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Keeping Pace with Targeted Therapies in Lung Cancer Highlights from the ASCO 2006 Annual Meeting. Introduction. Overview of Targeted Therapies and Focus on Monoclonals. Karen Kelly, MD Professor of Medicine Department of Medical Oncology University of Colorado at Denver Aurora, Colorado.

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Keeping pace with targeted therapies in lung cancer highlights from the asco 2006 annual meeting l.jpg

Keeping Pace with Targeted Therapies in Lung CancerHighlights from the ASCO 2006 Annual Meeting



Overview of targeted therapies and focus on monoclonals l.jpg

Overview of Targeted Therapies and Focus on Monoclonals

Karen Kelly, MD

Professor of Medicine

Department of Medical Oncology

University of Colorado at Denver

Aurora, Colorado


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FDA-Approved Agents BeingInvestigated for Lung Cancer Treatment

VEGF = vascular endothelial growth factor; CRC = colorectal cancer; EGFR = epidermal growth factor receptor; TK = tyrosine kinase; NSCLC = non–small-cell lung cancer; PDGFR = platelet-derived growth factor receptor; RCC = renal cell carcinoma; GIST = gastrointestinal stromal tumor;RXR = retinoid X receptor.


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Examples of Novel Targeted Agents Being Investigated for Lung Cancer Treatment

EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor; PDGFR = platelet-derived growth factor receptor; TGF = transforming growth factor.


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ASCO 2006 Update Lung Cancer TreatmentBevacizumab in NSCLC

Paclitaxel + carboplatin ± bevacizumab (updated results from randomized phase III trial E4599)

  • Sandler AB, et al.1

  • Brahmer JR, et al.2

  • Dowlati A, et al.3

1. Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4. 2. Brahmer JR, et al. 42nd ASCO;June 2-6, 2006. Abstract 7036. 3. Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.


Paclitaxel carboplatin bevacizumab previously reported ecog 4599 results l.jpg
Paclitaxel/Carboplatin ± Bevacizumab Lung Cancer TreatmentPreviously Reported ECOG 4599 Results

*As percent of patients with measurable disease, n = 350 for the PC arm and n = 357 for PCB arm.

ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab;

PFS = progression-free survival; OS = overall survival.

Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4.


Paclitaxel carboplatin bevacizumab possible gender differences in overall survival l.jpg
Paclitaxel/Carboplatin ± Bevacizumab Lung Cancer TreatmentPossible Gender Differences in Overall Survival

  • Unplanned subgroup analysis of ECOG 4599

  • Key finding: compared with males, females did not appear to gain same overall survival benefit from addition of bevacizumab

ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab.

Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.


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Paclitaxel/Carboplatin ± Bevacizumab Lung Cancer TreatmentNo Gender Differences in Overall Survival

  • Females on PCB arm had higher response rate and progression-free survival compared with females in the PC arm

P = paclitaxel; C = carboplatin; B = bevacizumab; CR = complete response; PR = partial response.

Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.


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Paclitaxel/Carboplatin ± Bevacizumab Lung Cancer TreatmentPerspective on Unplanned Analysis by Gender

  • Treatments at time of disease progression were not different, except that in the PCB arm, females were slightly less likely than males to get chemotherapy as 2nd-line therapy

  • Reasons for observed differences in overall survival are unclear, possibilities include

    • Random chance

    • Pitfalls of unplanned subgroup analysis

  • These results contrast with results in CRC trials where no gender differences reported in overall survival

  • PCB remains ECOG reference treatment in NSCLC

PCB = paclitaxel/carboplatin/bevacizumab; CRC = colorectal cancer; ECOG = Eastern Cooperative OncologyGroup; NSCLC = non–small-cell lung cancer.

Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.

Laskin JJ. 42nd ASCO; June 2-6, 2006. Lung Cancer I Poster Discussion. Discussant.Hurwitz H, et al. N Engl J Med. 2004;350:2335.

Genentech data on file


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Prospective Correlative Assessment of Biomarkers from ECOG 4599

Biomarkers studied

  • Endothelial leukocyte adhesion molecule-1 (E-selectin)

    • Expressed only on endothelial cell after activation by inflammatory cytokines

    • Elevated E-selectin seen in disorders characterized by endothelial cell apoptosis and malignancies

  • Intercellular adhesion molecule-1 (ICAM-1; CD54)

    • Expressed on endothelial, epithelial, lymphocytes, monocytes, hepatocytes, and hemapoietic cells

    • Elevated levels seen in many malignancies and alterations seen with vascular targeting and antiangiogenic agents

  • Vascular endothelial growth factor (VEGF) and basic-fibroblast growth factor (b-FGF)

    • Well-known angiogenic factors

Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.


