update nsclc

Clinical Update and Advances in the Treatment of NSCLC

Program Overview

• Incidence and epidemiology Subtypes Staging

• Adjuvant therapy for resectable disease Management of treatment-related toxicities Neoadjuvant therapy

• Treatment of metastatic disease• Treatment of the elderly and poor PS patients• Targeted therapy

Anti-EGFR targeted agents Antiangiogenic agents

• Summary and future directions

Lung CancerIncidence and Epidemiology

Leading Causes of Cancer-related Deaths

564,830 cancer deaths;162,460 (29%) due to lung cancer

174,470 new cases of lung cancer

Lung and bronchus 31%†

Colon and rectum 10%

Prostate 9%

Pancreas 6%

Leukemia 4%

Lung and bronchus 26%†

Breast 15%

Colon and rectum 10%

Pancreas 6%

Ovary 6%

Leading Sites* by Sex, United States, 2006 Estimates

*Excludes basal and squamous cell skin cancer and carcinoma in situ, except urinary bladder. †Includes both non-small cell lung cancer (NSCLC) and small cell lung cancer. American Cancer Society. Cancer Facts and Figures, 2006.

Lung Cancer: High Incidence, High Mortality

50,000

100,000

150,000

200,000

250,000

Breast Colon andrectum

Lung Prostate

IncidenceMortality

American Cancer Society. Cancer Facts and Figures, 2006.

Risk Factors for Lung Cancer

• Environmental factors Smoking/second-hand smoke Air pollution Lung disease (tuberculosis) Asbestos Radon

• Genetic predisposition Chronic obstructive pulmonary disease (COPD)

• Prevention

NCCN Guidelines. Version 2.2006; April 2006.

Lung Cancer Subtypes

Non-small Cell Lung Cancer

http://www.ncbi.nlm.nih.gov.

Small Cell Lung Cancer

Large Cell Carcinoma10%-15%

Adenocarcinoma35%-40%

Squamous Cell Carcinoma25%-30%

Squamous Cell Carcinoma

• Occurs most frequently in men and older people of both sexes

• Strongly associated with smoking

• Prominent EGFR over-expression and increased gene copy number per cell

McDoniels-Silvers A. Clinical Cancer Research. 2002;8:1127-1138; Movsas B, et al. Non-small cell lung cancer. Cancer Management: A Multidisciplinary Approach. CMP Media LLC, Lawrence KS, 2005, 111-154.

Adenocarcinoma

• Most common type of lung cancer

• Includes bronchioaveolar carcinoma (BAC) as a subtype

McDoniels-Silvers A. Clinical Cancer Research. 2002;8:1127-1138; Movsas B, et al. Non-small cell lung cancer. Cancer Management: A Multidisciplinary Approach. CMP Media LLC, Lawrence KS, 2005, 111-154.

Prognostic Factors in NSCLC

• Stage at presentation

• Performance status

• Weight loss

• Sex

• Age

• Molecular markers associated with poor prognosis ras mutations Overexpression of EGFR

Ciardiello F. Curr Opinion Oncology. 2004;16:130-135.

Non-small Cell Lung Cancer Stages: TNM Staging System

Nodes T1 T2 T3 T4

N0 IA IB IIB IIIB

N1 IIA IIB IIIA IIIB

N2 IIIA IIIA IIIA IIIB

N3 IIIB IIIB IIIB IIIB

Stage IV=M1

T, primary tumor; N, regional lymph nodes; M, distant metastasis.

NSCLC Stages at Presentation

31%Stage III

38%Stage IV

24%Stage I

7%Stage

Mountain CF. Semin Surg Oncol. 2000;18:106-115.

NSCLC Survival

StagePathologic

TNM 5-y Survival

Stage IA T1N0M0 67%

Stage IB T2N0M0 57%

Stage IIA T1N1M0 55%

Stage IIB T2N1M0

T3N0M0

Stage IIIA T1-2N2M0

T3N1-2M0

23%-25%

Stage IIIB T4N0-3M0T1-4N3M0

Stage IV Any T, Any N, M1 <1%

Mountain CF. Semin Surg Oncol. 2000;18:106-115; Fry WA, et al. Cancer. 1996;77:1949-1995.

NSCLC: Stage IA/B

2 cmStage IAStage IA

N0: No lymph node involvement

M0: No distant metastasis

Stage IBStage IB

T: T <3 cm; no lobar bronchus involvement

Any of the following • T >3 cm• Main bronchus

involvement 2 cm distal to carina

• Tumor invades visceral pleura

• Tumor with distal atelectasis

NSCLC: Stage IIA/B

Stage IIAStage IIA

T: T <3 cm; no lobar bronchus involvement

N1: Ipsilateral peribronchial and/or hilar nodes involved

M0: No distant metastasis

Stage IIBStage IIB2 cm

• Any of the following • Tumor with main

bronchus involvement <2 cm distal to carina

• Tumor that invades chest wall, diaphragm, mediastinal pleura, parietal pericardium

• Tumor with distal atelectasis

NSCLC: Stage IIIA

N1: Ipsilateral

peribronchial and/or

hilar nodes involved

N2: Ipsilateral

mediastinal and/or

subcarinal nodes

involved

M0: No distant

metastasis

<2 cm 2 cmT3N1-2M0

Tumor that invades

chest wall, diaphragm,

mediastinal pleura,

parietal pericardium

T1-2N2M0

T >3 cm Tumor invades

visceral pleura

Tumor with distal

atelectasis

T 3 cm; no lobar-bronchus involvement

Current Treatment Approaches

Stage Standard Treatment

Stage IA Surgical resection

Stage IB Surgical resection +/- adjuvant chemotherapy*

Stage IIA Surgical resection/adjuvant chemotherapy

Stage IIB Surgical resection/adjuvant chemotherapy

Stage IIIA Surgical resection/adjuvant chemo and/or RT

Concurrent chemotherapy/RT

Stage IIIB Concurrent chemotherapy/RT

Stage IV Doublet chemotherapy**

*Strauss GM, et al. ASCO 2006. Abstract 7007.

**Single-agent chemotherapy recommended for the elderly and individuals with poor performance status (PS 2).

Adjuvant Therapy for Resectable Non-small

Cell Lung Cancer

Adjuvant Chemotherapy Rationale

• Adjuvant treatment decisions are based on determining the relative benefit of a treatment

• Reducing the risks for relapse and mortality vs potential side effects and complications

Adjuvant Therapy for Resectable NSCLC: Recommendations

Stage Recommended Treatment

Stage IA Surgical resection + observation

Stage IB Surgical resection +/- cisplatin-based* chemotherapy

Stage II Surgical resection + cisplatin-based chemotherapy

Stage IIIA Surgical resection in select patients + cisplatin-based chemotherapy

*Strauss GM, et al. ASCO 2006. Abstract 7007.

Common Adjuvant Therapy Combinations

• Drug combinations most frequently used in first-line chemotherapy for NSCLC Vinorelbine and cisplatin Gemcitabine and cisplatin Paclitaxel and cisplatin Docetaxel and cisplatin

Meta-analysis of Prior Adjuvant Chemotherapy Studies

Overall Survival by Therapy Type

Hazard Ratio (95% CI) P-value

Absolute Benefit

at 5 Years

Meta-analysis of

cisplatin-based drugs

0.87 (0.74-1.02) 0.08 5%

Efficacy of Adjuvant Chemotherapy vs Observation Alone

Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995;311:899-909.

No. at risk:Surgery plus chemotherapy 706 649 590 526 462 419 371 330 295 255 206Surgery 688 633 648 482 433 382 353 307 258 215 177

Meta-analysis of Prior Adjuvant Chemotherapy Studies (cont.)

0 6 12 18 24 30 36 42 48 54 60

Time from randomization (months)

Surgery pluschemotherapy

Surgery

Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995;311:899-909.

HR=0.86 [0.74-1.02]P=0.08

Randomized Adjuvant Chemotherapy Trials

• IALT Cisplatin-based chemotherapy vs observation

• BR.10 Cisplatin/vinorelbine vs observation

• CALGB 9633 Carboplatin/paclitaxel vs observation

• ANITA Cisplatin/vinorelbine vs observation

IALT Schema: Cisplatin-based Adjuvant Chemotherapy

RANDOMIZE

Cisplatin-based chemotherapy+ etoposide or vinorelbine

(as prespecified by treating center)(n=935)

Observation(n=932)

Follow-upanalysis

N=1867• Completely resected stage I-III NSCLC

• Age >18• PS 0-1

Le Chevalier T, et al. N Engl J Med. 2004;350:351-360.

IALT: Patient Characteristics

Le Chevalier T, et al. N Engl J Med. 2004;350:351-360.

Outcome Chemotherapy Control

N 932 935

Median age 59 59

Sex (M/F) 81%/19% 80%/20%

IALT: Effects of Cisplatin on Overall Survival

0 1 2 3 4 5Years

Chemotherapy

Control

Arriagada R, et al. N Engl J Med. 2004;350:351-360.

At risk:Chemotherapy 932 775 624 450 308 181Control 935 774 602 432 286 164

HR=0.86 [0.76-0.98]P<0.03

• Absolute benefit at 5 years: 4.1%• 7,000 lives saved per year worldwide

IALT Survival Rates and Toxicities

• Survival OS at 5 years: 44.5% vs 40.4% (P<0.03)

• 4.1% absolute benefit DFS at 5 years: 39.4% to 34.3% (P<0.003)

• 5.1% absolute benefit ERCC1 may predict benefit of cisplatin-based adjuvant

chemotherapy• Toxicities

0.8% risk of treatment-related death with chemotherapy (7 patients)

23% risk of grade 4 toxicity, primarily neutropenia

Arriagada R, et al. N Engl J Med. 2004;350:351-360; Soria J, et al. ASCO. 2006. Abstract 7010.

JBR.10 Schema: Phase III Trial of Adjuvant Chemotherapy

RANDOMIZE

Vinorelbine 25 mg/m2 every week for 16 weeks +

cisplatin 50 mg/m2 on days 1 and 8every 4 weeks for 4 cycles

(n=242)

Observation(n=240)

Follow-upanalysis

N=482• Completely resected stage IB/II NSCLC

• Age ≥18• PS 0-1• +/- K-ras mutations

Winton T, et al. N Engl J Med. 2005;352:2589-2597.

JBR.10: Effects of Vinorelbine and Cisplatin Adjuvant Chemotherapy

OutcomeChemotherapy

GroupObservation

Group P-value

Median overall survival 94 months 73 months 0.009

5-year survival 69% 54% 0.03

JBR.10: Effects of Vinorelbine and Cisplatin Adjuvant Chemotherapy

P=0.006

Overall Survival, All Patients

0 2 4 6 8 10Years

Vinorelbine plus cisplatin

Observation

Hazard ratio for death: 0.69 (P=0.04)

No. at risk:Observation 108 91 57 29 8 0

Vinorelbine 111 91 65 27 6 0 plus cisplatin

JBR.10: Survival for Stage IB and Stage II Subsets

0 2 4 6 8 10

ObservationVinorelbine plus cisplatin

0 2 4 6 8 10

ObservationVinorelbine plus cisplatin

Overall Survival, Patients with Stage IB Non-small Cell Lung Cancer

Overall Survival, Patients with Stage II Non-small Cell Lung Cancer

No. at risk:Observation 112 91 57 18 5

0Vinorelbine 111 100 54 24 6

0 plus cisplatin

P=0.79 P=0.004

JBR.10: Adjuvant Chemotherapy in the Elderly

Pepe C, et al. ASCO 2006. Abstract 7009.

All randomized patients N=482

Observation N=240

*18 patients who received vinorelbine 30 mg/m2/week excluded

Prognostic factors

Dose intensity (N=150 vs 63

Chemotherapy toxicities (N=150 vs 63)

Elderly (>65)N=67

Young (<65)N=157

*Chemotherapy N=224

JBR.10: Adjuvant Chemotherapy in the Elderly

Pepe C, et al. ASCO 2006. Abstract 7009.

