understanding recent progress in head and neck squamous cell carcinoma
TRANSCRIPT
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Understanding Recent Progress in Head and Neck Squamous Cell
CarcinomaMaura L. Gillison, MD, PhD
Professor of MedicineThe Ohio State University
Comprehensive Cancer Center
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Dr. Gillison discloses the following commercial relationships: Consultant: Amgen, AstraZeneca, Celgene,
Bristol-Myers Squibb, Lilly, Merck, GlaxoSmithKline
Disclosures
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Describe the diagnostic evaluation and staging of HNSCC
Evaluate prognostic markers that can optimize treatment selection for patients with locally advanced and recurrent/metastatic HNSCC
Assess efficacy and safety data on novel therapies for patients with locally advanced and recurrent/metastatic HNSCC
HNSCC = head and neck squamous cell carcinoma.
Learning Objectives
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NCI, 2012.
Head and Neck Cancer
Paranasal sinusNasopharynxOral cavityPharynx
OropharynxHypopharynxLarynx
Salivary glands
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Worldwide 2012:→ 599,000 cases worldwide in 2012→ 325,000 deaths worldwide in 2012
US 2016:→ 61,760 cases→ 13,190 deaths
Ferlay et al, 2015; ACS, 2016.
Head and Neck Cancer Burden
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Gillison, 2013.
Global Incidence in 2012
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Tobacco use Alcohol use HPV Oral hygiene Diet Family history Age, gender, race
HPV = human papillomavirus.Gillison, 2007.
Established Risk Factors
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Population Attributable Risk (PAR), Oral Cancer, France
Risk Factor PARa (%) 95% CIAlcohol alone 0.3 -3.0-3.9
Tobacco alone 12.7 6.9-18.0Tobacco and alcohol 69.9 64.4-74.7
Tobacco and/or alcohol 82.9 73.8-88.5
Adjusted for gender, age, BMI, education, exercise, family history of HNC, alcohol, residence, history of candidiasis, tea drinking.
CI = confidence interval; BMI = body mass index; HNC = head and neck cancer. Radoi et al, 2015.
Tobacco Use
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Unique Characteristics of HPV-HNC
BOT = base of tongue; SE = socioeconomic.Gillison et al, 2008.
HPV-Positive HPV-NegativeAnatomic siteHistologyAge GenderSE statusRisk factorsCofactorsGeneticsIncidenceSurvival
Tonsil/BOTBasaloidYounger3:1 men
HighSexual behavior
Marijuana, immunosuppression
p53WT, p16+Increasing
High
All sites Keratinized
Older3:1 men
LowAlcohol/tobaccoDiet, hygienep53Mu, p16-Decreasing
Worse
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In US from 1988 to 2004:
Similar changes in numerous developed countries worldwide
Rapidly Changing Incidence of HPV-Positive vs HPV-Negative
HNC Oropharynx rates
increasing overall HPV-positive increased
by 225% HPV-negative declined
by 50%
Chaturvedi et al, 2011; Chaturvedi et al, 2013.
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Oral pain or sore throat Ulcer or mass Dysphagia or odynophagia Hoarseness Dyspnea Headache or ear pain Sinus congestion or bleeding Neck mass
NCCN, 2016.
Common Presenting Symptoms
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Physical exam Indirect laryngoscopy Imaging studies Panendoscopy with biopsy Fine needle aspiration Chest imaging PET scan
PET = positron emission tomography.
Head and Neck Cancer Staging
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New staging system specific to HPV-positive oropharynx cancer went into effect January 1, 2017
It has not yet been released, but is based upon an analysis published by O’Sullivan and colleagues (2016)
TNM = extent of tumor, extent of spread to lymph nodes, presence of metastasis.O’Sullivan et al, 2016.
8th Edition AJCC TNM Staging System
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Tumor stage T1: Tumor ≤2 cm T2: Tumor >2 cm and ≤4 cm T3: Tumor >4 cm T4: Tumor invades adjacent structures
Edge et al, 2010.
7th Edition AJCC TNM Staging System: Oropharynx Cancer
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Edge et al, 2010.
TNM Staging: Cervical Lymph Nodes
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Edge et al, 2010.
7th Edition AJCC TNM Staging System: Oropharynx Cancer
StageStage 1 T1N0Stage 2 T2N0Stage 3 T3N0, T1-3N1Stage 4A T1-4N2, resectableStage 4B T1-4N0-3,
“unresectable”Stage 4C Any T, Any N, M1
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HPV-positive OPC HPV-negative OPC
TNM stage discriminates prognostic groups for HPV-negative but not HPV-positive oropharynx cancer.
