BALKAN MCO 2011 - J. Vermorken - Head and neck cancer - essential messages

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  • M225, a murine monoclonal antibody, competitively binds to the EGFR and inhibits EGFR pathways. Clinical trials using murine monoclonal antibodies have been complicated by the development of the human antimouse antibody (HAMA) immune response. The HAMA response not only carries the risk of serious allergic reactions but also increases the clearance of the murine proteins. Thus, the clinical utility of murine monoclonal antibodies has been limited. Cetuximab is a human:murine chimeric anti-EGFR IgG monoclonal antibody that binds exclusively to the EGFR. Chimeric antibodies are composed of the variable regions of murine antibody (the regions responsible for antigen binding) and the constant region of the human Fc fragment.[1] Chimeric monoclonal antibodies have demonstrated specificity and a diminished incidence of immunologic reactions.[2,3] Cetuximab binds to the EGFR with a binding affinity that is approximately one log higher than natural ligands.[4] Cetuximab prevents binding of endogenous ligands and induces receptor internalization, which ultimately blocks the activities of the EGFR pathway. Owens RJ, Young RJ. The genetic engineering of monoclonal antibodies. J Immunol Methods 1994; 168:149–165. Shitara K, Kuwana Y, Nakamura K, et al. A mouse/human chimeric anti-(ganglioside GD3) antibody with enhanced tumor activities. Cancer Immunol Immunother . 1993; 36:373–380. LoBuglio AF, Wheeler RH, Trang J, et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A . 1989; 86:4220–4224. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res . 1995; 1:1311–1318.
  • Clavel M, et al. Ann Oncol 1994;5:521–526; Forastiere A, et al. J Clin Oncol 1992;10:1245–1251; Gibson MK, et al. J Clin Oncol 2005;23:3562–3567;Grose WE, et al. Cancer Treat Rep 1985;69:577–581; Vermorken JB, et al. N Engl J Med 2008;359:1116–1127; Wittes RE, et al. Cancer Treat Rep 1977;61359–61366.
  • Petrelli NJ et al. J Clin Oncol 2009;27:6052–6069; Gr é goire et al Annals of Oncology 21 (Supplement 5): v184–v186, 2010
  • BALKAN MCO 2011 - J. Vermorken - Head and neck cancer - essential messages

    1. 1. Head and Neck Cancer – Essential Messages Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium Balkan Masterclass in Clinical Oncology, Dubrovnik, Croatia 2011, 11-15 May
    2. 2. <ul><li>5-6% of all cancers (about 650.000 new cases/year) </li></ul><ul><li>> 90% squamous cell origin (Western world) </li></ul><ul><li>Risk factors: </li></ul><ul><ul><li>tobacco smoking </li></ul></ul><ul><ul><li>alcohol use </li></ul></ul><ul><ul><li>betel chewing </li></ul></ul><ul><ul><li>HPV </li></ul></ul><ul><li>Localized disease 40%, regional mets 50% distant mets 10% </li></ul><ul><li>2/3 locally/regionally advanced </li></ul><ul><li>Major threat: local recurrence, SPT, SFT </li></ul>Head and Neck Cancer Epidemiology, risk factors and presentation
    3. 3. Treatment Modalities in SCCHN 2011 <ul><li>Surgery as single modality </li></ul><ul><li>Radiotherapy (RT) or in combination </li></ul><ul><li>Chemotherapy (CT) </li></ul><ul><ul><li>combined modality treatment (CMT): </li></ul></ul><ul><ul><li>Induction CT (ICT); concomitant CT and RT (CCRT); sequential therapy (ICT  CCRT); adjuvant CCRT postoperative </li></ul></ul><ul><ul><li>Palliative therapy </li></ul></ul><ul><li>Targeted therapy (TT) </li></ul><ul><ul><li>Alone or combined with RT, CMT or palliative CT </li></ul></ul>
    4. 4. Results of Present Therapies <ul><li>Early stages (I and II)  single modality TRT </li></ul><ul><li> 5-yr S: 60-90% </li></ul><ul><li>Advanced stages (III and IV)  combined modality </li></ul><ul><li> 5-yr S: < 35% </li></ul><ul><ul><li>Resectable: > 60% LRR, 20% DM, 10-40% SPT </li></ul></ul><ul><ul><li>Unresectable: 5-yr S < 20%, majority † < 18 months </li></ul></ul><ul><li>Recurrent/metastatic disease  chemotherapy </li></ul><ul><li>Median survival 6-12 months, 1-year survival 20-40% </li></ul>
    5. 5. Evolving Systemic Therapies Alone or with Radiation Head and Neck squamous cell cancer 1960s Methotrexate (IC, CRT) 1970s Bleomycin, 5-fluorouracil, cisplatin Combination chemotherapy regimens 1980s Carboplatin Organ preservation trials start 1990s Paclitaxel, docetaxel CRT>RT 2000s Targeted therapies (MoAb) Evolving role for ICT Sequential therapy (ICT  CRT)?