0 2 4 6 8 1012

H-R=0.61Log-rank, P=0.04

Overall Survivalby Treatment Arm, Age >65

Observation N=78Chemotherapy N=77

Time in years

0 2 4 6 8 1012

H-R=0.66Log-rank, P=0.13

Disease Specific Survivalby Treatment Arm, Age >65

Observation N=78Chemotherapy N=77

Time in years

JBR.10 Survival Rates and Toxicities

• Survival OS at 5 years was 69% vs 54% (P=0.012) RFS at 5 years was 61% vs 48% (P=0.012)

• Toxicities Febrile neutropenia occurred in 7% of patients Neurotoxicity (paresthesias, numbness, and hearing

problems) was also observed

RFS, relapse-free survival.

CALGB 9633 Schema: Randomized Trial of Adjuvant Chemotherapy

RANDOMIZE

Paclitaxel 200 mg/m2 over 3 hours+ carboplatin AUC 6

both on day 1 every 3 weeks for 4 cycles

(n=173)

Observation

(n=171)

Follow-upanalysis

N=384• Completely resected stage IB NSCLC

• Age >18

CALGB, cancer and leukemia group B.Strauss GM, et al. J Clin Oncol. 2004;22:7019; Strauss GM, et al. ASCO 2006. Abstract 7007.

CALGB 9633: Overall Survival - ASCO 2004 vs ASCO 2006

Strauss GM, et al. J Clin Oncol. 2004;22:7019; Strauss GM, et al. ASCO 2006. Abstract 7007.

ASCO: 2004 ASCO: 2006

0 2 4 6 8Survival Time (Years)

ObservationChemo

0 1 2 3 4 5 6 7 8 90 2 4 6 8

Survival Time (Years)

ObservationChemo

0 1 2 3 4 5 6 7 8 9

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

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

ObservationChemo

Survival time (years) Survival time (years)

CALGB 9633: Disease-free Survival – ASCO 2004 vs ASCO 2006

ASCO: 2004 ASCO: 2006

0 2 4 6 8

Survival time (years)

0 1 2 3 4 5 6 7 8 9

ObservationChemo

0 2 4 6 8

Survival time (years)

ObservationChemo

0 1 2 3 4 5 6 7 8 9

HR=0.69; 90% CI: 0.51-0.92 P=0.02

HR=0.74; 90% CI: 0.57-0.96 P=0.03

Strauss GM, et al. J Clin Oncol. 2004;22:7019;Strauss GM, et al. ASCO 2006. Abstract 7007.

CALGB 9633 Survival Rates and Toxicities

• Study was closed early after an interim analysis showed a P-value for OS less than pre-specified stopping boundary DFS improved in intent to treat analysis with adjuvant

chemotherapy Trend toward improvement in OS but not significant (P=0.10) 3-year survival (79% vs 70%, P=0.45) compared with 5-year

survival (60% vs 57%, P=0.32) • Toxicities

No treatment-related deaths were observed Myelosuppression was the most common grade 3 or 4

toxicity Grade 3 neuropathy occurred in 5% of patients

Strauss GM, et al. J Clin Oncol. 2004;22:70192; Strauss GM, et al. J Clin Oncol. 2004;Suppl. 22:621a; Strauss GM, et al. ASCO 2006. Abstract 7007.

ANITA Schema: Randomized Phase III Trial of Adjuvant Chemotherapy

RANDOMIZE

Vinorelbine 30 mg/m2/weekfor 16 weeks

+ cisplatin 100 mg/m2

on day 1 every 4 weeks for 4 cycles

(n=407)

Observation(n=433)

Follow-upanalysis

N=840• Completely resected stage IB, II, or IIIA NSCLC

• PS 0,1, or 2• Age 18-75

Douillard J, et al. ASCO 2005. Abstract 7013.

ANITA: Effects of Vinorelbine and Cisplatin Adjuvant Chemotherapy

OutcomeChemotherapy

GroupObservation

GroupHazard Ratio

(95% CI) P-value

Median overall survival

65.8 months 43.8 months 0.79 (0.66-0.95)

7-year survival 45.2% 36.8%

Stage I (p T2N0)

ANITA: Effects of Vinorelbine and Cisplatin in Stage I (p T2N0) Disease

0 20 40 60 80 100

OBSNVB + CDDP

Months

Stage I (p T2N0)

OBSn=155

NVB + CDDPn=146

Death 61 58

Median months

99.7 Not reached

Overall Survival

ANITA: Effects of Vinorelbine and Cisplatin in Stage II Disease

Stage II

Stage IIOBS

n=114NVB + CDDP

Death 70 46

Median months

36.5 65.8

0 20 40 60 80 100

OBSNVB + CDDP

Months

ANITA: Effects of Vinorelbine and Cisplatin in Stage IIIA Disease

Stage IIIA

Stage IIIAOBS

n=159NVB + CDDP

Death 118 99

Median months

24.1 38.6

0 20 40 60 80 100

OBSNVB + CDDP

Months

ANITA Survival Rates and Toxicities

• Survival Median survival was 65.8 months vs 43.7 months (P=0.0131) OS at 2 years was 68% vs 63% OS at 5 years was 51% vs 43% OS at 7 years was 45% vs 37%

• Toxicities Grade 3/4 toxicities

• Neutropenia 86%

• Febrile neutropenia 8.5%

• Peripheral neuropathy 3% 5 patients (1%) died of drug-related toxicity

Summary: Randomized Adjuvant Chemotherapy Trials

• IALT Supported platinum-based chemotherapy, results were

moderately significant

• BR.10 Statistical advantage in prolonging overall survival

demonstrated

• CALGB 9633 Risk of death found to be significantly lower

• ANITA Overall survival and relapse rate significantly improved

LACE: Adjuvant Cisplatin-based Chemotherapy Improves Survival

• Meta-analysis of individual patient data collected and pooled from the 5 largest trials (ALPI, ANITA, BLT, IALT and JBR10) of cisplatin-based therapy in completely resected patients

• Compared cisplatin-based CT vs no CT, or cisplatin-based CT + radiotherapy vs postoperative radiotherapy

• Primary endpoint Overall survival

Pignon JP, et al. ASCO 2006. Abstract 7008.

LACE: Overall Survival By Trial

Trials (associated drug(s)): ALPI, MTC+VDS; ANITA, NVB; BLT, NVB/VDS/MTC+VDS/MTC+IFM; JBR10, NVB; IALT, NVB/VDS/VLB/VP16. Pignon JP, et al. ASCO 2006. Abstract 7008.

OS by Trail

TrailNo. Deaths/No. Entered

Hazard Ratio(Chemotherapy/Control) HR [95% CI]

ALPI 569/1088 0.95 [0.81; 1.12]

ANITA 458/840 0.82 [0.68; 0.98]

BLT 152/307 1.00 [0.72; 1.38]

IALT 980/1867 0.91 [0.80; 1.03]

JBR10 197/482 0.71 [0.54; 0.94]

Total 2356/4584 0.89 [0.82; 0.96]

Tests for heterogeneity: P=0.34 Chemotherapy effect: P=0.004

Chemotherapy better Control better0.0 0.5 1.0 1.5 2.0

LACE: Benefit Appears to Be Stage Dependent

CT Effect and Stage

CategoryNo. Deaths/No. Entered

Hazard Ratio(Chemotherapy/Control) HR [95% CI]

Stage IA 102/347 1.41 [0.96; 2.09]

Stage IB 509/1371 0.92 [0.78; 1.10]

Stage II 880/1616 0.83 [0.73; 0.95]

Stage III 865/1247 0.83 [0.73; 0.95]

Tests for trend: P=0.051CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin+vinorelbine (13% of stage IA patients vs ~43% for other stages)

Chemotherapy better Control better0.5 1.0 1.5 2.0 2.5

LACE: Summary

• Cisplatin-based chemotherapy improves overall and disease-free survival in patients with NSCLC

• Multi-variant analyses were not able to study the role of the associated drug and cisplatin dose, despite the large number of patients

• Cisplatin-based chemotherapy is effective in stage II and III NSCLC

CISCA: Cisplatin vs Carboplatin Meta-analysis

• Randomized trials comparing cisplatin- and carboplatin-based chemotherapy Primary endpoint

• Overall survival Secondary endpoints

• Response rate and toxicity• 2,968 patients were randomized to receive CT with

cisplatin (1,489) or with carboplatin (1,479), respectively RR was 30% (cisplatin) vs 24% (carboplatin)

• Carboplatin was associated with a relative risk of death 7% higher compared with cisplatin, P=0.101)

Ardizzoni A. ASCO 2006. Abstract 7011.

Adjuvant Chemotherapy: Summary

• Adjuvant chemotherapy in the setting of completely resected NSCLC is a subject of controversy

• Statistically significant survival benefit to such chemotherapy

• Toxicities related to treatment call into question whether this apparent clinical benefit warrants the risk

Management of Treatment-related Toxicities

Common Symptoms/Side Effects in NSCLC

• Symptoms related to disease Dyspnea Pain Fatigue

• Symptoms related to treatment Myelosuppression Pain Fatigue

Management of Dyspnea

• Assessment challenging, subjective; based on patient’s responses

• Activity planning to avoid symptoms and allow relief

• Medications Corticosteroids Opioids Oxygen therapy

• Nontraditional/investigational therapies Acupuncture Massage Exercise

Bruera E, et al. Principles and Practice of Supportive Oncology. Philadelphia, PA: Lippincott-Raven Publishers; 1998:295-308.

Management of Pain

• Assessment Must identify etiology for effective treatment

• Medications Opioids NSAIDs Corticosteroids

• Nonpharmacologic interventions Heat/cold Topical agents Massage Behavioral therapy

National Cancer Institute. Pain (PDQ) Health Professional Version. Available at: http://www.cancer.gov/cancertopics/pdq/supportivecare/pain/Patient/page4. Accessed January 30, 2006.

Myelosuppression

• Most common side effect of chemotherapy Neutropenia Anemia

• Neutropenia is the primary dose-limiting toxicity of chemotherapy Often results in dose reductions or delays in treatment

Rivera E. Breast Cancer Res. 2003; 5(5): R114-R120; Crawford J. J Support Oncol. 2004;2(suppl 2):36-39.

Neutropenia

• Chemotherapy-induced neutropenia can lead to febrile neutropenia

• Febrile neutropenia (FN) ANC >1.0×109/L with a temperature >100.6°F ~30% of patients receiving CT for NSCLC Regimens with an intermediate risk of FN (10%-20%)

• Cisplatin, paclitaxel Regimens with a high risk of FN (>20%)

• Docetaxel, carboplatin

• Gemcitabine, ifosfamide, vinorelbineANC, absolute neutrophil count; CT, chemotherapy.Rivera E. Breast Cancer Res. 2003; 5(5): R114–R120; Kuderer NM, et al. Proc Am Soc Clin Oncol. 2002;21:250a; Bonadonna G, et al. BMJ. 2005;330:217.

Neutropenic Complications and Considerations

• Febrile neutropenia, severe neutropenia, or dose delay or reduction due to neutropenia

• Prophylactic use of colony-stimulating factors can reduce the risk, severity, and duration of severe and FN

• Maintaining chemotherapy dose intensity in the initial cycles may be associated with improved outcomes

Caggiano V, et al. Cancer. 2005;103:1916-1924; Kuderer NM, et al. Proc Am Soc Clin Oncol. 2002;21:250a; Bonadonna G, et al. BMJ. 2005;330:217.

