Aktuelles aus der Onkologie

Transkript

1 Aktuelles aus der Onkologie Gabriela Kornek Univ.Klinik f. Innere Medizin AKH MedUni Wien Karzinome des oberen Aerodigestivtraktes, 19./

2 Conflicts of Interest Honorare für Vorträge und AdBoards Amgen, Bayer, Celgene, Cephalon, Lilly, Merck, Pfizer, Roche, Sanofi-Aventis seit November 2014: keine

3 Therapie - Entscheidung QoL Überleben Lebensqualität Organ Funktion Organerhalt

4 Indikationen für medikamentöse Therapie Resektable Tumoren: Organerhalt Lokal-fortgeschrittenen Tumoren: Heilungsraten Rezidivtumoren und Metastasen: Palliation

5 Therapieoptionen bei resektablen Tumoren Operation Induktionschemotherapie gefolgt von Radiotherapie Radiochemotherapie

6 Laserresektion

7 Laterale Pharyngektomie Univ. Prof. Dr. Martin Burian

8 Rekonstruktion mit Radialislappen Univ. Prof. Dr. Martin Burian

9 1. Generation der Larynxerhalt -Studien: OP + Radiotherapie versus Induktions-Chemo + RT multizentrische, prospektive Studie 332 Patienten mit resektablem Larynx-, Hypopharynxkarzinom (Stadium III/IV) R Induktions-CT Cisplatin+5-FU (2 Zyklen) Induction cisplatin and 5-FU (2 cycles) Ansprechen? > 50% Tumor < 50% Tumor Cisplatin + 5-FU (1 Zyklus) gefolgt von RT OP + RT The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324:1685

10 1. Generation der Larynxerhalt -Studien: OP + Radiotherapie versus Induktions-Chemo + RT Laryngektomierate 36% OP > RT CT > RT Larynxerhalt 64% 2 Jahres ÜL-Rate 68% (p=0.9846) Ansprechrate nach 2 Zyklen 85% Percentage of patients The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324:1685

11 1. Generation der Larynxerhalt -Studien: OP + RT versus Induktions-CT + RT Cumulative incidence of first progression Lefebvre J et al. Ann Oncol 2012;annonc.mds065

12 Take home message aus der 1. Studiengeneration Organerhalt: Induktions-CT + RT ist eine Alternative zur Laryngektomie + RT Kein Überlebensvorteil (aber auch kein Nachteil) 66% Larynxerhalt nach 2 Zyklen: Ansprechen evaluieren bei > 50% Tumor : 1 weiterer Zyklus RT Bei < 50% Tumor : Laryngektomie!!! RT Induktions-CT: Cisplatin/5-FU nicht mehr adäquat RT ohne CT?

13 2. Generation der Larynxerhalt-Studien : RT versus konkomitante RCT versus Induction-CT+RT RTOG Patienten mit resektablem Larynxkarzinom (Stadium III oder IV ) Induktion-CT: Cisplatin + 5-FU (2 Zyklen) > 50% Tumor Ansprechen? Cisplatin + 5-FU (1 Zyklus) gefolgt von RT R Cisplatin + RT < 50% Tumor Laryngektomie gefolgt von RT RT Forastiere AA, et al. N Engl J Med 2003;349:

14 2. Generation der Larynxerhalt-Studien : Radiotherapie vs.konkomitante RCT vs. Induktions-CT+RT Forastiere AA, et al. N Engl J Med 2003;349:

15 2. Generation der Larynxerhalt-Studien : RT versus konkomitante RCT versus Induction-CT+RT RTOG 91 11

16 Take home message aus der 2. Studiengeneration Organerhalt: RCT war signifikant besser als RT bzw. Induktions-CT gefolgt von RT wenn Patient Laryngektomie ablehnt: RCT konventionelle RT (70Gy) Cisplatin 100mg/m 2, Tag 1, 21, 43 Nachteil: Non-Responder! Resektion nach RCT bestenfalls salvage Wann evaluiert man Response nach RCT?

17 3. Generation der Larynxerhalt -Studien: effektivere Induktions-CT (DCF versus CF) Design Vermorken et al. NEJM x TPF vs. PF Posner et al. NEJM x TPF vs. PF N, TPF PF 3J-OS, TPF PF 3J-PFS, TPF PF Letalität TPF PF RT 66-70Gy % 26% 17% 14% 2,3% 5,5% RCT (70-74Gy, Carbo wö. AUC 1,5) % 48% 54% 40% Fernmetastasen: 5% vs. 9%, p=0,14 Lokalrezidiv: 30% vs. 38%, p=0,01 - -

18 3. Generation der Larynxerhalt-Studien: effektivere Induktions-CT (DCF versus CF) PFS PFS OS OS Vermorken et al., N Engl J Med 2007 Posner et al., N Engl J Med 2007

