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Transcript of Copyright © 2011 Research To Practice. All rights reserved. Faculty Meet The Professors Oncologist...
Copyright © 2011 Research To Practice. All rights reserved.
Faculty
Meet The Professors
Oncologist and Nurse Investigators Consult on Challenging Patient Cases
in Non-Small Cell Lung Cancer
Saturday, November 13, 20106:30 AM – 8:00 AM
Peabody Orlando Hotel
ModeratorNeil Love, MD
Mark A Socinski, MDMichelle M Turner, MS, CRNP
Beth Eaby-Sandy, MSN, CRNP, OCNRogerio C Lilenbaum, MD
Copyright © 2011 Research To Practice. All rights reserved.
Agenda
Module 1 Biomarker- and Histology-Guided Treatment of NSCLC: Ms Eaby-Sandy
Module 2 Current Options for Adjuvant Systemic Treatment of NSCLC: Ms Turner
Module 3 The Use of EGFR Tyrosine Kinase Inhibitors in NSCLC and Relevance of EGFR Tumor Mutations: Ms Eaby-Sandy
Module 4 Chemobiologic Management of Advanced NSCLC: Ms Turner
Panel Discussion and Response to Audience Questions
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Temel JS et al. N Engl J Med 2010;363(8):733-42.
Copyright © 2011 Research To Practice. All rights reserved.
Case 1 (Ms Eaby-Sandy)
A 71-year-old woman and never smoker with EGFR wild-type metastatic NSCLC receives six cycles of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab but then experiences disease progression. Assay of the tumor is positive for the EML4-ALK mutation, and she is currently participating in a clinical trial of crizotinib.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
KRAS
Unknown
EGFRHER2
BRAFALK fusion
PIK3CAMEK1
ROS fusionPDGFR amp
Adeno
Squam
Large
Small
Courtesy of William Pao, AAAS-FDLI Colloquium on Personalized Medicine, 2009.
Lung Cancer Histologic and Molecular Subsets
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Sandler A et al. N Engl J Med 2006;355:2542-50.Reck M et al. J Clin Oncol 2009;27(8):1227-34.Crinò L et al. Lancet Oncol 2010;11:733-40.
Copyright © 2011 Research To Practice. All rights reserved.
Faculty
Meet The Professors
Oncologist and Nurse Investigators Consult on Challenging Patient Cases
in Non-Small Cell Lung Cancer
Saturday, November 13, 20106:30 AM – 8:00 AM
Peabody Orlando Hotel
ModeratorNeil Love, MD
Mark A Socinski, MDMichelle M Turner, MS, CRNP
Beth Eaby-Sandy, MSN, CRNP, OCNRogerio C Lilenbaum, MD
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Patel JD et al. J Clin Oncol 2009;27(20):3284-9.
Copyright © 2011 Research To Practice. All rights reserved.Patel JD et al. J Clin Oncol 2009;27(20):3284-9.
Efficacy Endpoints
Median progression-free survival 7.8 mos
Median overall survival 14.1 mos
Objective response rate 55%
Select Adverse Events Grade 3 Grade 4
Diverticulitis1 6% 2%
Thrombocytopenia 0% 8%
Neutropenia 4% 0%
Venous thrombosis 4% 2%1 One case of Grade IV diverticulitis with bowel perforation
Pem/Carbo/Bev with Maintenance Pem/Bev as First-Line Therapy for Nonsquamous NSCLC (N = 49)
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POINTBREAK Phase III Trial Pemetrexed (Pem)/Carboplatin (C)/Bevacizumab (Bev) Maintenance Pem/Bev versus Paclitaxel/C/Bev Maintenance Bev in Patients with NSCLC
www.ClinicalTrials.gov, November 2010.
Eligibility
• Stage IIIB or IV nonsquamous NSCLC
RPemetrexed + Carboplatin +
Bevacizumab
Target accrual = 900
Paclitaxel + Carboplatin + Bevacizumab
MaintenancePemetrexed + Bevacizumab
MaintenanceBevacizumab
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Pirker R et al. Lancet 2009;373(9674):1525-31.
