Head and Neck Squamous Cell Carcinoma (HNSCC) Medical Education - PowerPoint Presentation

Head and Neck Squamous Cell Carcinoma (HNSCC) Medical Education This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). Afatinib is subject to country-specific regulations and the approved product label may vary from country to country. Information on this website is derived from the approved European Summary of Product Characteristics. Please refer to your local product label for full details. © Boehringer Ingelheim International GmbH 2017. This document and its contents are property of Boehringer Ingelheim (third party sources are indicated) and are, inter alia, protected by copyright law. Complete or partial passing on to third parties as well as copying, reproduction, publication or any other use by third parties is not permitted . Procedure ID : 5955. Slides last updated: 31 st March 2017.

HNSCC epidemiology HNSCC, head and neck squamous cell carcinoma.This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ).

What is head and neck cancer? 1. Stewart BW and Wild CP. 2014 (eds ). World Cancer Report. Lyon: WHO IARC Press, 2014. pp. 423; 2. Ferrarotto R, Gold K A. Expert Opin Investig Drugs 2014;23(1):135–43; 3. Mountzio G, et al Ann Oncol 2014;25(10):1889–900; Image from: https://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet. HNSCC, head and neck squamous cell carcinoma.This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).

Global incidence of head and neck cancer Worldwide, head and neck cancer accounts for more than 550,000 cases annually 1 1. Head and neck cancer. Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines. http://www.who.int/selection_medicines/committees/expert/20/applications/HeadNeck.pdf (Accessed: March 2017); 2. Siegel RL, et al. Cancer Statistics, 2017. CA Cancer J Clin 2017;67:7; 3. Gatta G, et al. Eur J Cancer 2015; 51:2130; 4. Bray F, et al. Int J Cancer 2013;132:1133; 5. Lambert R et al. Eur J Gastroenterol Hepatol 2011;23:633. HNSCC, head and neck squamous cell carcinoma.This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). In the US, approximately 62,000 Americans develop head and neck cancer annually2 In Europe, there were approximately 140,000 cases in 20123 Mouth and tongue cancers are the most prevalent cancer type in Indian men4 Nasopharyngeal cancer is endemic in South East Asia 5

Older males are more commonly affected by HNSCC 1. Head and neck cancer. Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines. http://www.who.int/selection_medicines/committees/expert/20/applications/HeadNeck.pdf ( Accessed: March 2017); 2. Forman et al 2014 ,Vol x, IARC Scientific Publications 164; 3. Vigneswaran et al Oral Maxillofac Surg Clin North Am 2014;26(2):123–41; 4. De Santis et al CA Cancer J Clin 2013;63:151–66. HNSCC, head and neck squamous cell carcinoma . This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ).

Global mortality caused by HNSCC 1. Machiels JP, et al. BMC Cancer 2014;14:473; 2. Head and neck cancer. Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines. http ://www.who.int/selection_medicines/committees/expert/20/applications/HeadNeck.pdf; 3. Siegel RL, et al. CA Cancer J Clin 2017;67(1):7; 4. Gatta G, et al. Eur J Cancer 2015;51:2130; 5. Settle K, et al. Cancer Prev Res 2009;2(9)776–81. HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).

