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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
  • 14/04/11 m Adding Erbitux to different chemotherapies has demonstrated consistent efficacy in several trials in first-line R/M SCCHN. In a randomized, phase III trial of Erbitux plus cisplatin vs cisplatin alone (n=117), Burtness and colleagues demonstrated that the addition of Erbitux to cisplatin significantly increased the overall response rate compared with cisplatin alone (26% vs 10%, p=0.03). The addition of Erbitux to cisplatin also produced longer progression-free survival (median 4.2 vs 2.7 months) and longer overall survival (median 9.2 vs 8.0 months) compared with cisplatin alone, although these differences did not reach statistical significance. In a phase I/II trial of Erbitux combined with platinum (cisplatin or carboplatin) plus 5-FU (n=53) in the first-line treatment of R/M SCCHN, Bourhis and colleagues reported an overall response rate of 36%, with a 4% complete response rate. Median duration of response (95% CI) was 4.2 months (3.4 –9.9 months ), median time to progression (95% CI) was 5.1 months (4.2 –6.1 months ), and median survival (95% CI) was 9.8 months (8.0 –13.8 months ). In a phase II trial of Erbitux combined with paclitaxel in the first-line treatment of R/M SCCHN (n=42), Hitt and colleagues reported an overall response rate of 60%, with a 24% complete response rate. Median time to progression was 6.2 months, median progression-free survival was 5.0 months. These three trials, together with the EXTREME study, demonstrate that Erbitux combined with either platinum or taxane provides consistent clinical benefits in the first-line treatment of R/M SCCHN.
  • As a final slide I would like to put these data into perspective with other reports of anti-EGFR agents. Jan Vermorken reported in 2007 the response rate for Cetuximab to be 13% For Erlotinib the response reported rate is 4.3% For Gefitinib it varies dpending on the report between 1.8 and 10.6%. The phase III IMEX study puts it at 7.9% In our study we now confirm the cetuximab response rate of 13% Furthermore BIBW 2992 shows a response rate that is substantially above that of other small molecule TKIs
  • Epidermal growth factor receptor (EGFR) is one of several targets for next-generation therapy for metastatic colorectal cancer.

MCO 2011 - Slide 17 - J.B. Vermorken - Systemic therapy MCO 2011 - Slide 17 - J.B. Vermorken - Systemic therapy Presentation Transcript

  • Systemic Treatment in Head & Neck Cancer Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium ESO-ESMO Masterclass in Clinical Oncology Zürich, April 4, 2011
  • Case 1: Locoregionally Advanced Head and Neck Cancer in 66 Year Old Man from Nigeria
    • Symptoms: Anorexia, weight loss, asthenia, dysphagia, dyspnoe (exhaustion), night sweat
    • Lab test: leucocytosis, anemia (infection?)
    • Therapy: antibiotics
    • Biopsy: squamous cell carcinoma (referral)
    • Staging: No distant metastases (TxN3M0)
  • Case 1: Locoregionally Advanced Head and Neck Cancer 09.07.2003 09.07.2003
    • What type of treatment would you choose?
    • Surgery: RT ± CT?
    • Concurrent chemoradiation?
    • Induction chemotherapy  RT ± CT?
    • Induction chemotherapy  RT + cetuximab?
    • Other?
    Case 1: Locoregionally Advanced Head and Neck Cancer
  • Case 1: Locoregionally Advanced Head and Neck Cancer Treatment: 11.07.2003 PF regimen cycle I 01.08.2003 PF regimen cycle II PR (CT-scan) 26.08.2003 PF regimen cycle III 06.10.2003 RT 70 Gy in 35 sessions concomitant gemcitabine 100 mg/m²/week > 90% PR starting 01.10.03 for 7 times (CT-scan)
  • Case 1: Locoregionally Advanced Head and Neck Cancer 08.07.2003 09.01.2004
  • Case 1: Locoregionally Advanced Head and Neck Cancer
  • Outline
    • Milestones
    • Treatment modalities
    • Locoregionally advanced disease
      • Concurrent chemoradiation
      • Bioradiation
      • Induction chemotherapy
    • Recurrent/metastatic disease
      • New standard
      • New directions
    • Conclusions
  • 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
  • Milestones in Systemic Therapies (± RT) in Head and Neck Squamous Cell Cancer 1960s Methotrexate (ICT, CRT) 1970s Bleomycin, 5-fluorouracil, cisplatin Combination chemotherapy regimens 1980s Carboplatin Organ preservation trials start (ICT) 1990s Paclitaxel, docetaxel CCRT>RT 2000s Targeted therapies (MoAb) ICT revisited Sequential therapy (ICT  CCRT)?