Assessment of Febrile Neutropenia

• Assessment Risk factors predictive for febrile neutropenia

Increasing age Active tissue infection Preexisting neutropenia from prior myelosuppressive therapy

Poor performance status

History of recurrent chemotherapy-induced

neutropenia

Preexisting neutropenia from radiation therapy to bone marrow

Bone marrow involvement

Comorbid disease

Ozer H, et al. J Clin Oncol. 2000;18:3558-3585. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. v2.2005. 2005.

2005 NCCN Guidelines: Decision Tree for Primary Prophylaxis

Disease

Intermediate10%-20%

Consider

Use G-CSF

No Routine G-CSF

1. Evaluate1. Evaluate 2. Assess Risk*2. Assess Risk* 3. Intervene3. Intervene

Chemotherapy Regimen

Patient Risk Factors

Treatment Intent

High >20% Risk

Low<10% Risk

*Risk of FN or neutropenic event compromising treatment.

Clinical Benefit of Pegfilgrastim in First and Subsequent Cycles

S CR E E NING

C H EMO T H E RA P Y *

RANDOM I Z A T I ON

Febrile Neutropenia

Placebon = 465

Pegfilgrastimn = 463

Double-blind Phase

Docetaxel+

Pegfilgrastim

Docetaxel Alone

Docetaxel+

Pegfilgrastim

Docetaxel Alone

Open-label Phase

**Docetaxel 100 mg/m2 IV given on day 1 and blinded product given on day 2. Four 21- day cycles were planned.Vogel C, et al. J Clin Oncol. 2005;23:1178-1184.

Clinical Benefit of Pegfilgrastim in First and Subsequent Cycles (cont.)

Efficacy of Pegfilgrastim for Preventing Febrile Neutropenia

OutcomePegfilgrastim

(n=463)Placebo (n=465)

% Reduction P-value

Febrile neutropenia 1% 17% 94 <0.001

Hospitalization for febrile neutropenia

1% 14% 93 <0.001

Use of IV anti-infectives 2% 10% 80 <0.001

Vogel C, et al. J Clin Oncol. 2005;23:1178-1184.

Use of Pegfilgrastim in NSCLC

• 2 small trials performed in NSCLC patients A single pegfilgrastim dose per cycle maintains

neutrophil counts after docetaxel and gemcitabine chemotherapy for advanced NSCLC1

A single pegfilgrastim dose per cycle of dose-dense carboplatin/vinorelbine protects against FN2

1. Fortner BV, et al. 2003 ASCO Annual Meeting. Abstract 2799; 2. Riedel R, et al. Abstract 2826.

Prevention of FN: Growth Factor Support

Misset JL, et al. Ann Oncol. 1999;10:553-560; Green MD, et al. Ann Oncol. 2003;14:29-35; Holmes FA, et al. J Clin Oncol. 2002;20:727-731.

Pegfilgrastim

Control

Filgrastim

(n=42) (n=80) (n=77) (n=156) (n=154)

Misset et al. Green et al. Holmes et al*.

N=157 N=310

Colony Stimulating Factor Support: Summary

• Dose delay and dose reduction can result in care that is less than optimal

• Reductions in total dose and dose intensity have an adverse effect on DFS and OS

• Prophylactic growth-factor support appears to decrease treatment-related morbidity and to increase the likelihood of the administration of full-dose chemotherapy on time

Crawford J. J Support Oncol. 2004;2(suppl 2):36-39.

Growth Factor Support: Unanswered Questions

• If growth factor support is provided, would the dose intensity delivered increase and by how much?

• Would the rate of neutropenic complications increase because of the higher chemotherapy dose delivered?

Crawford J. J Support Oncol. 2004;2(suppl 2):36-39.

Anemia

• Anemia defined as hemoglobin <11 g/dL

• Anemia is a common complication of cancer and cancer treatment 50%-60% patients will develop anemia Severity of anemia increases with the use of platinum

combination chemotherapy

• Anemia treatment can improve quality of life (QOL) and clinical outcomes

Okamoto, et al. Ann Oncol. 1992;3:819-824; Langer C. Chemotherapy Foundation Symposium XXI 2003.

Causes of Cancer-related Anemia

• Disease-related anemia Tumor type Stage and duration of disease Presence of infection

• Treatment-related anemia Regimen and intensity of therapy

• Chemotherapy• Radiation therapy• Surgical intervention

Prior cancer treatment

Hemoglobin and Performance Status

• A significant correlation was found between poor performance status score and low Hb level breast cancer (P<0.001)

Barrett-Lee P. Oncologist, 2005;10:743-757.

WHO Performance Score

0 1 2 3 4

Breast cancer

Gynecologic cancer

95% CI: WHO 0, 12.654-12.785; WHO 1, 12.423-12.587; WHO 2, 11.878-12.222; WHO 3, 11.484-12.223; WHO 4, 8.613-13.634

Clinical Consequences of Anemia

Decreased Quality of Life

Reduced Treatment Success

Decreased Survival

Cella D. Semin Oncol. 198;25(suppl 7):43-46; Ludwig H, et al. Semin Oncol. 198;25(suppl 7):2-6; Grogan M, et al. Cancer. 1999;86:1528-1536; Dubray B, et al. Radiology. 1996;201:553-558; Lee W, et al. Int. J. Radiol. Oncol Biol. Phys. 1998;42:1069-1075.

• Chemotherapy may be more toxic or less effective when patients are anemic Fatigue “Full dose on time”

Patient-reported Areas Negatively Affected by Fatigue

Vogelzang NJ, et al. Semin Hematol. 1997;34(suppl 2):4-12.

0 10 20 30 40 50 60 70

Concerns about mortality and survival

Relationships with family and friends

Ability to take care of family

Intimacy with partner

Emotional well-being

Ability to enjoy lifein the moment

Physical well-being

Ability to work

Patients (%)

Lung Head andneck

Prostate Lymphoma Overall

Anemia and Risk of Death

Stasi R, et al. Oncologist. 2005;10:539-554.

Management of Anemia

• Iron supplementation

• Change in chemotherapy regimen

• RBC transfusion

• Erythropoietic-stimulating agents Recombinant human erythropoietin (rHuEPO)

• eg, epoetin alfa, epoetin beta

• Only 50%-60% of patients respond Darbepoetin alfa (erythropoiesis-stimulating protein)

• 2 to 3 times longer serum half-life than rHuEPO

Dicato M. Oncologist. 2003;8:19-21. Gordon MS. Oncologist. 2002;7:331-341; NCCN. Clinical Practice Guidelines in Oncology: Cancer- and Treatment-Related Anemia. v1.2006. 2006.

Erythropoietin Therapy

• Advantages Avoids risks of transfusion therapy

• Allergic/febrile reactions

• Transfusion-associated immunosuppression

• Formation of alloantibodies

• Disadvantages Response not as rapid as therapy via transfusion

• Response can take >4 weeks Can cause hypertension or splenomegaly

Dicato M. Oncologist. 2003;8:19-21. Goodnough LT, et al. N Engl J Med. 1999;340:438-447;Ludwig H, et al. Semin Oncol.1998;25(suppl 7)2-6.

Erythropoietic Agents for Treatment of Anemia in Cancer Patients

• Recombinant human erythropoietin (rHuEPO) eg, epoetin alfa, epoetin beta Has the same biological effects as erythropoietin Only 50%-60% of patients respond

• Darbepoetin alfa Erythropoiesis-stimulating protein 2 to 3 times longer serum half-life than rHuEPO

Erythropoietic Therapy Recommendations

• National Comprehensive Cancer Network (NCCN) Initiate erythropoietic therapy in patients with

Hg <11 g/dL

• American Society of Hematology (ASH) and American Society of Clinical Oncology (ASCO) Initiate erythropoietic therapy in patients with

Hg <10 g/dL RBC transfusion should be considered depending on

the severity of anemia or clinical consequences

NCCN Practice Guidelines in Oncology – v.1.2006. Rizzo JD, et al. J Clin Oncol. 2002;20: 4083-4107.

Erythropoietic Intervention

Late Intervention/ Hb Correction

Transfusion

Chemotherapy treatment

Erythropoietic Treatment

Early Intervention/ Hb Maintenance

Erythropoietic Treatment

Transfusion?

Chemotherapy treatment

Adapted from Rearden, TP. J Clin Oncol, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 8064.

79Schwartzberg LS, et al. Oncologist. 2004;9:696-707.

Clinical Benefit of Darbepoetin alfa and Epoetin alfa

RANDOMIZE

Darbepoetin alfa200 g q2 wk

TREATMENT

2 weeks after last dose of

darbepoetin alfa

1 week after last dose of epoetin alfa

Epoetin alfa40,000 U q wk

2 weeks after

end-of-treatment

Concurrent chemotherapy

1 5 9 13 17 19

(Baseline) Study week

80Schwartzberg LS, et al. Oncologist. 2004;9:696-707.

Individual Analysis by Tumor Type

16%18% 17%

Breast Lung Gyn

Q2W Darbepoetin alfa

QW Epoetin alfa

n= 72 69 51 51 34 35

Combined Analysis by BaselineHemoglobin and Overall

14% 16%

<10 g/dL >10 g/dL Overall

n= 38 38 119 117 157 155

Q2W Darbepoetin alfa

QW Epoetin alfa

Darbepoetin alfa vs Epoetin alfa for Treating Anemia

Outcome

Darbepoetin alfa

(n=157)

Epoetin alfa

(n=155)

Patients achieving target hemoglobin ≥11 g/dL

82% 86%

Median time to target hemoglobin

5 weeks 4 weeks

Mean duration of treatment 9.3 weeks 10.1 weeks

Mean hemoglobin level after achieving target

12.1 g/dL 12.2 g/dL

Schwartzberg LS, et al. Oncologist. 2004;9:696-707.

Noninferiority Study of Darbepoetin alfa (DA) and Epoetin alfa (EA)

• Randomized, open-label, active-controlled, multicenter study DA at a starting dose of 200 µg Q2W over 16 weeks

for the treatment of anemia in patients receiving multicycle chemotherapy

The active control arm received EA at a starting dose of 40,000 U QW

• After the 16-week treatment period, patients were monitored for 2 weeks for adverse events, concomitant medications, and transfusions received

Glaspy J, et al. J Clin Oncol. 2006;24:2290-2297.

Incidence of RBC Transfusions and Sensitivity Analyses

A: Percentages of patients receiving ≥ one transfusionB: Sensitivity analyses—adjusted by screening hemoglobin category (<10 g/dL vs 10 g/dL) and type of chemotherapy administered (platinum-based vs nonplatinum-based) Glaspy J, et al. J Clin Oncol. 2006;24:2290-2297.

Mean (95% CI) Difference between Treatment Groups

In favor of darbepoetin alfa In favor of epoetin alfa

Per protocol analysis set(16 week cohort)

Primary transfusion analysis set/primary analysis set

(16 week cohort)

Per protocol analysis set(all cohorts)

-16 -12 -8 -4 0 4 8 12 16

Noninferiority margin 11.5%

In favor of darbepoetin alfa In favor of epoetin alfa

-16 -12 -8 -4 0 4 8 12 16

Darbepoetinalfa

Epoetin alfa Historical(placebo)

Historical(epoetin alfa)

Darbepoetinalfa

Epoetin alfa Historical(placebo)

Historical(epoetin alfa)

21%16%

26%27%

Effect of Darbepoetin alfa and Epoetin alfa on Hemoglobin

Hemoglobin (Hb) Concentration over Treatment Period

Achievement of Target Hemoglobin Range (11 g/dL to 13 g/dL) by Study Week

11.4411.75

11.7611.85

Baseline Week 9 Week 17

Darbepoetin alfa

Epoetin alfa

Target range

n=606 n=603 n=433 n=431 n=278 n=245

0 1 2 3 4 5 6 7 8 9 1011 12 13 1415 16 17

Time (weeks)

Darbepoetin alfa

Epoetin alfa

Patients at risk:Darbepoetin alfa 606 606 586 521 395 360 290 266 220 194 164 150 122 116 98 86 69 42Epoetin alfa 603 603 577 515 344 302 220 195 147 132 106 97 66 57 48 38 30 21

Darbepoetin alfa and Epoetin alfa Provide Comparable Outcomes

• Safety profiles of DA and EA were consistent with adverse events in anemic cancer patients receiving chemotherapy with no differences observed between groups

• The ability to extend dosing intervals represents an important potential benefit for patients and their caregivers

Overall health

Daily activity

Energy

FACT-anemia

FACT-fatigue

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6

Mean (95% CI) Difference between Treatment Groups

In favor of epoetin alfa In favor of darbepoetin alfa

86Boccia R, et al. Oncologist. 2006;11:409-417.