76 68 53 45 34
5-year OS5-year OS8882848160
OS = overall survival; OPC = oropharyngeal cancer. O’Sullivan et al, 2016.
7th Edition AJCC Staging System: OS
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5-year OS
7th Edition AJCC ICON-S
None N0 N0Unilateral N1, N2a, N2b N1Bilateral N2c N2>6 cm N3 N3
ICON-S = International Collaboration on Oropharyngeal Cancer Network for Staging. O’Sullivan et al, 2016.
ICON-S Proposal for HPV-Positive HNC
8th Edition AJCC Staging
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Associations between ICON-S stage and OS in training (left) and validation (right) data
sets.76 68 53 45 34
5-year OS5-year OS88828481605-year OS
857853
5-year OS888165
AHR = adjusted hazard ratio. O’Sullivan et al, 2016.
ICON-S Proposal for HPV-Positive HNC
8th Edition AJCC Staging (cont.)
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Age Race Performance status Comorbidity HPV status Weight loss Anemia Smoking status Social support
Prognostic Factors
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Arm 1:Standard fractionation (SFX) 70 Gy/35 Fx/7 weeksplus cisplatin 100 mg/m2 on D 1, 22, 43
RANDOMIZE
Tumor Site1. Larynx2. Non-larynxS
TRATIFY
Nodal Stage1. N02. N1 or N2a-b3. N2c or N3Zubrod Performance
Status1. 02. 1
Arm 2:Accelerated Fractionation by Concomitant Boost (AFX-C)72 Gy/42 Fx/6 weeksplus cisplatin 100 mg/m2 on D 1, 22
Ang et al, 2010.
Radiation Therapy Oncology Group 0129
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Ang et al, 2010.
RTOG 0129 OS by HPV Status
log-rank p<0.001
3-year difference26%, 12-40
Ove
rall S
urviv
al (%
)
0
25
50
75
100
Years after Randomization0 1 2 3 4 5
Patients atRiskHPV Pos.HPV Neg.
Patients atRisk
206117
Patients atRisk
19389
Patients atRisk
18076
Patients atRisk
16264
Patients atRisk
11934
Patients atRisk
309
HPV Positive
HPV Negative
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Ang et al, 2010.
HPV Status and Survival
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HR = hazard ratio. Ang et al, 2010.
Risk Model for Death and Progression: Oropharynx Cancer
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New Data From Surgical Trials
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Arm 2 (C+RT) N=282
PET-CT at 12 weeks
Eligibility Oral cavity,
oropharynx, larynx, hypopharynx, unknown primary
N2 or N3 Suitable for
chemoRT No neck dissection
contraindications No prior treatment Age ≥18 years
C = chemotherapy; RT = radiation therapy; CT = computed tomography. Mehanna et al, 2016.
PET-NECK Noninferiority Trial
Arm 1 (C+RT) N=282
Planned neck dissection
1:1
90% power, 2-year OS 75% , Δ<10%, HR<1.5
Primary End Point: OS
RANDOMIZE
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PET-NECK: Patients Characteristics
Mehanna et al, 2016.
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2-year OS 84.9% vs 81.5%, HR 0.92, (95% CI 0.65-1.32)Mehanna et al, 2016.
PET-CT Surveillance vs Neck Dissection in Advanced HNC
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PET-CT reduced neck dissections (54 vs 221)
Surgical complications were similar OS was similar Quality of life was similar PET-CT was cost effective
Mehanna et al, 2016.
PET-CT Surveillance vs Neck Dissection in Advanced HNC
(cont.)
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Arm 2 N=255Surveillance
Elective vs Therapeutic Neck Dissection in Node-Negative Oral
CancerEligibility SCC oral cavity Lateralized T1-
2 N0 No history of
HNC No prior
treatment Age 18-75
years
Arm 1 N=245
Planned neck dissection
1:1
80% power, 5-year OS 60% , Δ>0%, HR<1.5
STRATIFY
Tumor siteT1 vs T2Gender+ vs-US
RANDOMIZE
D’Cruz et al, 2015.
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Median depth of invasion 6 mm, range 0-20D’Cruz et al, 2015.
