Emerging Treatment Paradigms in NSCLC

Edward S. Kim, MDMD Anderson Cancer Center

Tobacco Use in the USA1900-1999

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

Year

Per

Cap

ita C

igare

tte C

on

su

mp

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n

0

10

20

30

40

50

60

70

80

90

100

Ag

e-A

dju

ste

d L

un

g C

an

cer

Death

R

ate

s*

Per capita cigarette

consumption

Male lung cancer death rate

Female lung cancer death rate

*Age-adjusted to 2000 US standard population.

Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

†Uterine cancer death rates are for uterine cervic and uterine corpus combined.

Source: US Mortality Public Use Data Tapes 1960-1996. US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 1999.

Year

Female

Uterus†

BreastPancreasOvaryStomachLung & bronchusColon & rectum

1930

Rat

e p

er 1

00,0

00

1940

1950

1960

1970

1980

1990

80

60

40

20

0

1990

Rat

e p

er 1

00,0

00

Male

1930

1940

1950

1960

1970

1980

80

60

40

20

0

PancreasLiverProstateStomachLung & bronchusColon & rectum

Cancer Deaths in the US

Food and Drug Administration. At http://www.fda.gov/cder/cancer/druglistframe.htm. Accessed August 28, 2006.; National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology. Non-small cell lung cancer v2.2006. Accessed August 28, 2006. Schrump et al.

Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

History of Therapy in Advanced NSCLC: FDA Approval Dates

*Label does not include NSCLC-specific indication

First-line

Second-line

Third-line

Not approved

First-line

Second-line

Third-line

Not approved

19701970 19801980 19901990 20002000

Medianoverallsurvival,months

12+

~8–10~6

~2–4

Best supportive careBest supportive care Single-agent platinumSingle-agent platinum DoubletsDoublets Bevacizumab + PCBevacizumab + PC

Cisplatin*Cisplatin*19781978

Carboplatin*Carboplatin*19891989

ErlotinibErlotinibPemetrexedPemetrexed

20042004

DocetaxelDocetaxel19991999

PaclitaxelPaclitaxelGemcitabineGemcitabine

19981998

VinorelbineVinorelbine19941994

DocetaxelDocetaxel20022002

BevacizumabBevacizumab20062006

GefitinibGefitinib20032003

Standard Therapies

FDA Approved Chemotherapy Regimens for Advanced NSCLC

• First-Line– Cisplatin + paclitaxel (24 hour infusion)– Cisplatin + vinorelbine (4 week)– Cisplatin + gemcitabine (3 or 4 week)– Cisplatin + docetaxel (3 week)– Bevacizumab + carboplatin + paclitaxel

• Second-Line– Docetaxel– Pemetrexed – Erlotinib

ECOG 1594: Treatment Schema

Schiller JH et al. N Engl J Med. 2002;346:92-98

*Control arm.

Arm A* q 3 wkStage IIIB or IV

NSCLC Stratified by:• Extent of disease • PS• Weight loss• Brain metastases

Cisplatin: 100 mg/m2, day 1Gemcitabine: 1000 mg/m2, days 1,8,15

Docetaxel: 75 mg/m2, day 1Cisplatin: 75 mg/m2, day 1

Arm C q 3 wk

Paclitaxel: 225 mg/m2, day 1Carboplatin: AUC=6, day 1

Arm D q 3 wk

Arm B q 4 wk

Paclitaxel: 135 mg/m2, day 1Cisplatin: 75 mg/m2, day 2R

ANDOM

I

ZE

ECOG 1594 Survival by Treatment Group

0 5 10 15 2520 30

0.0

1.0

0.8

0.2

0.4

0.6

Months

Cisplatin + PaclitaxelCisplatin + GemcitabineCisplatin + DocetaxelCarboplatin + Paclitaxel

Schiller JH et al. N Engl J Med. 2002;346:92-98

TAX 326: Schema

Fossella FV et al: JCO 2003

Docetaxel: 75 mg/m2 IV + Cisplatin: 75 mg/m2 IV

Docetaxel: 75 mg/m2 IV + Carboplatin: AUC 6 IV

Vinorelbine: 25 mg/m2 IV d 1, 8, 15, 22 + Cisplatin: 100 mg/m2 IV d 1

Premed: Dexamethasone 8 mg PO bid 6 doses (first dose on evening prior to docetaxel infusion) for the docetaxel groups.