Darbepoetin alfa 300 g Q3W: Study Schema

Key Eligibility Criteria

Patients ≥18 years old with nonmyeloid malignancies Baseline Hb ≥11 g/dL No RBC transfusion within 2 weeks of screening

No erythropoietic agent within 4 weeks of screening At least 8 additional weeks of chemotherapy Adequate renal and liver function

N=1225, 29% breast cancer

SCREENING

ENROLLMENT

7 days max

4 daysmax

2 3 4 5 6 7* 8 9 10 11 12 13 14 15 16

Darbepoetin alfa300 g Q3W

Darbepoetin alfa administration

Study week

Darbepoetin alfa300 g Q3W500 g Q3W

Darbepoetin alfa (DA) 200 g Q2W vs 300 g Q3W

• DA 200 g Q2W has been shown to be as effective as epoetin alfa 40000 U QW for the treatment of chemotherapy-induced anemia1

• DA 300 g Q3W is well-tolerated and effective for achieving and maintaining evidence-based target Hb levels, allowing for synchronous administration with common chemotherapy regimens2

1. Schwartzberg LS, et al. Oncologist. 2004;9:696-707; 2. Boccia R, et al. Oncologist. 2006; 11:409-417.

500 g Darbepoetin alfa Q3W for Chemotherapy-induced Anemia

• Chemotherapy-induced anemia can be treated with a fixed dose of 500 g Q3W of darbepoetin alfa with comparable efficacy to 2.25 g/kg weekly dosing

• Patients receiving Q3W dosing received fewer blood transfusions than in the weekly arm

• 84% of Q3W patients achieved the target hemoglobin levels (>11 g/dL) compared with 77% QW patients

• Synchronous administration of darbepoetin alfa Q3W with many chemotherapy schedules would be convenient to patients and their healthcare providers

Canon JL et al. J Natl Cancer Inst. 2006;98(4):273-284.

Anemia and Erythropoietic Therapy: Summary

• Cancer-related anemia is common but under-recognized and under-treated

• Anemia is associated with reduced survival

• Darbepoetin alfa has an approximate threefold longer half-life than epoetin alfa and is effective at weekly, Q2W, and Q3W dosing intervals

• Less frequent dosing schedules that have equal efficacies are an obvious benefit to patients

Neoadjuvant Therapy

Neoadjuvant Chemotherapy

• Preoperative chemotherapy may improve the prognosis and survival

• Goal Downstage the tumor before surgery, increasing the

chances for resection

Neoadjuvant Therapy Plus Surgery vs Surgery Alone

• Survival improves significantly with neoadjuvant therapy

Treatment (N=60) Induction CT surgery Surgery alone P-value

Median overall survival 26 months 8 months

5 months

74 months

<0.001

Disease-free survival

Rate of recurrence

20 months

56 months

<0.001

Rosell R, et al. N Engl J Med. 1994;330(3):153-158.

SWOG 9900 Trial: Schema

RANDOMIZE

Paclitaxel carboplatin x 3 cycles

Surgery

SurgeryELIGIBLE

N=600• Clinical stage: T2N0,

T1-2N1, T3N0-1

Pisters K, et al. ASCO 2005. Abstract 7012.

SWOG 9900: Induction Chemotherapy

HR=0.84 [0.60-1.18]P=0.32

Median 1 y 2 y

Preop 47 mo 82% 68%

Control 40 mo 79% 64%

0 12 24 36 48 60

Months

Control

SWOG 9900: Induction Chemotherapy (cont.)

• Overall survival favors and the role of preoperative chemotherapy

TreatmentMedian Overall

Survival P-value

SWOG 9900 Induction CT surgery 47 months 0.32

Surgery alone 40 months

Treatment-related Toxicities and Induction Therapy

• Death

• Neutropenia

• Esophagitis

• Nausea/emesis

• Pneumonia

Adjuvant vs Neoadjuvant Therapy: Summary

• Preoperative treatment may have a favorable effect on outcome

• Aggressive neoadjuvant approaches may be accompanied by treatment-related toxicities, including death

Treatment of Advanced Non-small Cell Lung Cancer

Stage IV Disease: Goals of Therapy

• Stage IV NSCLC Indicates presence of metastatic disease Largely incurable Properly selected patients may benefit from

chemotherapy with regard to survival and palliation

• Goals of treatment are To prolong survival Palliative To improve quality of life

Best Supportive Care vs Chemotherapy in Advanced Patients

Socinski M. Chest. 2003;123:226S-243S.

0 6 12 18 24

Time from randomization (months)

Best supportive care (BSC)+ chemotherapy

Supportive care

No. at risk:BSC + chemotherapy 416 219 98 47 28Supportive care 362 125 55 28 14

Best Supportive Care and Chemotherapy Prolong Survival

Socinski M. Chest. 2003;123:226S-243S.

BSC CT+BSC BSC CT+BSC

20No. of patients alive in the US at 1 year

Current Treatment Guidelines for Metastatic NSCLC

• BSC, best supportive care

Stage IV NSCLCPS 3, 4 PS 0-2

BSC 1st Line Platinum-based Chemotherapy

ProgressionPS 3, 4 PS 0-2

BSC 2nd Line Platinum-based Chemotherapy

Progression

PS 3, 4 PS 0-2

BSC Gefitinib or Phase I/II Clinical TrialAdapted from NCCN Practice Guidelines in Oncology v.2.2006.

ECOG E1594 Schema: Efficacy in Comparable Platinum-based Regimens

RANDOMIZE

Paclitaxel 175 mg/m2/week over 24 hours, day 1Cisplatin 75 mg/m2 day 2,

every 3 weeks (n=288)

N=1155• Stage IIIB/IV

• PS 0-2 • Weight loss• Brain metastases (+/-)

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

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

Paclitaxel 225 mg/m2 over 3 hours, day 1Carboplatin AUC=6 day 1,

ECOG E1594: Comparable Efficacy in Platinum-based Regimens

Cis/PaclitaxelCis/GemcitabineCis/DocetaxelCarbo/Paclitaxel

0 5 10 15 20 25 30

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

Survival by Treatment Group

ECOG 1594: Regimens and Efficacy

RegimenResponse

Median Survival (weeks)

1-year Survival

Time to Progression

(months)

Paclitaxel 175 mg/m2

Cisplatin 75 mg/m2 21% 7.8 31% 3.5

Gemcitabine 1000 mg/m2

d1, 8, 15

Cisplatin 100 mg/m2 d121% 8.1 36% 4.5

Docetaxel 75 mg/m2

Cisplatin 75 mg/m217% 7.4 31% 3.6

Paclitaxel 225 mg/m2

Carboplatin AUC=6 15% 8.2 38% 3.3

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

ECOG 1594 Findings

• Survival curves demonstrate comparable efficacy between various platinum-based regimens

• No difference in long-term survival was observed

“Modern Agents” for Treatment of Advanced NSCLC

• Paclitaxel-based regimens

• Docetaxel-based regimens

• Vinorelbine-based regimens

• Gemcitabine-based regimens

• Irinotecan-based regimens

Comparison of Advanced NSCLC Therapies

Survival Supportive CarePlatinum-based Chemotherapy

Modern Doublet Chemotherapy

Median survival time

4 months 6 months ~10 months

1 year 10% 20% 30%

2 years 0% <5% 10%

Wakelee H, Belani CP. Oncologist. 2005;10(suppl 3):1-10.

First-line Chemotherapy in Advanced Disease: Summary

• Platinum-based therapy is standard first-line treatment for advanced NSCLC

• Non-platinum regimens have similar efficacy and prolong survival to similar extents as platinum-based therapy

• Non-platinum regimens do not show substantially decreased toxicity but may be better tolerated

1. Georgoulias V, et al. J Clin Oncol. 2005;23:2937-2945; 2. Pujol JL, et al. Ann Oncol. 2005;16:602-610; 3. Kosmidis PA, et al. J Clin Oncol. 2005;23:621s; 4. Gridelli C, et al. J Clin Oncol. 2003;21:3025-3034.

Stage IV Disease: Second-line Therapy

Study Treatment

OverallResponse

RateMedian Survival

Time P-value

Hanna et al.1 Pemetrexed 9.1% 8.3 monthsNS

Docetaxel 8.8% 7.9 months

Shepherd et al.2 Erlotinib 8.9% 6.7 months<0.001

Placebo <1.0% 4.7 months

Shepherd et al.3 Docetaxel 7.0 months0.047

Best supportive care

4.6 months

Second-line Treatment for Advanced NSCLC

1. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597; 2. Shepherd FA, et al. N Engl J Med. 2005;353:123-132; 3. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.

Second-line Therapy vs BSC: Shepherd et al.

Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.

RANDOMIZE

Docetaxel 100 mg/m2

(n=49)

Best supportive care(n=100)

N=204• Stage IIIB/IV NSCLC

• Failed/intolerant to ≥1 prior chemotherapy regimen

• PS 0-2

Primary endpoint• Overall survival

Secondaryendpoints• Objective tumor response

• Duration of response

• Changes in quality of life

Docetaxel 75 mg/m2

(n=55)

Chemotherapy Still Shows Benefits vs BSC as Second-line Therapy

0 3 6 9 12 15 18 21

Survival time (months)

0 3 6 9 12 15 18 21

Docetaxel 100 mg/m2 (n=49)

BSC100 (n=51)

Log-rank test, P=0.780 Log-rank test, P=0.010

Docetaxel 75 mg/m2 (n=55)

BSC75 (n=49)

Chemotherapy Still Shows Benefits vs BSC as Second-line Therapy (cont.)

Outcome ArmsBest Supportive

Care P-value

Median overall survival 7.0 months 4.6 months 0.047

1-year survival 29% 19%

Hematologic Toxicities Associated with Treatment

Toxicity

Docetaxel *

Overall 75 mg/m2 100 mg/m2

No. % No. % No. %

Total no. of patients 104 55 49

Anemia 11 10.6 3 5.5 8 16.3

Neutropenia 79 76.0 37 67.3 42 85.7

Thrombocytopenia 1 1.0 0 0 1 2.0

Febrile neutropenia 12 11.5 1 1.8 11 22.4

Septic deaths 3 2.9 0 0 3 6.1

*Incidence of grade 3/4 toxicity per patient.Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.

Phase III Pemetrexed vs Docetaxel for Second-line NSCLC

Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.

RANDOMIZE

Pemetrexed 500 mg/m2

+ Vitamin B12

+ Folic acid + Dexamethasone

(n=283)

Docetaxel 75 mg/m2 +Dexamethasone

(n=288)

• Failed/intolerant to 1 prior chemotherapy regimen

• PS 0-2

Secondaryendpoints

• Toxicity

• Objective response rate

• Progression-free survival

• Time to progression

• Quality of life

Phase III Pemetrexed vs Docetaxel for Second-line: Survival

Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.

0 5 10 15 20

Pemetrexed (n=265)

Docetaxel (n=276)

Patients at risk:Pemetrexed 283 189 78 16 0Docetaxel 288 177 78 19 1

MST 1-y OS

HR=0.99 (95% CI, 0.8 to 1.2)

Stage IV Disease: Current Questions

• In which patients is chemotherapy appropriate?

