Aktuelle Entwicklung der molekular zielgerichteten Therapie von Kopf-Hals-Karzinomen

Zusammenfassung

Rezidivsituation und Fernmetastasierung stellen bei Plattenepithelkarzinomen des Kopf-Hals-Bereichs (HNSCC) eine große therapeutische Herausforderung dar. Es besteht für die betroffenen Patienten eine hohe Morbidität sowie meist eine unbefriedigende, mediane Gesamtüberlebensrate selbst unter intensiven Kombinationschemotherapien. Die Einführung des Epidermal Growth Factor Receptor (EGFR)-Antikörpers Cetuximab 2008 stellte in Verbindung mit einer platinhaltigen Chemotherapie eine erste Verbesserung in Bezug auf das Gesamtüberleben seit Jahrzehnten dar. Da aber eine Monotherapie mit Cetuximab bei besserer Verträglichkeit eine deutlich geringere Effektivität als eine Kombination mit platinhaltiger Chemotherapie aufweist, besteht großer Bedarf, neue Ziele für zielgerichtete Therapien zu identifizieren und mögliche Kombinationen zu evaluieren. Neue Zielstrukturen umfassen EGFR und seine nachgeschalteten Rezeptor- Tyrosinkinasen, sowie Inhibitoren des VEGF- und des PI3K/AKT/ mTOR-Signalweges. Ferner liegt aktuell großes Potenzial in einer Immuntherapie mittels Checkpoint-Blockade. Aufgrund der nur eingeschränkten Effektivität einer zielgerichteten Monotherapie sind gegenwärtig mögliche Kombinationstherapien und deren Toxizitäten sowie der Zeitpunkt des Therapiebeginns von großem klinischem Interesse.

Abstract

Recurrent squamous cell carcinomas of the head and neck (HNSCC) is a challenging disease due to morbidity and limited median overall survival rates even after aggressive chemotherapeutic regimen. The clinical establishment of the epidermal growth factor receptor (EGFR) antibody Cetuximab in 2008 brought the first significant survival benefit in palliative chemotherapy of HNSCC for decades. With regard to rather high toxicity of palliative chemotherapy and low remission rates after Cetuximab monotherapy, there is an urgent need for new targeted therapies.

New targeted therapeutics include antagonists of EGFR and its downstream kinases, as well as inhibitors of VEGF- and PI3K/AKTmTOR signaling pathways. Furthermore, novel immunological checkpoint inhibition provides new hopeful perspectives.

Due to limited remission rates of monotherapies using antibodies or tyrosine kinase inhibitors the evaluation of less toxic combination therapies is of great current clinical interest.

• Literatur

• 1 Williams SD, Velez-Garcia E, Essessee I. et al. Chemotherapy for head and neck cancer. Comparison of cisplatin + vinblastine + bleomycin versus methotrexate. Cancer 1986; 57: 18-23
• 2 Morton RP, Rugman F, Dorman EB. et al. Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomised factorial phase III controlled trial. Cancer Chemother Pharmacol 1985; 15: 283-289
• 3 A phase III randomised trial of cisplatinum m, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group. British Journal of Cancer 1990; 61: 311-315
• 4 Kish JA, Weaver A, Jacobs J. et al. Cisplatin and 5-fluorouracil infusion in patients with recurrent and disseminated epidermoid cancer of the head and neck. Cancer 1984; 53: 1819-1824
• 5 Jacobs C, Lyman G, Velez-Garcia E. et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992; 10: 257-263
• 6 Forastiere AA, Metch B, Schuller DE. et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992; 10: 1245-1251
• 7 Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2006; 24: 2644-2652
• 8 Clavel M, Vermorken JB, Cognetti F. et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 1994; 5: 521-526
• 9 Clavel M, Cognetti F, Dodion P. et al. Combination chemotherapy with methotrexate, bleomycin, and vincristine with or without cisplatin in advanced squamous cell carcinoma of the head and neck. Cancer 1987; 60: 1173-1177
