Καρκίνος κεφαλής- τραχήλου: Εξατομικεύοντας τη θεραπεία

Αμάντα ΨυρρήΕπίκουρη Καθηγήτρια

Αττικό Νοσοκομείο

OUTLINE

• Incidence• Etiology• EGFR as a target• Studies using EGFR-targeted therapies• Checkpoint Inhibitors

Incidence

• In 2015, 45.780 new cases of oral cavity and pharynx cancer and 8.650 deaths are expected to occur in the United States

Stage Distribution by Race, United States 2004-2010

5-year Relative Survival Rates by Race and Stage , United States, 2004-2010

Etiology

• Traditionally, tobacco and alcohol use account for the majority of HNSCC

• A growing proportion of oropharyngeal squamous cell carcinomas is caused by high-risk Human Papillomaviruses (HPV), especially HPV16

Epidemic of HPV-associated OPC*

Staging and treatment overview

Early stages (I&II):30% to 40% of patients• Surgery (PLUS: no long-term radiation (RT) toxicities)• Definitive RT (PLUSES: organ preservation, patients with

comorbidities)Locally advanced non metastatic (III&IVA/B)• Definitive cisplatin chemoradiotherapy • Surgery followed by RT or cisplatin-chemoradiotherapyMetastatic disease• Palliative chemotherapy

Mountzios G, T Rampias and A.Psyrri. Ann Oncol 2014;25:1889-1900

EGFR as a molecular target in HNSCC

• EGFR expression linked to poorer outcome1 and reduced response to radiotherapy2,3

1. Psyrri, et al. Clin Can Res 2005;11:5856-622. Baumann M, Krause M. Radiother Oncol 2004;72:257‒266

3. Ang KK, et al. Cancer Res 2002;62:7350–7356

Cetuximab• Cetuximab

– IgG1 mAb– Chimeric protein– Specifically binds with

high affinity to FcγRI (EC50 = 0.13 nM) and FcγRIIIa (EC50 = 6 nM)

– Induces apoptosis and ADCC*

– Preclinical synergistic activity in combination with chemotherapy and radiotherapy

*ADCC: antibody dependent cellular cytotoxicity

Cancer Cell Volume 7, Issue 4 2005 301 - 311

EGFR, epidermal growth factor receptor; mAb

Strategies to improve outcomes in HNSCC utilizing EGFR inhibitors

• Treatment intensification of locally advanced HNSCC to improve OS

- Randomized trials: CRT+EGFR inhibitor versus CRT• EGFR inhibition in the post-induction setting to

reduce toxicity in sequential design- Randomized phase II studies of induction

chemotherapy followed by either chemoradiotherapy or cetuximab radiotherapy to reduce toxicity without compromising efficacy

CRT: chemoradiotherapy; OS: overall survival

Randomized trials of EGFR inhibitor plus chemoradiation in HNSCC

AUTHOR # pts Treatment Comparator Primary Endpoint Setting S vs E P

value

Giralt et al 2012 150 C+EBRT+P C+ EBRT 2 yr LRC Locally

advanced

68% vs

61%0.3

Martins et al2013 204 C+RT+

ErlotinibC+RT CRR Locally

advanced

40% vs

52%0.08

Ang et al2011 895 C+RT+

cetuximab C+RT PFS Locallyadvanced

64%vs

63%NS

C: cisplatin; EBRT: external beam radiation therapy; RT: radiation therapy; S: standard, E: experimental arm; P: Panitumumab; CRR: complete response rate

EGFR inhibitor + Chemoradiation: Toxicity

TOXICITY GRADE > 3 Author Mucositis Skin

ReactionsSkin

Reactions out of Field

E S E S E S

Ang 43% 33% 25% 15% 29% 1%Giralt 11% 5% 28% 13% 11% 0%Martins 48% 48% 13% 2% NR NR

