everett e. vokes, md director, section of hematology/oncology
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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 1Locoregionally 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 1Locoregionally 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 1Locoregionally 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 CancerPost-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 Post-operative ChemoXRT vs. XRT Treatment Schema
Primary Surgery
RANDOMIZE
Post-op XRT66 Gy / 33 f / 6.5 wks
Post-op XRT66 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 Post-operative ChemoXRT vs. XRT Overall Survival
(years)
0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :94 167 139 87 60 45 25 16 5
73 167 140 111 81 64 38 24 6
XRT
XRT+DDP
Overall survival
P = 0.010
3-year estimate 47% 61%
5-year estimate 40% 53%
Hazard ratio 1 0.67
XRT CT/XRT
%
A L
I V
E
0
25
50
75
100
MONTHS FROM RANDOMIZATION0 6 12 18 24 30 36 42 48 54 60
Patients at risk
RTRT + CT
209206
168159
106126
5873
3137
913
RTOG 95-01 Overall Survival
RT
RT + CT
INT-026: A Phase III Trial of Chemoradiotherapy in Unresectable Patients
RANDOMIZE
A
CDDP
CDDP
XRT
5-FU
B
C
XRT
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.
• 3-year OS and median survival
– RT: 23%, 12.6 mos.
– CDDP/RT: 37%, 19.1 mos.
A
B
C
CDDP/RT vs. RTP = 0.014
Adelstein et al: JCO, 2003; 21:92-98.
Garden et al. J Clin Oncol; 22:2856-2864 2004.
RTOG 9703Overall Survival
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.
Induction Chemotherapy
Concurrent Chemoradiation
(CRT)
Paclitaxel 175 mg/m2 IV+
Carboplatin AUC 6 IV
Repeat every 21 days for 2-cycles
REGISTER
RESPONSE
70 Gy / 35 fx / 7 weeks+
Paclitaxel 30 mg/m2/wk
RESPONSE
ECOG 2399 Study Design
Fakhry et al. ASCO 2007. Abstract 6000.
HPV-positive HPV-negative %, (95% CI)
OP 38 24 61 (48-73)
Larynx 0 34 0
TOTAL 38 (40%) 58 (60%)
HPV Detection Results
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
Induction
CR or PR 82% 55% 0.01
Protocol Therapy
CR or PR 84% 57% 0.07
Fakhry et al. ASCO 2007. Abstract 6000.
Tumor HPV Status and Survival
Time in Months
Pro
babi
lity
0 10 20 30 40 50
0.0
0.2
0.4
0.6
0.8
1.0 95%
62%
Two-year Overall Survival
Log-rank test, P = 0.005
HPV-negative
HPV-positive
Fakhry et al. ASCO 2007. Abstract 6000.
Tumor HPV Status and Survival
Time in Months
Pro
babi
lity
0 10 20 30 40 50
0.0
0.2
0.4
0.6
0.8
1.0
HPV-negative
HPV-positive
86%
53%
Two-year Progression-Free Survival
Log-rank test, P = 0.02
Fakhry et al. ASCO 2007. Abstract 6000.
Tumor HPV Status and SurvivalOropharynx Cancers Only
Two-year Overall Survival
Time in Months
Pro
babi
lity
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
HPV-negative
HPV-positive
94%
58%
Log-rank test, P = 0.004
Fakhry et al. ASCO 2007. Abstract 6000.
Survival Outcomes by Tumor HPV Status
HR* 95% CI
Overall
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
Progression-free
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
*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
Lefebvre et al JNCI 88, 890, 1996.
Site:
• Hypopharynx
• AE fold
RANDOMIZE
Surgery/Radiotherapy
PF x 3 and XRT
No surgery for patients with cCR after 3-cycles
EORTC Organ Preservation StudySurvival
Lefebvre et al JNCI 88, 890, 1996.
EORTC Organ Preservation StudySurvival 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 TrialRadiotherapy
Sequential(N = 224)
Alternating(N = 226)
Pts receiving RT (%)
200 (89) 220 (97)
Total dose RT, Gy
Median
71.5 62.8
Range
14.0 - 79.3 2.0 - 76.6
Lefebvre et al. ASCO 2007. Abstract LBA6016.
EORTC TrialSurvival with Functional Larynx
Years0 2 4 6 8 10
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Arm160 224 105 64 28 12
154 226 117 73 39 18
Sequential
Alternating
Overall Logrank test: P = 0.155
HR = 0.85 CI (0.68, 1.06)
Lefebvre et al. ASCO 2007. Abstract LBA6016.
