Recurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive Care

Recurrent/Metastatic HNSCC: Harnessing
Immunotherapy in Comprehensive Care
Glenn J. Hanna, MD
Director, Center for Cancer
Therapeutic Innovation
Medical Oncologist
Center for Head & Neck Oncology
Dana-Farber Cancer Institute
Deborah Wong, MD, PhD
Associate Clinical Professor of Medicine
Division of Hematology-Oncology
UCLA Medical Center

Disclosures
Glenn J. Hanna, MD
Advisory/board panel or consultant: Bicara, Bio-Rad, Boxer Capital, Bristol Myers Squibb,
Coherus, Elevar, Exicure, General Catalyst, Guardian Bio, Inhibrx, KSQ Therapeutics, Kura
Oncology, Maverick Therapeutics, Merck, Naveris, Nextech, PDS Biotech, Prelude, Rain
Therapeutics, Regeneron, Remix, Replimune, Sanofi Genzyme, SIRPant, Surface Oncology
Grants/research support: Actuate Therapeutics, Bicara, Bristol Myers Squibb, Elevar, Exicure,
Genentech, GlaxoSmithKline, ImmunityBio, Kartos Therapeutics, Kite Pharma, KSQ
Therapeutics, Kura Oncology, Regeneron, Repertoire, Sanofi Genzyme, Secura Bio
Deborah Wong, MD, PhD
Consultant: Merck, Regeneron
Grants/research support: AstraZeneca, Bicara Therapeutics, Bristol Myers Squibb, Checkmate,
Flamingo Pharma, Genentech, Gilead, Hookipa, invoX Pharma, Kura Oncology, Lilly, Merck,
Pfizer, Regeneron, TopAlliance BioSciences
i3 Health has mitigated all relevant financial relationships

Learning Objectives
HNSCC = head and neck squamous cell carcinoma.
Distinguish histopathological, molecular, and clinical biomarkers that can
inform prognosis and management of HNSCC
Assess emerging efficacy and safety data on novel agents and immune
checkpoint inhibitors for recurrent/metastatic HNSCC
Apply strategies to prevent and mitigate immune-mediated adverse events
Apply a multidisciplinary team approach to the implementation of surveillance
and survivorship care plans for patients with recurrent/metastatic HNSCC

Part 1:
Novel Therapies in Advanced,
Recurrent/Metastatic HNSCC

KEYNOTE-048: Study Design
SCC = squamous cell carcinoma; R/M = recurrent/metastatic; ECOG = Eastern Cooperative Oncology Group; PS = performance status;
PD-L1 = programmed death-ligand 1; TPS = tumor proportional score; PFS = progression-free survival; pembro = pembrolizumab; Q3W = every 3 weeks;
AUC = area under the curve; 5-FU = 5-fluorouracil; QOL = quality of life ; Q1W = every 1 week.
Burtness et al, 2019.
First-Line Pembrolizumab for Recurrent or Metastatic HNSCC
Pembro
Pembro
plus chemo
EXTREME
Primary end points: overall survival, PFS Secondary end points: safety, tolerability, objective response, QOL
Key Eligibility Criteria
• SCC of the oropharynx, oral
cavity, hypopharynx, or larynx
• R/M disease incurable by local
therapy
• ECOG PS 0 or 1
• Tissue sample for PD-L1
assessment
• Known p16 status in the
oropharynx
Stratification Factors
• PD-L1 expression (TPS ≥50%
vs <50%)
• p16 status in oropharynx
(positive vs negative)
• ECOG PS 0 vs 1
Pembrolizumab
200 mg Q3W for up to 35 cycles
Pembrolizumab
200 mg plus carboplatin AUC 5
mg/m2 or cisplatin 100 mg/m2 plus
5-FU 1,000 mg/m2/d for 4 days for
6 cycles (every 3 weeks)
Cetuximab
400 mg/m2 loading dose, 250
mg/m2 Q1W plus carboplatin AUC
5 mg/m2 or cisplatin 100 mg/m2
plus 5-FU 1,000 mg/m2/d for 4 days
for 6 cycles
Cetuximab 250 mg/m2 Q1W
Pembrolizumab 200 mg Q3W
for up to 35 cycles total
R
A
N
D
O
M
I
Z
A
T
I
O
N
1:1:1

KEYNOTE-048: Overall Survival
PD-L1+ = PD-L1–positive; CPS = combined positive score; OS = overall survival; HR = hazard ratio; CI = confidence interval.
Harrington et al, 2023.
Pembrolizumab alone demonstrates improved outcomes compared with
chemotherapy-cetuximab in PD-L1+ patients
First-Line Pembrolizumab for R/M HNSCC

KEYNOTE-048: Overall Survival (cont.)
Pembrolizumab alone demonstrates improved outcomes compared with
chemotherapy-cetuximab in PD-L1+ patients

KEYNOTE-048: Overall Survival (cont.)
Chemoimmunotherapy improves survival in this population over platinum-
based chemotherapy with cetuximab

KEYNOTE-B10: Study Design
Dzienis et al, 2022.
First-Line Pembro/Carboplatin/Paclitaxel for R/M HNSCC
• Previously untreated R/M HNSCC of oral
cavity, oropharynx, larynx, hypopharynx
• PD-L1–agnostic
• ECOG 0-1
• Stage IVC or M1
Pembrolizumab
200 mg IV Q3W
Paclitaxel (investigator’s choice) for 6 cycles
Carboplatin AUC 5 Q3W for 6 cycles
Primary end point
• Overall response rate
Secondary end points
• Duration of response (DOR)
• Progression-free survival
• Overall survival
• Safety

KEYNOTE-B10: ORR and DOR per RECIST v1.1 by BICR
BICR = blinded independent central review; ORR = overall response rate; DOR = duration of response;
RECIST = Response Evaluation Criteria in Solid Tumors; carbo = carboplatin; pacli = paclitaxel; CR = complete response; PR = partial response;
SD = stable disease; PD = progressive disease; TTR = time to response; DCR = disease control rate.
Dzienis et al, 2022.
First-Line Pembro/Carboplatin/Paclitaxel for R/M HNSCC
Pembro + Carbo + Pacli
n=82
ORR, % (95% CI) 42.7% (31.8-54.1)
Best objective response, n (%)
CR 4 (4.9%)
PR 31 (37.8%)
SD 24 (29.3%)
PD 15 (18.3%)
No assessment 8 (9.8%)
TTR, median (range), months 1.5 (1.1-4.2)
DCR, % (95% CI) 58.5% (47.1-69.3)
Taxane therapy seems to yield comparable outcomes when compared with
5-FU use as part of chemoimmunotherapy