• What is the optimal chemotherapeutic approach? Regimen? Duration?

• Does second-line chemotherapy improve survival?

• How do outcomes and adverse effects associated with chemotherapy compare with the natural history of the disease?

Treatment in the Elderly Population and Poor

Performance Status Patients

Elderly and Poor Performance Status Patients

• Cisplatin regimens provide a slight advantage over supportive care but can induce severe toxic effects

• Consequently, treatment is frequently contraindicated in the elderly and patients with poor PS Reduction in the functional reserve of many organs

and comorbid conditions

CALGB 9730: Monotherapy vs Combination Therapy

Lilenbaum RC, et al. J Clin Oncol. 2005;23:190-196.

Outcome Paclitaxel Paclitaxel + Carboplatin P-value

Response rate, % 17 30 <0.0001

Median failure-free survival, mo 2.5 4.6 0.0002

1-year survival, % 32 27 NS

CALGB 9730: Age >70

Paclitaxel + Carboplatin Paclitaxel

Response rate 36% 21%

Median survival 8.0 5.8

CALGB 9730: PS 2

Paclitaxel + Carboplatin Paclitaxel

n 40 50

Response rate 24% 10%

Median survival 4.7 2.4

Efficacy of Platinum-based Doublets: STELLAR 3

Outcome

Paclitaxel Poliglumex + Carboplatin

(n=199)Paclitaxel + Carboplatin

(n=198)

Median overall survival, months 7.9 8.0

1-year overall survival 31% 31%

Grade 3/4 neuropathy 17% 10%

Grade 3/4 neutropenia* 28% 17%

Arthralgia/myalgia* (all grades) 17% 31%

All cardiac events* 2% 6%

Alopecia* 14% 43%

*P<0.05. Langer CJ, et al. ASCO 2005. Abstract 7011.

• Efficacy and tolerability similar in older vs younger patients and poor vs good PS patients

SWOG 9308 and 9509: Retrospective Analysis in Advanced NSCLC

SWOG 9308: Vinorelbine + cisplatin vs cisplatin.SWOG 9509: Paclitaxel + carboplatin vs vinorelbine + cisplatin.Kelly K, et al. ASCO 2001. Abstract 1313.

SWOG 9509 SWOG 9308

Paclitaxel/Carbo(N=202)

Vinorelbine/Cis*(N=406)

Total(N=608)

Age <70 164 (82%) 327 (81%) 491 (71%)

Age >70 38 (18%) 79 (19%) 117 (19%)

SWOG 9308 and 9509: Results

<70(n=491)

70(n=117) P-value

TTP (mo) 4.2 3.9 0.62

Median survival (mo) 8.6 6.9 0.06

1-y OS 40% 30% 21%

2-y OS 16% 10% 22%

Kelly K, et al. ASCO 2001. Abstract 1313.

Poor Performance Status Patients

Treatment Arm

Grade 3/4 Toxicity, %

PS 0-1 PS 2

Paclitaxel + cisplatin 20%-68% 30%-60%

Gemcitabine + cisplatin 20%-69% 8%-67%

Docetaxel + cisplatin 22%-61% 12%-59%

Paclitaxel + carboplatin 28%-53% 27%-33%

Death due to drug toxicity 4% 3%

Sweeney CJ, et al. Cancer. 2001;92:2639-2647.

• ECOG E1594 adverse events High number of adverse events in PS 2 and PS 0-1 groups Events and shorter survival in PS 2 patients (n=64) related to disease process rather than treatment

ECOG 1594: Outcome Based on Age

<70 y 70 y

n=912 n=227 P- value

Grade 4 toxicity 66% 71.2% 0.04

OR(%) 22.1 24.5 0.76

PFS (mo) PS 0-1 3.71 3.75

PFS 1-y (%) 6.5 8.6 0.37

PFS 2-y (%) 0.5 2.2 0.04

MS (mo) 8.15 8.25

1-y OS(%) 32.8 35.2 0.53

2-y OS(%) 10.6 13.7 0.24

Langer CJ, et al. ASCO 2003. Abstract 2571.

ELVIS (Elderly Lung Cancer Vinorelbine Italian Study)

Vinorelbine BSC

Response rate 19.7 0

Median survival 28 wk 21 wk

1-y survival 32% 14%

• Statistically significant benefit for patients receiving vinorelbine

Gridelli C. J Nat Cancer Inst. 1999;85:365-376.

Efficacy of Nonplatinum Single-agent vs Doublet Chemotherapy

Outcome Vinorelbine GemcitabineVinorelbine + Gemcitabine

Overall survival 38% 28% 30%

Median time to progression, weeks 18 17 19

Tumor response rate 18% 16% 21%

Overall survival among patients with PS=2 20% 18% 22%

MILES Comparison of Single-agent vs Double-agent Chemotherapy

Gridelli C, et al. J Natl Cancer Inst. 2003;95:362-372.

Targeted Therapy for Non-small Cell Lung Cancer

Targeted Therapy Goals

• Identify drug targets that Are responsible for tumor growth Are key mechanisms in cancer progression Are reversible by inhibition Are dispensable to normal cells Can be measured in tumor tissue

• Identify tumor-specific molecules to minimize risk to other cells Increased specificity leads to reduced toxicity

Thomas M. Chemotherapy Foundation Symposium and Online Education Program. Advances In Research and Practice. November 15, 2003.

Tumorigenic Pathways in the Cell Are Complex

Sigma Aldrich, Inc., St. Louis, MO

Targets for Drug Development

• Angiogenesis VEGF VEGFR FGF Integrin

• Apoptosis Bcl-2 Survivin XIAP p53 Clusterin

• Signaling Ras Raf kinase MEK mTOR PKC

• HER family EGFR HER-2

• Cell cycle Cdks

• Extracellular MMP

• Receptors/kinases c-Kit PDGFR Abl

• Other DNA MTase HDAC Proteasome

EGFR Targeting Strategies in NSCLC

• EGFR is a tyrosine kinase growth factor receptor

• Activated by binding of natural ligands– TGF-– EGF

• Activated EGFR signals through multiple pathways

• Potential to block at various steps in the pathway– Extracellular surface– Intracellular targets

Invasion/metastasis

ProliferationSurvival/anti-apoptosis

Angiogenesis

Gene transcriptionCell-cycle progression

RafRas

PTEN AktSTAT

XXXXXX

EGFR Anti-EGFR(+)XX

Perez-Soler R. Oncologist. 2004;9:58-67.

EGF-induced Signal Transduction and Tumorigenesis

Anti-EGFR Targeted Agents: Biological Rationale

• Activation of EGFR linked with Increased cell proliferation Angiogenesis Metastasis

• Agents that selectively target EGFR could inhibit and prevent the pathogenesis of various cancers

• EGFR expression correlates with Poor response to treatment Disease progression Poor survival

Anti-EGFR Strategies

Signal transduction

mAbs TKIsLigand

Ligand

Survivaland metastasis

Cetuximab

Gefitinib

Erlotinib

Ligand

Cell death

Ligand

Protein synthesis

KK KKKK

Toxinconjugates Antisense

Panitumumab

mAb, monoclonal antibody; TKI, tyrosine kinase inhibitor.Adapted from Raymond E, et al. Drugs. 2000;60(suppl 1):15-23.

Monoclonal Anti-EGFR Antibodies

Pao W, Miller VA. J Clin Oncol. 2005;23:2556-2568.

Monoclonal Antibodies

Under developmentmAb 80

Under developmenth-R3 (TheraCIM)

Under developmentMDX-447 (HuMab-Mouse)

Under developmentEMD-72000 (matuzumab)

Under developmentABX-EGF (panitumumab)

Approved, refractory metastatic CRC, pancreatic, head and neckCetuximab

StatusAgent

Phase I/II EGFR Antibodies

• Cetuximab competes with endogenous ligands for binding at EGFR, functioning as an EGFR antagonist at EGFR

• Once bound to EGFR, cetuximab induces the internalization of EFGR

Compound Class Phase Treatment

Panitumumab Humanized, chimeric monoclonal antibody

II Previously treated metastatic CRC

Cetuximab Human monoclonal antibody

II Treatment-naive and previously treated

Ng M, Cunningham D. Int J Clin Pract. 2004;58:970-976.

Phase II Trials of Cetuximab in Advanced NSCLC

No Prior Chemotherapy

Study Treatment Patients, n PRMedianSurvival

Rosell et al.1 Cetuximab + cisplatin + vinorelbine

43 31.7% 8.3 months

Cetuximab + vinorelbine

43 20% 7.0 months

Robert et al.2 Cetuximab + gemcitabine + carboplatin

35 28.6% 10.3 months

Thienelt et al.3 Cetuximab + paclitaxel + carboplatin

31 26% 11.0 months

PR, partial response.1. Rosell R, et al. Proc Am Soc Clin Oncol. 2004;23:618a; 2. Robert F, et al. J Clin Oncol. 2005;23:9089-9096; 3. Thienelt CD, et al. J Clin Oncol. 2005;23:8786-8793.

Prior Chemotherapy

Study TreatmentNo. Prior Chemo Patients, n PR

MedianSurvival

Lynch et al.1 Cetuximab >1 29 7%

Kim et al.2 Cetuximab + docetaxel

>1 47 28% TTP 3 months

PR, partial response; TTP, time to progression.1. Lynch TJ, et al. Proc Am Soc Clin Oncol. 2004;23:634a; 2. Kim ES, et al. Proc Am Soc Clin Oncol. 2003;22:642a.

Phase II Trials of Cetuximab in Advanced NSCLC

Phase III Trial of Cetuximab in Advanced NSCLC

RANDOMIZE

Cetuximab + cisplatin

+ vinorelbine

Cisplatin +vinorelbine

N=1037• Stage IIIB/IV• EGFR-expressing NSCLC

Secondaryendpoints• Progression-freesurvival

• Tumor response• Disease control• Safety• Quality of life

Von Pawel J, et al. ASCO 2006. Abstract 7109.

EGFR-targeted Agents: Small Molecule Tyrosine

Kinase Inhibitors

Class Agent Status

Small molecule tyrosine kinase inhibitors

Gefitinib Approved for advanced NSCLC

Erlotinib Approved for advanced NSCLC

EKB-569 Under development

CI-1033

HKI 272

BIBW2922

Under development

Tyrosine Kinase Inhibitors

EGFR Tyrosine Kinase Inhibitors: Gefitinib and Erlotinib

• Gefitinib and erlotinib selectively inhibit EGFR tyrosine kinase (aka HER-1 or ErbB-1)

Pavletich N. Structural Biology Program, Memorial Sloan-Kettering Cancer Center.

Gefitinib Molecular Structure Erlotinib Molecular Structure

EGFR Tyrosine Kinase Inhibitors in Recurrent NSCLC

ParameterGefitinib

Monotherapy1

Gefitinib Monotherapy2

Erlotinib Monotherapy3

Study population N=210 N=216 N=57

Overall response rate 18.7% 10.3% 12.3%

Median overall survival 7.8 months 8.4 months

Median progression-free survival 2.75 months

Phase II Trials Assessing Second-line Treatment

1. Fukuoka M, et al. J Clin Oncol. 2003;21:2237-2246; 2. Kris MG, et al. JAMA. 2003; 290:2149-2158; 3. Perez-Soler R, et al. Proc Am Soc Clin Oncol. 2001;20:310a. Abstract.

Patient Characteristics Associated with Response

Response Rate Symptom Improvement

Characteristic (%) Rate (%)

PS 0-1 9 40

PS 2 14 36

2 prior regimens 8 39

3 prior regimens 10 44

>4 prior regimens 15 32

Women 19 49

Men 3 31

Adenocarcinoma 13 43

Other 4 30

Response to Second-line Treatment with Gefitinib

Fukuoka M, et al. J Clin Oncol. 2003;21:2237-2246.

