Biologic Therapy in Head and Neck : A road with hurdles

Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium

Preceptorship Course in Head and Neck Cancer Management, Kashiwa, Japan, December 5-7, 2016 Outline of the Presentation

• Milestones in treatment management of HNC • Potential therapeutic targets in SCCHN • only FDA / EMA approved targeted agent for locoregionally advanced SCCHN for recurrent/metastatic SCCHN • The hurdles to take with respect to cetuximab • Other targeted agents of interest • A new immunologic approach • Takehome messages Milestones in Head and Neck Cancer Management

MARCH MACHNC

XIXème. 1900 1970s 1980s 1990s 2000s 2010 2014

laser Targeted surgery radiotherapy ASCO TORS IT CTscan 1982 PET therapies Xrays MRI Single agent → PF→ TPF Courtesy of Jean-Louis Lefebvre Treatment Modalities in SCCHN 2016

• 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 Palliative therapy

• (TT) Alone or combined with RT, CMT or palliative CT

• (IT) Innovations in Treatment of HNC

• Surgery reconstructive surgery organ sparing techniques TORS

• Radiotherapy altered fractionation schedules Better targeting (CT MRI, PET, IGRT) New RT techniques (IMRT, STRT, PT) Combined approach: CT, TT, hypoxic mod.

• Systemic therapy Introduction of taxanes Molecular targeted therapies Immunotherapy Potential Therapeutic Targets in SCCHN

1. Growth factors and growth factor receptors (HER family, VEGF/R, HGF/cMet, IGF1R/IR) 2. Signal transduction pathways (Ras, raf, Src, MAPK, MEK, ERK, Cetuximab , Tumor cell protein kinase C, PI3K) , 1 AZD0530 2

6 3 3. Tumorassociated or markers 6. Extracellular matrix (Gangliosides, CEA, 4 and angiogenesis MAGE, CD20, CD22) (MMP, VEGF, 5 ) 4. Proteasome Bortezomib 5. Cell cycle and cell survival pathways (Cyclindependent kinases, mTOR, cGMP, COX2, p53, Bcl2, HDAC, gene methylation (MGMT)) Vorinostat, Arteaga, The Oncologist, 2002; 7 (suppl 4): 31-39 EGFR Expression in Human Tumors

EGFR expression High expression generally associated with • NSCLC 4080% • Prostate 4080% • Invasion • Head & Neck 90 100% • • Gastric 3374% • Latestage disease • Breast 1491% • Chemotherapy resistance • Colorectal 7589% • Radioresistance • Pancreatic 3095% • Poor outcome • Ovarian 3577% • Bladder 3172% • Glioma 4063% EGFRtargeting Agents under Clinical Investigation in SCCHN

Monoclonal antibodies Toxicity Cetuximab IMC225 chimeric human/murine IgG1 skin EMD72000 humanized mouse IgG1 skin hR3 humanized mouse IgG1 systemic/hemodynamic 2F8 human IgG1 skin Panitumumab ABXEGF human IgG2 skin inhibitors ZD1839 reversible EGFR skin/gastrointestinal (GI) OSI774 reversible EGFR skin/GI GW572016reversible EGFR/erbB2 skin/GI/systemic BIBW2992 irreversible Pan Her* skin/GI/systemic PF00299804 irreversible Pan Her* skin/oral/GI/systemic

* EGFR/Her2/Her4 Cetuximab: Properties and Mechanism of Action

• IgG 1 • 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 and ADCC1 • Preclinical synergistic activity in combination with chemotherapy and radiotherapy

ADCC = antibody-dependent cellular cytotoxicity Courtesy Courtesy Dr. Ang Tumor Size (cm 3) 2 1 3 4 0 0 Fan (Mendelsohn), Cancer Res 53:4637, 1993 A431 Background & Rationale &Rationale Background 52 35 25 15 5 Cetuximab Cisplatin 02 30 20 10 Cetuximab Cetuximab enhances tumor response to Time (days) Cetuximab Control Control (PBS) cisplatin cisplatin or radiation Cetuximab + Cisplatin Cisplatin