Novel ICI Combinations for HNSCC
ICI = immune checkpoint inhibitor; 1L = first-line; 2L = second-line; HRAS = Harvey Rat sarcoma virus; EGFR = epidermal growth factor receptor;
VEGF = vascular endothelial growth factor; STAT3 = signal transducer and activator of transcription 3; PI3K = phosphatidylinositol 3-kinase. mPFS = median PFS;
mOS = median OS.
Wise-Draper et al, 2022.
Strategies have focused on enhancing the durable benefit observed in 1L with anti–
PD-1 therapy, and on anti–PD-1 refractory patients in the 2L+ setting
Enhancing Durable Benefit in HNSCC
Class Drug or Molecule Key Findings
Phase ORR mPFS (months) mOS (months)
Targeted agents
HRAS Tipifarnib Phase 2 (30 pts) 55% 5.4 15.4
EGFR
Cetuximab/pembrolizumab Phase 2 45% - 18
Cetuximab/avelumab Phase 2 50% - -
Afatinib/pembrolizumab Phase 2 41% 4.1 8.4
VEGF
Lenvatinib/cetuximab Phase 1/2b (9/12 pts) 67% 3.6 -
Lenvatinib/pembrolizumab Phase 1/2b (22 pts) 46% 4.7 -
STAT3 Danvatirsen/durvalumab Phase 1b/2 (38 pts) 26% - -
PI3K Buparlisib vs placebo + paclitaxel Phase 2 (158 pts) 31% 4.5% 10.4%

Novel ICI Combinations for HNSCC (cont.)
IDO = indoleamine 2,3-dioxygenase; ICOS = anti-inducible T-cell costimulator; HPV = human papillomavirus.
Phase ORR mPFS (months) mOS (months)
Other ICI combinations
IDO
Epacadostat/
pembrolizumab
Phase 2 ORR: 34%; DCR: 61% - -
Phase 2 ORR: 23%; DCR: 61% - -
Costimulatory
agents
GSK609 (ICOS agonist)/
pembrolizumab
Phase 1 26% 5.6 -
B7-H3
Enoblituzumab/
pembrolizumab
Phase 1 study (19 pts) 33% - -
NK2GA
Monalizumab/cetuximab
Phase 2
36% in immunotherapy-naive,
naive, 17% in immunotherapy-
immunotherapy- pretreated
- -
Monalizumab/cetuximab
Phase 2 study, cohort 3 33% - 15
T-cell exhaustion
exhaustion (LAG-
(LAG-3)
Eftilagimod alpha/
pembrolizumab
Phase 2 (36 pts) 36% - -
TLR-9
Intratumoral SDS-101/
pembrolizumab
Phase 1b/2
ORR: 22%
DCR: 48%
- -
TGF-beta Bintrafusp alfa Phase 1 study (32 pts)
22%, 75% had >2 prior lines of
of therapy
HPV+ group ORR 50%
- -

Novel ICI Combinations for HNSCC (cont.)
TIL = tumor-infiltrating lymphocytes.
Phase ORR
mPFS
(months)
mOS
(months)
Cellular therapy
TIL LN-145/pembrolizumab Phase 2 study (18 pts)
ORR: 38.9%
88.9%
- -
Vaccines
Peptide/protein-based
based vaccines
ISA101b/nivolumab
Phase 2 HPV+
oropharyngeal SCC
33% - -
Nucleic acid-based
vaccines
MEDI0457/durvalumab Phase 2 22.2% - -
Oncolytic virus
Intratumoral talimogene
laherparepvec/
pembrolizumab
Phase 1b 14% 3 5.8

ICI + Cetuximab for R/M HNSCC
mAB = monoclonal antibody; NK = natural killer; ADCC = antibody-dependent cell-mediated cytotoxicity; PD-1 = programmed cell death protein 1;
Q2W = every 2 weeks.
Sacco et al, 2021; Chung et al, 2022; Gulati et al, 2023.
Adding an EGFR mAb to anti–PD-1 treatment offers synergistic immune
stimulation; activation of NK cells and promoting ADCC
Signal robust in HPV-negative tumors
• Platinum-resistant or platinum-ineligible HNSCC
• ≥18 years old
• ECOG 0-1
• No previous immunotherapy or EGFR inhibitor
Cetuximab 400 mg/m2 IV initial dose,
250 mg/m2 Q1W
Overall response rate
Cohort A: Any prior systemic therapy including
cetuximab or PD-1 inhibitors and persistent or
platinum-refractory disease
Cohort B: No prior systemic therapy
Cetuximab 500 mg/m2 Day -14 before
Cycle 1
Nivolumab 240 mg IV Q2W
Cetuximab 500 mg/m2 Q2W
Overall survival
• Metastatic HNSCC
• No prior cetuximab or immunotherapy
Durvalumab 1,500 mg IV Q4W
Cetuximab 400 mg/m2 IV initial dose,
250 mg/m2 Q1W

Durvalumab + Cetuximab
Nivolumab + Cetuximab
Pembrolizumab + Cetuximab
Prior systemic therapy
No prior therapy
ORR: 39%
ORR: 22% Median OS: 9.6 months
Median OS:
11.4 months
ORR: 37%
Median OS: not reached
Sacco et al, 2021; Chung et al, 2022; Gulati et al, 2023.
Median OS: 18.4 months
ORR: 45%
ICI + Cetuximab for R/M HNSCC: Efficacy