Strategies to improve outcomes in HNSCC utilizing EGFR inhibitors

• Treatment intensification of locally advanced HNSCC to improve OS

-Randomized trials: CRT+EGFR inhibitor versus CRT• EGFR inhibition in the post-induction setting to

reduce toxicity in sequential design-Randomized phase II studies of induction chemotherapy followed by either chemoradiotherapy or cetuximab radiotherapy to reduce toxicity without compromising efficacy

CRT: chemoradiotherapy; OS: overall survival

The Randomized Phase II Study: TREMPLIN

P: cisplatin; F: 5-fluorouracil; T: docetaxel; TL: total laryngectomy; PR: partial response ; RT: radiotherapy; CT: computed tomography; Tx: treatment

TPF (153 patients)3 cycles, 1 cycle q3w

T = 75 mg/m² on day 1P = 75 mg/m² on day 1

F = 750 mg/m² on day 1 to 5

60 patients: RT 70 Gy Cisplatin 100 mg/m² on days 1, 22 and 43

56 patients: RT 70 GyERBITUX 400 mg/m² 1 wk prior to RT then 250 mg/m² weekly on wks 1 to 7

R

Total laryngectomy + post-op RT

< PR 23

≥ PR116

•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

Lefebvre et al: JCO 2013Mar;31(7):853-9

Acute toxicity during RT

Cisplatinn = 58

ERBITUXn = 56

p-value

Grade 3 mucositisGrade 4 mucositis

25 (43%)2

24 (43%)1 NS

Grade 3 in field skin toxicityGrade 4 in field skin toxicity

14 (24%)1

29 (52%)3

< 0.001

Other toxicities, any grade, justifying a protocol modification Renal toxicity Hematological toxicity Poor general condition Infusion-related reaction

9 (15.5%)8 (14.0%)7 (12.0%)

0

00

1 (1.7%)3 (5.0%)

Protocol modification due to acute toxicity 33 (57%) 19 (29%) 0.02

* 2 patients did not start the treatment in the cisplatin arm

Lefebvre et al: JCO 2013Mar;31(7):853-9

Carcinologic events (ITT)

At 18 months after endof treatment

Last evaluation with a median follow-up of 36 months

Cisplatin ERBITUX p-value Cisplatin ERBITUX p-value

Total of local (+/- regional) failures 5 (8.3%) 8 (14.3%) Log-rank:

0.307 (11.7%) 12 (21.4%) Log-rank:

0.14

Feasible salvage total laryngectomy 0/4* 7/8 0.01 1/6* 9/12

(1 refused) 0.04

Successful salvage total laryngectomy 0/1 7/8

Ultimate local failure rate 6 (10%)* 5 (8.9%) NS

Regional failure alone 5 (8.3%) 5 (8.9%) NS 5 (8.3%) 5 (8.9%) NS

Distant metastases 2 (3.3%) 2 (3.6%) NS

Second primary tumor 3 (5.0%) 3 (5.3%) NS

* Data missing for 1 patient lost to follow-up at 5 months

ITT: intention to treat

Lefebvre et al: JCO 2013Mar;31(7):853-9

Endpoints (ITT)

Primary endpoint (3 months after end of Tx)

Cisplatin n = 60

ERBITUXn = 56

p-value

Larynx preservation, n (%)(larynx in place without tumor)

57 (95%) 52 (93%) 0.63

Secondary endpoints (18 months after end of Tx)

Cisplatin n = 60

ERBITUXn = 56

p-value

Larynx function preservation, n (%)(larynx in place without tumor/trach/feeding tube)NB: at 18 months or at death

52 (87%) 46 (82%) 0.68

Overall survivalNB: since randomization 92 % 89 % Log-rank: 0.44

NB: 1 pt lost to FU in the Cisplatin arm is considered as failure

OS by HPV status in prospectiveclinical trials

Regimen Time HPV + vs HPV - P value

Induction+CRT(ECOG)

2 year 95% vs 62% 0.005

CRT (TROG2.2) 2year 94% vs 77% 0.007

CRT (RTOG0129) 3 year 79%vs 46% 0.002

Induction+CRT (TAX324)Radiation (DAHANCA) 5year

5year

93% vs 35%

62% vs 26%

<0.001

0.003

Rationale for treatment de-intensification

• The better outcome of HPV+ HNSCC raises the question as to whether we can reduce the intensity of treatment in this patient population

