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1 HPV-Associated Head and Neck Cancer: Controversies and Challenges NONE DISCLOSURES RESEARCH: Lilly, GSK, MERCK Stuart J. Wong, MD Associate Professor of Medicine and Otolaryngology Medical College of Wisconsin Case 1 54 year old man who presented to his primary physician with a sore throat and neck swelling. History of smoking quit 5 years ago (50 pack year history); 3-4 mixed drinks per day PE: normal except 2cm right anterior cervical LN Case 1 (con t) Antibiotics: No improvement Increase size of cervical mass Second Course Antibiotics Increase cervical mass Third Course Antibiotics Dysphagia Odynophagia Case 2 39 year old man presents with sore throat Never smoked doesn t drink PE normal Case 2 (con t) Antibiotics minor short lived symptom relief 2 nd course of antibiotics 3 rd course of antibiotics 6 months later sought 2 nd opinion on his own from ENT specialist R Tonsil mass, ulceration Neck mass, right cervical 1

2 Learning Objectives Understand the increasing incidence of HPV- Associated Head and Neck Cancer in the US Recognize common clinical features of HPV- Associated Head and Neck Cancer in contrast to Non-HPV Head and Neck Cancer Understand the prognosis, molecular underpinnings, and management of HPV- Associated HNCa Head and Neck Anatomy OBSERVED AND PROJECTED INCIDENCE OF SCCHN 2

3 HPV OPC Epidemiology 3

4 Global Burden of HPV OPC Global Burden of HPV OPC Anil K. Chaturvedi, PhD, National Cancer Institute Anil K. Chaturvedi, PhD, National Cancer Institute Global Burden of HPV OPC Squamous Cell Cancer of Head & Neck (SCCHN) SCCHN Non-HPV HPV Anil K. Chaturvedi, PhD, National Cancer Institute The Changing Face of Head &Neck Cancer The Changing Face of Head &Neck Cancer HPV Younger Age (40-50 s) Non-smokers Sexual Behaviors Oropharynx Disproportionate large cystic lymph nodes Basaloid histology Non-HPV Older Age (60-70 s) Tobacco use No sexual association Upper aerodigestive 4

5 Molecular carcinogenesis Transmission Immunology PATHOGENESIS OF HPV ASSOCIATED- HEAD AND NECK CANCER Risk Factors HPV-OPC HPV Oropharynx Cancer: Pathogenesis Immune pathogenesis HPV HNSCC Duray, Clinical and Developmental Immunology,

6 National Health and Nutrition Examination Cross-sectional Survey N=5579 HPV infection 6.9% Gillison,M, et al MANAGEMENT OF HPV ASSOCIATED SCCHN Stratify by Primary site Tumor stage: AJCC T1-3 vs. T4 Nodal Status No vs. N1 vs. N2-3 R A N D O M I Z E Adelstein, et al. J Clin Oncol 21: Arm 1 (RT) Radiation therapy Alone Arm 2 (RT+E) Radiation therapy + Cisplatin 100 mg/m 2, d 1, 22, 43 Arm 3 (RT+E) Radiation therapy (split course) Cisplatin + 5FU Kaplan-Meier projected over-all survival Adelstein, et al. J Clin Oncol 21:

7 HPV Oropharynx Cancer: Prognosis Conventional Chemo: Cisplatin HPV+, No TOB HPV+, TOB Use Non-HPV Cisplatin: The Penicillin of Cancer Radiosensitization: In vitro 1845 described Peyrones Salt, Peyrones Chloride 1893 structure deduced by Alfred Werner 1965 inhibits binary fission of E. coli 1970 s revolutionary anti cancer effect Got Barf? Cisplatin Toxicity GI-Nausea, vomiting Nephrotoxicity Ototoxicity Neurotoxicity Hematologic 7

8 Molecular Targeted Chemotherapy TARGETED THERAPY IN HNSCC EGFR-Epidermal Epidermal Growth Factor Receptor EGFR Overexpression in HNSCC Zhu et al. IgG 1 chimerized MAb Specific to EGFR Cetuximab Binds to EGFR with high affinity The variable region mediates binding The variable region confers absolute specificity for an antigen * The constant region mediates immune response after binding Different isotypes (IgG 1, IgG 2, IgG 3 ) of antibody have differing properties Erbitux (cetuximab) Package Insert, June 2004 Fan Z et al. J Biol Chem. 1994;269: Data on file, ImClone Systems Incorporated and Bristol-Myers Squibb Company. Study Study Agents EMR-001 (Baseglia,et al) Cetuximab +Cisplatin or Carboplatin IMC-9816 (Herbst,et al) Cetuximab + Cisplatin EMR-016 (Trigo,et al) Cetuximab Number of Patients Response Rate (CR+PR) Disease Control (RR + SD) Median Time to progression Median Overall Survival Cetuximab in Platinum-Refractory SCCHN Vermorken J, et al. ASCO 2005; Abstract 5505 and slide presentation 10% 10% 13% 53% 56% 46% 2.8 months 2.2 months 2.3 months 6.1 months 5.2 months 5.9 months 8