Pembrolizumab + BCA-101 in R/M HNSCC
AE = adverse event; TGF = transforming growth factor; G2 = grade 2; G3 = grade 3; alk phos = alkaline phosphatase; AST = aspartate transaminase;
ALT = alanine transaminase.
Hanna et al, 2023a; Hanna et al, 2023b.
BCA-101: novel EGFR-TGF-beta bispecific protein
Appears safe, well-tolerated
Enhanced TGF-beta neutralization or trap to promote
immunity and augment EGFR inhibition
Signal most robust in HPV-negative tumors
Safety:
AEs of interest
Acneiform rash in 74% (7% G3)
Mucosal bleeding, generally low-grade
1 G3 related tracheal hemorrhage
AEs most commonly leading to dose interruption
4x rash, 4x anemia, 3x infusion-related reaction, 3x colitis
3/42 had dose reduction (G2 acneiform rash, G3 alk
phos/AST/ALT increased, G3 maculopapular rash)
6/42 had permanent discontinuation (2x G3 colitis, G3 alk
phos/AST/ALT increased, G3 diarrhea, G3 tracheal hemorrhage,
G4 pericarditis
Median PFS: not reached
ORR DCR
Total population 18/39 (46%) 31/39 (79%)
HPV-pos 2/11 (18%) 6/11 (55%)
CPS 1-19 0/6 (0%) 2/6 (33%)
CPS≥20 2/5 (40%) 4/5 (80%)
HPV-neg 16/28 (57%) 25/28 (89%)
CPS 1-19 7/13 (54%) 12/13 (92%)
CPS≥20 9/15 (60%) 13/15 (87%)

Petosemtamab in Advanced HNSCC
Cohen et al, 2023.
Novel EGFR-LGR5 bispecific antibody
Appears safe, well-tolerated (some
infusion reactions)
Focused on 2L patients
Most Frequent AEs All Grades Grade 3/4
Rash 33% 0%
Hypotension 26% 6%
Dyspnea 26% 4%
Nausea 26% 1%
Dermatitis acneiform 24% 1%
Blood magnesium decreased
decreased
19% 5%
Erythema 19% 0%
Diarrhea 19% 0%
Infusion-related reactions
(composite)
74% 21%
ORR: 37.2%
DCR: 72.1%
Median PFS 5.3 months
Median DOR: 6.0 months

LEAP-010 and LEAP-090: Pembrolizumab + Lenvatinib
VEGFR = vascular endothelial growth factor receptor; TKI = tyrosine kinase inhibitor; IA = interim analysis.
Siu et al, 2020; Merck and Eisai, 2023.
Multitargeted VEGFR TKI to augment or rescue anti–PD-1 effects
Safety concerns with VEGFR TKIs (bleeding)
Focused on 1L and 2L patients (PD-L1+)
LEAP-010 did not meet OS endpoint in IA and was discontinued
PD-L1+ Patients with HNSCC

Pembrolizumab + Cabozantinib in R/M HNSCC
Saba et al, 2023.
Multitargeted VEGFR TKI to
augment anti–PD-1 effects
Toxicity seems more manageable
Focused on 1L patients (PD-L1+)
ORR: 52%
Median PFS: 14.6 months
Most Common
AEs
All
Grades
Grade
3/4
Fatigue 44.4% 0
Diarrhea 33.3% 2.8%
Hypothyroidism
m
33.3% 0
Constipation 30.6% 0
Dysphagia 19.4% 8.3%
Hypertension 25.0% 8.3%
Increased AST 11.1% 5.6%
Back pain 16.7% 5.6%
Hypotension 11.1% 5.6%
Oral mucositis 25.0% 5.6%

STELLAR-305: Study Design
Clinicaltrials.gov, 2023a.
Novel oral multitargeted VEGFR TKI to augment anti–PD-1 effects
Focused on 1L patients (PD-L1+)
Pembrolizumab + Zanzalintinib (XL092) for PD-L1+ R/M HNSCC
Primary end points:
overall survival, PFS
Secondary end points:
investigator-assessed PFS,
ORR, DOR
• R/M HNSCC incurable by local
therapy
• CPS ≥ 1
• ≥18 years old
• ECOG 0-1
• No prior immunotherapy or
zanzalintinib
Zanzalintinib + pembrolizumab
Placebo + pembrolizumab
R
A
N
D
O
M
I
Z
A
T
I
O
N
1:1

EV-202 Cohort 5: Study Design
ADC = antibody-drug conjugate.
Swiecicki et al, 2023; Clinicaltrials.gov, 2023a.
Nectin-4 targeting ADC
Demonstrates activity in platinum-/anti–PD-1–refractory HNSCC
Manageable safety profile
Now being combined with pembrolizumab in 1L PD-L1+ HNSCC cohort in EV-202
Enfortumab Vedotin for Previously Treated R/M HNC
EV-202 Cohort 5
• Locally advanced or metastatic HNC
• ECOG 0-1
• Prior platinum-based chemotherapy for
locally advanced/metastatic HNC
• Prior PD(L)-1 inhibitor or immunotherapy
contraindicated
• No more than 2 lines of chemotherapy in
the locally advanced/metastatic setting
Enfortumab vedotin 1.25 mg/kg Days 1,
8, 15 of a 28-day cycle
Primary End Point
Secondary End Points
Duration of response
Disease control rate (DCR)
PFS
OS
Safety/tolerability

EV-202 Cohort 5: Efficacy and Safety
HNC = head and neck cancer; STD = standard deviation.
Swiecicki et al, 2023.
ORR: 23.9%
Safety:
Common AEs were fatigue, alopecia,
peripheral neuropathy
Grade ≥3 AEs included anemia,
decreased neutrophil count,
progression of HNC
AEs of special interest: skin reactions
(45.7%), peripheral neuropathy
(32.6%), hyperglycemia (4.3%)
Enfortumab Vedotin for Previously Treated R/M HNC

TROPiCS-03: Study Design
Michel et al, 2023.
Trop-2–targeting ADC
Demonstrates activity in platinum and anti–PD-1 refractory HNSCC
Sacituzumab Govitecan for R/R Metastatic or Locally Advanced HNSCC
EV-202 Cohort 5
• Locally advanced or metastatic HNC
• ECOG 0-1
• Prior platinum-based chemotherapy for
locally advanced/metastatic HNC
• Prior PD(L)-1 inhibitor or immunotherapy
contraindicated
• No more than 2 lines of chemotherapy in
the locally advanced/metastatic setting
Enfortumab vedotin 1.25 mg/kg Days
1, 8, 15 of a 28 Day cycle
Primary End Point
Secondary End Points
Duration of response
DCR
PFS
OS
Safety/tolerability

TROPiCS-03: Efficacy and Safety
TRAE = treatment-related AE.
Michel et al, 2023.
Trop-2 targeting ADC
Demonstrates activity in
platinum-/anti–PD-1–
refractory HNSCC
ORR: 16%
Median DOR: 4.2 months
Sacituzumab Govitecan for R/R Metastatic or Locally Advanced HNSCC
Safety:
Any-grade AEs: 100%
Grade ≥3 AEs: 44%
TRAEs leading to discontinuation: 0
Deaths due to TRAE: 2% (1/43)

