1. Not A love story Head and neck cancer Dr Marco Matos Gold Coast Cancer Care, Gold Coast University Hospital and Pacific Private Group

2. A love story?

3. Head and Neck Cancer Nasal antrum Nasopharynx Oropharynx Base of tongue Soft palate Tonsillar pillar and fossa Hypopharynx Esophagus Supraglottis False cords Arytenoids Epiglottis Arytenoepiglottic fold Glottis Subglottis Lip Buccal mucosa Alveolar ridge and retromolar trigone Floor of mouth Hard palate Oral tongue (anterior two thirds) Oral cavity Larynx Pharynx

4. Head and Neck Cancer Estimated 39,250 cases in US in 2005*  5th leading cancer in US  10% of all cancers worldwide 11,000 deaths—3% of all cancer deaths Patients typically aged > 50 yrs, with tobacco and alcohol use Emerging cohort of HPV-positive cancers in the OP (oropharynx) Histology: > 90% squamous cell carcinoma Early-stage disease (I, II) curable: > 80% Locally advanced disease has poorer prognosis  5-yr survival rate: < 40% *Oral cavity, pharynx, and larynx.

5. INCIDENCE AND MORTALITY IN AUSTRALIA - 2006 2,756 new cases (2.6 per cent of all new cancer cases). Most common in males= 2,059 than females = 697. The lifetime risk of developing a head or neck cancer before the age of 75 is 1 in 95 The most common forms of head and neck cancers in 2003* were: o Larynx (557 cases; 498 male, 59 female) o Tongue (492 cases; 343 male, 149 female) o Mouth (466 cases; 287 male, 179 female). In 2007, head and neck cancers were responsible for 898 deaths in Australia, accounting for 2.3 per cent of all cancer deaths

7. Head and Neck Cancer: Prognosis Stages I and II 1/3 of patients Curative results: 60% to 80% SPTs: greater risk than recurrence Stages III and IV 2/3 of patients Multimodal treatment 40% to 80% local recurrence 10% to 30% distant disease Cases, %5-Yr Survival, % Stage I1585 Stage II2070 Stage III2555 Stage IV2530 Unresectable1510

9. Risk Factors Age (majority of patients: older than 50 yrs) Tobacco Alcohol Viral (25% to 35% of patients with SCC)  EBV causes endemic Nasopharyngeal cancer (internationally greater representation) [1]  HPV (increasing incidence in Europe and North America; associated with > 50% of oropharyngeal tumors) 1. National Cancer Institute. Fact sheet on head and neck cancers. 2. Dayyani F, et al. Head Neck Oncol. 2010;2:15. 3. Chaturvedi AK, et al. J Clin Oncol. 2011;29:4294-4301.

10. Smoking trends in Australia

11. Tobacco Use in the US, 1900-1999 Per capita cigarette consumption Male lung cancer death rate Female lung cancer death rate *Age-adjusted to 2000 US standard population. 1. CDC. MMWR Morb Mortal Wkly Rep. 1999;48:986-993. 2. Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. 5000 4500 4000 3500 3000 2200 2000 1500 1000 500 0 100 90 80 70 60 50 40 30 20 10 0 Age-Adjusted Lung Cancer Death Rates* [2] Per Capita Cigarette Consumption [1] 1900 1905191019151920 1925193019351940 194519551960 1965197019751980 1985199019501995 Yrs

12. Rising Incidence of HPV-Associated Oral Squamous Cell Cancers in US Chaturvedi AK, et al. J Clin Oncol. 2008;26:612-619. Smoking related *P <.05. APC, annual percentage change. HPV related 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 Age-Adjusted Incidence/ 100,000 Person-Yrs 1975198019851990199520002004 Yr of Diagnosis HPV-U, APC1: 0.82 HPV-U, APC2: -1.85* HPV-R, APC3: 5.22* HPV-R, APC1: 2.06* HPV-R, APC2: -0.05 We have a decline in smoking ‑ related cancers and at the same time we have seen an increase in human papillomavirus–related cancers.