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Prospective Correlative Assessment of Biomarkers From ECOG 4599—Results

  • Baseline plasma ICAM may be prognostic for response and survival in advanced NSCLC

    • This might be useful stratification factor in future trials

    • Low levels indicate a 2-fold increase in likelihood of response to chemotherapy (unclear if this is prognostic or predictive)

  • Future trials are needed to determine if these will be better markers for clinical outcome than conventional radiographic response assessment

Survival by Baseline ICAM

1.0 -

0.8 -

0.6 -

0.4 -

0.2 -

0.0 -

<260.5 (62 deaths/75 cases)>260.5 (70 deaths/75 cases)

P = .000050

Probability

1 y 60%

1 y 25%

0 10 20 30 40

Months

Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027. Reprinted with permission from Dr. Dowlati.

Hirsch F. 42nd ASCO; June 2-6, 2006. Lung Cancer III. Discussant.


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Risk Factors for Pulmonary Hemorrhage (PH) in Bevacizumab-Treated Patients

Retrospective study of ECOG 4599 data examining association between baseline clinical factors and incidence of early onset (< 150 d from initial treatment) PH

  • Grade  3 PH occurred in 2.3% of patients

  • Of 10 cases identified, 6 met criteria for early onset PH related to bevacizumab

  • Pretreatment cavitation may be associated with increased risk of PH

  • Hemoptysis was predicative of possible future PH

Sandler AB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7068.


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ASCO 2006 Update on Bevacizumab-Treated PatientsCetuximab in NSCLC

  • SWOG 0342 phase II trial of chemotherapy + cetuximab vs chemotherapy followed by cetuximab1

  • FLEX phase III trial of cisplatin/vinorelbine ± cetuximab2

1. Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.

2. Von Pawl, J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.


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Paclitaxel/ carboplatin + cetuximab Bevacizumab-Treated Patients

× 4 cycles

(n = 106)

Cetuximab weekly × 1 year

Randomize stage IIIB/IVNSCLC

Cetuximab weekly × 1 year

Paclitaxel/

carboplatin

× 4 cycles

(n = 119)

Preliminary Results of SWOG 0342 Phase II Trial of Paclitaxel/Carboplatin + Cetuximab

Primary objectives

  • Compare response rate and toxicity of concurrent vs sequential platinum-based chemotherapy + cetuximab regimens as 1st-linetreatment for advanced NSCLC

  • Select regimen for future trials based on overall survival

Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly.


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Phase II Trial of Bevacizumab-Treated PatientsPaclitaxel/Carboplatin + CetuximabPreliminary Efficacy Results

*Patients evaluable for response: 71 in the chemo + cetuximab arm and 87 in the chemo-only arm.

Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.


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SWOG 0342—Phase II Trial of Paclitaxel/Carboplatin + CetuximabPreliminary Safety Results

Adverse Events (grade 3/4)

80 -

70 -

60 -

50 -

40 -

30 -

20 -

10 -

0 -

67

55

Grade 3/4 AE (>5%) on Chemo (+/-C)

N=101

N=94

% of Evaluable Patients

Sequential

Concurrent

27

20

N=20

N=22

Chemo +/- C

Post-Chemo C

Rash (grade 3/4)

14 -

12 -

10 -

8 -

6 -

4 -

2 -

0 -

12

10

N=94

N=20

N=22

No new cases concurrent ann

% of Evaluable Patients

Sequential

Concurrent

1

N=101

Chemo = paclitaxel/carboplatin; C = cetuximab.

Chemo +/- C

Post-Chemo C

Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly.


Phase ii trial of paclitaxel carboplatin cetuximab preliminary conclusions l.jpg
Phase II Trial of CetuximabPaclitaxel/Carboplatin + CetuximabPreliminary Conclusions

  • Concurrent cetuximab + chemotherapy arm met predetermined 10-month minimal median survival requirement

  • Trend toward higher response rate in concurrent arm

  • Rash only significant additional toxicity seen with concurrent administration of cetuximab + chemotherapy

  • Biomarker correlative studies ongoing

  • New trials with this concurrent regimen + bevacizumab planned

Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.


