Zeroing in on Non-Small Cell Lung Cancer: Integrating Targeted Therapies into Practice.

Zeroing in on Non-Small CellLung Cancer: Integrating Targeted Therapiesinto Practice

Genomic Profiling of NSCLC forEGFR Inhibitors

Fred R. Hirsch, MD, PhDProfessor of Medicine and Pathology

University of Colorado Denver Aurora, Colorado

Presentation

Genetic profiling of lung tumors– EGFR mutations and overexpression

– K-ras mutations

Genomic profiles inform therapy and outcomes

Implications of proteomic profiling

Selection of EGFR TKIs

Clinical– Gender

– Histology

– Smoking status

– Race

Biologic– EGFR protein (IHC)

– EGFR gene (FISH)

– EGFR mutation

– K-ras mutation

IPASS—Study Design

Gefitinib(250 mg/day)

Carboplatin (AUC 5 or 6)/

paclitaxel (200 mg/m2)

3 weeklyb

1:1 randomization

PatientsPatients ChemonaiveChemonaive

Age ≥18 yearsAge ≥18 years

Adenocarcinoma Adenocarcinoma histologyhistology

Never or light Never or light ex-smokersex-smokersaa

Life expectancyLife expectancy≥12 weeks≥12 weeks

PS 0–2PS 0–2

Measurable stage Measurable stage IIIB/IV diseaseIIIB/IV disease

EndpointsEndpoints PrimaryPrimary

– Progression-free survival Progression-free survival (noninferiority) (noninferiority)

SecondarySecondary– Objective response rateObjective response rate– Overall survival Overall survival – Quality of lifeQuality of life– Disease-related Disease-related

symptoms symptoms – Safety and tolerabilitySafety and tolerability

ExploratoryExploratory– BiomarkersBiomarkers

EGFR mutationEGFR mutation EGFR-gene-copy EGFR-gene-copy

numbernumber EGFR protein EGFR protein

expressionexpression

aNever smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked <10 pack years. bLimited to a maximum of 6 cycles.

Carboplatin/paclitaxel was offered to gefitinib patients upon progression.

Abbreviations:EGFR, epidermal growth factor receptor; PS, performance status.

PFS in EGFR Mutation Positive and Negative Patients

Treatment by subgroup interaction test, P <.0001ITT population. Cox analysis with covariates.

HR (95% CI) = 2.85 (2.05, 3.98) P <.0001

No. events gefitinib, 88 (96.7%)No. events C/P, 70 (82.4%)

HR (95% CI) = 0.48 (0.36, 0.64) P <.0001


Abbreviations: C/P, carboplatin/paclitaxel; EGFR, epidermal growth factor receptor; PFS, progression-free survival.

With permission from Mok T, et al. Ann Oncol. 2008;19(suppl 8):abstract LBA2.

OSI STUDY 402—Phase II Study Schema and Results

C/Pd1 x 4;

erlotinib 150 mg/d,

d2–15N = 71

Primary endpoint = 6-month PFS rate (% of patients not progressing at 6 months).Abbreviations: C/P, carboplatin/paclitaxel; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization;

IHC, immunohistochemistry; PD, progressive disease; PFS, progression-free survival; NSCLC, non–small cell lung cancer.

Erlotinib150 mg/d

N = 72

Erlotinib150 mg/d

PD

PD

Chemonaiveadvanced NSCLCEGFR IHC and/or

FISH+N = 143

RANDOMIZE

Hirsch FR, et al. J Thorac Oncol. 2008;3(suppl 2):s138-s142.

6 Mo PFS

Median PFS

31% 2.7 mo

26% 4.6 mo

Efficacy by EGFR Mutation

CP + intercalated erlotinib (N = 6)Median: 4.90 mo6-mo rate: 41.7%

Erlotinib (N = 9)Median: 18.20 mo6-mo rate: 88.9%

HR: 3.0595% CI: (0.73, 12.65)P = .109

PF

S-E

GF

R A

cti

va

tin

g M

uta

tio

ns

Pro

ba

bil

ity

0 3 6 9 12 15 18 21 24 27 30

0.00

0.25

0.50

0.75

1.00

PFS-EGFR Activating Mutations (mo)

PF

S-E

GF

R W

T P

rob

ab

ilit

y

0 3 6 9 12 15 18 21 24 27 30

0.00

0.25

0.50

0.75

1.00

PFS-EGFR WT (mo)

CP + intercalated erlotinib (N = 45)Median: 5.06 mo6-mo rate: 30.4%

Erlotinib (N = 45)Median: 2.10 mo6-mo rate: 22.2%

HR: 0.6695% CI: (0.42, 1.03)P = .066

Kaplan-Meier Plots of PFS-EGFR Activating Mutations Kaplan-Meier Plots of PFS- EGFR WT

Hirsch FR, et al. J Thorac Oncol. 2008;3(suppl 2):s138-s142.

Erlotinib: 8 exon 19 del, 1 L858R; CP+E: 3 exon 19 del, 3 L858R

EGFR FISH in NSCLC

EGFR CEP7

Balanced disomy74 patients (40%)

Balanced trisomy70 patients (38%)

Balanced polysomy23 patients (13%)

Gene amplification16 patients (9%)

Hirsch FR, et al. J Clin Oncol. 2003;21:3798-3807.

FISH Predicts Benefit of EGFR-TKIs

Log-rank: P = .008HR = 0.44 (0.23, 0.82)

Log-rank: P = .59HR = 0.85 (0.48, 1.51)

ISEL FISH+ BR21 FISH+

Cox: P = .07HR = 0.61 (0.36, 1.04)

BR21 FISH–ISEL FISH–

Cox: P = .42 HR = 1.16 (0.81, 1.64)

Hirsch FR, et al. J Clin Oncol. 2006;24:5034-5042. Tsao MS, et al. N Engl J Med. 2005;353:133-144.

INTEREST—Study Design

Gefitinib250 mg/day

Docetaxel75 mg/m2 every

3 weeks

1:1 randomization

PatientsAge ≥18 years

Life expectancy≥8 weeks

Progressive or recurrent disease following CT

Considered candidates for further CT with docetaxel

1 or 2 CT regimens(≥1 platinum)

PS 0–2

Endpoints Primary

– Overall survival(co-primary analyses of noninferiority in all patients and superiority in patients with high EGFR gene copy number)

Secondary– Progression-free

survival– Objective response rate– Quality of life– Disease-related

symptoms– Safety and tolerability

Exploratory– Biomarkers

Kim ES, et al. Lancet. 2008;372:1809-1818.