Stratification by: • Stage IIIB or IV• Geographic region

q3 wk

q4 wk

RANDOM

I

ZE

q3 wk

TAX 326: SurvivalDocetaxel/Cisplatin vs. Vinorelbine/Cisplatin

Fossella FV et al: JCO 2003

Docetaxel/Cisplatin

Vinorelbine/Cisplatin

Cum

ulat

ive

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

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

Survival Time (months)

P = .044, Adjusted Log-Rank

1-yr Survival 46 vs 41%

2-yr Survival 21 vs 14%

The Bottom Line: Metastatic NSCLC Study N ORR(%) MST (mos) SWOG 9509 Carbo-Pac 208 25 8.0 Cis-Vino 202 28 8.0

EGOG 1594 Cis-Pac 292 21.3 8.1 Cis-Gem 288 21 8.1 Cis-Doce 293 17.3 7.4 Carbo-Pac 290 15.3 8.3

Italian Study Cis-Gem 205 30 9.8 Carbo-Pac 201 32 9.9 Cis-Vino 201 30 9.5

EORTC 08975 Cis-Pac 159 31 8.1 Cis-Gem 160 36 8.8 Gem-Pac 161 27 6.9

TAX 326 Doce-Cis 408 NA 10.9 Doce-Carbo 406 NA 9.1 Cis-Vino 404 NA 10.0

Chemotherapy and Targeted Therapy

Biological Agent

Class Trial PhaseTarget

Population Outcome

Gefitinib EGFR-TKIIII All NSCLC Negative for

survival

Gefitinib EGFR-TKI IIIAll NSCLC Negative for

survival

Erlotinib EGFR-TKI IIIAll NSCLC Negative for

survival

Erlotinib EGFR-TKI IIIAll NSCLC Negative for

survival

Bexarotene Rexinoid IIIAll NSCLC Negative for

survival

Bexarotene Rexinoid IIIAll NSCLC Negative for

survival

LonafarnibFarnesyl

TransferaseIII

All NSCLC Negative for survival

Bevacizumab VEGF IIINon-squamous, no brain mets

Positive for survival

Case 1: NSCLC

• HPI: 76 year old female with choking episode. Heimlich maneuver x 3 successful. Hospital w/u revealed 2 cm RLL nodule.

• PMH: Asthma, HTN, DM Type II, R RCCA – 1997

• Meds: HCTZ, Inderal, Nabumetone

• Allergies: None

• SH: Widow, cigarettes: 20 pack-years

• ETOH: 3 beers/day

• FH: Negative

• ROS: Rib pain, unsteady gait, no weight loss

• PE: No supraclavicular nodes, C/V: RRR, Resp: clear to A&P, Abd: no masses Ext: no C/C/E Neuro: no focal deficits

Case 1: NSCLC

• What is the desired work-up for the nodule?1. Biopsy

2. Biopsy, CT chest, abdomen

3. Biopsy, CT chest, abdomen, bone scan, MRI brain

4. Referral to medical oncology

• What is the desired work-up for the nodule?1. Biopsy

2. Biopsy, CT chest, abdomen

3. Biopsy, CT chest, abdomen, bone scan, MRI brain

4. Referral to medical oncology

34% 36%

43%

22%

13%

8%

17% 28%

Outside U.S.

U.S.

1 2 3 4

Case 1: NSCLC

• FNA: NSCLC• Bone Scan: Multiple increased rib lesions• MRI Brain: No metastases• CT Chest: 2 cm lesion RLL, no adenopathy• CT-PET: FDG avid lesion RLL, no other abns

Case 1: NSCLC

• What is the optimal treatment for this patient at this time?1. Lobectomy

2. Lobectomy and nodal sampling

3. Lobectomy and nodal dissection

4. Surgery followed by radiation

• What is the optimal treatment for this patient at this time?1. Lobectomy

2. Lobectomy and nodal sampling

3. Lobectomy and nodal dissection

4. Surgery followed by radiation

32% 29%

37%

32%

22%

7%

15% 26%

Outside U.S.

U.S.

1 2 3 4

VATS LobectomyTechnique

Courtesy S. Swisher

Case 1: NSCLC

Pathology: T2N0M0

Case 1: NSCLC

• What is the appropriate next therapy for this patient?1. Adjuvant chemotherapy

2. Adjuvant chemotherapy followed by radiation

3. Observation

4. Radiation alone

• What is the appropriate next therapy for this patient?1. Adjuvant chemotherapy

2. Adjuvant chemotherapy followed by radiation

3. Observation

4. Radiation alone

30% 20%

20%

7%

3%

43%

44% 33%

Outside U.S.

