Research To Practice

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Anti-EGFR Antibodies Lung Cancer

• Thomas J. Lynch, Jr., M.D.
• Director, Yale Cancer Center
• Physician-in-Chief, Smilow Cancer Hospital

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Cetuximab Background

• Monoclonal anti-EGFR IgG1 antibody
• Inhibits EGFR signaling
• Mediates ADCC
• Effective across several solid tumors, improving
  overall survival in
• mCRC (Van Cutsem E. J Clin Oncol, 2011)
• SCCHN (Bonner JA. N Engl J Med, 2006 and Lancet
  Oncol, 2009 Vermorken J. N Engl J Med, 2008)
• Advanced NSCLC (Pirker R. Lancet, 2009)
• In first-line treatment of advanced NSCLC,
  cetuximab significantly increased OS when added
  to cisplatin/vinorelbine (phase III FLEX) (Pirker
  R. Lancet, 2009)

EGFR epidermal growth factor receptor ADCC
antibody-dependent cell-mediated cytotoxicity
mCRC metastatic colorectal cancer SCCHN
squamous cell carcinoma of the head and neck
NSCLC non-small cell lung cancer
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BMS099 Background and Overall Results
Phase III of cetuximab added to taxane/carboplatin for the first-line treatment of advanced NSCLC Phase III of cetuximab added to taxane/carboplatin for the first-line treatment of advanced NSCLC Phase III of cetuximab added to taxane/carboplatin for the first-line treatment of advanced NSCLC Phase III of cetuximab added to taxane/carboplatin for the first-line treatment of advanced NSCLC Phase III of cetuximab added to taxane/carboplatin for the first-line treatment of advanced NSCLC
Endpoints Primary PFS by IRRC Primary PFS by IRRC Key Secondary OS ORR by IRRC Key Secondary OS ORR by IRRC
Patients Chemonaïve, stage IIIb (pleural effusion) or IV NSCLC No inclusion criteria by EGFR expression, histology, or comorbidities Randomized 11 Tissue collection not required per trial protocol Chemonaïve, stage IIIb (pleural effusion) or IV NSCLC No inclusion criteria by EGFR expression, histology, or comorbidities Randomized 11 Tissue collection not required per trial protocol Chemonaïve, stage IIIb (pleural effusion) or IV NSCLC No inclusion criteria by EGFR expression, histology, or comorbidities Randomized 11 Tissue collection not required per trial protocol Chemonaïve, stage IIIb (pleural effusion) or IV NSCLC No inclusion criteria by EGFR expression, histology, or comorbidities Randomized 11 Tissue collection not required per trial protocol
n 338 n 338 n 338 HR P-value
Treatment Cetuximab Taxane/Carboplatin Taxane/Carboplatin Taxane/Carboplatin
OS, Median 9.7 mo 8.4 mo 8.4 mo 0.89 0.17
PFS - IRRC, Median 4.0 mo 4.2 mo 4.2 mo 0.90 0.24
ORR - IRRC 25.7 17.2 17.2 P lt 0.01
Lynch TJ. J Clin Oncol, 2010 Lynch TJ. J Clin Oncol, 2010 Lynch TJ. J Clin Oncol, 2010 Lynch TJ. J Clin Oncol, 2010 Lynch TJ. J Clin Oncol, 2010
A prior retrospective study investigated EGFR
expression by IHC as a potential predictive
biomarker of cetuximab benefit

• EGFR status tumors classified as EGFR (-) with
  no observable staining, and EGFR () with any
  staining
• No significant correlations between EGFR IHC
  status and outcome were noted
• Khambata-Ford S. J Clin Oncol, 2010

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EGFR Expression Analysis as Continuous
VariableThe H-Score for IHC Staining
Calculating H-Score
How is H-Score calculated?