• These patients are young and should not suffer the consequences of unnecessary overtreatment

LRC (months)

Results: LRC of RT + cetuximab compared with RT alone in p16-positive OPC

No. risk OPC p16 positive (n=75)RT 34 24 20 12 6 0RT + cet 41 33 30 21 12 0

0.00.10.20.30.40.50.60.70.80.91.0

Prob

abili

ty o

f LR

C

0 12 24 36 48 60

RT + cet; p16 +

RT; p16 +

87%

65% HR=0.31 [0.11–0.88]

Rosenthal D et al: ICHNO 2015

Presented by: Anthony J. Cmelak, MD

Cisplatin 75/m2 d1Paclitaxel 90/m2 d1,8,15Cetuximab 250/m2 d1,8,15

Q 21 days for 3 cycles

ER VE AS LP UO AN TS I E O

N

CLINICAL CR Low dose IMRT 54Gy/27fx* + Cetuximab qWeek

CLINICAL PR/SDFull dose IMRT 69.3Gy/33fx* + Cetuximab qWeek

Induction Chemotherapy

Concurrent Chemoradiation

IMRT margins for primary: 1.0 to 1.5cm around gross dz Nodal margin: 1cm margin minimum, treat entire nodal level

Eligibility•OPSCC•resectable•HPV ISH + and / or p16+•Stage III,IVA

ECOG 1308: Phase II Schema

Response: Induction

Presented by: Anthony J. Cmelak, MD

Clinical Response Primary Site NodesCR 75 (71%)* 48 (61%)

PR 7 (9%) 19 (24%)

SD 11 (14%) 7 (9%)

Unevaluable 5 (6%) 5 (6%)

Radiographic Response Primary Site Nodes

CR 38 (48%) 4 (5%)

PR 24 (30%) 55 (70%)

SD 9 (11%) 17 (22%)

Unevaluable 9 (11%) 3 (4%)

* 6 patients had biopsies performed on primary after baseline scans

Response: Following Cetux/IMRT

Presented by: Anthony J. Cmelak, MD

Clinical Response Primary Site NodesCR/PR 75 (94%) 74 (94%)

SD 0 (0%) 19 (24%)

Unevaluable 5 (6%) 2 (3%)

Radiographic Response Primary Site Nodes

CR/PR 65 (81%) 74 (94%)

SD 5 (6%) 3 (4%)

Unevaluable 10 (13%) 2 (3%)

Endpoint: 2yr PFS and OS

Presented by: Anthony J. Cmelak, MD

Cohort (n) 2 year PFS (90% CI) 2 year OS (90% CI)All low dose pts (62) 0.80 (0.70, 0.88) 0.93 (0.85, 0.97)

T4a (7) 0.54 (0.19, 0.79) 0.86 (0.45, 0.97)

Non-T4a (55) 0.84 (0.73, 0.91) 0.94 (0.86, 0.98)

N2c (19) 0.77 (0.56, 0.89) 0.95 (0.76, 0.99)

Non-N2c (43) 0.82 (0.69, 0.90) 0.93 (0.82, 0.97)

Smoker >10pk-yrs (22) 0.57 (0.35, 0.73) 0.86 (0.67, 0.94)

Smoker ≤10pk-yrs (40) 0.92 (0.81, 0.97) 0.97 (0.87, 0.995)

Smoker ≤10k-yrs, <T4, N2c (27)

0.96 (0.82, 0.99) 0.96 (0.82, 0.99)

All high-dose pts (15)* 0.65 (0.41, 0.82) 0.87 (0.63. 0.96)

* 3 high-dose pts did not go on to receive RT

PFS and Survival: Dose

Presented by: Anthony J. Cmelak, MD

2-yr = 80%

2-yr = 65%

2-yr = 87%

2-yr = 93%

Best Outcome: <T4, T1-N2b, <10 pk-yr

Presented by: Anthony J. Cmelak, MD

2-yr = 96%

2-yr = 64%

Radiation Therapy Oncology Group 1016 : Study Design

• Stage III/IV • Oropharynx• P16+

RANDOMIZE

II: Accelerated IMRT 70Gy/6weeks (cetuximabx8)