19 Take home message aus der 3. Studiengeneration Organerhalt: DCF (Docetaxel/Cis/5-FU) war signifikant besser als Cis/5FU RT oder RCT? Posner-Studie: RCT: Carboplatin AUC x 1.5/Woche andere Studien: nur RT

20 4. Generation der Larynxerhalt-Studien : Cetuximab oder Cisplatin? RCT versus RT+Cetuximab : Tremplin Studie (Larynx / Hypopharynx) Durchführbarkeit Effizienz Cis + RT 60 Pat. 43% Therapie lt Protokoll 93% LP TPF 153 Pat. Cetuxi + RT 56 Pat. 71% Therapie lt Protokoll 96% LP LP = Larynxprävention good Responders only gleichwertig in Bezug auf Larynxerhalt geringere Toxizität von Cetuximab + RT Lefebvre: The immediate Larynx-Preservation after TPF followed by RT+Cetuximab was similar to TPF followed by RT + Cis (Lefebvre et al, ASCO 2009)

21 4. Generation der Larynxerhalt-Studien : Cetuximab oder Cisplatin? TREMPLIN Studie: Gleiche Wirksamkeit, weniger Nebenwirkungen Keine permanente Niereninsuffizienz (0% vs. 16%) Keine Verstärkung der Mukositis (4% vs. 13%) Klinische Relevanz: Weniger Therapieunterbrechungen Senkung der Dialyserate Möglichkeit für spätere platinbasierte Therapieoptionen (Lefebvre #6010 and oral presentation, ASCO 2009)

22 4. Generation der Larynxerhalt-Studien : Cetuximab oder Cisplatin? Overall survival (OS) Until 18 months: HR with 95% CI=0.98 [0.26, 3.66] logrank p=0.68 Until 36 months: HR with 95% CI=0.84 [0.34, 2.08] logrank p= Erbitux Cisplatin Months Patients at risk Erbitux (0.93) 51 (0.84) 32 (0.78) 13 (0.70) Cisplatin (0.93) 45 (0.82) 25 (0.71) 11 (0.71) Lefebvre J, et al. J Clin Oncol 2011;29:15s (5501) ASCO 2011

23 Take home message aus der 4. Studiengeneration Organerhalt: Nach Induktions-CT mit DCF Cisplatin zu toxisch! Cetuximab scheint vergleichbar effektiv Carboplatin in Posner-Studie alleinige RT

24 DeLOS II: Protocol ( ) A 1 cycle Surgery no 2 cycles TPF yes PR TPF RT R B TPF + cetuximab PR yes TPF + cetuximab RT + cetuximab no Surgery TPF T 75 mg/m² d1 P 75 mg/m² d1 F 750 mg/m² d1 5 Cetuximab 400 mg/m² d 1, then 250 mg/m² q1w TP both 75 mg/m² day 1 and F 750 mg/m²/day on days 1 5 without (arm A) or with (arm B) standard dose of cetuximab for 16 weeks. RT: concomitant boost radiotherapy (69.6 Gy) Dietz A, et al. J Clin Oncol 2014;32:5s(Abs 6016)

25 DeLOS II: Interim analysis Interim analysis for early response and toxicity of 113 pts in 2011 showed no differences in efficacy between TPF vs TP, and no more treatment related deaths Decision to continue and finalize the trial Without 5-FU With 5-FU p value Without cetuximab Treatment arm TP (26) TPF (31) Response rate 76.9% 61.3% Mean age 53.8 years 59.3 years With cetuximab Treatment arm TPE (28) TPFE (28) Response rate 75.0% 82.1% Mean age 58.2 years 57.2 years Wilcoxon-test, exact test f Fisher, 2-sided (response defined as 30% surface shrinkage in endoscopy after first cycle) Dietz A, et al. J Clin Oncol 2014;32:5s(Abs 6016)

26 DeLOS II: Predictive value of early response High predictive value of early response after one cycle and overall response after end of complete treatment within the subgroup of early responders (n=116) Early responder TPF/TP, n=54 Late responder* n (%) TPF/TP + cetuximab, n=62 Late responder n (%) Total, n=116 Late responder n (%) No Yes No Yes No Yes Yes 2 (3.7) 52 (96.3) 5 (8.1) 57 (91.9) 7 (6.0) 109 (94.0) *CR and PR at final assessment Dietz A, et al. J Clin Oncol 2014;32:5s(Abs 6016)

27 Take home message Organerhalt: Patient lehnt OP strikt ab RCT Patient akzeptiert OP OP (postoperative RT +/- CT) Patient bevorzugt konservative Therapie, lehnt OP nicht kategorisch ab Chemoselektion Induktions-CT > RT+/- Carbo- oder Cisplatin oder Cetuximab

28 Organerhalt: DCF (=Docetaxel/Cisplatin/5-FU) ist Standard! nach 2 Zyklen: Ansprechen evaluieren bei > 50% Tumor : 1 weiterer Zyklus RT oder RCT bei < 50% Tumor : Laryngektomie!!! RT oder RCT Radiotherapie oder RCT oder RIT? Posner-Studie: RCT: Carboplatin AUC x 1.5/Woche andere Studien: nur RT Tremplin-Studie: RIT mit Cetuximab