  • Treatment Modalities in SCCHN 2011
    • Surgery as single modality
    • Radiotherapy (RT) or in combination
    • Chemotherapy (CT)
      • combined modality treatment (CMT):
      • Induction CT (ICT); concomitant CT and RT (CCRT); sequential therapy (ICT  CCRT); adjuvant CCRT postoperative
      • Palliative therapy
    • Targeted therapy (TT)
      • Alone or combined with RT, CMT or palliative CT
  • Results of Present Therapies
    • Early stages (I and II)  single modality TRT
    •  5-yr S: 60-90%
    • Advanced stages (III and IV)  combined modality
    •  5-yr S: < 35%
      • Resectable: > 60% LRR, 20% DM, 10-40% SPT
      • Unresectable: 5-yr S < 20%, majority † < 18 months
    • Recurrent/metastatic disease  chemotherapy
    • Median survival 6-12 months, 1-year survival 20-40%
  • Treatment of Locoregionally Advanced SCCHN
    • Historically: Surgery ( + RT) or RT alone
    • Outcomes poor for OS and OP
    • Currently there are three multimodality treatment approaches:
    • Surgery  adjuvant concurrent CRT
    • Definitive concurrent CRT, with surgery as an optional salvage or completion treatment
    • Induction CT  definitive local therapy
    • Seiwert et al, 2007; OS = overall survival; OP = organ preservation
  • 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
  • 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)
  • Pignon et al, Radioth Oncol 2009: 92; 4-14 (87 trials/16.485 patients) (50 concomitant trials/9615 patients)
  • Conclusion of 2009 MACH-NC Meta-Analysis
    • The analysis concerns 50 trials on concurrent CRT, including 9615 patient (6560 deaths), median FUP 5.6 years
    • Adding chemotherapy leads to a risk reduction in death of 19% (HR 0.81 [0.78; 0.86, p<0.0001])*
    • There is benefit in all potential clinical situations, including PORT, curative RT, altered fractionation
    • The main beneficial effects is on local failure, but there is a modest, thought significant, effect on distant failures
    • *with mono Platin: 0.74 (0.67-0.82, p=0.006)
  • CRT: Significant Increase in Acute Toxicity 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
  • CRT: 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
  • 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)
  • 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
  • Cetuximab: Properties and Mechanism of Action
    • IgG 1 monoclonal antibody
    • Specifically binds to the EGFR with higher affinity than its natural ligands (TGFα, EGF), thus competitively inhibiting their binding
    • H igh affinity: K d = 0.39 nM
    • Induces apoptosis and ADCC1
    • Preclinical synergistic activity in combination with chemotherapy and radiotherapy
    ADCC = antibody-dependent cellular cytotoxicity
  • Bonner et al. N Engl J Med 2006; 354: 567-578
  • Cetuximab + RT in locally advanced SCCHN: Study design Bonner et al. N Engl J Med 2006; 354: 567-578 RT as before + ERBITUX initial 400 mg/m 2 2-h infusion then 250 mg/m 2 1-h infusion weekly for at least 7 doses RT once or twice daily or concomitant boost for 7 – 8 weeks Patients with measurable locally advanced SCCHN (stratified by KPS;node+/0;T1-3/4; RT regimen) Randomization Follow-up until disease progression or up to 5 years
  • The Cetuximab/Radiotherapy Phase III Trial
    • Radiotherapy BioRadiotherapy P-value
    • (n=213) (n=211)
    • Toxicity *
    • Mucositis 52% 56%
    • Acneiform rash 1% 17% < .001
