Everett E. Vokes, MD Director, Section of Hematology/Oncology

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


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


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


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


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


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


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


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



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%



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


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


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


EORTC Organ Preservation StudySurvival with Functional Larynx


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


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)


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)


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


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)


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)


Failed / Total



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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/

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// // /// / /

/ / //////// //

/ / // / // ///

Overall Survival(RTOG 91-11)


Dead / Total



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

///

/ /

///

///

/ // /// / /// /////////////// / //////////// /////////////// // ///// / /

////

/// ////

//////// / // //// ////// // / //// //////// /// / /// //

//

//

/

//

/ //// / / /// /// //

/ //// // //////////// ////////

/// //////// ///////

/ ///

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)


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)


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%)


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)


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


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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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


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


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


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


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


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


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.


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)


0 200 400 600 8000

20

40

60

80

100

Time [days]

Sur

viva

l [%

]


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


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

Documents

Everett E. Vokes, MD Director, Section of Hematology/Oncology