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HPV and clinical trial design for head and neck cancer:

Rationale for ECOG 1308 and RTOG 1016

Maura L. Gillison M.D. Ph.D.

Professor and Jeg Coughlin Chair of Cancer Research The Ohio State University Comprehensive Cancer Center

Amsterdam November 12, 2010

Two distinct head and neck cancers

HPV-positive

Anatomic site Histology Age Gender SE status Risk factors Cofactors Incidence Survival Tonsil / BOT Basaloid Younger 3:1 men High Sexual behavior Marijuana, immunosuppression? Increasing Improved

HPV-negative

All sites Keratinized Older 3:1 men Low Alcohol / tobacco Diet, hygiene Decreasing Worse

OS by HPV status in prospective trials

Regimen Induction + CRT

(ECOG)

HR 0.36 0.29 0.44 0.20 0.44

95% CI 0.15-0.85 NR 0.29-0.69 NR 0.28-0.68

Author Fakhry Rischin Gillison Settle Lassen

CRT

(TROG 2.2)

CRT

(RTOG 0129)

Induction + CRT

(TAX324)

Radiation

(DHANCA5)

Fakhry JNCI; Rischin ASCO 2009;Gillison submitted; Settle Clin Cancer Prev; Lassen JCO

OS by HPV status in prospective trials

Regimen Induction + CRT

ECOG

Time 2-year 2-year 3-year 5-year 5-year

HPV pos 95% 94% 79% 93% 62%

HPV neg 62% 77% 46% 35% 26%

P-value 0.005 0.007 0.002 <0.001 0.003

CRT

TROG 2.2

CRT

RTOG 0129

Induction + CRT

TAX324

Radiation

DHANCA5

Fakhry JNCI; Rischin ASCO 2009;Gillison submitted; Settle Clin Cancer Prev; Lassen JCO

What do we know about treatment response for HPVpositive disease?

HPV and OS: DHANCA 5 Control Arm

Radiation alone

P + L cases (N= 156) 22.4% p16-positive Median follow-up >60 mo.

Five-year OS ~62 vs. 26% HR 0.44, 0.28-0.68

Lassen P J Clin Oncol 2009

DAHANCA 5,7,&10: OP only

95%

62% Log-rank test, p=0.005

Courtesy of J Overgaard

Fractionation and local-regional control

p16-positive p16 negative

DAHANCA 5,7,&10

Courtesy of J Overgaard

ECOG 2399 STUDY DESIGN

Induction chemotherapy R E G I S T E R Repeat every 21 days for two cycles Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV R E S P O N S E 70 Gy / 35 fx / 7 weeks + Paclitaxel 30 mg/m2/wk Concurrent chemoradiation (CRT) R E S P O N S E

E2399: Response by tumor HPV status

HPV-pos HPV-neg p-value

Induction Complete or Partial Protocol therapy Complete or Partial

82%

55%

0.01

84%

57%

0.007

Tumor HPV status and survival

Figure 3a Overall Survival By HPV Two-year overall survival

1.0

95%

0.8

Probability

0.4

0.6

62% Log-rank test, p=0.005

0.2

0.0

Negative Positive

0 10 20 30 40 50

Time in Months

HPV and IC response

63% of 47 oropharynx cases HPV16-pos Response to one cycle cisplatin (carboplatin) / 5-FU induction chemotherapy. Categories of clinical response correlated with HPV16 viral load. The median viral load appeared higher among patients with CR or PR than with SD or PD.

Worden F P J Clin Oncol 2008

Radiation Therapy Oncology Group 0129

S T R A T I F Y Tumor Site 1. Larynx 2. Non-Larynx Nodal Stage 1. N0 2. N1 or N2a-b 3. N2c or N3 Zubrod Performance Status 1. 0 2. 1 R A N D O M I Z E Arm 1: Standard Fractionation (SFX) 70 Gy/35 Fx/7 weeks plus cisplatin 100 mg/m2 on days 1, 22, 43 Arm 2: Accelerated Fractionation by Concomitant Boost (AFX-C) 72 Gy/42 Fx/6 weeks plus cisplatin 100 mg/m2 on days 1, 22

RTOG 0129: AFX-cis vs. SFX-cis

HPV-positive HR 0.89 95%CI 0.51-1.55 HPV-negative HR 0.91 95%CI 0.69-1.19

Ang et al NEJM 2010

RTOG 0129 OS by HPV Status

100 HPV Positive Overall Survival (%) 75

50 HPV Negative 25

3-year difference 26%,12-40

log-rank p<0.001

0 1 2 3 4 Years after Randomization 193 89 180 76 162 64 119 34 5 30 9

0 Patients at Risk HPV Pos. 206 HPV Neg. 117

Three-year outcomes

Variable Overall survival Progression-free survival Local-regional failure Distant metastases Second primary tumor HPVpositive (%) 83 74 14 8.7 5.9 HPVnegative (%) 57 43 35 14.6 14.6 p-value <0.001 <0.001 <0.001 0.23 0.02