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Phase III Trial of CetuximabCisplatin/Vinorelbine ± CetuximabPreliminary Safety Report

  • Stage IIIB with documented malignant pleural effusion or stage IV previously untreated NSCLC

  • Epidermal growth factor receptor expression by immunohistochemistry

  • Patients recruited from 166 centers in 29 countries in Europe, Asia, Australia, and South America

  • Primary objective: overall survival

  • Preplanned analysis by Data Safety Monitoring Board (DSMB) of baseline and safety data from 365 patients

  • Results

    • Recruitment completed in February 2006

    • 1125 patients randomized

    • Trial continues

Von Pawl J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.


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SWOG S0339—Phase II Trial of Bortezomib + Gemcitabine/Carboplatin

  • Design

    • Primary endpoint: OS (goal 10 month median OS to rule out null hypothesis)

    • Stage IIIB (with pleural effusion) or IV NSCLC, chemotherapy-naive

    • PS = 0 or 1

  • Results

    • N = 121 accrued (116 eligible)

    • Median age: 64 years (range, 28–78)

    • 11% stage IIIB, 86% stage IV

    • Median follow-up: >15 months

    • Median number of cycles: 3.6

SWOG = Southwest Oncology Group; OS = overall survival; PS = performance status.

Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.


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Phase II Trial of Bortezomib Gemcitabine/Carboplatin+ Gemcitabine/ CarboplatinEfficacy and Safety Results

  • Overall survival 11 months (95% CI 8.2–13 months)

  • 1-year survival 47%; 2-year survival 14%

  • Results above predetermined statistical endpoint to proceed to a phase III trial

ORR = overall response rate; CR = complete response; PR = partial response; SD = stable disease;PD = progressive disease; AST = aspartate aminotransferase; ALT = alanine aminotransferase.

Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.


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Summary Gemcitabine/Carboplatin

  • Clarification with regards to carboplatin/paclitaxel ± bevacizumab phase III trial ECOG 4599

    • Bevacizumab does have some differential gender effect on overall survival, but not clinically meaningful

    • Potential predictive or prognostic biomarkers

    • Risk factors for bevacizumab-associated pulmonary hemorrhage

  • Promising results from phase II trials

    • Cetuximab + carboplatin/paclitaxel

    • Cetuximab + cisplatin/vinorelbine

    • Bortezomib + gemcitabine/carboplatin

  • Data from phase III trials needed for cetuximab and bortezomib


Focus on small molecules and investigational agents l.jpg

Focus on Small Molecules and Investigational Agents Gemcitabine/Carboplatin

Roy S. Herbst, MD, PhD

Professor of Medicine

Department of Thoracic/Head and Neck Medical Oncology

University of Texas M.D. Anderson Cancer Center

Houston, Texas


Update on small molecule and investigational agents l.jpg

Tyrosine kinase inhibitors with FDA approvals Gemcitabine/Carboplatin

Sunitinib

Sorafenib

Erlotinib

Gefitinib

Investigational agents

Vatalanib

ZD6474

ABI-007

AMG706/panitumumab

Biomarkers

Osteopontin

EGF, Her2, p-Akt

RXR-beta, pPARy

Update on Small Molecule and Investigational Agents


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Tyrosine Kinase Inhibitors Target Both the Tumor and Endothelial Cells

Growth Factor Receptor

VEGFR/PDGFR

EGFRRAS-RAF

VEGFRNRP1

VEGFR 1,2,3PDGFR

Nucleus

Nucleus

Tumor Cell

Endothelial Cell

VEGF

PDGF

Endothelial Cell

Pericytes


Similarities and differences in targets for tkis and monoclonals l.jpg
Similarities and Differences in Targets for TKIs Endothelial Cellsand Monoclonals

Inhibitor

Erlotinib

Bevacizumab

Mechanism

Inhibits tumor cell growth and blocks synthesis of angiogenetic proteins(eg, bFGF, VEGF, TGF-by tumor cells

Inhibits endothelial cells from responding to the angiogenic protein VEGF

bFGF

VEGF

TGF-

Tumor

Endothelial cells

Herbst RS, et al. J Clin Oncol. 2005;23:2544. Reprinted with permission from theAmerican Society of Clinical Oncology.


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Sunitinib Phase II Trial in Previously Treated Advanced NSCLC

  • Open-label, single-arm, 2-stage multicenter trial

  • Patients had recurrent stage IIIB/IV NSCLC that had failed 1 or more chemotherapy regimens (with/out EGFR inhibitor)

  • Sunitinib given at 50 mg/d for 4 wk followed by 2 wk off treatment before next 6-week cycle

  • Primary endpoint: overall confirmed objective response rate (ORR)

  • Enrollment

    • 63 patients

    • 64% had adenocarcinoma, 90% had stage IV disease

    • 43% had 1 prior regimen, 44% had 2 prior regimens, 13% had 3 or more prior regimens

    • 33% had received prior EGFR inhibitor

Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.