    • Radiation dermatitis 18% 23%
    • Infusion reactions NA 3%
    • (Late Peg dependency 17% 19% )
    • Efficacy
    • 3-Yr Survival 45% 55% .03
    • 2-yr PFS 37% 46% .006
    • 2-Yr LRC 41% 50% .005
    • 2- Yr DM 17% 16%
    Bonner et al. N Engl J Med 2006; 354: 567-578; (*Grade 3-5)
  • 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
  • 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
  • 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
  • Analysis of Failures in Phase III CRT or BRT Trials Trials Group Year Published Locoregional failure (%) Distant metastases (%) % of failures due to DM INT 2003 22 23 51 EORTC 2005 18 21 54 RTOG 2005 16 20 65 GORTEC Bonner 2005 2006 57 53 18 17 32 30 Modified from Posner and Vermorken, 2008
  • Rationale for Induction Chemotherapy (ICT)
    • Optimal drug delivery: high response rates: transient toxicity
    • Improves nutritional status and performance status
    • Has an established efficacy in organ preservation strategies
    • No compromise of subsequent RT or surgery
    • Response to ICT predicts response to RT
    • Is an early systemic treatment of occult disease
    • Improves survival (MACH-NC): ICT with PF in 15 trials (2487 pts) leads to 5% increase in 5-yr survival (p=0.01)
  • Randomized Trials of ICT in LA-HNC Revisited Trial Arms Outcome CA 139-322 (2005) PF vs PPF CCR (TTP , OS*) Resectable/nonresectable CRT (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 CRT (Cb) Improved with TPF GORTEC 2000-01 PF vs TPF LP (OS, DFS) + Resectable (2006) T(P)L vs RT Improved with TPF *significant only in unresectable disease (JCO); °NEJM; + ASCO 2006
  • 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, 2007 Resectable/unresectable disease Vermorken et al, 2007 Unresectable disease
  • EORTC 24971/TAX 323 Toxicity NCIC-CTC Grade 3-4 PF (n=179) TPF (n=173) Toxicity % % Anemia/ thrombocytopenia 13/ 18 9/ 3 Neutropenia 53 77 Nausea/vomiting 7/4 <1/<1 Diarrhea 3 3 Stomatitis 11 5 Infection 6 7 Febrile neutropenia 3 5 Hearing loss 3 0 Toxic deaths 5.5 2.3 Primary prophylactic antibiotics were given per protocol for TPF Vermorken et al, N Engl J Med 2007; 357: 1695-1704
  • EORTC 24971/TAX 323 Quality of Life Analysis: QLQ-C30 Global Health Bernier et al. ASCO 2006; Abstract 5522 PF TPF (N=142) (N=143) Cycle 2 Least Square Mean QLQ-C30 Score [99% CI] 100 90 80 70 60 50 40 30 20 10 0 Cycle 4 6 mos. Post RT 9 mos. Post RT Least Square Mean TPF vs PF: p=0.01 CI=Confidence Interval; RT=Radiotherapy
  • Questions Raised after Bioradiation and TPF Studies (1)
    • Is Bioradiation (BRT)  concurrent Chemoradiation (CRT)?
      • panitumumab + AF-RT vs cisplatin + SF-RT (NCT00820248)
      • zalutumumab + RT vs cisplatin+RT (NCT00496652)
    • Will EGFR inhibition enhance the effect of CRT?
      • cetuximab + CDDP + AF-RT vs CDDP + AF-RT (RTOG 0522)
      • panitumumab + CRT vs CRT postop (EORTC 22071-24071)
      • panitumumab + CCDP + SF-RT vs CDDP + SF-RT (NCT00500760)
      • erlotinib + CRT vs CRT (NCT00410826)
      • lapatinib + CRT vs CRT (NCT00387127)
  • Questions Raised after Bioradiation and TPF Studies (2)
    • Is TPF induction followed by RT ≥ CRT?
    • Is TPF induction followed by CRT > CRT?
    • Can EGFR inhibition be used in the post-induction setting, thereby reducing toxicity in sequential design?
    • Can EGFR inhibition be combined with ICT?
    • Can we be more selective in the choice of HNC treatment?