5-year survival rates1 5 -year survival has improved for head and neck cancer patients over the past twenty years, and is currently around 66% The greatest improvement was seen in tonsillar and tongue cancers 1. Pulte D, Brunner, H. Oncologist 2010;15(9):994 –1001.*Difference between values in 1992–1996 and those in 2002-2006. p-value stated is for comparison of trend between1992–1996 and 2002–2006. PE, point estimate; SE, standard error.This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ). Location 1982–1986 PE ( SE) 1987–1991 PE ( SE) 1992–1996 PE (SE)1997–2001 PE (SE) 2002-2006 PE (SE)Difference*p-value All52.7 (0.5)53.2 (0.5)54.7 (0.5) 58.6 (0.5) 65.9 (0.5) +11.2 <0.0001 Lip 92.5 (1.3) 95.6 (1.4) 95.5 (1.4) 90.9 (1.5) 97.4 (1.7) +1.9 0.5 Tongue 45.2 (1.2) 48.1 (1.2)50.5 (1.2)55.6 (1.1)64.9 (1.0)+14.4<0.0001Oral cavity53.6 (1.0)52.6 (1.0)51.1 (1.0)56.6 (1.1)62.9 (1.2)+11.8<0.0001Nasopharynx47.1 (2.2)47.6 (2.1)53.8 (2.1)58.3 (1.9)62.3 (1.9)+8.30.002Tonsil39.7 (1.7)41.8 (1.7)47.6 (1.7)56.5 (1.5)69.8 (1.3)+22.2<0.0001Oropharynx26.2 (2.9)23.4 (2.6)33.3 (3.2)37.8 (3.1)42.2 (3.1)+8.90.2Hypopharynx24.2 (1.4)26.2 (1.5)29.8 (1.6)29.7 (1.6)33.8 (2.0)+4.00.3Larynx66.8 (0.8)66.3 (0.8)64.9 (0.9)64.3 (0.9)66.8 (0.9)+1.90.2 % patients surviving for 5 years:

Prognosis in HNSCC 5-year relative survival rate improved from 52.7% to 65.9% between 1982–1986 and 2002–2006 in all head and neck cancers 1The exceptions to this trend were lip, oropharyngeal and hypopharyngeal cancer However, there has been little improvement since then: recent SEER statistics indicate that 5-year survival is 64% in patients with oral cavity and pharynx cancer, and 61% in patients with laryngeal cancer (data from period 2006–2012) 2Better prognosis for HPV-associated HNSCC 3HPV and p16 detection are established markers for HPV-related HNSCCBoth are accepted as predictors of survivalSurvival of patients with HNSCC is prolonged if disease is HPV (+)/p16(+) or HPV (–) /p16(+) 1. Pulte D, Brunner, H. Oncologist 2010;15(9):994– 1001; 2. SEER Cancer Statistics. https://seer.cancer.gov/statfacts/html/oralcav.html and https://seer.cancer.gov/statfacts/html/laryn.html (Accessed: March 2017); 3. Coordes A, et al. Eur Arch Otorhinolaryngol 2016;273(8):2157-69. HNSCC, head and neck squamous cell carcinoma, HPV, human papillomavirus; PE, point estimate; SE, standard error; SEER, Surveillance, Epidemiology, and End Results Program. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).

HNSCC risk factors HNSCC, head and neck squamous cell carcinoma. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ).

Lifestyle risk factors account for the development of approximately 80% of cases of head and neck cancer 1 HPV and EBV are also known risk factors 2 Variations in prevalence of these risk factors contribute to geographical differences in the observed distribution of head and neck cancer 3 Main risk factors for head and neck cancers Tobacco use Alcohol consumption HPV infection ( for oropharyngeal cancer) EBV infection ( for nasopharyngeal cancer) 1 . Stewart BW and Wild CP. 2014 ( eds ). World Cancer Report. Lyon: WHO IARC Press, 2014. pp. 423; 2 . Deng Z, et al. PLoS One 2014;9(11):e113702; 3. Lubin JH, et al. Am J Epidemiol 2009;15;170 (8):937–047. EBV, Epstein -Barr virus; HVP, human papillomavirus. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ).

Tobacco and alcohol are key risk factors for HNSCC 1 . Wyss A, et al. Am J Epidemiol 2013;178:679. 2. Proia NK, et al. Cancer Epidemiol Biomarkers Prev 2006;15:1061; 3. Dasgupta S, et al. J Cell Physiol. 2012;227:467–73; 4. Freedman ND, et al. Br J Cancer 2007;96,1469–74; 5. Znaor A, et al. Int J Cancer 2003;105:681; 6. Druesne-Pecollo N, et al. Lancet Oncol 2009;10:173.HNSCC, head and neck squamous cell carcinoma. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).