ISEL Trial 709: Phase III Gefitinib in Second- or Third-line NSCLC

RANDOMIZE

Gefitinib 250 mg/day + best supportive care

(n=1129)

Placebo +best supportive care

(n=563)

• Failed/intolerant to prior chemotherapy regimen

Primary endpoints• Survival in overall population

• Survival in those with adenocarcinoma

ISEL, Iressa Survival Evaluation in Lung Cancer. Thatcher N, et al. Lancet. 2005;366:1527-1537.

Adenocarcinoma

All patients

Female

PS 0,1

1 prior chemo

Refractory

Never smoked

Non-adenocarcinoma

Ever smoked

Intolerant

2 prior chemos

PS 2,3

Hazard ratio and 95% CIFavors gefitinib Favors placebo

Survival Response Rate

0.4 0.6 0.8 1 1.5

ISEL Trial 709: Phase III Gefitinib in Second- or Third-line NSCLC (cont.)

Thatcher N, et al. Lancet. 2005;366:1527-1537.

Gefitinib Efficacy and Somatic Mutations in EGFR

• Gefitinib and erlotinib target the ATP cleft within the tyrosine kinase EGFR

• Only about 10% of patients have a rapid and dramatic clinical response to gefitinib

• Most NSCLC patients do not respond to gefitinib

• Efficacy may be attributed to somatic mutations in EGFR gene

Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139.

Characteristics of Patients Responding to Gefitinib

Patient Sex Age Pathological

TypePrior

Regimens Smoker?

Duration

of Therapy

Overall Survival

(mo)EGFR

Mutation Response

1 F 70 BAC 3 Never 15.6 18.8 Yes Major

2 M 66 BAC 0 Never >14.0 >14.0 Yes Major

3 M 64 Adeno 2 Never 9.6 12.9 Yes Partial

4 F 81 Adeno 1 Former >13.3 >21.4 Yes Minor

5 F 45 Adeno 2 Never >14.7 >14.7 Yes Partial

6 M 32 BAC 3 Never >7.8 >7.8 Yes Major

7 F 62 Adeno 1 Former >4.3 >4.3 Yes Partial

8 F 58 Adeno 1 Former 11.7 17.9 Yes Partial

9 F 42 BAC 2 Never >33.5 >33.5 No Partial

Response to Gefitinib May Be Due to Somatic Mutation of EGFR

• Majority of patients responding to gefitinib were Women Had never smoked Had BAC

• Heterozygous mutations were detected in 8/9 patients 4 mutations were in frame deletions No mutations were detected when matched with

normal tissue

• Diagnostic testing may identify patients for gefitinib therapy

EGFR Somatic Mutation: Summary

• A subgroup of patients have specific mutations in the EGFR gene that Correlate with clinical responsiveness Lead to increased growth factor signaling Confer susceptibility to gefitinib

• Screening for such mutations may identify patients who will respond to gefitinib therapy

Fluorescence In Situ Hybridization (FISH) Testing

• FISH testing can detect amplification (high gene copy number) of EGFR in NSCLC tumors

http://www.accessexcellence.org/AB/GG/fish.html

Anti-EGFR Targeted Agents: EGFR Copy Number in NSCLC

OutcomeEGFR-FISH

PositiveEGFR-FISH

Negative P-value

Median overall survival Not yet reached 8 months 0.042

Median progression-free survival

9 months 4 months 0.072

Hirsch FR, et al. J Clin Oncol. 2005;23:6838-6845; Cappuzzo F, et al. J Natl Cancer Inst. 2005;97:643-655.

FISH and EGFR Summary

• FISH may allow for informed treatment decisions based on patient characteristics

• Recent data suggest an association between high EGFR gene copy number and favorable clinical benefit

JBR.21 Trial: Phase III Erlotinib in Second- or Third-line NSCLC

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

RANDOMIZE

Erlotinib 150 mg/day

(n=488)

Placebo

(n=243)

• Failed/intolerant to >1 prior chemotherapy regimen

• PS 0-3

Secondaryendpoints• Time to symptom deterioration

• Progression-free survival

• Tumor response rate

Overall Survival

0 6 12 18 24 30

Months

BR.21 Trial: Overall Survival

No. at risk:Placebo 243 107 50 9 0 0Erlotinib 488 255 145 23 1 0

HR=0.70 (95% CI, 0.58 to 0.85)P<0.001 by stratified log-rank test

Erlotinib

Placebo

Progression-free Survival

0 6 12 18 24 30

Months

BR.21 Trial: Progression-free Survival

No. at risk:Placebo 243 20 3 0 0 0Erlotinib 488 115 27 2 1 0

HR=0.70 (95% CI, 0.58 to 0.85)P<0.001 by stratified log-rank test

Erlotinib

Placebo

BR.21 Trial: Outcomes

Outcome Erlotinib Placebo P-value

Median overall survival, mo 6.7 4.7 <0.001

Response rate 8.9% <1.0% <0.001

Median PFS, mo 2.2 1.8 <0.001

Survival in EGFR-negative Patients

0 6 12 18 24 30

Survival in EGFR-positive Patients

0 6 12 18 24 30

BR.21 Trial: Survival in Expressing vs Nonexpressing EGFR Patients

HR: 1.01 95% CI: 0.65 to 1.57

Erlotnib (N=74)

Placebo (N=37)

HR: 0.65 95% CI: 0.43 to 0.97

Erlotinib (N=78)

Placebo (N=49)

BR.21 Trial: Survival in EGFR Unmeasured Patients

HR: 0.76 95% CI: 0.61 to 0.93

Survival in EGFR Unmeasured Patients

0 6 12 18 24 30

Erlotinib (N=336)

Placebo (N=157)

BR.21 Trial: K-ras Mutations Can Predict Outcome

• K-ras analysis from 206 patient samples Oncogenic missense mutations on codon 12 or 13 in

30 samples (14.6%) 22 (erlotinib) vs 8 (placebo)

• Overall response rates were 5% in K-ras mutant patients vs 10.2% in K-ras wild type patients

• Patients with K-ras mutations do not appear to derive any survival benefit from erlotinib therapy

Tsao C, et al. ASCO 2006. Abstract 7005 .

Treatment-related Toxicities

• Skin rash was seen in 76% of treated patients (9% grade 3)

• 55% of treated patients experienced diarrhea (6% grade 3)

• Pneumonitis was noted in 3% of patients

• Mild ocular toxicities were reported in 28% of patients

EGFR Inhibitor-associated Rash

• Rash associated with superior responses to treatment

• Rash may be surrogate marker of activity

• Presence of any rash conferred significant survival benefit (P=0.02) Trend toward improved survival with increasing

severity of rash

• Cause of correlation currently unknown

Cunningham D, et al. N Engl J Med. 2004;351:337-345.

EGFR Inhibitor-associated Rash

Acneform rash on face

Acneform rash on chest

Paronychial inflammation

Type Severity Treatment

Macular rash Grade 1 Hydrocortisone cream 1%

Grade 2 Topical steroids: fluticasone propionate

Grade 3/4 Oral steroids: methylprednisolone

Pustular/ papular rash

Grade 1 Antibiotics: clindamycin gel for limited single areas; clindamycin lotion for multiple scattered areas

Grade 2/4 Antibiotics: minocycline hydrochloride 200 mg bid, d1; then 100 mg bid OR trimethoprim/sulfamethoxazole bid

Dry skin Grade 1 NA

Grade 2/4 Perfume-, alcohol-, dye-free lotion applied bid

Consider dermatology consultation for grade 3/4 symptoms. Kim ES. ASCO 2005 Poster Session. Abstract 5546.

MD Anderson Prospective Treatment Algorithm

MD Anderson Prospective Treatment Algorithm (cont.)

Type Severity Treatment

Pruritus Grade 1 NA

Grade 2 Antihistamine: topical or oral diphenhydramine 25-50 mg q6 h prn OR

hydroxyzine hydrochloride 25-50 mg PO q6 h prn

Grade 3/4 Antihistamine: diphenhydramine 25-50 mg PO q6 h prn OR

hydroxyzine hydrochloride 25-50 mg PO q6 h prn

Ulcerative lesions

Grade 1/2 NA

Grade 3 Petroleum jelly or silver sulfadiazine ointment

Grade 4 Silver sulfadiazine ointment

Consider dermatology consultation for grade 3/4 symptoms. Kim ES. ASCO 2005 Poster Session. Abstract 5546.

Rash Management: Recommendations for Patients

• Moisturizer Emollients to alleviate skin dryness

• Sunlight Appropriate sunscreens

• OTC products Acne medications are not recommended

• Makeup Dermatologist-approved cover-up Skin-friendly liquid cleansers

Perez-Soler R, et al. Oncologist. 2005;10:345-356.

EGFR Tyrosine Kinase Inhibitors Plus Chemotherapy

Trial Agent ChemotherapyStudy

Population Outcome

INTACT 11 GefitinibGemcitabine +

cisplatinN=1093 Negative

INTACT 22 GefitinibPaclitaxel + carboplatin

N=1037 Negative

TRIBUTE3 ErlotinibGemcitabine +

cisplatinN=1059 Negative

TALENT4 ErlotinibPaclitaxel + carboplatin

N=1172 Negative

Phase III Trials Assessing First-line Treatment

1. Giaccone G, et al. J Clin Oncol. 2004;22:777-784; 2. Herbst RS, et al. J Clin Oncol. 2004;22:785-794; 3. Herbst RS, et al. ASCO 2004;23:617; 4. Gatzemeier U, et al. ASCO 2004;23:617.

Additional TKIs of Interest

Compound Class Phase Treatment

EKB-569 Small-molecule EGFR tyrosine kinase inhibitor

II Previously treated advanced CRC

CI-1033 Small-molecule EGFR tyrosine kinase inhibitor

II Previously treated advanced ovarian cancer

Lapatinib Small-molecule ErbB-1 and ErbB-2 tyrosine kinase inhibitor

II Previously treated breast cancer, locally advanced or metastatic biliary tract

or liver cancer, metastatic prostate cancer

Angiogenesis-targeted Agents in NSCLC

Rationale for Targeting Angiogenesis in NSCLC

• Angiogenesis is key to the metastatic process

• VEGF is the most potent regulator of angiogenesis

• Binds to the extracellular domain of the VEGF inhibitor

• VEGF binds to VEGFR2

• Anti-VEGF therapy may increase the efficacy of chemotherapy and have direct antitumor effect

Duff SE, et al. Eur J Cancer. 2006;42:112-117.

VEGF Family and Its Receptors

RTK, receptor tyrosine kinase.Dvorak HF. J Clin Oncol. 2002;20:4368; Ferrara N, et al. Nat Med. 2003;9:669.

VEGFR-3(Flt-4)

VEGFR-2(Flk-1/KDR)VEGFR-1

(Flt-1)

Angiogenesis(RTK)

Angiogenesis,lymphangiogenesis

Lymphangiogenesis(RTK)

PIGF VEGF-A VEGF-B VEGF-C VEGF-D

NRP-1(Neuropilin)

Unclear, but likely involved in tumor

growth(non-RTK)

Ligand sequestration: mAbs, soluble receptors

(eg, bevacizumab)

Receptor-blockingmAbs (eg, IMC-1121)

Tyrosine kinase inhibition: TKIs

(eg, SU11248)

PLC GRB2 SOS

Transcriptionfactor inhibition

VEGF Signal Inhibition

Inhibition of VEGF

• Increases killing of established tumors Improves chemotherapy delivery to entire tumor,

including center of tumor

• Inhibits metastasis Blocks VEGF-induced increase in peritumor lymph

drainage Blocks VEGF(-A)-induced dysfunctional angiogenesis Maintains endothelial cell barrier function; inhibits

invasion of circulation by the tumor Decreases vascular density of tumor

Dafni H, et al. Cancer Res. 2002;62:6731-6739; Nagy JA, et al. J Exp Med. 2002;196:1497-1506; Weis S, et al. J Cell Biol. 2004;167:223-229.