EORTC TrialOverall Survival
Years0 2 4 6 8 10
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :125 224 157 97 52 20
122 226 160 105 57 29
Sequential
Alternating
Overall Logrank test: P = 0.446
HR = 0.91 CI (0.71, 1.16)
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 XRT (70 Gy)/Cisplatin
(excluding T4)
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)
Forastiere et al. ASCO 2006. Abstract 5517
Failed / Total
RT + Induction 54 / 173
RT + Concomitant 30 / 171
RT Alone 60 / 171
% P
rese
rved
0
25
50
75
100
Years from Randomization
0 1 2 3 4 5 6 7 8 9 10
Disease-Free Survival(RTOG 91-11)
Forastiere et al. ASCO 2006. Abstract 5517
Failed / Total
RT + Induction 120 / 173
RT + Concomitant 120 / 171
RT Alone 136 / 171
% A
live
with
out
Dis
ease
0
25
50
75
100
Years from Randomization0 1 2 3 4 5 6 7 8 9 10
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Overall Survival(RTOG 91-11)
Forastiere et al. ASCO 2006. Abstract 5517
Dead / Total
RT + Induction 89 / 173
RT + Concomitant 106 / 171
RT Alone 96 / 171
% A
live
0
25
50
75
100
Years from Randomization
0 1 2 3 4 5 6 7 8 9 10
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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
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
RANDOMIZE
P
P
F
F
Daily Radiotherapy
EUA
T
Surgery
Remenar et al, ASCO 2006.
TAX 323: Survival Update
P = 0.0052 HR = 0.71
Survival Time (months)
Sur
viva
l Pro
bab
ility
(%
)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (N = 177)
PF (N = 181)
Patients at RiskTPF: PF:
177 163 127 91 74 64 60 43 26 16 7
181 150 98 77 57 47 39 33 25 15 8 4
1
PF TPFMedian OS 14.2 mos. 18.6 mos.
Remenar et al, ASCO 2006.
Sequential Combined-Modality Therapy A Phase III Study: TAX 324
TPF vs. PF Followed by Chemoradiotherapy
RANDOMIZE
P
P
F
F
Carboplatin - AUC 1.5 Weekly
Daily Radiotherapy
EUA
T
Surgery
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
TPF 62%
PF 48%
Log-rank P = 0.0058 Hazard Ratio = 0.70
TPF 67%
PF 54%
Survival Time (months)
Sur
viva
l Pro
bab
ility
(%
)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (N = 255)PF (N = 246)
Number of patients at risk
TPF:
PF:
255 234 196 176 163 136 105 72 52 45 37 20 11
246 223 169 146 130 107 85 57 36 32 28 10 7 1
Posner et al, ASCO 2006.
Is There a Role for Induction Chemotherapy Prior to Chemoradiotherapy?
Eligibility:- Locoregionally advanced HNC
- Treatment naïve
RANDOMIZE
Enrollment: 400 patients (200 each arm)Primary Objective: Overall Survival
TPF INDUCTION – 6 weeks
(repeated every 21 days for 2 cycles)
D oc etaxel75mg/m2
C is platin75mg/m2
5-F U750mg/m2
D ay 1 D ay 2 D ay 3 D ay 4 D ay 5
D oc etaxel25mg/m2
5-F luorourac il600mg/m2
H ydroxyurea500mg
R adiation150cG y H ype rfx.
D ay 0 D a y 1 D ay 2 D ay 3 D ay 4 D ay 5 D ay 6 T O D ay14
D oc etaxel25mg/m2
5-F luorourac il600mg/m2
H ydroxyurea500mg
R adiation150cG y H ype rfx.
D ay 0 D a y 1 D ay 2 D ay 3 D ay 4 D ay 5 D ay 6 T O D ay14NO INDUCTION
DFHX Chemoradiotherapy – 10 weeks
(week on/ week off - for 5 cycles)
DFHX Chemoradiotherapy – 10 weeks
(week on/ week off - for 5 cycles )
Off week –
no treatment
Off week –
no treatment
DeCIDE - Phase III Induction Trial
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 StudySequential Therapy vs. Chemoradiotherapy
A Phase III Study of TPF/C-XRT vs. P-ACBXRT
RANDOMIZE
P
P
F
XRT
C
Daily Radiotherapy
3 Cycles of Chemotherapy
T
Surgery
Q 3 WeeksSurgery
ACB Radiotherapy
*T + ACB for Non-Responders
T*ACB
NR
PR,CR
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 boostvs. Once dailyvs. Twice daily
Arm 2Radiation therapy +Cetuximab, weeklyWk 1: 400 mg/m2 IV no RTWk 2-8: 250 mg/m2 followed by RT
RANDOI
MIZE
Arm 1Radiation therapy
Bonner J, et al. NEJM, 2006.
Cetuximab + RadiotherapyOverall Survival Data
RT=radiotherapy
P = 0.02
RT (28 months)
RT + Cetuximab (54 months)
0 6 12 18 24 30 36 42 48 54 60
0.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Pro
babi
lity
Time (months)
Bonner J, et al. NEJM, 2006.
RTOG 0522 Phase III Trial for Stage III-IV HNSCC
Schema – Sample Size: 720
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
RANDOMIZE
*Exclude T1 any N or T2N1
1. Accelerated FX + CDDP: 100 mg/m2, q3W X 2
2.Accelerated FX + CDDP: 100 mg/m2, q3W X 2C225: 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
Radiotherapy Chemoradiotherapy
Patients with T1,2 Patients with T3,4 or unresectable nodal disease
Kies et al. ASCO 2006. Abstract 5520.
