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1 1:30 2:25pm An Update on HPV Cancer Prevention SPEAKERS Kenneth Alexander, MD, PhD Anna Giuliano, PhD Presenter Disclosure Information The following relationships exist related to this presentation: Dr Alexander receives Medical Advisory Board fees from Merck & Co., Inc; and Speakers Bureau honorarium from Merck & Co., Inc Dr Giuliano receives Contracted Research fees from Merck & Co., Inc. and GSK; Medical Advisory Board fees from Merck & Co., Inc. and TrovaGene, Inc; Speakers Bureau honorarium from Merck & Co., Inc. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. At the completion of this activity, participants will be better able to : 1. Summarize the epidemiology and burden of disease associated with the human papilloma virus (HPV) 2. Identify those HPV types most often associated with particular cancers and genital warts 3. Apply strategies to reduce the prevalence of these diseases 4 Generic Trade Name HPV/qHPV Cervarix, Gardasil 9vHPV Gardasil 9 Tdap Adacel, Boostrix MCV4 Menactra, Menveo MenACWY Worldwide, HPV causes ~5% of all new cancers occurring in males and females annually 1 Globally, HPVs are responsible for: Virtually 100% of cervical cancers 1 70% of vaginal cancers 1 43% of vulvar cancers 1 Almost all cases of genital warts and RRP 1,2 88% of anal cancers 1 50% of penile cancers 1 At least 26% of oropharyngeal cancers 1 HPV=human papillomavirus; RRP=recurrent respiratory papillomatosis Forman D et al. Vaccine. 2012;30 suppl 5:F12-F Lacey CJ et al. Vaccine. 2006;24 suppl 3:S3/35-S3/41. 11

2 Pseudovirion based vaccines Based on L1 (capsid) protein Highly immunogenic Bivalent vaccine HPV 16, HPV 18 pseudovirions ASO4 adjuvant Combination of aluminum hydroxide and monophosphoryl lipid A Quadrivalent vaccine HPV 6, HPV 11, HPV 16, HPV18 pseudovirions Amorphous aluminum hydroxyphosphate sulfate adjuvant Syrjänen K, Syrjänen S. Scand J Infect Dis Suppl. 1990;69: Dunne EF et al. JAMA. 2007;297 (8): Human Papillomavirua. In: Atkinson W et al, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases, 12th Edition. Washington DC: The Public Health Foundation/Centers for Disease Control and Prevention; 2011: Accessed March 14, ASO4=Adjuvant System valent vaccine HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 pseudovirions Amorphous aluminum hydroxyphosphate sulfate adjuvant In females 98% for prevention of genital warts and for prevention of CIN2/3 and AIS In males 90% for prevention of external genital lesions 75% for prevention of AIN2/3 AIN=anal intraepithelial neoplasia; AIS=adenocarcinoma in situ; CIN=cervical intraepithelial neoplasia; PPE=parapneumonic pneumococcal empyema; qhpv=quadrivalent human papillomavirus If you immunize with an HPV vaccine, how long must you wait until you see clinical benefit? It depends on what disease you are talking about. Persistent infection: Weeks to months Genital warts: Months to 2 3+ years Anogenital dysplasias: 2 5+ years Anogenital cancers: years Oral cancers: years 17 Franco EL, et al. J Infect Dis. 1999;180: Moscicki AB. J Adolesc Health. 2005;37:53-9. Molano M, et al. Am J Epidemiol. 2003;158:

3 Objective Measure the effect on the prevalence of genital warts of the National Human Papillomavirus Vaccination Program in Australia (started in mid 2007). Quadrivalent vaccine was used Coverage rates decreased with increasing age The highest rates were achieved in 12 to 13 year olds in the school based program 83% received at least 1 dose Intermediate rates were achieved in 20 to 26 year olds in the community catch up program 52% received at least 1 dose Lowest rates were among women who were aged older than 26 years Few males were vaccinated Ali H et al. BMJ. 2013;346:f Ali H et al. BMJ. 2013;346:f Conclusions Vaccine efficacy is high The vaccine induces herd immunity Efficacy, Safety, and Tolerability of anovel 9 Valent HPV L1 Virus like Particle Vaccine in Boys/Girls Aged 9 15 Years and Women Aged Years Anna R Giuliano, PhD on behalf of the V and 002 study teams Director Center for Infection Research in Cancer Moffitt Cancer Center Ali H et al. BMJ. 2013;346:f Worldwide HPV related Disease Burden: 607,000 Cancer Cases in Men and Women Relative Contribution of 7 and 2 HPV Types to HPV Positive Cancers By Site Penile cancer 1 11,000 Male 21,000 Vulvar & vaginal cancer 1 Oropharyngeal cancer 1 17,000 4,400 Oropharyngeal cancer 1 x 60 fold Anal cancer 1 11,000 13,000 Anal cancer 1 530,000 Cervical cancer 1 9,000,000 21,900,000 Female High-grade cervical dysplasia 2,3,* Genital warts 4,5, 17,300,000 14,700,000 Genital warts 4,5, * Estimated 90% of high-grade cervical lesions are HPV related 3 ; Estimated 73% of low-grade cervical lesions are HPV related 3 ; Estimated gender ratio of genital warts: 54% males; 46% females 6 1. Forman D et al. Vaccine. 2012;30 suppl 5:F12-F23; 2. World Health Organization; 3. Guan P et al. Int J Cancer. 2012;131(10): ; 4. World Health Organization; 5. Greer CE et al. J Clin Microbiol. 1995;33(8): ; 6. Public Health England. Low-grade cervical dysplasia 2,3, 25 HPV-positive Cases, % HPV Types* HPV 16/ % 5% 15% 15% 10% 2% 1 Cervix Anus Vulva Vagina 2 Penis 3 Pharynx Cancer Site 2%-20% *HPV 6/11/16/18/31/33/45/52/58 Overall contribution of HPV in cases of cervical cancer (100%), anal cancer (88%), vulvar cancer (25%), vaginal cancer (70%), penile cancer (30%), and oropharyngeal cancer (26%). 1. Serrano B et al. Infect Agent Cancer. 2012;7(1): Merck Data on File. 3. Castellsagué X et al. Presented at: 28th International Papillomavirus Conference; November 30-December 6, 2012; San Juan, Puerto Rico. 26

4 Relative Contribution of 7 and 2 HPV Types to HPV Positive Cervical Cancer and Precancerous Lesions Rationale for Multivalent Vaccine Cases, % % 70 7 HPV types HPV 16/ Cervical Cancer CIN 3 CIN 2 CIN 1 a. HPV 6/11/16/18/31/33/45/52/58 b. Overall contribution of HPV in cases of CIN 1 (73%), CIN 2 (86%), CIN 3 (93%), cervical cancer (100%) 3,4 CIN=cervical intraepithelial neoplasia 1. Serrano B et al. Infect Agent Cancer. 2012;7(1): Merck Data on File. 3. Guan P et al. Int J Cancer. 2012;131(10): Forman D et al. Vaccine. 2012;30 suppl 5: F12-F % 30% 20% 20%-30% Cervical Cancer 16/18 5 new types other CIN 2/3, AIS AIS=adenocarcinoma in situ de Sanjose S et al; Retrospective International Survey and HPV Time Trends Study Group. Lancet Oncol. 2010;11(11): ; Hariri 2011; Serrano 2012; Joura EA et al. Cancer Epidemiol Biomarkers Prev. 2014;23(10): /18 5 new types other 28 9 Valent HPV Vaccine Trials V Efficacy, Immunogenicity, and safety study of the 9vHPV vaccine in young women, 16 to 26 years (N~14,000) Subjects equally randomized to 9vHPV vaccine and qhpv vaccine* (3 dose regimen) V Immunogenicity and safety study of 9vHPV vaccine in adolescent girls (N~1800) and boys (N~600), 9 to 15 years, with a comparison to young women, 16 to 26 years of age (N~400) All subjects received 9vHPV vaccine (3 dose regimen) Study Population Vaccination Key End Points 14,000 young women (16 26 years old) randomized to 9vHPV vaccine or qhpv 3 dose V503 Study Design Protocol 001 V503 Study Design Protocol 001 Efficacy: Genital swab (PCR) and Pap test every 6 months Triage/colposcopy if abnormal Pap test Immunogenicity: Anti HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 titers Safety: Vaccination Report Card (VRC) Serious Adverse Experiences vHPV=9-valent human papillomavirus; PCR=polymerase chain reaction Anti HPV 6, 11, 16, 18 GMTs Month 7 Non inferiority Criterion Was Met for All 4 HPV Types Geometric Mean Titer (mmu/ml) Ratio: 1.02 Ratio:0.80 Ratio: 0.99 Anti HPV 6 Anti HPV 11 Anti HPV 16 Anti HPV 18 9vHPV vaccine qhpv vaccine Ratio:1.19 HPV 31/33/45/52/58 Vaccine Efficacy End Point 9vHPV n qhpv n CIN, VIN, VaIN 3 / / % (91.8, 99.2) CIN2, VIN2/3, VaIN2/3 6 month persist. infection Per-Protocol Efficacy Population VE 1 / / % (80.9, 99.8) 35 / / % (94.4, 97.2) GMTs=geometric mean titers. VaIN=vaginal intraepithelial neoplasia; VIN=vulvar intraepithelial neoplasia. Joura E et al; Broad Spectrum HPV Vaccine Study. N Engl J Med. 2015;372(8): Joura E et al; Broad Spectrum HPV Vaccine Study. N Engl J Med. 2015;372(8):