Tumor Size (mm) 10 12 14 4 6 8 Cetuximab Control 62 24 85 472 64 56 48 40 32 24 16 8 0 Milas (Fan), Clin Cancer Res 6:701, 2000 Preclinical Studies Studies Preclinical Days After Initial Treatment Cetuximab x 3 1 8 G y Cetuximab x3 + 18 Gy A431 80 Background & Rationale – Clinical Studies Phase III trials of cetuximab with radiotherapy or platinumbased chemotherapy improves survival

1.0 | Overall Survival 0.9

0.8 Locally Advanced HNSCC Bonner et al, NEJM , 2006 0.7 HR: 0.73 (0.56, 0.95), P= 0.02 0.6 RT + Cetuximab (≤8 doses ) 0.5 2.7 Months 20 Months 0.4 10% Proportion Alive Alive ProportionProportion 0.3 Chemotherapy ≤6 cycles + RT Alone Cetuximab (Med: 29 doses ) 0.2 Recurrent/Metastatic HNSCC Vermorken et al, NEJM, 2008 0.1 Chemo Alone HR: 0.80 (0.64, 0.99), P= 0.04 0.0 0 10 20 30 40 50 60 70 Months

Courtesy Dr. Ang Cetuximab: FDA a/o EMA Approved Indications in Head and Neck Cancer

• In combination with radiation for locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN)

• As single agent for R/MSCCHN in 2nd line after failure of platinumbased chemotherapy*

• In combination with platinum/5fluorouracil in the firstline R/MSCCHN disease setting

* Not applicable for Japan Study Design of Phase III Radiotherapy ± Cetuximab in Head and Neck Cancer

RT + Cetuximab Locally advanced Cet initial dose (400 mg/m 2) N=424 SCCHN Cet (250 mg/m 2) + RT (wks 2–8) stage III/IV, R nonmetastatic oropharynx, hypopharynx or RT larynx

Primary endpoint : Duration of locoregional control Secondary endpoints : OS, PFS, RR, QoL, and safety

Bonner JA, et al. N Engl J Med 2006;354:567–578 Cet, cetuximab; OS, overall survival; PFS, progressionfree survival; Curran D, et al. J Clin Oncol 2007;25:2191–2197 QoL, quality of life ; RR, relative response; RT radiotherapy; SCCHN, squamous cell carcinoma of the head & neck RT + Cetuximab Significantly Improves LRC and 5year OS in LASCCHN

LRC OS RT + cet RT

100 100 HR=0.73 [95% CI: 0.56–0.95] HR=0.68 [95% CI: 0.52–0.89] p=0.018 p=0.005 80 80 5year survival rate 3year control rate

60 60 49.0 months 46% 24.4 months 47%

14.9 (%) OS 40 40 29.3 months months Locoregional control (%) (%) control control LocoregionalLocoregional 20 20 36%36% 34%

0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60

Months Months No. at risk No. at risk RT 213 122 80 51 30 10 RT 213 162 122 98 85 77 49 RT + cet 211 143 101 66 35 9 RT+ cet 211 177 136 117 105 90 49

Bonner JA, et al. N Engl J Med 2006;354:56778 HR, hazard ratio; LASCCHN, locally advanced squamous cell Bonner JA, et al. Lancet Oncol 2010;11:21–28 carcinoma of the head & neck; LRC, locoregional control The Cetuximab/RadiotherapyCetuximab /Radiotherapy Phase III Trial (IMCL9815)(IMCL 9815)

Radiotherapy BioRadiotherapy Pvalue (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 3Yr Survival 45% 55% .03 2yr PFS 37% 46% .006 2Yr LRC 41% 50% .005 2Yr DM 17% 16%

Bonner et al. N Engl J Med 2006; 354: 567-578; (*Grade 3-5) Compliance with Cetuximab or Chemotherapy when Administered with RT CRT arms of studies comparing CRT vs RT alone

Weekly doses (median 8 doses) Cetuximab 1 90%

2 cycles at weeks 1 and 5 Cisplatin 2 2nd cycle 71%

3 cycles at weeks 1, 4, and 7 Carboplatin / 5FU 3 3rd cycle 51%

3 cycles at weeks 1, 3, and 6 Cisplatin / 5FU / FA 4 3rd cycle 46%

010 2030 4050 60 70 80 90 100

Patients receiving all planned doses (%)