• 10 Browman GP, Cronin L. Standard chemotherapy in squamous cell head and neck cancer: what we have learned from randomized trials. Semin Oncol 1994; 21: 311-319
• 11 Dreyfuss AI, Clark JR, Norris CM. et al. Docetaxel: an active drug for squamous cell carcinoma of the head and neck. J Clin Oncol 1996; 14: 1672-1678
• 12 Couteau C, Chouaki N, Leyvraz S. et al. A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck. Br J Cancer 1999; 81: 457-462
• 13 Catimel G, Verweij J, Mattijssen V. et al. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994; 5: 533-537
• 14 Smith RE, Thornton DE, Allen J. A phase II trial of paclitaxel in squamous cell carcinoma of the head and neck with correlative laboratory studies. Semin Oncol 1995; 22: 41-46
• 15 Forastiere AA, Shank D, Neuberg D. et al. Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group trial (PA390). Cancer 1998; 82: 2270-2274
• 16 Gibson MK, Li Y, Murphy B. et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005; 23: 3562-3567
• 17 Adamo V, Ferraro G, Pergolizzi S. et al. Paclitaxel and cisplatin in patients with recurrent and metastatic head and neck squamous cell carcinoma. Oral Oncol 2004; 40: 525-531
• 18 Pivot X, Raymond E, Laguerre B. et al. Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer 2001; 85: 649-655
• 19 Samlowski WE, Gundacker H, Kuebler JP. et al. Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study. Invest New Drugs 2001; 19: 311-315
• 20 Catimel G, Vermorken JB, Clavel M. et al. A phase II study of Gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994; 5: 543-547
• 21 Sandler A, Saxman S, Bandealy M. et al. Ifosfamide in the treatment of advanced or recurrent squamous cell carcinoma of the head and neck: a phase II Hoosier Oncology Group trial. Am J Clin Oncol 1998; 21: 195-197
• 22 Martin M, Diaz-Rubio E, Gonzalez Larriba JL. et al. Ifosfamide in advanced epidermoid head and neck cancer. Cancer Chemother Pharmacol 1993; 31: 340-342
• 23 Huber MH, Lippman SM, Benner SE. et al. A phase II study of ifosfamide in recurrent squamous cell carcinoma of the head and neck. Am J Clin Oncol 1996; 19: 379-382
• 24 Cervellino JC, Araujo CE, Pirisi C. et al. Ifosfamide and mesna for the treatment of advanced squamous cell head and neck cancer. A GETLAC study. Oncology 1991; 48: 89-92
• 25 Martinez-Trufero J, Isla D, Adansa JC. et al. Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment. Br J Cancer 2010; 102: 1687-1691
• 26 Murphy BA. Topoisomerases in the treatment of metastatic or recurrent squamous carcinoma of the head and neck. Expert Opin Pharmacother 2005; 6: 85-92
• 27 Testolin A, Recher G, Cristoferi V. et al. Vinorelbine in pre-treated advanced head & neck squamous cell carcinoma. A phase II study. Invest New Drugs 1994; 12: 231-234
• 28 Saxman S, Mann B, Canfield V. et al. A phase II trial of vinorelbine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Am J Clin Oncol 1998; 21: 398-400
• 29 Degardin M, Oliveira J, Geoffrois L. et al. An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 1998; 9: 1103-1107
• 30 Burtness BA, Manola J, Axelrod R. et al. A randomized phase II study of ixabepilone (BMS-247550) given daily x 5 days every 3 weeks or weekly in patients with metastatic or recurrent squamous cell cancer of the head and neck: an Eastern Cooperative Oncology Group study. Ann Oncol 2008; 19: 977-983
• 31 Price KA, Cohen EE. Current treatment options for metastatic head and neck cancer. Curr Treat Options Oncol 2012; 13: 35-46
• 32 Pignon JP, Bourhis J, Domenge C. et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355: 949-955
• 33 Furness S, Glenny AM, Worthington HV. et al. Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy. Cochrane Database Syst Rev 2011; CD006386
• 34 Blanchard P, Baujat B, Holostenco V. et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol 2011; 100: 33-40