5 HPV 31/33/45/52/58 Vaccine Efficacy End Point Per-Protocol Efficacy Population 9vHPV Vaccine n qhpv Vaccine n Vaccine Efficacy CIN 1+ 2 / / % (92.2, 99.6) CIN 2+ 1 / / % (79.5, 99.8) VIN, VaIN 1 / / % (61.5, 99.7) VIN/ VaIN 2+ 0 / / % ( 71.5, 100) Reduction of HPV 31/33/45/52/58 Related Procedures Per-Protocol Efficacy Population 9vHPV qhpv Risk Reduction Reduction of nhpv 31/33/45/52/58 n (%) Related Procedures Biopsy 7 / 6, / 6, (93.6, 98.6) External Genital 2 / 6, / 6, (65.7, 98.5) Cervical Biopsy 6 / 6, / 6, (93.9, 98.8) Definitive Therapy 4 / 6, / 6, (65.7, 96.0) Joura E et al; Broad Spectrum HPV Vaccine Study. N Engl J Med. 2015;372(8): Joura, Giuliano and V study team, manuscript in preparation, Month 7 clia GMT in Girls vs Women 9vHPV Vaccine Month 7 clia GMT in Boys vs Women 9vHPV Vaccine mmu (milli Merck Units) Measured GMT (mmu/ml) Chart Title 9 to 15 Year Old Girls 16 to 26 Year Old Women mmu (milli Merck Units) Measured GMT (mmu/ml) to 15 Year Old Boys 16 to 26 Year Old Women HPV Strains HPV Strains Van Damme and V study team, manuscript in preparation, Van Damme and V study team manuscript in preparation, Safety Assessments Vaccination Report Card (VRC) aided surveillance Elevated temperatures (Days 1 to 5 following any vaccination) Injection site and systemic AEs (Days 1 to 15 following any vaccination) Serious adverse experiences (SAEs) SAEs regardless of causality (Day 1 through 180 days postdose 3)* Vaccine related SAEs and deaths (Day 1 to end of study) Pivotal Efficacy, Immunogenicity and Safety Study (V ) *This generally represents the period from day 1 through month 12 AEs=9-adverse events; PCR=polymerase chain reaction