1. Membrane staining intensity determined for each
   cell in a fixed field

1. Percent of cells at each staining intensity level
   calculated in a fixed field

• No staining
• Weak staining
• Moderate staining
• Strong staining

0
0
1
25
2
50
3
100

• EGFR IHC H-score1 x ( cells 1) 2 x ( cells
  2) 3 x ( cells 3)
• The final score gives more relative weight to
  higher-intensity membrane staining (3 gt 2 gt 1)

An individual EGFR IHC score value ranging from
0?300 is generated from the tumor sample of each
patient
Hirsch FR, et al. J Clin Oncol, 2003 Cappuzzo F,
et al. J Natl Cancer Inst, 2005 Hirsch FR, et
al. Cancer, 2008 Felip E, et al. Clin Cancer
Res, 2008 Gori S, et al. Ann Oncol, 2009 Lee
HJ, et al. Lung Cancer, 2010. Atkins D, et al. J
Histochem Cytochem, 2004
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EGFR Expression Analysis as Continuous
VariableH-Score vs. Intensity Scale for IHC
Staining
H-Score may give a different distribution pattern
and greater granularity for determining EGFR
expression data, compared to classical intensity
scale
Individual Cell Staining Intensity Individual Cell Staining Intensity Individual Cell Staining Intensity Individual Cell Staining Intensity Comparison Comparison
0 1 2 3 Intensity Scale H-Score
Sample 1 0 10 60 30 3 220
Sample 2 90 0 0 10 3 30
Sample 3 0 0 100 0 2 200
Sample 4 50 0 0 50 3 150
Hypothetical examples
NSCLC specimens evaluated with classical
intensity scale
0 No staining 1 Weak staining 10 cells
2 Moderate staining 10 cells 3 Strong
staining 10 cells
Atkins D, et al. J Histochem Cytochem, 2004
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EGFR Expression Analysis as Continuous
VariableH-Score vs. Intensity Scale for IHC
Staining
H-Score may give a different distribution pattern
and greater granularity for determining EGFR
expression data, compared to classical intensity
scale
Individual Cell Staining Intensity Individual Cell Staining Intensity Individual Cell Staining Intensity Individual Cell Staining Intensity Comparison Comparison
0 1 2 3 Intensity Scale H-Score
Sample 1 0 10 60 30 3 220
Sample 2 90 0 0 10 3 30
Sample 3 0 0 100 0 2 200
Sample 4 50 0 0 50 3 150
Hypothetical examples
NSCLC specimens from BMS099
0 H-Score 0 1 H-Score 35 2 H-Score 70
3 H-Score 150-300
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Rationale for EGFR Expression Analysis as
Continuous Variable Results from FLEX ITT
Analysis of OS

• Overall survival
• CT cetuximab (n 557), 11.3 mo
• CT (n 568), 10.1 mo
• HR 0.871 (95 CI 0.762-0.996)
• Two-sided log-rank p 0.044
• 1-year OS 47 vs 42

Pirker R, et al. Lancet, 2009
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Rationale for EGFR Expression Analysis as
Continuous Variable Results from FLEX
H-Score-Based Analysis of OS

• No benefit to the use of cetuximab for patients
  with H-scores under 200
• For patients with H-scores over 200
• CT cetuximab, OS 12.0 mo
• CT, OS 9.6 mo
• HR 0.73 95 CI 0.58-0.93 p 0.011
• 1-year OS 50 vs 37
• 2-year OS 24 vs 15

Pirker R, et al. WCLC 2011
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MethodsEGFR H-score Assessment of BMS-099

• Original PharmDxTM EGFR-stained slides from
  BMS-099 were submitted for evaluation at a
  US-based reference lab
• Percentage of membrane staining and intensity
  were recorded by a single pathologist and H-score
  calculated.
• Pathologist performed analysis without
  pre-training(see Round Robin Test Ruschoff J.
  WCLC and ESMO, 2011)
• Of 148 available samples (22 of ITT), 5 could
  not be scored with confidence and were excluded
  from analysis
• Statistical Analyses
• Patients classified in 2 groups based on H-score
  cut-off of 200
• Low expression EGFR IHC lt200
• High expression EGFR IHC 200
• OS and PFS data summarized in low and high groups
  