• 35 Vermorken JB, Remenar E, van Herpen C. et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007; 357: 1695-1704
• 36 Posner MR, Hershock DM, Blajman CR. et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007; 357: 1705-1715
• 37 Marur S, Forastiere AA. Head and Neck Squamous Cell Carcinoma: Update on Epidemiology, Diagnosis, and Treatment. Mayo Clin Proc 2016; 91: 386-396
• 38 Haddad R, O'Neill A, Rabinowits G. et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 2013; 14: 257-264
• 39 Cohen EE, Karrison TG, Kocherginsky M. et al. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol 2014; 32: 2735-2743
• 40 Blanchard P, Bourhis J, Lacas B. et al. Taxane-cisplatin-fluorouracil as induction chemotherapy in locally advanced head and neck cancers: an individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group. J Clin Oncol 2013; 31: 2854-2860
• 41 Machiels JP, Subramanian S, Ruzsa A. et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol 2011; 12: 333-343
• 42 Sacco AG, Cohen EE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. J Clin Oncol 2015; 33: 3305-3313
• 43 Mesia R, Rivera F, Kawecki A. et al. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2010; 21: 1967-1973
• 44 Vermorken JB, Mesia R, Rivera F. et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116-1127
• 45 Ho CM, Lam KH, Wei WI. et al. Occult lymph node metastasis in small oral tongue cancers. Head Neck 1992; 14: 359-363
• 46 Cognetti DM, Weber RS, Lai SY. Head and neck cancer: an evolving treatment paradigm. Cancer 2008; 113: 1911-1932
• 47 Bonner JA, Harari PM, Giralt J. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567-578
• 48 Ang KK, Berkey BA, Tu X. et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002; 62: 7350-7356
• 49 Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Exp Cell Res 2003; 284: 2-13
• 50 Freudlsperger C, Burnett JR, Friedman JA. et al. EGFR-PI3K-AKT-mTOR signaling in head and neck squamous cell carcinomas: attractive targets for molecular-oriented therapy. Expert Opin Ther Targets 2011; 15: 63-74
• 51 Lee JW, Soung YH, Kim SY. et al. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res 2005; 11: 2879-2882
• 52 Chung CH, Ely K, McGavran L. et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 2006; 24: 4170-4176
• 53 Rubin Grandis J, Melhem MF, Gooding WE. et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 1998; 90: 824-832
• 54 Li S, Schmitz KR, Jeffrey PD. et al. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 2005; 7: 301-311
• 55 Lopez-Albaitero A, Ferris RL. Immune activation by epidermal growth factor receptor specific monoclonal antibody therapy for head and neck cancer. Arch Otolaryngol Head Neck Surg 2007; 133: 1277-1281
• 56 Markovic A, Chung CH. Current role of EGF receptor monoclonal antibodies and tyrosine kinase inhibitors in the management of head and neck squamous cell carcinoma. Expert Rev Anticancer Ther 2012; 12: 1149-1159
• 57 Husain ZA, Burtness BA, Decker RH. Cisplatin Versus Cetuximab With Radiotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck. Journal of Clinical Oncology 2016; 34: 396-398
• 58 Magrini SM, Buglione M, Corvo R. et al. Cetuximab and radiotherapy versus cisplatin and radiotherapy for locally advanced head and neck cancer: a randomized phase II trial. J Clin Oncol 2016; 34: 427-435
• 59 Ang KK, Zhang Q, Rosenthal DI. et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 2014; 32: 2940-2950
• 60 Nguyen-Tan PF, Zhang Q, Ang KK. et al. Randomized Phase III Trial to Test Accelerated Versus Standard Fractionation in Combination With Concurrent Cisplatin for Head and Neck Carcinomas in the Radiation Therapy Oncology Group 0129 Trial: Long-Term Report of Efficacy and Toxicity. Journal of Clinical Oncology 2014; 32: 3858-3867