1Bonner JA, et al. N Engl J Med 2006; 354: 567–578; 2Huguenin P, et al. J Clin Oncol 2004; 22: 4665–4673; 3Calais G, et al. J Natl Cancer Inst 1999; 91: 2081–2086; 4Wendt TG, et al. J Clin Oncol 1998; 16: 1318–1324 Curran Curran Clin J D, Oncol 2007 25:2191-2197. Cetuximab RT + in Locally Advanced SCCHN QoL: QoL: Postbaseline the scores for EORTCQLQC30

Global health status/QoL score 100 20 40 60 80 0 Baseline Week 4 Month 4 Month 8 Month 12 Month 8 Month 4 Month Week 4 Baseline QoL assessment of studyBonner Quality of life Visit Cetuximab Cetuximab +RT RT Subset analysis of the IMCL9815 Trial

Bonner JA et al, Lancet Oncol 2010; 11: 21-28 Chemoradiation (CRT) vs Bioradiation (BRT)

CRT : 50 trials, 9615 pts (MA)* BRT : 1 trial, 424 patients

HR of death 0.74 (0.670.82) + HR of death 0.74 (0.570.97)**

Main effect on local failure Only effect on local failure Modest effect on DM No effect on DM

Efficacy irrespective of site and of Effect may be site and RT schedule fractionation schedule specific (in OPC irrespective of HPV)

Significant acute toxicity which may Grade 34 mucositis and radiation inflict on late toxicity, in particular dermatitis not significantly increased. swallowing dysfunction Late toxicity does not seem increased. High compliance. No direct comparison in phase III reported

* Pignon et al, Radioth Oncol 2009: 92; 4-14 (level I evidence); **Bonner et al. N Engl J Med 2006; 354: 567-578 (level II evidence); +with mono Platin therapy Chemoradiation vs Bioradiation (cetuximab) A metaanalysis of published data

Search in PubMED, EMBASE, SCOPUS, Web of Science and the Cochrane Register of Controlled Trials Included were 15 studies and 1,808 patients Endpoint CCRT RT+CET Risk Ratio (95%CI) 2yr OS 71.0% 60.7% 0.66 (0.460.94), p=0.02 2yr DFS 61.7% 43.1% 0.68 (0.530.87), p=0.002 2yr LRR 19.6% 32.3% 0.63 (0.450.87), p=0.005

Barni et al, ASCO 2014 (abstr.#6014) Randomized Trials of CCRT vs BRT

Study Country Drug (exp) Comparator Phase (no pts) NCT 1302834 USA Cetuximab Cisplatin III (987) 1 NCT 01874171 UK Cetuximab Cisplatin III (304) 2 NCT 01855451 Australia Cetuximab Cisplatin III (200) 3 NCT 00169247 France Cetuximab Cisplatin II (156) 4

NCT 00716391 Spain Cetuximab Cisplatin III (458) 5

NCT 01216020 Italy Cetuximab Cisplatin II (140)

NCT 00547157 “Concert 2” Panitumumab Cisplatin II (150)

NCT 00820248 Canada Panitumumab Cisplatin III (320) 6

NCT 00496652 Denmark Zalutumumab Cisplatin III (600) 7

1in HPV(p16)+OPC (RTOG-1016); 2De-Escalate study in HPV(p16)+OPC; 3TROG 12.01 study in HPV(p16)+OPC; 4Tremplin (after TPF); 5after TPF; 6AF (in exp. arm) vs SF (comparator); 76 fraction/week (RT ± Zalutumumab or CCRT ± zalutumumab) HighDose Cisplatin still Standard in 2015 Randomized Trials of CCRT vs BRT

• Phase II versus phase III

• In none of the reported trials there is sufficient data that allow to conclude that BRT can replace CCRT.