HPV Therapeutic Vaccines: Study Designs
HLA = human leukocyte antigen; SC = subcutaneous; IM = intramuscular.
Chung et al, 2023; Price et al, 2023; Aggarwal et al, 2023.
Variety of proprietary platforms targeting HPV16/18, some HLA-restricted
Modest activity in HPV+ R/M HNSCC alone and in combination with anti–PD-1/L1 therapies
HPV-Positive R/M HNSCC
PDS0101: VERSATILE-002
HPV16+ R/M HNSCC
Stratified by ICI-naive and ICI-refractory
Pembrolizumab IV Q3W
PDS0101 SC concurrently on Cycles 1, 2, 3, 4,
and 12 (5 doses)
End points: overall response
rate, safety PFS, OS
MEDI0457
• HPV16+ or HPV18+ R/M HNSCC
• ≥1 prior platinum chemotherapy
• No prior immunotherapy
MEDI0457 7 mg IM Day 1 of Weeks 1, 3, 7, 12
(4 doses)
Durvalumab 1,500 mg IV Day 1 of Weeks 4, 8,
12, continuing every 4 weeks
End points: overall response
rate, safety, 16-week DCR,
OS, PFS
CUE-101
• HLA-A*0201 genotype
• HPV16+ R/M HNSCC
CUE-101 Q3W
End points: safety,
pharmacokinetics,
pharmacodynamics, efficacy
CUE-101 Q3W

Efficacy of HPV Therapeutic Vaccines
Chung et al, 2023; Price et al, 2023; Aggarwal et al, 2023.
CUE-101
CUE-101 +
pembrolizumab
PDS0101 +
pembrolizumab
MEDI0457 +
durvalumab
N evaluable 19 12 34 29
ORR 1/19 (5%) 5/12 (42%) 9/34 (26.5%) 8/29 (27.6%)
Median PFS - - 10.4 months 3.5 months
Median OS 24.4 months - Not estimable 29.2 months
Safety
Fatigue, anemia, chills, infusion-related reactions,
constipation, lymphopenia, nausea
Fatigue,
injection site reactions
Fatigue,
injection site pain
HPV-Positive R/M HNSCC

Case Study 1: Mr. KF
R = right; BOT = base of tongue; SCC = squamous cell carcinoma; IMRT = intensity-modulated radiation therapy; fx = fractions; LRR = locoregionally recurrent;
TL = total laryngectomy; ND = neck dissection; AT = anterolateral; PEG = percutaneous endoscopic gastrostomy; TEP = tracheoesophageal puncture;
TTMV = tumor tissue–modified viral; UD = undetected; SOC = standard of care; chemoIO = chemoimmunotherapy.
62-year-old male, former smoker
T4N0, stage III, HPV18+ R BOT SCC treated with IMRT 35 fx to
70 Gy with bolus cisplatin in September 2021
LRR disease in the BOT with TL and glossectomy with NDs and
ATL flap salvage surgery in November 2023
PEG-dependent, uses TEP
December 2023: new locoregional unresectable recurrence
PD-L1 CPS 5, TTMV-HPV DNA always UD
1L SOC: pembro or chemoIO (KN-048)
1L trial option: pembro + BCA-101

Part 2: Prevention and
Mitigation of Immune-Related
Related Adverse Events (irAEs)

Toxicity of Anti–PD-1 Immunotherapy in R/M HNSCC
Ferris et al, 2016; Cohen et al, 2019; Harrington et al, 2021; Burtness et al, 2019; Rischin et al, 2022.
Treatment with nivolumab (Checkmate 141) or pembrolizumab
(KEYNOTE-040) in the 2L setting or pembrolizumab in the 1L setting
(KEYNOTE-048) is effective and well-tolerated
Most toxicities low-grade, not requiring treatment interruption or
discontinuation
Quality-of-life outcomes consistently better than with investigator’s
choice standard-of-care therapy

CheckMate 141: Study Design
Ferris et al, 2016.
Nivolumab for R/M HNSCC
Primary end point:
Overall survival
PFS, ORR, safety, DOR,
biomarkers, quality of life
• R/M HNSCC of the oral cavity,
pharynx, or larynx
• Within 6 months of last dose of
platinum therapy
• Known p16 status
assessment
Stratified by
• Prior cetuximab
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
R
A
N
D
O
M
I
Z
A
T
I
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N
2:1

CheckMate 141: Health-Related Quality-of-Life Results
Ferris et al, 2016.

CheckMate 141: Adverse Events
Nivo = nivolumab.
Ferris et al, 2016.
TRAES in ≥5%
Nivo Group
Nivolumab (n=236) Standard Therapy (n=111)
Any Grade Grade 3/4 Any Grade Grade 3/4
Any event 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%)
Rash 18 (7.6%) 0 5 (4.5%) 1 (0.9%)
Decreased
appetite
17 (7.2%) 0 8 (7.2%) 0
Pruritus 17 (7.2%) 0 0 0
Diarrhea 16 (6.8%) 0 15 (13.5%) 2 (1.8%)
Anemia 12 (5.1%) 3 (1.3%) 18 (16.2%) 2 (1.8%)
Standard therapy: single-agent methotrexate, docetaxel, or cetuximab

KEYNOTE-040: Study Design
TTP = time to progression.
Cohen et al, 2019; Harrington et al, 2021.
Pembrolizumab for R/M HNSCC
Primary end point:
Overall survival
OS in CPS ≥1 population
PFS in all, PFS in CPS ≥1,
ORR in all, ORR in CPS
≥1, DOR in all, DOR in
CPS ≥1, TTP in all, TTP in
CPS ≥1, safety
• R/M HNSCC of the oral cavity,
oropharynx, hypopharynx, or
larynx
• Progression after platinum
regimen for R/M HNSCC or
recurrence or PD within 3-6
months of multimodal platinum
therapy
• ECOG PS 0 or 1
• Known p16 status
assessment
Stratified by
• ECOG PS
• p16 status
• PD-L1 TPS (≥50% vs <50%)
Pembrolizumab 200 mg IV Q3W
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
R
A
N
D
O
M
I
Z
A
T
I
O
N
1:1

KEYNOTE-040: Quality of Life With Pembrolizumab
R/M HNSCC
Time to Deterioration in QOL Change from Baseline in QOL Scores Over Time