Copyright © 2011 Research To Practice. All rights reserved.Pirker R et al. Lancet 2009;373(9674):1525-31.
Efficacy Parameter
Cetux + CV
(n=557)
CV
(n=568)Hazard Ratio p-value
Median overall survival
All patients
Nonsquamous
Squamous
11.3 mos
12.0 mos
10.2 mos
10.1 mos
10.3 mos
8.9 mos
0.87
0.94
0.80
0.044
Median progression-free survival 4.8 mos 4.8 mos 0.94 0.39
Overall response rate 36% 29% — 0.010
FLEX: Efficacy OutcomesEGFR expression-positive by IHC (>1 positive tumor cell)
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Case 1 (Ms Eaby-Sandy)
A 71-year-old woman and never smoker with EGFR wild-type metastatic NSCLC receives six cycles of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab but then experiences disease progression. Assay of the tumor is positive for the EML4-ALK mutation, and she is currently participating in a clinical trial of crizotinib.
Copyright © 2011 Research To Practice. All rights reserved.
Kwak EL et al. N Engl J Med 2010;363(18):1693-703.
Copyright © 2011 Research To Practice. All rights reserved.
Crizotinib Inhibition of the ALK Signaling Pathway
Bang Y et al. Proc ASCO 2010;Abstract 3.
ALK
Tumor cellproliferation
Cell survival
PI3K
BAD
AKT
STAT3/5
mTOR
S6K
RAS
MEK
ErKErK
PLC-Y
PIP2
IP3
Crizotinib
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Best Response to Crizotinib in Patients with ALK-Positive Advanced NSCLC
Kwak EL et al. N Engl J Med 2010;363(18):1693-703. © 2010. Massachusetts Medical Society. All rights reserved.
60
40
0
20
10 20 70 7960504030
60
40
0
20
10 20 70 7960504030
Patient No.
Per
cen
t C
han
ge
fro
m B
ase
lin
e Disease progressionDisease progression Stable diseaseStable disease Partial responsePartial response Complete responseComplete response
-30%-30%
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Grade 3/4 Adverse Events
Adverse Event (AE) Grade 3 Grade 4
ALT elevation 5% 1%
AST elevation 6% 0%
Lymphopenia 2% 0%
Hypophosphatemia 1% 0%
Neutropenia 1% 0%
Hypoxia 1% 0%
Pneumonitis 1% 0%
Pulmonary emoblism 1% 0%
Kwak EL et al. N Engl J Med 2010;363(18):1693-703.
Copyright © 2011 Research To Practice. All rights reserved.
Case 1 (Ms Eaby-Sandy)
A 71-year-old woman and never smoker with EGFR wild-type metastatic NSCLC receives six cycles of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab but then experiences disease progression. Assay of the tumor is positive for the EML4-ALK mutation, and she is currently participating in a clinical trial of crizotinib.
Copyright © 2011 Research To Practice. All rights reserved.
Case 2 (Ms Turner)
A 61-year-old man with Stage II NSCLC received adjuvant docetaxel/cisplatin and bevacizumab on the ECOG-E1505 clinical trial and completed one year of maintenance bevacizumab in early 2010. The patient is now found on imaging to have a solitary metastasis in the adrenal gland.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Chemotherapy
Adjuvant chemotherapy (vinorelbine + cisplatin OR docetaxel + cisplatin OR gemcitabine + cisplatin OR pemetrexed + cisplatin)
Chemotherapy + bevacizumab
Adjuvant chemotherapy (as described above) with bevacizumab on d1 q3wk x 1y
Eligibility (Target accrual = 1,500)• Resection within the past six to 12 weeks
• ECOG PS 0-1• No history of CVA or TIA
• History of myocardial infarction or anginaacceptable if no evidence of active diseasewithin the past 12 months
* Patients are stratified according to type of chemotherapy, stage, histology and gender.
ECOG-E1505: A Phase II Study of Adjuvant Chemotherapy with or without Bevacizumab for Stage IB-IIIA NSCLC
R*
www.ClinicalTrials.gov, November 2010.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Bria E et al. Lung Cancer 2009;63(1):50-7.