INTEREST—OS in EGFR FISH+ Patients (Co-primary Endpoint)

8572 (84.7%)

8971 (79.8%)

nEvents

Cox analysis without covariates

HR (95% CI) = 1.09 (0.78, 1.51), P = .6199

Median OS (mo)1-y survival

8.432%

7.535%

Conclude no statistical superiorityin EGFR FISH+ patients

Gefitinib Docetaxel

85 44 26 13 10 6 4 3 0 089 42 31 22 14 7 4 1 0 0

6663

0 4 8 12 16 20 24 28 32 36 40

0.0

0.2

0.4

0.6

0.8

1.0

MonthsAt risk :

GefitinibDocetaxel

Pro

bab

ilit

y o

f S

urv

ival

Kim ES, et al. Lancet. 2008;372:1809-1818.

MARVEL—Predictive MarkerStudy Design

PFS endpoint– Less influenced by treatment crossover

– Will require synchronized treatment schedules, independent blinded imaging review

Power– 90% to detect 50% PFS improvement favoring erlotinib in FISH+

– 90% to detect 30% PFS improvement favoring pemetrexed in FISH−

– >90% to detect interaction

2nd-line NSCLC

with specimen

InitialRegistration

FISHtesting

EGFR FISH+(~30%)

EGFR FISH−(~70%)

Erlotinib

Pemetrexed

Erlotinib

Pemetrexed

Strata RandomizeOutcome

1° PFS2° OS, ORR

NCCTG, CALGB, ECOG, SWOG, NCICOthers: C-Path & industry partners, Pharma

957 patients4 years accrual, 1196 patients

1–2 years minimum additional follow-up

Proteomic Predictive Marker(Veristrat®)

Italian NSCLC patients treated with gefitinib (n = 67)

1. Generation and initial testing of predictive algorithm

2. Refinement of predictive algorithm and independent blinded validation

3. Determination of prognostic significance of algorithm in NSCLC patients not treated with EGFR TKIs

NSCLC patients treated with second-line chemotherapy—no EGFR TKI (n = 32)

Patients with advanced NSCLC—no EGFR TKI (n = 61)

Italian NSCLC patients Italian NSCLC patients treated with gefitinib treated with gefitinib (n = 70)(n = 70)

Japanese NSCLC Japanese NSCLC patients treated with patients treated with gefitinib (n = 69)gefitinib (n = 69)

Taguchi F, et al. J Natl Cancer Inst. 2007;99:838-846.

Blinded Validation in E3503—Patients Treated with Erlotinib

n = 96 Patients with Available Plasma or Serum

Taguchi F, et al. J Natl Cancer Inst. 2007;99:838-846.

Cetuximab in NSCLC

S0342—Phase II Selection Design

PaclitaxelPaclitaxelcarboplatincarboplatincetuximabcetuximabx 4 cyclesx 4 cycles

RANDOMIZE

CetuximabCetuximabweekly xweekly x

1 year1 year

Paclitaxel: 225 mg/m2 Cetuximab: 400 mg/m2 then 250 mg/m2 weeklyCarboplatin: AUC = 6

ConcurrentConcurrent

PaclitaxelPaclitaxelcarboplatincarboplatinx 4 cyclesx 4 cycles

CetuximabCetuximabweekly xweekly x

1 year1 year

SequentialSequential


S0342—Response Rate and Disease Control Rate by EGFR FISH

EGFR FISH Status

# Patients OR (CR/PR)

DCR (CR/PR/SD)

FISH– 31 26% 55%

FISH+ 45 45% 81%(P = .02)


S0342 Unselected Versus Selected

PFS OS

FISH + FISH +

With permission from Hirsch FR, et al. J Clin Oncol. 2008;26:3351-3357.

BMS 099 Treatment Schema

Advanced NSCLCChemonaive

R 1:1

Paclitaxel 225 mg/m2 d1a or

Docetaxel 75 mg/m2 d1a

+

Carboplatin AUC = 6 d1 q3wk for a maximum of 6 cycles

+

Cetuximab 400 mg/m2 d1 wk1; 250 mg/m2 weekly

Paclitaxel 225 mg/m2 d1a or

Docetaxel 75 mg/m2 d1a

+

Carboplatin AUC = 6 d1 q3wk for a maximum of 6 cycles

Stratification

Site

ECOG PS

Taxane

aChoice of taxane per individual patient, by investigator.

K-Ras Mutation Analysis—PFS

K-ras Status Cetuximab/TC TC HR (95% CI) P-value

MedianPFS

Wild type 5.1 mo 5.3 mo1.07

(0.77–1.50).69

Mutant 5.6 mo 2.8 mo0.64

(0.27–1.50).30

— Cetuximab/TC (n = 85)— TC (n = 82)

K-ras WT (82.7%) K-ras Mutant (17.3%)


Khambata-Ford S, et al. J Thorac Oncol. 2008;3(suppl 4):S304.

EGFR Mutation Analysis—PFS

EGFR Mutation Status

Cetuximab/TC TC HR (95% CI) P-value

Median PFS

Wild type 5.1 mo 4.6 mo0.95

(0.66–1.35).76

Mutant 6.1 mo 6.4 mo1.17

(0.36–3.77).79

EGFR WT (89.8%)


EGFR Mutant (10.2%)



EGFR IHC Analysis—PFS

EGFR IHC Status Cetuximab/TC TC HR (95% CI) P-value

Median PFS

IHC positive 4.6 mo 4.5 mo1.15

(0.78–1.68).48

IHC negative 4.1 mo 6.4 mo1.17

(0.37–3.72).79

EGFR IHC Positive (88.5%)


EGFR IHC Negative (11.5%)



EGFR FISH Analysis—PFS



EGFR FISH Positive EGFR FISH Negative

EGFR FISH Status

Cetuximab/TC TC HR (95% CI) P-value

Median PFS

FISH positive 5.4 mo 5.4 mo1.54

(0.81–2.93).18

FISH negative 4.3 mo 3.8 mo0.65

(0.35–1.18).15


S0819—SWOG Phase III Trial of Chemotherapy +/- Cetuximab

PaclitaxelCarboplatin

Bevacizumab

RANDOMIZE

Bevacizumab

PaclitaxelCarboplatinCetuximab

Bevacizumab

CetuximabBevacizumab

PC: paclitaxel 200 mg/m2 and carboplatin: AUC = 6 Cetuximab: 400 mg/m2, then 250 mg/m2 weekly

Correlative science: Tumor—EGFR/HER pathways; K-ras Genomic DNA—EGFR polymorphisms Plasma—proteomic predictor

NSCLCadvanced

stage

(EGFR FISHtesting)

1.550 patients screened

Is There Difference in Biomarker Expression—Early-Stage vs

Late-Stage NSCLC?