13. Trends of Tobacco Use and Head & Neck Cancer Sturgis and Ang, JNCCN, 2011 A B

14. Human Papilloma Virus Human Papillomavirus (HPV) HPVs are common papilloma (wart)- causing viruses Many (~ 200) different strains exist Most common sexually transmitted disease: 440 million Low-risk HPV types 6,11 cause genital and laryngeal papillomas High-risk HPVs cause cancer (16,18,31,33,35,39,45, 51,66) Cervical, anogenital, and oropharyngeal cancers

15. HPV and HNSCC Mork J, et al. NEJM 2001

16. Social Habits and HNSCC Gillison, JNCI 2008 Tobacco, alcohol consumption and poor oral hygine increased the risk of HPV –ve HNSCC. More than 5 oral sexual partners or 5 marihuana joints years increased the risk of HPV +ve HNSCC

17. Association Between OPC and Sexual Behavior Modified from D’Souza et al., NEJM, 2007 Sexual Behavior OPC Patients Control Patients Adjusted Odd Ratio (95% CI) N=100N=200All PatientsHPV-16 + Lifetime number of vaginal sex partners 0-531 (31%)108 (54%)11 6-2541 (41%)63 (32%)2.2 (1.2-4.0)2.7 (1.4-5.5) >2528 (28%)29 (14%)3.1 (1.5-6.5) 1 4.2 (1.8-9.4) 2 Lifetime number of oral sex partners 012 (12%)38 (19%)11 1-546 (46%)110 (55%)1.9 (0.8-4.5)3.8 (1.0-14.0) >544 (44%)52 (26%)3.4 (1.3-8.8) 3 8.6 (2.2-34.0) 4 P for Trend= 1 0.002, 2 0.001, 3 0.009, and 4 <0.001

18. Human Papillomavirus (HPV) Hellner & Münger, JCO 29:1785-94, 2011

19. Human Papillomavirus (HPV) Hellner & Münger, JCO 29:1785-94, 2011 Chronic HPV infection and viral persistence and viral genome integration will conduct to dysplasia and invasion

20. HPV and Oropharyngeal Carcinogenesis Apoptosis is a potent host defense against microbes Viruses counteract this response  E6/E7 inactivate p53 and Rb  Rb normally downregulate p16.  p16 expression increased with Rb downregulation  Postmitotic keratinocytes enter S phase and replicate viral genomes Narisawa-Saito M, et al. Cancer Sci. 2007;98:1505-1511. Accumulation of mutations Inhibition of apoptosis Transformation Telomerase activation (TERT transcription) UbiquitinationDegradation 26s proteosome subunit? calpain RB E6 p53 PDZ E6AP NFX1 E7 E6AP

21. p16 Proposed as Diagnostic Marker Weinberger PM, et al. J Clin Oncol. 2006;24:736-747. Reprinted with permission. © 2006 American Society of Clinical Oncology. All rights reserved. Proposed 3-Class Model for Oropharyngeal Carcinogenesis 4000 3000 2000 1000 0 HPV-16 Viral LoadClass IClass IIClass III 250 200 150 100 0 p53 AQUA Score Class IClass IIClass III 50 225 200 150 100 0 pRb AQUA Score Class IClass IIClass III 25 175 125 75 50 200 150 100 0 p16 AQUA Score Class IClass IIClass III 50 Healthy cell High-risk HPV infection Tumor Tumor Tobacco/ETOH High-risk HPV infection Class I p16 inactivation p53 mutation HPV negative Class II p16 inactivation p53 mutation HPV positive Class III p16 not inactivated p53 wild type (E6 degrades) HPV positive

22. Clinical Features & Assay Methods

23. Clinical Presentation – HPV+ Oropharyngeal location; small primary T with advanced nodal disease

24. Histology Non-keratinizing or “Basaloid” Carcinoma

25. Demographics of HPV+ vs HPV- OPC Variable Ang et al. NEJM 2010 N= 323 Rischin et al. JCO 2010 N= 185 Posner et al. Ann Oncol 2011 N= 111 HPV+HPV-P=P=HPV+HPV-P=P=HPV+HPV-P=P= Age Median Range 53.5 31-78 57.0 37-82 0.02 54 32-80 58 39-74 ? 54 39-71 58 41-78.02 PS 0 ≥1 68% 32% 56% 44%.03 78% 22% 57% 43%.002 77% 23% 49% 51%.003 Smoking Never Former Current ? 29% 53% 12% 6% 12% 46% 27% 15% <.001 15% 45% <.001 ??? Gender Male Female 86% 14% 80% 20%.10 87% 13% 81% 19%.31 80% 20% 80% 20% 1.0 HPV +ve patients are younger, with good performance status,and non- smokers

