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Recurrent and Metastatic HNSCC: New Insights and
Real-World Evidence for Improved Patient Outcomes
Assuntina G. Sacco, MD
Associate Professor of Internal Medicine, Division of Hematology/Oncology
Medical Director of UCSDH Infusion Services
Head and Neck Disease Team Leader, Gleiberman Head and Neck Cancer Center
UC San Diego Health, Moores Cancer Center
Disclosures
Advisory board/panel: Bicara
Consultant: First Thought
Grants/research support: Bicara, Merck, Nektar
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
Incorporate emerging efficacy and safety data on novel immune
checkpoint inhibitors into personalized care plans for patients with
advanced recurrent/metastatic HNSCC
Apply strategies to prevent and mitigate immune-mediated adverse
events
Evaluate supportive care measures that can help optimize
survivorship care in patients who have received treatment for
advanced recurrent/metastatic HNSCC
Outline
HNSCC epidemiology and clinical burden
Diagnosis, staging, risk assessment
Mechanisms of immune escape and implications for immunotherapy
Novel immune checkpoint inhibitors for recurrent/metastatic (R/M)
HNSCC:
Guideline recommendations
Insights from recent trials
Real-world evidence
Monitoring and managing immune-related adverse events
Supportive care measures to optimize survivorship
Case studies in R/M HNSCC
HNSCC Epidemiology and
Clinical Burden
Global HNSCC Incidence Rate: 2020
GLOBOCAN = Global Cancer Observatory; HPV = human papillomavirus; EBV = Epstein-Barr virus.
Graphic generated at gco.iarc.fr/today.
Johnson et al, 2020.
HNSCC is the sixth most common cancer
worldwide
By 2030, GLOBOCAN estimates HNSCC
incidence will increase by 30% (1.08
million new cases per year)
Increasing rates of HPV-related
oropharyngeal cancer in US and Western
Europe
Higher HNSCC prevalence in Southeast
Asia and Australia attributable to
consumption of carcinogen-containing
products and EBV
Estimated age-standardized incidence rates (world) in 2020:
hypopharynx, larynx, lip, oral cavity, nasopharynx, oropharynx
(both sexes, all ages)
HNSCC Risk Factors
E-cigarettes = electric cigarettes.
Johnson et al, 2020.
Tobacco
Alcohol
Viral etiologies
HPV 16 (some 18), EBV
Aging
Poor oral hygiene
Diets lacking vegetables
Exposure to environmental pollutants
(organic/inorganic chemicals,
particulate matter)
Areca nut (betel quid, betel leaf,
slaked lime and/or tobacco, spices)
Fanconi anemia (500-700–fold
increased HNSCC risk, primarily oral
cavity)
E-cigarettes? Unclear at this time
Slowly Moving the Survival Needle
aDifference between values in 1992-1996 and those in 2002-2006.
bP value for trend 1992-1996 to 2002-2006.
PE = probable error; SE = standard error.
Pulte & Brenner, 2010; Chaturvedi et al, 2011.
Modest improvement in survival
55% (1992-1996)  66% (2002-2006)
Sub-analysis (not shown) indicated overall improvement except for larynx subsite and age >75
HPV-associated HNSCC, in part, is driving improved prognosis
5-Year Relative Survival Rate by Period Analysis
Location
1982-1986 PE
(SE)
1987-1991 PE
(SE)
1992-1996 PE
(SE)
1997-2001 PE
(SE)
2002-2006 PE
(SE)
Differencea P valueb
All 52.7 (0.5) 53.2 (0.5) 54.7 (0.5) 58.6 (0.5) 65.9 (0.5) +11.2 <0.0001
Lip 92.5 (1.3) 95.6 (1.4) 95.5 (1.4) 90.9 (1.5) 97.4 (1.7) +1.9 0.5
Tongue 45.2 (1.2) 48.1 (1.2) 50.5 (1.2) 55.6 (1.1) 64.9 (1.0) +14.4 <0.0001
Oral cavity 53.6 (1.0) 52.6 (1.0) 51.1 (1.0) 56.6 (1.1) 62.9 (1.2) +11.8 <0.0001
Nasopharynx 47.1 (2.2) 47.6 (2.1) 53.8 (2.1) 58.3 (1.9) 62.3 (1.9) +8.3 0.002
Tonsil 39.7 (1.7) 41.8 (1.7) 47.6 (1.7) 56.5 (1.5) 69.8 (1.3) +22.2 <0.0001
Oropharynx 26.2 (2.9) 23.4 (2.6) 33.3 (3.2) 37.8 (3.1) 42.2 (3.1) +8.9 0.2
Hypopharynx 24.2 (1.4) 26.2 (1.5) 29.8 (1.6) 29.7 (1.6) 33.8 (2.0) +4.0 0.3
Larynx 66.8 (0.8) 66.3 (0.8) 64.9 (0.9) 64.3 (0.9) 66.8 (0.9) +1.9 0.2
HNSCC Survivors Have Second Highest Rate of Suicide
Osazuwa-Peters et al, 2018.
Multiple sources of unique
distress
Persistent, late treatment
effects
Functional/esthetic
compromise
Dysgeusia, dysphagia,
xerostomia
Ototoxicity, neuropathy
Depression
Pain and substance abuse
Financial toxicity/inability
to return to work
86.4
63.4
23.6
17.4
0 20 40 60 80 100
Pancreatic Cancer
Head and Neck Cancer
Survivors of Other Cancers
General US Population
Rate per 100,000 person-years
Rate per 100,000 person years
Diagnosis, Staging, and
Risk Assessment
Diagnosis: Clinical Presentation
p16 = protein 16; CN = cranial nerve.
Johnson et al, 2020; Bean et al, 2019.
