Challenging Cases in Cancer:
Integration of Findings from ASCO 2007
into Clinical Practice
Head & Neck Cancer
Everett E. Vokes, MD
Director, Section of Hematology/Oncology
Vice-Chairman for Clinical Research, Department of Medicine
Deputy Director, Cancer Research Center
John E. Ultmann Professor of Medicine, Radiation, and Cellular Oncology
University of Chicago Medical Center
Chicago, IL
Head & Neck Cancer
• 40,000 cases per year in USA
• Risk factors (tobacco, alcohol, viral)
• Squamous cell histology
• Locoregional failure
• Infrequent distant disease at presentation
• Combined modality therapy goals:
- Cure
- Organ preservation
Head & Neck Cancer
• Three common clinical presentations:
– Stage I/II
– Stage III/IV (M0)
• Resectable
• Unresectable
• Organ preservation goal
– Stage IV (M1), recurrent
Case 1
Locoregionally Advanced H&N Cancer
• 48-year-old male with 3-month history of throat
discomfort
• One month ago noted left neck mass
• He has remote smoking history
• Exam/bx/CTs reveal T2 N2bM0 SCCA of left tonsillar
fossa
• No significant co-morbidities
Case 1
Locoregionally Advanced H&N Cancer
Which of the following treatments would you choose for
this patient?
1. Surgical resection/ND followed by chemotherapy/XRT
2. Concomitant chemotherapy/XRT
3. Induction chemotherapy
4. XRT/cetuximab
Case 1
Locoregionally Advanced H&N Cancer
Which of the following treatments would you choose for
this patient?
1. Surgical resection/ND followed by chemotherapy/XRT
2. Concomitant chemotherapy/XRT
3. Induction chemotherapy
4. XRT/cetuximab
Recommended Approach:
 Concomitant chemotherapy/XRT
Intermediate Stage H&N Cancer
Post-operative Therapy
• Traditional therapy is surgery and/or XRT
– Recent trials demonstrate efficacy of post-op CRT
– Organ preservation
– Novel agents
Post-operative ChemoXRT vs. XRT Treatment
Schema
Primary Surgery
RANDOMIZE
Post-op XRT
66 Gy / 33 f / 6.5 wks
Post-op XRT
66 Gy / 33 f / 6.5 wks
Cisplatin 100 mg/m2 d1,22,43
• Primary endpoint:
Disease-free survival
• Secondary endpoints:
Acute tolerance, local control,
overall survival, late complications
Post-operative ChemoXRT vs. XRT
Overall
Overall
survival Survival
90
3-year estimate
XRT
47%
80
5-year estimate
40%
53%
70
Hazard ratio
1
0.67
100
CT/XRT
61%
60
P = 0.010
50
40
30
20
10
0
(years)
0
1
2
3
4
5
6
7
8
O N
94 167
Number of patients at risk :
139
87
60
45
25
16
5
XRT
73 167
140
38
24
6
XRT+DDP
111
81
64
RTOG 95-01
Overall Survival
100
% A LIVE
75
50
25
RT
RT + CT
0
0
Patients at risk
RT
209
RT + CT
206
6
12
168
159
18
24
30
36
42
48
MONTHS FROM RANDOMIZATION
106
126
58
73
31
37
54
60
9
13
INT-026: A Phase III Trial of Chemoradiotherapy
in Unresectable Patients
R
A
N
D
O
M
I
Z
E
XRT
A
CDDP
B
XRT
C
CDDP
5-FU
XRT
Surgery
Adelstein et al: JCO, 2003; 21:92-98.
INT-026: A Phase III Trial of Chemoradiotherapy
in Unresectable Patients
• Median f/u: 41 mos.
CDDP/RT vs. RT
P = 0.014
• 3-year OS and median survival
– RT: 23%, 12.6 mos.
– CDDP/RT: 37%, 19.1 mos.
B
C
A
Adelstein et al: JCO, 2003; 21:92-98.
