ASCO – Oral Session 2009 Merrill S. Kies M. D. Anderson Cancer Center 1 August 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 323 TAX 324 27% reduction in 30% reduction in 100 risk of death risk of death 90 80 Survival Probability (%) 70 TPF 60 PF 50 TPF 40 30 PF 20 10 0 0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72 Survival Time (months) Survival Time (months) Survival Time (months) Survival Time (months) Posner et al, 2007 Vermorken et al, 2007 Resectable/unresectable disease Unresectable disease
DECIDE Phase III Trial: TPF Followed by ChemoRT Versus Concurrent ChemoRT T R A P N F D N2/N3 SCCHN O M DFHX Concurrent I DFHX ChemoRT Z Concurrent ChemoRT E TPF: docetaxel + cisplatin + 5-FU q 3 wk x 2 DFHX: docetaxel + hydroxyurea + FU + hyperfractionated RT PI: Ezra Cohen
The PARADIGM Study: Sequential Therapy vs Chemoradiotherapy A Phase III Study of TPF/C-XRT vs P-ACBXRT ACB T T R NR P 3 Cycles A Surgery N F C D PR, CR O Daily Radiotherapy M I Z P q 3 wks Surgery E XRT ACB Radiotherapy PI: Marshall Posner
Study Design (Abs 6009) CRT N=128 Neck dissection PF CRT R 3 cycles q3w N=156 Surgery N=439 TPF CRT 3 cycles q3w N=155 - Primary endpoint: time to treatment failure (TTF) - Secondary endpoints: LRC, TTP, OS and safety
Patient characteristics (ITT) PF CRT TPF CRT CRT Characteristic (N=128) (N=156) (N=155) Median age, 56 (25 – 80) 57 (35 – 85) 58 (36 – 78) years (range) Male/female, % 90/10 93/7 94/6 ECOG PS 0/1, % 26/74 31/66 29/70 Primary site, % Oropharynx 42 43 42 Hypopharynx 18 18 18 Larynx 20 17 19 Oral cavity 20 22 21 Hitt, ASCO 2009
Tumor characteristics (ITT) PF CRT TPF CRT CRT Characteristic (N=128) (N=156) (N=155) TN stage, % 15 17 17 T4 N0 20 14 14 T4 N1 34 44 44 T4 N2 5 6 1 T4 N3 Total T4 74 81 76 (N0/1/2/3), % Hitt, ASCO 2009
Safety: Adverse Events PF plus TPF plus Total ICT Grade 3/4 AEs, CRT CRT CRT (TPF + PF) % patients (N=119) (N=156) (N=153) (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 PF TPF (128) (156) (155) ICT % 3 cycles - 76% 68% CRT med CT cycles 3 2 2 % RT per protocol 80 68 62 median f/u 38 mos
Locoregional Control Rate - Complete Response p=0.002 70 63.1 61.5 60.2 LRC % 60 rate 50 44.5 40 30 20 10 0 PF TPF CRT Combined IC CRT CRT CRT Hitt, ASCO 2009
Time to treatment failure (EP) IC CRT CRT Median, months 12.5 4.9 (range) (9.7-16.7) (4.3-17.3) HR (95% CI) 0.57 (0.44-0.74) p <0.0001 Time to Treatment Failure ICT+ CRT CRT Hitt, ASCO 2009
All Treatment Groups/ Months Any IC CRT Median CRT TPF CRT PF CRT (TPF + PF) HR(CI 95%) (N=309) (N=118) (N=153) (N=156) vs CRT 5.0 13.4 12.3 12.5 TTF 0.55 (0.41-0.75) 0.60 (0.44-0.80) 0.57 (0.45-0.74) 13.1 20.4 18.5 18.5 TTP 0.74 (0.53-1.02) 0.83 (0.61-1.13) 0.79 (0.60-1.03) 27.1 37.2 33.6 37.1 OS 0.82 (0.57-1.18) 0.87 (0.62-1.24) 0.85 (0.63-1.15) Hitt, ASCO 2009
Overall survival (EP) IC CRT CRT Median, months 37.1 29.7 (range) (29.1-NA) (20.3-NA) HR (95% CI) 0.86 (0.63-1.18) p 0.354 ICT+ CRT CRT 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?
Epidermal Growth Factor Receptor (EGFR) Cell- Signaling Pathways Herbst, NEJM, 2008
Overall Survival - improved LRC - No Δ mucocutanteous toxicity Bonner, NEJM 2006
EGFR RESISTANCE MECHANISMS – GF RECEPTORS Ratushny, Cell Signal 2009
EXTREME Study Design Randomized Group A Group B Cetuximab 400 mg/m 2 initial dose EITHER carboplatin (AUC 5, d1) then 250 mg/m 2 weekly + OR cisplatin (100 mg/m 2 IV, d1) EITHER carboplatin (AUC 5, d1) + 5-FU (1000 mg/m 2 IV, d1-4): OR cisplatin (100 mg/m 2 IV, d1) 3-wk cycles + 5-FU (1000 mg/m 2 IV, d1-4): 3-wk cycles 6 chemotherapy cycles maximum Cetuximab No treatment Progressive disease or unacceptable toxicity Vermorken, NEJM 2008
EXTREME Overall Survival Overall Survival 1.0 | || | | CTX only CET + CTX 0.9 || | | HR (95%CI): 0.797 (0.644, 0.986) 0.8 HR (95%CI): 0.797 (0.644, 0.986) | | | Log-rank test: 0.0362 Strat. log-rank test: P = 0.036 0.7 Survival Probability | 0.6 0.5 10.1 mo | 7.4 mo 0.4 | | | | | ||| | 0.3 || | | | | ||| | || | |||| | | || | | || | ||| | | | 0.2 | | | | ||| ||| | | | | || | | | | | | | || | | | | || || 0.1 0.0 0 3 6 9 12 15 18 21 24 Survival Months Vermorken, NEJM 2008
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 overall survival and FISH score • In either treatment arm • For any model OS time versus FISH score OS time versus FISH score per patient in Model B per patient in Model B Cetuximab + CT (n=158) CT alone (n=154) 30 30 Survival time (months) Survival time (months) 20 20 10 10 0 0 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 FISH score (%) FISH score (%) 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 1 st -line SCCHN Licitra, ASCO 2009
HPV TRANSMISSION Grandis, Clin Cancer Res 2008
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.
Radiation Therapy Oncology Group 0129 Tumor Site Arm 1: 1. Larynx Standard Fractionation (SFX) R S 2. Non-Larynx 70 Gy/35 Fx/7 weeks A plus cisplatin 100 mg/m 2 T N R Nodal Stage on days 1, 22, 43 D A 1. N0 O T 2. N1 or N2a-b Arm 2: M I 3. N2c or N3 Accelerated Fractionation by I F Concomitant Boost (AFX-C) Z Y Zubrod Performance Status 72 Gy/42 Fx/6 weeks E plus cisplatin 100 mg/m 2 1. 0 2. 1 on days 1, 22 Gillison, ASCO 2009
Methods Laboratory methodology HPV16 in situ hybridization (ISH) HPV16 negative – wide spectrum ISH (HPV 18, 31, 33, 35, 39, 45, 52, 56, 59, 68) P16 immunohistochemistry 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 HPV - HPV - Variable positive 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
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