U.S.

1 2 3 4

International Adjuvant Lung Cancer Trial Collaborative Group. N Engl J Med. 2004;350 (4):351-360

*Each center selected chemotherapy regimen†Optional, but predefined by N stage at each center

N=1867Select eligibility criteria:

• Stage I-III

• Complete surgical resection within 60 days

• Age ≤ 75

RANDOMIZE*

Cisplatin 80 mg/m2 q 3 wk 4 ORCisplatin 100 mg/m2 q 4 wk 3-4 ORCisplatin 120 mg/m2 q 4 wk 3

PLUS

Etoposide 100 mg/m2 3 days/cycle ORVinorelbine 30 mg/m2 weekly ORVinblastine 4 mg/m2 weekly OR Vindesine 3 mg/m2 weekly

No chemotherapy

± Thoracic Radiotherapy 60 Gy†

Randomized International Adjuvant Lung Cancer Trial (IALT): Design

IALT: Overall Survival

Control

Chemotherapy

Years

164286432602774935181308450624775932

At risk:

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5

HR = 0.86 [0.76-0.98]P < 0.03O

vera

ll S

urvi

val (

%)

Median 5-yr OS (mos) OS (%)

Chemotherapy 50.8 44.5Control 44.4 40.4

International Adjuvant Lung Cancer Trial Collaborative Group. N Engl J Med. 2004;350 (4):351-360

Phase III Trial of Adjuvant Chemotherapy in Completely Resected Stage IB/II NSCLC

Intergroup JBR.10 Trial

Observation(n = 238)

Cisplatin-Vinorelbine

(n = 243)HR P value

Median Survival, months 73 94 0.7 0.012

5-Year Survival, % 54% 69% 0.0022

Winton et al. Proc Am Soc Clin Oncol. 2004;22(No 14S):621s. Abstract 7018

ASCO: 2006

0 2 4 6 8

Survival Time (Years)

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

ObservationChemo

0 1 2 3 4 5 6 7 8 9

HR = 0.80; 90% CI: 0.60-1.07 P = 0.10

ASCO: 2004

0 2 4 6 8

Survival Time (Years)

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

0 1 2 3 4 5 6 7 8 9

HR = 0.62; 90% CI: 0.44-0.89 P = 0.01

ObservationChemo

CALGB 9633: Overall Survival Then and Now

ANITA: Phase III Adjuvant Vinorelbine (N) and Cisplatin (P) vs. Observation (OBS) in Completely Resected (Stage I-III)

Non-Small Cell Lung Cancer (NSCLC) Patients (pts)

• 840 patients• Median age: 59 (range 18-75) • 35% stage I, 30% II, 35% IIIA • Median survival 65.8 vs. 43.7 months• 5-year survival by stage I-II-IIIA

– NP: 62% - 52% - 42% – OBS: 63% - 39% - 26%

• No benefit was observed in stage I

RADIANTErlotinib NSCLC Adjuvant Trial

Primary Endpoint: Progression-free survival • Overall population• Never smokers

Eligible pts:• Stage IB /

IIIA NSCLC

Placebo

Erlotinib

Collect tissue

Treatment for 2-years

Stratify by smoking HX

1st Line platinum–based chemo x 4 cycles

Approved: ECOG Executive Committee and CTEP

Principal investigator: Heather Wakelee

*Specified regimens• Carboplatin and paclitaxel• Cisplatin and docetaxel• Cisplatin and vinorelbine• Cisplatin and gemcitabine

• Primary end point: overall survival

• Secondary end points: disease-free survival, safety [bleeding and arterial thromboembolic events (ATEs)]

E1505: Phase III Adjuvant Chemotherapy Bevacizumab

RANDOMI ZE

Chemotherapy* x 4 cycles

Chemotherapy* x 4 cycles +Bevacizumab x 1 year

Eligibility• Resected IB–IIIA• ≥ lobectomy• No previous

chemotherapy• No planned XRT• No CVA/TIA• No ATE in 12 months

N = 1,500

Case 2: NSCLC

• HPI: 69 year old female with h/o T1N1 breast CA x 22 yrs. F/U CXR reveals 3 cm RUL mass.

