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Molecular Therapeutics with Chemotherapy in SCCHN by J. Vermorken
 

Molecular Therapeutics with Chemotherapy in SCCHN by J. Vermorken

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    Molecular Therapeutics with Chemotherapy in SCCHN by J. Vermorken Molecular Therapeutics with Chemotherapy in SCCHN by J. Vermorken Presentation Transcript

    • The International Federation of Head and Neck Oncologic SocietiesCurrent Concepts in Head and Neck Surgery and Oncology 2012 Molecular Therapeutics with Chemotherapy in SCCHN Jan B. Vermorken
    • Outline Innovations in the treatment of head & neck cancer Locoregionally advanced disease •  Research directions with targeted therapy (TT) Recurrent/metastatic disease •  Studies with cetuximab •  Non cetuximab-containing randomized trials with anti-EGFR therapies •  Novel targeted agents Conclusions2012
    • Innovations in Treatment of HNC Surgery - reconstructive surgery - organ sparing techniques Radiotherapy - altered fractionation schedules - chemoradiation, IMRT - bioradiation Chemotherapy - introduction of taxanes (TPF induction)2012 - molecular targeted therapies
    • Locoregionally Advanced SCCHN What do we know? 1.  CT-RT is an important standard therapy for resectable and unresectable SCCHN and for organ preservation. It induces 8% survival benefit at 5-yrs in MACH-NC (Lancet, 2000) 2.  Major drawback of this approach: acute and late side effects (JCO, 2008) 3.  RT + EGFRI (cetuximab) is superior to RT alone, but without additional toxic effects to the mucosa or increased late side effects (NEJM, 2006) 4.  CT-RT and RT – EGFRI (cetuximab) generally do not reduce2012 distant metastasis
    • Locoregionally Advanced SCCHN What do we know? 5.  PF induction induces 5% survival benefit at 5-yrs in MACH-NC and is effective in organ preservation in patients with larynx and hypopharynx cancer (Ann Oncol, 2002) 6.  TPF is the new standard ICT, with less toxicity and with better QoL than with PF (NEJM, 2007) 7.  TPF is superior to PF with respect to larynx preservation (JNCI, 2009) 8.  There is an increasing incidence of HPV-associated oropharynx cancers, that seem to respond differently to induction chemotherapy and RT and carry a better prognosis (JNCI, 2008)2012
    • What are the Challenges? •  To find ways to minimize toxicity and maximize efficacy (less LRR, DM, SPT) •  To better predict those who need more aggressive treatment vs those who need less •  To find ways to adapt treatment in individual cases2012
    • Targets for Next-Generation Therapy Tumor cell1. Growth factors and 3. Signal transduction pathways growth-factor receptors 1   Ras, raf, MAPK, MEK, ERK, AKT HER family, c-kit/SCFR protein kinase C, PI3K 3   2   Nucleus2. Extracellular matrix/ 4   angiogenic pathways 5   4. Cell-survival pathways VEGFR, integrins, MMPs Cyclin-dependent kinases, mTOR, cGMP, COX-2, p53, Bcl-2 2012 5. Protein production Proteasome
    • EGFR Expression in Human Tumors EGFR Expression: High Expression Generally Associated with:•  NSCLC 40-80%•  Prostate 40-80%•  Head & Neck 90-100% •  Invasion•  Gastric 33-74% •  Metastasis •  Late-stage disease•  Breast 14-91% •  Chemotherapy resistance•  Colorectal 75-89%•  Pancreatic 30-95% •  Poor outcome•  Ovarian 35-77%•  Bladder 31-72%•  Glioma 40-63% 2012
    • 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/gastrointestinal (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/systemic2012
    • Cetuximab: Properties and Mechanism of Action •  IgG1 monoclonal antibody •  Specifically binds to the EGFR with higher affinity than its natural ligands (TGFα, EGF), thus competitively inhibiting their binding •  High affinity: Kd = 0.39 nM •  Induces apoptosis and ADCC1 •  Preclinical synergistic activity2012 in combination with chemotherapy ADCC = antibody-dependent cellular cytotoxicity and radiotherapy