KEYNOTE-040: Adverse Events With Pembrolizumab
R/M HNSCC
Pembrolizumab Group (n=246) Standard-of-Care Group (n=234)
Any grade Grade 3, 4, or 5 Any grade Grade 3, 4, or 5
Treatment-related adverse event
Any event 155 (63%) 33 (13%) 196 (84%) 85 (36%)
Event leading to treatment
treatment discontinuation
15 (6%) 12 (5%) 12 (5%) 9 (4%)
Event leading to death 4 (2%) 4 (2%) 2 (1%) 2 (1%)
Event occurring in ≥5% of patients in the pembrolizumab group
Hypothyroidism 33 (13%) 1 (<1%) 2 (1%) 0
Fatigue 31 (13%) 4 (2%) 43 (18%) 2 (1%)
Diarrhea 20 (8%) 4 (2%) 24 (10%) 1 (<1%)
Rash 19 (8%) 1 (<1%) 34 (15%) 1 (<1%)
Asthenia 18 (7%) 1 (<1%) 28 (12%) 4 (2%)
Anemia 17 (7%) 1 (<1%) 33 (14%) 9 (4%)
Nausea 12 (5%) 0 29 (12%) 1 (<1%)
Event of interest occurring in ≥3% of patients in the pembrolizumab group
Any 63 (26%) 11 (4%) 28 (12%) 11 (5%)
Hypothyroidism 37 (15%) 1 (<1%) 9 (4%) 0
Pneumonitis 10 (4%) 3 (1%) 3 (1%) 3 (1%)
Infusion-related reaction 8 (3%) 1 (<1%) 7 (3%) 1 (<1%)
Severe skin reaction 7 (3%) 4 (2%) 9 (4%) 7 (3%)

KEYNOTE-048: Pembrolizumab for HNSCC
EORTC = European Organisation for Research and Treatment of Cancer; QLQ-C30 = Quality of Life Questionnaire–Core 30;
QLQ-H&N35 = Quality of Life Questionnaire–Head & Neck 35; TTD = time to treatment discontinuation.
Burtness et al, 2019; Rischin et al, 2022.
Health-Related Quality-of-Life Results
EORTC QLQ-C30 GHS/QOL
and QLQ-H&N35 Pain Swallowing Scores
Estimates of Time to Deterioration by Treatment

KEYNOTE-048: Pembrolizumab for HNSCC (cont.)
Adverse Events
Adverse events in ≥10%:
pembrolizumab alone
Pembrolizumab alone
(n=300)
Pembrolizumab with chemo
(n=276)
Cetuximab with chemo
(n=287)
Any grade Grade 3-5 Any grade Grade 3-5 Any grade Grade 3-5
Blood and lymphatic system
system disorders
78 (26%) 20 (7%) 206 (75%) 131 (47%) 189 (66%) 113 (39%)
Anemia 62 (21%) 14 (5%) 161 (58%) 70 (25%) 134 (47%) 49 (17%)
Endocrine disorders 65 (22%) 5 (2%) 51 (18%) 2 (<1%) 22 (8%) 0
Hypothyroidism 55 (18%) 0 44 (16%) 0 18 (6%) 0
Gastrointestinal disorders 170 (57%) 23 (8%) 228 (83%) 68 (25%) 239 (83%) 55 (19%)
Constipation 59 (20%) 1 (<1%) 102 (37%) 0 95 (33%) 4 (1%)
Diarrhea 46 (15%) 2 (<1%) 78 (28%) 8 (3%) 99 (34%) 8 (3%)
Nausea 49 (16%) 0 141 (51%) 16 (6%) 147 (51%) 17 (6%)
Vomiting 33 (11%) 1 (<1%) 90 (33%) 10 (4%) 80 (28%) 8 (3%)

KEYNOTE-048: Pembrolizumab for HNSCC (cont.)
Adverse Events
Adverse events in ≥10%:
pembrolizumab alone
Pembrolizumab alone Pembrolizumab with chemo Cetuximab with chemo (n=287)
General disorders and
administration site conditions
conditions
162 (54%) 22 (7%) 209 (76%) 62 (22%) 210 (73%) 40 (14%)
Fatigue 83 (28%) 9 (3%) 95 (34%) 20 (7%) 102 (36%) 14 (5%)
Pyrexia 38 (13%) 1 <1%) 45 (16%) 2 (<1%) 35 (12%) 0
Investigations 107 (36%) 31 (10%) 154 (56%) 70 (25%) 158 (55%) 61 (21%)
Weight decreased 44 (15%) 7 (2%) 44 (16%) 8 (3%) 60 (21%) 3 (1%)
Metabolism and nutrition
disorders
122 (41%) 43 (14%) 166 (60%) 74 (27%) 187 (65%) 71 (25%)
Decreased appetite 45 (15%) 3 (1%) 80 (29%) 13 (5%) 85 (30%) 10 (3%)
Respiratory, thoracic and
mediastinal disorders
139 (46%) 34 (11%) 130 (47%) 37 (13%) 126 (44%) 20 (7%)
Cough 40 (13%) 0 53 (19%) 0 37 (13%) 0
Skin and cutaneous tissue
disorders
96 (32%) 10 (3%) 98 (36%) 7 (3%) 235 (82%) 28 (10%)
Rash 30 (10%) 2 (<1%) 29 (11%) 1 (<1%) 111 (39%) 17 (6%)

Toxicity of Anti–PD-1 Immunotherapy in R/M HNSCC
Serious grade 3-5 toxicities occur at a low incidence
But serious, life-threatening toxicity can occur
Close monitoring, early recognition, and intervention are key
Adverse events of
interest in ≥1%
Pembrolizumab (n=300)
Pembrolizumab-
chemotherapy (n=276)
Cetuximab-
(n=287)
Any grade Grade 3-5 Any grade Grade 3-5 Any grade Grade 3-5
Any event 93 (31%) 21 (7%) 73 (26%) 15 (5%) 68 (24%) 30 (10%)
Hypothyroidism 55 (18%) 0 44 (16%) 0 18 (6%) 0
Pneumonitis 19 (6%) 5 (2%) 15 (5%) 5 (2%) 3 (1%) 2 (<1%)
Hyperthyroidism 8 (3%) 1 (<1%) 12 (4%) 0 3 (1%) 0
Severe skin reactions 8 (3%) 6 (2%) 2 (<1%) 2 (<1%) 20 (7%) 19 (7%)
Infusion reactions 4 (1%) 2 (<1%) 6 (2%) 2 (<1%) 27 (9%) 6 (2%)
Colitis 3 (1%) 2 (<1%) 7 (3%) 2 (<1%) 2 (<1%) 2 (<1%)
Hepatitis 3 (1%) 2 (<1%) 1 (<1%) 1 (<1%) 0 0
Nephritis 3 (1%) 2 (<1%) 2 (<1%) 0 1 (<1%) 0