• Trials are suffering from methodological issues. Randomized Trials of CCRT ± EGFR Inhibition

Study Country AntiEGFR CCRT (drug) Phase (no pts)

NCT 00265941 USA Cetuximab Cisplatin III (720) 1 NCT 01301248 Greece Cetuximab Cisplatin II (80) NCT 00401401 Denmark Zalutumumab Cisplatin III (619) NCT 00500760 Concert1 Panitumumab Cisplatin II (153) NCT 00229723 International Gefitinib Cisplatin II (224) 2 NCT 00169225 GORTEC Gefitinib Cisplatin II (54) 3 NCT 00410826 USA Erlotinib Cisplatin II (204) NCT 01074021 China Nimotuzumab Cisplatin III (480) 4 NCT 00957086 Singapore Nimotuzumab Cisplatin III (710) 5 NCT 01516996 China Nimotuzumab TP II (80) 6

1RTOG0522; 2published (no effect); 3post operative; 4study (placebo-controlled) in NPC (2008 stages III/IVa); 5placebo controlled in the postoperative setting; 6nimotuzumab during 2x ICT and CRT RTOG 0522: Study Objective & Design

Test hypothesis that adding cetuximab to the radiation cisplatin platform for frontline therapy of stage IIIIV HNSCC improves progressionfree survival (PFS)

Stage III & IV* SCC of: • Oropharynx R • Larynx A 1. AFX CB: 72 Gy/42 F/6 W + 2 • Hypopharynx N Cisplatin: 100 mg/m , q3W x 2 Stratify : D O • Lx vs NonLx 2. AFXCB: 72 Gy/42 F/6 W + M 2 • N0 vs N12b vs N2c3 Cisplatin: 100 mg/m , q3w x 2 I Cetuximab:: 400 mg/m 2 x1, then • Zubrod PS Z 250 mg/m 2/w • 3D vs IMRT E • PET (yes vs no ) Excluded T1N+, T2N1

Ang KK et al, ASCO 2011 (abstract #5500) RTOG 0522 ProgressionFree Survival & Overall Survival

100 100 Primary Endpoint

75 75

Hazard Ratio (95% CI) Hazard Ratio (95% CI) 50 1.05 (0.84, 1.29) 50 0.87 (0.66, 1.15) Free Survival FreeFree Survival Survival (%) (%) P= 0.66 (logrank, 1sided) P= 0.17 (logrank, 1sided)

25 2Year Rate (95% CI) Overall Overall Survival Survival (%) (%) 25 2Year Rate (95% CI) Cisplatin 64.3% (59.7, 68.8) Cisplatin 79.7% (75.9, 83.6) Progression Cisplatin+Cet 63.4% (58.7, 68.0) Cisplatin+Cet 82.6% (78.9, 86.3) 0 0 0 1 2 3 0 1 2 3 Years after Randomization Years after Randomization # Patients at Risk # Patients at Risk 448 316 217 78 448 385 266 96 447 302 197 80 447 378 251 94

Ang KK et al, ASCO 2011 (abstract #5500) Randomized Trials of CCRT ± EGFR Inhibition

None of trials reported to date showed any beneficial effect of adding antiEGFR to concurrent chemoradiotherapy GORTEC 200701 Phase III randomized trial

Presented By Jean Bourhis at 2016 ASCO Annual Meeting Study design

Eligible: stage III/IV (T0-T4, N0-N2a (N2b if not palpable), M0 BCRT arm n=204, BRT arm 201 pts) Primary endpoint: PFS

Presented By Jean Bourhis at 2016 ASCO Annual Meeting PFS (primary endpoint)

Presented By Jean Bourhis at 2016 ASCO Annual Meeting Locoregional progression

Presented By Jean Bourhis at 2016 ASCO Annual Meeting Overall survival

Presented By Jean Bourhis at 2016 ASCO Annual Meeting Conclusions

Presented By Jean Bourhis at 2016 ASCO Annual Meeting Cetuximab in Locally Advanced SCCHN Unanswered Questions

• Bioradiation (BRT) equals CCRT in HPV negative SCCHN?

• BRT a better option for HPV positive SCCHN?

• BRT better option for elderly patients?

• BRT better option for patient with poor PS?

• BRT an option for organ preservation?

• Other antiEGFR mAbs or TKIs better?