29 Chirurgie = Therapie der ersten Mundhöhlen-CA Wahl Nasen- und Nasennebenhöhlen-CA T4 Larynx- und Hypopharynx-CA Speicheldrüsen-CA Schilddrüsen-CA Sarkome Melanome und andere Hauttumoren Shah, presentation 2010

30 Limitationen für organerhaltende Therapiekonzepte Vorangegangene Radiotherapie Knorpelinfiltration T4-Infiltration (Larynx, Pharynx) andere Lokalisationen < 50% Ansprechen auf Induktionschemotherapie Kontraindikation gegen DCF Shah, presentation 2010

31 Resektable Tumoren

32 Locally-advanced non-resectable SCCHN Benefit at all sites MACH-NC analysis: Oral cavity 8.9% survival benefit of adding chemotherapy to local Oropharynx treatment 8.1% Larynx 5.4% Hypopharynx 4% Timing of CT Adjuvant Neoadjuvant Concomitant Absolute benefit after 5 years -2% 2% 8% Total* 5% Pignon JP, et al. Radiother Oncol 2009 Pignon JP, et al. Lancet 2000;355: ;

33 Dosierung von Cisplatin? EHNS-ESTRO-ESMO (European Head and Neck Society-European Society for Radiotherapy and Oncology-European Society for Medical Oncology) cisplatin-based concomitant chemoradiation NCCN (National Comprehensive Cancer Network) 3 cycles of concomitant high-dose cisplatin at 100 mg/m 2 40% to 50% of patients are not able to receive the 3 planned CT cycles! it is not clear whether the survival benefit is limited only to patients who are able to receive all 3 cycles of concomitant CT or whether it is equally in all treated patients, independent of the actual cisplatin dose received

34 Dosierung von Cisplatin? Adjuvant chemoradiation therapy with high-dose versus weekly cisplatin for resected, locally-advanced HPV/p16-positive and negative head and neck squamous cell carcinoma Geiger JL et al; Oral Oncology Volume 50, Issue 4, Pages , April Patients 3-yr overall survival: 84% and 75% (high dose vs. weekly cisplatin; p=0.30) 3-yr recurrence free survival: 71% and 74% (high dose vs. weekly cisplatin; p=0.95). 3-yr overall survival rates: 91% and 86% (high dose vs. weekly cisplatin; p=0.56), 3-3-yr recurrence free survival: 84% and 82% (high dose vs. weekly cisplatin; p=0.93) No significant survival difference, although there was a trend for improved survival with high-dose cisplatin. Weekly cisplatin in the adjuvant setting may be a better treatment for patients with HPV-positive oropharynx cancer to preserve survival and minimize toxicity.

35 nicht-resektable HNO-Tumoren Radiotherapie versus Radiotherapie + Cetuximab (Antikörper) RT (n=213) Stage III and IV non-metastatic SCCHN (n=424) Stratified by Karnofsky PS Nodal involvement Tumor stage RT regimen R Cetuximab + RT (n=211) Cetuximab initial dose (400 mg/m 2 ) 1 week before RT Cetuximab (250 mg/m 2 ) + RT (weeks 2 8) Bonner et al. N Eng J Med 2006;354:

36 nicht-resektable HNO-Tumoren Radiotherapie versus Radiotherapie + Cetuximab (Antikörper) Bonner et al. N Eng J Med 2006;354:

37 nicht-resektable HNO-Tumoren Radiotherapie versus Radiotherapie + Cetuximab (Antikörper) Akneforme Hautreaktion korreliert mit besserem Outcome Prominent rash, grade 2 4 (n=127) Mild rash, grade 0/1 (n=81) >68.8 months Overall survival months p=0.002, HR=0.49 ( ) Time (months) Bonner J et al. Lancet Oncology 2009

38 RTOG 0522 Trial A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC); ASCO 2011, Abstract 5500, Presenter: Ang K.

39 RTOG 0522 Trial A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC); ASCO 2011, Abstract 5500, Presenter: Ang K.

40 RTOG 0522 Trial A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC); ASCO 2011, Abstract 5500, Presenter: Ang K.

41 N2/N3 SCCHN R A N D O M I Z E Docetaxel Based Chemoradiotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer (DeCIDE) D D F 2 Cycles H P X F D F H X DFHX Concurrent Chemoradiotherapy TPF: Docetaxel (75 mg/m 2 ) + Cisplatin (75 mg/m 2 ) + 5-FU (750 mg/m 2, 120 hours) Q3 weeks DFHX: Docetaxel (25mg/m 2 ) + Hydroxyurea (500mg, q 12h) + 5FU (600mg/m 2 /day) + hyperfractionated RT (150 cgy bid) Ezra E. W. Cohen et al; ASCO 2012

