1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

4. Anti-EGFR Antibodies Lung Cancer
Thomas J. Lynch, Jr., M.D.
Director, Yale Cancer Center
Physician-in-Chief, Smilow Cancer Hospital

5. 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

6. BMS099 Background and Overall Results
Phase III of cetuximab added to taxane/carboplatin for the first-line treatment of advanced NSCLC
Endpoints
Primary
PFS 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 1:1
Tissue collection not required per trial protocol
n = 338
HR; P-value
Treatment
Cetuximab + Taxane/Carboplatin
Taxane/Carboplatin
OS, Median
9.7 mo
8.4 mo
0.89; 0.17
PFS - IRRC, Median
4.0 mo
4.2 mo
0.90; 0.24
ORR - IRRC
25.7%
17.2%
P < 0.01
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

7. How is H-Score calculated?
EGFR Expression Analysis as Continuous Variable The H-Score for IHC Staining: Calculating H-Score
How is H-Score calculated?
Membrane staining intensity determined for each cell in a fixed field
Percent of cells at each staining intensity level calculated in a fixed field
No staining
Weak staining
Moderate staining
Strong staining 0% 1+
25% 2+
50% 3+
100%
EGFR IHC H-score [1 x (% cells 1+) + 2 x (% cells 2+) + 3 x (% cells 3+)]
The final score gives more relative weight to higher-intensity membrane staining (3+ > 2+ > 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, Atkins D, et al. J Histochem Cytochem, 2004

8. EGFR Expression Analysis as Continuous Variable H-Score vs
EGFR Expression Analysis as Continuous Variable H-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
Comparison 0+ 1+ 2+ 3+
Intensity Scale
H-Score
Sample 1*
10%
60%
30%
220
Sample 2*
90% 30
Sample 3* 0%
100%
200
Sample 4*
50%
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

9. Individual Cell Staining Intensity NSCLC specimens from BMS099
EGFR Expression Analysis as Continuous Variable H-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
Comparison 0+ 1+ 2+ 3+
Intensity Scale
H-Score
Sample 1*
10%
60%
30%
220
Sample 2*
90% 30
Sample 3* 0%
100%
200
Sample 4*
50%
150
*Hypothetical examples
NSCLC specimens from BMS099
0 = H-Score 0; 1+ = H-Score 35; 2+ = H-Score 70; 3+ = H-Score

10. 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 = (95% CI )
Two-sided log-rank p = 0.044
1-year OS: 47% vs 42%
Pirker R, et al. Lancet, 2009

11. For patients with H-scores over 200: CT + cetuximab, OS = 12.0 mo
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 ]; p = 0.011
1-year OS: 50% vs 37%
2-year OS: 24% vs 15%
Pirker R, et al. WCLC 2011 11

12. Methods EGFR 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 <200
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

13. BMS-099 EGFR IHC Analysis by H-Score Clinical Outcomes in Evaluable Patients
All patients (n = 676)
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 ( ) 0.24
1.08 ( ) 0.68
OS Median, mo
9.7
8.4
8.3
9.8
0.89 ( ) 0.17
1.09 ( ) 0.65
ORR - IRRC, % (95% CI)
25.7 ( )
17.2 ( )
29.9 ( )
22.5 ( )
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).

14. Secondary Endpoint Overall Response Rate (by IRC Evaluation)
EGFR H-Score <200
EGFR H-Score ≥200
CT + Cetuximab (n = 39) CT
(n = 36)
CT + Cetuximab (n = 35)
(n = 33)
PR or CR (n) 8 9 14 6
ORR (%)
20.5
25.0
40.0
18.2
95% CI
Test for interaction of ORR and biomarker status
P = 0.087

15. Primary Endpoint Progression-Free Survival (by IRC Evaluation)
CT + cetuximab CT
HR (95% CI)
EGFR H-Score <200 (n = 75)
5.7 mo
4.3 mo
1.06 ( )
EGFR H-Score ≥200 (n = 68)
4.6 mo
4.2 mo
1.18 ( )
Test for interaction of PFS and biomarker status
P = 0.73

16. Secondary Endpoint Overall Survival
CT + cetuximab CT
HR (95% CI)
EGFR H-Score <200 (n = 75)
12.2 mo
7.5 mo
1.28 ( )
EGFR H-Score ≥200 (n = 68)
9.3 mo
7.6 mo
0.93 ( )
Test for interaction of OS and biomarker status
P = 0.35

17. 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.

18. Saturday, February 11, 2012 Hollywood, 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