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Magnitude of Benefit of Adjuvant Chemotherapy for NSCLC: A Meta-analysis of Randomized Clinical Trials • Meta-analysis of 12 Phase III trials (from 1994-2007), and an
individual patient meta-analysis were conducted to determine if cisplatin-based chemotherapy improves survival over surgery (seven subpopulations examined, n = 7,334).
• Absolute benefit and the number of patients treated for one patient to benefit (NNT) were evaluated for magnitude of benefit.
Bria E et al. Lung Cancer 2009;63(1):50-7.
Results from Pooled Data
Adjuvant Chemotherapy vs. Surgery Only Relative Benefit Absolute Benefit NNT
Overall survival (n = 7,334) 7%-12% 2.5%-4.1% 24-39
Disease-free survival (n = 6,396) 11%-12% 4.2%-4.6% 22-24
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What patient education information do you consider essential in a patient with non-small cell lung cancer about to begin treatment with….
Adjuvant cisplatin/paclitaxel
Copyright © 2011 Research To Practice. All rights reserved.Pfannschmidt J, Dienemann H. Lung Cancer 2010;69(3):251-8.
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Surgical Treatment of Oligometastatic NSCLC: Analysis of Retrospective Cases Series
Site of Metastasis 5-Year Survival
Satellite nodules 28%
Ipsilateral nodules 21%
Brain metastasis 11% - 30%
Adrenal metastasis 26%
Pfannschmidt J, Dienemann H. Lung Cancer 2010;69(3):251-8.
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Case 3 (Ms Eaby-Sandy)
A 71-year-old man with EGFR-mutated metastatic NSCLC and limited family support begins front-line therapy with erlotinib 150 mg daily. Significant side effects require dose reduction to 100 mg, which he is now tolerating well.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Epidermal Growth Factor Receptor (EGFR) Mutations
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EGFR Signaling
Adapted by permission from Macmillan Publishers Ltd. (Arteaga CL. HER3 and mutant EGFR meet MET. Nat Med 13:675-7), copyright 2007.
Copyright © 2011 Research To Practice. All rights reserved.Adapted by permission from Macmillan Publishers Ltd. (Arteaga CL. HER3 and mutant EGFR meet MET. Nat Med 13:675-7), copyright 2007.
EGFR-TKI Mechanism of Action
Copyright © 2011 Research To Practice. All rights reserved.Adapted by permission from Macmillan Publishers Ltd. (Arteaga CL. HER3 and mutant EGFR meet MET. Nat Med 13:675-7), copyright 2007.
Resistance Mechanisms
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Mok TS et al. N Engl J Med 2009;361(10):947-57.
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Efficacy of Gefitinib vs C/P in East Asian Patients with NSCLC
Objective Response Rate (ORR) Gefitinib C/P P-value
Intent-to-treat population (n = 609; 608)
43.0% 32.2% <0.001
EGFR mutation-positive (n = 132; 129) 71.2% 47.3% <0.001
EGFR mutation-negative (n = 91; 85) 1.1% 23.5% 0.001
Progression-Free Survival (PFS) Hazard Ratio P-value
Intent-to-treat population 0.74 <0.001
EGFR mutation-positive 0.48 <0.001
EGFR mutation-negative 2.85 <0.001
Mok TS et al. N Engl J Med 2009;361(10):947-57.
Copyright © 2011 Research To Practice. All rights reserved.www.ClinicalTrials.gov, November 2010.Wakelee H et al. Oncologist 2007;12(3):331-7.
RADIANT Trial: A Phase III Study of Erlotinib or Placebo with or without Adjuvant Chemotherapy for Patients with Resected, EGFR-Positive NSCLC
Eligibility
• Resected Stage IB to IIIA• EGFR-positive by FISH or IHC4 cycles of platinum-based
chemotheraphy (optional)
Erlotinib 150 mg daily x 2 years
Observation
Protocol IDs: OSI-774-302, NCT00373425
Target accrual: 945 (Open)
* Stratified by histology (squamous versus other), gender, age, EGFR status, smoking status and adjuvant chemotherapy
2:1R*
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Copyright © 2011 Research To Practice. All rights reserved.