    6. 6. New Findings in Recent Years <ul><li>HPV is a risk factor for cancer of the oropharynx </li></ul><ul><li>Therapeutic agents against molecular targets (EGFR) </li></ul><ul><li>Expanded role of chemotherapy (IC, CCRT) </li></ul><ul><li>Improved irradiation techniques (IMRT) </li></ul><ul><li>New imaging techniques (PET) </li></ul><ul><li>Survivorship issues </li></ul><ul><li>Haddad RI, Shin DM N Engl J Med 2008; 359: 1143-54 </li></ul>
    7. 7. <ul><li>Incidence increasing for HPV-related </li></ul><ul><li>Incidence decreasing for HPV-unrelated </li></ul><ul><li>Equalization in 2004 </li></ul>Incidence Trends in the US Chaturvedi et al, J Clin Oncol 2008; 26: 612-619
    8. 8. Actuarial Life-table Estimates of Survival Chaturvedi et al, J Clin Oncol 2008; 26: 612-619 *Tumor extended directly into surrounding organs or tissues, into regional lymphnodes, or by both and treated by RT Period Two-year survival HPV-R vs. HPV-U* P-value 1973-1982 46.6 vs. 47.2% 0.71 1983-1992 56.0 vs. 49.6% <0.01 1993-2004 69.7 vs. 50.3% <0.01
    9. 9. EGFR Expression in Human Tumors <ul><li>NSCLC 40-80% </li></ul><ul><li>Prostate 40-80% </li></ul><ul><li>Head & Neck 90-100% </li></ul><ul><li>Gastric 33-74% </li></ul><ul><li>Breast 14-91% </li></ul><ul><li>Colorectal 75-89% </li></ul><ul><li>Pancreatic 30-95% </li></ul><ul><li>Ovarian 35-77% </li></ul><ul><li>Bladder 31-72% </li></ul><ul><li>Glioma 40-63% </li></ul><ul><li>Invasion </li></ul><ul><li>Metastasis </li></ul><ul><li>Late-stage disease </li></ul><ul><li>Chemotherapy resistance </li></ul><ul><li>Poor outcome </li></ul>EGFR expression High expression generally associated with
    10. 10. EGFR-targeting Agents under Clinical Investigation in SCCHN Monoclonal antibodies Toxicity Cetuximab IMC225 chimeric human/murine IgG1 skin Matuzumab EMD72000 humanized mouse IgG1 skin Nimotuzumab h-R3 humanized mouse IgG1 systemic/hemodynamic Zalutumumab 2F8 human IgG1 skin Panitumumab ABX-EGF human IgG2 skin Tyrosine kinase inhibitors Gefitinib ZD1839 reversible EGFR skin/gastrointesinal (GI) Erlotinib OSI-774 reversible EGFR skin/GI Lapatinib GW-572016 reversible EGFR/erbB2 skin/GI/systemic Afatinib BIBW-2992 irreversible EGFR/erbB2 skin/GI/systemic Canertinib CI-0033 irreversible EGFR skin/oral/GI/systemic
    11. 11. Cetuximab: Properties and Mechanism of Action <ul><li>IgG 1 monoclonal antibody </li></ul><ul><li>Specifically binds to the EGFR with higher affinity than its natural ligands (TGFα, EGF), thus competitively inhibiting their binding </li></ul><ul><li>H igh affinity: K d = 0.39 nM </li></ul><ul><li>Induces apoptosis and ADCC1 </li></ul><ul><li>Preclinical synergistic activity in combination with chemotherapy and radiotherapy </li></ul>ADCC = antibody-dependent cellular cytotoxicity
    12. 12. HN Surgeon Radiation Oncologist Medical Oncologist Anesthesiologist Internist GP Radiologist Social worker Psychologist Patient Guidelines Clinical trials Biologist Pathologist Dietician Speech Therapist
    13. 13. Multimodality Treatment Approaches (MMTAs) in Locoregionally Advanced SCCHN <ul><li>Historically: Surgery ( + RT) or RT alone </li></ul><ul><li>Outcomes poor for OS and OP </li></ul><ul><li>Currently there are three multimodality treatment approaches: </li></ul><ul><li>Surgery  adjuvant concurrent CRT </li></ul><ul><li>Definitive concurrent CRT, with surgery as an optional salvage or completion treatment </li></ul><ul><li>Induction CT  definitive local therapy </li></ul><ul><li>Seiwert et al, Nat Clin Pract Oncol 2007; 4 (3): 156-171; OS = overall survival; OP = organ preservation </li></ul>