Are There Differences in EGFR Biology Between Early and Late Stages

of NSCLC?

RADIANT BR21

N % Positive N % Positive

IHC 665 92 325 57

FISH 665 73 159 38

EGFR mutations* 402 12 204 17

K-ras mutations 398 20 296 15

*Exon 19 del or Exon 21 L858R*Exon 19 del or Exon 21 L858R

Zhu C, et al. J Clin Oncol. 2008;26:4268-4275. Tsao M, et al. N Engl J Med. 2005;325:133-144.

Biomarker Expression—The Role of Race?

Race/Ethnicity in Lung Cancer

Are there racial and ethnic variations that influence EGFR tumor biology and response to EGFR inhibitors?

No. of Patients

EGFRMutations

Japan 755 225 (33%)

Taiwan 93 32 (34%)China 41 10 (24%)

Korea 153 30 (20%)

Other Asian areas 361 107 (30%)

United States 395 48 (12%)

Italy 860 39 (5%)

Australia 83 6 (7%)

Other areas 158 13 (8%)

Sekine I, et al. Br J Cancer. 2008;99:1757-1762.

EGFR Pathway in African-American Patients with NSCLC

Tissue AssayAfrican

AmericansWhite

ItaliansUnivariate Analysis

EGFR mutation n = 53 n = 89

Positive 2% (1) 19% (17)P = .003*

Negative 98% (52) 81% (72)

FISH for EGFR n = 53 n = 102

Positive 51% (27) 32% (33) P = .024*

Negative 49% (26) 68% (69)

K-ras mutation n = 53 n = 79

Positive 23% (12) 20% (16)P = .742

Negative 77% (41) 80% (63)

*Remained significant in the multivariate analysisEGFR mutation P = .016FISH P = .033

*Remained significant in the multivariate analysisEGFR mutation P = .016FISH P = .033

Hamdan A, et al. J Thorac Oncol. 2008;3(suppl 4):abstract 15.

Cetuximab + Cisplatin + Vinorelbine

n = 550Stage IIIB or IV

EGFR POSITIVE

Stage IIIB or IV

EGFR POSITIVE

Eligibility Criteria:Eligibility Criteria: EGFR-expressing, advanced stage NSCLC; No EGFR-expressing, advanced stage NSCLC; No prior CTprior CT

Primary Endpoint:Primary Endpoint: Median overall survival Median overall survival

Secondary Endpoints:Secondary Endpoints: Survival rate (1 and 2 y), PFS rate (6 and 12 Survival rate (1 and 2 y), PFS rate (6 and 12 mo), response rate, safety, QoLmo), response rate, safety, QoL

Sample Size:Sample Size: 1100 in 170 centers in EU, Latin America, Asia 1100 in 170 centers in EU, Latin America, Asia

Cisplatin + Vinorelbine

n = 550

Cisplatin + Vinorelbine

n = 550

SurvivalRR

FLEX FLEX

Pirker R, et al. Lancet. 2009;373:1525-1531.

FLEX STUDY: BIOMARKERS

KRAS mutation analysis: OS

FISH analysis: OS 1st-cycle rash and OS

Cl, confidence interval; CT, chemotherapy; HR, hazard ratio; OS overall survival

K-ras wild type

CT + Cetuximab (N = 49)

CT (N = 53)

K-ras mutant

CT + Cetuximab (N = 82)

CT (N = 95)

Any grade: CT + Cetuximab(N = 290)

Grade ): CT + Cetuximab(N = 228)

FISH+CT + Cetuximab (N = 49)CT (N = 53)

FISH-CT + Cetuximab (N = 82)CT (N = 95)

With permission from O’Byrne KJ, et al. J Clin Oncol. 2009;27:15s. Abstract 8007.

Sensitivity ( + )

Sensitivity (–)

Responders

Survival benefit

Nonresponders

Toxicity without survival benefit

Delay of effectivetreatment

Anticancer agent

Today—One Size Fits All

The Future—Tailored Therapy

Sensitivity ( + )

Sensitivity (–)

Responders

Survival benefit

Nonresponders

Toxicity without survival benefit

Delay of effectivetreatment

Molecular profiling

1

Right therapy for right patient

2

EGFR inhibitor

EGFR FISH, IHC, mutation, serum, MiRNA

Genomic classifierERCC1

PROGNOSTIC tests:

PREDICTIVE tests:

ProteomicsRRM1

Ideal Trial Combining Prognostic and Predictive Molecular Markers

Stage IA NSCLCpatients

SurgeryGene expression analysis

Lung metagenepredictor

Observation Randomize

Observation Chemotherapy

HighLow

THE FUTURE

STANDARDIZATIONSTANDARDIZATIONSTANDARDIZATIONVALIDATIONVALIDATIONVALIDATION

Current and EmergingTherapies in NSCLC

George R. Blumenschein, Jr., MD

Associate Professor of Medicine Department of Thoracic/Head & Neck Medical Oncology The University of Texas, M. D. Anderson Cancer Center

Houston, Texas

Upstream Block

Downstream Block

Both

Angiogenesis

Downstream Block

Epidermal Growth Factor ReceptorInhibitors in NSCLC

(Gefitinib, Erlotinib)

Signal Transduction

Blocked

TKI

Ligand

KKTKI

Signal Transduction

Blocked

MoAb

KK

CetuximabCetuximab

Abbreviations: MoAb, monoclonal antibody; TKI, tyrosine kinase inhibitor.

BR.21 SCHEMA

Stratified by:

Center

PS(0/1 vs 2/3)

Response prior Rx (CR/PR:SD:PD)

Prior regimens(1 vs 2)

Prior platinum(yes vs no)

Erlotinib150 mg daily

Placebo“150 mg” daily

* 2:1 Randomization

Shepherd FA, et al. N Engl J Med. 2005;353:123-132.

RANDOM I ZE*

Overall SurvivalAll Patients

* HR and P-value adjusted for stratification factors at randomization + EGFR status.

With permission from Shepherd FA, et al. N Engl J Med. 2005;353:123-132.