RTOG 9703
Overall Survival
Garden et al. J Clin Oncol; 22:2856-2864 2004.
HPV-Associated HNSCC
• HPV-16
• Oropharynx
• Palatine and lingual tonsils
• Poorly differentiated (basaloid)
• Non-smokers, non-drinkers
• Younger age
• Sexual behaviors
Gillison et al., J Natl Canc Inst 2000.
D’souza et al., NEJM 2007.
ECOG 2399 Study Design
R
E
G
I
S
T
E
R
Induction
Chemotherapy
Paclitaxel 175 mg/m2 IV
+
Carboplatin AUC 6 IV
R
E
S
P
O
N
S
E
Concurrent
Chemoradiation
(CRT)
70 Gy / 35 fx / 7 weeks
+
Paclitaxel 30 mg/m2/wk
R
E
S
P
O
N
S
E
Repeat every 21 days for 2-cycles
Fakhry et al. ASCO 2007. Abstract 6000.
HPV Detection Results
HPV-positive
HPV-negative
%, (95% CI)
OP
38
24
61 (48-73)
Larynx
0
34
0
TOTAL
38 (40%)
58 (60%)
Fakhry et al. ASCO 2007. Abstract 6000.
Prognostic Variables by HPV
HPV-positive
(N = 38)
HPV-negative
(N = 58)
P-value
Median age
56
60
0.19
Male gender
90%
74%
0.07
ECOG PS 0 vs. 1-2
66%
38%
0.01
Weight loss > 10%
13%
18%
0.07
Smoking > 20 PY
45%
90%
< 0.001
Hemoglobin < 12 g/dL
14%
14%
1.0
Fakhry et al. ASCO 2007. Abstract 6000.
Tumor Characteristics by HPV
HPV-positive
(N = 38)
HPV-negative
(N = 58)
P-value
Stage IV
71%
60%
0.62
T2 vs. T3-4
58%
33%
0.02
N2-3
66%
50%
0.32
Oropharynx
100%
39%
< 0.001
Tonsil / BOT
68%
32%
< 0.001
Basaloid
66%
21%
< 0.001
Fakhry et al. ASCO 2007. Abstract 6000.
Response Rate by Tumor HPV Status
HPV-positive
HPV-negative
P-value
82%
55%
0.01
84%
57%
0.07
Induction
CR or PR
Protocol Therapy
CR or PR
Fakhry et al. ASCO 2007. Abstract 6000.
Tumor HPV Status and Survival
1.0
Two-year Overall Survival
0.4
0.6
62%
0.2
Log-rank test, P = 0.005
HPV-negative
HPV-positive
0.0
Probability
0.8
95%
0
10
20
30
40
50
Time in Months
Fakhry et al. ASCO 2007. Abstract 6000.
Tumor HPV Status and Survival
1.0
Two-year Progression-Free Survival
0.4
0.6
53%
Log-rank test, P = 0.02
0.2
HPV-negative
HPV-positive
0.0
Probability
0.8
86%
0
10
20
30
40
50
Time in Months
Fakhry et al. ASCO 2007. Abstract 6000.
Tumor HPV Status and Survival
Oropharynx Cancers Only
Two-year Overall Survival
0.4
0.6
58%
Log-rank test, P = 0.004
0.2
HPV-negative
HPV-positive
0.0
Probability
0.8
1.0
94%
0
10
20
30
40
50
60
Time in Months
Fakhry et al. ASCO 2007. Abstract 6000.
Survival Outcomes by Tumor HPV Status
HR*
95% CI
HPV-positive tumor
0.21
0.06-0.74
ECOG PS 1-2
3.0
1.3-7.2
Stage IV
4.5
1.6-12
HPV-positive tumor
0.28
0.07-1.0
ECOG PS 1-2
2.8
1.2-6.4
Stage IV
3.7
1.4-10
Overall
Progression-free
*Cox proportional hazard model adjusted for age, gender, race, smoking and tumor site
Fakhry et al. ASCO 2007. Abstract 6000.