• 61 Pfister DG, Su YB, Kraus DH. et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006; 24: 1072-1078
• 62 Pinto C, Barone CA, Girolomoni G. et al. Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy. Oncologist 2011; 16: 228-238
• 63 Chung CH, Mirakhur B, Chan E. et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 2008; 358: 1109-1117
• 64 Vermorken JB, Trigo J, Hitt R. et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007; 25: 2171-2177
• 65 Martin NV, Pacifico V, Lai SE. et al. Management of rash to erlotinib (E) and cetuximab (C): Results from the SERIES (Skin and Eye Reactions to Inhibitors of EGFR and kinaseS) clinic algorithm. Journal of Clinical Oncology 2007; 25: 19556-19556
• 66 Rischin D, Spigel DR, Adkins D. et al. PRISM: Phase 2 trial with panitumumab monotherapy as second-line treatment in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Head Neck 2016; 38 (Suppl. 01) E1756-E1761
• 67 Saadeh CE, Lee HS. Panitumumab: a fully human monoclonal antibody with activity in metastatic colorectal cancer. Ann Pharmacother 2007; 41: 606-613
• 68 Tejani MA, Cohen RB, Mehra R. The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer. Biologics 2010; 4: 173-185
• 69 Vermorken JB, Stohlmacher J, Davidenko I. et al. Primary efficacy and safety results of SPECTRUM, a Phase 3 trial in patients (pts) with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) receiving chemotherapy with or without panitumumab (pmab). Ann Oncol 2010; 21 (Suppl. 08) Abstract LBA26
• 70 Harding FA, Stickler MM, Razo J. et al. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs 2010; 2: 256-265
• 71 Desjarlais JR, Lazar GA, Zhukovsky EA. et al. Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective. Drug Discov Today 2007; 12: 898-910
• 72 Patel D, Guo X, Ng S. et al. IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab. Hum Antibodies 2010; 19: 89-99
• 73 Schneider-Merck T, Trepel M. Lapatinib. Recent Results Cancer Res 2010; 184: 45-59
• 74 Rizzo S, Bronte G, Fanale D. et al. Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?. Cancer Treat Rev 2010; 36 (Suppl. 03) S56-S61
• 75 Lynch TJ, Bell DW, Sordella R. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129-2139
• 76 Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009; 28 (Suppl. 01) S24-S31
• 77 Soulieres D, Senzer NN, Vokes EE. et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004; 22: 77-85
• 78 Cohen MH, Williams GA, Sridhara R. et al. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8: 303-306
• 79 Cohen EE, Rosen F, Stadler WM. et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003; 21: 1980-1987
• 80 Cohen EE, Kane MA, List MA. et al. Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2005; 11: 8418-8424
• 81 Li D, Ambrogio L, Shimamura T. et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702-4711
• 82 Kondo N, Tsukuda M, Ishiguro Y. et al. Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma. Oncol Rep 2010; 23: 957-963
• 83 Engelman JA, Zejnullahu K, Gale CM. et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007; 67: 11924-11932
• 84 Harrington KJ, Berrier A, Robinson M. et al. Phase II study of oral lapatinib, a dual-tyrosine kinase inhibitor, combined with chemoradiotherapy (CRT) in patients (pts) with locally advanced, unresected squamous cell carcinoma of the head and neck (SCCHN). Journal of Clinical Oncology 2010; 28: 5505-5505
• 85 Yap TA, Vidal L, Adam J. et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 2010; 28: 3965-3972
• 86 Seiwert TY, Fayette J, Cupissol D. et al. A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck. Ann Oncol 2014; 25: 1813-1820
• 87 Janne PA, Boss DS, Camidge DR. et al. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res 2011; 17: 1131-1139
