abstract 7509.