HR* = 0.70, P <.001

FLEX—Pivotal TrialCetuximab + Chemotherapy in 1st-Line

Advanced NSCLC

Chemotherapy-naive advanced

NSCLC

Stratified by• IIIB or IV• ECOG PS 0,1,

or 2

Vinorelbine 25 mg/m2 d1, 8

+ cisplatin 80 mg/m2 d1, q3wk

Primary endpoint: overall survivalSecondary endpoints: PFS, ORR, DCR, QOL, safety, PK

n = 557

n = 568

Cetuximab 400 mg/m2 d1 wk1, then 250 mg/m2, qwk

+ vinorelbine 25 mg/m2 d1, 8

+ cisplatin 80 mg/m2 d1, q3wk

RANDOMIZE

Up to 6 cycles of chemotherapy; patients not progressing continue on cetuximab maintenance

• All histologic subtypes included• ECOG PS 0–2• No known brain metastases• EGFR expression by IHC (≥1 positive tumor cells)

Pirker R, et al. 2008 ASCO; May 31-June 3, 2008. Oral presentation and abstract 3.

FLEX—Results

CV + Cetuximab CV P-value

RR 36% 29% .012

PFS 4.8 mo 4.8 mo NS

TTF 4.2 mo 3.7 mo .015

Abbreviations: CV, cisplatin/vinorelbine; NS, not significant; OS, overall survival; PFS, progression-free survival; RR, response rate; TTF, time to treatment failure.

Median OS 1-Y OS

CV + Cetuximab 11.3 mo 47%

CV 10.1 mo 42%

HR: 0.871; P = .044

With permission from Pirker R, et al. J Clin Oncol. 2008;26:3 (abstract).

Ov

era

ll S

urv

iva

l (%

)

Months

Median Overall Survival

1-YearSurvival

CV + cetuximab(N = 466) 10.5 mo 45%

CV(N = 480) 9.1 mo 37%

HR = 0.803; P = .003P-value: stratified log-rank test (2-sided)

FLEX: Overall Survival- Caucasians (N = 946)Prespecified Analysis

Months

Ov

era

ll S

urv

iva

l (%

)

Median Overall Survival CV + Cetuximab CV HR

Caucasian (N = 946) 10.5 mo 9.1 mo 0.803

Adenocarcinoma (N = 413) 12.0 mo 10.3 mo 0.815

Squamous cell (N = 347) 10.2 mo 8.9 mo 0.794

Other (N = 185) 9.0 mo 8.2 mo 0.807

Abbreviation: CV, cisplatin/vinorelbine.

With permission from Pirker R, et al. J Clin Oncol. 2008;26:3 (abstract).

Patients at RiskGrade 0 228 145 88 54 15 0Any grade 290 238 163 101 38 3

CV + cetuximab Any grade Grade 0

OS 15.0 mo 8.8 mo

RR 44% 28%

PFS 5.4 mo 4.3 mo

Months

Any grade: CT + cetuximab(N = 290)

Grade 0: CT + cetuximab(N = 228)

HR = 0.631 (95% CI: 0.515–0.774)a

P <.001

aLandmark analysis.

Gatzemeier J, et al. J Thorac Oncol. 2008;3(suppl 4):abstract 8.

FLEX—OS Early Acne-Like RashPreplanned Analysis

Ov

era

ll S

urv

iva

l (%

)

Agents Targeting the VEGF Pathway

Podar K, Anderson KC. Blood. 2005;105:1383-1395.

Small-molecule VEGFR inhibitors– Motesanib (AMG706)– Sunitinib (SU11248)– Sorafenib (Bay 43-9006)– Vandetanib (ZD6474)

Phase III Trial of Bevacizumab in Nonsquamous NSCLC

ECOG 4599

(PC)Paclitaxel 200 mg/m2

Carboplatin AUC = 6(q3wk) x 6 cycles

(PCB)PC x 6 cycles

+ bevacizumab

(15 mg/kg q3wk) 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 nonmeasurable

Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

Overall Survival by Treatment

12 mo 24 mo RR 44% 15% 15% 51% 23% 35%

0

.2

.4

.6

.8

1.0

Pro

babi

lity

PCPCB

P = .003

0 6 12 18 24 30 36

Months

Medians: 10.3, 12.3

HR: 0.79 (0.67, 0.92)

With permission from Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

Tumors Are Organs and it Makes Sense to Target Multiple Compartments

2. Anti-EGFR: at the tumor cell

Inhibits cell proliferation

Decreases invasion

Promotes apoptosis

Inhibits metastasis

Decreases VEGF production

1. Anti-VEGFR: at the tumor endothelial cell

Inhibits angiogenesis by decreasing endothelial cell proliferation and migration

Inhibits VEGF-dependent endothelial cell survival

Decreases vascular permeability

Examples of Recent Drug Development Strategies

2-drug clinical combinations– Bevacizumab + EGFR inhibitors

Multikinase inhibitors– Sorafenib

– Sunitinib

– Vandetanib

Sunitinib (SU11248)—MultitargetedTyrosine Kinase (TK) Inhibitor

Oxindole TK inhibitor Orally bioavailable small molecule Selective multitargeted Inhibition

of– PDGFR

– VEGFR

– KIT

– FLT3 Antitumor and anti-angiogenic

activity Long plasma half-life

≈ 40 hours Active metabolite

NH

O

NH

F

H3C

CH3

NH

O

N

CH3

CH3

Tumor cell Blood vessel cell

Sorafenib inhibits tumor cell proliferation/survival by targeting the RAF/MEK/ERK pathway at the level of RAF kinase

Sorafenib exerts an antiangiogenic effect by targeting the receptor tyrosine kinases VEGFR-2 and PDGFR- and their associated signaling cascades

BAY 43-9006: Sorafenib

Sorafenib

Vandetanib

A once-daily oral agent that targets VEGFR and EGFR signaling Preclinical data suggest vandetanib has potential to inhibit

VEGFR and EGFR signaling in the clinic at doses of 100 mg/day

Vandetanib

EGFR inhibitionRET inhibition

Tumor cell growth Tumor angiogenesis

VEGFR inhibition

Kinase IC50 (µM)

VEGFR-2 (KDR) 0.04

VEGFR-3 (Flt-4) 0.11

RET 0.13

EGFR 0.50

Wedge SR, et al. Cancer Res. 2002;62:4645-4655.Herbst RS, et al. J Clin Oncol. 2009;27:18s. Abstract CRA 8003.Herbst RS, et al. Expert Opin Invest Drugs. 2007;16:239-249.