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Sunitinib Phase II Trial in NSCLCPreviously Treated Advanced NSCLCSafety Results

  • Most toxicities were grade 1 or 2

  • 3 hemorrhage-related deaths on study: 2 (a pulmonary hemorrhage and a cerebral hemorrhage) were considered study-drug related

Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.


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Sunitinib Phase II Trial in NSCLCPreviously Treated Advanced NSCLCEfficacy Results

Best Response forTarget Lesions by Patient

100

80

60

40

20

0

-20

-40

-60

-80

-100

Partial Responses by RECIST

Stable Disease/Progressive Disease

Change from Baseline (%)

  • Median duration of response: 12.2 weeks (range, 4.3–30.1+ weeks)

  • Median PFS: 11.3 weeks (95% CI 10.0–15.7)

  • Median OS: 23.9 weeks (95% CI 17.0–28.3)

ORR = overall response rate; PR = partial response; SD = stable disease; PD = progressive disease;RECIST = response evaluation criteria in solid tumors.

Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001. Reprinted with permission from Dr. Socinski.


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Phase II Trial of Sorafenib in Advanced NSCLC NSCLC

  • Primary objective: tumor response by RECIST of sorafenib 400 mg BID in previously treated pts

  • Eligibility

    • 1–2 prior treatments

    • No prior gefitinib

    • Asymptomatic brain metastases permitted

  • Enrollment

    • 52 patients

    • Median age 62 years (range, 26–85)

    • 85% ECOG PS = 1

    • 54% adenocarcinoma, 31% squamous cell carcinoma

    • 94% stage IV

    • 67% 1 prior chemotherapy; 29% 2 prior chemotherapy

RECIST = response evaluation criteria in solid tumors; ECOG = eastern cooperative oncology group;PS = performance status.

Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.


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Phase II Trial of Sorafenib in Advanced NSCLC NSCLCEfficacy Results

Maximum Percentage Reduction of Target Lesion by Patient (N = 48)†

60

40

20

0

-20

-40

-60

SD Patients PD Patients

  • Tumor cavitation in 4 patients

  • Median PFS: 2.7 mo; median OS: 6.7 mo

  • SD patients: median PFS 5.5 mo

  • 2 patients treated for > 2 years with ongoing treatment

SD = stable disease; PD = progressive disease; PFS = progression-free survival; OS = overall survival.

*Patients died prior to tumor assessment. †48 patients with postbaseline tumor measurements available.

Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier.


Phase ii trial of sorafenib in advanced nsclc safety and biomarker analysis results l.jpg

Safety NSCLC

No grade 4 events

Grade 3 events: hand-foot skin reactions (20%), hypertension (4%), diarrhea (2%), fatigue (2%), headache (2%)

4 patients had sorafenib-related bleeding events (3 epistaxis, 1 fatal pulmonary hemorrhage 30 days after stopping sorafenib)

Biomarker analysis

Plasma biomarkers evaluated by ELISA

High VEGF at baseline correlated with shorter survival (P < .05)

Phase II Trial of Sorafenib in Advanced NSCLCSafety and Biomarker Analysis Results

1.0

0.5

0.0

Low VEGF

High VEGF

Survival Fraction

300

0

100

200

400

500

600

700

Time to Death (Days)

ELISA = enzyme-linked immunosorbent assay; VEGF = vascular endothelial growth factor.

Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier.


Phase ii trial of sorafenib in advanced nsclc conclusions l.jpg
Phase II Trial of Sorafenib in Advanced NSCLC NSCLCConclusions

  • Sorafenib has some activity in NSCLC

  • Historical comparisons show that 59% stable disease is in same range as other targeted agents in NSCLC

  • Agent generally well tolerated, with low incidence of bleeding

  • Deterioration of quality of life not seen

  • Shorter median overall survival correlated with high baseline VEGF and greater decreases in plasma VEGF during sorafenib treatment

  • Phase III study of carboplatin/paclitaxel ± sorafenib is currently accruing patients

Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.


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Randomized Phase II Trial of Chemotherapy ± Bevacizumab vs Erlotinib + Bevacizumab

  • Phase II, multicenter 3-arm randomized trial

    • Arm 1: chemotherapy (docetaxel or pemetrexed) + placebo

    • Arm 2: chemotherapy (docetaxel or pemetrexed) + bevacizumab

    • Arm 3: erlotinib + bevacizumab

  • Arms 1 and 2 were double-blinded

  • Patients stratified by ECOG performance status and smoking history

  • Eligibility: recurrent unresectable NSCLC

  • Primary endpoint: safety and preliminary efficacy

Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062.