VEGF Overexpression in Select Tumors

Tumor Type% of Tumors with VEGF

Overexpression Correlation

NSCLC 45%-55% Recurrence, survival

Colorectal 40%-60% Recurrence, survival

Breast 30%-60% Recurrence, survival

Prostate 30% Recurrence, survival, vascular density

Renal cell 30%-100% Vascular density

Class Examples TargetsStage of

Development

Agents Targeting the VEGF Ligand

Antibodies

Bevacizumab VEGF Phase III

HuMV833 VEGF Phase I completed

Soluble

receptors

VEGF-Trap VEGF

Phase I

Selected Agents Targeting the VEGF Ligand

Class Examples TargetsStage of

Development

Agents Targeting the VEGF Receptors

Antibodies IMC-1121 VEGFR-2 Phase I

Ribozymes Angiozyme VEGFR-1 Phase III

Selected Agents Targeting the VEGF Receptors

Bevacizumab

• Recombinant humanized monoclonal antibody to VEGF-A

• Selectively targets, binds to, and inhibits the activity of VEGF

Risk Factors of Bevacizumab

• Bevacizumab is associated with an increased risk of serious bleeding Infrequent cases of hemoptysis GI hemorrhage Subarachnoid hemorrhage Hemorrhagic stroke

• Risk factors include pulmonary bleeding and life-threatening hemorrhages

Bevacizumab: Patient Selection and Safety Considerations

• Bevacizumab contraindications History of thrombotic or hemorrhagic disorders History of hemoptysis Central nervous system metastases

• Potential predictors of response Treatment-induced reduction in VEGF expression Reduced tumor blood flow on functional CT or MRI Biopsy proof of decreased angiogenesis VEGF molecule/receptor polymorphisms

Phase II Bevacizumab Plus Chemotherapy in First-line NSCLC

RANDOMIZE

Bevacizumab* 7.5 mg/kg + PC 200 mg/m2 +

carboplatin AUC 6 on d 1 every 6 weeks

(n=32)

PC 200 mg/m2 +carboplatin AUC 6 on d 1

every 6 weeks(n=32)

nonsquamous NSCLC

• Treatment naive• PS 0-1• Adequate

hematologic, renal, and hepatic function

Primary endpoints• Response rate• Time to progression

*Bevacizumab continued beyond progression with crossover in chemotherapy: PC; paclitaxel.Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191.

Bevacizumab* 15 mg/kg + PC 200 mg/m2 +

(n=35)

Phase II Bevacizumab Plus Chemotherapy in First-line NSCLC

OutcomeBevacizumab 7.5

mg/kgBevacizumab

15 mg/kg Control Arm

Response rate 28.1% 31.5% 18.8%

Median overall

survival

11.6 months 17.7 months 14.9 months

Median time to

progression

4.3 months 7.4 months 4.2 months

Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191.

ECOG 4599: Phase II/III Paclitaxel/Carboplatin +/- Bevacizumab in First-line NSCLC

RANDOMIZE

Bevacizumab 15 mg/kg + paclitaxel 200 mg/m2 +

(n=434)

Paclitaxel 200 mg/m2 +carboplatin AUC 6 on d 1

every 6 weeks

(n=444)

nonsquamous NSCLC

• Treatment naive• PS 0-1• Adequate

hematologic, renal, and hepatic function

Secondary endpoints• Response rate• Time to progression• Tolerability

Sandler AB, et al. ASCO 2005. Abstract LBA4.

ECOG E4599: Median Survival

12 mo 24 mo

43.7% 16.9%51.9% 22.1%

P=0.007

0 6 12 18 24 30 36Months

Medians: 10.2, 12.5

HR: 0.77 (0.65, 0.93)

ECOG E4599: Results

Outcome

Bevacizumab + Paclitaxel + Carboplatin

Paclitaxel + Carboplatin P-value

Overall response rate 27.2% 10.0% <0.0001

Median overall survival 12.5 months 10.2 months 0.0075

Median progression-free survival

6.4 months 4.5 months <0.0001

ECOG E4599: Toxicity

Outcome

Bevacizumab + Paclitaxel

+ CarboplatinPaclitaxel + Carboplatin P-value

Grade 3/4 hemorrhage 4.5% 0.7% <0.001

Grade 4 neutropenia 24.0% 16.4% <0.01

Grade 4 thrombocytopenia 1.4% 0.0% <0.01

Hypertension 6.0% 0.7% <0.001

Deaths, n* 8 2

*5 deaths due to hemoptysis, all in bevacizumab-treated arm.Sandler AB, et al. ASCO 2005. Abstract LBA4; Sandler AB, et al. ASCO 2006. Abstract 7068.

ECOG E4599: Risk Factors for Pulmonary Hemorrhage

• Severe PH occurred in 2.3% of bevacizumab-treated patients

• Primary radiographic analysis showed cavitation in intrathoracic lesion at baseline may be associated with increased risk of severe early-onset PH Hemoptysis prior to treatment in 2/2 cases with

cavitation

• Tumor cavitation and hemoptysis confirmed as potential risk factors for severe PH

Sandler AB, et al. ASCO 2006. Abstract 7068.

ECOG E4599: Prognostic Biomarkers

• VEGF, ICAM, and bFGF were assessed as potential biomarkers

• ELISA measurements of pretreatment and week 7 bFGF, ICAM, and E-selectin and pretreatment of plasma VEGF Low ICAM correlated with a higher response rate (29%

vs 13%, P=0.03) Low ICAM correlated with significantly better overall

survival (P=0.00005) as well as better 1-year survival (65% vs 25%)

• Baseline ICAM levels are strongly prognostic for survival and response to chemotherapy

Dowlati A, et al. ASCO 2006. Abstract 7027.

ECOG E4599: Summary

• Addition of bevacizumab to paclitaxel-carboplatin provides statistically and clinically significant survival advantage

• Paclitaxel-carboplatin-bevacizumab is the new ECOG reference standard in this patient population

• Other trials evaluating bevacizumab in combination with other chemotherapy doublets ongoing

Combining Bevacizumab and Erlotinib: Rationale

Phase I/II Bevacizumab plus Erlotinib

• Study design Patients (34 patients) with nonsquamous stage IIIB/IV

NSCLC with >1 prior chemotherapy regimen Erlotinib 150 mg/day + bevacizumab 15 mg/kg Efficacy, tolerability, and pharmacokinetic parameters

of erlotinib + bevacizumab assessed

Herbst RS, et al. J Clin Oncol. 2005;23:2544-2555.

Phase I/II Bevacizumab plus Erlotinib: Results

• Median overall survival 12.6 months

• Median progression-free survival 6.2 months

• Most common adverse events Mild/moderate rash Diarrhea Proteinuria

Efficacy of Bevacizumab in Combination with Chemotherapy or Erlotinib

• Phase II trial Combining bevacizumab with chemotherapy (docetaxel

or pemetrexed) or with erlotinib• Assess the efficacy of combining bevacizumab with

chemotherapy or erlotinib relative to chemotherapy alone End-point

• Progression-free survival • 120 patients were randomized and treated

68/85 PFS events

Fehrenbacher L, et al. ASCO 2006. Abstract 7062 .

Antiangiogenic Tyrosine Kinase Inhibitors

Target

Inhibitor Company VEGFR-1 VEGFR-2 VEGFR-3 PDGFR c-KIT FGFR

PTK787 Novartis

Schering

+ + + + + ?

AZD2171 AstraZeneca + + + ? ? ?

ZD6474 AstraZeneca - + - ? ? +

GW786034 GSK + + + ? ? ?

SU11248 Pfizer - + - + + +

AG013736 Pfizer + + + + + ?

AMG 706 Amgen + + + + + ?

All agents in early phase I/I development except for PTK787 in phase III.

ZD6474: Antiangiogenic Tyrosine Kinase Inhibitor

ZD6474 Mode of Action

Image obtained from: http://www.cancerline.com/cancerlinehcp/15602_18171_10_1_1.aspx

Indirect tumour effects through endothelial cell targeting

VEGFR inhibition• Inhibits angiogenesis by decreasing endothelial cell proliferation and migration• Inhibits VEGF-dependent endothelial cell survival• Decreases vascular permeability

Direct effects at the tumour cell• EGFR inhibition• Inhibits cell proliferation• Decreases invasion• Promotes apoptosis• Inhibits metastasis• Decreases VEGF production

RET inhibition:

• Inhibition of proliferation and survival in certain thyroid turmors

Phase II Trial of ZD6474 vs Gefitinib

• Study design 168 patients with stage IIIB/IV NSCLC who had failed ≥1

platinum-based chemotherapy regimen administered

• ZD6474 300 mg/day or

• Gefitinib 250 mg/day

• Adverse events for ZD6474 included diarrhea (grade 3/4, 8.4%), rash (grade 3/4, 4.8%) and asymptomatic QTc prolongation (grade 1, 20.5%)

• There were no unexpected safety findings with gefitinib

Natale R, et al. Chemotherapy Foundation Symposium XXIII 2005. Natale R, et al. ASCO 2006. Abstract 7000.

Outcome ZD6474 Gefitinib

Median time toprogression, weeks

11.0 8.1

Phase II Trial of ZD6474 vs Gefitinib: Progression-free Survival

Natale R, et al. Chemotherapy Foundation Symposium XXIII 2005.

HR=0.632 (95% CI=0.44 to 0.90)Two-sided P-value=0.011

Primary Endpoint: Progression-free Survival

0 1 2 3 4 5 6 7 8 9 10 11

Progression-free survival in part A (months)

ZD6474Gefitinib

ZD6474 +/- Docetaxel: Schema

Heymach R, et al. IASLC 11th World Congress on Lung Cancer. 2005. Abstract 3023; Heymach R, et al. ASCO 2006. Abstract 7016.

RANDOMIZE

ZD6474 100 mg +

Docetaxel 75 mg/m2 q21 d

(n=42)

NSCLC• Failure of 1st-line

platinum-based chemotherapy

Primary endpoint• Progression-free

survival

Secondary endpoints• Overall survival

ZD6474 300 mg +

(n=44)

(n=41)

Kaplan-Meier Curve for Progression-free Survival

0 50 100 150 200 250 300 350 400

Progression-free survival (days)

ZD6474 +/- Docetaxel: Progression-free Survival

Heymach R, et al. IASLC 11th World Congress on Lung Cancer. 2005. Abstract 3023.

Placebo + docetaxelZD6474 100 mg + docetaxelZD6474 300 mg + docetaxelCensoredCensoredCensored

ZD6474 +/- Docetaxel: Results

• No significant difference in overall survival, however a trend towards shorter survival in ZD6474 300 mg arm

Outcome ZD6474 + Docetaxel Docetaxel P-value

Median TTP, weeks

(ZD6474 100 mg)

12.0 0.074

(ZD6474 300 mg)

12.0 0.461

Heymach R, et al. ASCO 2006. Abstract 7016.

Sunitinib: Multi-targeted Tyrosine Kinase Inhibitor

• Targets VEGF-R, PDGF-R, KIT, FLT3, and RET

• 63 patients treated with 50 mg/day of sunitinib (SU11248) 6 confirmed partial responses (9.5%) Stable disease observed in 12 additional patients

(19.0%) Survival data pending

• Well tolerated

• Provocative single agent activity

Socinski MA, et al. ASCO 2006. Abstract 7001.