Male-to-female predominance irrespective of etiology
Median age at diagnosis: 50s for EBV/HPV–mediated HNSCC, 60s for
HPV-negative HNSCC
Majority of patients present with locally advanced disease
10% have distant disease at initial presentation
Common presenting symptoms by subsite
Oral cavity: non-healing sore/ulcer
Oropharynx/hypopharynx:
p16-negative: dysphagia, odynophagia, otalgia
p16-positive: asymptomatic primary tumor, painless level II neck mass
Larynx: voice change/hoarseness, dyspnea/airway compromise
EBV-positive nasopharynx: neck mass, epistaxis, unilateral nasal
obstruction, hearing loss, CN palsies
Staging Evaluations
DL = direct laryngoscope; FNA = fine needle aspirate; IHC = immunohistochemistry; ISH = in situ hybridization; CT = computed tomography;
MRI = magnetic resonance imaging; PET = positron emission tomography.
Johnson et al, 2020.
Physical exam
Complete head and neck exam with direct inspection of oral cavity, fiberoptic
nasopharyngolaryngoscopy as indicated
Panendoscopy under anesthesia including DL, esophagoscopy, bronchoscopy for
tobacco-related, non-viral HNSCC to rule out second primary
Pathology
Biopsy of the primary tumor and/or neck mass (FNA for the latter)
Excisional node biopsy is not recommended unless FNA is persistently non-diagnostic,
primary site not identified or lymphoma suspected
HPV testing (p16 IHC and/or HPV ISH) for all oropharynx and unknown primaries
Imaging
Cross-sectional imaging of head/neck with diagnostic CT or MRI
CT chest to rule out distant disease
PET/CT preferred for distant metastatic workup for locally advanced or
locoregionally advanced disease
Staging and Risk Assessment
AJCC = American Joint Committee on Cancer; T = tumor; N = node; M = metastasis; DNA = deoxyribose nucleic acid.
Johnson et al, 2020; Amin et al, 2017.
AJCC 8th Edition
3 important changes to improve hazard discrimination/outcome
prediction
Addition of depth of invasion to T stage in oral cavity tumors
Addition of extranodal extension to N stage in non-viral HNSCC
Codification of novel staging system for HPV-positive HNSCC
Revision of nodal staging led to stage migration stage III-IVA  stage I-II
Only M1 disease is now classified as stage IV
Do not “under-treat” stage I-II as this still includes locoregionally advanced
disease requiring multimodality therapy
Does not account for tobacco use (important modifier of prognosis)
Nasopharynx cancer staging still based on anatomy
Future editions may include nomograms incorporating plasma EBV DNA
Mechanisms of Immune
Escape and Implications for
Immunotherapy
Immune Escape Mechanisms As a Guide for Cancer Immunotherapy
PD-L1 = programmed death ligand 1.
Beatty et al, 2015.
Key Immune Checkpoint Targets For Cancer Immunotherapy
APC = antigen-presenting cell; CD = cluster of differentiation; SIRP = signal regulatory protein; TIM3 = T cell immunoglobulin and mucin domain 3;
NICD = NAD+-induced cell death; CTLA-4 = cytotoxic T-lymphocyte–associated protein 4; A2AD = adenosine A2A receptor; PD-1 = programmed cell death
protein 1; TIGIT = T-cell immunoreceptor with immunoglobulin and ITIM domains; NK = natural killer; LAG3 = lymphocyte activation gene 3;
TIGIT = T cell immunoreceptor with immunoglobulin and ITIM domain; MHC = major histocompatibility complex; HLA = human leukocyte antigen;
SS = single-stranded; PARP = poly-ADP-ribose polymerase.
Dutta et al, 2023.
The Immunotherapy Ride
CAR T = chimeric antigen receptor T cell; IL-2 = interleukin-2; I/O = immuno-oncology; IDO = indoleamine 2,3-dioxygenase; GITR = glucocorticoid-induced tumor necrosis factor receptor.
Sell, 2017; Zhang & Zhang, 2020; NCI, 2022; Van den Eynde et al 2020; Buzzatti et al, 2019; Chauvin & Zarour, 2020; Huo et al, 2022;
Tumor immunosurveillance
Thomas & Burnet (1957)
Benefit of high-dose IL-2
(1985)
Skepticism around I/O
First cancer vaccine
(2010)
Sipuleucel-T
Reported failures
with IDO, GITR, others
(2017-2019)
Anti-TIGIT
(2020)
Anti-LAG3
(2021)
Trough of disillusionment
Trough of disillusionment
Slope of enlightenment
Peak of inflated expectations
IL-2 approved
(1992)
First anti-CTLA-4
(2011)
First anti–PD-1
(2012-2014)
First anti–CTLA-4 & –PD-1 combo
(2015)
First CAR T
(2017)
Nivolumab Pembrolizumab
Ipilimumab
Tisagenlecleucel
Aldesleukin
Excitement
Time (not drawn to scale)
Predictive Biomarkers of Checkpoint Inhibitors
TMB = tumor mutational burden; DDR = DNA damage response; dMMR = deficient mismatch repair; MSI = microsatellite instability; IFN = interferon;
KRAS = Kirsten ras oncogene homolog; TME = tumor microenvironment; TAM = tumor-associated macrophage; TIL = tumor-infilitrating lymphocytes;
TCR = T-cell receptor; CTC = circulating tumor cells; ctDNA = circulating tumor DNA; irAE = immune-related adverse event.
Bai et al, 2020.