6 Adverse Event (AE) Summary Days 1 to 15 Following Any Vaccination 9vHPV Vaccine n (%) qhpv Vaccine n (%) Subjects in population with 1 or more AEs 6640 (93.9) 6419 (90.7) injection site 6423 (90.8) 6023 (85.1) non injection site 3948 (55.8) 3883 (54.9) with no AE 431 (6.1) 659 (9.3) with vaccine related* AEs 6519 (92.2) 6200 (87.6) injection site 6422 (90.8) 6023 (85.1) non injection site 2086 (29.5) 1929 (27.3) with serious AEs 25 (0.4) 17 (0.2) with serious vaccine related AEs 2 (0.0) 1 (0.0) who died 1 (0.0) 1 (0.0) discontinued** due to an AE 7 (0.1) 3 (0.0) discontinued due to a vaccine related AE 5 (0.1) 3 (0.0) discontinued due to a serious AE 2 (0.0) 0 (0.0) discontinued due to a serious vaccine related AE 1 (0.0) 0 (0.0) Injection Site AEs Higher for 9 Valent vs 4 Valent Vaccine Days 1 to 5 Following Any Vaccination Visit All Vaccinated Subjects Injection site erythema Injection site pain Injection site swelling 9vHPV Vaccine (N=7071) qhpv Vaccine (N=7078) % % %Risk Difference (95% CI) 8.5 (7.0; 10.0) 6.4 (5.3; 7.5) 11.3 (9.7; 12.8) p Value <.001 <.001 < Injection Site AEs Intensity Appears Higher for 9 Valent vs 4 Valent Vaccine Days 1 to 5 Following Any Vaccination Visit All Vaccinated Subjects 9vHPV Vaccine (N=7071) qhpv vaccine (N=7078) % % Injection site pain Mild Moderate Severe Injection site erythema Mild ( 1 inch [2.5 cm]) Moderate (>1 2 inches [2.5 5 cm]) Severe (>2 inches [5 cm]) Injection site swelling Mild ( 1 inch [2.5 cm]) Moderate (>1 2 inches [2.5 5 cm]) Severe (>2 inches [5 cm]) Vaccine Related* Systemic AEs ( 1% in Any Group) Appear Similar Days 1 to 15 Following Any Vaccination Visit 9vHPV Vaccine N= 7071 qhpv Vaccine N= 7078 Vaccine Related* Headache Systemic 1031 (14.6) AEs ( 1% 969 (13.7) in Any Pyrexia Group) Appear 357 (5.0) Similar 301 (4.3) Nausea 311 (4.4) 261 (3.7) Dizziness 211 (3.0) 197 (2.8) Fatigue 166 (2.3) 150 (2.1) Diarrhea 87 (1.2) 71 (1.0) Oropharyngeal pain 73 (1.0) 40 (0.6) Myalgia 69 (1.0) 48 (0.7) 42 Immunogenicity and Safety Study in Adolescent Girls and Boys and Young Women (V ) 43 Injection Site AEs Intensity Differed by Sex and Age Group Days 1 to 5 Following Any Vaccination Visit All Vaccinated Subjects Girls (N=1923) Boys (N=662) Women (N=466) % % % Injection site pain Mild Moderate Severe Injection site erythema Mild ( 1 inch [2.5 cm]) Moderate (>1 2 inches [2.5 5 cm]) Severe (>2 inches [5 cm]) Injection site swelling Mild ( 1 inch [2.5 cm]) Moderate (>1 2 inches [2.5 5 cm]) Severe (>2 inches [5 cm])

7 Vaccine Related Systemic AEs ( 1% in Any Group) Days 1 to 15 Following Any Vaccination Visit Girls N=1923 Boys N=662 Women N=466 Headache 183 (9.5) 60 (9.1) 46 (9.9) Pyrexia 128 (6.7) 57 (8.6) 32 (6.9) Dizziness 32 (1.7) 4 (0.6) 8 (1.7) Nausea 24 (1.2) 8 (1.2) 6 (1.3) Fatigue 19 (1.0) 3 (0.5) 12 (2.6) Malaise 6 (0.3) 4 (0.6) 8 (1.7) Feeling hot 4 (0.2) 1 (0.2) 6 (1.3) Maximum Temperatures Did Not Differ by Age Group and Sex Days 1 to 5 Following Any Vaccination Visit Girls N=666 n (%) Boys N=666 n (%) Women N=468 n (%) <37.8 C 1,747 (91.6) 594 (90.0) 424 (91.6) 37.8 C and <38.9 C 133 (7.0) 57 (8.6) 31 (6.7) 38.9 C and <39.9 C 24 (1.3) 8 (1.2) 7 (1.5) 39.9 C and <40.9 C 3 (0.2) 1 (0.2) 1 (0.2) 40.9 C 1 (0.1) 0 (0.0) 0 (0.0) 37.8 C (100.0 F) 161 (8.4) 66 (10.0) 39 (8.4) Conclusions V Acceptable safety profile in young women, aged 16 to 26 years Frequencies of clinical adverse experiences generally comparable between 9vHPV vaccine and qhpv vaccine Differences with respect to injection-site swelling Higher frequency of injection-site AEs with 9vHPV vs qhpv vaccine Majority of injection-site AEs are mild-moderate intensity with both vaccines V Acceptable safety profile in all 3 demographic groups Similar frequencies of severe injection-site AEs among the 3 groups Safety profile similar or slightly more favorable in boys vs girls and women Similar to previous findings with qhpv vaccine Predicted Effect of an HPV 16, 18, 31, 33, 45, 52, 58 / 6, 11 Vaccine Following a sex-neutral national approach to HPV vaccination, the vaccinated cohort is expected to experience a lifetime reduction of the following diseases: 90% of cervical cancer 77% of all HPV-related cancers (men and women) 80% of high-grade cervical pre-cancers 90% of genital warts (men and women) Joura E et al; Broad Spectrum HPV Vaccine Study. N Engl J Med. 2015;372(8): Serrano B et al. Infect Agent Cancer. 2012;7(1):38. Castellsague X et al. Presented at 28 th International Papillomavirus Conference; Nov 30 Dec 6, 2012; San Juan, PR 50