    • Background & Rationale - Preclinical Studies Cetuximab Enhances Tumor Response to Cisplatin or Radiation A431 Tumor Cetuximab Control Cetuximab x 3 14 Cisplatin 4Tumor Size (cm3) Tumor Size (mm) Control (PBS) 12 18 Gy 3 Cetuximab 10 Cetuximab x3 + 18 Gy 2 8 Cisplatin 1 A43 Cetuximab 6 A43 1 + Cisplatin Cetuxima 1 0 4 b 0 5 10 15 20 25 30 35 0 8 16 24 32 40 48 56 64 72 80 Time (days) Days After Initial Treatment 2012 Fan (Mendelsohn), Cancer Res 53:4637, 1993 Courtesy Dr. Ang Milas (Fan), Clin Cancer Res 6:701, 2000
    • Background & Rationale – Clinical Studies Phase III Trials of Cetuximab with Radiotherapy or Platinum-Based Chemotherapy Improves Survival 1.0 | Overall Survival 0.9 0.8 Locally Advanced HNSCC Bonner et al, NEJM, 2006Proportion Alive 0.7 HR: 0.73 (0.56, 0.95), P= 0.02 0.6 RT + Cetuximab (≤8 doses) 0.5 Δ 2.7 Months 20 Months 0.4 10% 0.3 Chemotherapy ≤6 cycles + RT Alone Cetuximab (Med: 29 doses) 0.2 Recurrent/Metastatic HNSCC 0.1 Vermorken et al, NEJM, 2008 Chemo Alone HR: 0.80 (0.64, 0.99), P= 0.04 0.0 2012 0 10 20 30 40 50 60 70 Months Courtesy Dr. Ang
    • MACH-NCMeta-Analysis of Chemotherapy in Head & Neck Cancer Taxane-Cisplatin-5-Fluorouracil as Induction Chemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: an Individual Patient Data Meta-analysis of the MACH-NC Group 2012 Pierre Blanchard, Abderrahmane Bourredjem, Jean Bourhis, Ricardo Hitt, Marshall R. Posner, Jan B. Vermorken, Gilles Calais, Adriano Paccagnella, Jean Pierre Pignon on behalf of the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) Collaborative Group
    • Randomized Trials of Sequential Therapyversus 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)2012 TPF x 3 XRT (PF) GCTCC (It) XRT (cetuximab) XRT (PF)
    • Induction Chemotherapy (ICT) and Targeted Therapy Superior to standard ICT? Induction Concurrent D P F E C T P E C TWanebo 200 2 90 200 1 30 2010Ferris 75 75 250 30 250 2010Argiris 75 75 250 30 250 2010Posner 75 100 1000 x5 1.5 2007 2012 D=docetaxel; P=cisplatin; F=5-FU; E=cetuximab (Erbitux® ); C=carboplatin; T: paclitaxel (Taxol®)
    • Induction Chemotherapy (ICT) and Targeted Therapy Superior to standard ICT? Wanebo Ferris Argiris PosnerNo. of pt 63 39 39 255Stage IV (%) 64 92 92 84OPC (%) 61 59 59 52HPV + - 65 68 29PFS (%) 66 (2yr) 70 (3yr) 70 (3yr) 52 (3yr)OS 82 (2yr) 74 (3yr) 74 (3 yr) 62 (3yr)ICT-resp (%) 74 86 86 72 2012
    • Conclusions on Adding Cetuximab to TPF •  Difficult with full dose TPF (EORTC 24061: EHNS 2012) •  Feasible in combination with 2 drug regimens (as in R/M disease) •  Superiority of ICT + cetuximab over ICT alone difficult to detect in nonrandomized trials (patient and tumor characteristics)2012 •  Randomized trials are needed
    • Recurrent and/or Metastatic SCCHN Introduction •  Over 50% of newly diagnosed cases are not cured and will relapse locally or at distant sites •  10% of newly diagnosed cases present with distant metastases •  Treatment options: - Chemotherapy (CT) 10-15% of - Re-irradiation localized - Salvage surgery recurrences - Best supportive care (BSC)2012 •  Cisplatin-based CT: - Response rate: 30% - Overall survival: 6–9 months
    • Platinum-Refractory R/M SCCHN Therapeutic options •  Best supportive care (BSC) Chemotherapy (CT) Radiation therapy (RT) Other local therapies •  In a retrospective analysis of 151 patients with platinum- refractory disease 45% received BSC, and 55% any form of treatment (Leon et al, Clin Oncol 2005; 17: 418-424) •  Overall response rate was 2.6%, the clinical benefit rate 15.2%,2012 and survival 103 days. (for patients receiving BSC 56.5 days, CT 107 days)