42 Blue: Induction-CT Red: CRT Blue: Induction-CT Red: CRT Recurrence-Free Survival by Treatment Arm Distant Failure Free Survival by Treatment Arm Blue: Induction-CT Red: CRT Docetaxel Based Chemoradiotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer (DeCIDE) Overall Survival by Treatment Arm Primary Endpoint Ezra E. W. Cohen et al; ASCO 2012

43 Docetaxel Based Chemoradiotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer (DeCIDE) 3-year Outcomes Endpoint IC arm (%) CRT arm (%) HR 95% CI P value Overall Survival Distant-Failure Free Survival Recurrence Free Survival Cumulative incidence of distant failure Cumulative incidence of locoregional failure Ezra E. W. Cohen et al; ASCO 2012

44 PARADIGM Study Stage III/IV SCC Oral cavity, Oropharynx, Hypopharynx, Larynx Expected N=330 R A N D O M I Z E Docetaxel Cisplatin 5-FU every 3 wks, 3 cycles A NR CR Docetaxel (wkly for 4 wks) Accelerated Boost RT (d1-5) 6 wks A1 Carboplatin (every wk) Daily RT (d1-5) 7 wks Cisplatin (wks 1,4) Accelerated Boost RT (d1-5) 6 wks A2 B Haddad RI et al.; Journal of Clinical Oncology, 2010 ASCO Annual Meeting Abstracts. Vol 28, No 15_suppl (May 20 Supplement), 2010: 5563

45 PARADIGM: Gesamtüberleben und PFS Haddad RI et al.; Journal of Clinical Oncology, 2010 ASCO Annual Meeting Abstracts. Vol 28, No 15_suppl (May 20 Supplement), 2010: 5563

46 Conclusions Vermorken, ASCO 2012 TPF is superior to PF as induction chemotherapy (ICT), both with respect to locoregional and distant failure. The question whehter ICT RCT is superior to RCT alone is still unanswered and ICT RCT remains experimental. Both -PARADGIM and DeCIDE- suffered from poor accrual, an unexpected high survival rate in the control arm and a lack of information about HPV status. Small, but relevant differences between the two study arms -overall or in subgroups- were not able to be detected. Longer follow-up in particular of DeCIDE study is os interest. Considering the fact that HPV-positive tumors have increased response to platinum-based ICT and RT and smoking has negative effect on RT results, these elements should be taken into account in future studies.

47 nicht-resektable HNO-Tumoren DCF-Induktion: Standard bei nicht-resektablen Tumoren? RCT (Cisplatin 100 mg/m 2 Tag 1,22, 43) R n=439 Cisplatin /FU 3 Zyklen RCT (Cisplatin 100 mg/m 2 Tag 1,22, 43) Cisplatin 100 mg/m 2 d1, 5-FU 1000 mg/m 2 /d d1-5 (CIV) Docetaxel/Cispaltin/FU 3 Zyklen RCT (Cisplatin 100 mg/m 2 Tag 1,22, 43) Neck dissection Resektion Docetaxel 75 mg/m 2 d1, Cisplatin 75 mg/m 2 Tag1, 5-FU 750 mg/m 2 /d Tag 1-5 (CIV) mit G-CSF Prophylaxe Hitt R et al. Ann Oncol 2014;25:

48 nicht-resektable HNO-Tumoren DCF-Induktion: Standard bei nicht-resektablen Tumoren? (C) Overall survival (OS, ITT pop) Hitt R et al. Ann Oncol 2013;annonc.mdt461

49 (A) PFS (ITT pop) (B) TTF (ITT pop) (A) PFS (PP pop) (B) TTF (PP pop) Hitt R et al. Ann Oncol 2013;annonc.mdt461

50 nicht-resektable HNO-Tumoren Induktionschemotherapie Studie Induktion RT ÜL Benefit Decide Cohen E. et al. Paradigm Haddad RI et al. Hitt et al. 2x DCF Docetaxel (25mg/m 2 ) + Hydroxyurea (500mg, q 12h) + 5FU (600mg/m 2 /day) + hyperfractionated RT 3x DCF 3xDCF vs. 3x PF vs. keine ICT Responder: Carboplatin (every week) daily RT (d1-5), week 1-7 Non-responder: Docetaxel (wkly for 4 wks) Accelerated Boost RT (d1-5) daily RT (d1-5), week 1-7 Cisplatin 100 mg/m 2 day 1,22, 43 nein nein nein

51 Induktionschemotherapie: Pro & Kontra mögliche Indikationen: keine Kontraindikationen gegen Taxane oder Platine PS 0-1 große Tumorlast rasche Verkleinerung notwendig Larynx-, Hypopharynx-, Oropharynx-CA Vorbehalte: Verlängerung der Therapiedauer Beeinflussung (?) der Compliance des Patienten bei starken Nebenwirkungen: vorzeitiger Abbruch Benefit hinsichtlich Gesamtüberleben nicht bewiesen