HPV Conclusions
• ~60% of OP-HNSCC in U.S. are HPV-positive
• HPV status is associated with prognostic factors
• HPV status is of prognostic significance
• Explained by increased sensitivity to chemotherapy and
chemo-radiation
Fakhry et al. ASCO 2007. Abstract 6000.
Induction Chemotherapy and
Organ Preservation
EORTC Organ Preservation Study
Site:
• Hypopharynx
• AE fold
R
A
N
D
O
M
I
Z
E
Surgery/Radiotherapy
PF x 3 and XRT
No surgery for patients with cCR after 3-cycles
Lefebvre et al JNCI 88, 890, 1996.
EORTC Organ Preservation Study
Survival
Lefebvre et al JNCI 88, 890, 1996.
EORTC Organ Preservation Study
Survival with Functional Larynx
Lefebvre et al JNCI 88, 890, 1996.
EORTC Trial Design
Eligible pts were randomized between:
Sequential arm (SEQ)
2 cycles CF*
if PD, NC → TL ± PORT
if PR, CR → 2 cycles CF* → RT 70 Gy
Alternating arm (ALT)
1 cycle CF** – RT 20 Gy – 1 cycle CF** – RT 20 Gy →
1 cycle CF** – RT 20 Gy – 1 cycle CF** (RT 60 Gy)
* C: 100 mg/m2 D1 + 5-FU: 1,000 mg/m2 D1-5
** C: 20 mg/m2 D1-5 + 5-FU: 200 mg/m2 D1-5
Lefebvre et al. ASCO 2007. Abstract LBA6016.
EORTC Trial
Radiotherapy
Sequential
Alternating
(N = 224)
(N = 226)
200 (89)
220 (97)
Median
71.5
62.8
Range
14.0 - 79.3
2.0 - 76.6
Pts receiving RT (%)
Total dose RT, Gy
Lefebvre et al. ASCO 2007. Abstract LBA6016.
EORTC Trial
Survival with Functional Larynx
100
90
80
70
60
Overall Logrank test: P = 0.155
HR = 0.85 CI (0.68, 1.06)
50
40
30
20
10
0
Years
0
O
N
160 224
154 226
2
4
Number of patients at risk :
105
64
117
73
6
28
39
8
12
18
10
Arm
Sequential
Alternating
Lefebvre et al. ASCO 2007. Abstract LBA6016.
EORTC Trial
Overall Survival
100
90
80
Overall Logrank test: P = 0.446
HR = 0.91 CI (0.71, 1.16)
70
60
50
40
30
20
10
0
Years
0
O
N
125 224
122 226
2
4
Number of patients at risk :
157
97
160
105
6
8
52
57
20
29
10
Sequential
Alternating
Lefebvre et al. ASCO 2007. Abstract LBA6016.
Conclusions
• Despite a 6.7% difference in larynx function preservation
rate at 3-years favoring the alternating arm
– This did not translate into significant difference in survival with a
functional larynx
• Overall and disease free survivals were identical in both
arms, around 50% and 40%,respectively, at 5-years
• Alternating chemotherapy and radiotherapy, as a form of
chemoradiation, did not lead to an increased incidence
and severity of mucositis
• There was no relevant long-term sequelae in either arm
Lefebvre et al. ASCO 2007. Abstract LBA6016.
Larynx Intergroup Study
(RTOG 91-11)
XRT (70 Gy)
Dx, Staging
(excluding T4)
XRT (70 Gy)/Cisplatin
PF x 3 → XRT (70 Gy) (VA Larynx)
Note: Primary Organ Preservation with surgical salvage accepted for all 3 study
arms. Neck dissection included N2 and N3 disease.