ELECTIVE-NECK: Patient Characteristics
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Median follow-up 39 months3-year OS 80.0% vs 67.5%
DFS = disease-free survival. D’Cruz et al, 2015.
Elective vs Therapeutic Neck Dissection in Node-Negative Oral Cancer
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Median follow-up 39 months3-year DFS 69.5 vs 45.9%
D’Cruz et al, 2015.
Elective vs Therapeutic Neck Dissection in Node-Negative Oral Cancer (cont.)
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D’Cruz et al, 2015.
Overall Survival According to Subgroup
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D’Cruz et al, 2015.
Pattern of Recurrence
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OS and DFS were superior with neck dissection
Depth of invasion predicted node positivity in END arm
Factors associated with worse OS were poor grade, LVE and PNI, higher depth of invasion
Adverse events were similar Study controversial due to undertreatment of
surveillance arm. No RT given to patients with depth of invasion >4 mm
LVE = lymphovascular embolization; PNI = perineural invasion.
Elective vs Therapeutic Neck Dissection in Node-Negative Oral
Cancer
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New Data on Induction Chemotherapy for
Nasopharyngeal Cancer
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CRT IMRT ≥66 Gy 6-7 weeksCisplatin 100
mg/m2 D 1, 22, 43
Induction Chemotherapy For NPCA
Eligibility WHO II/III NPCA Stage III/IV M0 No prior treatment KPS ≥70 Age 18-59 years Adequate organ
function
NPCA = nasopharyngeal carcinoma; WHO = World Health Organization; KPS = Karnofsky performance status; TPF = cisplatin, fluorouracil, docetaxel; FFS = failure-free survival; CRT = chemoradiotherapy; IMRT = intensity-modulated radiation therapy.Sun et al, 2016.
RANDOMIZE
TPF X 3 N=241
1:1
80% power, 3-year FFS 78%, Δ>10, HR<0.52, N=452
Primary end point: FFS
N=239TPF: Cisplatin 60 mg/m2
Docetaxel 60 mg/m2
5-FU 600 mg/m2/d X4
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Variable Subset Induction + CRT CRTGender Men 193 (80%) 174 (73%)
Women 48 (20%) 65 (27%)
Age, years
42 (36-49) 44 (39-50)KPS 90-100 217 (90%) 211 (88%)
70-80 24 (10%) 28 (12%)T category T1 15 (6%) 6 (3%)
T2 27 (11%) 19 (8%)T3 112 (47%) 121 (51%)T4 87 (36%) 93 (39%)
N category N1 97 (40%) 107 (45%)N2 105 (44%) 106 (44%)N3a 13 (5%) 11 (5%)N3b 26 (11%) 15 (6%)
Stage III 129 (54%) 133 (56%)IVA 73 (30%) 80 (33%)IVB 39 (16%) 26 (11%)
Sun et al, 2016.
Patient Characteristics
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IC = induction chemotherapy; CCRT = concurrent chemoradiotherapy.Sun et al, 2016.
FFS and OS
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Sun et al, 2016.
FFS and OS (cont.)
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FFS Induction + CRT CRT HR (95%CI) P ValueNo. failures 52 (22%) 71 (30%) – –3-year FFS 80% (75–85) 72% (66–78) 0.68 (0.48-0.97) 0.034Overall survivalNo. Deaths 26 (11%) 43 (18%) – –3-year OS 92% (87–94) 86% (81–90) 0.59 (0.36-0.95) 0.029Distant FFSDistant failures 27 (11%) 43 (18%) – –3-year DM FFS 90% (86–93) 83% (77–87) 0.59 (0.37–0.96) 0.031Locoregional FFSLR failures 20 (8%) 30 (13%) – –3-year LR FFS 92% (87–95) 89% (84–92) 0.64 (0.36–1.13) 0.12Response rate after CRTOverall 238 (99%) 239 (100%) – –Complete 237 (98%) 232 (97%) – 0.35Partial 1 (<1%) 7 (3%) – –Unassessable 3 (1%) 0 (0%) – –
DM = distant metastasis; LR = locoregional. Sun et al, 2016.