52 Nicht-resektable Tumoren

53 Therapieansprechen und HVP: TAX 324 Posner M R et al. Ann Oncol 2011;22:1071 Kaplan-Meier curves of survival according to HPV status (HPV+ or HPV ) and treatment arm (TPF or PF)

54 HPV-Associated Oropharyngeal Cancer Rates by Race and Ethnicity

55

56 HPV viele offene Fragen HPV-associated head and neck cancer: a virus-related cancer Epidemic, S Marur, G D Souza, WH Westra, A A Forastiere, Lancet Oncol 2010; 11:

57 Tumorcharakteristika in Abhängigkeit vom HVP-Status Lokalisation HPV positiv Zungengrund Tonsille Nasennebenhöhlen Larynx HPV negativ alle Histologie basaloid keratinisierend T-Stadium niedrig (1/2) höher (3/4) N-Stadium höher (>2a) alle Alter jünger älter Geschlecht 3:1 3:1 Sozialstatus hoch niedrig Risikofaktoren Sexualverhalten Alkohol, Tabak Ko-Faktoren Marihuana Hygiene, Ernährung Prognose gut Schlecht Inzidenz steigend Rückläufig

58 Überleben und HVP:RTOG-0129

59 Palliative medikamentöse Therapie bei Rezidivtumoren und/oder Fernmetastasen > 50% der Patienten: Erstdiagnose mit lokal-fortgeschrittenem Tumor 10% haben zum Zeitpunkt der Diagnose bereits Fernmetastasen Therapieziel bei Rezidiv-TU/Fernmetastasen Symptomkontrolle Lebensverlängerung Parkin DM, et al. CA Cancer J Clin 2005;55:74 108

60 Rezidivtumoren und/oder Fernmetastasen Mono- oder Kombinationschemotherapie? Author n Regimen Grose, Methotrexat Cisplatin Williams, Cisplatin + Bleomycin + Vincristine Methotrexat Forastiere, Cisplatin + 5-FU Carboplatin + 5-FU Methotrexat Clavel, CABO Cisplatin + 5-FU Cisplatin Gibson, Cisplatin + 5-FU Cisplatin + Paclitaxel Ansprechraten (%) a b 31 c Medianes ÜL (Monate) 5.0 (ns) 4.5 (ns) 7.2 (ns) 7.8 (ns) 6.6 (ns) 5.0 (ns) 5.6 (ns) 7.3 across the 3 arms (ns) 8.7 (ns) 8.1 (ns) CABO, cisplatin, methotrexate, bleomycin, vincristine; a p<0.001; b p<0.001; c p=0.003 Kombinations-CT führt zu einer Steigerung der Ansprechraten However, kein Überlebensbenefit für Kombinations-CT gegenüber platinbasierter CT seit >30 Jahren Clavel M, et al. Ann Oncol 1994;5: ; Forastiere A, et al. J Clin Oncol 1992;10: ; Gibson MK, et al. J Clin Oncol 2005;23: ; Grose WE, et al. Cancer Treat Rep 1985;69: ; Williams SD et al. Cancer 1986;57:18 23.

61 Rezidivtumoren und/oder Fernmetastasen Chemotherapie (Cis/FU) +/- Cetuximab (Antikörper) 1.0 Vermorken et al. New Engl J Med 2008;359: Survival probability months 10.1 months CT alone ERBITUX + CT HR [95%CI]: 0.80 [ ] p=0.04 Medianes Gesamtüberleben um 2.7 Monate verlängert 20% Reduktion des Mortalitätsrisikos (p = 0.04) Survival time (months) Vermorken et al. New Engl J Med 2008;359:

62 Rezidivtumoren und/oder Fernmetastasen Chemotherapie (Cis/FU) +/- Cetuximab (Antikörper) % % Platinum/5-FU Platinum/5-FU + ERBITUX a Ansprechraten (CR+PR) Vermorken JB, et al. New Engl J Med 2008;359:

63 21. Okt SCCHN palliativ Ad-Board BI, Wien Palliative Systemtherapie bei SCCHN Problemstellungen G. Pall Weitere Therapieintensivierung möglich/sinnvoll? AIO Studie 1108 Knödler M et al., ESMO 2014: abstr # 987O

64 21. Okt SCCHN palliativ Ad-Board BI, Wien Palliative Systemtherapie bei SCCHN Problemstellungen G. Pall Weitere Therapieintensivierung möglich/sinnvoll? G3/4-Toxizitäten: 21% bzw. 30% Therapieassoziierte Mortalität: 11,2% bzw. 6,2% AIO Studie 1108 Knödler M et al., ESMO 2014: abstr # 987O

65 Chemotherapie Backbone? Regimen Study Median OS, months Erbitux + Cisplatin/Carboplatin + 5-FU vs. Cisplatin/Caboplatin + 5-FU Erbitux + Cisplatin vs. Cisplatin Erbitux + Cisplatin/Carboplatin + 5-FU Erbitux + Carboplatin + Paclitaxel Erbitux + Paclitaxel Phase III (n=442) Phase III (n=117) Median PFS, months ORR, % Phase I/II (n=53) (TTP) 36 Phase II (n=23) (TTP) 56 Phase II (n=42) NR