26. HPV+ vs HPV- OPC Stage Distribution at Diagnosis T & N Ang et al. (323) NEJM 2010 N= 323 Rischin et al. JCO 2010 N= 185 Posner et al. Ann Oncol 2011 N= 111 HPV+HPV-HPV+HPV-HPV+HPV- T(1)-235%24%37%15%49%20% T3 - 465%76%63%85%51%80% P=P=0.0060.001 N07% (18%) 8% (28%)14%35%23%33% N111%20% N271% (82%) 64% (72%)86%65%77%67% N311%8% P=P=0.460.0010.30 HPV +ve tumours are smaller tumours with more advanced nodal disease than HPV –ve tumours

27. Optimal Testing for HPV Schache AG, et al. Clin Cancer Res. 2011;17:6262-6271. Test, % SensitivitySpecificityHPV Positive by EraTotal P Value* (Compared With RNA qPCR)1988- 97 2004- 07 2008- 09 1988- 2009 14415736.001 p16 IHC 948219367743<.001 HR HPV ISH 88 13396037.001 p16/HR HPV ISH 889013336035.001 DNA qPCR 978723465741.02 p16/DNA qPCR 979412415738.002 p16/RNA qPCR 9410011435537.008 DNA/RNAqPCR 941009415232.001 *For difference by presentation era. Note: P =.001 for increasing HPV positive over time by RNA qPCR. p16 immunohistochemistry had a sensitivity of 94% and a specificity of 82%, and in situ hybridization had a slightly lower sensitivity at 88% but slightly better specificity at 88%. DNA qPCR, which was taken as the gold standard, had a sensitivity of 97 and a specificity of 87%. And when you had dual testing that incorporated p16 plus PCR you could get sensitivities of 94% to 97% and specificities of 94% to 100%.

28. Emergency influence of HPV infection in HNSCC CharacteristicsHPV positiveHPV negative Anatomic siteOropharyngeal, base of tongue Larynx, oral cavity and hypopharynx AgeYoungerOlder Male / female1:13:1 Risk factorsSexualTobacco, alcohol CofactorsMarihuanaDiet/ hygiene Clnical presentationUnknown or cystic primary Classical IncidenceIncreasingDecreasing ComorbiditiesFewerGreater PrognosisBetterWorse

30. Prognostic Significance

31. Prognosis of HPV+ vs HPV- Carcinoma Retrospective Series SeriesNAssays Outcome HPV+ vs. HPV- EndpointHR (95% CI) P=P= Mellin, IJC, 2000 60PCR (L1)Risk of relapse 0.24 (not reported) 0.025 Gillison, JNCI, 2000 253 PCR, ISH, etc. D-S Survival0.41 (0.20-0.88)0.020 Schwartz, OHNS, 2001 254 PCR (L1 & E6) Overall Survival0.34 (0.14-0.83)-- Lindel, Cancer, 2001 99 PCR (L1 & E2) Local Failure0.31 (0.09-0.99)0.048 Weinberger, CCR, 2004 120p16Overall Survival0.42 (0.2–0.9)0.021

32. Prognosis of HPV+ vs HPV- Carcinoma Cooperative Group Series SeriesNAssays Outcome HPV+ vs. HPV- EndpointHR (95% CI)P=P= 1 Fakhry, JNCI, 2008 96 ISH, p16, etc. Tumor Progression 0.27 (0.10-0.75)0.01 2 Ang, NEJM, 2010 323ISH & p16 Overall Survival P-F Survival 0.42 (0.27–0.66) 0.49 (0.33–0.74) <0.001 2 Rischin, JCO, 2010 2 185p16 Overall Survival P-F Survival 0.36 (0.17-0.74) 0.39 (0.20-0.74) 0.004 0.003 2 Posner, Ann Oncol, 2011 111 PCR (E6-E7) Overall Survival0.20 (0.10-0.38)<0.0001 3 Lassen, R&O, 2011 794 (200*) p16 Overall survival D-S Survival 0.62 (0.49-0.78) 0.58 (0.41-0.81) <0.001 0.001 1 Phase II; 2 Oropharynx carcinoma (OPC) only series; 3 Mixed sites; *OPC