Novel Immune Checkpoint Inhibitors
for R/M HNSCC:
Guideline recommendations
Insights from recent trials
Real-world evidence
Monitoring and managing
immune-related adverse events
NCCN Guideline Recommendations: Version 1.2023
Principles of Systemic Therapy for Non-Nasopharyngeal Cancers: Oral Cavity (Including Mucosal Lip), Oropharynx, Hypopharynx, Glottic Larynx,
Supraglottic Larynx, Ethmoid Sinus, Maxillary Sinus, and Occult Primary
Recurrent, Unresectable, or Metastatic Disease (No Surgery or Radiotherapy Option)
Preferred Regimens
First Linea
• Pembrolizumab/platinum
(cisplatin or carboplatin)/5-
fluorouracil (FU) (category 1)
• Pembrolizumab (for tumors
that express PD-L1 with CPS
≥1) (category 1)
Subsequent Line
(If Not Previously Used)
• Nivolumab (if disease
progression on/after platinum
therapy) (category 1)
• Pembrolizumab (if disease
progression on/after platinum
therapy) (category 1)
Other Recommended Regimens (First and Subsequent Line)
Combination Regimens
• Cetuximab/platinum (cisplatin or carboplatin)/5-FU (category 1)
• Cisplatin/cetuximab
• Cisplatin or carboplatin/docetaxel or paclitaxel
• Cisplatin/5-FU
• Cisplatin or carboplatin/docetaxel/cetuximab
• Cisplatin or carboplatin/paclitaxel/cetuximab
• Pembrolizumab/platinum (cisplatin or carboplatin)/docetaxel
• Pembrolizumab/platinum (cisplatin or carboplatin)/paclitaxel
(category 2B)
Single Agents
• Cisplatin
• Carboplatin
• Paclitaxel
• Docetaxel
• 5-FU
• Methotrexate
• Cetuximab
• Capecitabine
• Afatinib (subsequent line only, if disease progression on/after
platinum therapy) (category 2B)
Useful in Certain Circumstances (First
and Subsequent Line)
• Squamous cell carcinoma
• Cetuximab/nivolumab
• Cetuximab/pembrolizumab
(category 2B)
• For select ethmoid/maxillary sinus
cancers (ie, small cell, SNEC, high-
grade olfactory
esthesioneuroblastoma, SNUC with
neuroendocrine features)
• Cisplatin/etoposide or
carboplatin/etoposide
• Cyclophosphamide/doxorubin/
vincristine (category 2B)
• Pembrolizumab (for MSI-H, dMMR,
or TMB-H [≥10 mut/Mb] tumors)
• Cisplatin/pemetrexed (for PS 0-1)
(category 2B)
• Gemcitabine/paclitaxel
aIf not previously used, these regimens may be considered in subsequent-line therapy as other recommended regimens.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN = National Comprehensive Cancer Network; 5FU = fluorouracil; SNEC = sinonasal neuroendocrine carcinoma; SNUC = sinonasal undifferentiated carcinoma;
MSI-H = MSI–high; TMB-H = TMB–high; mut = mutations; PS = performance status.
NCCN, 2022b.
CheckMate-141: Nivolumab for Recurrent
HNSCC
Q2W = every 2 weeks.
Ferris et al, 2016.
Study Design
Platinum-refractory head
and neck squamous cell
carcinoma (N=361)
Investigator’s choice:
cetuximab OR docetaxel OR methotrexate
Nivolumab 3 mg/kg Q2W
Randomizatio
n
2:1
Primary end point
• Overall survival
Secondary end points
• Progression-free
survival
• Response rate
• Toxicity
• Safety
CheckMate-141: Nivolumab for Recurrent HNSCC (cont.)
CI = confidence interval; mo = month.
Ferris et al, 2016.
Overall and Progression-Free Survival Primary Analysis
OS = overall survival; ORR = overall response rate; PFS = progression free survival; AE = adverse event.
Ferris et al, 2016; Ferris et al, 2018.
For patients who progress following platinum-based therapy for R/M
HNSCC, nivolumab is superior to standard second-line therapy
Improved OS (median 7.5 vs 5.1 months)
Improved ORR (13.3% vs 5.8%)
Similar PFS (median 2.3 vs 2.0 months)
Fewer Grade 3 or 4 AEs (13.1% vs 35.1%)
Most frequent AEs with nivolumab:
Fatigue, nausea, rash, decreased appetite, and pruritus
Trend towards benefit regardless of PD-L1 or p16 status and
maintained at 2-year follow-up
FDA approved in 2016 for use in previously treated R/M HNSCC
Conclusions
CheckMate-141: Nivolumab for Recurrent HNSCC (cont.)
KEYNOTE-040: Pembrolizumab
Q3W = every 3 weeks.
Cohen et al, 2019.
Platinum refractory head
and neck squamous cell
carcinoma (N=247)
Investigator’s choice:
cetuximab OR docetaxel OR methotrexate
Pembrolizumab 200 mg IV Q3W
Randomizatio
n
1:1
Primary end point
• Overall survival
Study Design: Recurrent or Metastatic HNSCC
KEYNOTE-040: Pembrolizumab (cont.)
TRAE = treatment-related adverse event; HR = hazard ratio.
Cohen et al, 2019.
Numerically improved overall survival with pembrolizumab:
8.4 vs 6.9 months
Fewer grade ≥3 TRAEs with pembrolizumab
Most common TRAE with pembrolizumab was hypothyroidism (13%)
FDA-approved in 2016 for platinum refractory R/M HNSCC
Recurrent or Metastatic HNSCC
KEYNOTE-048: Pembrolizumab
SCC = squamous cell carcinoma; ECOG = Eastern Cooperative Oncology Group; TPS = tumor proportional score; pembro = pembrolizumab;
AUC = area under the curve; QOL = quality of life ; Q1W = every 1 week.
Burtness et al, 2019.
Study Design: Recurrent or Metastatic HNSCC
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
Pembro
Pembro
plus chemo
EXTREME
Primary end points: overall survival, PFS
Secondary end points: safety, tolerability, objective response,
QOL
KEYNOTE-048: Pembrolizumab (cont.)