9 Results Stratify by Karnofsky score: vs Regional nodes: Negative vs. Positive Tumor stage: AJCC T1-3 vs. T4 RT fractionation**: Concomitant boost vs. Once daily vs. Twice daily R A N D O M I Z E Arm 1 (RT) Radiation therapy Arm 2 (RT+E) Radiation therapy + Cetuximab, weekly RT RT+C No. of Patients Locoregional Control 1-year 59% 69% 2-year 48% 56% Median 19 m 36 m Log-rank p 0.02 Overall Survival 2-year 55% 62% 3-year 44% 57% Median 28 m 54 m Log-rank p 0.02 Cetuximab + RT RT Locoregional Control P = 0.02 Cetuximab + RT RT Overall Survival P = 0.02 Grade 3/4 Toxicity Toxicity RT n=212 (%) RT + Cetuximab n=208 (%) Mucositis/Stomatitis Dysphagia Skin reaction Fatigue 5 4 Xerostomia 3 4 Infusion reaction 0 3 A. Trotti et al, Lancet Oncology 2007 RTOG 1016 Primary Endpoint: To determine whether substitution of cetuximab for cisplatin will result in comparable 5 y OS Secondary Function and Quality of Life Endpoints: Hearing Speech Swallow Return to work 9

10 Mitigation and Prevention of Long- Term Cisplatin-Induced Toxicities in Head and Neck Tumor Patients Head and Neck Cancer Program Medical Team Speech & Swallow Audiology Physical Therapy Nutrition Patient Psychology The Influence Of Institutional Head And Neck Cancer (HNC) Clinical Trial Accrual On Overall Survival (OS): An Analysis Of RTOG 0129 Outcome HAC (%) LAC (%) P value OS (5 y) PFS LRF J Clin Oncol 30, 2012 (suppl; abstr 5530) 10

11 Molecular Targeted Chemotherapy TARGETED THERAPY Targeted Anti-Cancer Therapy Block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression Preferential effect on cancer cells rather than normal tissue cells Higher Therapeutic Ratio = Anti-tumor tumor effect Toxic side effects HPV-Specific Therapeutic Strategies A Phase II TIL for Human Papillomavirus-Associated Cancers (NCT ) HPV-Specific Therapeutic Strategies HPV-Specific Therapeutic Strategies HPV 16 and MAGE-A3 A3 Trojan peptides for the immunotherapy of SCCHN (NCT ) 11

12 HPV positive: 90% 5-year survival 40-50% PIK3CA alteration Minimal EGFR alterations Hayes, et al. AACR 2013 N= 279: 80% Tobacco related; 13% HPV HPV-negative % LN positive 50% five year survival HPV-negative HRAS mutations- 5% NOTCH, NFE2L % PIK3CA TP53 Hayes, et al. AACR 2013 CDKN2A Molecular Targeted Therapy for Melanoma 12

13 60 Oral Chemotherapy on the Market FDA Approved Oral Chemotherapy Agents 50 Number Approved /1/53 1/1/62 1/1/71 1/1/80 1/1/89 1/1/98 1/1/07 Drugs@FDA Foundation EGFR Signaling and Dimerization TRYHARD: A PHASE II, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED CONTROLLED STUDY OF LAPATINIB (TYKE YKERB ) FOR NON-HPV LOCALLY ADVANCED HEAD AND NECK CANCER WITH CONCURRENT CHEMORADIATION RTOG FOUNDATION STUDY 3501 Stuart Wong, MD SCHEMA: TRYHARD-RTOG Foundation Study 3501 Stratify by > 65 vs < 65 T2-3 vs T4 Nodal Status N0-2a vs. N2b-3 R A N D O M I Z E Arm 1 AFX + Cisplatin 100 mg/m 2, d 1, 22 + Lapatinib Arm 2 AFX + Cisplatin 100 mg/m 2, d 1, 22 + Placebo HNSCC immune escape response T-cell inflamed phenotype (TILs, PD-L1+) HYPOTHESIS: Inhibition of PD-1 with ligand PD-L1, PD-L2 may restore immune activation and immune mediated antitumor effects Foundation

14 Pembrolizumab (MK-3475) MERCK Fully humanized α PD-1 IgG4/kappa isotype No ADCC Dual ligand binding PD-L1 PD-L2 Phase Ib trial of pembrolizumab (MK-3475) in HPV pos/neg Head and Neck Cancer 79 Seiwert, ASCO Case 1 Complete Response 1 (1.8%) Partial Response 10 (17.9%) Best Overall Response 11 (19.6%) 54 year old man who presented to his primary physician with a sore throat and neck swelling. History of smoking quit 5 years ago (50 pack year history); 3-4 mixed drinks per day PE: normal except 2cm right anterior cervical LN Seiwert, ASCO Case 1 (con t) Antibiotics: No improvement Increase size of cervical mass Second Course Antibiotics Increase cervical mass Third Course Antibiotics Dysphagia Odynophagia Case 2 39 year old man presents with sore throat Never smoked doesn t drink PE normal 14

15 Case 2 (con t) Antibiotics minor short lived symptom relief 2 nd course of antibiotics 3 rd course of antibiotics 6 months later sought 2 nd opinion on his own from ENT specialist R Tonsil mass, ulceration Neck mass, right cervical Learning Objectives Understand the increasing incidence of HPV- Associated Head and Neck Cancer in the US Recognize common clinical features of HPV- Associated Head and Neck Cancer in contrast to Non-HPV Head and Neck Cancer Understand the prognosis, molecular underpinnings, and management of HPV- Associated HNCa Parting Shots Acknowledgments Recognition of HPV oropharynx cancer in contrast to Non-HPV cancer Early diagnosis impacts outcome Multidisciplinary treatment and supportive care improves outcome RTOG: Kian Ang Quynh Le Walter Curran MCW Koss Hearing and Balance Center: Chris Runge David Freeland MCW Head Neck Program: Bruce Campbell Becky Massey Michael Stadler Christopher Schultz Dian Wang Selim Firat Kathy Myers MCW Dept. Pediatrics: Fritz Sieber MKE 15