66 Docetaxel +/- Cisplatin + Cetuximab every other week Docetaxel Cisplatin Cetuximab-maintenance Until PD or toxicity every 2 weeks Cetuximab day in case of remission or stabilization Docetaxel iv (40-50 mg/m² every 2 weeks) Cisplatin iv (40-50 mg/m² every 2 weeks) Cetuximab iv (500 mg/m² every 2 weeks) Cetuximab iv (500 mg/m² every 2 weeks) Median PFS :10 months (range, 3 42 months)

67 EGFR & HPV? - Panitumumab 657 patients in SPECTRUM, 411 (63%) assessable for HPV status; of these, 23% were HPVpositive (ie, staining of 10% of cells) and 77% were HPV-negative r/m SCCHN n= 657 R Panitumumab + Cisplatin + 5-FU Cisplatin + 5-FU Panitumumab + PF all patients HPV - all patients HPV - PF Overall survival 11.1 mos HR=0.87, 95% 11.8 mos HR= mos 8,6 mos PFS 5.8 mos HR = 0.78, 95% 6.5 mos HR= mos 5.1 mos ORR 35% 25% Vermorken JP. ESMO 2010 & 2011

68 HPV testing EXTREME: p16 was assessed by p16ink4a (CINtec Histology Kit) p 16 positivity was considered to be strong and diffuse nuclear staining in >70% to tumor cells SPECTRUM: p16 was assessed by p16ink4a (CINtec Histology Kit) p 16 positivity was considered to be strong and diffuse nuclear staining in >10% to tumor cells

69 EGFR-inhibitors & HPV Pts, tumors, therapies & effects EXTREME SPECTRUM Pts. available, No. pts No. with Oropharynx (%) 136 (35.7) 124 (28.0%) No. p16 positive 41 (10.9) 99 (22.3) Predicitive (OS&HR, 95%CI) in p16 positive tumors 12.6 vs. 9.6; 0.63 ( ) in p16 negative tumors 9.7 vs. 7.3; 0.82 ( ) Prognostic (OS&HR, 95% CI) in pts. With CT+MoAb 12.6 vs. 9.7; 0.59 ( ) in pts. With CT alone 9.6 vs. 7.3; 0.83 ( ) 11.0 vs. 12.6; 1.00 ( ) 11.7 vs. 8.6; 0.73 ( ) NR 12.6 vs. 8.6; 0.70 ( )

70 Treatment algorithm for r/m SCCHN clinical trial preferred r/m SCCHN PS 0-1 combination chemo or single agent +cetuximab clinical trial or cetuximab mono or best supportive care standard therapy PS 2 single agent +cetuximab PS 3 best supportive care clinical trial or cetuximab mono or best supportive combination chemotherapy single agent Cis- or Carboplatin + 5-FU Cis- or Carboplatin 5-FU Cis- or Carboplatin + Pacli- or Docetaxel Pacli- or Docetaxel Methotrexate Bleomycin Ifosfamide

71 Molecular targeted therapeutics Phase Reference Drug Erlotinib II Vermorken, JCO % Erlotinib II Souliers, JCO % Gefitinib II Cohen, JCO % Gefitinib II Cohen, CCR % Gefitinib II Kirby, BJC % Gefitinib III Stewart, JCO % Lapatinib II Abidoye, ASCO % Cetuximab II Seiwert, ASCO % BIBW 2992 II Seiwert, ASCO % Panitumumab II No data as single agent Zalemtumumab III Machiels, ASCO % Pemetrexed + Bevacizumab II Agiris, ASCO %

72 Historical studies Patients with recurrent and/or metastatic SCCHN that had progressed on platinum-based therapy Trigo 1 Baselga 2 Herbst 3 León 4 ERBITUX 400 mg/m 2 followed by 250 mg/m 2 weekly 50% of patients received ERBITUX + cisplatin/carboplatin upon disease progression ERBITUX 400 mg/m 2 followed by 250 mg/m 2 weekly + cisplatin/carboplatin Stable disease or response ERBITUX alone until disease progression ERBITUX 400 mg/m 2 followed by 250 mg/m 2 x 4 cycles + cisplatin 75 or 100 mg/m 2 q 3 weeks BSC or single-agent/ combination CT or RT 1 Trigo, et al. J Clin Oncol 2004;22(Suppl. 14S):488s (Abstract No. 5502); 2 Baselga, et al. J Clin Oncol 2005;23: ; 3 Herbst, et al. J Clin Oncol 2005;23: ; 4 Leόn, et al. Clin Oncol (R Coll Radiol) 2005;17:

73 Tumor response n CR + PR CR + PR + NC ERBITUX monotherapy % 46% ERBITUX + cisplatin 96 10% 53% or carboplatin 2 ERBITUX + cisplatin % 56% Retrospective analysis 4 All patients 151 3% 15% Patients with CT only 43 0% 9% 1 Trigo, et al. J Clin Oncol 2004;22(Suppl. 14S):488s (Abstract No. 5502); 2 Baselga, et al. J Clin Oncol 2005;23: ; 3 Herbst, et al. J Clin Oncol 2005;23: ; 4 Leόn, et al. Clin Oncol (R Coll Radiol) 2005;17:

74 Overall survival and time to progression n Median OS Median TTP ERBITUX monotherapy months 2.3 months ERBITUX + cisplatin or carboplatin months 2.8 months ERBITUX + cisplatin 3, months 2.2 months Retrospective analysis 4 All patients months N/A Patients with CT only months 2.2 months 1 Trigo, et al. J Clin Oncol 2004;22(Suppl. 14S):488s (Abstract No. 5502); 2 Baselga, et al. J Clin Oncol 2005;23: ; 3 Herbst, et al. J Clin Oncol 2005;23: ; 4 Leόn, et al. Clin Oncol (R Coll Radiol) 2005;17: ; 5 Vermorken, et al. Proc ASCO 2005;16(Suppl. 16S) (Abstract No. 5505)

75 Afatinib versus methotrexate as second-line treatment for patients with R/M HNSCC who progressed after platinum-based therapy: primary efficacy results of LUX-Head & Neck 1, a Phase III trial J-P. H. Machiels, R. I. Haddad, J. Fayette, L. F. Licitra, M. Tahara, J. B. Vermorken, P. M. Clement, T. Gauler, D. Cupissol, J. J. Grau, J. Guigay, F. Caponigro, G. de Castro Jr, L. de Souza Viana, U. Keilholz, J. M. del Campo, X. Cong, L. Svensson, E. Ehrnrooth, and E. E. W. Cohen on behalf of the LUX-H&N 1 investigators

76 Afatinib: Irreversible ErbB Family Inhibition EGFR/ HER2 HER2/ ErbB3 ErbB3/ ErbB4 Gefitinib Erlotinib Afatinib Afatinib Afatinib is an irreversible ErbB-family blocker1-3 Inhibits all kinase-active members: EGFR, HER2 and HER4 Proof of concept in squamous histology in various trials in lung, and head and neck cancer Approved* in the major ICH regions of US,4 EU5 and Japan6 for the treatment of patients with NSCLC harbouring distinct types of EGFR-activating mutations RAS RAF MEK P13K AKT EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor-2; HER4, human epidermal growth factor receptor-4; ICH, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; *Indications differ between countries ERK PROLIFERATION mtor SURVIVAL 1. Li D, et al. Oncogene 2008;27: ; 2. Solca F, et al. J Pharmacol Exp Ther 2012;343:342 50; 3. Gilotrif prescribing information (Accessed: 05 Sept 2014); 4. Giotrif EPAR assessment EMA (Accessed 05 Sept 2014); 5. PMDA Japan new drug approvals (Accessed 05 September 2014) 6. Goss et al. ESMO Abstract

77 LUX-Head & Neck 1: study design Patients with incurable R/M HNSCC progressing on/after first-line platinumbased therapy (N=474) Randomisation (2:1) Stratified by: ECOG PS (0 vs 1) and prior use of EGFR mab therapy (Yes/No) Afatinib 40 mg orally once daily (n=316) Methotrexate 40 mg/m 2 IV weekly (n=158) Primary endpoint: PFS Key secondary endpoint: OS Secondary endpoints: ORR, patient-reported outcomes, safety

78 Primary Endpoint: PFS Independent Review Estimated PFS Probability % 42.8% Afatinib (n=322) MTX (n=161) PFS event, n (%) 275 (85.4) 135 (83.9) Median PFS (mo) HR (95% CI) Log-rank test P value 0.80 ( ) P=0.030 Number at risk Afatinib MTX Months Machiels et al. ESMO Abstract LBA 29.

79 Key Secondary Endpoint: Overall Survival Estimated OS Probability % 58.4% Afatinib (n=322) MTX (n=161) OS event, n (%) 237 (73.6) 121 (75.2) Median OS (mo) HR (95% CI) Log-rank test P value 0.96 ( ) P=0.700 Number at risk Afatinib MTX Months Machiels et al. ESMO Abstract LBA 29.

80 Tumour Shrinkage Independent Review Afatinib 40 MTX 40 Maximum Decrease From Baseline (%) % had tumour shrinkage Number of patients 20% increase (n=53) 0 <20% increase (n=78) >0 <30% decrease (n=76) 30 <50% decrease (n=20) 50% decrease (n=16) Patient Index Sorted by Maximum % Decrease Maximum Decrease From Baseline (%) % had tumour shrinkage Number of patients 20% increase (n=34) 0 <20% increase (n=50) >0 <30% decrease (n=26) 30 <50% decrease (n=7) 50% decrease (n=3) Patient Index Sorted by Maximum % Decrease Machiels et al. ESMO Abstract LBA 29.