    14. 14. 63 randomized trials MACH-NC = Individual patients data base 7,307 deaths (68 %) 10,741 patients Lancet 2000;355:949-55 IGR 10.00 Meta-Analysis of Chemotherapy in Head & Neck Cancer MACH-NC
    15. 15. MACH-NC: Results - Overall Survival Chemotherapy Risk P Absolute benefit timing reduction value at 5 years Adjuvant 2% NS 1% Neoadjuvant* 5% NS 2% Concomitant 19% < 0.0001 8% Total 10% < 0.0001 4% * 15 studies with PF 5% Pignon et al, 2000 (63 trials / 10.741 patients)
    16. 16. MACH-NC Analysis: Survival Benefit of Concomitant Chemotherapy to Local Treatment a 50 concomitant trials; CRT, chemoradiation; CT, chemotherapy; RT, radiotherapy Pignon JP et al. Radiother Oncol 2009;92:4–14 Absolute survival benefit at 5 years: 6.5% (CRT) p=0.41 CRT regimen a Hazard ratio Postoperative RT 0.79 Conventional RT 0.83 Altered fractionated RT 0.73 Mono - CT 0.84 MonoPlatin 0.74 Poly - CT 0.78 5-FU + platinum 0.75 5-FU/platinum 0.83 Other CT 0.73 Pooled 0.81 (p<0.0001)
    17. 17. Acute adverse effects: Grade ≥ 3 p<0.05 ns Patients (%) p<0.01 Wendt TG, et al. J Clin Oncol 1998;16:1318–1324 0 10 20 30 40 50 60 Xerostomia Nausea/emesis Leukopenia Dermatitis Mucositis RT alone (n=140) CRT (n=130) ns, not significant CRT = CDDP + 5-FU + RT Late Toxicity Analysis of 230 patients receiving CRT in 3 studies (RTOG 91-11, 97-03, 99-14) 10% 12% 27% 13% 43% 0 10 20 30 40 50 Patients (%) Any severe late toxicity Feeding-tube dependence >2 yrs post-RT Pharyngeal dysfunction Laryngeal dysfunction Death Machtay M, et al. J Clin Oncol 2008; 26: 3582–3589
    18. 18. Enhancement of Radiation Effects Selective Targeting of Hypoxic Cells Induction of Pro-Apoptotic Mechanisms Anti- Angiogenesis Strategies Inhibition of Cox-2 Replacement of Mutated Tumor Suppressor Genes Inhibition of EGFR Several biological mechanisms that have potential to alter sensitization strategies (Choy and MacRae, 2003)
    19. 19. Bonner et al. N Engl J Med 2006; 354: 567-578
    20. 20. The Cetuximab/Radiotherapy Phase III Trial <ul><li>Radiotherapy BioRadiotherapy P-value </li></ul><ul><li> (n=213) (n=211) </li></ul><ul><li>Toxicity * </li></ul><ul><li>Mucositis 52% 56% </li></ul><ul><li>Acneiform rash 1% 17% < .001 </li></ul><ul><li>Radiation dermatitis 18% 23% </li></ul><ul><li>Infusion reactions NA 3% </li></ul><ul><li>(Late Peg dependency 17% 19% ) </li></ul><ul><li>Efficacy </li></ul><ul><li>3-Yr Survival 45% 55% .03 </li></ul><ul><li>2-yr PFS 37% 46% .006 </li></ul><ul><li>2-Yr LRC 41% 50% .005 </li></ul><ul><li>2- Yr DM 17% 16% </li></ul>Bonner et al. N Engl J Med 2006; 354: 567-578; (*Grade 3-5)
    21. 21. 5-Years Survival Update and QoL Assessment 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 60 70 Time (months) Probability of overall survival Bonner JA, et al. Presented at ASTRO 2008 ERBITUX + RT RT ERBITUX + RT RT 5-year survival rate 46% 36% p=0.018, HR=0.73 (0.56-0.95) 29.3 49.0 ERBITUX + RT does not adversely affect QoL, while significantly improving overall survival Curran D, et al. J Clin Oncol 2007; 25: 2191 –2197 a Post-baseline scores for the EORTC QLQ-C30 Global health status/QoL score a 100 80 60 40 20 0 RT RT + ERBITUX Baseline Week 4 Month 4 Month 8 Month 12