  • 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)
  • The Randomized Phase II Study: TREMPLIN
    • Previously untreated SCC larynx/hypopharynx suitable for TL
    • Primary endpoint : larynx preservation 3 months after treatment
    • Secondary endpoints : larynx function preservation and survival 18 months after treatment
    Total laryngectomy + postop RT RT 70 Gy Cisplatin 100 mg/m² on days 1, 22 and 43 RT 70 Gy Cetuximab 400 mg/m² 1 wk prior to RT then 250 mg/m² weekly on wks 1 to 7 TPF 3 cycles, 1 cycle q3weeks T = 75 mg/m² on day 1 P = 75 mg/m² on day 1 5-FU = 750 mg/m² on day 1 to 5 Response evaluation by endoscopy and CT scan R <PR Lefebvre et al for GORTEC and GETTEC groups (abstract #6010) 5-fluorouracil, T=docetaxel TL=total laryngectomy, PR=partial response, RT=radiation therapy, CT=computed tomography ≥ PR
  • Results of Tremplin (ASCO 2009)
    • Induction chemotherapy in 153 patients
      • 126 (82%) responded to TPF
      • 116 (76%) were randomized ( 60 to CRT , 56 to BRT )
    • CRT (n=58)  33 (57%) did not receive full protocol
    • 25 received 2 cycles (43%), 8 had 1 cycle (14%)
    • - renal failure (9), mucositis (7), HTOX (10), other (2)
    • BRT (n=55)  16 (29%) did not receive full protocol
    • - allergic reaction (2), cardiac (1), skin (9), mucositis (2), other (2). One pt stopped for G4 skin toxicity
    • Lefebvre et al, abstract #6010
    • Incidence increasing for HPV-related
    • Incidence decreasing for HPV-unrelated
    • Equalization in 2004
    Incidence Trends in the US Chaturvedi et al, J Clin Oncol 2008; 26: 612-619
  • Prognostic Significance of HPV Overall Survival Ang K et al. N Engl J Med 2010;361:24-35
  • 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
  • Conclusions
    • Many questions on bioradiation are still unanswered
    • Bioradiation might be a good alternative for CCRT in patients with a relatively good prognosis (HPV+ OPC) and needs to be studied
    • The integration of bioradiation in combined modality approaches (BCCRT; BICT->RT/CCRT; ICT->BRT; BICT->BCCRT) needs to be further studied in patients with a more unfavorable prognosis.
  • Recurrent and/or metastatic SCCHN: Background
    • 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) - Re-irradiation - Salvage surgery - Best supportive care (BSC)
    • Cisplatin-based CT: - Response rate: 30% - Overall survival: 6 – 9 months
  • 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
  • Vermorken et al. N Engl J Med 2008: 359: 1116-27
  • EXTREME: Responses to Treatment and Survival Variable PF+cetuximab n=222 PF n=220 HR or OR (95% CI) P value Survival – mo overall progression-free 10.1 (8.6 -11.2) 5.6 (5.0 - 6.0) 7.4 (6.4-8.3) 3.3 (2.9-4.3) HR 0.80 (0.60-0.99) HR 0.54 (0.43-0.67) 0.04 <0.001 Best response - % overall disease control 36 (29-42) 81 (75-86) 20 (15-25) 60 (53-67) OR 2.33 (1.50-3.60) OR 2.88 (1.87-4.44) <0.001 <0.001 Time to TRT failure-mo 4.8 (4.0-5.6) 3.0 (2.8-3.4) HR 0.59 (0.48-0.73) <0.001 Duration of response 5.6 (4.7-6.0) 4.7 (3.6-5.9) HR 0.76 (0.50-1.17) 0.21 PF=cisplatin or carboplatin + 5-FU; HR=hazard ratio; OR: odds ratio Vermorken et al. N Engl J Med 2008: 359: 1116-27
  • EXTREME: Symptom Control Mean change from boaseline t worst post-baseline score Pain Swallowing problems Sense problems Speech problems Social eating problems Problems with social contact p=0.0027 p=0.0162 p=0.5702 p=0.0787 p=0.0694 p=0.7732 p=0.2237 -9.99 +3.51 -9.17 +5.21 -2.60 +4.42 -7.81 +1.33 -9.98 +0.24 -2.64 - 0.43 -2.55 +4.37 Problems with reduced sexuality Worsening symptoms Improving symptoms Cetuximab + chemotherapy Chemotherapy alone Mesia et al, Ann Oncol 2010 (doi 10,1093/annonc/mdq077)
  • EXTREME: Most relevant grade 3/4 adverse events Modified from Vermorken et al, N Engl J Med 2008: 359: 1116-27