RR = response rate.
Burtness et al, 2019.
Overall Survival: PD-L1 CPS ≥20
43% of patients in this category
With pembro vs EXTREME:
Improved OS: 14.9 vs 10.7
months
Lower RR: 23% vs 36%
With pembro/chemo vs
EXTREME:
Improved OS: 14.7 vs 11.0
months
Similar RR: 43% vs 38%
Overall
survival
(%)
Overall
survival
(%)
KEYNOTE-048: Pembrolizumab (cont.)
Burtness et al, 2019.
85% of patients in this category
With pembro vs EXTREME:
Improved OS: 12.3 vs 10.3
months
Lower RR: 19% vs 35%
With pembro/chemo vs
EXTREME:
Improved OS: 13.6 vs 10.4
months
Same RR: 36%
Overall Survival: PD-L1 CPS ≥1
Overall
survival
(%)
Overall
survival
(%)
Burtness et al, 2019.
With pembro vs EXTREME:
Similar OS: 11.6 vs 10.7
months
Lower RR: 17% vs 36%
With pembro/chemo vs
EXTREME:
Improved OS: 13.0 vs 10.7
months
Same RR: 36%
Overall Survival: Total Population
KEYNOTE-048: Pembrolizumab (cont.)
Overall
survival
(%)
Overall
survival
(%)
KEYNOTE-048: Pembrolizumab (cont.)
EMA = European Medicines Agency.
EMA, 2022.
Not included in peer-reviewed publication
Available in submission to the EMA (see link below)
https://www.ema.europa.eu/en/documents/variation-
report/keytruda-h-c-3820-ii-0065-epar-assessment-report-
variation_en.pdf
For patients with CPS ≥1 but <20:
No OS improvement with pembrolizumab monotherapy vs
EXTREME (10.8 vs 10.1 months, HR 0.86, 95% CI 0.66-1.12)
Improvement in overall survival with pembro/chemo vs EXTREME
(12.7 vs 9.9 months, HR 0.71, 95% CI 0.54-0.94)
What About Overall Survival for CPS ≥1 but <20?
EMA, 2022.
Not included in peer reviewed publication
Available in submission to the EMA (see link below)
https://www.ema.europa.eu/en/documents/variation-
report/keytruda-h-c-3820-ii-0065-epar-assessment-report-
variation_en.pdf
For patients with CPS < 1:
No overall survival improvement with pembrolizumab monotherapy
vs EXTREME (7.9 vs 11.3 months, HR 1.51, 95% CI 0.96-2.37)
No overall survival improvement with pembro/chemo vs EXTREME
(11.3 vs 10.7 months, HR 1.21, 95% CI 0.76-1.94)
What About Overall Survival for CPS <1?
KEYNOTE-048: Pembrolizumab (cont.)
EMA, 2022.
Conclusions: Pembro Plus Platinum and 5-FU vs EXTREME
KEYNOTE-048: Pembrolizumab (cont.)
Superior OS for pembro/chemo in the PD-L1 CPS ≥20 and CPS ≥1 and
total populations
Longer duration of response for pembro/chemo
Overall, comparable safety profiles for pembro/chemo and EXTREME
Most common AEs:
Anemia (58.3% vs 46.7%)
Nausea (51.1% vs 51.2%)
Constipation (37% vs 33.1%)
Fatigue (34.4% vs 35.5%)
Neutropenia (33.7% vs 32.8%)
Vomiting (32.6% vs 27.9%)
Mucosal inflammation (30.8% vs 28.2%)
Higher incidence of hypothyroidism, anemia, and blood creatinine
increase with pembro/chemo
EMA, 2022; Burtness et al, 2019.
Conclusions: Pembrolizumab Monotherapy vs EXTREME
KEYNOTE-048: Pembrolizumab (cont.)
Superior OS for pembro in the CPS ≥20 and CPS ≥1 populations
Noninferior OS for pembro in the total population
Substantially longer duration of response for pembro
Favorable safety profile for pembro vs EXTREME
Most common AEs:
Fatigue (28% vs 36%)
Anemia (21% vs 47%)
Constipation (20% vs 33%)
Hypothyroidism (18% vs 6%)
Nausea (16% vs 51%)
Diarrhea (15% vs 34%)
Platinum/Taxane/Pembrolizumab
SWOG = Southwest Oncology Group.
Burtness et al, 2019; Gibson et al, 2005; Samlowski et al, 2007; Dizenis et al, 2022.
KEYNOTE-048 supporting platinum + anti–PD-1 as backbone
(Burtness et al, Lancet 2019)
E1395 phase 3 randomized cooperative group trial showing no
statistically significant difference in response or survival with
cisplatin/paclitaxel vs cisplatin/5-FU (Gibson et al, JCO 2005)
SWOG phase 2 study showing activity/safety of carboplatin/docetaxel
(Samlowski et al, Cancer Invest 2007)
Phase 4 KEYNOTE-B10 trial (ESMO 2022, proffered paper)
Rationale for Swapping out 5-FU in Favor of Taxane
KEYNOTE-B10: Pembro/Carboplatin/Paclitaxel
BICR = blinded independent central review.
Dzienis et al, 2022.
Study Design, Phase 4 Trial
Key Eligibility Criteria
• 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: Pembro/Carbo/Paclitaxel (cont.)
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; DOR = duration of response.
Dzienis et al, 2022.
Most common any grade TRAEs: neutropenia (57%), anemia (43%), fatigue (40%)
ORR and DOR per RECIST v1.1 by BICR
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)
Pembrolizumab/Cetuximab for R/M HNSCC
Sacco et al, 2021.
Study Design: Open-Label Non-Randomized Phase 2 Trial
Pembro/Cetuximab for R/M HNSCC (cont.)
Sacco et al, 2021.