81 Overall tumour response 60 Afatinib 50 Methotrexate 49,1 Percentage of patients ,2 * 5,6 38,5 0 afatinib mtx ORR DCR * Odds ratio: 1.9 ( ); p-value = Odds ratio: 1.5 ( ); p-value = Disease control rate (DCR): includes objective response and stable disease Machiels et al. ESMO Abstract LBA 29.

82 PRO: Proportion of Patients Improved Afatinib MTX 36, ,7 36,5 Patients Improved, % ,4 26,9 24, ,3 23,1 23, ,7 27,4 26,1 23,2 24,4 24,3 22,7 14,5 24, ,8 19,3 30,3 29,1 5 0 Machiels et al. ESMO Abstract LBA 29. Pain Swallowing Global Health Status

83 Adverse Events Overall Summary Afatinib (n=320) n (%) MTX (n=160) n (%) Any AEs, n (%) 318 (99) 158 (99) Drug-related AEs, n (%) 303 (95) 137 (86) Grade (40) 57 (36) Leading to dose reduction 103 (32) 67 (42) Leading to discontinuation 23 (7) 26 (16) Serious AEs 44 (14) 18 (11) Leading to death 2 (0.6)* 5 (3) Treatment duration (median) Afatinib: 83 days (range 2 546); MTX: 43 days (range 1 442) *One septic shock and one aspiration pneumonia Two septicemia, one aspiration pneumonia, one general health deterioration, and one renal failure and pancytopenia Machiels et al. ESMO Abstract LBA 29. Yang JC, et al.

84 Drug-Related Adverse Events (>10%)* Afatinib (n=320) MTX (n=160) All Gr (%) Gr 3 (%) Gr 4 (%) All Gr (%) Gr 3 (%) Gr 4 (%) Higher on MTX Higher on afatinib Rash/Acne Diarrhoea Paronychia Decreased appetite Vomiting 13 1 < Dry skin Stomatitis < Fatigue Nausea Neutropenia <1 < Anaemia *There were no Grade 5 drug-related AEs observed in >10% of patients Grouped term Machiels et al. ESMO Abstract LBA 29.

85 Conclusions Afatinib significantly improved PFS vs methotrexate Tumour shrinkage was greater, response rate higher, and DCR significantly higher with afatinib compared with methotrexate Patient-reported outcomes favoured afatinib over methotrexate OS was not significantly different between afatinib and methotrexate Overall AE profiles were as expected Fewer treatment-related dose reductions, discontinuations, and fatal events with afatinib compared with methotrexate Afatinib is the first oral tyrosine kinase inhibitor to demonstrate efficacy and improved PROs in a phase III trial in this setting Investigations with adjuvant afatinib in LA HNSCC following CRT are ongoing Machiels et al. ESMO Abstract LBA 29.

86 A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck Seiwert T Y et al. Ann Oncol 2014;25: The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology.

87 Treatment duration and disease control in stages I and II. Each line denotes one patient and the blue portion is the treatment duration with afatinib and yellow corresponds to cetuximab. Seiwert T Y et al. Ann Oncol 2014;25: The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology.

88 Waterfall plot of maximum percentage tumor shrinkage in stage I and stage II according to independent central review. Seiwert T Y et al. Ann Oncol 2014;25: The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology.

89

90 Treatment algorithm for r/m SCCHN clinical trial preferred r/m SCCHN PS 0-1 combination chemo or single agent +cetuximab clinical trial or cetuximab mono or best supportive care or afatinib? standard therapy PS 2 single agent +cetuximab PS 3 best supportive care clinical trial or cetuximab mono or best supportive or afatinib?

91 Immuntherapie durch Checkpoint-Inhibitoren

92 Immuntherapie durch Checkpoint-Inhibitoren? Seiwert T et al., ASCO Annual Meeting 2014; #6011

93 Immuntherapie durch Checkpoint-Inhibitoren? Seiwert T et al., ASCO Annual Meeting 2014; #6011

94 Immuntherapie durch Checkpoint-Inhibitoren? Seiwert T et al., ASCO Annual Meeting 2014; #6011

95 Immuntherapie durch Checkpoint-Inhibitoren? Seiwert T et al., ASCO Annual Meeting 2014; #6011

96 Immuntherapie durch Checkpoint-Inhibitoren? Seiwert T et al., ASCO Annual Meeting 2014; #6011

97 Immuntherapie durch Checkpoint-Inhibitoren? Seiwert T et al., ASCO Annual Meeting 2014; #6011

98

99 Indikationen für medikamentöse Therapie Resektable Tumoren: Induktionschemotherapie + RT Lokal-fortgeschrittenen Tumoren: RCT oder RIT (Cetuximab) Rezidivtumoren und Metastasen: CT+ Cetuximab