Forastiere, NEJM, 2003
Forastiere et al. ASCO 2006. Abstract 5517
Larynx Preservation
(RTOG 91-11)
100
% Preserved
75
50
Failed / Total
25
0
0
1
2
RT + Induction
54 / 173
RT + Concomitant
30 / 171
RT Alone
60 / 171
3
4
5
6
7
8
9
10
Years from Randomization
Forastiere et al. ASCO 2006. Abstract 5517
Disease-Free Survival
(RTOG 91-11)
100
% Alive without Disease
Failed / Total
/
75
/
/
RT + Induction
120 / 173
RT + Concomitant
120 / 171
RT Alone
136 / 171
/
/ / //
/
50
/
/ / //////
/ ///
/ /// /// / / ///
//////
/ //
/
// / /
/ /
///
/
25
/ //// //
//// // / /////
///
/ / / / / // /
//
/ //
//// /
// // / /
//
0
0
1
2
3
4
5
6
7
8
9
10
Years from Randomization
Forastiere et al. ASCO 2006. Abstract 5517
Overall Survival
(RTOG 91-11)
100
/
/
Dead / Total
//
/
RT + Induction
// /
% Alive
75
89 / 173
RT + Concomitant
//
/ /
/ / //
//
50
RT Alone
106 / 171
96 / 171
/
/
/
/ / // ///
////// / /// /
/// /
//
/////////// / //////// / /
/ / //
/////
/// /////// //
// /
///
/ /////////
//// / // / / /// / /
/ ///// ///
/////
/// //// //
/ / / //// / / //
25
//
0
0
1
2
3
4
5
6
7
8
9
10
Years from Randomization
Forastiere et al. ASCO 2006. Abstract 5517
Cause of Death
(RTOG 91-11)
Induction
(N = 89)
# (%)
Concomitant
(N = 106)
# (%)
RT Alone
(N = 96)
# (%)
Larynx cancer
41 (46)
37 (35)
56 (58)
Second primary
11 (12)
17 (16)
12 (13)
Complication of protocol
treatment
8 (9)
10 (9)
5 (5)
Complication of other
treatment
2 (2)
2 (2)
0 (0)
Unrelated to cancer
or treatment
18 (20)
36 (34)
18 (19)
Unknown
9 (10)
4 (4)
5 (5)
Forastiere et al. ASCO 2006. Abstract 5517
Larynx Preservation
• Concurrent chemoradiotherapy remains the standard
treatment
• No role for an “alternating” approach
• Induction chemotherapy is a possible alternative
• Studies investigating the addition of induction to
concomitant CT/X are in progress
TAX 323: TPF vs. PF Followed by Radiotherapy
A Phase III Study in Unresectable SCCHN
R
A
N
D
O
M
I
Z
E
T
P
F
EUA
P
Surgery
Daily Radiotherapy
F
TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750CI- D1-5 Q 3 weeks x4
PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 4
Remenar et al, ASCO 2006.
TAX 323: Survival Update
100
Survival Probability (%)
90
80
Median OS
PF
14.2 mos.
70
TPF
18.6 mos.
P = 0.0052
HR = 0.71
60
50
40
30
20
TPF (N = 177)
PF (N = 181)
10
0
0
6
12
18
24
30
36
42
48
54
60
66
16
15
7
8
1
72
Survival Time (months)
Patients at Risk
TPF: 177
PF: 181
163
150
127
98
91
77
74
57
64
47
60
39
43
33
26
25
4
Remenar et al, ASCO 2006.
Sequential Combined-Modality Therapy
A Phase III Study: TAX 324
TPF vs. PF Followed by Chemoradiotherapy
R
A
N
D
O
M
I
Z
E
T
Carboplatin - AUC 1.5
Weekly
P
F
EUA
Surgery
Daily Radiotherapy
P
F
TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000CI- D1-4 Q 3 weeks x3
PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 3
Posner et al, ASCO 2006.
TAX 324: Survival
100
Log-rank P = 0.0058
Hazard Ratio = 0.70
90
Survival Probability (%)
80
70
60
50
40
TPF 67%
PF 54%
30
TPF 62%
PF 48%
20
TPF (N = 255)
PF (N = 246)
10
0
0
6
12
18
24
30
36
42
48
54
60
66
72
52
45
37
20
11
36
32
28
10
7
Survival Time (months)
Number of patients TPF: 255 234 196 176 163 136 105 72
at risk
PF: 246 223 169 146 130 107 85 57
1
Posner et al, ASCO 2006.