I: accelerated IMRT 70Gy/6weeks(cisplatin 100 mg/m², d1, 22)

Stratification factors: , cN-stage (cN0-2a vs cN2b- cN3), cT-stage (T1-2 vsT3-4) Zuprod Performance Status (0 vs 1), smoking history (<10py vs >10py)

Presented by: Amanda Psyrri

Recurrent/Metastatic HNSCC: Cytotoxic Agents

First-line therapy• For fit patients: first-line option should include the combination of

cetuximab with cisplatin or carboplatin plus 5-Fluorouracil (PF)4,5 (category 1) or platinum-taxane combinations+/- cetuximab or cisplatin plus 5-Fluorouracil or cetuximab

• For patients with poor PS: use single agent chemotherapy or cetuximab4

Second-line therapy• For fit patients: chemotherapy, cetuximab, clinical trial or best

supportive care5-median overall survival 3-6 months 4. Gregoire V et al: Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice

Guidelines for diagnosis, treatment and follow-up Ann Oncol 2010 5. NCCN guidelines v2.2014

32. NCCN. Clinical practice guidelines in oncology: head and neck cancers. v.2.2013.

EXTREME: Phase III Study Design

cetuximabuntil PD

R/M SCCHN• Prior CT• KPS (<80 vs. ≥80) CT + cetuximab

Primary endpoint: OS Secondary endpoints: PFS, RR, safety

CT Cisplatin (100 mg/m2 IV, day 1) orCarboplatin (AUC 5, day 1) + 5-FU (1000 mg/m2 IV, days 1–4)Every 3 weeks, up to 6 cycles

cetuximabInitial dose 400 mg/m2

then 250 mg/m2 weeklyuntil PD

n=442

CT

Vermorken et al. N Engl J Med 2008CT, chemotherapy; KPS, Karnofsky performance status; OS, overall survival; PD, progressive disease; PFS, progression free survival; RR, response rate

127153

83118

6582

4757

1930

173184

220222

815

13

HR : 0.80 (95% CI: 0.64-0.99; P = .04)

Chemotherapy only (n = 220) 20Chemo + cetuximab (n = 222) 36

Surv

ival

Pro

babi

lity

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24

10.1 mos7.4 mos

Pts at Risk, nCTX only

CET + CTX

Survival Time (Mos)

Cetuximab ± First-line Platinum in Recurrent or Metastatic HNSCC: OS

ORR, %

37. Vermorken JB, et al. N Engl J Med. 2008;350:1116-1127.

Cetuximab ± First-line Platinum in Recurrent or Metastatic HNSCC:

Safety

38. Vermorken JB, et al. N Engl J Med. 2008;350:1116-1127.

Grade 3/4 AEs in ≥ 5% of Pts, n (%)

Cetuximab +Chemotherapy

(n = 219)

Chemotherapy Alone (n = 215) P Value*

Grade 3/4 Grade 4 Grade 3/4 Grade 4

Any event 179 (82) 67 (31) 164 (76) 66 (31) .19

Neutropenia 49 (22) 9 (4) 50 (23) 18 (8) .91

Anemia 29 (13) 2 (1) 41 (19) 2 (1) .12

Thrombocytopenia 24 (11) 0 24 (11) 3 (1) 1.00

Leukopenia 19 (9) 4 (2) 19 (9) 5 (2) 1.00

Skin reactions 20 (9) 0 1 (< 1) 0 < .001

Hypokalemia 16 (7) 2 (1) 10 (5) 1 (< 1) .31

Cardiac events 16 (7) 11 (5) 9 (4) 7 (3) .22

Vomiting 12 (5) 0 6 (3) 0 .23

Asthenia 11 (5) 1 (< 1) 12 (6) 1 (< 1) .83

Anorexia 11 (5) 2 (1) 3 (1) 1 (< 1) .05

Hypomagnesemia 11 (5) 8 (4) 3 (1) 1 (< 1) .05

Febrile neutropenia 10 (5) 2 (1) 10 (5) 4 (2) 1.00

*Comparing Grade 3 and 4 combined.

