2009 Merrill S. Kies M. D. Anderson Cancer Center 1 August 2009 - - PowerPoint PPT Presentation

Merrill S. Kies

• M. D. Anderson

Cancer Center

1 August 2009

ASCO – Oral Session 2009

Combined Treatment Strategies in Locoregionally Advanced SCCHN

Historically: Surgery (+ RT) or RT alone Outcomes poor for OS and OP Currently:

• 1. Surgery followed by RT/CRT
• 2. CRT, with surgery as an optional salvage or completion treatmen
• 3. Induction CT  definitive local therapy

Vermorken 2009

ASCO – 2009

• More on Sequential Therapy
• EGFR Inhibition
• HPV data
• Miscellaneous Notes

The Sequential CT and RT platform for Locally Advanced SCCHN

Systemic Rx RT (+/- CT) S

SCCHN: Docetaxel in Locally-Advanced Disease Overall Survival

TAX 324

30% reduction in risk of death

TAX 323

27% reduction in risk of death

TPF PF

50 Survival Time (months)

Survival Probability (%)

Survival Time (months) 6 12 18 24 30 36 42 48 54 60 66 72 10 20 30 40 60 70 80 90 100

TPF PF

Survival Time (months) Survival Time (months) 6 12 18 24 30 36 42 48 54 60 66 72 Posner et al, 2007 Resectable/unresectable disease Vermorken et al, 2007 Unresectable disease

DECIDE Phase III Trial: TPF Followed by ChemoRT Versus Concurrent ChemoRT

R A N D O M I Z E

P T

DFHX Concurrent ChemoRT TPF: docetaxel + cisplatin + 5-FU q 3 wk x 2 DFHX: docetaxel + hydroxyurea + FU + hyperfractionated RT

F

DFHX Concurrent ChemoRT N2/N3 SCCHN

PI: Ezra Cohen

The PARADIGM Study: Sequential Therapy vs Chemoradiotherapy A Phase III Study of TPF/C-XRT vs P-ACBXRT R A N D O M I Z E

P F XRT C

Daily Radiotherapy 3 Cycles

T Surgery

P q 3 wks

Surgery

ACB Radiotherapy

PI: Marshall Posner

T ACB

NR PR, CR

Neck dissection Surgery

R

Study Design (Abs 6009)

TPF 3 cycles q3w CRT N=155 PF 3 cycles q3w CRT N=156 CRT N=128 N=439

• Primary endpoint: time to treatment failure (TTF)
• Secondary endpoints: LRC, TTP, OS and safety

Patient characteristics (ITT)

Characteristic CRT (N=128) PF  CRT (N=156) TPF  CRT (N=155) Median age, years (range) 56 (25–80) 57 (35–85) 58 (36–78) Male/female, % 90/10 93/7 94/6 ECOG PS 0/1, % 26/74 31/66 29/70 Primary site, % Oropharynx Hypopharynx Larynx Oral cavity 42 18 20 20 43 18 17 22 42 18 19 21

Hitt, ASCO 2009

Tumor characteristics (ITT)

Characteristic CRT (N=128) PF  CRT (N=156) TPF  CRT (N=155) TN stage, % T4 N0 T4 N1 T4 N2 T4 N3 Total T4 (N0/1/2/3), % 15 20 34 5 74 17 14 44 6 81 17 14 44 1 76

Hitt, ASCO 2009

Safety: Adverse Events

Grade 3/4 AEs, % patients CRT (N=119) PF plus CRT (N=156) TPF plus CRT (N=153) Total ICT (TPF + PF) (N=309) Granulocytopenia 20 38 34 36 Febrile neutropenia 1 3 18* 10 Thrombocytopenia 4 10 10 10 Asthenia 3 9 14 11 Mucositis 31 46 42 44

*Febrile neutropenia 22% before G-CSF amendment (N=97) and 11% after G-CSF amendment (N=56). Compliance to receiving 3 cycles of cisplatin during CRT after ICT was 40-47% and after CRT alone 79%.

Compliance

(RT (128) PF (156) TPF (155) ICT % 3 cycles

• 76%

68% CRT med CT cycles % RT per protocol 3 80 2 68 2 62 median f/u 38 mos

p=0.002 LRC % rate

Locoregional Control Rate

• Complete Response

CRT Combined IC  CRT PF  CRT TPF  CRT

60.2 63.1 44.5 61.5 10 20 30 40 50 60 70

Hitt, ASCO 2009

ICT+ CRT CRT

Time to Treatment Failure

Time to treatment failure (EP)

ICCRT CRT Median, months (range) 12.5 (9.7-16.7) 4.9 (4.3-17.3) HR (95% CI) 0.57 (0.44-0.74) p <0.0001

Hitt, ASCO 2009

All Treatment Groups/ Months

Median

HR(CI 95%) vs CRT

CRT (N=118) TPFCRT (N=153) PFCRT (N=156) Any ICCRT (TPF + PF) (N=309)