A Phase III Study: TAX 324 TPF vs PF Followed by Chemoradiotherapy

R A N D O M I Z E

T P F

Carboplatinum - AUC 1.5 Weekly

EUA P F Daily Radiotherapy

Surgery

TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 Posner, NEJM, 2007 PF: Cisplatin 100 + 5-FU 1000 Q 3 weeks x 3

TAX 324: Oropharynx Survival: 5-year

1.00 p= 0.0453 Survival Distribution Function 0.80

HR = 0.69 CI: .48.99

0.60

0.40 PF TPF

0.20

0.00 0 Number of patients at risk PF : 132 TPF : 132 12 24 36 48 60 72 84 96 108 120

Survival Time 100 108 81 92 70 78 59 70 50 63 32 43 15 21 9 13 2 5

5 Years (P=0.045, Median Not Reached In TPF)

Lorch, ESMO, 2009

TAX 324: Survival and HPV Status

1.00

Oropharynx Cancer

P < .0001 p= 6.63e-8

Survival Distribution Function

0.80

Survival

0.60

HPV+

0.40 HPV+ HPV-

0.20

HPV-

0.00 0 Number of patients at risk HPV+ : 56 HPV- : 55 12 24 36 48 60 72 84 96 108 120

Survival Time 53 38 51 27 49 23 42 22 40 20 35 10 20 6 13 3 3 2

Courtesy of Marshall Posner

Randomized phase III radiotherapy +/- cetuximab

Radiation Stage III/IV HNSCC

KPS 60-80 vs 90-100 N0 vs N+ T1-3 vs T4

N = 424 63% Oropharynx

Cetuximab Radiation

2 Gy QD X 35 to 70 Gy 1.2 Gy BID to 72-76.8 Gy 1.8 Gy QD x 30 + 1.5 Gy X 12 to 70 Gy

Bonner Lancet Oncology 2010

Radiotherapy +/- cetuximab

5-year survival 36.4 vs 45.6% HR 0.73, 95% CI 0.56-0.98 P=0.018

Median survival 29.3 vs 49.0 mo.

Bonner JA The Lancet Oncology 2010

Forest Plot of the Hazard Ratios by Pre-Treatment Characteristics ­Five-year Median Follow-up

Improvement With Cetuximab

* *

*

* NS

Bonner, ASTRO, 2008

HPV and Survival

The relative survival for HPV-positive patients is independent of therapy. The absolute survival difference between HPV-pos and HPV-neg at 5-yrs is consistently 30%. We do not know to what extent the absolute survival for HPV-positive patients is dependent on therapeutic choice.

Risk-benefit analysis

Morbidity

Survival

Statement: The patient will not compromise survival for quality of life. Solution: Do not de-escalate therapy...continue to intensify. Problem: We do not know if intensive therapy results in a survival benefit.

Risk-benefit analysis

Survival

Morbidity

Statement: Treatment intensification has increased toxicity of therapy. Solution: De-escalate therapy to improve quality of life. Problem: De-intensification may compromise survival and methods for measurement and definition of meaningful changes in quality of life are uncertain.

What we know

Favorable prognostic factors account for ~10% of relative survival benefit. Increased response to radiation therapy Acceleration may be beneficial in RT only therapy, but perhaps not with Chemo-RT Cetuximab benefit observed in patients with "HPV profile." Increase response to platinum induction chemotherapy Decreased risk of second primary tumors

E1308 Induction followed by IMRT/Cetuximab

ELIGIBILITY

Stage: III, IV A,B resectable Site: Oropharynx only HPV 16 ISH +ve or p16 IHC + N=83

R E G I S T R A T I O N

INDUCTION (3 cycles)

Paclitaxel : 90mg/m2 qwk Cisplatin: 75/m2 q21 Cetuximab: 250mg/m2 qwk

R E S P CR* O N S E

CONCURRENT

IMRT 54Gy/27 fxs** Cetuximab 250mg/m2 qwk

R E S P O N S E

*Complete response at primary site assessed by clinical and radiological exam. **Patients with <CR at primary will receive 69.3Gy/33 Fxs with Cetuximab 250mg/m2 q wk

Radiation Therapy Oncology Group 1016

Tumor Stage 1. T1-2 2. T3-4 Nodal Stage 1. N0-2a 2. N2b-3 Zubrod Performance Status 1. 0 2. 1 Smoking history 1. 10 pack-years 2. > 10 pack-years Arm 1: Accelerated IMRT 70 Gy/6 weeks plus cisplatin 100 mg/m2 on days 1, 22 Arm 2: Accelerated IMRT 70 Gy/6 weeks plus cetuximab 8 doses

S T R A T I F Y

R A N D O M I Z E

Collaborators and funding

National Cancer Institute Anil Chaturvedi Eric Engels William Anderson Centers for Disease Control Blyth Ryerson ECOG Arlene Forastiere RTOG Jon Harris Tom Pajak Christine Chung Andy Trotti Richard Jordan Kian Ang Wally Curran Johns Hopkins Gypsyamber D'souza Carole Fakhry William Westra Raphael Viscidi Wayne Koch Arlene Forastiere Funding NIDCR NCI Damon Runyon CRF RTOG Merck Inc Oral Cancer Foundation Ohio State University

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