Impact of Human Papillomavirus (HPV) and p16 Status on Survival and Response with Cisplatin plus 5-FU and Cetuximab in

Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

(R/M SCCHN): Analysis of the Phase III EXTREME Trial

A. Psyrri, R. Mesía, F. Peyrade, F. Beier, B. de Blas, I. Celik,

L. Licitra, Jan B Vermorken ESMO 2012

Overall Survival: Interaction-HPV Status and Treatment

Number of subjects at riskGroup 1 :Group 2 :Group 3 :Group 4 :

11145 13152

10123 8119

8101 8 83

7 75 4 52

6 52 4 40

4 34 3 29

2 18 2 12

0 10 1 5

0 2 1 0

0 0 0 0

'

'

'

'

'

Group 1: Cetuximab + CTX Positive Results Censored Event Group 2: Cetuximab + CTX Negative Results Censored event

Group 3: CTX Positive Results Censored Event Group 4: CTX Negative Results Censored event

Sur

viva

l Dis

tribu

tion

Func

tion

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Survival Time (months)

0 3 6 9 12 15 18 21 24 27

Protocol: EMR 62 202 - 002 - Clinical data cut-off: 12MAR2007- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Figure 1.3.2.1: Overall Survival - Interaction ITT Population (HPV Evaluable Subjects)

Note: Analysis performed based on the 28MAR2007 data snapshot.

Overall Survival by HPV StatusHPV+ patients HPV- patients

HR (95% CI) 0.63 (0.30–1.34)p-value 0.22

HR (95% CI) 0.82 (0.65–1.04)p-value 0.11

Number of subjects at riskGroup 1 :Group 2 :

11 13

10 8

8 8

7 4

6 4

4 3

2 2

0 1

0 1

0 0

'

'

'

''

Group 1: Cetuximab + CTX Censored Event

Group 2: CTX Censored event

Sur

viva

l Dis

tribu

tion

Func

tion

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Survival Time (months)

0 3 6 9 12 15 18 21 24 27

Protocol: EMR 62 202 - 002 - Clinical data cut-off: 12MAR2007- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Figure 1.1.2.2: Overall Survival by Treatment Group ITT Population (HPV Positive Subjects)

Note: Analysis performed based on the 28MAR2007 data snapshot.

Number of subjects at riskGroup 1 :Group 2 :

145152

123119

101 83

75 52

52 40

34 29

18 12

10 5

2 0

0 0

'

'

'

'

'

Group 1: Cetuximab + CTX Censored Event Group 2: CTX Censored event

Sur

viva

l Dis

tribu

tion

Func

tion

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Survival Time (months)

0 3 6 9 12 15 18 21 24 27

Protocol: EMR 62 202 - 002 - Clinical data cut-off: 12MAR2007- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Figure 1.1.2.3: Overall Survival by Treatment Group ITT Population (HPV Negative Subjects)

Note: Analysis performed based on the 28MAR2007 data snapshot.

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

• Afatinib is an irreversible ErbB-family blocker1–3

– Inhibits all kinase-active members: EGFR, HER2 and HER4

– Approved* in the major ICH regions of US, EU and Japan for the treatment of patients with NSCLC harbouring distinct types of EGFR-activating mutations

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

1. Li D, et al. Oncogene 2008;27:4702–11; 2. Solca F, et al. J Pharmacol Exp Ther 2012;343:342–50; 3. Yarden Y, Pines G. Nat Rev Cancer. 2012;12:553–563;

Afatinib: irreversible ErbB-family inhibitor

PROLIFERATION SURVIVAL

RAS

ERK

AKT

RAF

MEK

P13K

mTOR

EGFR/HER2

HER2/ErbB3

ErbB4/ErbB3

AfatinibGefitinibErlotinib

Afatinib

Primary endpoint: PFS independent review

CI, confidence interval; MTX, methotrexate

Time (months)