• PMH: HTN, PVD, R Breast CA – 1983

• Meds: Lipitor, Atenolol, Naproxen

• Allergies: None

• SH: Widow, cigarettes: 50 pack-years

• ETOH: none x 1 year

• FH: Negative

• ROS: Rib pain, unsteady gait, no weight loss

• PE: No supraclavicular nodes, C/V: RRR, Resp: clear to A&P, Chest: well healed mastectomy scar, Abd: no masses, Ext: no C/C/E, Neuro: no focal deficits

Case 2: NSCLC

• What is the optimal work-up for this patient?1. Biopsy

2. Biopsy, CT chest, abdomen

3. Biopsy, CT chest, abdomen, bone scan, MRI brain

4. Referral to medical oncology

• What is the optimal work-up for this patient?1. Biopsy

2. Biopsy, CT chest, abdomen

3. Biopsy, CT chest, abdomen, bone scan, MRI brain

4. Referral to medical oncology

21% 68%

70%

4%

8%

7%

0% 22%

Outside U.S.

U.S.

1 2 3 4

Case 2: NSCLC

• FNA: NSCLC• CT Chest: 3.7 cm lesion RUL, no adenopathy• CT-PET: FDG avid lesion RUL, R paratrach node avid, no other

nodes or metastases• EBUS: R4 LN: positive, all other negative

Case 2: NSCLC

• What is the preferred treatment at this time for this patient?1. Surgery followed by radiation

2. Induction chemotherapy followed by surgery

3. Induction chemoradiotherapy followed by surgery

4. Concurrent chemotherapy and radiation

• What is the preferred treatment at this time for this patient?1. Surgery followed by radiation

2. Induction chemotherapy followed by surgery

3. Induction chemoradiotherapy followed by surgery

4. Concurrent chemotherapy and radiation

32% 32%

18%

28%

33%

8%

16% 33%

Outside U.S.

U.S.

1 2 3 4

Case 2: NSCLC

• Induction Chemotherapy: Docetaxel, cisplatin, no RT• Surgery: FOB/MED, RUL, MLND

Case 2: NSCLC

• What is the appropriate next therapy for this patient?1. Adjuvant chemotherapy

2. Adjuvant chemotherapy followed by radiation

3. Observation

4. Radiation alone

• What is the appropriate next therapy for this patient?1. Adjuvant chemotherapy

2. Adjuvant chemotherapy followed by radiation

3. Observation

4. Radiation alone

49% 12%

10%

10%

6%

29%

51% 33%

Outside U.S.

U.S.

1 2 3 4

Approach to Resectable Stage IIIA, N2 NSCLC

Survival Comparison of Preoperative Chemotherapy

Endpoint BLOTS9900 DePierre

Preop Surgery Preop Surgery

OS, median 43 mo 47 mo 40 mo 37 mo 26 mo

1-yr survival 84% 82% 79% 77% 73%

2-yr survival 68% 69% 63% 59% 52%

Adapted from Pisters et al. J Clin Oncol. 2005;23(No16s):624s. Oral Presentation.

Current Issues for Stage IIIA N2 LN+ Resectable NSCLC

• The role of surgery?

• Addition of RT to induction chemo increases pathologic CR rates, but also toxicity

• Does RT add survival benefit to justify the increased toxicity of bimodality induction therapy for this group of patients?

• An ongoing dilemma reflected by variability in treatment approaches across the country

• Published clinical trials limited by heterogeneity of patient population(s) studied

INT 0139: Definitive CT/RT vs Induction CT/RT Surgery for Stage IIIA NSCLC

Stage IIIA (T1-3, pN2,

M0)NSCLCN = 429

(396 eligible)

Considered Resectable

RANDOMIZE

Cis/VP16 x 2 cycles

w/concurrent XRT 45Gy

Cis/VP16 x 2 cycles

w/concurrent XRT 45Gy

Surgery

Cis/VP16 x 2 cycles

Cis/VP16 x 2 cycles

Re-evaluate 2 to 4 weeks post RT; if no PD

Re-evaluate 7 days prior to RT completion; if no PD

Albain et al. J Clin Oncol. 2005;23(No16s):624s. Abstract 7014.