2nd- and 3rd-Line NSCLCTargeted Monotherapies

Prior Therapy Response

Sunitinib1 1–2 prior chemotherapeutic regimens (N = 63)

39.7% disease control rate (DCR) (SD + PR); median PFS 12 wk; median OS of 23.4 wk

Erlotinib2 1–2 prior chemotherapeutic regimens (N = 731)

45% DCR; median PFS 9.4 wk; median OS 29.1 wk

Sorafenib3

Vandetanib4

1–2 prior treatments (N = 51)

1–2 prior chemotherapeutic regimens (N = 83)

59% DCR; PFS 11.9 wk; median OS of 29.3 wk

45% DCR; PFS 11 wk; median OS of 26.4 wk

1. Socinski MA, et al. J Clin Oncol. 2008;26:650-656. 2. Shepherd FA, et al. N Engl J Med. 2005;353:123-132. 3. Gatzemeier U, et al. J Clin Oncol. 2006;24:abstract 7002.4. Natale RB, et al. J Clin Oncol. 2006;24:abstract 7000.

Combinations withTargeted Therapies

Phase II 2nd and 3rd-Line NSCLC TrialErlotinib +/- Sorafenib

N = 168

1–2 prior chemotherapies ECOG PS 0–2 Prior antiangiogenic

therapy limited to bevacizumab only

Squamous cell histology allowed

IIIB/IV NSCLC

RANDOMIZE

2:1

Erlotinib 150 mg QD + sorafenib 400 mg BID

Erlotinib 150 mg QD + placebo BID

Randomized (2:1) double-blind placebo-controlled study Primary endpoint: progression-free survival, response rate Secondary endpoints: overall survival, safety, duration response, biomarkers PI: David Spigel (SCRI LUN160)

Cycle = 4 wk Restage q2 cycles until PD, then off-study

Phase II Study of Erlotinib with or Without Sunitinib

A Randomized, Double-Blind, Multicenter Study

RANDOM I ZE

Erlotinib daily

+

Sunitinib daily

Erlotinib daily

+

Placebo daily

Run-in phase

Erlotinib 150 mg daily

+

Sunitinib 37.5 mg daily

Eligibility NSCLC 1–2 prior therapies No CNS metastases

ZODIAC—Vandetanib + Docetaxel vs Docetaxel in 2nd-Line NSCLC

A Randomized, Double-Blind, Parallel-Group, Multicenter Study

Primary endpoint of progression-free survival (PFS) >90% power to detect 25% prolongation of PFS (hazard ratio <0.80) Efficacy and safety in females assessed as coprimary analysis population All histologies of NSCLC eligible Treated CNS metastases and previous use of bevacizumab permitted

Placebo + docetaxel 75 mg/m2

(Max six 21-d cycles)

n = 697

Vandetanib 100 mg/day + docetaxel 75 mg/m2

(Max six 21-d cycles)

n = 694Recurrent (stage IIIB/IV) NSCLC after failure of 1st-line chemotherapy

Total recruitment = 1391 patients

1:1

ran

do

miz

atio

n

Herbst RS, et al. J Clin Oncol. 2009;27:18s. Abstract CRA 8003.

Primary Endpoint—Progression-Free Survival

All Patients (n = 1391)

Females Only(n = 421)

Hazard ratio 0.79 0.79

97.58% CI 0.70, 0.90 0.62, 1.002-sided P-value <.001 .0240

Estimated median PFS

Vandetanib 100 mg + docetaxel

Placebo + docetaxel

4.0 mo

3.2 mo

4.6 mo

4.2 mo

% progression-free at 6 mo

Vandetanib 100 mg + docetaxel

Placebo + docetaxel

28.0%

22.2%

33.9%

29.6%

The treatment effect observed in Japan and China was consistent with that seen outside each country.

Herbst RS, et al. J Clin Oncol. 2009;27:18s. Abstract CRA 8003.

Phase III Trial of Erlotinib +/- Bevacizumab in Nonsquamous NSCLC (BETA Lung)

• 1o Endpoint: OS; 2o endpoints: PFS, ORR, DOR• E dosing was at 150 mg daily. • B/P dosing was 15mg/kg intravenous every 3 weeks. • Responses were assessed every 6 weeks until week 24 and every 12 weeks thereafter.

• Recurrent NSCLC• 1 prior regimen• Bevacizumab -appropriate• ECOG PS 0 – 2

(n=636)

Arm 1

erlotinib [E] + placebo [P]

(n=317)

Arm 2

erlotinib [E] + bevacizumab [B]

(n=319)

1:1 randomizationstratified by ECOG PS, smoking history, sex, and study site

FPI: June 2005, LPI: April 2008. Follow Up: Median 19 mos (0.2 -34)

Treatment continued until disease progression or unacceptable toxicity

Hainsworth, J. et al. J Thorac Oncol. 2008;3(suppl 4):S302.

Results in ITT Population (BETA Lung)

•The OS and PFS results for patients in the biomarker defined subgroups was consistent with the overall results of the trial.

Erlotinib alone (n = 317) Bevacizumab + Erlotinib (n = 319)

PFS

Median, mo 1.7 3.4

Overall survival

Median, mo 9.2 9.3

Response rate, %

CR/PR 6 12

OS PFS

Hainsworth, J. et al. J Thorac Oncol. 2008;3(suppl 4):S302.

SWOG 0536—Phase II Trial of Carboplatin, Paclitaxel, Cetuximab, and Bevacizumab, Followed by Cetuximab and Bevacizumab in Advanced NSCLC

Paclitaxel 200 mg/m2

Carboplatin AUC = 6(q3wk) x 6 cycles

+Bevacizumab 15 mg/kg

(q3wk)+

Cetuximab 250 mg/m2

weekly

Eligibility Nonsquamous NSCLC No Hx of hemoptysis No CNS metastases

Bevacizumab +

Cetuximab until

progression

N = 110

EndpointsPrimary: feasibility defined by the frequency/severity of grade ≥4 hemorrhagic toxicitiesSecondary: response rate, progression-free survival, overall survival, and toxicity

Gandara D, et al. J Clin Oncol. 2009;27:15s. Abstract 8015.

SWOG 0536—Results

Gandara D, et al. J Clin Oncol. 2009;27:15s. Abstract 8015.