0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12

Estim

ated

PFS

pro

babi

lity

15 18

No. of patientsAfatinib 322 93 26 9 3 1 0MTX 161 28 6 2 0 0 0

Afatinib(n=322)

MTX(n=161)

PFS event, n (%) 275 (85.4) 135 (83.9)Median PFS (months) 2.6 1.7HR (95% CI) 0.80 (0.65–0.98)Log-rank test p-value 0.030

42.8%

30.5%

+ 0.9 months

 

Overall survival – LUX-1

Time (months)

Estim

ated

OS

prob

abili

ty

No. of patientsAfatinib 322 255 172 89 53 28 14 6 1 0MTX 161 115 76 48 29 16 9 7 3 0

Afatinib(n=322)

MTX(n=161)

OS event, n (%) 237 (73.6) 121 (75.2)Median OS (months) 6.8 6.0HR (95% CI) 0.96 (0.77–1.19)Log-rank test p-value 0.700

0

0.2

0.4

0.6

0.8

1.0

0 3 9 15 21 24 2718126

+ 0.8 months

 

PD-1/PD-L1 in Immune Response Blockade

26-30 September 2014, Madrid, Spain esmo.org

Antitumor Activity of the anti-PD-1 Antibody Pembrolizumab in biomarker-unselected Patients with

R/M Head and Neck Cancer: Preliminary Results from the KEYNOTE-012 Expansion Cohort

Tanguy Seiwert,1 Robert Haddad,2 Shilpa Gupta,3 Ranee Mehra,4 Makoto Tahara,5 Raanan Berger,6 Se-Hoon Lee,7 Barbara Burtness,4 Dung Le,8 Karl Heath,9 Amy Blum,9 Marisa

Dolled-Filhart,9 Kenneth Emancipator,9 Kumudu Pathiraja,9 Jonathan D. Cheng,9 Laura Q Chow10

1Department of Medicine, The University of Chicago, Chicago, IL, USA; 2Dana Farber Cancer Institute, Boston, MA, USA; 3H.Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 4Fox Chase Cancer Center, Philadelphia, PA, USA; 5National Cancer Center Hospital East, Kashiwa, Japan; 6Sheba Medical Center, Tel Hashomer, Israel, 7Seoul National University

Hospital, Seoul, Korea; 8Johns Hopkins University, Baltimore, MD, USA; 9Merck & Co., Inc. Kenilworth, NJ, USA, 10University of Washington, Seattle, WA, USA.

Presented by:

Tanguy Seiwert, MDAssistant Professor of Medicine

Associate Director Head and Neck Cancer ProgramFellow, Institute of Genomics and Systems Biology

The University of Chicago

42

HNSCC expansion cohort of the KEYNOTE-012 Nonrandomized, Phase 1b Multi-cohort trial*

*Additional cohorts included bladder cancer, TN breast cancer, and gastric cance †Treatment beyond progression was allowed. ‡Re-treatment was permitted.

Patients: • Recurrent or metastatic

HNSCC, regardless of PD-L1 or HPV status

• Have measurable disease based on RECIST 1.1

• ECOG performance status of 0 or 1

Pembrolizumab 200 mg Q3W

• Treatment for 24 months†

• Documented disease progression‡

• Intolerable toxicity

Response assessment: Every 8 weeks

Primary end points: ORR per modified RECIST v1.1 by investigator review; safety

Secondary end points: PFS, OS, duration of response

43

Baseline DemographicsCharacteristic N = 132*

N (%)

Median age (range), years 60 (25−84)

Male 110 (83.3)

Race

White 96 (72.7)

Asian 28 (21.2)

Other 8 (6.1)

ECOG PS

[0] Normal Activity

38 (28.8)

[1] Symptoms, but ambulatory

94 (71.2)

Characteristic N = 132*N (%)

Prior adjuvant/neoadjuvant systemic therapy

Yes 53 (40.2)