• 88 Hecht M, Hahn D, Beutner D et al. Cetuximab in combination with platinum-based chemotherapy or radiotherapy in recurent and/or metastatic SCCHN in a non-selected patient cohort (interim analysis of the phase IV SOCCER trial). Annals of Oncology 2016; 27:
• 89 Liu P, Cheng H, Roberts TM. et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8: 627-644
• 90 Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489-501
• 91 Carnero A, Blanco-Aparicio C, Renner O. et al. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets 2008; 8: 187-198
• 92 Liao YM, Kim C, Yen Y. Mammalian target of rapamycin and head and neck squamous cell carcinoma. Head Neck Oncol 2011; 3: 22
• 93 Qiu W, Schonleben F, Li X. et al. PIK3CA mutations in head and neck squamous cell carcinoma. Clin Cancer Res 2006; 12: 1441-1446
• 94 Yaguchi S, Fukui Y, Koshimizu I. et al. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 2006; 98: 545-556
• 95 Howes AL, Chiang GG, Lang ES. et al. The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther 2007; 6: 2505-2514
• 96 Garlich JR, De P, Dey N. et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 2008; 68: 206-215
• 97 Soulieres D, Faivre S, Mesia R, Remenar E, Li S-H, Karpenko A, Dechaphunkul A, Keilholz U, Kiss LA, Lin J-C, Nagarkar RV, Tamas L, Kim S-B, Erfán J, Turri S, Dey D, Chakravartty A, Aimone P, Massacesi C, Licitra LF. BERIL-1: A phase II, placebo-controlled study of buparlisib (BKM120) plus paclitaxel in patients with platinum-pretreated recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). J Clin Oncol 2016; 34 (suppl; abstr 6008)
• 98 Patel V, Lahusen T, Sy T. et al. Perifosine, a novel alkylphospholipid, induces p21(WAF1) expression in squamous carcinoma cells through a p53-independent pathway, leading to loss in cyclin-dependent kinase activity and cell cycle arrest. Cancer Res 2002; 62: 1401-1409
• 99 Hideshima T, Catley L, Yasui H. et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006; 107: 4053-4062
• 100 Argiris A, Cohen E, Karrison T. et al. A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer. Cancer Biol Ther 2006; 5: 766-770
• 101 Clark C, Shah S, Herman-Ferdinandez L. et al. Teasing out the best molecular marker in the AKT/mTOR pathway in head and neck squamous cell cancer patients. Laryngoscope 2010; 120: 1159-1165
• 102 Amornphimoltham P, Patel V, Sodhi A. et al. Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res 2005; 65: 9953-9961
• 103 Massarelli E, Lin H, Ginsberg LE. et al. Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol 2015; 26: 1476-1480
• 104 Bauman JE, Arias-Pulido H, Lee SJ. et al. A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma. Oral Oncol 2013; 49: 461-467
• 105 Saba NF, Hurwitz SJ, Magliocca K. et al. Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck. Cancer 2014; 120: 3940-3951
• 106 Fury MG, Sherman E, Ho A. et al. A phase I study of temsirolimus plus carboplatin plus paclitaxel for patients with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Cancer Chemother Pharmacol 2012; 70: 121-128
• 107 Fury MG, Xiao H, Baxi SS, Sherman EJ, Smith-Marrone S, Ho AL, Sima CS, Nwankwo OG, Haque S, Katabi N, Pfister DG. A phase II trial of temsirolimus plus low-dose weekly carboplatin and paclitaxel for recurrent/metastatic HNSCC. J Clin Oncol 2014; 32: 5s (suppl; abstr 6019^) 2014
• 108 Grunwald V, Keilholz U, Boehm A. et al. TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) of the German SCCHN Group (AIO). Ann Oncol 2015; 26: 561-567
• 109 Riedel F, Gotte K, Hormann K. et al. Antiangiogenic therapy of head and neck squamous cell carcinoma by vascular endothelial growth factor antisense therapy. Adv Otorhinolaryngol 2005; 62: 103-120
• 110 Shang ZJ, Li ZB, Li JR. VEGF is up-regulated by hypoxic stimulation and related to tumour angiogenesis and severity of disease in oral squamous cell carcinoma: in vitro and in vivo studies. Int J Oral Maxillofac Surg 2006; 35: 533-538
