ASCO Highlights Head and Neck Cancer Anne S. Tsao, M.D. Director, - PowerPoint PPT Presentation

ASCO Highlights Head and Neck Cancer Anne S. Tsao, M.D. Director, Mesothelioma Program Assistant Professor July 11, 2009 The Univers rsit ity y of Texas Department of Thoracic/Head & Neck MD AN ANDER ERSON SON Medical Oncology CA CANCE CER R CE CENTER ER

Outline Abstract 6001 HPV and tobacco Abstract 6002 HPV RTOG0129 HPV Abstract 6004 HPV/p16 phase III EGFR Abstract 6005 EXTREME / EGFR FISH Biomarkers Abstract 6000 Mass Spectrometry Abstract 6007 Darbepoetin alpha ChemoXRT Abstract 6009 Phase III CRT vs Neoadjuvant neoadjuvant chemo-CRT (PF, TPF) Abstract 6003 Phase II Braf mutations Thyroid and sorafenib

Abstract 6001: tobacco and HPV outcomes UMMC 9921 UMMC 0221 • Retrospective review of tumor tissue from 124 pts with stage III/IV oropharynx cancer from 2 phase II chemoXRT trials. • Objectives: 1) Evaluate association of HPV status and long-term outcomes 2) Evaluate effect of tobacco use on long-term outcomes in HPV positive patients Worden et al. Abstract #6001, ASCO 2009

Definitions • HPV analysis: pre-treatment biopsies tested for HPV DNA by multiplex pCR/mass spect analysis (detects 15 subtypes) (Sequenome) • Smoking status: determined by chart review and self-reporting • Never tobacco: < 100 cigarettes per lifetime, never used any chewing tobacco/cigars/pipes • Current smoker: present, including those who quit < 1 year prior to diagnosis • Former smoker: Quit > 1 year prior to diagnosis Worden et al. Abstract #6001, ASCO 2009

Patient characteristics Characteristic N=124 Male 83% Age 57 HPV (+) HPV (-) Tobacco status HPV (+) 82% N=102 N=22 HPV (+) never tobacco 27% Never (n=33) 32% 0% HPV (+) any tobacco 56% Former (n=52) 45% 28% HPV (-) never tobacco 0% Current (n=39) 23% 72% HPV (-) any tobacco 18% Primary oropharynx site: 50% BOT 46% Tonsil 4% other Stage III 14% Stage IVA 74% Stage IVB 12% Worden et al. Abstract #6001, ASCO 2009

Efficacy by HPV status DFS by HPV status OS by HPV status TTR by HPV status and Treatment and Treatment and Treatment HPV (+) status leads to improved DFS, OS, and time to disease recurrence regardless of treatment. Worden et al. Abstract #6001, ASCO 2009

HPV status by tobacco usage Time to recurrence In HPV (+) pts by tobacco usage Risk of recurrence in HR P-value HPV (+) patients Current vs never 5.2 0.038 Former vs never 2.9 0.18 Current vs Former 1.8 0.24 P=0.063 for overall effect of tobacco Smoking while HPV (+) leads to a worse time to recurrence. Worden et al. Abstract #6001, ASCO 2009

Disease specific survival (DSS) Disease specific survival by tobacco usage DSS in HPV (+) HR P-value pts Current vs never 7.2 0.07 Former vs never 3.6 0.24 Current vs 1.99 0.22 Former P=0.064 for overall effect of tobacco Smoking while HPV (+) leads to a worse DSS. Worden et al. Abstract #6001, ASCO 2009

Summary Abstract 6001 • In this retrospective analysis, HPV (+) tumors have better OS and DSS and less risk of recurrence than HPV (-) tumors. • Patients with HPV (+) disease and current tobacco users have an increased risk of disease recurrence compared to HPV (+) never tobacco users. Worden et al. Abstract #6001, ASCO 2009

Abstract #3 Survival outcomes by HPV status in oropharynx cancer patients in RTOG 0129 Lab methodology: HPV 16 in situ hybridization (ISH) HPV 16 negative – wide spectrum ISH (HPV18, 31, 33, 35, 39, 45, 52, 56. 59, 68) P16 IHC Primary endpoint: Correlate HPV to OS, PFS Gillison et al. Abstract #6003, ASCO 2009

Baseline Lab analysis 323 patients had oropharynx primary and HPV determination 206 (64%) were HPV-positive, 96% of which were HPV-16 P16 positive P16 negative HPV positive 192 (96%) 7 (4%) HPV negative 22 (19%) 94 (81%) Characteristic HPV + HPV - P-value Treatment 51.5% 50.4% 0.86 Age 53.5 57 0.02 Caucasian 92.2% 75.2% <0.001 PS 68.4% 56.4% 0.03 Stage IV 87.9% 83.8% 0.3 T stage 75.2% 60.7% 0.008 N stage 30.1% 38.5% 0.14 Pack years < 20 51% 22.2% <0.001 Gillison et al. Abstract #6003, ASCO 2009

Overall Survival by HPV Status Variable at 2 years HPV + HPV - P-value OS rate 87.9% 65.8% <0.001 PFS rate 71.8% 50.4% <0.001 Local-regional control 13.6% 24.8% 0.004 Distant mets 9.7% 12.9% 0.26 Second primary 3.9% 11.1% 0.01 Aerodigestive SPT 2.9% 7.7% 0.04 Gillison et al. Abstract #6003, ASCO 2009