Is There a Role for Induction
Chemotherapy Prior to
Chemoradiotherapy?
DeCIDE - Phase III Induction Trial
Eligibility:
- Locoregionally
advanced HNC
- Treatment naïve
TPF INDUCTION – 6 weeks
DFHX Chemoradiotherapy – 10 weeks
(repeated every 21 days for 2 cycles)
(week on/ week off - for 5 cycles)
Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 TO
Day 1
R
A
N
D
O
M
I
Z
E
Day 2
Day 3
Day 4
Day14
Day 5
Docetaxel
Docetaxel
75mg/m2
25mg/m2
Cisplatin
5-Fluorouracil
75mg/m2
600mg/m2
5-FU
Hydroxyurea
750mg/m2
500mg
Off week –
no treatment
Radiation
150cGy Hyperfx.
DFHX Chemoradiotherapy – 10 weeks
(week on/ week off - for 5 cycles )
Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 TO
Day14
NO INDUCTION
Docetaxel
25mg/m2
5-Fluorouracil
600mg/m2
Hydroxyurea
Enrollment: 400 patients (200 each arm)
Primary Objective: Overall Survival
500mg
Radiation
150cGy Hyperfx.
Off week –
no treatment
Randomized Phase II Trial
Role of Induction CT in H&N Cancer
Paccagnella, et al.
TPF → PF/X
vs.
PF/X
• Endpoint: CR at 6-8 weeks after Rx
• Enrollment goal: 96 pts.
• CR rate: 19.2 vs. 46.8 (15% difference)
• Endpoint met: proceed with phase III
The Paradigm Study
Sequential Therapy vs. Chemoradiotherapy
A Phase III Study of TPF/C-XRT vs. P-ACBXRT
T*
R
A
N
D
O
M
I
Z
E
T
P
3 Cycles of
Chemotherapy
F
ACB
NR
Surgery
C
PR,C
R
Daily Radiotherapy
P
Q 3 Weeks
Surgery
XRT
ACB Radiotherapy
*T + ACB for Non-Responders
Integration of Molecular Therapies
into First-Line Regimens
Cetuximab + Radiotherapy
Phase III Study Design
Stratify by
• Karnofsky score:
90-100 vs. 60-80
• Regional Nodes:
Negative vs. Positive
• Tumor stage:
AJCC T1-3 vs. T4
• RT fractionation:
Concomitant boost
vs. Once daily
vs. Twice daily
R
A
N
D
O
I
M
I
Z
E
Arm 1
Radiation therapy
Arm 2
Radiation therapy +
Cetuximab, weekly
Wk 1: 400 mg/m2 IV no RT
Wk 2-8: 250 mg/m2 followed by RT
Bonner J, et al. NEJM, 2006.
Cetuximab + Radiotherapy
Overall Survival Data
1.0
0.9
RT + Cetuximab (54 months)
RT (28 months)
0.8
Probability
0.7
0.6
0.5
P = 0.02
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
Time (months)
RT=radiotherapy
Bonner J, et al. NEJM, 2006.
RTOG 0522
Phase III Trial for Stage III-IV HNSCC
Schema – Sample Size: 720
Stage III & IV* SCC of:
• Oropharynx
• Hypopharynx
• Larynx
Stratify:
• Larynx ~ Others
• N0~N1,2a,2b~N2c-3
• KPS
60-80 ~ 90-100
• 3-D vs IMRT
*Exclude T1 any N or T2N1
R
A
N
D
O
M
I
Z
E
1. Accelerated FX +
CDDP: 100 mg/m2, q3W X 2
2.
Accelerated FX +
CDDP: 100 mg/m2, q3W X 2
C225: 400 mg/m2 Pre-RT, then
250 mg/m2/w x 7
One of Nine Protocols Covered Under the Medicare Anti-Cancer Drug National Coverage Decision.