Response Type N (%)
Overall response rate by 6 months 15 (45%)
Complete response 1 (3%)
Partial response 14 (42.4%)
Stable disease 5 (15.2%)
Disease control rate 20 (61%)
Progressive disease 13 (39.4%)
Overall Response Rate and Best Response
Overall response rate beyond 6 months was 48%
3 withdrew consent during Cycle 1,
per protocol classified as PD
HPV-positive patients were less likely to
respond (not significant); no association with
response and CPS
Pembro/Cetuximab for R/M HNSCC (cont.)
Sacco et al, 2021.
Response Type N (%)
Overall response rate by 6
months
15 (45%)
Complete response 1 (3%)
Partial response 14 (42.4%)
Stable disease 5 (15.2%)
Disease control rate 20 (61%)
Progressive disease 13 (39.4%)
Overall Response Rate and Best Response
Overall response rate beyond 6 months was 48%
3 withdrew consent during Cycle 1,
per protocol classified as PD
HPV-positive patients were less likely to
respond (not significant); no association with
response and CPS
Pembro/Cetuximab for R/M HNSCC (cont.)
IQR = interquartile range.
Sacco et al, 2021.
Outcomes Over Time
John T
Response Type
Median Duration in
Months
Complete or partial 13.1 (95% CI: 6.5-NR)
Stable disease 8.9 (95% CI: 4.0-NR)
Median duration of follow-up: 7.3 months
(IQR 3.9-10.9)
Pembro/Cetuximab for R/M HNSCC (cont.)
Sacco et al, 2021.
Overall Survival and Progression-free Survival
John T
Median OS: 18.4 months
(95% CI: 11 months - NR)
Median PFS: 6.5 months
(95% CI: 2.1 months - NR)
No difference in OS or PFS based on HPV status or CPS (not
powered to assess); data not shown
Pembro/Cetuximab for R/M HNSCC (cont.)
Sacco et al, 2021.
Treatment-Related Adverse Events
John T
Most common grade ≥3 TRAE
was oral mucositis
Grade 1-2 Grade 3 Grade 4 Grade 5
Rash acneiform 25 (76%) 2 (6%) 0 0
Hypomagnesaemia 11 (33%) 2 (6%) 0 0
Dry skin 11 (33%) 0 0 0
Increase in aspartate aminotransferase 9 (27%) 0 0 0
Nausea 8 (24%) 0 0 0
Fatigue 7 (21%) 1 (3%) 0 0
Vomiting 6 (18%) 0 0 0
Increase in alanine aminotransferase 6 (18%) 0 0 0
Increase in alkaline phosphatase 6 (18%) 0 0 0
Skin and subcutaneous tissue disorders (others) 6 (18%) 0 0 0
Hypothyroidism 5 (15%) 0 0 0
Paronychia 5 (15%) 0 0 0
Diarrhea 4 (12%) 1 (3%) 0 0
Mucositis oral 4 (12%) 3 (9%) 0 0
Pruritus 4 (12%) 0 0 0
Colitis 0 2 (6%) 0 0
Acidosis 0 1 (3%) 0 0
Laryngeal oedema 0 1 (3%) 0 0
Sepsis 0 0 1 (3%) 0
Nivolumab Plus Cetuximab
TTMV = tumor tissue–modified viral.
Chung et al, 2022.
Median OS in previously treated R/M HNSCC =
11.4 months, with 1-year OS 50%
Median OS in first-line R/M HNSCC = 20.2
months, with 1-year OS 66%
In the total population:
p16-negative patients had higher response
rate but no survival advantage
Higher PD-L1 score was associated with
higher response rate and longer OS
p16-positive patients with lower median TTMV
DNA counts had higher RR and longer OS
Grade ≥3 TRAE: hypophosphatemia (5%), skin-
and nail-related (14%), hypomagnesemia (5%)
Grade 3 irAE: fatigue (5%)
Phase 2 Trial for R/M HNSCC (Treatment-Exposed or -Naive)
Key Eligibility Criteria
• SCC of oral cavity,
oropharynx, paranasal
sinuses, nasal cavity,
larynx, hypopharynx
• HPV p16-positive
unknown primary in
cervical node
• Incurable R/M
HNSCC
Nivolumab
240 mg Q2W
Cetuximab
500 mg/m2 Q2W
Lead in
cetuximab cycle
followed by 24
Cycles
Primary end point
• Overall response rate
N=95
CheckMate 651: Ipi/Nivo vs EXTREME
aInitial cetuximab dose of 400 mg/m2 once only, then cetuximab 250 mg/m2 Q1W plus cisplatin 100 mg/m2 or carboplatin AUC 5 on Day 1, plus fluorouracil
1,000 mg/m2/day for 4 days for 6 cycles (Q3W).
bCetuximab 250 mg/m2 Q1W;
Ipi = ipilimumab; nivo = nivolumab; BICR = blinded independent review committee.
Haddad et al, 2023.
Study Design
Key Eligibility Criteria
• R/M HNSCC (oral cavity, oropharynx,
hypopharynx, or larynx)
• No prior treatment for R/M disease
• Prior chemotherapy for locally
advanced disease permitted if
progression-free ≥6 months post-
treatment
Stratification
• p16 status in oropharynx
• Tumor PD-L1 status (<1% vs ≥1%)
• Prior chemotherapy (yes vs no)
Nivo 3 mg/kg Q2W
Ipi 1 mg/kg Q6W
EXTREME Regimena
Cetuximab plus cisplatin/carboplatin plus
5-FU Q3W for 6 cycles followed by
cetuximabb monotherapy Q1W
Primary End Points
• OS in all randomized
• OS in PD-L1 CPS ≥20
Secondary End Points
• OS in PD-L1 CPS ≥1
• PFS by BICR
(all randomized, PD-L1 CPS ≥20)
• ORR/DOR by BICR
(all randomized, PD-L1 CPS ≥20)
Exploratory End Points
• PFS and ORR/DOR in PD-L1 CPS ≥1
• Patient-reported outcomes
• Safety
Until disease
progression,
unacceptable toxicity, or
2 years for nivo plus ipi
R
A
N
D
O
M
I
Z
E
1:1
N=947
CheckMate 651: Ipi/Nivo vs EXTREME (cont.)
a95% CI: 12.1-15.8 (nivo + ipi) and 12.6-15.2 (EXTREME).
b95% CI: 13.8-22.0 (nivo + ipi) and 12.3-16.0 (EXTREME).
cConfidence intervals are adjusted based on the final α levels for each primary end point.