Outcomes Summary
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Induction + CRT (n=239) CRT (n=238) P Value
Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4Any† 132 (55%) 42 (18%) 125 (53%) 3 (1%) 0·55 <0·0001heme Neutropenia 64 (27%) 37 (15%) 16 (7%) 1 (<1%) <0·0001 <0·0001
Febrile neutropenia 5 (2%) 2 (1%) 0 0 0·061 0·50Neutropenic infection 1 (<1%) 0 0 0 1·00 --Leucopenia 86 (36%) 12 (5%) 40 (17%) 1 (<1%) <0·0001 0·0020Anaemia 4 (2%) 0 5 (2%) 0 0·75 --Thrombocytopenia 5 (2%) 1 (<1%) 2 (1%) 0 0·45 1·00
Non-heme
Stomatitis (mucositis) 96 (40%) 2 (1%) 82 (34%) 2 (1%) 0·20 1·00Vomiting 52 (22%) 4 (2%) 45 (19%) 0 0·44 0·12Nausea 46 (19%) 4 (2%) 40 (17%) 0 0·49 0·12Dry mouth 13 (5%) -- 13 (5%) -- 0·99 --Dermatitis 8 (3%) 1 (<1%) 10 (4%) 0 0·62 1·00Oesophagitis dysphagia or odynophagia
5 (2%) 0 9 (4%) 0 0·27 --
Hepatoxicity 7 (3%) 0 2 (1%) 0 0·18 --Allergic reaction 2 (1%) 0 0 0 0·50 --
Sun et al, 2016.
Toxicity Experience
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Reduced-dose TPF induction chemotherapy improved FFS and OS for patients with stage III/IV NPCA
Induction chemotherapy reduced distant failure rates As expected, TPF induction increased grade 3/4 heme
events Majority of patients completed TPF, but only 30%
completed 3 cycles of cisplatin with radiotherapy First clinical trial to demonstrate a survival benefit for
induction vs chemoradiotherapy Results will need to be confirmed A meta-analysis of 19 trials and 4,800 patients
revealed improved OS, PFS, LRC, and DM with chemoradiotherapy ± adjuvant vs adjuvant or induction alone
PFS = progression-free survival; LRC = locoregional control. Blanchard et al, 2015.
Induction Chemotherapy for NPCA
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Immunotherapy forPlatinum-Refractory HNC
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Patients with platinum-refractory R/M HNSCC have a dismal prognosis, with median overall survival ≤6 months No anticancer agent improves survival for this patient
population No new treatments have been approved in >10 years
HNSCC recurrence and metastasis are facilitated by immune evasion mediated by PD-L1 and PD-L2
Both HPV-positive and HPV-negative HNSCC frequently express PD-L1
R/M = recurrent/metastatic.Herbst et al, 2015; Ferris, 2015; Badoual et al, 2013; Concha-Benavente et al, 2015.
Introduction
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Sharpe et al, 2007.
Blocking PD-1/PD-L1 Restores T-Cell Function
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HNSCC Cohorts of Nonrandomized, Phase Ib,
Multicohort KEYNOTE-012 Triala
aAdditional cohorts included bladder cancer, TN breast cancer, and gastric cancer. bTreatment beyond progression was allowed.cInitial cohort only. ECOG PS = Eastern Cooperative Oncology Group performance status; ORR = objective response rate.
Pembrolizumab
200 mg Q3WN=132
Continue until:• 24 months
of treatmentb
• PD• Intolerable
toxicity
Response assessment: Every 8 weeksPrimary end points: ORR (RECIST v1.1, central imaging vendor), safetySecondary end points: ORR (investigator), PFS, OS, response duration, ORR in HPV+ patientsc
Pembrolizumab
10 mg/kg Q2WN=60
Initial Cohort
Expansion Cohort
Combined
analyses of initial
and expansio
n cohorts
Patients• R/M HNSCC• Measurable
disease (RECIST v1.1)
• ECOG PS 0-1• PD-L1+
(initial cohort)• PD-L1+ or PD-
L1- (expansion cohort)
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Overall Response RateKeynote 12
Data cutoff date: Apr 26, 2016. Response assessed per RECIST v1.1 (central imaging vendor review, all patients as treated)
Only confirmed responses are included
Best Overall Response
TotalN=192a
HPV+ n=45b
HPV-n=147b
n % 95% CI n % 95% CI n % 95% CI
ORR 34 18 13-24 11 24 13-40 23 16 10-23 CR 8 4 – 4 9 – 4 3 – PR 26 14 – 7 16 – 19 13 –
SD 33 17 – 7 16 – 26 18 – PD 93 48 – 19 42 – 74 50 – NAc 32 17 – 8 18 – 24 16 –
aIncludes patients who received ≥1 dose of pembrolizumab in the initial or expansion cohort.bHPV status was determined by the local institution. Cancers outside the oropharynx, identified from primary diagnosis/prior radiation/prior surgery, were considered HPV negative. cNo assessment because patient did not have central imaging review data or images were not evaluable.CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.