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Phase II Chemotherapy ± Bevacizumab vs Erlotinib + BevacizumabEfficacy

*Adjusted by randomization stratification factors (ECOG PS, smoking history).

HR = hazard ratio; NA = not applicable; CR = complete response; PR = partial response; SD = stable disease.

Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher.


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Phase II Chemotherapy ± Bevacizumab vs BevacizumabErlotinib + BevacizumabSafety

Percent of Patients

Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher.


Phase ii trial of erlotinib vs carboplatin paclitaxel in nsclc l.jpg
Phase II Trial of Erlotinib vs Carboplatin/Paclitaxel in NSCLC

  • Primary endpoint: PFS (treatment worthy of further evaluation if PFS  3.5 months)

  • Study design

    • Eligibility: stage IIIB or IV no prior chemotherapy

    • Performance status 2

    • No prior treatment with any EGFR inhibitor; no uncontrolled brain metastases

    • Optional cross-over to erlotinib

  • Enrollment: 103 patients

  • Arms well balanced in demographics and baseline characteristics

PFS = progression-free survival; EGFR = epidermal growth factor receptor.

Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.


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Phase II Trial of Erlotinib vs Carboplatin/ Paclitaxel (CP) in NSCLCEfficacy Results

Progression-Free Survival (PFS)

1.0 -

0.9 -

0.8 -

0.7 -

0.6 -

0.5 -

0.4 -

0.3 -

0.2 -

0.1 -

0.0 -

Group N Median(M) 95% Cl

Erlotinib 52 1.91 (1.28, 2.69)

PC 51 3.52 (1.48, 4.87)

PFS Probability

0 6 12 18 24 36

PFS (Months)

Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022. Reprinted with permission from Dr. Lilenbaum.


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Phase II Trial of Erlotinib vs in NSCLCCarboplatin/Paclitaxel in NSCLCConclusions

  • Single-agent erlotinib treatment did not meet progression-free survival endpoint to warrant further evaluation

  • Results in erlotinib-treated patients who developed grade 2+ rash were “in closer range to chemotherapy”

  • Sample size too small to make significant correlation between biomarkers analyzed and outcome

  • Quality of life parameters similar between 2 treatment arms

  • Development of erlotinib in 1st-line NSCLC centers on

    • Molecular selection of patients

    • Combination with other targeted agents

    • Dosing optimization

Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.


Molecular predictors of outcome with erlotinib in bronchioloalveolar cell carcinoma bac l.jpg
Molecular Predictors of Outcome with Erlotinib in Bronchioloalveolar Cell Carcinoma (BAC)

  • Results of a prospective phase II trial

  • Objective: compare clinical, pathologic, and molecular characteristics of tumor specimens associated with response, PFS, and OS

  • Marker analysis: EGFR (mutations, amplification, polysomy, chromogenic in situ hybridization [CISH]), KRAS (mutations)

Molecular Characteristics and Outcome

Outcome of Patients Treated with Erlotinib

Median PFS Median OS

n RR(%) P (mo) P (mo) P

EGFR mut + 18 83 <.01 13 <.01 23 .65

EGFR wt 64 7 2 17

CISH ≥ 4 24 43 <.01 9 <.01 25.38

CISH < 4 53 13 2 16

IHC ≥ 1 25 20 .99 4 .76 19 .60

IHC 0 39 21 4 16

KRAS mut + 19 0 <.01 4 .25 13 .24

KRAS wt 62 32 5 21

n Median PFS Median OS

(mo) (mo)

All 102 4 17

CR+PR 22 15 24

Stable disease 38 6 29

Progression 36 1 8

Not evaluable 6 1 1

P < .01

Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003. Adapted with permission from Dr. Miller.


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Molecular Predictors of Outcome Bronchioloalveolar Cell Carcinoma (BAC)with Erlotinib in BACConclusions

  • Erlotinib resulted in 23% overall response rate (ORR) and 17 mo median overall survival (OS) in BAC

  • Presence of EGFR mutation associated with an 83% ORR, 13 mo progression-free survival (PFS) and 22 mo OS

  • EGFR amplification in BAC rare

  • EGFR polysomy predictive of improvement in PFS

  • KRAS exon 2 mutation associated with no responses and poorer OS

  • Patients with EGFR mutation + CISH  4 had ORR 90%, PFS 15 mo, OS 35 mo

  • Patients with wild type EGFR + CISH < 4 had ORR 4%, PFS 2 mo, OS 15 mo

Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003.