Continue RT to 61GY

Median F/U 81 months

INT 0139: Exploratory Analyses

Pneumonectomy “Matched” CT/RT/S CT/RT

OS, median 19 mo 29 mo

3-yr survival 36% 45%

5-yr survival 22% 24%

# Dead (Total matched n=51of 54) 38 42

Lobectomy “Matched” CT/RT/S CT/RT

OS, median 34 mo 22 mo

5-yr survival 36% 18%

# Dead (Total matched n=90 of 98) 57 74

Albain et al. J Clin Oncol. 2005;23(No16s):624s. Abstract 7014.

MDACC Neoadjuvant Trial Schema

Patients with stage I-III NSCLC

No prior chemotherapy or radiotherapy

Cisplatin 80 mg/m2 +

Docetaxel 75 mg/m2

For 3 cycles

Surgical resection ± XRT

Erlotinib 150 mg po for 1 year

Who’s Appropriate for Multimodality Surgical Resection?

• Microscopic single station N2• T4 N0-1• Perhaps responding larger N2

Stage IIIA “Bulky” N2 and Stage IIIB NSCLC

• Multimodality approach with chemotherapy and radiation therapy– Randomized evidence of survival benefit of chemo-RT over RT

alone– Concurrent: generally accepted as standard definitive treatment of

patients with good PF– Sequential: less toxic; defendable treatment option

• Unclear impact of surgery on local control in combined modality approach– Downstaging

Case 3: NSCLC

• HPI: 62 year old male with DJD. C/o 8-10 months of progressive SOB. Spirometry normal.

– Continued SOB for few months, saw pulmonologist. Repeat spirometry, Advair started. CXR revealed 4 cm RML lesion and moderate pleural effusion.

• PMH: DJD

• Meds: Celebrex prn

• Allergies: None

• SH: Married, never smoker

• ETOH: Rare

• FH: Negative

• ROS: Rib pain, SOB, no weight loss

• PE: No supraclavicular nodes, C/V: RRR, Resp: clear to A&P, Chest: well healed mastectomy scar, Abd: no masses, Ext: no C/C/E, Neuro: no focal deficits

Case 3: NSCLC

• What is the optimal work-up at this time?1. Biopsy, CT chest, abdomen

2. Thoracentesis, CT chest, abdomen, bone scan

3. Thoracentesis, CT chest, abdomen, bone scan, brain scan

4. Hospice care

• What is the optimal work-up at this time?1. Biopsy, CT chest, abdomen

2. Thoracentesis, CT chest, abdomen, bone scan

3. Thoracentesis, CT chest, abdomen, bone scan, brain scan

4. Hospice care

32% 46%

53%

6%

5%

16%

16% 26%

Outside U.S.

U.S.

1 2 3 4

Case 3: NSCLC

• CT Chest: 4.2 cm lesion extending across mediastinum, no adenopathy

• Thoracentesis: 600 cc drained

• Bone scan: Lytic bone lesion right 5th rib

• Brain scan: Clean

• Pathology: Metastatic adenocarcinoma

Case 3: NSCLC

• What is the optimal treatment for this patient?1. Cisplatin doublet

2. Carboplatin + docetaxel

3. Carboplatin + paclitaxel

4. Carboplatin + gemcitabine

5. Carboplatin + taxane + bevacizumab

6. Bevacizumab + erlotinib

• What is the optimal treatment for this patient?1. Cisplatin doublet

2. Carboplatin + docetaxel

3. Carboplatin + paclitaxel

4. Carboplatin + gemcitabine

5. Carboplatin + taxane + bevacizumab

6. Bevacizumab + erlotinib

15% 10%

8%

12%

3%

43%

6%

18%

5% 78%

2%Outside U.S.

U.S.

1 2 3 4 5 6

Case 3: NSCLC

• Standard– Doublet chemotherapy

• Standard “plus”– Doublet chemotherapy + bevacizumab

• Non-standard– Erlotinib

Case 3: NSCLC

• Started: carboplatin + docetaxel + bevacizumab

9-12-05 11-30-05

Case 3: NSCLC

11-15-06

Progression on maintenance bevacizumab

1-10-07

Erlotinib added to bevacizumab

EGFR Inhibitors in Lung Cancer

Agent (Manufacturer) MechanismPhase in

DevelopmentClinical Toxicities

Gefitinib(AstraZeneca)

HER1/EGFR TK inhibitor Limited accessInterstitial lung disease,

diarrhea, skin rash

Erlotinib(Genentech)

HER1/EGFR TK inhibitor ApprovedInterstitial lung disease,

diarrhea, skin rash

Lapatinib(GlaxoSmithKline)