N = 110 (95 evaluable) Efficacy/Toxicity

Partial response 54%

Stable disease 23%

Median progression-free survival 7 mo

Median overall survival

Pulmonary hemorrhage rate (severe)

14 mo

2%

S0819—SWOG Phase III Study

PaclitaxelCarboplatin

aBevacizumab

RANDOMIZE

aBevacizumab

PaclitaxelCarboplatinCetuximab

aBevacizumab

CetuximabaBevacizumab

PC: paclitaxel: 200 mg/m2 & carboplatin: AUC = 6cetuximab: 400 mg/m2, then 250 mg/m2 weeklyCorrelative Science: Tumor: EGFR/HER pathways; K-rasGenomic DNA: EGFR polymorphismsPlasma: Proteomic predictor

NSCLCAdv Stage

Tumor Tissue

Available

Co-Primary Endpoints:

1545 patients(618 FISH +)

Primary Endpoints: OS (entire study), PFS (EGFR FISH)

aIn bevacizumab eligible: 15 mg/kg q3wk (piloted in S0536)

Enriched Populations

Iressa Pan Asian Study (IPASS) Phase III Trial—Gefitinib vs Carboplatin/Paclitaxel in Selected

Patients With Advanced NSCLC

Never or lightex-smoker* withadenocarcinoma

histology

PS 0–2

Stage IIIB or IVchemotherapy-naive

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: progression-free survival (noninferiority)Secondary endpoints: ORR, OS, QOL, disease-related symptoms, safety, and tolerabilityExploratory: biomarkers – EGFR mutation, gene copy number, and protein expression

Mok T, et al. Ann Oncol. 2008;19:abstract LBA2.

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

IPASS—Results in ITT Population

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f P

FS

Progression-Free SurvivalGefitinibCarboplatin/paclitaxel

Months0 4 8 12 16 20 28

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f S

urv

ival

24

Gefitinib

Overall Survival

Months

G C/P

N 609 608

Events 453 (74.4%) 497 (81.7%)

Median PFS5.7 mos 5.8 mos

HR = 0.741; P <.0001

12-Mo PFS 25% 7%

Carboplatin/paclitaxel

G C/P

Events 223 (36.6%) 227 (37.3%)

ORR 43.0% 32.2%

Median OSa18.6 mos 17.3 mos

HR = 0.91; P = NR

12-Mo OS 68% 64%aFollow-up ongoing.

Abbreviations: C/P, carboplatin/paclitaxel; G, gefitinib; NR, not reported.Abbreviations: C/P, carboplatin/paclitaxel; G, gefitinib; NR, not reported.

Mok T, et al. Ann Oncol. 2008;19:abstract LBA2.

Progression-Free Survival (PFS)in EGFR Mutation

Positive and Negative PatientsEGFR mutation positive EGFR mutation negative

Treatment by subgroup interaction test, P <.0001

HR (95% CI) = .48 (.36, .64) P <.0001


Gefitinib (n = 132)Carboplatin/paclitaxel (n = 129)

ITT population – mutation rate ~60%.Cox analysis with covariates.

HR (95% CI) = 2.85 (2.05, 3.98) P <.0001


132 71 31 11 3 0129 37 7 2 1 0

108103

0 4 8 12 16 20 24

GefitinibC/P

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of P

FS

At risk :91 4 2 1 0 085 14 1 0 0 0

2158

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of P

FS

Gefitinib (n = 91)Carboplatin/paclitaxel (n = 85)

Months Months

With permission from Mok T, et al. Ann Oncol. 2008;19:abstract LBA2.

Biomarker-Integrated Targeted Therapy for Lung Cancer Elimination

Hypotheses of the BATTLE Program

Multiple hubs of dysregulated signaling pathways associated with lung cancer

Specific altered dominant signaling pathways – EGFR axis

– VEGF axis

– Retinoid axis

– Cyclin D1 axis

– Ras/Raf axis

– PI3 K/AKT-mTOR axis

Altered biomarkers representing aberrant pathways of lung cancer can be detected

Molecularly targeted agent(s) matched dysregulated pathways lead to improved clinical response or disease control

BATTLE: Overall Schema

Enrollment into BATTLE Umbrella Protocol

Biomarker Profile and Equal & Adaptive Randomization

ZD6474 Erlotinib + Bexarotene

SorafenibErlotinib

Endpoints

Primary endpoint– Anticancer activity (progression-free survival rate at 2

months) in patients with stage IV NSCLC

Secondary endpoints– Response rate

– Overall survival

– Time to progression

Biologic endpoint inclusive of a tissue biopsy – Receptor modulation, endothelial cell apoptosis

– To explore the effects of therapy on surrogate markers in serum

Summary

New targeted therapies may improve treatment outcomes either in combination with chemotherapy or as part of a biologic therapy cocktail

Patient selection may be critical, and toward this end further molecular studies are needed

Correlative scientific enquiries with tissue analysis and blood based biomarkers to match predictive markers with clinical outcome should become a component of future trials

Targeted Therapy and Multimodality Treatment in NSCLC

Walter J. Curran, Jr., MD

Lawrence Davis Professor and ChairDepartment of Radiation Oncology

Emory UniversityAtlanta, Georgia

Nonoperative Care of Good PS Patients

with Stage III NSCLCWhat Do We Know?Chemotherapy-radiotherapy (CT-RT)

results in better survival than RT alone– CALGB 84331, RTOG 88082, EORTC3, CEBI4

Concurrent is better than sequential CT-RT – West Japan Trial5, RTOG 94106, GLOT7,

Czech Trial8

1. Dillman RO, et al. J Natl Cancer Inst. 1996;88:1210-1215. 2. Sause W, et al. Chest. 2000;117:358-364. 3. Uitterhoeve AL, et al. Radiat Oncol. 2007;2:27. 4. Le Chevalier T, et al. J Natl Cancer Inst. 1991;83:417-423. 5. Wada H, et al. J Clin Oncol. 1996;14:1048-1054. 6. Curran WJ, et al. Proc Am Soc Clin Oncol. 2002;19:484a. 7. Fournel P, et al. J Clin Oncol. 2005;23:5910-5917. 8. Zatloukal P, et al. Lung Cancer. 2004;46:87-98.

Meta-Analysis of Concurrent vs Sequential CT-RT—Overall Survival

Median follow-up:6 years

RT + conc CTeffect:P = .004

CALGB 8831 45/46 39/45 1.12 (0.73;1.72)

TrialNo. Deaths/No. Entered

RT + conc CT RT + seq CT Hazard Ratio HR (95% CI)

RT + conc CT better | RT + seq CT better

WJLCG 131/156 142/158 0.78 (0.61;0.99)

RTOG 9410 180/204 189/203 0.80 (0.65;0.98)

GMMA Ankara 95 15/15 15/15 0.87 (0.41;1.82)

GLOT-GFPC NPC 87/102 96/103 0.80 (0.60;1.07)

EORTC 08972 63/80 66/78 0.98 (0.69;1.39)

Total 521/603 547/602

Test for heterogeneity: P = .66 I2 = 0 %

0.84 (0.74;0.95)

0.25 1.00 4.00

Auperin A, et al. J Thorac Oncol. 2007;2:S310.