Sorafenib: Multi-targeted Tyrosine Kinase Inhibitor

• Targets the Raf/MEK/ERK pathway at the level of Raf kinase and receptor tyrosine kinases

• 52/54 patients received sorafenib 59% of patients 51 had stable disease (SD)

• Median PFS of 23.7 weeks Median PFS of 11.9 weeks and median OS of 29.3

• Adverse events: diarrhea (40%), hand-foot skin reaction (37%), fatigue (27%), and nausea (25%)

• 9 deaths within 30 days of discontinuation of sorafenib

Gatzemeier, et al. ASCO 2006. Abstract 7002.

Combining Targeting Strategies: VEGF + EGFR Synergy?

• Combining agents targeting 2 critical pathways may be more effective than targeting 1 pathway

• Potential targets Growth factors, hormones, and receptors

• HER-2/neu, EGFR, PDGFR, ER Signaling intermediate

• Ras, Src, MAPK, Akt, Cox2 Nuclear/transcription factors

• p53,VHL

Targeted Therapy: Summary and Clinical Implications

• Several new agents recently approved for treatment of NSCLC Gefitinib Erlotinib Bevacizumab

• Therapies targeting EFGR and antiangiogenic agents show promise

• Ongoing investigation provides promise for more effective, less toxic treatment

Targeted Therapy: Future Directions

• Combining anti-EGFR agents with cytotoxic agents May achieve additive or even synergistic benefits Potent combinations inhibiting multiple signaling

pathways to achieve greater activity• Signal transduction inhibitors are clinically viable

therapeutic options • Selectively targeting oncogenes for suppression and/or

destruction• Development of vaccines that stimulate the immune

system to recognize cancer-promoting proteins as foreign and mark them for destruction

Summary and Future Directions

Summary and Clinical Implications

• NSCLC is difficult to treat due to late diagnosis and high relapse rate

• Current treatment approaches Resectable NSCLC

• Surgical resection + adjuvant platinum-based chemotherapy

Metastatic disease

• Platinum- or nonplatinum-based chemotherapy with possible addition of targeted therapy agents

Future Directions

• Promising new agents currently under investigation Epothilones New topoisomerase I inhibitors Paclitaxel poliglumex Bortezomib and bexarotene Cetuximab, panitumumab ZD6474

• Possibility of combining EGFR monoclonal antibodies and tyrosine kinase inhibitors to broaden spectrum of activity

• Potential to use targeted agents alone in monotherapy, in combination with chemotherapy, and in combination with other targeted therapies

Considerations in Future Directions

• Patient selection Which patients are most likely to benefit from a

particular treatment? Prognostic baseline variables or markers

• Treatment based on tumor biology

• Development of less toxic therapy

• Design of more effective regimens

• Optimal sequence of surgery, chemotherapy, radiation therapy, and/or targeted therapy

Appendix

Adjuvant Therapy Supplement

ALPI: Effects of Mitomycin, Vindesine, and Cisplatin Adjuvant Chemotherapy

Overall Survival by Therapy Type

Hazard Ratio (95% CI) P-value

Absolute Benefit

at 5 Years

Mitomycin + vindesine + cisplatin

0.96 (0.81-1.13) 0.589 1%

ALPI, Adjuvant Lung Project Italy. Scagliotti GV, et al. J Natl Cancer Inst. 2003;95:1453-1461.

ALPI: Effects of Mitomycin, Vindesine, and Cisplatin Adjuvant Chemotherapy (cont.)

N=1088 patients with resected stage I, II, or IIIA NSCLC

ALPI, Adjuvant Lung Project Italy. Scagliotti GV, et al. J Natl Cancer Inst. 2003;95:1453-1461.

HR=0.87 (95% CI=0.81 to 1.13)P=0.589

Events Total

MVP 279 548

Control 289 540

0 1 2 3 4 5

Years from randomization

Treatment of Advanced NSCLC

Supplement

FDA-approved Treatment for Advanced NSCLC

Paclitaxel

Cisplatin

135 mg/m2 over 24 h every 3 weeks 75 mg/m2 after paclitaxel every 3 weeks

Vinorelbine

Cisplatin

30 mg/m2 weekly 120 mg/m2 days 1 and 19, then every 6 weeks

Gemcitabine

Cisplatin

1000 mg/m2 days 1, 8, and 15 every 4 weeks 100 mg/m2 after gemcitabine day 1

Gemcitabine

Cisplatin

1250 mg/m2 days 1 and 8 every 3 weeks100 mg/m2 after gemcitabine day 1

Docetaxel

Cisplatin

75 mg/m2 day 1 every 3 weeks75 mg/m2 day 1 every 3 weeks

Second-line Therapy Studies

Study Dose/Schedule N

Overall Response

Rate (%)

Median Survival (weeks)

Murphy, 1994 Paclitaxel 175 mg/m2 40 3 18

Hainsworth, 1995 Paclitaxel 135 or 200 mg/m2 26 23 NR

Burris, 1993 Docetaxel 100 mg/m2 35 17 NR

Rinaldi, 1994 Vinorelbine 20 mg/m2 18 0 NR

Nakai, 1991 Irinotecan 200 mg/m2 22 14 NR

Gridelli, 1999 Gemcitabine 1000 mg/m2 30 20 22

Mattson, 1999 Pemetrexed 500 mg/m2 22*

Targeted Therapy Supplement

Anti-EGFR Targeted Agents: Patient Selection

• No factors predict objective response, time to progression, and survival

• EGFR expression levels may be able to select patients who are least likely to derive benefits from treatment

• Subgroup of patients with mutated EGFR may derive great benefit from treatment Patients who are female, nonsmokers, and who have

adenocarcinoma (particularly those of Asian descent) might derive the most benefit from treatment

• Most patients do not fall into categories of patients who might derive benefit; however, these patients should not be excluded from analyses

Inhibition of Xenograft Tumor Growth: Gefitinib with Paclitaxel

Control

Paclitaxel

Gefitinib

Gefitinib + paclitaxel

LX-1 Lung

0 4 8 12 16 20 24 28 32 36

Time (days)

Sirotnak FM, et al. Clin Cancer Res. 2000;6:4885-4892.

Preclinical Antitumor Activity of EGFR Tyrosine Kinase Inhibitors

• Growth inhibition/regression observed in multiple tumor types in xenografts

• Enhanced growth inhibition/regression observed with both chemotherapy and radiation

• Activity observed in hormone-resistant tumor cell models

Sirotnak FM, et al. Clin Cancer Res. 2000;6:4885-4892; Ciardiello F, et al. Clin Cancer Res. 2000;6:2053-2063; Ciardiello F, et al. Clin Cancer Res. 2001;7:1459-1465; Williams KJ, et al. Proc AACR. 2001;42:715. Abstract 3840.

Anti-EGFR Targeted Agents: Measurement of Response

• Response rate not an appropriate surrogate for survival in studies of agents that target EGFR

Subgroup Analysis Response Rate P-valueHR (95% CI) for

Survival P-value

Overall <0.001

Erlotinib 8.9% 0.7 (0.6-0.9) <0.001

Placebo 0.9%

By gender 0.006

Female 14.4% 0.8 (0.6-1.1) 0.13

Male 6.0% 0.8 (0.6-0.9) 0.01

By pathological subtype <0.001

Adenocarcinoma 13.9% 0.7 (0.6-0.9) 0.008

Other 4.1% 0.8 (0.6-1.0) 0.07

CI, confidence interval; HR, hazard ratio. Shepherd FA, et al. N Engl J Med. 2005;353:123-132.

Antiangiogenic Targeted Agents: Biological Rationale

Other Emerging Antiangiogenic Agents

• AMG 706 Multikinase inhibitor that targets all known VEGF receptors, the PDGF

receptor, KIT, and RET• Open-label phase I study of 56 evaluable patients with advanced solid tumors,

refractory to standard therapy or no standard therapy available AMG 706 125 mg/day

• Results Partial response: 2 (4%) Stable disease: 34 (61%)

• 17 patients had up to 29% decrease in sum of longest diameter of target lesions

MRI showed tumor vascular permeability• Reduced by 37% in initial area under curve on day 3• Reduced by 61% in initial area under curve on day 21

Rosen L, et al. ASCO 2005. Abstract 3013.

Targeted Therapies for the Elderly and Patients with PS 2

• Targeted therapies have the potential to be less toxic, especially beneficial for elderly/poor PS patients Anti-EGFR

• Gefitinib• Erlotinib• Cetuximab

Anti-VEGF antibodies• Bevacizumab

VEGF receptor tyrosine kinase inhibitors• ZD6474• ZD2171

Eicosanoid pathway inhibitors• COX-2 inhibitors• LOX inhibitors

Gridelli C, et al. Cancer. 2004;101:1733-1744.

Novel Cytotoxic Agents for the Treatment of NSCLC: Epothilones

CompoundPhase of

DevelopmentEfficacy in NSCLC

PatientsOther Cancers

Tested

BMS-247550

(aza-epothilone B)

II 1 CR, 13 PR, and 31 SD in 111 assessable

patients

Metastatic gastric cancer, metastatic

breast cancer, GI tract tumors

BMS-310705 I 1 CR Ovarian, bladder, stomach, and breast

cancers

EPO906 II ND Ovarian, prostate, breast, colorectal, and metastatic renal cell

cancers

KOS-862

(epothilone D)

I ND Testicular, ovarian, pancreatic, and breast

cancers

CR, complete response; ND, not determined; PR, partial response; SD, stable disease. Goodin S, et al. J Clin Oncol. 2004;22:2015-2025.

Novel Cytotoxic Agents for the Treatment of NSCLC: Topoisomerase I Inhibitors

Study Treatment Patients, n

Partial Response,

Minor Response/Stable Disease,

First-line Treatment

Baka et al.1 Rubitecan 17 0 (0%) 10 (58.8%)

Braybrooke et al.2 Exatecan 39 2 (5.1%) 15 (38.5%)

Sigma Tau Research Gimatecan 30 (planned)

In phase I analysis

Springett et al.3 Polyglutamate camptothecin

(CT-2106)

19 – 4 (21.1%; includes 2 lung cancer

patients)

Second-line Treatment

Miller et al.4 Karenitecin 52 2 (3.8%) 24 (46.1%)

1. Baka S, et al. Eur J Cancer. 2005;41:1547-1550; 2. Braybrooke JP, et al. Lung Cancer. 2003;41:215-219; 3. Springett GM, et al. J Clin Oncol. 2004;22(14S):3127; 4. Miller AA, et al. Lung Cancer. 2005;48:399-407; Sigma Tau Research Data on file.

Novel Agents: Bortezomib

PR, partial response; SD, stable disease. 1. Stevenson JP, et al. Proc Am Soc Clin Oncol. 2004;23:649a; 2. Fanucchi MP, et al. ASCO 2005. Abstract 7034.

Study Treatment Patients, n PR, n (%) SD, n (%)

Stevenson et al.1 Bortezomib 23 1 (4.3%) 9 (39.1%)

Fanucchi et al.2 Bortezomib 30 3 (10.0%) 8 (26.7%)

Bortezomib + docetaxel 32 5 (15.6%) 19 (59.3%)

• Bortezomib is a proteasome inhibitor Interferes with the ubiquitin-proteasome complex Causes breakdown of cell-cycle regulators and

cell-cycle arrest

Novel Agents: Bexarotene

RXR, retinoid X receptors.1. Khuri FR, et al. J Clin Oncol. 2001;19:2626-2637; 2. Rizvi NA, et al. ASCO 2002; Abstract 1334; 3. Bordoni R. ASCO 2006. Abstract 17070.

Study Treatment Patients, n PR, n (%) SD, n (%)

Khuri et al.1 Bexarotene + cisplatin + vinorelbine 28 7 (25%) 14 (50%)

Rizvi et al.2

Bordoni3

Bexarotene + paclitaxel + carboplatin

1 CR + 5 PR (40%)

30 (58%)

Not given

16 (31%)

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