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Molecular Therapeutics with Chemotherapy in SCCHN by J. Vermorken
This document discusses innovations in the treatment of head and neck cancer, including molecular targeted therapies used with chemotherapy. It summarizes research showing that adding cetuximab, an anti-EGFR monoclonal antibody, to chemotherapy or radiotherapy improves survival rates for patients with locoregionally advanced or recurrent/metastatic squamous cell carcinoma of the head and neck compared to chemotherapy or radiotherapy alone. The document also reviews several clinical trials that have evaluated adding cetuximab to induction chemotherapy regimens or using it in combination with other targeted agents for these cancer types and stages.
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Molecular Therapeutics with Chemotherapy in SCCHN by J. Vermorken
- 1. The International Federation of Head and Neck Oncologic Societies Current Concepts in Head and Neck Surgery and Oncology 2012 Molecular Therapeutics with Chemotherapy in SCCHN Jan B. Vermorken
- 2. 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 Conclusions 2012
- 3. Innovations in Treatmentof HNC Surgery - reconstructive surgery - organ sparing techniques Radiotherapy - altered fractionation schedules - chemoradiation, IMRT - bioradiation Chemotherapy - introduction of taxanes (TPF induction) 2012 - molecular targeted therapies
- 4. 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 reduce 2012 distant metastasis
- 5. 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
- 6. What are theChallenges? • 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 cases 2012
- 7. Targets for Next-GenerationTherapy Tumor cell 1. 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 Nucleus 2. 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
- 8. EGFR Expression inHuman 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
- 9. EGFR-targeting Agents underClinical 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/systemic 2012
- 10. Cetuximab: Properties andMechanism 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 activity 2012 in combination with chemotherapy ADCC = antibody-dependent cellular cytotoxicity and radiotherapy
- 11. Background & Rationale- Preclinical Studies Cetuximab Enhances Tumor Response to Cisplatin or Radiation A431 Tumor Cetuximab Control Cetuximab x 3 14 Cisplatin 4 Tumor 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
- 12. 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, 2006 Proportion 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
- 13. MACH-NC Meta-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
- 15. Randomized Trials ofSequential 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) 2012 TPF x 3 XRT (PF) GCTCC (It) XRT (cetuximab) XRT (PF)
- 16. Induction Chemotherapy (ICT)and Targeted Therapy Superior to standard ICT? Induction Concurrent D P F E C T P E C T Wanebo 200 2 90 200 1 30 2010 Ferris 75 75 250 30 250 2010 Argiris 75 75 250 30 250 2010 Posner 75 100 1000 x5 1.5 2007 2012 D=docetaxel; P=cisplatin; F=5-FU; E=cetuximab (Erbitux® ); C=carboplatin; T: paclitaxel (Taxol®)
- 17. Induction Chemotherapy (ICT)and Targeted Therapy Superior to standard ICT? Wanebo Ferris Argiris Posner No. of pt 63 39 39 255 Stage IV (%) 64 92 92 84 OPC (%) 61 59 59 52 HPV + - 65 68 29 PFS (%) 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
- 18. Conclusions on AddingCetuximab 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
- 19. Recurrent and/or MetastaticSCCHN 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
- 20. 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)
- 21. EGFR Inhibitor ResponseRates 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 16 2012 Prior CT= for recurrent/metastatic disease
- 22. CT plus Cetuximabin 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 2011 Buentzel 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
- 23. 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 + cetuximab Vermorken et al. NEJM 2008
- 24. EXTREME: Symptom Control Improving -20 CT CT + cetuximab symptoms -15 Mean 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
- 25. EXTREME: Quality ofLife 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=45 2012 EORTC QLQ-C30 Mesía et al. Ann Oncol 2010
- 26. The Role ofCetuximab 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-SCCHN3,4 2012 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
- 27. Cetuximab and Beyond Where do we go from here? 2012
- 28. 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** 11.1 Vermorken 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° 1 IMEX 486 Gefitinib (250 mg) 2.7 ND 5.6 Stewart et al, 2009 Gefitinib (500 mg) 7.6 ND 6.0 Methotrexate ND 6.7 3.9 ECOG 1302 270 D + Gefitinib 12 3.3 6.8 Argiris 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
- 29. The Problem ofResistance 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 amplification 2012
- 30. Other Novel TargetedAgents in SCCHN Anti-angiogenesis • VEGF • VEGFR Integrin inhibitors Histone deacetylase inhibitors PI3K/Akt/mTOR Proteasome inhibitors IGFR inhibitors 2012 SRC inhibitors No phase III data!
- 31. VEGF Ligand TargetedTherapy in R/M SCCHN Drugs N RR (%) SD (%) Reference Bevacizumab 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
- 32. Phase III RandomizedTrial of Cisplatin- Based Chemotherapy with or without Bevacizumab in SCCHN (E1305) R A Cisplatin doublet* Recurrent/ N Every 21 days metastatic D SCCHN O Endpoint: survival PS 0-1 N=400 M Cisplatin doublet* No prior I + Bevacizumab 15 mg/kg chemo Z E Every 21 days 2012 * Cisplatin/docetaxel or cisplatin/5-FU Study Chair: A. Argiris
- 33. Anti-Angiogenic Agents inRecurrent 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 III 2012 randomized trial in rec/met SCCHN
- 34. Novel Agents notTargeting 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
- 35. Targeted Therapies: Combinations* Drugcombinations with cetuximab Phase II Sample Size Target Bevacizumab + cetuximab II 48 VEGF Dasatinib + cetuximab I 30 Scr Cilengitide + cetuximab (+ PF) I/II 194 Integrins Cixutumumab ± cetuximab II 90 IGF-1R Cetuximab ± EMD1201081 II 104 TLR9 Raf, VEGF1,2,3, Flt3, Cetuximab ± sorafinib II 88 PDGFß, c-KIT, RET Temsirolimus ± cetuximab II 80 mTOR *Available on clinicaltrials.gov 2012
- 36. 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