ID 03-0919Grade 3/4 Adverse Events
(N = 47) Grade 3/4 (%)
ANC 8 / 8 (34)
Abdominal pain 6 (13)
Anxiety 6 (13)
Dermatologic / rash 22 (47)
Diarrhea 7 (15)
Hypersensitivity 2 (4)
Ruptured gallbladder 1 (2)
Kies et al. ASCO 2006. Abstract 5520.
ID 03-0919Response to Induction Chemotherapy
Primary Site
(N = 42)
Neck
(N = 46)
Overall
(N = 47)
NR – 1 1
PR 8 32 34
CR 34 (81%) 13 (28%) 12 (26%)
Kies et al. ASCO 2006. Abstract 5520.
Overall Events/N = 3/47
1-year Time-to-Event Rate (95%CI): 0.96 (0.90,1)
Kies et al. ASCO 2006, Abstract 5520.
ID 03-0919Overall Survival (H/N SPORE)
Case 2Recurrent/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 2Recurrent/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 2Recurrent/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 /
Author
Eligibility
(N)
RR %Median
PFS / OS (mos.)
Cetuximab
Trigo 2004
Platinum-refractory
(103)13 2.8 / 5.7
Gefitinib
Cohen 2003
One treatment for recurrence
(47)
11 3.4 / 8.1
Erlotinib
Soulieres 2004
One treatment for recurrence
(115)
4 2.3 / 6
EXTREME Trial Study design
Group ACetuximab 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 BEITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1) + 5-FU (1,000 mg/m2 IV, d1-4):
3-week cycles
No treatmentCetuximab
Randomized
Progressive disease or unacceptable toxicity
6-cycles chemotherapy maximum
Vermorken et al, ASCO 2007, Abstract 6091
10.1 mos.7.4 mos.
Patients at RiskSurvival Time [Months]
CTX only
CET + CTX
220 173 127 83 65 47 19 8 1
222 184 153 118 82 57 30 15 3
HR (95%CI): 0.797 (0.644, 0.986)Strat. log-rank test: 0.0362
CTX onlyCetuximab + CTX
Sur
viva
l Pro
babi
lity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24
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Vermorken et al, ASCO 2007, Abstract 6091
EXTREME TrialOverall Survival
EXTREME TrialConclusions
• 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
• 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
SCCHNRecurrent/Progressive
Gefitinib 250 mg
Gefitinib 500 mg
Methotrexate 40 mg/m2 IV weekly
477 patients
1:1:1 ratio
Gefitinib in H&N CancerOverall Survival – IMEX
Gefitinib in H&N CancerOverall Survival by FISH Status
Overall Survival
HR (95% CI) P-value
EGFR FISH Status
Gefitinib 250 mg/day vs. methotrexate
Positive 1.02 (0.54, 1.90) 0.959
Negative 1.24 (0.74, 2.06) 0.415
Gefitinib 500 mg/day vs. methotrexate
Positive 1.30 (0.71, 2.37) 0.393
Negative 1.23 (0.77, 1.96) 0.392
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.
• 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
– Erlotinib 150 mg po daily until progression
– Growth factor support recommended
• Required with cycle 1 after patient #18 (sepsis)
Erlotinib in H&N Cancer Treatment Schedule
Up to 6 cycles
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 6Kim 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
Time (Months)
Pro
babi
lity
0 6 12 18 24
6 months (95% CI, 4.37 to 8.25)
0.0
0.2
0.4
0.6
0.8
1.0
Kim et al, ASCO 2007, Abstract 6013.
Erlotinib in H&N Cancer Overall Survival
Time (Months)
Pro
babi
lity
0 6 12 18 24
11 months
(95% CI, 8.34 to 17)
1-year survival 48%
0.0
0.2
0.4
0.6
0.8
1.0
Kim et al, ASCO 2007, Abstract 6013.
Erlotinib + Bevacizumab for Metastatic or Locally Recurrent SCCHN
Phase II-R (Univ. of Chicago)
Vokes et al. ASCO 2005; Abstract 5504
Biopsy performed pre-therapy and at day 15 before bevacizumab dose
Cycle #1 = 28 daysErlotinib Days 1-28
Bevacizumab Day 15
Cycle #1 = 28 daysErlotinib Days 1-28Bevacizumab Day 1
Subsequent Cycles21 days
Erlotinib Days 1-21
Bevacizumab Day 1
RANDOMIZE
B
A
Erlotinib + Bevacizumab for Metastatic or Locally Recurrent SCCHN
Phase II-R (Univ. of Chicago)
• ORR 14.6% (6.1-27.8)
• 19 patients achieved SD or better for 6-cycles or more
• Phase I (7 pts): 6 SD, 1 PD
Best Response(N = 48)
N (%)
CR 2 (4)
PR 5 (10)
SD 26 (54)
PD 15 (31)
Seiwert et al. ASCO 2007; Abstract 6021.
Erlotinib + Bevacizumab for Metastatic or Locally Recurrent SCCHN
Updated Survival
• 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)
Seiwert et al. ASCO 2007; Abstract 6021.
0 200 400 600 8000
20
40
60
80
100
Time [days]
Sur
viva
l [%
]
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 CancerCommentary
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