    22. 22. Compliance with Cetuximab or Chemotherapy when Administered with RT 1 Bonner JA, et al. N Engl J Med 2006; 354: 567 –578; 2 Huguenin P, et al. J Clin Oncol 2004; 22: 4665–4673; 3 Calais G, et al. J Natl Cancer Inst 1999; 91: 2081 – 2086; 4 Wendt TG, et al. J Clin Oncol 1998; 16: 1318 –1324 CRT arms of studies comparing CRT vs RT alone Cisplatin / 5-FU / FA 4 46% 51% 71% 90% 0 20 40 60 80 100 Carboplatin / 5-FU 3 Cisplatin 2 Cetuximab 1 Patients receiving all planned doses (%) 10 70 50 30 90 Weekly doses (median 8 doses) 2 cycles at weeks 1 and 5 3 cycles at weeks 1, 4, and 7 3 cycles at weeks 1, 3, and 6 2nd cycle 3rd cycle 3rd cycle
    23. 23. Overall Conclusion No direct comparison *level I evidence; **level II evidence; + with mono Platin therapy Chemoradiation Bioradiation ( cetuximab ) 50 trials, 9615 pts (MA)* 1 trial, 424 pts (Bonner trial)** HR of death 0.74 (0.67-0.82) + HR of death 0.74 (0.57-0.97) Main effect on local failure Modest effect on DM Only effect on local failure No effect on DM Efficacy irrespective of site and of fractionation schedule Effect may be site and RT schedule specific Significant acute toxicity which may inflict on late toxicity, in particular swallowing dysfunction Skin reaction?? Late toxicity as RT Compliance of receiving cetuximab 90% in the Bonner trial
    24. 24. Multimodality Treatment Approaches (MMTAs) in Locoregionally Advanced SCCHN <ul><li>Historically: Surgery ( + RT) or RT alone </li></ul><ul><li>Outcomes poor for OS and OP </li></ul><ul><li>Currently there are three multimodality treatment approaches: </li></ul><ul><li>Surgery  adjuvant concurrent CRT </li></ul><ul><li>Definitive concurrent CRT, with surgery as an optional salvage or completion treatment </li></ul><ul><li>Induction CT  definitive local therapy </li></ul><ul><li>Seiwert et al, Nat Clin Pract Oncol 2007; 4 (3): 156-171; OS = overall survival; OP = organ preservation </li></ul>
    25. 25. 1 st. TL 1 st. PLs 1 st. RT SCPL Laser CO² ASCO 1982 trial VA trial EORTC trial RTOG trial EORTC 1873 1903 1878 1970s 1994 1996 2003 2005 2007 CTscan MRI surgery radiotherapy laser Milestones in Larynx/Hypopharynx Management trial GORTEC
    26. 26. 1st Generation Larynx Preservation Trials Study Tumor Size Treatment No. of Survival LP Group and stage arms pts (at 2 or 5 yrs) VA 1 Larynx TL + RND + RT 332 60% (2) T1-T4, N2-3 CT  RT* 68% (2) 64% EORTC 2 Hypopharynx TL + RND + RT 202 35% (5) T2-T4, N0-2b CT  RT* 30% (5) 57% * non-responders  S + RT 1 VALCSG, N Engl J Med 1991; 324: 1865-1690 2 Lefebvre et al, J Natl Cancer Inst 1996; 88: 890-899
    27. 27. 2nd Generation Larynx Preservation Trials Patients PF x 3  RT (n=173) Stage III or IV Glottic/supraglottic CCRT (n=172) SCC (excl. T1 and Large volume T4) RT (n=173) PF = P 100 mg/m² (d1) and F 1000 mg/m d x 5 P during CRT = 100 mg/m² d1, 22, 43 RT = 70 Gy, given in 35 fractions of 2 Gy over 7 weeks Forastiere et al, N Engl J Med 2003; 349: 2091-2098 (RTOG # 91-11) R A N D O M I Z E
    28. 28. RTOG 91-11 Phase III Trial of Larynx Preservation Forastiere. ASCO. 2006 LFS=laryngectomy-free survival LFS Overall Survival