  • EXTREME: Quality of life a a <50% of patients completed a baseline questionnaire; = 95% CIs for difference in treatment groups 100 80 60 40 20 0 -20 Global health status/QoL Erbitux + CTX CTX Erbitux + CTX CTX Baseline (n=109) (n=94) Cycle 3 (n=80) (n=63) 6 months (n=45) (n=20) Mesia et al, Ann Oncol 2010 (doi 10,1093/annonc/mdq077 )
  • Cetuximab in 1 st -line SCCHN A Major Clinical Advance
    • ASCO Clinical Cancer Advances 2009
    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”
  • Adding Cetuximab to Chemotherapy Shows Consistent Efficacy in 1st-line R/M SCCHN Vermorken JB, et al. N Engl J Med 2008;359:1116–1127; Burtness B, et al. J Clin Oncol 2005;23:8646–8654; Bourhis J, et al. J Clin Oncol 2006;24:2866–2872; Hitt R, et al. ASCO 2007 (Abstract No. 6012; updated information presented); Buentzel J, et al. ASCO 2007 (Abstract 6077) a p<0.001; b p=0.04; c p=0.03; d Median OS not reached after a median follow-up of 5.6 months; e TTP Author Phase Regimen ORR (% ) Median PFS (months ) Median OS (months) Burtness et al. III CDDP + cetuximab CDDP + placebo 26 c 10 4.2 2.7 9.2 8.0 Bourhis et al. I/II PF + cetux i ma b 36 5.1 e 9.8 Vermorken et al. III PF + cetuximab PF 36 a 20 5.6 a 3.3 10.1 b 7.4 Hitt et al. II Pacli + cetuxima b 60 5.0 NR d Buentzel et al. II Pacli/Carbo + cetuximab 56 5.0 e 8.0
  • 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
  • EGFR Inhibitor Response Rates in SCCHN Prior CT= for recurrent/metastatic disease Drug Phase/ prior CT Reference Response Rate Cetuximab II Pt- refract Vermorken, JCO, 2007 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 8% Lapatinib II unclear Abidoye, ASCO 2006 0% Cetuximab II prior Pt Seiwert, ASCO 2010 13% BIBW 2992 II prior Pt Seiwert, ASCO 2010 22%
  • 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
  • Cetuximab and Beyond Where do we go from here?
    • 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
    The Problem of Resistance
  • Other Novel Targeted Agents in SCCHN
    • Anti-angiogenesis
      • VEGF
      • VEGFR
    • Integrin inhibitors
    • Histone deacetylase inhibitors
    • SRC inhibitors
    • Proteasome inhibitors
    • IGFR inhibitors
    • No phase III data!
  • Novel Agents Not Targeting EGFR in Recurrent or Metastatic SCCHN Target Single agent Combination Bevacizumab Angiogenesis No data Promising/ongoing Sorafenib Angiogenesis Low/mod activity Ongoing Sunitinib Angiogenesis Low activity - Dasatinib Src, others Low activity Planned Bortezomib Proteasome Low activity Low activity Vorinostat HDAC Low activity - Figitumumab IGF-1R Low activity - Cixutumumab IGF-1R Ongoing Ongoing Everolimus mTOR Ongoing Ongoing
  • Treatment Combined anti-EGFR Treatment with Gefitinib and Cetuximab P. Matar et al Clin Cancer Res 2004; 10: 6487-6501 Courtesy of Dr. Baselga, 2006
  • Combinations of Targeted Agents
    • Anti-EGFR medication with:
      • angiogenese inhibitors
      • integrin inhibitors
      • mTor inhibitors
      • SRC inhibitors
      • IGFR inhibitors
  • 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
    • Better selection of patients for specific treatment approaches may become an important issue in future trials
    • In R/M SCCHN the PFE regimen is a new standard. Regimens with higher efficacy (and less toxicity) are urgently needed.
    • 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.
  • Targets for Next-generation Therapy Tumor cell Nucleus 3 3. Signal transduction pathways Ras, raf, MAPK, MEK, ERK, AKT protein kinase C, PI3K 1 1. Growth factors and growth-factor receptors HER family, c-kit/SCFR 2 2. Extracellular matrix/ angiogenic pathways VEGFR, integrins, MMPs 4 4. Cell-survival pathways Cyclin-dependent kinases, mTOR, cGMP, COX-2, p53, Bcl-2 5. Protein production Proteasome 5