33. Phase III RTOG 0129: Study Design and Primary Outcomes lPrimary endpoint: OS HR (AFX-CB vs SFX): 0.90 (95% CI: 0.72-1.13; P =.18) lSecondary endpoints  PFS HR: 1.00 (95% CI: 0.81-1.23; P =.50)  Local regional failure HR: 1.11 (95% CI: 0.85-1.44; P =.80)  Distant metastasis HR: 0.81 (95% CI: 0.54-1.22; P =.14) Key eligibility criteria:  Stage III or IV (except T1 N+ and T2 N1) SCC of oral cavity, oropharynx, larynx, or hypopharynx Stratification factors:  Tumor site (larynx vs nonlarynx)  Nodal stage (N0 vs N+)  Karnofsky PS (60-80 vs 90-100) (n = 743) RANDOMIZERANDOMIZE Accelerated Fractionation by concomitant boost (AFX-CB) 72 Gy/42 fractions for 6 wks + Cisplatin100 mg/m 2 q 3 wks for 2 cycles Standard Fractionation (SFX) 70 Gy/35 fractions for 7 wks + Cisplatin100 mg/m 2 q 3 wks for 3 cycles Ang K, et al. ASCO 2010. Abstract 5507.

34. High Concordance Rate between ISH and p16 p16-positivep16-negative HPV-positive192 (61%)7 (2%) HPV-negative22 (7%)94 (30%) Kappa = 0.80: 95%CI 0.73-0.87  RTOG 0129: 433 of 721 (60%) patients had OPC  HPV status determined in 323 of 433 (75%) OPCs HPV16 in situ hybridization (ISH) HPV16 negative  wide spectrum ISH (HPV 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) p16 immunohistochemistry Ang et al., NEJM 363: 24, 2010

35. RTOG 0129: 3-Year Outcome by HPV Status VariableHPV-Pos (%)HPV-Neg (%)p-value Overall survival82.457.1<0.001 P-F survival73.743.4<0.001 Local-regional control86.464.9<0.001 Distant metastases8.714.60.23 Second primary tumor5.914.60.02 Ang (Gillison) et al., NEJM 363: 24, 2010

36. Risk Classification for Overall survival by p-16, Smoking, & T-N Category Overall Survival A B Recursive Partitioning Analysis (RPA)

37. R0129 Survival According to Tumor HPV Status or p16-Expression Status Ang KK, et al. N Engl J Med. 2010;363:24-35. OS (%) 100 75 50 25 0 0 Yrs Since Randomization 12345 HR for death: 0.38 (95% CI: 0.26-0.55; P <.001) HPV negative HPV positive PFS (%) 100 75 50 25 0 0 Yrs Since Randomization 12345 HR for relapse or death: 0.40 (95% CI: 0.29-0.57; P <.001) HPV negative HPV positive OS (%) 100 75 50 25 0 0 Yrs Since Randomization 12345 HR for death: 0.29 (95% CI: 0.20-0.43; P <.001) p16 negative p16 positive PFS (%) 100 75 50 25 0 0 Yrs Since Randomization 12345 HR for relapse or death: 0.33 (95% CI: 0.24-0.46; P <.001) p16 negative p16 positive OS (%) 100 75 50 25 0 0 Yrs Since Randomization 12345 High risk Low risk Intermediate risk

38. Phase III TAX 324 Trial: TPF vs PF Carboplatin—AUC 1.5 Weekly Daily radiotherapy P P F F T Surgery as needed TPF: docetaxel 75 mg/m 2 on Day 1 + cisplatin 100 mg/m 2 on Day 1 + 5-FU 1000 mg/m 2 /day by continuous infusion on Days 1-4; q 3 wks x 3 cycles. PF: cisplatin 100 mg/m 2 on Day 1 + 5-FU 1000 mg/m 2 /day as continuous infusion on Days 1-5; q 3 wks x 3 cycles. RANDOMIZERANDOMIZE Posner MR, et al. N Engl J Med. 2007;357:1705-1715. Patients with stage III-IV head and neck SCC without distant metastases and with unresectable tumors

39. OS and PFS by HPV Status in TAX 324 Posner MR, et al. Ann Oncol. 2011;22:1071-1077. Survival Distribution Function 1.00 0.80 0.60 0.40 0.20 0 01224364860728496108120 Survival Time, mos Pts at Risk, n HPV positive HPV negative HPV+ HPV- 56 55 53 38 51 27 49 23 42 22 40 20 35 10 20 6 13 3 3232 P = 6.63e-8 PFS Distribution Function 1.00 0.80 0.60 0.40 0.20 0 01224364860728496108120 Time to Progression, mos Pts at Risk, n HPV positive HPV negative HPV+ HPV- 56 55 47 29 46 20 44 19 40 18 39 15 35 8 20 6 13 3 3232 P = 5.64e-7