HPV is a risk factor for HNSCC 1. zur Hausen H. J Natl Cancer Inst 2000;92:690–8; 2. Pytynia et al Oral Oncol 2014;50(5):380–86; 3. D’Souza et al Prev Med 2011;53(Suppl. 1):S5–S11; 4. Spence T, et al Cancers 2016;8:75; doi:10.3390/cancers8080075; 5.. Weinberger PM, et al. J Clin Oncol 2006;24:736. HNSCC, head and neck squamous cell carcinoma; HVP , human papillomavirus. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). HPV-positive tumours are associated with better prognosis than HPV-negative HNSCC tumours and so testing for HPV status may be useful as a prognostic marker5

HNSCC clinical staging HNSCC, head and neck squamous cell carcinoma. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ).

HNSCC categorisation by location Head and neck cancer is categorised by the area of the head or neck in which it occurs Sites include:LarynxOral cavity, including the tongue Oropharynx, including the base of the tongue and tonsilsNasopharynx 1. Head and neck cancer fact sheet. http://www.cancerresearchuk.org/about-cancer/type/head-and-neck-cancer/ (Accessed: March 2017). HNSCC, head and neck squamous cell carcinoma. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ).

Staging of HNSCC (T)1 Stage Example (oral cavity) TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ T1 ≤2 cm T2 >2 cm to 4 cm T3 >4 cm T4a Through cortical bond, deep/extrinsic muscle of tongue, maxillary sinus and skin T4b Masticator space, pterygoid plates, skull base and internal carotid artery 1. Deschler DG, Moore MG, Smith RV, eds. Quick Reference Guide to TNM Staging of Head and Neck Cancer and Neck Dissection Classification, 4th ed. Alexandria, VA : American Academy of Otolaryngology–Head and Neck Surgery Foundation, 2014. HNSCC, head and neck squamous cell carcinoma; T, tumour . This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ). Staging is essential to the proper and successful management of HNSCCHNSCC is staged according to the Tumour – Node – Metastasis (TNM) systemT (Tumour) staging is described below

Staging of HNSCC (N and M)1 1. Deschler DG, Moore MG, Smith RV, eds. Quick Reference Guide to TNM Staging of Head and Neck Cancer and Neck Dissection Classification, 4th ed. Alexandria, VA: American Academy of Otolaryngology–Head and Neck Surgery Foundation, 2014. HNSCC, head and neck squamous cell carcinoma; M, metastases; N, nodes. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ). Definitions of N (regional lymph nodes) and M (metastases) are shown below NX Regional lymph nodes cannot be assessed N0 No regional lymph nodes metastases N1 Ipsilateral single ≤3 cm N2 a. Ipsilateral single >3 up to 6 cm   b. Ipsilateral multiple ≤6 cm   c. Bilateral, contralateral ≤6 cm N3 >6 cm MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

Staging of HNSCC: Permutations of TNM staging1 1. Gregoire V, et al. Ann Oncol 2010;21(Suppl. 5):v184–v186. HNSCC, head and neck squamous cell carcinoma; M, metastases; N, node; T, tumour.This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). Stage 0 T N M Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0   T1,T2,T3 N1 M0 Stage IVA T1, T2, T3 N2 M0  T4aN0, N1, N2M0Stage IVB Tb Any N M0   Any T N3 M0 Stage IVC Any T Any N M1

Diagnostic work-up of HNSCC HNSCC, head and neck squamous cell carcinoma. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK ).

Common signs and symptoms of head and neck cancer Signs and symptoms vary depending on the location of the cancer 1. Cancer Research UK. http :// www.cancerresearchuk.org/about-cancer/laryngeal-cancer/symptoms and http://www.cancerresearchuk.org/about-cancer/type/nasopharyngeal-cancer/ (Accessed 13 March 2017); 2. Luryi AL, et al. JAMA Otolaryngol Head Neck Surg 2014;140(7):639 –46. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).