    29. 29. Randomized Trials of ICT in LA-HNC Revisited Trial Arms Outcome CA 139-322 (2005) PF vs PPF CCR (TTP , OS*) Resectable/nonresectable CCRT (CDP) Improved with PPF EORTC 24971/TAX 323 PF vs TPF PFS (RR, OS)° Nonresectable (2007) RT Improved with TPF TAX 324 (2007) PF vs TPF OS (PFS , RR)° Resectable/nonresectable CCRT (Cb) Improved with TPF GORTEC 2000-01 PF vs TPF LP (OS, DFS) + Resectable (2009) T(P)L vs RT Improved with TPF *significant only in unresectable disease (JCO); °NEJM; + JNCI
    30. 30. SCCHN: Docetaxel in Locally-Advanced Disease Overall Survival TAX 324 30% reduction in risk of death TAX 323 27% reduction in risk of death TPF PF 50 Survival Time (months) Survival Probability (%) Survival Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 0 10 20 30 40 60 70 80 90 100 TPF PF Survival Time (months) Survival Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 Posner et al, NEJM 2007 Resectable/unresectable disease Vermorken et al, NEJM 2007 Unresectable disease
    31. 31. GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF induction therapy for hypopharynx and larynx cancer At 3 years: LP 70.3% with TPF, 57.5% with PF (p=0.03) Pointreau Y, et al. J Natl Cancer Inst 2009; 101: 498-506
    32. 32. Eligibility criteria : Trials properly randomized Performed before 2007 R RT + induction 5-FU/cisplatin (PF) RT + induction taxane/5-FU/cisplatin Materials and Methods Blanchard et al, Radioth Oncol 2011; 98 (suppl 1), S6 (abstract)
    33. 35. Randomized Trials of Sequential Therapy versus Concurrent Chemoradiation Only Group Regimen TPF (or PF) x 3  CRT (cisplatin) TTCC (Sp) CRT (cisplatin) TPF x 3  CRT (carboplatin) Boston (US) CRT (cisplatin) TPF x 2  THFX Chicago (US) THFX XRT (cetuximab) TPF x 3 XRT (PF) GCTCC (It) XRT (cetuximab) XRT (PF)
    34. 36. Prognostic Significance of HPV RTOG 0129, PI: K. Ang Stage III & IV SCC of : • Oral cavity • Oropharynx • Larynx • Hypopharynx Stratify : • Lx vs Non-Lx • No vs N+ • KPS 60-80 VS 90-100 R A N D O M I Z E Accrued 743 patients (by 6/’05) Collected 596 tumor specimens Excluded T1-2N1 Oropharyngeal Cancer Enrolled: 433 - Specimens: 317 Ang K et al. N Engl J Med 2010;361:24-35 2. AFX-CB: 72 Gy/42 F/6 W + CDDP: 100 mg/m 2 (d 1, 22) 1. SFX: 70 Gy/35 F/7 W + CDDP: 100 mg/m 2 (d 1, 22, 43)
    35. 37. Prognostic Significance of HPV Overall Survival Ang K et al. N Engl J Med 2010;361:24-35
    36. 38. The 3-year rates of overall survival were 93.0% (95% CI, 88.3 to 97.7) in the low-risk group, 70.8% (95% CI, 60.7 to 80.8) in the intermediate-risk group, and 46.2% (95% CI, 34.7 to 57.7) in the high-risk group. Ang K et al. N Engl J Med 2010;361:24-35
    37. 39. Recurrent and/or metastatic SCCHN: Background <ul><li>Over 50% of newly diagnosed cases are not cured and will relapse locally or at distant sites </li></ul><ul><li>10% of newly diagnosed cases present with distant metastases </li></ul><ul><li>Treatment options: - Chemotherapy (CT) - Re-irradiation - Salvage surgery - Best supportive care (BSC) </li></ul><ul><li>Cisplatin-based CT: - Response rate: 30% - Overall survival: 6 – 9 months </li></ul>