40. Survival According to HPV Status and Treatment Arm in TAX 324 Posner MR, et al. Ann Oncol. 2011;22:1071-1077 Survival 1.00 0.80 0.60 0.40 0.20 0 01224364860728496108120 Survival Time, mos Pts at Risk, n PF HPV+ PF HPV- TPF HPV+ TPF HPV- 28 29 28 26 25 21 27 16 24 15 26 11 24 13 24 9 19 13 22 8 18 12 21 7 15 5 19 4 9 3 10 2 527527 1212

41. ECOG 2399: Study Design REGISTERREGISTER RESPONSERESPONSE RESPONSERESPONSE Induction chemotherapy Paclitaxel 175 mg/m 2 Carboplatin AUC 6 q21days 2 cycles Concurrent chemoradiation RT 70 Gy/35 fx/7 wks Paclitaxel 30 mg/m 2 /wk Fakhry C, et al. J Natl Cancer Inst. 2008;100:261-269.

42. ECOG 2399: Efficacy by HPV Status HPV Positive, % (n = 38; 40%) HPV Negative, % (n = 58; 60%) P Value Response  Induction  Protocol 82 84 55 57.01.07 2-yr PFS8653.02 2-yr OS9562.005 Survival, OP cancers  2-yr PFS  2-yr OS 85 94 50 58.05.004 Fakhry C, et al. J Natl Cancer Inst. 2008;100:261-269.

43. Induction (3 cycles) Paclitaxel Cisplatin Cetuximab Eligibility Stage III/IVa,b Resectable HPV+ Oropharynx Concurrent IMRT 69.3 Gy Cetuximab wkly CR <CR Concurrent IMRT 54 Gy Cetuximab wkly SIMULATIONSIMULATION Goal is to maintain outstanding PFS and minimize late toxicity Completed accrual October, 2011 No results available and this remains investigational E1308: Induction Followed by IMRT/ Cetuximab ClinicalTrials.gov. NCT01084083.

44. R1016: Cetuximab-RT vs ChemoRT ClinicalTrials.gov. NCT01302834. www.rtog.org. STRATIFYSTRATIFY RANDOMIZERANDOMIZE Eligibility Oropharynx p16 pos  T1-2, N2a-3 or  T3-4 any N T-Stage T 1,2 T 3,4 N-Stage N0-2A N2B-C Smoking ≤ 10 PY > 10 PY Zubrod 0 1 AFX 70 Gy for 6 wks + cisplatin x 2 AFX 70 Gy for 6 wks + cetuximab for 8 wks Activated: June 2011 Target N = 706

45. Trials for HPV/p16-Positive OPC GroupPhaseTreatment RegimensNStatus ECOGII [Paclitaxel + Cisplatin + Cetuximab*] x3   CR: 54 Gy/27 F + Cetuximab* or  <CR: 69.3 Gy/33 F + Cetuximab* 83 Activated 03/2010 Accrued 10/2011 RTOGIII 70 Gy in 6 W + Cisplatin (100 mg/m 2, q3W) versus 70 Gy in 6 W + Cetuximab (400 mg/m 2 loading dose  250 mg/m 2 /W x7) 700Activated 06/2011 UK*III 70 Gy in 7 W + Cisplatin (q3W) vs. 70 Gy in 7 W + Cetuximab (400 mg/m 2 loading dose  250 mg/m 2 /W x7) 330Activated 01/2012 TROG*III 70 Gy (7 W) + Cisplatin versus 70 Gy (7 W) + Cetuximab In planning *400 mg/m 2 on day 1 of cycle 1, 250 mg/m 2 for the remaining 2 cycles of chemortherapy, then weekly during radiation

46. A french love story?

47. TREATMENT Up or down

48. Nonsurgical Treatment Options for SCCHN 1. Pignon JP, et al. Lancet. 2000;355:949-955. 2. Bonner JA, et al. Lancet Oncol. 2009 Nov 6;[Epub ahead of print]. 3. Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704. 4. Posner MR, et al. N Engl J Med. 2007;357:1705-1715. Rx RegimensHR (95% CI)Absolute Benefit 2-Yr, %5-Yr, % RT + concurrent Ctx [1] 0.81 (0.76-0.88) 78 RT + Cetuximab [2] 0.73 (0.56-0.94) 910 TPF → RT [3] 0.70 (0.54-0.90) 11NA TPF → RT + carboplatin [4] 0.74 (0.67-0.82) 12NA