Toxicities of ICIs in Phase 3 HNSCC Studies
GI = gastrointestinal; LFT = liver function test; Cr = creatinine; CBC = complete blood count.
Haanen et al, 2022; NCCN, 2024b; Schneider et al, 2021.
Fatigue
Hypothyroidism
Skin toxicity (rash)
Decreased appetite
GI (diarrhea)
Pneumonitis
Hepatitis
Monitoring guidelines
History and physical prior to each
dose of ICI
Lab assessment:
Thyroid function tests every 4-6 weeks
LFTs, Cr, CBC prior to each dose
More frequent assessment if toxicity
develops to monitor for resolution
Early referral to specialists

Proposed Mechanisms of Immune Toxicity
TCR = T-cell receptor; CD = cluster of differentiation; MHC = major histocompatibility complex; CTLA = cytotoxic T-lymphocyte–associated protein;
ADCC = antibody-dependent cellular cytotoxicity; NK = natural killer; IL6 = interleukin 6.
Johnson et al, 2022; Ghisoni et al, 2021; Postow et al, 2018.
Tumor/tissue specific factors:
Common T-cell receptor sequences
upregulated transcripts in tumor and affected
normal tissue
Non-tumor specific factors:
Microbiome
Tissue specific factors
Viral factors
T-cell type
Inhibition of cytokines such as IL6
Modest correlation between response to immunotherapy and incidence of immune related
adverse events (irAEs)—most data in melanoma and lung cancer

General Guidelines for Management of irAEs
Haanen et al, 2022; NCCN, 2024b; Schneider et al, 2021.
Grade 1
Continue ICI with close monitoring
Grade 2
Hold ICI until resolution to grade ≤1
Consider corticosteroids (prednisone 0.5-1 mg/kg/day or equivalent)
Grade 3:
Hold ICI
Initiate high-dose steroids (prednisone 1-2 mg/kg/day or equivalent), tapering over 4-6 weeks
Cases refractory to steroids may require other immunosuppressants/biologics
Grade 4
High-dose steroids, permanent discontinuation of ICI
Organ-specific exceptions
Endocrinopathies—hormone replacement and can continue ICI if corrected
Grade 2 dermatologic toxicity can be managed with topical steroids and emollients while continuing
ICI

Case Study 2: Ms. MC
SOB = shortness of breath.
65-year-old woman with metastatic HNSCC, former smoker
Initially presented with T3N1 SCC oral cavity
Resection  adjuvant chemo-RT
At 1 year post-resection, develops lung metastases
Lung biopsy: SCC, PD-L1 CPS 5
Chemoimmunotherapy with carboplatin/5FU + pembrolizumab x4 cycles
Maintenance pembrolizumab x2 months
Develops cough, SOB
Improves somewhat with antibiotics

Case Study 2: Ms. MC (cont.)
CT chest
Interval decreased size of left upper lobe lung mass
New/increased airspace consolidations of the right upper lobe and
right lower lobe lung fields
Constellation of findings is most concerning for organizing
pneumonia in the setting of drug toxicity, although infectious
pneumonia cannot be excluded
Right upper lung transbronchial biopsy
Intra-alveolar fibrin deposition with focal increased eosinophils,
neutrophils, reactive pneumocyte hyperplasia
Acid-fast (AFB) and Methenamine silver (GMS) stain negative for
organisms
Negative for carcinoma
Comment: the biopsy shows a nonspecific pattern of acute lung
injury with intra-alveolar fibrin and an increase in eosinophils and
neutrophils. The differential diagnosis includes drug reaction,
eosinophilic pneumonia, and infectious etiologies

Case Study 2: Ms. MC
Prednisone 1 mg/kg followed by slow taper
Follow-up CT chest 3 months later
Stable left upper lobe, mass-like consolidation
Improved airspace opacities
Remains in continued response off therapy

Future Directions: Areas of Need
Ghisoni et al, 2021; Johnson et al, 2022.
Most studies on toxicity and QOL focus on short-term follow-up
CheckMate 141 and KEYNOTE-040 primarily reported data at Week 15 therapy
Anticipated dropoff of subjects completing QOL questionnaires after 15 weeks
Ghisoni et al reported of 56 publications of ICI registration trials, 90.3% did not report
duration of irAEs or data on patients experiencing ongoing irAEs at data cutoff (median
23.5% patients on ongoing treatment, range 1%-63%)
More common long-term toxicities: endocrinopathies, arthralgias/inflammatory arthritis
Management guidelines for emerging combination therapy given overlapping
toxicity
Dermatologic toxicity with combined ICI with anti-EGFR directed therapies
Diarrhea, hepatotoxicity, mucositis with combined ICI with anti-VEGFR therapies

Part 3: Clinical and Molecular
Biomarkers in Advanced HNSCC
HNSCC to Inform Management

Biomarkers of HNSCC: HPV
EBV = Epstein-Barr virus.
Fakhry et al, 2014.
One of our most important prognostic biomarkers even in the setting of
R/M disease
Despite this, we treat HPV-positive (HPV+) and -negative R/M HNSCC
similarly for now (with some caveats)
EBV is another example of a viral biomarker

Biomarkers: Circulating Tumor DNA (ctDNA)
Aulakh et al, 2022.
Powerful tool to monitor disease status and response
Several commercial assays available
Some platforms are tumor-informed

Biomarkers for HNSCC: HPV (ct)DNA
Rettig et al, 2022.
TTMV-HPV DNA
Baseline detectability and levels correlate with nodal burden
Not all cases are detectable at baseline (could be prognostic)

Biomarkers for HNSCC: HPV (ct)DNA (cont.)
PPV = positive predictive value; NPV = negative predictive value.
Hanna et al, 2023; Berger et al, 2022.
TTMV-HPV DNA
Powerful tool to monitor disease status in surveillance
High PPV and NPV among large retrospective series
Prospective data emerging