Overall Survival—Meta-Analysis

Absolute benefit in OS with concomitant CT:

At 2 years: At 3 years: At 5 years:

5.3% 5.7% 4.5%

HR = 0.84 (0.74;0.95), P = .004

RT + conc CTRT + seq CTS

urvi

val (

%)

0

20

40

60

80

100

Time from Randomization (Years)0 1 2 3 4 >5

35.6

23.8

15.130.3

18.110.6

Auperin A, et al. J Thorac Oncol. 2007;2:S310.

Good PS Stage III NSCLC—What Don’t We Know?

Does radiotherapy dose/volume matter?Role of adjuvant chemotherapy

(SWOG/HOG)?Optimal chemotherapy doublet with

radiotherapy?Any role for targeted therapy?

Role of Targeted Therapyin Stage III NSCLC

EGFR Targeted Therapiesin Stage III NSCLC

RTOG 0324—Cetuximab/CT-RTStudy Rationale

EGFR and NSCLC– EGFR is over-expressed in NSCLC

– Associated with aggressive behavior and poor outcomes

– EGFR inhibition → radiosensitization in preclinical systems Cetuximab enhances antitumor efficacy of RT

– RT in head and neck cancer1 Prior randomized studies indicate that the addition of cetuximab to CT

may improve efficacy in advanced NSCLC The addition of cetuximab to CT-RT had not been evaluated in

NSCLC

1. Bonner JA, et al. N Engl J Med. 2006;354:567-578.

RTOG 0324—Treatment Schema

CetuximabCetuximab

Paclitaxel

Carboplatin

Cetuximab

CRT

Paclitaxel

Carboplatin

Cetuximab

CRT

400 mg/m2 day 1

Paclitaxel

Carboplatin

Cetuximab

Paclitaxel

Carboplatin

CetuximabPaclitaxel (45 mg/m2/wk) Carboplatin (AUC = 2/wk )

Cetuximab (250 mg/m2/wk) CRT (63 Gy/7 wk/35 daily fx)

Paclitaxel (200 mg/m2 q3wk x 2) Carboplatin (AUC = 6 q3wk x 2)

Cetuximab (250 mg/m2/wk)

CetuximabCetuximab

250 mg/m2/wk x 3

Weeks 2–8 Week 1 Weeks 9–11 Weeks 12–17

Follow-Up Time to DateMedian, 21.6 months

Range, 1.4–39.3 months

Komaki R, et al. Int J Rad Oncol Biol Phys. 2007;69:S57-S58.

RTOG 0324—Conclusions

The addition of cetuximab to CT-RT → CT is feasible and safe– RT was delivered per protocol for 86% of patients

– Cetuximab and the cetuximab/CT combination were delivered per protocol in the majority of patients

Loading dose, 96% CT-RT, 80% Consolidation, 68%

– Grade ≥3 nonhematologic adverse event rate was similar to historical control RTOG 0324, 67% BMS/ACR 427, 60%

– There were 5 grade 5 events on this trial. Three of these are felt to have been related to excessive V20 and unrelated to cetuximab

Median survival, 22.7 months 24-month survival is 49.3%!

Komaki R, et al. Int J Rad Oncol Biol Phys. 2007;69:S57-S58.

Long-Term Outcome in RTOG LA-NSCLC Trials

Trial Radiotherapy Chemotherapy Sequence MST 5-y OS

0324 63 Gy (SDFx) Pac-Carbo Con-Consol 22.7 m N/A

9801 69.6 Gy (BID Fx) Pac-Carbo/Amif Ind-Con 17.3 17%

9801 69.6 Gy (BID Fx) Pac-Carbo Ind-Con 17.9 16%

9410 63 Gy (SDFx) VBL-DDP Con 17.0 16%

9410 63 Gy (SDFx) VBL-DDP Ind 14.6 10%

9410 69.6Gy (BID Fx) VP-16/DDP Con 15.1 13%

Potential explanations True superiority (C225 enhances the efficacy of chemoradiation) Will Rogers phenomenon (routine PET scans stage migration) Improved RT technique and supportive care Patient selection Luck

CALGB 30407—Concurrent Carboplatin + Pemetrexed/RT Followed by Carboplatin +

Pemetrexed + Cetuximab for Stage III NSCLC

RANDOMIZE

Arm A

Arm B

Carboplatin AUC 6 q3wk x 4 Pemetrexed 500/mg² q3wk x 8 XRT – 70 Gy over 7 wk

Carboplatin AUC 6 q3wk x 4 Pemetrexed 500/mg² q3wk x 8 XRT – 70 Gy over 7 wk

+Cetuximab 400mg/m² loading and 250 mg/m² weekly during RT

A Randomized Phase II Trial

Govindan R, et al. J Clin Oncol. 2008;26:Abstract 7518.

CALGB 30407 Grades 3–4 Toxicities

Arm A (n = 54) No Cetuximab

Arm B (n = 52)Cetuximab

Neutropenia 36 37

Feb/neutropenia 5 7

↓ Platelets 30 34

Anemia 14 16

Esophagitis 35 22

Fatigue 22 18

Skin rash 3 22


CALGB 30407 Efficacy Data—ASCO 2009

Arm A (n = 54) No Cetuximab

Arm B (n = 52)Cetuximab

Adenocarcinoma 46% 41%

Partial/complete response

73% 71%

Median failure-free survival

12.9 mo 10.3 mo

18-mo survival 57% 47%

Median survival time

22.3 mo 18.7 mo


RTOG 0617Phase III Trial of Standard-Dose (60 Gy) vs

High-Dose (74 Gy) Conformal RT with Concurrent and Consolidation CT and +/- Cetuximab in Stage III NSCLC

Primary endpoint: survival (n = 512) (2 X 2 design evaluating dose and cetuximab independently)

Stratified by stage (A vs B), type of RT (3-D vs IMRT), and PS (0 vs 1)

Stage IIIA/B

PS 0–1

FEV1 ≥1.5 L; V20 <37%

No Supraclav LNs

PET recommended

RANDOMI ZE

Concurrent CT/RTPaclitaxel 45 mg/m2 Carboplatin AUC 2 Weekly x7

RT 60 Gy (2 Gy/d)

Concurrent CT/RTPaclitaxel 45 mg/m2 Carboplatin AUC 2Weekly x7

RT 74 Gy (2 Gy/d)