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Phase III CheckMate 141 Study Design
aTissue required for testing.DOR = duration of response; IV = intravenous; ORR = objective response rate; PFS = progression-free survival; Q2W = once every 2 weeks; R = randomized. Ferris et al, 2016.
Nivolumab in R/M SCCHN After Platinum Therapy
R2:1
Nivolumab 3 mg/kg IV Q2W
Investigator’s choice
• Methotrexate 40 mg/m² IV weekly
• Docetaxel 30 mg/m² IV weekly
• Cetuximab 400 mg/m² IV once, then 250 mg/m² weekly
Key eligibility criteria:
• R/M SCCHN of the oral cavity, pharynx, or larynx
• Progression on or within 6 months of last dose of platinum-based therapy
• Irrespective of no. of prior lines of therapy
• Documentation of p16 to determine HPV status (oropharyngeal)
• Regardless of PD-L1 statusa
Stratification factor:• Prior cetuximab
treatment
Primary end point:• OS
Other end points:• PFS• ORR• Safety• DOR• Biomarkers• Quality of
life
Randomized, global, phase III trial of the efficacy and safety of nivolumab vs investigator’s choice in patients with R/M SCCHN
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0 3 6 9 12 15 18
Median OS, mo
(95% CI)
HR(97.73%
CI)P
Value
Nivolumab (n=240) 7.5 (5.5, 9.1) 0.70
(0.51, 0.96)
0.0101Investigator’s choice
(n=121)5.1 (4.0,
6.0)
Ferris et al, 2016.
Overall Survival: CheckMate 141
MonthsNivolumab 240 167 109 52 24 7 0
Investigator’sChoice
121 87 42 17 5 1
No at Risk
0
0
10
20
30
40
50
60
70
80
90
100
Ove
rall
Surv
ival
(%
of p
atie
nts)
1-year OS rate (95% CI)
36.0% (28.5, 43.4)
16.6% (8.6, 26.8)
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Overall Survival by Tumor PD-L1 Expression at 1%
Ferris et al, 2016.
Nivolumab in R/M SCCHN After Platinum Therapy
Ove
rall
Surv
ival
(% o
f pat
ient
s)
Nivolumab (n = 88)
Investigator’s Choice (n = 61)
Months0 3 6 9 12 15 18
0
10
20
30
40
50
60
70
80
90
100PD-L1 ≥1% PD-L1 <1%
HR (95% CI)0.55 (0.36,
0.83)
Ove
rall
Surv
ival
(% o
f pa
tient
s)
NivolumabInvestigator’sChoice
No. at Risk88 67 44 18 6 061 42 20 6 2 0
Nivolumab (n = 73)
Investigator’s Choice (n = 38)
Months0 3 6 9 12 15 18
0
10
20
30
40
50
60
70
80
90
100
73 52 33 17 338 29 14 6
82 0
00
HR (95% CI)0.89 (0.54,
1.45)
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Overall Survival by P16 Status
Ferris et al, 2016.
Nivolumab in R/M SCCHN After Platinum Therapy
Ove
rall
Surv
ival
(% o
f pat
ient
s)
Months0 3 6 9 12 15 18
0
10
20
30
40
50
60
70
80
90
100
Months0 3 6 9 12 15 18
0
10
20
30
40
50
60
70
80
90
100
Ove
rall
Surv
ival
(% o
f pat
ient
s)
Nivolumab (n = 63)
Investigator’s Choice (n = 29)
Nivolumab (n = 50)
Investigator’s Choice (n = 36)
NivolumabInvestigator’sChoice
No. at Risk63 49 35 18 10 3 0
29 20 11 4 1 0 050 32 25 12 136 26 13 7
63 1
00
HR (95% CI)0.56 (0.32,
0.99)
HR (95% CI)0.73 (0.42,
1.25)
p16-Negativep16-Positive
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CheckMate 141: Treatment-Related AEs in ≥10% of Patients
AEs = adverse events.aOne grade 5 event (hypercalcemia) in the nivolumab arm and one grade 5 event (lung infection) in the investigator’s choice arm were reported. A second death occurred in the nivolumab arm subsequent to pneumonitis.Ferris et al, 2016.