CCRT= concurrent chemoradiotherapy Treatment of Locoregionally Advanced SCCHN Role of biologic therapy

Currently there are four multimodality treatment approaches:

1. Surgery → adjuvant RT or concurrent CRT (CCRT)

2. Definitive CCRT , with surgery as an optional salvage or completion treatment

3. Definitive RT + cetuximab (BRT), as an alternative when CCRT is not feasible or contraindicated, with surgery as an optional salvage or completion therapy

4. Induction CT → definitive local therapy (RT, CCRT, BRT )

CRT= chemoradiation; BRT= bioradiation Standard Treatment Options in R/MSCCHN 2016 • Resectable disease Surgery at all times if possible Postop RT or CCRT (if not complete) 1

• Nonresectable disease RT or CCRT (if no organ dysfunction/morbidiy) 1

• Recurrent/Metastatic disease PF+ cetuximab (in fit pts, performance status 0 or 1) 2,3 Single drug therapy with MTX, taxane or cetuximab (PS2) 3 Best supportive care only (PS3) 2,3

1Strojan et al. Head & Neck- DOI 10.1002/hed.23542; 2Gregoire V et al, Ann Oncol 2010: 21 (suppl 5): VI84-VI86; 3NCCN Guidelines Cetuximab in Platinum Pretreated Patients with R/M SCCHN

ORR Median PFS Median OS Author Phase N Regimen (%) (months) (months)

Vermorken* II 103 cetuximab 13 2.3 (TTP) 5.9 2007

Baselga* II 96 cetuximab + Platinum 10 2.8 (TTP) 6.1 2005

Herbst* II 79 cetuximab + Cisplatin 10 2.2 (TTP) 5.2 2005

Knoedler II 84 cetuximab + Docetaxel 11 3.1 6.7 2013

Baselga et al. JCO 2005; Herbst et al. JCO 2005; Knoedler et al. Oncology 2013; Vermorken et al. JCO 2007 *Platinum-refractory patients; TTP= time to progression AntiEGFR TKIs in Previously Treated SCCHN

Drug Phase/ prior CT Reference Resp. Rate,% Cetuximab II Pt refract Vermorken, Cancer, 2008 1013 Erlotinib II 01 lines Soulieres, JCO, 2004 4 Gefitinib II 01 lines Cohen, JCO, 2003 11 II 0 1 lines Kirby, BJC, 2006 9 II 05 lines Cohen, CCR, 2005 2 Lapatinib II unclear Abidoye, ASCO 2006 0 Dacomitinib II 0 line* Razak, Ann Oncol 2013 12.7 + Afatinib II R prior Pt Seiwert, Ann Oncol 2014 16/8*

MEHD7945A II R ≥1 line (Pt) Fayette, ESMO 2014 11.9

Prior CT= for recurrent/metastatic disease ( + by IR/ICR) * 49% had systemic therapy in the curative (primary) setting Secondline Treatment with AntiEGFR Drugs Randomized phase III trials in R/MSCCHN

Study/Reference N Regimen RR (%) PFS OS (mo)

IMEX 486 Gefitinib (250 mg) 3 ND 5.6 Stewart et al, 2009 Gefitinib (500 mg) 8 ND 6.0 Methotrexate 4 ND 6.7

ECOG 1302 270 D + Gefitinib 12 3.5 (TTP) 7.3 Argiris et al, 2013 D + placebo 6 2.1 (TTP) 6.0

ZALUTE 286 Z + BSC (MTX) 6 2.3* 6.7 ° Machiels et al, 2010 BSC (optional MTX) 1 1.9* 5.2 °

LUX HN1 483 Afatinib 10 2.6 6.8 Machiels et al, 2015 Methotrexate 6 1.7 6.0

BSC = best supportive care; Z = zalutumumab; MTX = methotrexate; ND = no data; TTP= time to progression *HR (95% CI): 0.62 (0.47-0.83), p=0,0010; °HR (95% CI): 0.77 (0.57-1.05), p=0.0648 Firstline Treatment with AntiEGFR MoAbs Randomized II/III trials in R/MSCCHN

Study/Reference N Regimen RR (%) PFS (mo) OS (mo)

ECOG 5397 117 Cisplatin + cetuximab 26 a 4.2 9.2 Burtness et al Cisplatin + placebo 10 2.7 8.0 J Clin Oncol 2005

EXTREME 442 PF 1 + cetuximab 36 a 5.6 b 10.1 c Vermorken et al PF 1 20 3.3 7.4 N Engl J Med 2008