Consolidation Paclitaxel 200 mg/m2 Carboplatin AUC 6 q3wk x2 cycles

RTOG 0617: Revised!Phase III Trial of Standard-Dose (60 Gy) vs

High-Dose (74 Gy) Conformal RT with Concurrent and Consolidation CT and +/- Cetuximab in Stage III NSCLC

Primary endpoint: survival (n = 512) (2 X 2 design evaluating dose and cetuximab independently)

Stratified by stage (A vs B), type of RT (3-D vs IMRT), and PS (0 vs 1)

Stage IIIA/B

PS 0–1

FEV1 ≥1.5 L; V20 <37%

No Supraclav LNs

PET recommended

RANDOMI ZE

Concurrent CT/RTPaclitaxel 45 mg/m2 Carboplatin AUC 2 Weekly x7

RT 60 Gy (2 Gy/d)

+ Cetuximab

Concurrent CT/RTPaclitaxel 45 mg/m2 Carboplatin AUC 2Weekly x7

RT 74 Gy (2 Gy/d)

+ Cetuximab

Consolidation Paclitaxel 200 mg/m2 Carboplatin AUC 6 q3wk x2 cycles

SWOG 0023—Schema

CDDP/VP-16 XRT 1.8–2 Gy/d 61 Gy

Docetaxel 75 mg/m2

x 3 cycles

1o Endpoint: overall survival; 2o Endpoint: PFS, toxicity, and correlative scienceMaintenance therapy could continue for a maximum of 5 years.Stratification factors: IIIA vs IIIB; measurable vs nonmeasurable disease; squamous vs nonsquamous.

PLACEBO

Gefitinib500 mg/d250 mg/d(5-1-03)

Definitive TX Consolidation Maintenance

RANDOMIZE

Kelly K, et al. J Clin Oncol. 2008;26:2450-2456.

SWOG 0023—Overall Survivalfrom Randomization

Median

0%

20%

40%

60%

80%

100%

0 12 24 36

Months After Randomization

Gefitinib

Placebo

N

118

125

Events

43

32

(mo)

23

35

P = .01 2-sided stratified

Log-rank

With permission from Kelly K, et al. J Clin Oncol. 2008;26:2450-2456.

EGFR-Directed Therapy inStage III NSCLC

RTOG 0324 encouraging for cetuximab/carboplatin/paclitaxel/RT regimen

CALGB 30407 not encouraging for adding cetuximab to a pemetrexed-based regimen

Cetuximab incorporated into the current RTOG/CALGB/NCCTG phase III trial

Data with EGFR TKIs (gefitinib, erlotinib) not encouraging

Vascular-Targeted Therapies in Stage III NSCLC

NSCLC TrialsSelected Bevacizumab/CT-RT Regimens

SITE REGIMEN STATUSCa Consortium (IIIB/IV)

RT → CP/bev Closed; 1 gr 5 hemorrhage

Northwestern (IIIB/IV)

RT → CP/bev Never opened

Dana Farber CP wkly + bev q3wk + RT → CP/bev q3wk → bev x 1 y

Closed; 4 patients – 1 gr 5 hemorrhage, 1 PE

NCI 7213 (Vokes)

CP/bev/RT Closed; 1 patient accrued

Sarah Cannon

(Spigel)

Carbo/pem/bev/RT → Carbo/pem/bev → bev

Closed; 5 patients – 2 TE fistulas

UNC (Socinski) CP/bev → CP/bev/RT → Bev/erlotinib

Active; 21 patients – 1 gr 5 and 1 gr 3 hemorrhage

Bevacizumab Phase I/II Stage III Unresectable NSCLC—LCCC 0511

Primary endpoint: progression-free survival at 1 year

PETInductionInduction

Bv ﾐ 15 mg/kgC ﾐ AUC 6P ﾐ 225 mg/m2

D1 D22

InductionInduction

Bv – 15 mg/kgC – AUC 6P – 225 mg/m2

D1 D22

Socinski MA, et al. J Clin Oncol. 2009;27:Abstract 7528.

Concurrent CT/RTx PlatformTCRT – 74 Gy (2 Gy/d)

C – AUC 2

P – 45 mg/m2

D43 q wk x 7 D92

Bv – 10 mg/kg q2wk x 4

Bv – 10 mg/kg q2wk x 4Er – 100 mg/d Tues–Fri during TCRT

Bv – 10 mg/kg q2wk x 4Er – 150 mg/d Tues–Fri during TCRT

Consolidation TherapyBv – 15 mg/kg q3wk x 6Er – 150 mg/d for the 6 cycles

D101 – 122

LCCC 0511—Summary ofConcurrent Therapy

25/26 patients completed therapy to 74 Gy Grade 3 neutropenia–30% Grade 3 esophagitis–19% Grade 3 pneumonitis–<10% Median days of RT delay–0 (0–8) One grade 3 and one grade 5 pulmonary hemorrhage

in 2 squamous cell patients 1-yr survival: 79% Encouraging preliminary data

Socinski MA, et al. J Clin Oncol. 2009;27:Abstract 7528.

SWOG 0533 Concurrent Chemoradiation

PE: Cisplatin 50 mg/m2 IV d 1, 8, 29, 36Etoposide 50 mg/m2 IV d 1–5, 29–33

RT: 1.8 Gy X 36 fractions

COHORT 1: No Bevacizumab (35 patients/risk group)

COHORT 2: Bevacizumab d 15, 36, 57 (28 patients/risk group)

COHORT 3: Bevacizumab d 1, 22, 43 (28 patients/risk group)

Consolidation (4–8 wk)Docetaxel 75 mg/m2 IV q21d x 3All cohorts: bevacizumab q21d x 3

Parallel studies: low-risk and high-risk patients

Unresectable stage III nonsquamous NSCLC

No cavitation and no tumor close to a major vessel

No hemoptysis (½ tsp within 28 days of registration)

Unresectable stage III squamous cell cancer

OR Tumor of any

histology with cavitation or close to a major vessel

OR History of hemoptysis

Stratum 2 closed to accrual in 2009 due to toxicity

Stratum 1Low Risk

Stratum 2High Risk

Stage III NSCLC Conclusions

Combined chemotherapy-radiotherapy represents the standard of care; no universal agreement as to specific optimal strategy

Novel approaches targeting loco-regional as well as systemic compartments are needed

Clinical trial enrollment paramount to making progress

Zeroing in on Non-Small Cell Lung Cancer: Integrating Targeted Therapies into Practice.

Documents

Transcript of Zeroing in on Non-Small Cell Lung Cancer: Integrating Targeted Therapies into Practice.