Dual HER1/EGFR & 2 inhibitor II

Diarrhea, skin rash, N/V, fatigue

Cetuximab(Imclone/BMS)

HER1/EGFR MoAbApproved CRC,

SCCHNSkin rash,

hypersensitivity reactions

Panitumumab(Amgen)

HER1/EGFR MoAb II Skin rash, asthenia

Matuzumab(EMD Pharmaceuticals)

HER1/EGFR MoAb II Skin rash, flushing

Agent MechanismPhase in

DevelopmentManufacturer

Bevacizumab MoAb-Inhibits VEGF binding III Genentech

AE-941 Inhibits VEGF binding & MMPs III AEterna Laboratories

VEGF trap Blocks VEGF-1 and VEGF-2 I → IIRegeneron/

sanofi-aventis

Multi-targeted TKIs that includes VEGF inhibition:

ZD6474 VEGFR-2, EGFR II → III AstraZeneca

ZD2171 VEGFR-1, VEGFR-2, VEGFR-3 I/II AstraZeneca

Sunitinib pan-VEGFR, PDGF, RET, others II Pfizer

Sorafenib VEGFR-2, PDGF, RAF, others II → III Bayer/Onyx

AMG 706 VEGFR, PDGF, Kit, RET II Amgen

AEE788 VEGFR, EGFR, HER2 I/II Novartis

Vatalanib pan-VEGF inhibitor II Schering/Novartis

Angiogenesis Inhibitors in Lung Cancer

Phase III Trial of Paclitaxel/Carboplatin Plus Bevacizumab (E4599)

First-line Stage IIIB/IV NSCLC

(N = 842)Non-squamous cell

CP 6*

CP 6 + Bevacizumab

(15 mg/kg q3wk), then

Bevacizumab until PD

PD

PD

• Primary end point: Survival

• Exclusion criteria: Squamous cell histology, CNS metastases, active cardiovascular disease

• Accrual complete April 2004

C: carboplatin; P: paclitaxel*No crossover allowed in this trial

Bevacizumab with Chemotherapy in NSCLC Survival

0 6 12 18 24 30 36

0

20

40

60

80

100

Months

Carboplatin and paclitaxel

Carboplatin and paclitaxel + bevacizumab

Hazard ratio = 0.77, P = 0.007Median survival: 12.5 vs. 10.2 monthsSurvival at 1-year: 52% vs. 44%Survival at 2-years: 22% vs. 17%

Pat

ient

s su

rviv

ing,

%

Sandler et al. NEJM 2006

Carboplatin + Docetaxel + Bevacizumab in NSCLC

• Phase II single institution• Similar eligibility as E4599• 20 patients enrolled• PR 74% • SD 26%• Disease control rate (PR+SD) was 100% after 4 cycles of

therapy• SAE: neutropenic fever, hemoptysis• Overall well tolerated

W. William et al. PASCO 2007 abstract

SWOG 0536: Phase II Study

• Chemo-naïve• Non-Squamous• No Hemoptysis• No Brain Mets

PaclitaxelCarboplatinCetuximab

Bevacizumab

CetuximabBevacizumab

until progression

N = 90

Goal to assess hemorrhage frequency

PI: Kim

Erlotinib in NSCLC BR.21: Overall Survival

1.00

0.75

0.50

0.25

0

*HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.

42.5% improvement in median survival

Sur

viva

l Dis

trib

utio

n F

unct

ion

Erlotinib

Placebo

0 5 10 15 20 25 30

31%

21%

HR = 0.73, P < 0.001

Erlotinib(n = 488)

Placebo(n = 243)

Median survival (months) 6.7 4.7

1-year survival (%) 31 21

Erlotinib + Bevacizumab in Refractory Advanced NSCLC

Median OS = 12.6 mos

73.2% alive at 6 mos (95% CI 59.6-89.9%)

51.8% alive at 12 mos (95% CI 36.5-73.6%)1.0

0.8

0.6

0.4

0.2

0

Ove

rall

Sur

viva

l Pro

babi

lity

Time (Months)0 5 10 15

Treatment Group

Chemo + Placebo (n = 41)

Chemo + Bevacizumab

(n = 40)

Bevacizumab + Erlotinib (n = 39)

ORR 12% 13% 18%

PFS, median 3 mos4.8 mos

HR = 0.66 (95% CI 0.38- 1.16)

4.4 mosHR = 0.72

(95% CI 0.42- 1.23)