Event
Nivolumab (n=236)
Investigator’s Choice (n=111)
Any Grade n (%)
Grade 3/4 n (%)
Any Grade n (%)
Grade 3/4 n (%)
Anya 139 (58.9) 31 (13.1) 86 (77.5) 39 (35.1)Fatigue 33 (14.0) 5 (2.1) 19 (17.1) 3 (2.7)Nausea 20 (8.5) 0 23 (20.7) 1 (0.9)Diarrhea 16 (6.8) 0 15 (13.5) 2 (1.8)Anemia 12 (5.1) 3 (1.3) 18 (16.2) 5 (4.5)Asthenia 10 (4.2) 1 (0.4) 16 (14.4) 2 (1.8)Mucosal inflammation 3 (1.3) 0 14 (12.6) 2 (1.8)Alopecia 0 0 14 (12.6) 3 (2.7)
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Nivolumab stabilized PROs while investigator’s choice led to meaningful declines in function and worsening of symptoms
NivolumabInvestigator's choice
EORTC QLQ-C30 Physical Function
Week9 15 21
-30
-20
-10
0
10
Mea
n C
hang
e Fr
om B
asel
ine
Bet
ter
Wor
se
EORTC QLQ-C30 Social Function
9 15 21-30
-20
-10
0
10
Week
Mea
n C
hang
e Fr
om B
asel
ine
Bet
ter
Wor
se
EORTC QLQ-H&N35 Absence of Sensory Problems
9 15 21-30
-20
-10
0
10
Week
Mea
n C
hang
e Fr
om B
asel
ine
Bet
ter
Wor
se
EORTC QLQ-H&N35 Absence of Trouble With Social Contact
9 15 21-30
-20
-10
0
10
Week
Mea
n C
hang
e Fr
om B
asel
ine
Bet
ter
Wor
se
Nivolumab in R/M HNSCC After Platinum TherapyQuality of Life and Symptom Burden
PROs = patient-reported outcomes.Ferris et al, 2016
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Nivolumab improved survival for patients with platinum-refractory HNC
1-year survival more than doubled compared with single-agent SOC options (docetaxel, methotrexate, or cetuximab)
All demographic and clinical subgroups appeared to benefit
The magnitude of the benefit appeared greatest for patients with PD-L1 >1% and HPV-positive tumors
SOC = standard of care.Ferris et al, 2016.
PD-1 Inhibitor Therapy for HNC
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PFS was not significantly different with nivolumab vs SOC
Response rates were higher with nivolumab vs SOC
Toxicity was less with nivolumab Nivolumab stabilized QOL in comparison to
worsening QOL with SOC Pembrolizumab and nivolumab are now
FDA approved for this indication
QOL = quality of life. Ferris et al, 2016.
PD-1 Inhibitor Therapy for HNC (cont.)
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Concurrent ChemoradiotherapyStandard of Care
NCCN, 2016.
Organ Preservation RegimenLarynx RT/cisplatinOropharynx RT/carboplatin/FUNasopharynx RT/cisplatin ± cis/FUUnresectable disease RT/cisplatin
RT/cetuximabPostoperative adjuvant
RT/cisplatin
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Chemotherapy for Recurrent or Metastatic Head and Neck
Cancer
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72-year-old presents with hoarseness and sudden onset bilateral level 2 and 3 anterior cervical adenopathy
7 pack-year smoker, nondrinker No significant comorbidities Physical exam notable for right BOT fullness and vocal
cord paralysis CT scan of the neck confirms bilateral necrotic
lymphadenopathy extending to the supraclavicular fossae
Biopsy of BOT confirms malignancy with basaloid features
PET confirms uptake in BOT, bilateral nodes, no distant metastases
Clinical stage T2N2CM0
Case Study
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Which of the following options for primary therapy is not supported as a
category 1 option in the NCCN guidelines?
a. IMRT with concurrent high-dose cisplatinb. IMRT with concurrent carboplatin/5-FUc. Induction cisplatin/5-FU followed by IMRT
with concurrent carboplatind. IMRT with concurrent cetuximab
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Patient receives IMRT to 72 Gy with cisplatin 100 mg/m2 x 3
PET scan at 12 weeks confirms complete response
He is well for 14 months and then develops RUQ pain
ECOG PS 1 CT scan confirms multiple liver metastases Liver biopsy confirms basaloid carcinoma Laboratory studies are notable for AST ALT 2-3 x
ULN Total bilirubin is top normal
RUQ = right upper quadrant; AST = aspartate aminotransferase; ALT = alanine aminotransferase; ULN = upper limits of normal.