Phase ii trial 1st line erlotinib in patients with nsclc and egfr mutations l.jpg
Phase II Trial 1st-Line Erlotinib in Patients Bronchioloalveolar Cell Carcinoma (BAC)with NSCLC and EGFR Mutations

  • Primary endpoint: time to progression

  • Eligibility

    • Stage IIIB/IV NSCLC + mutated EGFR

    • No prior chemotherapy

    • No prior EGFR targeted agents

Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020.


Phase ii trial 1st line erlotinib in nsclc with egfr mutations results l.jpg

Response Predictors Bronchioloalveolar Cell Carcinoma (BAC)

ORR P-value

PS .662

0 8 (73%)

1 18 (86%)

2 5 (83%)

Histology .754

Adeno 23 (79%)

BAC 4 (100%)

Other 4 (80%)

Stage 1.0

IIIB 4 (100%)

IV 27 (79%)

ORR P-value

EGFR Mutation .038

Exon 19 19 (95%)

Exon 21 12 (67%)

Smoking .038

Never 24 (90%)

Former 7 (70%)

Current 0 (0%)

Gender .203

Female 22 (88%)

Male 9 (69%)

Phase II Trial 1st-Line Erlotinib in NSCLCwith EGFR MutationsResults

TTP According to Mutational Status

Log Rank P =.06Breslow P =.06

TTP According to Smoking Habits

Log Rank P =.12Breslow P =.02

Conclusions

  • Most benefit: Exon 19 deletions, patients who never smoked, visceral site other than lung

  • Phase III trial planned (erlotinib vs platinum-based chemotherapy in EGFR-mutated NSCLC)

Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020. Reprinted with permission from Dr. Paz-Ares.


Randomized phase ii trial of zd6474 vs gefitinib in advanced nsclc part a results l.jpg
Randomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLCPart A Results

Individual Changes in Size of Target Lesions from Baseline: Part A

Primary Endpoint in Part A:Progression-Free Survival

ZD6474

Hazard ratio = 0.6995% Cl = 0.50 to 0.96Two-sided P-value = .025

Probability of RemainingProgression-Free

Median PFS

ZD6474 = 11.0

Gefitinib = 8.1 weeks

Best Confirmed Change from Baselinein Target Lesion Size (%)

Gefitinib

Final data cut-off, July 2005

Progression-free survival in Part A (months)

Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.


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Randomized Phase II Trial of ZD6474 vs NSCLCGefitinib in Advanced NSCLCPart B Results

Secondary Endpoint:Overall Survival

Median PFS

ZD6474 then gefitinib = 6.1 months

Gefitinib then ZD6474 = 7.4 months

Probability of Remaining Alive

Hazard ratio = 1.19(95% Cl = 0.84 to 1.68)Two-sided P-value = .34

Time to Death (months)

Final data cut-off, July 2005

Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.


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Randomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLC: Adverse Events

*AEs are all CTC grade 1 or 2 except where noted.

Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.


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Randomized Phase II Trial of ZD6474 vs NSCLC: Adverse EventsGefitinib in Advanced NSCLCConclusions

  • Part A met primary endpoint of prolonging progression-free survival (PFS)

    • ZD6474 prolonged PFS by 45% compared with gefitinib

  • PFS prolongation did not result in overall survival advantage in Part B

    • Why? Not clear, maybe optional switchover confounded survival assessment

  • Adverse events (AEs) for both agents mostly mild

  • Slight differences in AE profiles

Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000.


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Novel Targeted Agents Under NSCLC: Adverse EventsInvestigation for Lung Cancer TreatmentHighlights of ASCO 2006

CP = carboplatin/paclitaxel.


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Mack PC, et al NSCLC: Adverse Events1

Elevated osteopontin plasma levels may have prognostic value in advanced NSCLC

Osteopontin is a secreted glycoprotein involved in induction of urokinase (uPA) and increased cell migration

Toschi L, et al2

FISH or IHC analysis of samples from 190 consecutive patients treated for advanced NSCLC

EGFR, HEr2, and p-Akt status are not predictors of sensitivity to chemotherapy

EGFR FISH + and/or HER2 FISH+ patients seemed to benefit more from nonplatinum vs platinum-based combinations (but N small)

In EGFR FISH+ patients, RR and TTP after EGFR-TKI used as 2nd-line treatment were at least equal to 1st-line chemotherapy

Other Searches for Useful Biomarkers in NSCLC—ASCO 2006

Mack PC, et al. 42nd ASCO, June 2-6, 2006. Abstract 7198.

