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