49. 63 randomized trials (1965-1993) n = 10,717 (excludes NPC trials) Median follow-up: 6 yrs ORR: 0.89 (32% vs 36% at 5 yrs) Pignon JP, et al. Lancet. 2000;355:949-955. Meta-Analysis of Chemotherapy in HNC (MACH-NC) TrialsNRRP ValueAbsolute Benefit (5 Yrs), % Adjuvant818540.98NS1 Induction3152450.95NS2 Concomitant2637270.81<.00018

50. MACH-NC: An Update 24 added trials—93 randomized studies, 17,346 patients  Median follow-up: 5 yrs MACH-HN I: 8% abs benefit CMT MACH-HN II: more homogenous population Age matters  Younger than 50 yrs of age: 24% increased survival  Older than 70 yrs of age: 3% increased survival Pignon JP, et al. Radiother Oncol. 2009;92:4-14.

51. Concurrent Chemoradiation in LA-SCCHN: Long-term Survival Results NF/U, Yrs RT (Control) CT/RTP ValueAgents Used French trail22633151.002Carbo/5-FU German trial27032448<.0003cDDP/5-FU/LV NP intergroup19334778.005cDDP→DDP/ 5-FU Duke U11652842.05cDDP/5-FU Intergroup19932337.01cDDP Greek8331852<.001cDDP

52. Arm 2 (RT + C) Radiation therapy + Cetuximab wkly Phase III Study Design Stratified by lKarnofsky score: 90-100 vs 60-80 lRegional nodes: negative vs positive lTumor stage: AJCC T1-3 vs T4 lRT fractionation: concomitant boost vs once daily vs twice daily RANDOMIZERANDOMIZE Arm 1 (RT) Radiation therapy Bonner JA,, et al. N Engl J Med. 2006;354:567-578.

53. Patient Characteristics RTRT + C Median age, yrs (range)58 (35-83)56 (34-81) Male/female, %79/2181/19 Primary tumor site, % Oropharynx Hypopharynx Larynx 63 13 24 56 17 27 EGFR, % Detectable Nondetectable Unknown 80 1 19 79 0 21 Bonner JA, et al. N Engl J Med. 2006;354:567-578.

54. Most Common Adverse Events Toxicity, % RT (n = 212)RT + C (n = 208) All GradesGrades 3/4All GradesGrades 3/4 Skin reaction911897 † 34 ‡ Mucositis/stomatitis93529154 Dysphagia63306425 Xerostomia703644 Fatigue/Malaise505524 Infusion reaction*--–14 ‡ 3†3† *Listed for its relationship to cetuximab. † P <.05 ‡ P <.001, Fisher’s exact test. Bonner JA, et al. N Engl J Med. 2006;354:567-578.

55. Locoregional Control Locoregional Control, %RT (n = 213) RT + C (n = 211) 1 yr* 2 yrs* 59 48 69 56 Log rank P value0.02 Distant/second primary control  1 yr*  2 yrs* 71 56 77 62 Bonner JA, et al. N Engl J Med. 2006;354:567-578. *Kaplan-Meier estimates.

56. Overall Survival RT (n = 213) RT + C (N=211) Median survival,* mos29.349  95% confidence limits21-3836-58+ 2 yrs, %5562 3 yrs, %4457 5 yrs, %36.445.6 Log rank P value.018 HR (95% CI)0.71 (0.54-0.95) Bonner JA, et al. Lancet Oncol. 2009 Nov 6;[Epub ahead of print].

57. Improvement With Cetuximab Bonner JA, et al. Lancet Oncol. 2009 Nov 6. [Epub ahead of print]. Forest Plot of the HRs by Pretreatment Characteristics: 5-Yr Median Follow-up Tumor: oropharynx Tumor: hypopharynx Tumor stage: T1-T3 Region: other RT fract: once daily Overall stage: IV Nodal stage: N1-N3 Karnofsky 90-100 Sex: male EGFR unknown EGFR positive ≤ 50% Age < 65 yrs Tumor: larynx Tumor stage: T4 Region: US RT fract: twice daily RT fract: concomitant boost Overall stage: II-III Nodal stage: N0 Karnofsky 50-80 Sex: female EGFR positive > 50% Age ≥ 65 yrs 0.00.61.21.8

58. [TITLE]