• Using KM plots and median estimates
• HRs and interaction effect estimated from Cox PH
  model
• Tumor response data summarized in low and high
  groups
• Using RR and 95 CI
• Interaction effect estimated from logistic
  regression model

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BMS-099 EGFR IHC Analysis by H-ScoreClinical
Outcomes in Evaluable Patients
All patients (n 676) All patients (n 676) EGFR IHC data set (n 148) EGFR IHC data set (n 148)
CT Cetuximab n 338 CT n 338 CT Cetuximab n 77 CT n 71
PFS - IRRC Median, mo 4.0 4.2 4.6 5.3
HR (95 CI) P value 0.90 (0.76-1.07)0.24 0.90 (0.76-1.07)0.24 1.08 (0.75-1.55)0.68 1.08 (0.75-1.55)0.68
OS Median, mo 9.7 8.4 8.3 9.8
HR (95 CI) P value 0.89 (0.75-1.05)0.17 0.89 (0.75-1.05)0.17 1.09 (0.76-1.54)0.65 1.09 (0.76-1.54)0.65
ORR - IRRC, (95 CI) 25.7 (21.2-30.7) 17.2(13.3-21.6) 29.9(20.0-41.4) 22.5(13.5-34.0)
Outcomes in the evaluable population, although
consistent with the overall group for ORR, were
not fully representative in terms of PFS and OS
Same data set used in prior analysis
(Khambata-Ford S, et al. J Clin Oncol, 2010).
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Secondary EndpointOverall Response Rate (by IRC
Evaluation)
EGFR H-Score lt200 EGFR H-Score lt200 EGFR H-Score 200 EGFR H-Score 200
CT Cetuximab (n 39) CT (n 36) CT Cetuximab (n 35) CT (n 33)
PR or CR (n) 8 9 14 6
ORR () 20.5 25.0 40.0 18.2
95 CI 9.3-36.5 12.1-42.2 23.9-57.9 7.0-35.5
Test for interaction of ORR and biomarker
status P 0.087
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Primary Endpoint Progression-Free Survival (by
IRC Evaluation)
CT cetuximab CT HR (95 CI)
EGFR H-Score lt200 (n 75) 5.7 mo 4.3 mo 1.06 (0.63-1.86)
EGFR H-Score 200 (n 68) 4.6 mo 4.2 mo 1.18 (0.69-2.01)
Test for interaction of PFS and biomarker
status P 0.73
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Secondary EndpointOverall Survival
CT cetuximab CT HR (95 CI)
EGFR H-Score lt200 (n 75) 12.2 mo 7.5 mo 1.28 (0.78-2.11)
EGFR H-Score 200 (n 68) 9.3 mo 7.6 mo 0.93 (0.56-1.55)
Test for interaction of OS and biomarker status P
0.35
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Summary and Conclusions

• The EGFR IHC H-Score analysis of BMS-099, using a
  cutoff score of 200, showed
• An observed improvement in RR with cetuximab in
  the EGFRhigh cohort but no meaningful differences
  in EGFRlow subgroup (interaction P-value
  0.087)
• No meaningful PFS or OS differences between
  treatment arms in either the EGFRhigh or EGFRlow
  subgroups (interaction P-values PFS 0.73, OS
  0.35)
• Due to limited tissue availability (22) and
  possible convenience sampling, definitive
  conclusions can not be drawn from this analysis
• This analysis reflects the current level of
  understanding in the US for application of the
  Dako PharmDxTM assay for the assessment of EGFR
  IHC H-Score on tissue samples of patients with
  NSCLC
• The full role of EGFR IHC H-Score as a predictive
  marker for cetuximab benefit should be defined in
  larger, prospective studies.

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Saturday, February 11, 2012Hollywood, Florida
Co-Chairs Rogerio C Lilenbaum, MD Mark A
Socinski, MD
Co-Chair and Moderator Neil Love, MD

Faculty
Chandra P Belani, MD John Heymach, MD, PhD Pasi A
Jänne, MD, PhD
Thomas J Lynch Jr, MD Heather Wakelee, MD