Case Study
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Which of the following regimens is considered the regulatory standard
and is category 1 in the NCCN guidelines for first-line
recurrent/metastatic HNC?a. Cisplatin/5-FUb. Cisplatin/paclitaxel/cetuximabc. Carboplatin/paclitaxeld. Cisplatin/5-FU/cetuximab
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Patient receives 6 cycles of cisplatin/5-FU/cetuximab and has a >50% reduction in the size of his liver metastases
He is placed on maintenance cetuximab 5 months later, CT scans of the chest and
abdomen demonstrate new lung metastases and progression of liver metastases
Liver function tests and other laboratory studies are WNL
ECOG PS 1
WNL = within normal limits.
Case Study
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Which of the following treatment options has been shown to improve
survival in this setting?
a. Docetaxelb. Nivolumabc. Pembrolizumabd. Cetuximabe. Axitinib
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Patient receives nivolumab 3 mg/kg IV every 2 weeks for 4 cycles
He notes grade 1 fatigue, pruritus, and anorexia CT scan at 8 weeks demonstrates a partial
response to therapy After 2 more cycles of nivolumab, he presents
with low grade fever, SOB with minimal exertion, nonproductive cough, and an O2 saturation on room air of 88%
ECOG PS 2 CT scan of the chest demonstrates patchy
infiltrates
SOB = shortness of breath.
Case Study
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The patient is diagnosed with grade 2 dyspnea, hypoxia and is admitted to the hospital. Which of the following is
the most likely diagnosis and recommended intervention?
a. Aspiration pneumonia, start clindamycinb. Pneumocystis carinii pneumonia, start bactrim
and steroids c. Immune-mediated pneumonitis, hold nivolumab,
rule out infection, and start prednisone 1-2 mg/kg/day
d. Pneumococcal pneumonia, start ampicillin
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The patient receives high-dose steroid and symptoms resolve quickly within 48 hours. He is discharged from the hospital with a 4-week steroid taper
He arrives at the outpatient clinic without symptoms 1 week after completing steroids
Repeat CT scans confirm continued treatment response
Case Study
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Which of the following therapeutic options are likely to provide the best quality of life for this patient at this
point?a. Re-initiate nivolumab now that
pneumonitis has resolved because patient had clinical benefit
b. Discontinue nivolumab and start methotrexate
c. Best supportive care and referral to hospice
d. Discontinue nivolumab, start pembrolizumab
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HPV is changing the clinical landscape of HNC Be aware of new staging system specific to
HPV-positive oropharynx cancer PET surveillance after chemoradiotherapy has
similar survival to elective neck dissection with less morbidity and cost
Neck dissection improves OS and DFS in T1-T2N0 oral cavity cancer
PD1 inhibitor therapy results in clinical response and improved OS (nivolumab only) for patients with R/M platinum-refractory HNC
Key Takeaways
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American Cancer Society (2016). Cancer facts & figures. Available at: http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf
Ang K, Harris J, Wheeler R, et al (2010). Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med, 363(1):24-25. DOI:10.1056/NEJMoa0912217
Badoual C, Hans S, Merillon N, et al (2013). PD-1-expressing tumor-infiltrating T cells are a favourable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res, 73(1):128-138.
Bernier J, Domenge C, Ozsahin M, et al (2004). Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med, 350:1945-1952. DOI:10.1056/NEJMoa032641
Blanchard P, Lee A, Marguet S, et al (2015). Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol, 16(6):645-655. DOI:10.1016/S1470-2045(15)70126-9
Bonner JA, Harari PM, Azarnia N, et al (2006). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med, 354(6):567-578. DOI:10.1056/NEJMoa053422
Bonner JA, Harari P, Giralt J, et al (2010). Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol, 11(1):21-28. DOI:10.1016/S1470-2045(09)70311-0
Bristol-Myers Squibb (2016). Trial of nivolumab vs therapy of investigator’s choice in recurrent or metastatic head and neck carcinoma (CheckMate 141). Available at: http://clinicaltrials.gov. NLM Identifier:NCT02105636
Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al (2013). Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol, 31(36):4550-4559. DOI:10.1200/JCO.2013.50.3870
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