61. RTOG 0522: Study Objective and Design Stage III/IV* SCC of:  Oropharynx  Larynx  Hypopharynx Stratified by:  Larynx vs nonlarynx  N0 vs N1-2b vs N2c-3  Zubrod PS  3D vs IMRT  PET (yes vs no) RANDOMIZERANDOMIZE 1. AFX-CB: 72 Gy/42 F/6 W + Cisplatin: 100 mg/m 2, q3w x 2 2. AFX-CB: 72 Gy/42 F/6 W + Cisplatin: 100 mg/m 2, q3w x 2 + Cetuximab: 400 mg/m 2 x 1, then 250 mg/m 2 /wk Ang KK, et al. ASCO 2011. Abstract 5500. *Excluded T1N+, T2N1.

62. RTOG 0522: Patient and Tumor Features CharacteristicRT + Cisplatin (n = 448) RT + Cisplatin + Cetuximab (n = 447) Age, yrs 57 (31-79)58 (34-78) Male, % 8790 Zubrod score, % 00 6566 11 3534 Primary site, %  Oropharynx 70  Larynx 23 T3-4, % 6260 Node positive, % 9088 AJCC stage IV, % 8785 Ang KK, et al. ASCO 2011. Abstract 5500.

63. RTOG 0522: Progression-Free Survival and Overall Survival Pts at Risk, n 44831621778 44730219780 Pts at Risk, n 44838526696 44737825194 Ang KK, et al. ASCO 2011. Abstract 5500. PFS (%) 0 25 50 75 100 Yrs After Randomization 0123 HR: 1.05 (95% CI: 0.84-1.29; log-rank, 1-sided P =.66) 2-Yr Rate, % (95% CI) 64.3 (59.7-68.8) Cisplatin 63.4 (58.7-68.0) Cisplatin + cet Primary Endpoint OS (%) 0 25 50 75 100 Yrs After Randomization 0123 HR: 0.87 (95% CI: 0.66-1.15; log-rank, 1-sided P =.17) 2-Yr Rate, % (95% CI) 79.7 (75.9-83.6) Cisplatin 82.6 (78.9-86.3) Cisplatin + cet

64. RTOG 0522: Acute Toxicity Adverse Event, n (%)RT + Cisplatin (n = 448) RT + Cisplatin + Cetuximab (n = 447) Mucositis (P =.004)  None126 (28)85 (19)  Grade 1/2174 (39)172 (38)  Grade 3/4148 (33)190 (43) Skin reactions: in-field (P <.001)  None98 (22)104 (23)  Grade 1/2285 (64)231 (52)  Grade 3/465 (15)112 (25) Skin reactions: out-field (P <.001)  None385 (86)87 (19)  Grade 1/260 (13)273 (61)  Grade 3/43 (1)87 (19) Ang KK, et al. ASCO 2011. Abstract 5500.

65. RTOG 0522: Outcome by p16 Status and Treatment Regimen lHR < 1 indicates benefit for the cetuximab arm HR With 95% CI Oropharynx p16-pos (n = 235) p16-neg (n = 86) No specimens (n = 307) Nonoropharynx (n = 267) All patients (N = 895) 0.01.02.00.01.02.0 PFS OS Ang KK, et al. ASCO 2011. Abstract 5500.

66. Locoregionally Advanced HNSCC: Summary Chemoradiation remains standard of care High-dose cisplatin preferred in candidates expected to have good tolerability  Preference based on relatively extensive study of this agent in this setting In patients requiring substitution with carboplatin (instead of cisplatin), appropriate to add second agent (eg, 5-FU or paclitaxel) Currently, no evidence to support addition of cetuximab

67. Other take home mesagges for p16+ve patients HPV+ had 58% reduction in risk of death HPV+ had a 51% reduction in relapse Three year overall survival HPV+ 83.6% versus 51.3% in HPV- Risks of death and cancer relapse increased by 1% for each additional pack-year of tobacco smoking

68. Summary ●HPV-Associated oropharyngeal carcinoma is a distinct head and neck cancer entity ●Prevalence continues to increase for the next 2 decades ●The change in its incidence should be taken into account in interpreting data of completed trials ●Tumor HPV (p16) status is the strongest prognostic factor identified so far for HNSCC ●Many questions remained to be addressed √The search for effective, less toxic therapy has become a priority √How do other molecular changes affect its behavior? ●Therapy should not be changed outside trial setting

69. A love story with a happy ending…