OS (6-month rate) 62% 72% 78%

Toxicity SAEs Drug DC’d b/c AE Pulm hem (gr 3-5)

54%24%

0

40%25%5%

33%10%3%

Bevacizumab Plus Chemotherapy or Erlotinib Preliminary Results

Fehrenbacher et al. J Clin Oncol. 2006;24(No 18S):379s. Abstract 7062

Individualized Therapy

• Chemotherapy– Taxanes in breast cancer

• Targeted therapy– Trastuzumab in breast– Imitinab in GIST– ? Lung

Potti et al. NEJM 2006

Alive 5 years Dead of cancer by 2.5 years

Tumor Sample (Patients)

Gen

esLung Metagene Model to Refine the Assessment

of Risk and Guide the Use of Adjuvant Chemotherapy in Stage IA NSCLC

ERCC1 and Lung Cancer

• Patients with completely resected non-small-cell lung cancer and excision repair cross-complementation group 1 (ERCC1)-negative tumors appear to benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors do not.

Olaussen et al. NEJM 2006

BATTLE Biomarker-based Approaches of Targeted

Therapy for Lung Cancer Elimination

PI: Waun Ki Hong, MDCo-PI: Edward S. Kim, MD

Roy Herbst, MD, PhDLi Mao, MD

BATTLE Workflow Timeline

PatientRegistration

Consent

EvaluateEligibility

BaselineVisit

CollectTissue

BiomarkerProfile

2-weeks

AdaptiveRandomization

Trial SpecificConsent Signed

Drug Starts

8-weeks

Measure Response

Registration BIOPSY Assign Trial Response

RandomizeBiomarkers used to randomize based on pre-study hypothesis

Treatment

5 Biomarker Groups EGFR (+)

K-RAS(+) or B-RAF(+) VEGF(+) or VEGFR(+)

RXRs(+) or Cyclin D1(+) All(-)

EGFR mutationEGFR gene amplify

pEGFR (Y1068)ErbB3 expressionK-RAS mutationB-RAF mutation

VEGF expressionVEGFR-2 expression

RXR expressionRXR expressionRXR expression

Cyclin D1 expression Cyclin D1 amplification

At Progression 

Biopsy and Biomarker

assessment and profiling

(optional)

After Cycle 1 

Biopsy and Biomarker

assessment and profiling

(optional)CT scan

Proposed Phase II Trials

 ErlotinibZD6474

Bexarotene + Erlotinib

BAY43-9006

Proposed Phase II Trials

(optional) 

ErlotinibZD6474

Bexarotene + Erlotinib

BAY43-9006

1. Enrollment2. Biopsy3. Biomarker

assessment4. Place into

trials

CT scans after cycles 2, 4, 6

until progression

SCHEMA: BATTLE

Treatment OptionsMetastatic Breast Cancer

• Single Chemotherapy– Taxanes– Capecitabine– Gemcitabine– Navelbine– Trastuzumab

• Combos– Taxanes + trastuzumab– Navelbine + trastuzumab– Carboplatin + paclitaxel + trastuzumab– Gemcitabine + paclitaxel– Docetaxel + capecitabine

• ER-PR+– Aromatase inhibitors

• Exemestane, anastrozole, letrozole

– Tamoxifen– Fulvestrant– Megace

Treatment OptionsMetastatic Lung Cancer

• Chemotherapy– Platinums– Taxanes

• Docetaxel, paclitaxel

– Pemetrexed– Gemcitabine– Navelbine– CPT-11

• Combinations– Taxanes + EGFR– EGFR + VEGF– Mitomycin + vinblastine– Bevacizumab

• Targeted Agents– EGFR inhibitors

• Cetuximab, erlotinib, gefitinib

– Angiogenesis inhibitors• Sorafenib

– Proteosome inhibitors• Bortezomib

– Other TKIs– mTOR

• CCI-779• RAD001

– RAS/RAF

Future Objectives

• Define a high-risk population– Prior to diagnosis– After curative treatment

• Screening strategy• Better patient-defined treatments

– Chemotherapy– Targeted therapy

Principles of Lung Cancer Therapy

• Chemotherapy and targeted therapy with similar efficacy• Paradigm is in evolution• Targeted ± chemotherapy/targeted combinations

investigated• Performance status and quality of life very important to

patients• Tissue-based personalized therapy is the future• Looking forward to the next few years