• 111 Liang X, Yang D, Hu J. et al. Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis/angiogenesis in oral squamous cell carcinoma. Anticancer Res 2008; 28: 1659-1666
• 112 Metzger CS, Kammerer PW, Schmidtmann I. et al. Vascular endothelial growth factor polymorphisms as effect modifiers of oral squamous cell carcinoma risk: A systematic review and meta-analysis. Mol Clin Oncol 2015; 3: 347-352
• 113 Zang J, Li C, Zhao LN. et al. Prognostic value of vascular endothelial growth factor in patients with head and neck cancer: A meta-analysis. Head Neck 2013; 35: 1507-1514
• 114 Mineta H, Miura K, Ogino T. et al. Prognostic value of vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinomas. Br J Cancer 2000; 83: 775-781
• 115 Lothaire P, de Azambuja E, Dequanter D. et al. Molecular markers of head and neck squamous cell carcinoma: promising signs in need of prospective evaluation. Head Neck 2006; 28: 256-269
• 116 Shih T, Lindley C. Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 2006; 28: 1779-1802
• 117 Matta A, Ralhan R. Overview of current and future biologically based targeted therapies in head and neck squamous cell carcinoma. Head Neck Oncol 2009; 1: 6
• 118 Oc P, Rhys-Evans P, Modjtahedi H. et al. Vascular endothelial growth factor family members are differentially regulated by c-erbB signaling in head and neck squamous carcinoma cells. Clin Exp Metastasis 2000; 18: 155-161
• 119 Cohen EE, Davis DW, Karrison TG. et al. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol 2009; 10: 247-257
• 120 Argiris A, Karamouzis MV, Gooding WE. et al. Phase II trial of pemetrexed and bevacizumab in patients with recurrent or metastatic head and neck cancer. J Clin Oncol 2011; 29: 1140-1145
• 121 Yao M, Galanopoulos N, Lavertu P. et al. Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell carcinoma of the head and neck. Head Neck 2015; 37: 1665-1671
• 122 Nyflot MJ, Kruser TJ, Traynor AM. et al. Phase 1 trial of bevacizumab with concurrent chemoradiation therapy for squamous cell carcinoma of the head and neck with exploratory functional imaging of tumor hypoxia, proliferation, and perfusion. Int J Radiat Oncol Biol Phys 2015; 91: 942-951
• 123 Argiris A, Bauman JE, Ohr J. et al. Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer. Ann Oncol 2016; 27: 1594-1600
• 124 Choong NW, Haraf DJ, Cohen EE. et al. Randomized phase II study of concomitant chemoradiotherapy with 5-fluorouracil-hydroxyurea (FHX) compared to FHX and bevazicumab (BFHX) in intermediate stage head and neck cancer (HNC). Journal of Clinical Oncology 2007; 25: 6034-6034
• 125 Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 2013; 31: 2205-2218
• 126 Whirl-Carrillo M, McDonagh EM, Hebert JM. et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 2012; 92: 414-417
• 127 Elser C, Siu LL, Winquist E. et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol 2007; 25: 3766-3773
• 128 Siu LL, Winquist E, Agulnik M, Chin SF, Pond GR, Cheiken R, Francis P, Petrenciuc O, Chen E. A phase II study of BAY 43-9006 in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) and nasopharyngeal cancer (NPC). J Clin Oncol 2005; 23: 5566
• 129 Williamson SK, Moon J, Huang CH. et al. A phase II trial of BAY 43–9006 in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC): A Southwest Oncology Group (SWOG) trial. Journal of Clinical Oncology 2006; 24: 5550-5550
• 130 Machiels JP, Henry S, Zanetta S. et al. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol 2010; 28: 21-28
• 131 Choong NW, Kozloff M, Taber D. et al. Phase II study of sunitinib malate in head and neck squamous cell carcinoma. Invest New Drugs 2010; 28: 677-683
• 132 Ferris RL. Immunology and Immunotherapy of Head and Neck Cancer. J Clin Oncol 2015; 33: 3293-3304