TTF 5.0 13.4 0.55 (0.41-0.75) 12.3 0.60 (0.44-0.80) 12.5 0.57 (0.45-0.74) TTP 13.1 20.4 0.74 (0.53-1.02) 18.5 0.83 (0.61-1.13) 18.5 0.79 (0.60-1.03) OS 27.1 37.2 0.82 (0.57-1.18) 33.6 0.87 (0.62-1.24) 37.1 0.85 (0.63-1.15)

Hitt, ASCO 2009

ICT+ CRT CRT

Overall survival (EP)

ICCRT CRT Median, months (range) 37.1 (29.1-NA) 29.7 (20.3-NA) HR (95% CI) 0.86 (0.63-1.18) p 0.354

Hitt, ASCO 2009

Conclusions

• Interpretation is uncertain
• Analysis by ITT was not performed
• No  PF vs TPF
• Patterns of tumor failure were not

presented

OK! So Are We Ready for individualized targeted chemotherapy?

Herbst, NEJM, 2008

Epidermal Growth Factor Receptor (EGFR) Cell- Signaling Pathways

Overall Survival

• improved LRC
• No Δ mucocutanteous toxicity

Bonner, NEJM 2006

EGFR RESISTANCE MECHANISMS – GF RECEPTORS

Ratushny, Cell Signal 2009

EXTREME Study Design

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 (1000 mg/m2 IV, d1-4): 3-wk cycles Group B EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1) + 5-FU (1000 mg/m2 IV, d1-4): 3-wk cycles No treatment Cetuximab Randomized Progressive disease or unacceptable toxicity 6 chemotherapy cycles maximum

Vermorken, NEJM 2008

10.1 mo 7.4 mo

EXTREME Overall Survival

Vermorken, NEJM 2008

HR (95%CI): 0.797 (0.644, 0.986)

• Strat. log-rank test: P = 0.036

HR (95%CI): 0.797 (0.644, 0.986) Log-rank test: 0.0362

Overall Survival

CTX only CET + CTX

Survival Probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 3 6 9 12 15 18 21 24

| | | || | | | ||| |||| |||| | | | | ||| | | | | | || | | | | || || || | | | | | | | | | | ||| | || | | | | | || | | || | ||| | | | ||| | | | | || | |

Survival Months

EGFR Inhibition / Patient Selection

• Chung et al (abs 6000): Mass spectrometry

profile as [is] a predictor of overall survival benefit after treatment with epidermal growth factor receptor inhibitors in head and neck squamous cell carcinoma

• Licitra et al (abs 6005): Biomarker potential of

EGFR gene copy number by FISH in the phase III EXTREME study: Platinum-based CT plus cetuximab in first-line R/M SCCHN.

No association between

• verall survival and FISH score
• In either treatment arm
• For any model

OS time versus FISH score per patient in Model B Cetuximab + CT (n=158)

Survival time (months) 10 20 30 FISH score (%) 10 20 30 40 50 60 70 80 90 100

OS time versus FISH score per patient in Model B CT alone (n=154)

Survival time (months) 10 20 30 FISH score (%) 10 20 30 40 50 60 70 80 90 100 Licitra, ASCO 2009

Conclusions

• The EXTREME study was the first to demonstrate a

survival benefit from a combination of cetuximab with platinum-based CT in metastatic SCCHN

• Patients with SCCHN may benefit from treatment with

cetuximab irrespective of EGFR gene copy number, as determined by FISH

• Cetuximab + platinum-based CT represents a standard

treatment in 1st-line SCCHN

Licitra, ASCO 2009

Grandis, Clin Cancer Res 2008

HPV TRANSMISSION

HPV Data

• Worden et al (abs 6001): Association of tobacco (T) use with

risk of distant metastases (DM), tumor recurrence, and death in patients (pts) with HPV-positive (+) squamous cell cancer of the oropharynx (SCCOP). → HPV  T Θ pts have favorable prognosis

• Rischin et al (abs 6004): Prognostic significance of HPV and

p16 status in patients with oropharyngeal cancer treated on a large international phase III trial. → p16 associates with improved OS

• Gillison et al (abs 6003): Survival outcomes by tumor

papillomavirus (HPV) status in stage III-IV oropharyngeal cancer (OPC) in RTOG 0129.

Arm 1: Standard Fractionation (SFX) 70 Gy/35 Fx/7 weeks plus cisplatin 100 mg/m2

• n days 1, 22, 43

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

• n days 1, 22

Radiation Therapy Oncology Group 0129

Gillison, ASCO 2009

Methods

• HPV16 in situ hybridization (ISH)
• HPV16 negative – wide spectrum ISH

(HPV 18, 31, 33, 35, 39, 45, 52, 56, 59, 68)

• P16 immunohistochemistry

Laboratory methodology Statistical analysis

• OS – randomization to death
• PFS- randomization to progression or death
• Kaplan-Meier compared by log-rank
• Cox proportional hazards models
• Markov Chain Monte Carlo algorithm
• Cumulative incidence compared by Gray’s test