Prior lines of therapy for recurrent/metastatic disease

0 22 (16.7)

1 30 (22.7)

2 28 (21.2)

3 or more 50 (37.9)

Unknown 2 (1.5)

Data cutoff date: March 23, 2015*Includes patients who received ≥1 dose of pembrolizumab

44

Treatment-Related Adverse EventsGrades 3-5 (≥2 patients)

N = 132* N (%)

Any 13 (9.8)Swelling face 2 (1.5)Pneumonitis 2 (1.5)

AE in ≥5 % of Patients N = 132*N (%)

Any 79 (59.8)

Fatigue 20 (15.2)

Hypothyroidism 12 (9.1)

Decreased appetite 10 (7.6)

Rash 10 (7.6)

Dry skin 9 (6.8)

Pyrexia 9 (6.8)

Arthralgia 7 (5.3)

Nausea 7 (5.3)

Weight decreased 7 (5.3)

*Includes patients who received ≥1 dose of pembrolizumabData cut off date: March 23, 2015.

• No treatment-related deaths occurred

45

Overall Response Rate [Site Radiology Review]*

Best overall responseTotal

N = 117†

HPV+ n = 34

HPV−n = 81

n (%) 95% CI n (%) 95% CI n (%) 95% CI

ORR 29 (24.8) 17.3-33.6 7 (20.6) 8.7-37.9 22 (27.2) 17.9-38.2

Complete Response 1 (0.9) 0.0-4.7 1 (2.9) 0.1-15.3 0 (0) 0-4.5

Partial Response 28 (23.9) 16.5-32.7 6 (17.6) 6.8-34.5 22 (27.2) 17.9-38.2

Stable Disease 29 (24.8) 17.3-33.6 9 (26.5) 12.9-44.4 19 (23.5) 14.8-34.2

Progressive Disease 48 (41.0) 32.0-50.5 13 (38.2) 22.2-56.4 34 (42.0) 31.1-53.5

No Assessment# 9 (7.7) 3.6-14.1 4 (11.8) 3.3-27.5 5 (6.2) 2.0-13.8

Non-evaluable± 2 (1.7) 0.2-6.0 1 (2.9) 0.1-15.3 1 (1.2) 0.0-6.7

*Unconfirmed and confirmed RECIST v 1.1 responses†Includes patients who received ≥1 dose of pembrolizumab, had measurable disease at baseline and ≥1 postbaseline scan or discontinued due to PD or DRAE. 15 patients not included in this analysis: 2 did not

have baseline scans within screening window, 13 did not have post-baseline assessment and discontinued due to non-drug related AE (7), subject withdrawal of consent (4), other (2).#No assessment: Discontinued without post-baseline radiographic assessment due to drug related AE (2 patients), clinical PD (6 patients), death due to PD (1 patient)±Non-evaluable: Images were not of sufficient quality to be evaluableHPV status missing for 2 patients with oropharynx cancer. Cancers outside the oropharynx are considered HPV negative by convention.Data cutoff date: March 23, 2015.

Overall Survival Data Head & Neck Cancer Program

Durvalumab (MEDI4736) Efficacy in HNC:

Presented by: Matt Fury, ESMO 2014

Durvalumab/MEDI4736: Clinical Data – ASCO 2015

48ASCO 2015: Advances in Head

and Neck CancerSegal et al. ASCO 2015

Durvalumab/MEDI4736: Clinical Data – ASCO 2015

49ASCO 2015: Advances in Head and Neck CancerSegal et al. ASCO 2015

HPV(-) patients seemed to have improved responses over HPV(+) patients

Durvalumab was safe and tolerable– Drug-related AEs: 60% – Grade ≥3 drug-related AEs: 7%

Pis: Tanguy Seiwert and Amanda Psyrri

ConclusionsConclusions

• Cetuximab remains the only targeted therapy approved in HNSCC

• Until the results of RTOG1016 become available, cisplatin- containing

chemoradiotherapy remains the standard of care for HPV+ locally

advanced oropharyngeal cancer

• Immune checkpoint inhibitors hold promise in HNSCC