Diagnostic tests for HNSCC 1. Farah, et al. Chapter 2 in Contemporary Oral Oncology: Biology, Epidemiology, Etiology, and Prevention edited by Moni Abraham Kuriakose 2017 ; 2. Wemmert , et al Oncol Lett 2016;11:1661–70; 3. Thariat, et al. Clin Cancer Res;2012;18(5):1313–32; 4. Gregoire V, et al Ann Oncol 2010;21(Suppl. 5):v184–v186. CT, computed tomography; EGFR, epidermal growth factor receptor; HNSCC, head and neck squamous cell carcinoma; HVP, human papillomavirus; MRI, magnetic resonance imaging.This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). Physical examination: ¹ Feeling for lumps on the neck, lips, gums and cheeks, and physical inspection of the nose, mouth, throat and tongue Biopsy: ¹ Fine-needle aspiration is the preferred tissue sampling method for initial evaluation of neck masses or thyroid nodules HPV testing: ² HPV has been linked to increased risk of some HNSCC; its presence has significant prognostic value Molecular /biomarker testing:³ Biomarkers for HNSCC include EGFR Endoscopy: ¹ Including laryngoscopy, pharyngoscopy and nasopharyngoscopy Imaging: 1,4 Chest X-ray; head and neck CT scan or MRI (MRI preferable for all subsites except for laryngeal and hypopharyngeal cancers); thoracic CT scan to evaluate possible metastatic disease

Biomarkers 1. Wemmert S, et al. O ncology letters 2012;11:1661 –70; 2. Marur S, et al. Mayo Clin Proc 2016;91(3):386–96. HPV-positive tumours have increased expression of p16²DCR, distant metastases control rate; F, female; HNSCC , head and neck squamous cell carcinoma; HPV, human papillomavirus; M, male; N, node; OPSCC, oropharyngeal squamous cell carcinoma; T, tumour.This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). Variable HPV positive HPV negative Race White > black White > black Age (y) 40–60 >60 M:F 8:1 3:1 Socioeconomic status Higher Low-middle Smoking/alcohol dependence Never or minimal SignificantMarijuana useStrong associationUnknownEarly sexual experienceStrong association Unknown Multiple sexual partners Strong association Unknown Tumour (T) stage Early T stage More advanced T stage Nodal (N) stage Advanced N stage Early N stage Distant metastasis DCR (%) 70–90 70–90 Second primary rate (%) 11 4.6 Overall response to treatment 2-Year OS (%) 94 (95% CI, 87–100) 58 (95% CI, 49-74) 2-Year PFS (%) 85 (95% CI, 74-99) 53 (95% CI, 36-67) Sec62 is a novel potential biomarker for HNSCC¹ Patients with high Sec62 and high nuclear survivin demonstrated a poorer prognosis compared with patients exhibiting low Sec62 and low nuclear survivin expression (p=0.009 ) There is a distinct biology and molecular phenotype among HPV-positive OPSCCs when compared with HPV-negative HNSCCs

Other genetic markers Chromosomal abnormalitiesOver 20 recurrent chromosomal alterations have been identified in invasive HNSCC ¹ Loss of heterozygosity near 9p21 is significantly more frequent in recurrent tumours than in non-recurrent tumours 2 Amplification of region 11q13 encoding the EGFR gene leads to high expression level of EGFR³Mutations in genes responsible for squamous differentiation (Notch1, Irf6, Tp63 )⁴Inactivation of TP53 in most cases⁴Inactivating mutations in NOTCH1 ⁴ CDKN2A (p16) disruption is reported as a frequent event in HNSCC ⁵ 1. Wemmert S et al Oncol Lett 2016;11:1661–70; 2. Matsuura K et al Anticancer Res 1998;18(1A):453–8; 3. Rodrigo JP et al. Scientific Reports 2015; Article  number: 15698; 4. Stransky N et al. Science. 2011;26;333(6046):1157–60; 5. Lim AM et al Int. J. Cancer 2014;135:887–95. CDKN2A, cyclin-dependent kinase Inhibitor 2A; EGFR, epidermal growth factor receptor; HNSCC, head and neck squamous cell carcinoma.This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).

Treatment options in HNSCC HNSCC, head and neck squamous cell carcinoma. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).