SPECTRUM 657 PF 2 + panitumumab 36 a 5.8 b 11.1 Vermorken et al PF 2 25 4.6 9.0 Lancet Oncol 2013

PF 1 = cisplatin or carboplatin plus 5-FU; PF 2 = cisplatin plus 5-FU a, b, c : significant differences EXTREME: Symptom Control

Improving 20 CT CT + cetuximab symptoms

15

9.99 9.98 9.17 10 7.81

5 2.60 2.64 2.55 0.43 0 baselinebaselinescore score +0.24 +1.33 5 +3.51 +5.21 +4.42 +4.37

10 worst post worst p=0.0027 p=0.0162 p=0.5702 p=0.0787 p=0.0694 p=0.7732 p=0.2237 Mean change from changechangefrom from baselinebaseline to to MeanMean 15 Worsening symptoms 20 Pain Swallowing Sense Speech Social eating Problems Problems problems problems problems problems with social with contact reduced sexuality

QLQ-H&N35 module Modified from Mesía et al. Ann Oncol 2010 EXTREME – Overall Survival Longterm followup

Vermorken et al. ASCO 2014 (abstr. #6021) Cetuximab in Recurrent/Metastatic SCCHN Unanswered questions

• Do we need maintenance in EXTREME • Is the benefit of adding cetuximab different in patients with locoregional recurrence vs those with distant metastases? • Are there better regimens than EXTREME? • Can the ADCC be enhanced? • Are there biomarkers that will indicate who will respond? • What do we know from other biological agents • Can we overcome resistance? CT plus Cetuximab in FirstLine SCCHN Taxane regimens better partner?

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

Buentzel Pacli/Carbo + II 23 56 5.0** 8.0 2007 cetuximab Hitt II 46 Pacli + cetuximab 54 4.2 8.1 2011 Guigay II 54 Doce/Cis /cetuximab 54 7.1 15.3 2012

*Significant; **TTP Vermorken et al. NEJM 2008; Burtness et al. JCO 2005; Hitt et al. Ann Oncol 2011; Buentzel et al. ASCO 2007; Guigay et al. ASCO 2012 Treatment schedule

Maintenance: Chemotherapy + cetuximab:Up to 4 cycles cetuximab alone

1e 1 cycle

Until progression or Docetaxel unacceptable toxicity

Cisplatin Every 2 weeks

Cetuximab

Day 1 Day 8 Day 15 Day 22 Day 29 Evaluation after 2 cycles : if ORR or SD  2 additional cycles Docetaxel i.v. (75 mg/m² every 3 weeks) Cisplatin i.v. (75 mg/m² every 3 weeks) Cetuximab i.v. (500 mg/m² every 2 weeks ) Cetuximab i.v. (400 mg/m² at day 1 then 250 mg/m² once a week) ORR : 54% GCSF () delivered after every cycle Median PFS: 7.1 mo Median OS: 15.3 mo Guigay et al (ASCO 2012; abstract 5505) TPExtreme TRIAL GORTEC 201401 PI: J Guigay

Phase II (R 1:1) Control arm (EXTREME) Minimization on : (6 cycles every 3 weeks ) PS Metastatic status, Cisplatin : 100 mg/m2 iv • Cetuximab weekly until Previous cetuximab progression or unacceptable Country 5FU: 4000 mg/m2 during 96h in continuous infusion toxicity Cetuximab : 400 mg/m2 iv (loading dose), then 250 R mg/m2 iv

SCCHN R/M 1 st line (N = 416 ) Experimental arm (TPEx)  Age < 71 y (4 cycles every 3 weeks ) • Cetuximab every 2 weeks until  PS < 2 Cisplatine : 75 mg/m2 iv progression or unacceptable  Previous: Docetaxel: 75 mg/m2 iv toxicity cddp < 300mg/m 2 Cetuximab : 400 mg/m2 iv (loading dose), antiEGFR > 1y then 250 mg/m2 iv + G CSF after each cycle

 Primary objective: OS  Ancillary studies: QOL, costeffectiveness, p16 / HPV tumor status 46 Taxanes Enhance in vitro NK Cell Cytotoxicity

