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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
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
BMS099 Background and Overall Results
Phase III of cetuximab added to taxane/carboplatin for the first-line treatment of advanced NSCLC
Endpoints
Patients
Primary
• PFS by IRRC
•
•
•
•
Key Secondary
• OS
• ORR by IRRC
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
n = 338
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
Treatment
HR; P-value
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
EGFR Expression Analysis as Continuous Variable
The 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
2. Percent of cells at each staining
intensity level calculated in a fixed field
0
− No staining
1+
− Weak staining
25%
2+
− Moderate staining
50%
3+
− Strong staining
0%
100%
3. 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,
2010. Atkins D, et al. J Histochem Cytochem, 2004
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*
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
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*
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
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
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
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
BMS-099 EGFR IHC Analysis by H-Score
Clinical Outcomes in Evaluable Patients
All patients (n = 676)
PFS - IRRC
Median, mo
HR (95% CI)
P value
OS
Median, mo
HR (95% CI)
P value
ORR - IRRC, %
(95% CI)
EGFR IHC data set (n = 148)*
CT + Cetuximab
n = 338
CT
n = 338
CT + Cetuximab
n = 77
CT
n = 71
4.0
4.2
4.6
5.3
0.90 (0.76-1.07)
0.24
9.7
8.4
0.89 (0.75-1.05)
0.17
25.7
(21.2-30.7)
17.2
(13.3-21.6)
1.08 (0.75-1.55)
0.68
8.3
9.8
1.09 (0.76-1.54)
0.65
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).
Secondary Endpoint
Overall Response Rate (by IRC Evaluation)
EGFR H-Score <200
PR or CR (n)
ORR (%)
95% CI
EGFR H-Score ≥200
CT + Cetuximab
(n = 39)
CT
(n = 36)
CT + Cetuximab
(n = 35)
CT
(n = 33)
8
9
14
6
20.5
25.0
40.0
18.2
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
Primary Endpoint
Progression-Free Survival (by IRC Evaluation)
CT + cetuximab
CT
HR (95% CI)
5.7 mo
4.3 mo
1.06 (0.63-1.86)
4.6 mo
4.2 mo
1.18 (0.69-2.01)
EGFR H-Score <200
(n = 75)
EGFR H-Score ≥200
(n = 68)
Test for interaction of PFS and biomarker status
P = 0.73
Secondary Endpoint
Overall Survival
CT + cetuximab
CT
HR (95% CI)
12.2 mo
7.5 mo
1.28 (0.78-2.11)
9.3 mo
7.6 mo
0.93 (0.56-1.55)
EGFR H-Score <200
(n = 75)
EGFR H-Score ≥200
(n = 68)
Test for interaction of OS and biomarker status
P = 0.35
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.
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