See: http://www.cancer.gov/clinicaltrials/developments/NCD179N
2003-0919 Schema
Diagnosis & Staging + Biopsies
Weekly Induction Chemotherapy
Cetuximab 400 mg/m2 wk 1; 250 mg/m2 wkly 2-6
Paclitaxel 135 mg/m2 wkly 1-6
Carboplatin AUC 2 wkly 1-6
Response Assessment + Biopsies
Patients with T1,2
Radiotherapy
Patients with T3,4 or
unresectable nodal disease
Chemoradiotherapy
Kies et al. ASCO 2006. Abstract 5520.
ID 03-0919
Grade 3/4 Adverse Events
(N = 47)
Grade 3/4
(%)
8/8
(34)
Abdominal pain
6
(13)
Anxiety
6
(13)
Dermatologic / rash
22
(47)
Diarrhea
7
(15)
Hypersensitivity
2
(4)
Ruptured gallbladder
1
(2)
ANC
Kies et al. ASCO 2006. Abstract 5520.
ID 03-0919
Response to Induction Chemotherapy
Primary Site
Neck
Overall
(N = 42)
(N = 46)
(N = 47)
NR
–
1
1
PR
8
32
34
CR
34 (81%)
13 (28%)
12 (26%)
Kies et al. ASCO 2006. Abstract 5520.
ID 03-0919
Figure 3. Overall
Survival for 2003-0919
(H/N SPORE)
Overall
Survival
(H/N
SPORE)
1.0
Probability
0.8
0.6
0.4
0.2
Overall
Events/N
= 3/47
Overall
Events/N = 3/47
1-year
Time-to-Event
Rate
(95%CI):
(0.90,1)
One-year
Time-to-Event rate
(95%CI):
0.96 (0.90,0.96
1)
0.0
0.0
0.5
1.0
1.5
2.0
Time (in Year)
Kies et al. ASCO 2006, Abstract 5520.
Case 2
Recurrent/Metastatic H&N Cancer
• 72-year-old patient completed CT/X for T4N2b SCCA
of piriform sinus 7-months ago
• Now found to have 10 lbs weight loss, increased
dysphagia, and pulmonary metastases
• Both persistent local disease as well as metastatic
disease
• PS 1 (bordering on PS 2)
Case 2
Recurrent/Metastatic H&N Cancer
Which of the following treatment options would you
choose for this patient?
1. Chemotherapy
2. EGFR Inhibitor
3. Chemotherapy + EGFR Inhibitor
4. Best supportive care
Case 2
Recurrent/Metastatic H&N Cancer
Which of the following treatment options would you
choose for this patient?
1. Chemotherapy
2. EGFR Inhibitor
3. Chemotherapy + EGFR Inhibitor
4. Best supportive care
Recommended Approach:
 Chemotherapy + EGFR Inhibitor
 EGFR Inhibitor (milder therapy option)
Recurrent/Metastatic H&N Cancer
• Standard Therapy
– Methotrexate
– Cisplatin
– Cisplatin + 5-FU
– Platinum + taxane
• Goal of Therapy
– Palliation
• Outcome
– RR: 30%
– Median survival: 6-8 mos.
– QOL (likely improved)
EGFR Inhibitors in Recurrent H&N Cancer
Agent /
Eligibility
Author
(N)
Cetuximab
Platinum-refractory
Trigo 2004
(103)
Gefitinib
One treatment for
recurrence
Cohen 2003
Erlotinib
Soulieres 2004
RR %
Median
PFS / OS (mos.)