8 Predicted Effect of an HPV 16, 18, 31, 33, 45, 52, 58 / 6, 11 Vaccine Relative to a vaccine against HPV 16 and 18, the additional 5 HPV types are estimated to: - prevent an additional 100,000 cases of cervical cancer per year The 9-valent vaccine should work equally in any region of the world, overriding the variability observed in some countries in the distribution of HPV 16 and 18. Serrano B et al. Infect Agent Cancer. 2012;7(1):38. Castellsague X et al. Presented at 28 th International Papillomavirus Conference; Nov 30 Dec 6, 2012; San Juan, PR 51 Schuchat A. N Engl J Med. 2015;372(8): The 9 valent HPV vaccine is recommended for routine vaccination of 11 and 12 year old males and females As with the quadrivalent vaccine, immunization may be initiated as young as age 9 years The ACIP also recommended catch up immunization with the 9 valent vaccine for females aged years While the quadrivalent vaccine is recommended for catch up immunization of males through age 21, and is recommended for high risk males through age 26, the 9 valent vaccine is FDA licensed only in males through age 15 The ACIP is recommending off label catch up immunization of all males aged 16 to 21 years, and off label immunization of high risk males aged 22 to 26 years More recommendations will likely come in June ACIP=Advisory Committee on Immunization Practices FDA=US Food and Drug Administration. 58 For females, the ACIP does not make a preference among the 2 valent, 4 valent or 9 valent vaccines For females, a three dose series with any of the vaccines is recommended For males, a three dose series with either the 4 valent or 9 valent is recommended % 78% 57% Females 38% 70% 35% Males 14% 48% 59 MCV4=meningococcal conjugate vaccine; Tdap=tetanus, diphtheria, and pertussis. Morbidity and Mortality Weekly Report (MMWR). 2014;63(29):

9 % 81% Females 68% 72% Males % 51% 39% 20 17% 0 Morbidity and Mortality Weekly Report (MMWR). 2014;63(29): Adolescents need medical homes with providers who understand adolescent issues The vaccine works best when given at a younger age Obstetrician/Gynecologists do not care for early teens Obstetrician/Gynecologists do not see males Obstetrician/Gynecologists are poor immunizers Pediatric providers are vaccine enthusiasts Caring for teens is good business Pediatricians and FPs know how to talk with adolescents and their parents

10 When we speak doctor to doctor, we use the language of epidemiology. We talk about risk. We use statistics. Proven facts matter HPV stands for human papillomavirus HPV causes genital warts and cervical cancer HPVs are transmitted sexually Many adolescents become sexually active by age 13 years Do you want this vaccine for your 11 year old? 76 78

11 My child is not (and never will be) sexually active! Has anyone that you care about had cancer? What was it like for him or her? What was it like for you? We can reduce the chances of your son or daughter having a cancer experience Do you want to reduce your child s risk for cancer? Does it work? 2. Is it safe? 3. What is your recommendation? ) Does it work? Yes! Vaccine efficacy is high for prevention of cervical disease, genital warts, and anal malignancies. The vaccine may also protect against some head and neck cancers. 2) Is it safe? Yes! Large clinical trials and extensive post marketing surveillance have identified sore arms, and the occasional headache and fever, as the only vaccineassociated side effects

12 3) What is your recommendation?