Gillison, ASCO 2009

Results of laboratory analysis

• 433 (60%) of 721 had oropharynx primary
• 323 (75%) of 433 had HPV determination
• 206 (64%) of 323 were HPV-positive
• 198 (96%) of 206 were HPV16-positive

P16-positive P16-negative HPV-positive 192 (96%) 7 (4%) HPV-negative 22 (19%) 94 (81%) Kappa = 0.80: 95%CI 0.73-0.87

Gillison, ASCO 2009

Patient and tumor characteristics by HPV status

Variable HPV - positive HPV - negative p-value Treatment, SFX (%) 51.5 50.4 0.86 Age, years (median) 53.5 57.0 0.02 Race, white (%) 92.2 75.2 <0.001 Zubrod PS, 0 (%) 68.4 56.4 0.03 AJCC stage, IV (%) 87.9 83.8 0.30 T stage, 2-3 (%) 75.2 60.7 0.008 N stage, N0-2a (%) 30.1 38.5 0.14 Pack-years, < 20 (%) 51.0 22.2 <0.001

Multivariable model for PFS (n=433)

Variable Hazard ratio 95% CI P-value Age (≥50 vs.<50) 1.46 1.04 - 2.07 0.03 Race (non-white vs white) 1.53 1.04 – 2.24 0.03 Zubrod PS (1 vs 0) 1.44 1.06 - 1.95 0.02 T stage (T4 vs T2-3) 1.25 0.91 - 1.70 0.16 N stage (N2b-3 vs N0-2a) 1.51 1.08 - 2.10 0.02 Pack years (≥20 vs < 20) 1.68 1.15 – 2.45 0.008 HPV status (pos vs neg) 0.58 0.39 - 0.87 0.008 HPV status (neg vs pos) 1.72 1.16 – 2.57 0.008 Adjusted for treatment assignment

Gillison, ASCO 2009

Multivariable model for OS (n=433)

Variable Hazard ratio 95% CI P-value Age (≥50 vs.<50) 1.64 1.08 - 2.48 0.02 Race (non-white vs. white) 1.74 1.14 - 2.66 0.01 T stage (T4 vs. T2-3) 1.83 1.30 - 2.57 <0.001 N stage (N2b-3 vs. N0-2a) 1.82 1.23 - 2.70 0.003 Pack years (≥20 vs. < 20) 1.91 1.20 - 3.05 0.007 HPV status (pos vs. neg) 0.44 0.29 - 0.69 <0.001 HPV status (neg vs. pos) 2.25 1.44 - 3.50 <0.001 Adjusted for treatment assignment

Gillison, ASCO 2009

Two-year outcomes

Variable HPV-positive (%) HPV-negative (%) p-value Overall survival 87.9 65.8 <0.001 Progression-free survival 71.8 50.4 <0.001 Local-regional failure 13.6 24.8 0.004 Distant metastases 9.7 12.9 0.26 Second primary tumor 3.9 11.1 0.01 Aerodigestive SPT 2.9 7.7 0.04

Gillison, ASCO 2009

Overall Survival by HPV Status

log-rank p<0.001

5-year difference 29%,12-45

Gillison, ASCO 2009

Overall Survival (%) 25 50 75 100 Years after Randomization 1 2 3 4 5 HPV Pos HPV Neg 206 117 193 89 180 76 162 64 119 34 30 9 HPV Positive HPV Negative

Hazard ratio 95% CI HPV-positive, <20 pack-years 1.00

• HPV-positive, ≥ 20 pack-years

1.91 1.20 - 3.05 HPV-negative, < 20 pack-years 2.25 1.44 - 3.50 HPV-negative, ≥ 20 pack-years 4.30 2.40 - 7.71 Adjusted for age, race, T stage, N stage, and treatment assignment

Tumor HPV, Smoking Status, and OS

Gillison, ASCO 2009

Overall survival HPV-positive tumor 0.44 0.29 - 0.69 p16-positive tumor 0.35 0.23 - 0.54 Progression-free survival HPV-positive tumor 0.58 0.39 - 0.87 p16-positive tumor 0.46 0.31- 0.68

Survival outcomes by HPV or p16 status

HR 95% CI Adjusted for age, race, T stage, N stage, smoking, treatment assignment, and performance status (PFS only)

Gillison, ASCO 2009

Conclusions

• Tumor HPV status is a strong and independent predictor
• f OS and PFS for patients with oropharynx cancer.
• Rates for local-regional, but not distant, recurrence events

were lower for the HPV-positive patient.

• p16 IHC is highly correlated with tumor HPV status and is a

valid surrogate.

• Tobacco use appears to modify the biological behavior of an

HPV-positive tumor.

• Tumor HPV status or p16 must be a stratification factor in

clinical trials that include oropharynx patients. .

Sequential Therapy: “What Next”

• Sequential CT → RT / Surgery is highly active, but toxic
• “Careful study” is recommended

Patient selection Prognostic factors Long-term toxicity/ function

• “What next” will include increased focus on age,

precise site/stage, HPV status, correlative molecular studies, and re-thinking “definitive” treatment planning