13
2.8 / 5.7
11
3.4 / 8.1
4
2.3 / 6
(47)
One treatment for
recurrence
(115)
EXTREME Trial
Study design
Randomized
Group A
Cetuximab 400 mg/m2 initial dose
then 250 mg/m2 weekly +
EITHER carboplatin (AUC 5, d1)
OR cisplatin (100 mg/m2 IV, d1)
+ 5-FU (1,000 mg/m2 IV, d1-4):
3-week cycles
Group B
EITHER carboplatin (AUC 5, d1)
OR cisplatin (100 mg/m2 IV, d1)
+ 5-FU (1,000 mg/m2 IV, d1-4):
3-week cycles
6-cycles chemotherapy maximum
Cetuximab
No treatment
Progressive disease or unacceptable toxicity
Vermorken et al, ASCO 2007, Abstract 6091
EXTREME Trial
Overall Survival
1.0 |
| ||
|
|
0.9
CTX only
Cetuximab + CTX
|
||
Survival Probability
0.8
||
HR (95%CI): 0.797 (0.644, 0.986)
Strat. log-rank test: 0.0362
|
0.7
|
0.6
10.1 mos.
7.4 mos.
0.5
|
0.4
|
0.3
0.2
|
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0.1
0.0
0
3
6
9
12
15
18
21
24
Survival Time [Months]
Patients at Risk
CTX only
220
173
127
83
65
47
19
8
1
CET + CTX
222
184
153
118
82
57
30
15
3
Vermorken et al, ASCO 2007, Abstract 6091
EXTREME Trial
Conclusions
• The addition of cetuximab to platinum-based chemotherapy in the
first-line treatment of recurrent/metastatic SCCHN significantly
prolonged overall survival (HR = 0.797; P = 0.036)
• Median overall survival was prolonged by 2.7 months in cetuximab
and chemotherapy arm compared to chemotherapy alone arm (7.4
to 10.1 mos.)
• In the interim safety analysis, the addition of cetuximab did not
modify the characteristic adverse event profile of platinum-based
chemotherapy
• This is the first systemic treatment in 25-years to show a survival
benefit over platinum-based chemotherapy in recurrent/metastatic
SCCHN
Vermorken et al, ASCO 2007, Abstract 6091
Randomized Trial of Gefitinib
in H&N Cancer
Gefitinib 250 mg
SCCHN
Recurrent/Progressive
477 patients
Gefitinib 500 mg
1:1:1 ratio
Methotrexate 40 mg/m2
IV weekly
•
Stratum A: Failed CHT-RT / RT and, also, platinum-based CHT for
recurrent disease
•
Stratum B: Failed CHT-RT / RT and unsuitable for platinum-based CHT
Gefitinib in H&N Cancer
Overall Survival – IMEX
Gefitinib in H&N Cancer
Overall Survival by FISH Status
Overall Survival
HR (95% CI)
P-value
Positive
1.02 (0.54, 1.90)
0.959
Negative
1.24 (0.74, 2.06)
0.415
Positive
1.30 (0.71, 2.37)
0.393
Negative
1.23 (0.77, 1.96)
0.392
EGFR FISH Status
Gefitinib 250 mg/day vs. methotrexate
Gefitinib 500 mg/day vs. methotrexate
EGFR: epidermal growth factor receptor; FISH: fluorescence in situ hybridization;
HR: hazard ration; CI: confidence interval
Erlotinib in H&N Cancer
Study Design
• Investigator-initiated trial (Edward Kim, MDACC)
• Single-institution
• Open label phase II study
Recurrent/
Metastatic
HNSCC
Docetaxel
+
Cisplatin
+
Erlotinib
Erlotinib until
progression
Up to 6-cycles of combination therapy
Kim et al, ASCO 2007, Abstract 6013.
Erlotinib in H&N Cancer
Treatment Schedule
• First 6 patients dosed at
– Cisplatin 75 mg/m2 IV q 3wks
– Docetaxel 60 mg/m2 IV q 3wks
– Erlotinib 100 mg oral daily dose
• If no toxicity grade > 2, then dose escalated
– Cisplatin 75 mg/m2 IV q 3wk
– Docetaxel 75 mg/m2 IV q 3wk
Up to 6 cycles
– Erlotinib 150 mg po daily until progression
– Growth factor support recommended
• Required with cycle 1 after patient #18 (sepsis)
Kim et al, ASCO 2007, Abstract 6013.