Haddad et al, 2023.
Primary End Points: Overall Survival
Minimum follow-up: 27.3 months
CheckMate 651: Ipi/Nivo vs EXTREME (cont.)
aPer BICR.
B95% CI: 3.1-6.9 (nivo + ipi) and 5.6-8.7 (EXTREME).
C95% CI: 12.1-not reported (NR) (nivo + ipi) and 5.6-10.1 (EXTREME).
Haddad et al, 2023.
Efficacy of Ipi/Nivo vs EXTREME in CPS ≥20 Population
Minimum follow-up: 27.3 months
CheckMate 651: Ipi/Nivo vs EXTREME (cont.)
Haddad et al, 2023.
Incidence of TRAEs in All Treated Patients
Most common any-grade
TRAEs were fatigue (18.2%),
pruritus (15.0%), and
hypothyroidism (14.1%) with
ipi/nivo and nausea (44.7%),
rash (38.3%), and anemia
(34.9%) with EXTREME
Most common any-grade
IrAEs with ipi/nivo were
hypothyroidism/thyroiditis
(16.0%), rash (12.6%), and
hyperthyroidism (6.8%)
Ipi/Nivo
(n=468)
EXTREME
(n=441)
Any Grade Grade 3/4 Any Grade Grade 3/4
Any TRAEs 338 (72.2%) 132 (28.2%) 430 (97.5%) 312 (70.7%)
TRAEs leading to
discontinuation of any
component of the
regimen
58 (12.4%) 45 (9.6%) 57 (12.9%) 39 (8.8%)
Serious TRAEs 74 (15.8%) 57 (12.2%) 122 (27.7%) 105 (23.8%)
Treatment-related
deaths
6 (1.3%) 8 (1.8%)
Real-World Evidence of First-Line
Pembrolizumab
rwOS = real-world OS.
Black et al, 2022.
Retrospective cohort (Flatiron database in
the US) from 2019-2021 of R/M HNSCC
patients receiving first-line therapy
Pembro monotherapy: n= 337
Pembro + chemo: n=176
Median rwOS consistent with KEYNOTE-048
Higher survival rates at 24 months
compared with KEYNOTE-048
Age and ECOG were independent
predictors
In a secondary analysis, comparable
treatment duration noted when trial-
matched for ECOG PS 0-1
Real-World Evidence of Second-Line Nivolumab
Rajappa et al, 2022.
Despite fairly comparable outcomes to clinical trials (cannot make direct
comparisons given nuances of the patient populations), global access to
immunotherapy remains problematic
In India, only 0.25% of the patient population had access in 2016 compared
with 7.3% in 2019
Staying Vigilant
Martins et al, 2019.
Kinetics of irAEs with anti–PD-1/PD-L1 Agents
GI (n = 56; 14%)
10.1 (0.1-122.1)
N=406 Patients From Updated Results of Phase 3 CheckMate 025
Trial (Nivolumab for Renal Cancer)
n, %: AE incidence. n, %: pts whose AE resolved.
Time to Onset Time to Resolution From Start of AE
Wks
0 50 10
0
15
0
20
0
Skin (n = 107; 26%)
8.4 (0.1-100.1)
Renal (n = 28; 7%)
10.6 (4.0-79.1)
Endocrine (n = 41;
10%)
16.4 (2.1-112.3)
Pulmonary (n = 18; 4%)
17.4 (1.9-73.0)
Wks
7.86 (0.1-132.1+)
GI (n = 47; 84%)
NR (1.9-
141.9+)
Endocrine (n = 15;
37%)
26.14 (0.6-109.1+)
Renal (n = 17; 63%)
Hepatic (n = 45; 11%)
7.3 (2.0-71.1)
0 50 10
0
15
0
20
0
8.0 (1.6-127.1+)
Hepatic (n = 37; 84%)
16.0 (0.1-156.6+)
Skin (n = 83; 78%)
5.57 (1.3-96.1+)
Pulmonary (n = 16;
89%)
Median Time to Onset and Resolution
GI = gastrointestinal.
Plimack et al, 2016; Motzer et al, 2020.
Treatment-Related AEs of Any Grade
Managing irAEs: General Principles
CTCAE = Common Terminology Criteria for Adverse Events; G = grade; ICI = immune checkpoint inhibitor.
Martins et al, 2019; Owen et al, 2021; NCCN, 2023a.
Educate patients on what to look out for
Generally develop within first 6 months, but can also have late
onset of up to 1 year after treatment
If you have a high suspicion, grade the toxicity per CTCAE v5.0
G1: continue ICI with close monitoring
G2: typically hold ICI and consider steroids
G3: hold ICI and administer steroids
G4: permanently discontinue ICI and administer steroids
Managing irAEs: General Principles (cont.)
Martins et al, 2019; NCCN, 2023a.
Not responding to steroids? Consider additional
immunosuppression
Colitis: infliximab, vedolizumab
Pneumonitis: infliximab, mycophenolate
Hepatitis: mycophenolate/azathioprine/tacrolimus
NCCN supportive care guidelines: management of
immunotherapy-related toxicities is a helpful resource
Rechallenge? Depends on the health risk of the toxicity, steroid
responsiveness/resolution, patient goals
Managing irAEs: General Principles (cont.)