Skin Rash from Tyrosine Kinase Inhibitors
Ricciardi S et al. Clin Lung Cancer 2009;10(1):28-35.
• Most frequent dermatologic side effect reported is acneiform eruption.• Affects mainly face, upper chest and/or back• Also known as acne, acneiform skin reaction/rash, follicular rash and maculopapular skin rash.
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Case 3 (Ms Eaby-Sandy)
A 71-year-old man with EGFR-mutated metastatic NSCLC and limited family support begins front-line therapy with erlotinib 150 mg daily. Significant side effects require dose reduction to 100 mg, which he is now tolerating well.
Copyright © 2011 Research To Practice. All rights reserved.
Incidence of Acneiform Eruption During Therapy with Epidermal Growth Factor Receptor Inhibitors
Ricciardi S et al. Clin Lung Cancer 2009;10(1):28-35.
EGFR Inhibitor Incidence of Acneiform Eruption
Erlotinib 79% (10.4% >Grade 3)
Cetuximab 80% (18% >Grade 3)
Gefitinib 53% (1.6% >Grade 3)
Panitumumab 70%-100% (<10% severe)
Matuzumab 64% (0% >Grade 3)
Copyright © 2011 Research To Practice. All rights reserved.
Case 3 (Ms Eaby-Sandy)
A 71-year-old man with EGFR-mutated metastatic NSCLC and limited family support begins front-line therapy with erlotinib 150 mg daily. Significant side effects require dose reduction to 100 mg, which he is now tolerating well.
Copyright © 2011 Research To Practice. All rights reserved.
Case 4 (Ms Turner)
A 71-year-old man underwent concurrent docetaxel/carboplatin and radiation therapy in 2003 for localized NSCLC with positive margins. A biopsy of new pulmonary nodules in 2008 showed poorly differentiated adenocarcinoma. Paclitaxel/carboplatin/bevacizumab was administered but had to be discontinued because of toxicity issues.
Copyright © 2011 Research To Practice. All rights reserved.
What patient education information do you consider essential in a patient with non-small cell lung cancer about to begin treatment with….
carboplatin/pemetrexed/bevacizumab
Copyright © 2011 Research To Practice. All rights reserved.
Case 4 (Ms Turner)
A 71-year-old man underwent concurrent docetaxel/carboplatin and radiation therapy in 2003 for localized NSCLC with positive margins. A biopsy of new pulmonary nodules in 2008 showed poorly differentiated adenocarcinoma. Paclitaxel/carboplatin/bevacizumab was administered but had to be discontinued because of toxicity issues.
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Eligibility
Unresectable nonsquamousStage III NSCLC
Standard-dose radiotherapy+ chemo consolidation chemo
www.ClinicalTrials.gov, November 2010.
RTOG-0617: A Phase III Trial of High-Dose (74 Gy) or Standard-Dose (60 Gy) Radiation Therapy Plus Chemotherapy
High-dose radiotherapy+ chemo consolidation chemo
Standard-dose radiotherapy + chemo and cetuximab consolidation chemo and cetuximab
High-dose radiotherapy + chemo and cetuximab consolidation chemo and cetuximab
R
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Randomized, Double-Blind, Placebo-Controlled Multicenter Phase II Study of the Efficacy and Safety of Apricoxib in Combination With Either Docetaxel or Pemetrexed in NSCLC
Apricoxib 100 mg PO qd + docetaxel or pemetrexed q3 wks
Placebo PO qd + docetaxel or pemetrexed q3 wks
Protocol IDs: UMGCC 0822 (Open) Target Accrual: 130
Eligibility: Stage IIIb (pleural effusion) or IV NSCLC; progression after 1 prior platinum-based chemo; received prior erlotinib
R
www.ClinicalTrials.gov, November 2010.
Copyright © 2011 Research To Practice. All rights reserved.