• 133 Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27: 450-461
• 134 Li J, Jie HB, Lei Y. et al. PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res 2015; 75: 508-518
• 135 Concha-Benavente F, Srivastava RM, Trivedi S. et al. Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNgamma That Induce PD-L1 Expression in Head and Neck Cancer. Cancer Res 2016; 76: 1031-1043
• 136 Badoual C, Hans S, Merillon N. et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res 2013; 73: 128-138
• 137 Seiwert TY, Burtness B, Mehra R. et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016; 17: 956-965
• 138 Chow LQ, Haddad R, Gupta S. et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 2016;
• 139 Bauml J, TYS Pfister DG, Worden FP, Liu SV, Gilbert J, Saba NF, Weiss J, Wirth LJ, Sukari A, Kang H, Gibson MK, Massarelli E, Powell SF, Meister A, Shu X, Cheng JD, Haddad RI. Preliminary results from KEYNOTE-055: Pembrolizumab after platinum and cetuximab failure in head and neck squamous cell carcinoma (HNSCC). J Clin Oncol 2016; 34: (suppl; abstr 6011) 2016
• 140 Ferris RL, Blumenschein Jr. G, Fayette J. et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 2016;
• 141 Seiwert TY, JW Baxi SS, Ahn M-J, Fayette J, Gillison ML, Machiels J-PH, Takahashi S, Melillo G, Franks A, Emeribe U, Raben D, McDevitt M, Psyrri A. A phase 3, randomized, open-label study of first-line durvalumab (MEDI4736) ± tremelimumab versus standard of care (SoC; EXTREME regimen) in recurrent/metastatic (R/M) SCCHN: KESTREL. J Clin Oncol 2016; 34: (suppl; abstr TPS6101) 2016
• 142 Haddad AAMGRLFKHTKSCBWJGJSR. A randomized, open-label, phase 3 study of nivolumab in combination with ipilimumab vs extreme regimen (cetuximab + cisplatin/carboplatin + fluorouracil) as first-line therapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck-CheckMate 651. Ann Oncol 2016; 27 (suppl_6): 1016TiP 2016
• 143 Schwab KS, Heine A, Weimann T. et al. Development of Hemolytic Anemia in a Nivolumab-Treated Patient with Refractory Metastatic Squamous Cell Skin Cancer and Chronic Lymphatic Leukemia. Case Rep Oncol 2016; 9: 373-378
• 144 Kimura T, Fukushima S, Miyashita A. et al. Myasthenic crisis and polymyositis induced by one dose of nivolumab. Cancer Sci 2016; 107: 1055-1058
• 145 Johnson DB, Balko JM, Compton ML. et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016; 375: 1749-1755
• 146 Owonikoko TK, Kumar M, Yang S. et al. Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report. Cancer Immunol Immunother 2016;
• 147 Busch C-J, Laban S, Knecht R. et al. Immunotherapeutic studies of head and neck tumors. HNO 2016; 64: 708-716
• 148 Desai N, Trieu V, Damascelli B. et al. SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients. Transl Oncol 2009; 2: 59-64
• 149 Aquino G, Sabatino R, Cantile M. et al. Expression analysis of SPARC/osteonectin in oral squamous cell carcinoma patients: from saliva to surgical specimen. Biomed Res Int 2013; 2013: 736438
• 150 Adkins D, Ley J, Trinkaus K. et al. A phase 2 trial of induction nab-paclitaxel and cetuximab given with cisplatin and 5-fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck. Cancer 2013; 119: 766-773
• 151 Huang Y, Liang W, Yang Y. et al. Phase I/II dose-finding study of nanoparticle albumin-bound paclitaxel (nab(R)-Paclitaxel) plus Cisplatin as Treatment for Metastatic Nasopharyngeal Carcinoma. BMC Cancer 2016; 16: 464
• 152 Fury MG, Sherman EJ, Rao SS. et al. Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III-IVB head and neck squamous cell carcinoma (HNSCC). Ann Oncol 2014; 25: 689-694
• 153 Chun SG, Hughes R, Sumer BD. et al. A Phase I/II Study of Nab-Paclitaxel, Cisplatin, and Cetuximab With Concurrent Radiation Therapy for Locally Advanced Squamous Cell Cancer of the Head and Neck. Cancer Invest 2016; doi:10.1080/07357907.2016.1213275: 1-9