Martins et al, 2019.
Nervous system
• Encephalitis
• Meningitis
• Polyneuropathy
• Guillain-Barré
syndrome
• Subacute
inflammatory
neuropathies
Eyes
• Uveitis
• Sjogren syndrome
• Conjunctivitis and/or
blepharitis
• Episcleritis and/or scleritis
• Retinitis
Lungs
• Pneumonitis
• Pleuritis
• Sarcoid-like
granulomatosis
Skin
• Skin rash
• Pruritus
• Vitiligo
• Psoriasis
• Stevens-
Johnson
syndrome
• DRESS
Blood
• Anemia
• Neutropenia
• Thrombocytopenia
• Thrombotic
microangiopathy
• Acquired hemophilia
• Vasculitis
Gastrointestinal
• Colitis
• Enteritis
• Gastritis
Joints and muscles
• Arthralgia
• Arthritis
• Myositis
• Dermatomyositis
Kidneys
• Interstitial nephritis
• Glomerulonephritis
Pancreas
• Pancreatitis
• Autoimmune
diabetes
Heart
• Myocarditis
• Pericarditis
Adrenal glands
• Adrenalitis
Liver
• Hepatitis
Pituitary
• Hypophysitis
Thyroid
• Thyroiditi
s
irAEs with Pembrolizumab: KEYNOTE-048
HD = high-dose; IO = immuno-oncology.
Burtness et al, 2018.
Treatment-Related Adverse Events: Summary
Tahara et al, 2022.
0
1
2
3
4
#
of
AEs
Reported
Attributable Toxicity (Grade ≥3) for
Pembro/Cetux
Cetux = cetuximab.
Sacco et al, 2020.
Supportive Care Measures to
Optimize Survivorship
It Starts With Embracing Survivorship at
Diagnosis
Adapted from the National Coalition for Cancer Survivorship.
An individual is considered a cancer survivor from the time of
diagnosis, through the balance of his or her life
Family members, friends, and caregivers are also impacted by the
survivorship experience and are therefore included in this definition
Prevention Detection Diagnosis Treatment Survivorship
Reactivity Often Drives Supportive Care Referrals
Images courtesy of Assuntina Sacco, MD.
A Missed Opportunity…
Silver et al, 2018.
>90% did not have an
easily identifiable
patient-facing link
Julie K Silver, Vishwa S Raj, Jack B Fu, Eric M Wisotzky,
Sean Robinson Smith, Sasha E Knowlton, and Alexander J Silver
Quaternary Care Cancer Center
Giuliani et al, 2016.
61% of Patients With at Least 1 Unmet Need
Top Unmet Needs
Emotional support
Help managing side effects
Local health care services
To feel like I am managing my health together with
the medical team
To know that all my doctors talk to each other to
coordinate my care
More accessible parking
Help getting life/travel insurance
Top 3 Resource Requests
Education about cancer prevention (50%)
Support/information for caregivers (40%)
Health insurance/drug coverage assistance (35%)
Proactivity Through Cancer Prehabilitation
Silver et al, 2013; Silver et al, 2014.
“Occurs between time of diagnosis and the beginning of acute
treatment and includes physical and psychological assessments that
establish a baseline functional level, identify impairments, and provide
interventions that promote physical and psychological health to
reduce the incidence and/or severity of future impairments”
Survivorship Care Continuum
Cancer diagnosis
Prehabilitation assessments
and interventions
Cancer treatment
Rehabilitation assessments
and interventions
Prehabilitation May Improve Health Above Baseline
Status
Silver, 2015.
New Cancer Diagnosis
Prehabilitation Assessments
Prehabilitation
Interventions
Acute Cancer Treatments
No Physical or
Psychological
Impairments
Psychological
Impairments
Physical
Impairments
Referral to Mental
Health Services
Referral to
Rehabilitation Services
Survivorship Care Planning
CT = computed tomography; ENT = ear, nose, and throat; SLP = speech-language pathologist; PT/OT = physical therapy/occupational therapy.
NCCN, 2023b; Cohen et al, 2016.
Care of the HNSCC cancer survivor should include the following:
Surveillance for HNSCC recurrence
Assessment and management of physical and psychological long-term and
late side effects of treatment
Screening for second primary cancers
Colonoscopy, mammogram, low-dose chest CT, skin examination
Health promotion
Vaccines, exercise, nutrition, sun exposure, tobacco/alcohol cessation, dental
cleanings and fluoride applications, swallowing exercises, and neck and
shoulder stretching
Care coordination
Oncology, ENT, radiation oncology, primary care, dentist, SLP, PT/OT, dietician
Treatment summary
Assessment/Management of Long-Term/Late
Effects
GERD = gastroesophageal reflux disorder; SPC = salivary pepsin concentration; TSH = thyroid-stimulating hormone.
Cohen et al, 2016.
Musculoskeletal/neuromuscular
Rehabilitation specialists, physical
therapists
Neuro-stabilizing agents
Dysphagia/aspiration/stricture
SLP specialists
Dilation
GERD
Prevents healing, risk of HNSCC
recurrence/SPC
Conservative measures first, then GI
Lymphedema
Rehab specialist for manual lymphatic
drainage ± compression bandaging
Hypothyroidism
TSH Q6-12 months
Fatigue
Assess for causative/reversible
factors
Assess for mood disorder
Encourage physical activity
Altered or loss of tase
Registered dietitian
Speech/voice
SLP specialists
Hearing loss, vertigo, vestibular
neuropathy
Audiology
Sleep disturbance/sleep apnea
Sleep study
Oral Health
ORN = osteoradionecrosis; HNS = head and neck surgeon; HBO = hyperbaric oxygen.