Primary systemic treatment of HNSCC: NCCN guidelines 1 * Category 1 for oropharynx, hypopharynx or larnyx ; 2B for lip, oral cavity, ethmoid sinus, maxillary sinus, occult primary. **Category 1 for high risk non- oropharyngeal cancers. 5-FU, fluorouracil; HNSCC, head and neck squamous cell carcinoma; NCCN, National Comprehensive Cancer Network; RT, radiotherapy. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). Treatment Category High dose cisplatin (preferred)1 Cetuximab1,2B*Carboplatin/infusional 5-FU15-FU/hydroxurea2A Cisplatin/paclitaxel2ACisplatin/infusional 5-FU2A Carboplatin/paclitaxel2BWeekly cisplatin 40mg/m ² 2B Post-operative chemoradiation Cisplatin 1** Treatment Category Cisplatin + RT followed by cisplatin /5-FU or carboplatin/5-FU 2B (Carboplatin/5-FU) Cisplatin + RT without adjuvant chemotherapy2B1. NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers, Version 1. Published: February 6th 2017. Lip, oral cavity, oropharynx, glottic larynx, supraglottic larynx, ethmoid sinus, maxillary sinus, occult primary: primary systemic therapy and concurrent RTNasopharynx: chemoradiation followed by adjuvant chemotherapy

Treatment of recurrent, unresectable or metastatic HNSCC: NCCN guidelines1 *Surgery or radiotherapy not an option. **Non-nasopharyngeal, if disease progression on or after platinum-containing chemotherapy. HNSCC, head and neck squamous cell carcinoma ; NCCN, National Comprehensive Cancer Network. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). Treatment Category Cisplatin or carboplatin/5-FU/ cetuximab (non-nasopharyngeal) 1Cisplatin or carboplatin/docetaxel or paclitaxel2A Cisplatin cetuximab (non-nasopharyngeal)2A Cisplatin/5-FU2ACisplatin or carboplatin/docetaxel/cetuximab (non-nasopharyngeal) 2ACisplatin or carboplatin/paclitaxel/cetuximab (non-nasopharyngeal) 2ACarboplatin/cetuximab (nasopharyngeal)2A Cisplatin/gemcitabine (nasopharyngeal) 2A Gemcitabine/ vinorelbine (nasopharyngeal) 2A Combination therapy* Single agents* Treatment Category Cisplatin 2A Carboplatin 2A Paclitaxel2ADocetaxel2A5-FU2AMethotrexate2ACetuximab (non-nasopharyngeal)2AGemcitabine (nasopharyngeal)2ACapecitabine2AAfatinib**2BPembrolizumab** 2A Nivolumab ** 1 1. NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers, Version 1. Published: February 6 th 2017.

Abbreviated EU SmPC EGFR M+ NSCLC and sqNSCLC GIOTRIF ® : Irreversible ErbB family blocker. Active substance: Afatinib. Indications: GIOTRIF is indicated as monotherapy for (1) patients with locally advanced or metastatic NSCLC with activating EGFR mutations not previously treated with EGFR TKIs, (2) patients with NSCLC of squamous histology progressing on or after platinum-based chemotherapy. Posology: The recommended dose is 40 mg once daily, orally. Not recommended in patients with an eGFR <15ml/min and severe hepatic impairment. Contraindications: Hypersensitivity to afatinib or any of the excipients. Interactions: Potent P- gp inhibitors may lead to increased afatinib exposure, concomitant treatment with potent P-gp inducers may lead to a reduction in afatinib exposure. Afatinib is not an inhibitor or inducer of CYP enzymes. Undesirable effects: Paronychia, cystitis, decreased appetite, dehydration, hypokalaemia, dysgeusia , conjunctivitis, dry eye, epistaxis, rhinorrhoea, diarrhoea, stomatitis, nausea, vomiting, cheilitis, dyspepsia, alanine aminotransferase increased, aspartate aminotransferase increased, rash, acneiform dermatitis, pruritus, dry skin, palmar-plantar erythrodysaesthesia syndrome, nail disorders, Stevens-Johnson syndrome, toxic epidermal necrolysis, muscle spasms, renal impairment/renal failure, pyrexia, weight decreased, interstitial lung disease, keratitis, pancreatitis. Presentations: 20 mg, 30 mg, 40 mg, and 50 mg film-coated tablets. For detailed information, please refer to the published Prescribing Information. Supply classification: POM.This medicine is subject to additional monitoring.Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany EGFR M+, epidermal growth factor receptor mutation positive; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.Date of text revision: July 2017