    38. 40. Development of Chemotherapy in R/M SCCHN 1977: cisplatin shows efficacy in 1 st -line SCCHN CABO, cisplatin, methotrexate, bleomycin, vincristine *significant Clavel et al. Ann Oncol 1994; Forastiere et al. JCO 1992; Gibson et al. JCO 2005; Grose et al. Cancer Treat Rep 1985; Vermorken et al. NEJM 2008; Wittes et al. Cancer Treat Rep 1977 N Regimen ORR (%) Median OS (months) Significant OS benefit Grose et al 1985 100 Methotrexate Cisplatin 16 8 5.0 4.5 No Forastiere et al 1992 277 Cisplatin + 5-FU Carboplatin + 5-FU Methotrexate 32* 21 10 6.6 5.0 5.6 No Clavel et al 1994 382 CABO Cisplatin + 5-FU Cisplatin 34* 31* 15 7.3 7.3 7.3 No Gibson et al 2005 218 Cisplatin + 5-FU Cisplatin + paclitaxel 27 26 8.7 8.1 No Vermorken et al 2008 442 Platinum + 5-FU Platinum + 5-FU + Cetuximab 20 36* 7.4 10.1* Yes
    39. 41. Cetuximab in 1 st -line SCCHN A Major Clinical Advance <ul><li>ASCO Clinical Cancer Advances 2009 </li></ul>Petrelli et al. JCO 2009; Gr é goire et al. Ann Oncol 2010 “ ... the results of this trial [EXTREME] are particularly noteworthy and are changing clinical practice.” EHNS-ESMO-ESTRO Clinical Practice Guidelines 2010 “ First-line options for fit patients should include the combination of cetuximab with cisplatin or carboplatin plus 5-FU”
    40. 42. Completed Randomized Trials in First-Line Recurrent/Metastatic SCCHN Study/Reference N Regimen RR (%) PFS (mo) OS (mo) ECOG 5397/ Burtness et al 2005 117 Cisplatin + cetuximab Cisplatin + placebo 26 a 10 4.2 2.7 9.2 8.0 EXTREME/ Vermorken et al 2008 442 PF 1 + cetuximab PF 1 36 a 20 5.6 b 3.3 10.1 c 7.4 SPECTRUM/ Vermorken et al 2010 657 PF 2 + panitumumab PF 2 36 a 25 5.8 b 4.6 11.1 9.0 PF 1 = cisplatin or carboplatin plus 5-FU; PF 2 = cisplatin plus 5-FU a, b, c : significant differences
    41. 43. Completed Randomized Trials in 2nd-Line Recurrent/Metastatic SCCHN Study/Reference N Regimen RR (%) PFS OS (mo) IMEX Stewart et al, 2009 486 Gefitinib (250 mg) Gefitinib (500 mg) Methotrexate 2.7 7.6 3.9 ND ND ND 5.6 6.0 6.7 ECOG 1302 Argiris et al, 2009 270 D + Gefitinib D + placebo 12 6 3.3 2.2 6.8 6.2 Zalute Machiels et al, 2010 286 Z + BSC (-MTX) BSC (optional MTX) 6 1 2.3* 1.9* 6.7° 5.2° BSC = best supportive care; Z = zalutumumab; MTX = methotrexate; ND = no data *HR (95% CI): 0.62 (0.47-0.83), p=0,0010; °HR (95% CI): 0.77 (0.57-1.05), p=0.0648
    42. 44. Other Novel Targeted Agents in SCCHN <ul><li>Anti-angiogenesis </li></ul><ul><ul><li>VEGF </li></ul></ul><ul><ul><li>VEGFR </li></ul></ul><ul><li>Integrin inhibitors </li></ul><ul><li>Histone deacetylase inhibitors </li></ul><ul><li>SRC inhibitors </li></ul><ul><li>Proteasome inhibitors </li></ul><ul><li>IGFR inhibitors </li></ul><ul><li>No phase III data! </li></ul>
    43. 45. Conclusions (1) <ul><li>Concurrent chemoradiation (CRT) has a very solid background and is still used for many advanced H&N tumors </li></ul><ul><li>CDDP 100 mg/m² 3x during RT most optimal CRT?? </li></ul><ul><li>Is bioradiation similar to CRT? </li></ul><ul><li>TPF is a more active and less toxic new standard for induction and its sequential use with CRT and BRT are presently tested </li></ul><ul><li>There is a tendency to a more personalized treatment, with selection based on risk considerations, HPV status and biomarkers </li></ul>
    44. 46. Conclusions (2) <ul><li>In R/M SCCHN the PFE regimen is a new standard. Regimens with higher efficacy (and less toxicity) are urgently needed. </li></ul><ul><li>A plethora of new targeted therapies are in various stages of preclinical and clinical development: how to integrate the active ones is an important goal. </li></ul>

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