Toschi L, et al. 42nd ASCO, June 2-6, 2006. Abstract 7111.


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Summary NSCLC: Adverse Events

  • First-generation TKIs (gefitinib, erlotinib) the search continues for

    • Molecular markers for patient selection

    • Optimal combinations

    • Improved dosing

  • Multitargeted TKIs currently on the market (sorafenib, sunitinib)

    • Some promising, but not yet conclusive results

  • Investigational multitargeted TKIs (vatalanib, ZD6474, AMG706, AZ2171)

    • Need data from randomized trials

    • Some differences in adverse event profiles

  • General areas of need

    • Surrogate markers for evaluation of agents

    • Biomarkers for patient selection

    • Optimization of clinical trial design


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Toxicity Management of Targeted Therapies: Implications for NSCLC: Adverse EventsNursing and Managed Care

Michelle Purdom, RN, BSN

Manager, Clinical Trials Operations

Phase I Program

University of Texas M.D. Anderson Cancer Center

Houston, Texas


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Overview NSCLC: Adverse Events

  • Management of side effects associated with targeted therapies

  • Pharmacoeconomics of cancer management and role/implications of targeted therapies in managed care setting


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Targeted Therapies and Approval Dates NSCLC: Adverse Events

February 12, 2004

January 26, 2006

May 2, 2003*

November 19, 2004

2003

2004

2005

2006

December 20, 2005

May 13, 2003

February 26, 2004

* Iressa was approved with contingencies on May 2, 2003.


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Most Common Side Effects Associated NSCLC: Adverse Eventswith FDA-Approved Targeted Therapies

Side Effect Bevacizumab* Sunitinib Bortezomib Sorafenib Cetuximab** Erlotinib† Gefitinib‡

Abdominal pain    

Acne and/or rash  

Alopecia  

Altered taste 

Anemia  

Anorexia and/or weight loss    

Appetite decrease/ taste disorder 

Arthralgia/myalgia   

Asthenia   

Bleeding 

Constipation     

Cough  

Dehydration 

Diarrhea      

Dizziness  

Dry and/or discolored skin  

Dysesthesia and/or paresthesia 

Dyspepsia  

Dyspnea     

Includes: *+IFL, +5-FU/LV, +FOLFOX4, and monotherapy; **+radiation, +irinotecan, and monotherapy; †+gemcitabine and monotherapy; ‡250 mg/d and 500 mg/d.


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Most Common Side Effects Associated NSCLC: Adverse Eventswith FDA-Approved Targeted Therapies (cont’d)

Side Effect Bevacizumab* Sunitinib Bortezomib Sorafenib Cetuximab** Erlotinib† Gefitinib‡

Edema  

Epistaxis 

Fatigue   

Fever    

GI hemorrhage 

Hand-foot skin reaction 

Headache    

Hypertension  

Insomnia 

Leukopenia and/or neutropenia and/or thrombocytopenia  

Mucositis/stomatits   

Nausea and/or vomiting      

Pain    

Peripheral neuropathy 

Pharyngitis 

Proteinuria 

Pruritis 

Upper respiratory infection 

Xerostomia 

Includes: *+IFL, +5-FU/LV, +FOLFOX4, and monotherapy; **+radiation, +irinotecan, and monotherapy; †+gemcitabine and monotherapy; ‡250 mg/d and 500 mg/d.


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Management of Bevacizumab-Associated NSCLC: Adverse EventsSide Effects

AT = arterial thromboembolic; B = bevacizumab; C = chemotherapy.

Sources: www.avastin.com/avastin/nurseFaqPro4.mAvastin (bevacizumab) prescribing information. Available at: http//www.gene.com/gene/products/information/oncology/avastin/insert.jsp


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Blood Pressure Diary NSCLC: Adverse Events

Courtesy of Michelle Purdom, RN, BSN


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Management of Bortezomib-Associated NSCLC: Adverse EventsSide Effects

Velcade (bortezomib) prescribing information.


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Management of Cetuximab-Associated NSCLC: Adverse EventsSide Effects

www.erbitux.com


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Management of Erlotinib-Associated NSCLC: Adverse EventsSide Effects

www.tarceva.com.