OS by HPV and Pack Years OS HR 95% CI HPV +, < 20 pack years 1 - HPV +, > 20 pack years 1.91 1.2-3.05 HPV-, < 20 pack years 2.25 1.44-3.5 HPV-, > 20 pack years 4.3 2.3-7.71 Gillison et al. Abstract #6003, ASCO 2009

Survival outcomes by HPV or p16 status Overall Survival HR 95% CI HPV-positive tumor 0.44 0.29-0.69 p16 positive tumor 0.35 0.23-0.54 Progression-free survival HR 95% CI HPV-positive tumor 0.58 0.39-0.87 P16-positive tumor 0.46 0.31-0.68 Gillison et al. Abstract #6003, ASCO 2009

Summary Abstract #6003 • Positive tumor HPV status predicts for improved OS and PFS in patients with oropharynx cancer, with less local-regional recurrence rates (but not distant recurrence). • P16 IHC correlates with HPV tumor status and is a reasonable surrogate. • Tobacco use modifies biological behavior of HPV positive tumors and leads to a worse outcome. • Future trials in oropharyngeal HNSCC need to stratify patients by HPV status or p16 IHC. Gillison et al. Abstract #6003, ASCO 2009

Abstract 6004 p16/HPV in phase III • Retrospective review of tumor tissue from pts with stage III/IV oropharynx cancer from Phase III HeadSTART trial. • HeadSTART showed no survival benefit to adding tirapazamine to cisplatin-XRT but major XRT violations were reported. • Objectives: 1) Determine the prognostic significance of HPV and p16 in oropharyngeal patients from an international phase III trial Rischin et al. Abstract #6004, ASCO 2009

Lab correlates • HPV16/18 ISH (DAKO Genpoint Tyamide Signal Amplification System) using biotinylated probes for HPV16/18 • p16 IHC (DAKO autostainer using p16 INK4a (Clone 16PO4) mouse monoclonal antibody. Nuclear and cytoplasmic staining intensity of tumor cells scored as grade 0-3 with grades 2-3 as positive. Rischin et al. Abstract #6004, ASCO 2009

Patient characteristics HPV (+) HPV (-) P16 (+) P16 (-) Characteristic n=55 N=140 N=108 N=78 Male 91% 83% 87% 81% Median Age 55 56 54 58 T stage 3-4 74% 75% 63% 84% N stage 2-3 87% 73% 86% 65% PS 0 76% 65% 79% 57% Current smoker 15% 37% 15% 45% HPV and p16 positive patients have higher N-stage, are less likely to be current smokers, and had an improved PS compared to HPV/p16 negative patients (p<0.05) Rischin et al. Abstract #6004, ASCO 2009

Overall Survival by HPV status HPV positive patients had improved OS. HPV (-) patients who received TPZ had a slight improvement in OS when compared to HPV (-) patients who received cisplatin alone. Rischin et al. Abstract #6004, ASCO 2009

HPV and p16 Failure-free survival by p16 • HPV (-) but p16 (+) found in 33% cases • Possible explanation: -some cases may be due to other HPV subtypes. -lack of sensitivity of HPV ISH assay (PCR analysis underway) Rischin et al. Abstract #6004, ASCO 2009

LRF by HPV/p16 status Time to Locoregional failure by treatment HPV or p16 (+) pts had improved LRF. HPV or p16 (-) patients who received TPZ had an improvement in LRF when compared to HPV/p16 (-) patients who received cisplatin Patterns of Failure alone; suggesting a benefit to modifying hypoxia with tirapazamine in these patients. Rischin et al. Abstract #6004, ASCO 2009

Overall Survival – multi-variate analysis Overall survival Factor P-value HR HPV (+) vs (-) 0.27 0.031 p16 (+) vs (-) 0.37 0.01 Stage III vs IV 0.34 0.28 PS 0 vs 1 0.57 0.12 Hgb high vs low 0.45 0.037 Rischin et al. Abstract #6004, ASCO 2009

Summary Abstract 6004 • HPV (+) oropharynx patients have an improved prognosis. • p16 IHC may identify more patients than HPV ISH. • Future trials need to stratify patients by HPV and p16 status • The optimal treatment for HPV (+) patients is unknown but they should be treated differently than HPV (-) patients. Rischin et al. Abstract #6004, ASCO 2009

Outline Abstract 6001 HPV and tobacco Abstract 6002 HPV RTOG0129 HPV Abstract 6004 HPV/p16 phase III EGFR Abstract 6005 EXTREME / EGFR FISH Biomarkers Abstract 6000 Mass Spectrometry Abstract 6007 Darbepoetin alpha ChemoXRT Abstract 6009 Phase III CRT vs Neoadjuvant neoadjuvant chemo-CRT (PF, TPF) Abstract 6003 Phase II Braf mutations Thyroid and sorafenib

Phase III EXTREME Trial Metastatic or Platinum recurrent 5-FU R HNSCC A excluding NP Stratified N by prior Maximum 6 chemo cycles D No prior chemo, KPS chemo unless O (<80 vs > 80) No crossover allowed over 8 months M prior for I definitive Platinum Z Primary endpoint : OS therapy 5-FU E Cetuximab PS 0-2 Q3 weeks Cisplatin 100 mg/m 2 d1 or Carboplatin AUC 5 d1 5-FU 1000 mg/m 2 d1-4 Cetuximab Weekly Cetuximab loading dose 400 mg/m 2 IV times one followed by weekly infusions at 250 mg/m 2 Vermorken et al. NEJM 359:1116-1127, 2008

EXTREME Response Rate Vermorken et al. NEJM 359:1116-1127, 2008

EXTREME PFS Vermorken et al. NEJM 359:1116-1127, 2008