• Paclitaxel enhances cytotoxicity of NKcells against breast carcinoma cells by increasing perforin production (Kubo et al, 2005)

Healthy donors PBMCs treated for 24h with different concentration of Paclitaxel From Kubo et al, Cancer Immunol Immunother (2005) 54: 468–476 2,0 1nM 10nM • Paclitaxel modulates dependent ADCC 100nM against breast lines 1,5 Healthy donors PBMCs and purified NK cells treated for 24h with different concentration of 1,0 Paclitaxel 4 1nM 3,5 10nM

ADCCADCCefficiencyefficiency ratioratioXnM/0nM XnM/0nM 0,5 100nM 3

2,5

2

• The enhanced efficacy of ADCC 1,5 induced by Palitaxel is more prominent in purified NK cells 1 ADCCefficiency XnM/0nM ratio 0,5 PBMCs NK EGFR inhibitors: Potential Biomarkers Predictive of Efficacy

• EGFR – IHC detection – FISH detection – Mutations – Gene levels/polymorphisms • EGFR ligands (EGF, heregulin, , ) • KRAS • COX2 • PTEN loss • PI3K mutations • HPV Other Novel Targeted Agents in SCCHN

• Antiangiogenesis – VEGF – VEGFR • inhibitors • Histone deacetylase inhibitors No phase III • PI3K/Akt/mTOR pathway inhibitors data available • Proteasome inhibitors • IGFR inhibitors • SRC inhibitors 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, such as – IGF1R, MET, erbB2 – PI3K/AKT mutations – Cycline D1 amplification Strategies to Overcome Resistance to AntiEGFR Drugs (in HNC)

• Blockage of multiple HER receptors Lapatinib : oral reversible dual TKI of EGFR and HER2 Afatinib and dacomitinib : irreversible panHER inhibitors

• Dual targeting mAbs or mixture of mAbs MEHD7945A (DAF): –Randomized phase II vs cetuximab in patients progressing on/after PtCT ( NCT01577173 ) (antiEpCAM xantiCD3), cytotoxicity assay (antiHER2/neu xantiCD3), cytotoxicity assay Sym004 (mixture of 2 mAbs targeting nonoverlapping epitopes on EGFR History of Immunotherapy

AntiPDL1/ PD1 enters clinical testing

2011

Courtesy of Dr. Seiwert. Presented at THNO-5 Modified from W. Joost Lesterhuis, John B. A. G. Haanen & Cornelis J. A. Punt Lisbon, Portugal, November 5-7, 2015 Nature Reviews Drug Discovery 10 , 591600 (August 2011) PD-1 / PD-L1 and CTLA-4 Targeting Agents

1. 2. – IgG4 – IgG4 – Humanized – Fully human – High Affinity for PD-1 – High Affinity for PD-1

(K D ~ 29 pM) (K D ~ 2.6 nM) – Approved for & – Approved for Melanoma & Lung Cancer Lung Cancer 3. Other PD-1/PD-L1 agents in development: • PD-L1 agents – , , • PD-1 agents – R2810, Tessaro, Novartis • Other Checkpoint targeted agents

4. CTLA-4 agents: • , Tremelimumab

Courtesy of Dr. Seiwert. Presented at THNO-5 Lisbon, Portugal, November 5-7, 2015. Patient Treated with Pembrolizumab

1) Single dose of Anti-PD-1 given

2) Develops Bleeding and enrolled in Hospice

3) Several weeks later tumor starts to respond and treatment with Pembrolizumab is restarted

Chow et al ECC 2015 Patient treated with Durvalumab (MEDI4736)

26-30 September 2014, Madrid, Spain esmo.org Presented by: Matt Fury, ESMO 2014 TakeHome Messages

• Understanding biology of SCCHN → change in treatment

• Bioradiation (cetuximab) may be a valuable option

• However, many questions on bioradiation unanswered

• PFE new standard regimen in 1 st line therapy for R/MSCCHN

• Role of maintenance cetuximab unclear

• Innate and required cetuximab resistance a problem

• Better partners of or alternatives for cetuximab under study

• Reactivation of immune surveillance by blocking PD1 inter action with its ligands seems a promising approach for HNC