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Management of Gefitinib-Associated NSCLC: Adverse EventsSide Effects

Most common gefitinib-associated adverse events: diarrhea, rash, acne, dry skin, nausea, vomiting

www.iressa.com


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Example of NSCLC: Adverse EventsTypical Rash Induced by EGFR Inhibitors

Courtesy of Michelle Purdom, RN, BSN


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EGFR Rash NSCLC: Adverse Events

Courtesy of Michelle Purdom, RN, BSN


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Management of Sunitinib-Associated NSCLC: Adverse EventsSide Effects

www.sutent.com


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Management of Sorafenib-Associated NSCLC: Adverse EventsSide Effects

www. nexavar.com


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Pharmacoeconomics of Cancer Management and Role/Implications of Targeted Therapies inManaged Care Setting

Cohen M, et al. Am J Manag Care. 2006;12:524.


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Targeted Therapies and Managed Care of Targeted Therapies in

  • New therapies need evidence of effectiveness and safety

  • Impact on quality of life

  • Net impact on total cost of care

  • Concept of value differs among patients, providers, health plans, and employers

Cohen M, et al. Am J Manag Care. 2006;12:524.


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Biotechnology Pipeline of Targeted Therapies in

Condition

Number of Agents

AIDS/HIV infections/related conditions

Autoimmune disorders

Blood disorders

Cancer/related conditions

Cardiovascular disease

Eye conditions

Diabetes/related conditions

Digestive disorders

Genetic disorders

Growth disorder

Infectious disease

Neurologic disorders

Other conditions not specified here

Respiratory disorders

Skin disorders

Transplantation

17

26

2

154

19

5

10

11

9

3

43

16

17

14

7

3

2004 Survey. Medicines in Development: Biotechnology. Available at: http://www.phrma.org/files/Biotech%20survey.pdf. Accessed February 15, 2006.


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Growth Drivers for Biologics of Targeted Therapies in

Key contributors from managed care perspective include

  • Increased availability of targets for biologic agents

  • Increased use of approved drugs

  • Increased approval of biotechnology drugs for more common conditions

  • Expanded indications for approved drugs

Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.


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Reasons for Off-Label Use of Biologics of Targeted Therapies in

  • Small population size and/or assessed cost of clinical trials may discourage marketers from seeking formal FDA approval

  • Potential of newer therapies for better efficacy and outcomes

  • Proven safety and efficacy in other disease states

  • Potential for increased quality of life

  • Thought leader advocacy/patient demand

  • Better understanding of disease pathways, particularly immune-modulating diseases

Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.


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Managed Care’s Concerns Regarding of Targeted Therapies inOff-Label Use of Biologics

  • Safety/efficacy questions

  • Differing dosing and administration

  • Potential for inappropriate care

  • Potential for cost increase

  • Paucity of data

  • Lack of uniform guidelines/best practices

  • Legal/ethical issues

Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.


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Recommendations for Managing Expanded Indications of Targeted Therapies in

  • Scan the pipeline to become aware of impending drug launches

  • Increase education for P&T committees

  • Define a process and clear criteria

  • Develop and/or augment treatment guidelines for expanded indications

  • Increase case management/disease management

  • Strive for innovative management strategies that contain cost and maintain access

Cohen M, et al. Am J Manag Care. 2006;12:524.


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Continued Challenges for of Targeted Therapies inManaged Care Organizations

  • Expanding indications for FDA-approved drugs present uniquechallenges for MCOs.

    • This translates into added expenditures for MCOs because of increased frequency of administration and/or longer duration of therapy

    • For patients, may result in higher copays and more restrictive access management strategies, particularly the use of prior authorization

  • Maintain focus on potential of agents for reduction in disease progression and disability rather than solely on patient copays and aggressive management strategies

    • Shift focus on cost to clinical decision making through evidence-based medicine

  • Adequately plan for agents with multiple indications

    • Need more definitive criteria for evaluating expanded indications and potential for cost savings

Cohen M, et al. Am J Manag Care. 2006;12:524.


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Nursing Implications of Targeted Therapies in

  • The nurse should help the patient understand importance of prior insurance authorization due to the high cost of biopharmaceuticals

  • The nurse should assist the patient as a liaison with the hospital business office/MCO by initiating the process early and often

  • Emotional support


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Summary of Targeted Therapies in

  • Expanding indications and off-label applications of FDA-approved targeted therapies present unique challenges

    • MCOs face added expenses

    • Patients face higher co-pays and more restrictive access

    • Clinicians need to expand their knowledge base and skill sets

  • Nurses have an important role in providing

    • Professional care

    • Toxicity management and side effect education

    • Assistance in navigating the preauthorization process

    • Emotional support


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Keeping Pace with Targeted Therapies in Lung Cancer of Targeted Therapies inHighlights from the ASCO 2006 Annual Meeting


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