    • EGFR Inhibitor Response Rates in SCCHN Drug Phase/ prior CT Reference Resp Rate, % Cetuximab II Pt- refract Vermorken, JCO, 2007 10-13 Erlotinib II 0-1 lines Soulieres, JCO, 2004 4 Gefitinib II 0-1 lines Cohen, JCO, 2003 11 II 0-5 lines Cohen, CCR, 2005 2 II 0-1 lines Kirby, BJC, 2006 9 III Pt + (A) Stewart, JCO, 2009 3-8 Lapatinib II unclear Abidoye, ASCO 2006 0 Cetuximab II prior Pt Seiwert, THNO 2011 7 Afatinib II prior Pt Seiwert, THNO 2011 162012 Prior CT= for recurrent/metastatic disease
    • CT plus Cetuximab in 1st-Line SCCHN:Consistent Efficacy Regardless of CT Type ORR Median PFS Median OS Author Phase N Regimen (%) (months) (months)Vermorken PF 20 3.3 7.4 III 442 2008 PF + cetuximab 36* 5.6* 10.1*Burtness Cis + Placebo 10 2.7 8.0 III 117 2005 Cis + cetuximab 26* 4.2 9.2 Bourhis I/II 53 PF + cetuximab 36 5.1** 9.8 2006 Hitt II 46 Pacli + cetuximab 54 4.2 8.1 2011Buentzel Pacli/Carbo + II 23 56 5.0** 2007 cetuximab 8.0 2012 *Significant; **TTP Vermorken et al. NEJM 2008; Burtness et al. JCO 2005; Bourhis et al. JCO 2006; Hitt et al. Ann Oncol 2011; Buentzel et al. ASCO 2007
    • Grade 3/4 AEs (%) A 0 5 10 15 20 25 2012 ne m N ia eu Th tr ro op m en bo ia cy to pe ni H a yp ok H al yp em om ia ag ne se C m ar ia di ac ev en ts Vo m iti ng A st he ni a Se Sk ps in is re ac In tio fu ns si on (n=219) re ac tio CT (n=215) n EXTREME: Safety Profile CT + cetuximabVermorken et al. NEJM 2008
    • EXTREME: Symptom Control Improving -20 CT CT + cetuximab symptoms -15Mean change from baseline to -9.99 -9.98 -9.17 worst post-baseline score -10 -7.81 -5 -2.64 -2.55 -2.60 -0.43 0 +0.24 +1.33 5 +3.51 +4.42 +5.21 +4.37 10 p=0.0027 p=0.0162 p=0.5702 p=0.0787 p=0.0694 p=0.7732 p=0.2237 15 Worsening symptoms 20 Pain Swallowing Sense Speech Social eating Problems Problems problems problems problems problems with social with contact reduced 2012 sexuality QLQ-H&N35 module Modified from Mesía et al. Ann Oncol 2010
    • EXTREME: Quality of Life Global health status/QoL 100 CT CT + cetuximab 80 60 <50% of patients completed a baseline Score questionnaire; 40 =95% CIs for difference in treatment 20 groups 0 -20 Baseline Cycle 3 6 months CT: n=94 n=63 n=20 CT + cetuximab: n=109 n=80 n=452012 EORTC QLQ-C30 Mesía et al. Ann Oncol 2010
    • The Role of Cetuximab in First-Line R/M - SCCHN Adding cetuximab to platinum/5-fluorouracil: •  significantly improves overall survival1 •  significantly increases PFS1 •  almost doubles the response rate1 •  is feasible with an acceptable side-effect profile1 •  significantly reduces pain and swallowing problems2 •  has no negative effect on quality of life2 First regimen to show survival benefit in 30 years Is a new standard regimen for R/M-SCCHN3,42012 1Vermorken et al, N Engl J Med 2008; 359: 1116-1127 2Mesia et al, Ann Oncol 2010 (doi 10,1093/annonc/mdq077) 3Licitra L and Felip E, Ann Oncol 2009; 20 (suppl 4): 121-122 4Petrelli et al, J Clin Oncol 2009; 27: 6052-6069
    • Cetuximab and Beyond Where do we go from here?2012
    • Non-Cetuximab Containing Randomized Trials in Recurrent/Metastatic SCCHN Anti-EGFR therapies Study/Reference N Regimen RR (%) PFS (mo) OS (mo)SPECTRUM/ 657 PF2 + panitumumab 36* 5.8** 11.1Vermorken et al 2010 PF2 4.6** 9.0 25*ZALUTE 286 Z + BSC (-MTX) 6 2.3… 6.7°Machiels et al, 2010 BSC (optional MTX)a 1.9… 5.2° 1IMEX 486 Gefitinib (250 mg) 2.7 ND 5.6Stewart et al, 2009 Gefitinib (500 mg) 7.6 ND 6.0 Methotrexate ND 6.7 3.9ECOG 1302 270 D + Gefitinib 12 3.3 6.8Argiris et al, 2009 D + placebo 2.2 6.2 2012 6 a87% received MTX *p=0.007; **p=0.004; …p=0.001; °p=0.0648
    • The Problem of Resistance EGFR is a validated therapeutic target in SCCHN Discordance between EGFR expression and response Possible mechanisms of resistance EGFR mutations Increased EGFR internalization Parallel signaling pathways •  IGF-1R, MET, erbB2 •  PI3K/AKT mutations •  Cycline D1 amplification2012
    • Other Novel Targeted Agents in SCCHN Anti-angiogenesis •  VEGF •  VEGFR Integrin inhibitors Histone deacetylase inhibitors PI3K/Akt/mTOR Proteasome inhibitors IGFR inhibitors2012 SRC inhibitors No phase III data!