Erlotinib in H&N Cancer
Common Grade 3/4 Toxicities
Grade 3-4 (% pts)
Neutropenia
64
Febrile neutropenia
10
Infection without neutropenia
8
Anemia
14
Dehydration
14
Diarrhea
14
Nausea
14
Skin toxicity
8
Stomatitis
6
Kim et al, ASCO 2007, Abstract 6013.
Erlotinib in H&N Cancer
Efficacy (N = 48)
• Complete response
4 pts (8%)
• Partial response
28 pts (58%)
• Stable disease
13 pts (25%)
• Overall response rate of 66%
• Disease control rate of 91%
• Only 3 pts progressed after 2-cycles of treatment
Kim et al, ASCO 2007, Abstract 6013.
Erlotinib in H&N Cancer
Progression-Free Survival
1.0
Probability
0.8
6 months
(95% CI, 4.37 to 8.25)
0.6
0.4
0.2
0.0
0
6
12
18
24
Time (Months)
Kim et al, ASCO 2007, Abstract 6013.
Erlotinib in H&N Cancer
Overall Survival
11 months
(95% CI, 8.34 to 17)
1-year survival 48%
1.0
Probability
0.8
0.6
0.4
0.2
0.0
0
6
12
18
24
Time (Months)
Kim et al, ASCO 2007, Abstract 6013.
Erlotinib + Bevacizumab for
Metastatic or Locally Recurrent SCCHN
Phase II-R (Univ. of Chicago)
R
A
N
D
O
M
I
Z
E
A
Cycle #1 = 28 days
Erlotinib Days 1-28
Bevacizumab Day 15
Subsequent Cycles
21 days
Erlotinib Days 1-21
B
Cycle #1 = 28 days
Erlotinib Days 1-28
Bevacizumab Day 1
Bevacizumab Day 1
Biopsy performed pre-therapy and at day 15 before bevacizumab dose
Vokes et al. ASCO 2005; Abstract 5504
Erlotinib + Bevacizumab for
Metastatic or Locally Recurrent SCCHN
Phase II-R (Univ. of Chicago)
Best Response
(N = 48)
N (%)
CR
2 (4)
• 19 patients achieved SD or
better for 6-cycles or more
PR
5 (10)
• Phase I (7 pts): 6 SD, 1 PD
SD
26 (54)
PD
15 (31)
• ORR 14.6% (6.1-27.8)
Seiwert et al. ASCO 2007; Abstract 6021.
Erlotinib + Bevacizumab for
Metastatic or Locally Recurrent SCCHN
Updated Survival
100
•
•
•
•
•
Survival [%]
80
60
40
20
Median OS 7.3 mos.
PFS 3.9 mos.
1-year survival 30%
2-year survival 8%
Median Follow-up (all/alive)
223 days/2.1 years
• 2 Patients with lasting &
ongoing CR (>2 years)
0
0
200
400
600
800
Time [days]
Seiwert et al. ASCO 2007; Abstract 6021.
Erlotinib + Bevacizumab for
Metastatic or Locally Recurrent SCCHN
Conclusions
• Bevacizumab + erlotinib is active in H&N cancer
• Occasional responses maintained for > 2-years
– Further study of this combination is indicated
• Correlative data indicate:
– The ratio of total pKDR/KDR is a possible predictive marker of
complete response
– Erlotinib or erlotinib + bevacizumab increases tumor cell and
endothelial cell apoptosis
Seiwert et al. ASCO 2007; Abstract 6021.
ASCO 2007 – H&N Cancer
Commentary
Conclusions
• Combined-modality therapy represents current
standard for most previously untreated patients
– Concurrent ChemoRT (current standard of care)
– Induction therapy with TPF (certain subsets of patients)
– Cetuximab + RT (certain subsets of patients)
• Molecular therapies are promising both in first- and
second-line therapy
• Identification of clinical and molecular subgroups have
begun