Biomarkers for HNSCC: PD-L1 Status
Haddad et al, 2022.
Inflammatory biomarkers may predict response to anti–PD-1 therapy in R/M HNSCC
KEYNOTE-012: nonrandomized phase 1b trial of pembrolizumab 10 mg/kg IV Q2W or
pembrolizumab 200 mg Q3W for patients with HNSCC with or without PD-L1 expression
KEYNOTE-012

KEYNOTE-048: PD-L1 Status as a Biomarker
RR = response rate.
Inflammatory biomarkers do seem to predict
response to anti-PD-1 therapy in R/M
HNSCC
KEYNOTE-048: pembro vs pembro/chemo
vs cetuximab/chemo
43% of patients had PD-L1 CPS ≥20
With pembro vs cetuximab/chemotherapy:
Improved OS: 14.9 vs 10.7 months
Lower RR: 23% vs 36%
With pembro/chemo vs
cetuximab/chemotherapy:
Improved OS: 14.7 vs 11.0 months
Similar RR: 43% vs 38%
Pembrolizumab for R/M HNSCC

Biomarkers for HNSCC: TMB
TMB = tumor mutational burden; tTMB = tissue TMB.
Wildsmith et al, 2023.
TMB also seems to predict response to anti–PD-1/L1 therapy in R/M HNSCC
Phase 2 HAWK and CONDOR and phase 3 EAGLE studies of durvalumab with or
without tremelimumab in platinum-resistant R/M HNSCC
HAWK, CONDOR, and EAGLE Trials
Durvalumab Durvalumab/tremelimumab Durvalumab

Biomarkers for HNSCC: TMB (cont.)
Haddad et al, 2022.
KEYNOTE-012: Pembro for R/M HNSCC
TMB also seems to predict response to anti–PD-1/L1 therapy in R/M HNSCC
KEYNOTE-012: nonrandomized phase 1b trial of pembro 10 mg/kg IV Q2W or pembro 200 mg
Q3W for patients with HNSCC with or without PD-L1 expression

Biomarkers for HNSCC: HRAS Mutations
VAF = high variant allele frequency.
Ho et al, 2021; Ho et al, 2023; Coleman et al, 2023; Hanna et al, 2022; Patel et al, 2023.
Proto-oncogene present in 4% to 8% of R/M HNSCC
Tipifarnib, a farnesyl transferase inhibitor (FTI), has demonstrated good safety and
antitumor activity, particularly among high VAF patients
Ongoing KURRENT trial combining tipifarnib with the PI3K pathway inhibitor
alpelisib in this population
Novel oral FTI (KO-2806) in clinical development
PR
SD

Biomarkers for HNSCC: PIK3CA Mutations
PIK3CA = phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit alpha.
Hanna et al, 2018; Geiger et al, 2016; Razak et al, 2023.
PI3KCA pathway important, particularly in HPV+ disease
May be associated with improved outcomes in the R/M setting
Cohort of 42 patients with metastatic HPV+
oropharyngeal cancer, 16 (38%) with PI3K
pathway mutations
Patients with PI3K pathway mutations had
significantly improved survival

Biomarkers for HNSCC: PIK3CA Mutations
mTOR = mammalian target of rapamycin.
Hanna et al, 2018; Geiger et al, 2016; Razak et al, 2023.
Trials have explored mTOR inhibition (everolimus), PIK3CA/EGFR inhibition
(alpelisib/cetuximab), etc
Everolimus and Alpelisib/Cetuximab
Everolimus Alpelisib/cetuximab vs cetuximab alone Alpelisib/cetuximab
n=71
ORR: 9.9%
DCR:43.7%
mPFS = 2.9 months
No advantage over
cetuximab alone
7 of 9 evaluable
ORR: 0
DCR: 28%
mPFS: 1.5 months
mOS: 4.5 months
33% discontinued due to toxicity

Case Study 3: Ms. JP
CUP = cancer of unknown primary; PR = partial response; PD = progressive disease; NGS = next-generation sequencing;
AKT2 = serine/threonine protein kinase 2; MS = microsatellite; mut = mutation.
65-year-old female, never-smoker
TXN2M1, stage IV, HPV16+ CUP treated with 1L chemoimmunotherapy
(platinum-taxane with pembrolizumab) through November 2021 (7 months) with
PR
At PD, in January 2022 started 2L protocol therapy on KURRENT trial
(tipifarnib/alpelisib)
PD-L1 CPS 80, TTMV-HPV DNA+
NGS: MS-stable, TMB 1 mut/Mb, AKT2 amplified, PIK3CA amplified, PIK3CA
E545K hotspot mutation
1L SOC: pembro + chemo
2L: trial of tipifarnib/alpelisib

Part 4: Multidisciplinary Approach to
Surveillance and Survivorship in R/M
R/M HNSCC

Multidisciplinary Care in Head and Neck Cancer
RT = radiotherapy.
Chow, 2020; Mody et al, 2021; Friedland et al, 2011; Licitra et al, 2016; Pillay et al, 2016.
Essential throughout the patient journey from initial diagnosis to survivorship
Best outcomes in patients treated at high-volume centers with
multidisciplinary team
Most R/M HNSCC patients are diagnosed with locally advanced disease
Locally advanced HNSCC requires multimodal therapy:
Surgery  adjuvant RT ± chemotherapy, definitive chemo-RT
Treatment goals balance best oncologic outcome with morbidity, minimizing
short- and long-term toxicity, and considerations of other factors that impact
care

Components of a Multidisciplinary Head and Neck Team
Chow, 2020; Mody et al, 2021; Friedland et al, 2011; Licitra et al, 2016; NCCN, 2024a; Pillay et al, 2016.
Surgeons
Surgical oncologist
Neurosurgeons
Plastic surgeons
Oral maxillofacial surgeon
Radiation oncologists
Medical oncologists
Palliative care
Pathologists
Radiologists
Clinical nutrition
Maxillofacial prosthetics
Dentists
Physical therapists
Occupational therapists
Speech language therapists
Audiologists
Nurses
Psychologists
Social workers

Post-Treatment Surveillance of HNSCC
NCCN, 2024a.
Approximately 50% of patients with locally advanced HNSCC will
develop R/M HNSCC
Annual incidence of second primary cancers is 3%-7%
Early detection of recurrence or second primary may improve prognosis
Allows identification of other long-term complications of treatment that
impact quality of life, function, and survival outcomes