    • VEGF Ligand Targeted Therapy in R/M SCCHNDrugs N RR (%) SD (%) ReferenceBevacizumab 15 mg/kg q. 21d 37 30 (5)* 57 Argiris++ pemetrexed 500 mg/m² q. 21d (2011)Bevacizumab 15 mg/kg q. 21d 48 15 (8)* 30 Cohen+ erlotinib 150 mg/day (2009)Bevacizumab+ 15 mg/kg q. 21d 46 18 (0)* 55 Argiris°cetuximab 250 mg/m²/wk (2011) 2012 *( ) = percentage CR; +Median TTP 5 months, median OS 11.3 months °PFS 2.8 months, median OS 7.6 months
    • Phase III Randomized Trial of Cisplatin- Based Chemotherapy with or without Bevacizumab in SCCHN (E1305) R A Cisplatin doublet*Recurrent/ N Every 21 daysmetastatic DSCCHN O Endpoint: survivalPS 0-1 N=400 M Cisplatin doublet*No prior I + Bevacizumab 15 mg/kgchemo Z E Every 21 days 2012 * Cisplatin/docetaxel or cisplatin/5-FU Study Chair: A. Argiris
    • Anti-Angiogenic Agents in Recurrent or Metastatic SCCHN: Conclusions Sorafenib and sunitinib cannot be recommended for further study as monotherapy (combination regimens?) Bevacizumab added to pemetrexed or cetuximab had promising preliminary activity in 2 ongoing trials Bevacizumab will be evaluated in a phase III2012 randomized trial in rec/met SCCHN
    • Novel Agents not Targeting EGFR in Recurrent or Metastatic SCCHN Target Single agent Combination Bevacizumab Angiogenesis No data Promising/ongoing Low/mod Sorafenib Angiogenesis Ongoing activity Sunitinib Angiogenesis Low activity - Dasatinib Src, others Low activity Ongoing Bortezomib Proteasome Low activity Low activity Vorinostat HDAC Low activity - Figitumumab IGF-1R Low activity -2012 Cixutumumab IGF-1R Ongoing Ongoing Everolimus mTOR Ongoing Ongoing
    • Targeted Therapies: Combinations*Drug combinations with cetuximab Phase II Sample Size TargetBevacizumab + cetuximab II 48 VEGFDasatinib + cetuximab I 30 ScrCilengitide + cetuximab (+ PF) I/II 194 IntegrinsCixutumumab ± cetuximab II 90 IGF-1RCetuximab ± EMD1201081 II 104 TLR9 Raf, VEGF1,2,3, Flt3,Cetuximab ± sorafinib II 88 PDGFß, c-KIT, RETTemsirolimus ± cetuximab II 80 mTOR*Available on clinicaltrials.gov 2012
    • Conclusions Better understanding of the biology of SCCHN has led to change in treatment approaches, which may end up with improved outcome and less toxicity The interaction between targeted therapies and cytotoxic chemotherapy is promising → survival benefit in R/M SCCHN, but improvement with ICT still uncertain. In R/M SCCHN regimens with less toxicity need to be further explored 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.2012