Post-Treatment Surveillance of HNSCC (cont.)
TSH = thyroid-stimulating hormone; T4 = thyroxine; IGF-2 = insulin-like growth factor 2; LH = luteinizing hormone; FSH = follicle-stimulating hormone;
ACTH = adrenocorticotropic hormone; CT = computed tomography; MRI = magnetic resonance imaging; PET/CT = positron emission tomography/CT.
NCCN, 2024a; Machiels et al, 2020; Nekhylyudov et al, 2017.
History and physical exam
Most recurrences within 2
years of treatment
Head and neck exam and
mirror and fiberoptic exam
Year 1: every 1-3 months
Year 2: every 2-6 months
Year 3-5: every 4-8 months
Annually after Year 5
Lab evaluation
If neck radiation: TSH every 6-12 months
If skull base radiation: annual evaluation for
panhypopituitarism (AM cortisol, growth
hormone, free T4, IGF-2, LH, FSH, ACTH,
TSH, testosterone)
Consider HPV DNA, EBV DNA if virally-
mediated HNC
Imaging
CT or MRI 3-4 months post surgery
PET/CT 3-6 months after definitive radiation
or chemoradiotherapy
Additional imaging thereafter for equivocal
findings or symptoms

Post-Treatment Surveillance of HNSCC (cont.)
NCCN, 2024a; Machiels et al, 2020; Nekhylyudov et al, 2017.
Dental evaluation
Every 6 months if radiation
Supportive care and rehabilitation
Speech and swallow for dysphagia
Physical therapy/rehab for trismus, cervical dystonia, muscle spasms, shoulder
dysfunction
Audiology
Lymphedema management
Nutrition
Smoking cessation
Screening for depression and distress management

Long-Term Complications in R/M HNSCC
Brauer 2022; Kuhn et al, 2023.
Psychosocial distress
60% of head and neck cancer patients report versus 40% of cancer patients
Treatment-related side effects, functional impairment, disfigurement, persistent pain,
fatigue
Distressed HNC patients have poorer outcomes: treatment delay, poor compliance,
longer hospitalizations, poorer quality of life and survival
Dysphagia
New symptoms should prompt workup for recurrence or second primary
Lifelong monitoring
Nutritional status, weight as surrogate indicators of dysphagia
Poor nutrition
Chronic pain due to dystonia, neuropathy, trismus, fibrosis
Fatigue: assess for endocrinopathies

Multidisciplinary Management of R/M HNSCC
In the context of locoregional relapse RM HNSCC, multimodal treatment
with salvage surgery, re-irradiation, ablation, systemic therapy is utilized
Utility of salvage surgery: curative intent, locoregional control, palliation of
symptoms
Re-irradiation
Consolidation local therapy or palliative re-RT
Long-term toxicity of immunotherapy-based regimens may require
multidisciplinary management of chronic irAEs
Riaz et al, 2014; Roland & Bradley, 2014.

Chronic irAEs From Immune Checkpoint Inhibition
irAEs persisting >12 weeks after discontinuation of anti–
PD-L1 treatment
Limited data, mostly retrospective
43.2% of patients
Most common long-term toxicities
Hypothyroidism
Diabetes mellitus type I
Inflammatory arthritis
Less common but reported: dermatologic toxicity,
neuropathy, pneumonitis
Mechanisms
Irreversible damage to cells (endocrinopathies, vitiligo)
Waxing/waning off-target T-cell activation—smoldering
toxicity (inflammatory arthritis, dermatologic toxicity)
Johnson et al, 2022.
Dermatitis/eczema Vitiligo

Case Study 4: Ms. CS
s/p = status post; L = left; FNA = fine needle aspiration; PET = positron emission tomography.
34-year-old woman, never-smoker with a painful lesion on the left lateral
oral tongue
pT2pN2bM0 SCC left oral tongue
s/p L hemiglossectomy, left selective neck dissection
Adjuvant chemoradiation 60 Gy with weekly cisplatin
8 months later, palpated lesion left lower neck
FNA + SCC
PET/CT imaging: isolated enlarged PET-avid left supraclavicular lymph node no distant
metastatic disease
Salvage surgery: left revision neck dissection
Adjuvant re-irradiation
4 months later noted increasing left neck and sternal pain

Case Study 4: Ms. CS (cont.)
FDG = fluorodeoxyglucose; mets = metastases.
PET/CT
Intense FDG uptake in left level II-IV
neck soft tissue, likely combination of
post treatment changes and recurrent
tumor
FDG avid lymph nodes left neck
supraclavicular, paratracheal, internal
mammary and axillary
Large lytic destructive soft tissue mass
centered in the manubrium compatible
with osseous metastasis
Additional bone mets at C5 and the left
first rib

Case Study 4: Ms. CS
Treated with cetuximab + pembrolizumab
Pain resolved 6 weeks into treatment
PET/CT at 3 months
Interval improvement in disease in neck soft tissues
Decrease in size and resolution of FDG avidity
manubrium soft tissue mass: 30 x26  14 x 8 mm
Cetuximab discontinued after 5 months for
grade 2 acneiform rash, paronychia
Pembrolizumab monotherapy continued
Baseline
3 months on cetuximab + pembrolizumab

Case Study 4: Ms. CS (cont.)
NSAID = nonsteroidal anti-inflammatory agent.
13 months into treatment
Swelling and pain in left knee and bilateral hands
NSAIDs
Partially improves with prednisone but recurs with discontinuing steroids
Referred to rheumatology
Joint injections
NSAIDs
Prednisone
Hydroxychloroquine
Pembrolizumab discontinued after 13 months of therapy
Remains off therapy >2 years
Last PET/CT
Manubrial lesion 30 x26  14 x 8 mm   5x4 mm, no FDG uptake
Persistent waxing / waning arthritis, continues hydroxychloroquine,
NSAIDs, low-dose prednisone (as needed)

Key Takeaways
Investigational therapies in R/M disease are currently focused on
novel immunotherapeutic combinations, ADCs, and EGFR-directed
therapies
Tumor NGS and PD-L1 CPS should be performed on all R/M patients
at the onset of advanced disease
HPV remains an important prognostic biomarker even in the R/M
setting

Key Takeaways (cont.)
Treatment with ICIs improves quality of life compared with palliative
chemotherapy or targeted therapy
Toxicity is low in most cases
Corticosteroids are the mainstay of treatment for serious immune-
related adverse events
Multidisciplinary care from initial diagnosis to survivorship is essential
for head and neck cancer patients

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