Cohen et al, 2016.
Surveillance, caries, periodontitis, xerostomia, osteonecrosis, oral
infections/candidiasis
Close follow-up with the dental professional
Avoid tobacco, alcohol, caffeine, spicy/abrasive foods, extreme
temperature liquids, sugary gum or soft drinks, acidic or citric liquids
Dental prophylaxis, including brushing with remineralizing toothpaste,
fluoride
Alcohol-free mouth rinses (salt/soda, chlorhexidine, etc)
For ORN, conservative measures (eg, antibiotics, chlorhexidine), HNS eval
for consideration of HBO or debridement
For candidiasis, systemic fluconazole and/or clotrimazole troches
Nystatin is administered in suspension with high-sugar solution
Mental Health and Well-Being
Cohen et al, 2016.
Psychosocial effects
Altered eating, speech, aesthetics, social disruption, depressive
symptoms, general health
Social disruption >80%
Depressive symptoms >70%
Body and self-image
Common and often ignored by treating clinicians
Distress/depression/anxiety
Multiple validated screening tools
Addressing Psychosocial Challenges
Prompt referrals to social work, palliative care, and mental health colleagues as
needed
NCCN Distress Thermometer
NCCN, 2022a.
NCCN Distress Thermometer
Distress is an unpleasant experience of a mental,
physical, social, or spiritual nature. It can affect the
way you think, feel, or act. Distress may make it
harder to cope with having cancer, its symptoms, or
its treatment.
Instructions: Please circle the number (0-10) that
best describes how much distress you have been
experiencing in the past week, including today.
1. No distress
10. Extreme distress
Addressing Psychosocial Challenges (cont.)
Problem List for Patients
NCCN, 2022a.
Post-Treatment Surveillance Recommendations
PCP = primary care physician.
NCCN, 2022b; NCCN, 2023b.
Exam Frequency Provider
History and physical including
head and neck exam, mirror, and
fibrotic evaluation
Year 1: every 1-3 months
Year 2: every 2-6 months
Year 3-5: every 4-8 months
>5 years: every 12 months
Oncologist/ENT/radiation
oncologist
TSH
Every 6-12 months if neck
irradiated
Oncologist/PCP
Dental evaluation At least every 6 months Dentist
Chest CT indicated for patients
with significant smoking history
Annually Oncologist/PCP
Surveillance for depression Every visit Oncologist/PCP
Speech, hearing, swallowing
evaluation
As clinically indicated
Speech and language pathology;
audiology
Nutrition evaluation As clinically indicated Oncologist/PCP/dietician
Smoking cessation and alcohol
counseling
As clinically indicated Oncologist/PCP
Case Study 1: Mary
Mary is an 89-year-old woman, never-smoker, who initially presented
with squamous cell carcinoma of the right inferior maxilla (pT3N0M0)
and underwent surgical resection followed by postoperative radiation
Three months after radiation, she has nodal disease (biopsy-proven
squamous cell carcinoma)
Right modified neck dissection was attempted but aborted secondary
to disease extent and morbidity
Distant metastatic workup was negative
Case Study 1: Mary (cont.)
ADLs = activities of daily living FAT1 = FAT atypical cadherin 1; TP53 = tumor protein 53; JAK = Janus kinase.
Medical history: stroke, renal insufficiency, hearing loss
Functional status: ECOG 1; still drives, goes to the gym,
volunteers as a nursing home assistant, able to perform ADLs
Genomic profiling:
Tumor: FAT1, MPL, NOTCH1, TP53
Blood: JAK
CPS/PD-L1 testing not performed
What would you do next?
Case Study 1: Mary (cont.)
a. Best supportive care only/hospice
b. Pembrolizumab or nivolumab monotherapy
c. Clinical trial
d. a, b, c are all appropriate
What Are Mary’s Options?
What are her options?
Case Study 1: Mary (cont.)
a. Best supportive care only/hospice
b. Pembrolizumab or nivolumab monotherapy
c. Clinical trial
d. a, b, c are all appropriate
What Are Mary’s Options?
What are her options?
Case Study 1: Mary (cont.)
Pembrolizumab initiated on 7/15/2016
Complete response noted on imaging
Pembrolizumab discontinued on 6/29/2018 after 2 years of
treatment
No treatment-related toxicities
Sustained remission as of last visit on 05/05/23, and she is
96 years young
Mary’s Journey
Case Study 2: Joon
Joon is a 64-year-old woman, never-smoker, initially diagnosed
with stage IVA (T4aN0M0) squamous cell carcinoma of the
mandible
She underwent upfront surgical resection followed by
postoperative radiation with cisplatin 100 mg/m2 every 3 weeks
due to involved margins
Her post-treatment imaging demonstrated interval development
of mediastinal adenopathy (biopsy-proven metastatic disease)
Case Study 2: Joon (cont.)
During this time, she is also diagnosed with latent tuberculosis
(TB) and bullous pemphigoid
Medical history: otherwise none
ECOG: 0
CPS 80, TMB ≥10
What would you do next?
Case Study 2: Joon (cont.)
a. Palliative radiation to mediastinum
b. Consider cytotoxic or targeted therapy
c. Give immunotherapy
d. Best supportive care/hospice
What Are Joon’s Options?
What are her options?
Case Study 2: Joon (cont.)
a. Palliative radiation to mediastinum
b. Consider cytotoxic or targeted therapy
c. Give immunotherapy
d. Best supportive care/hospice
What Are Joon’s Options?
What are her options?
Case Study 2: Joon (cont.)
Joon receives palliative RT to the mediastinal disease for disease
control while on active therapy for latent tuberculosis, which she
completes
8 months later, she develops metastatic right-sided pleural
disease
She has neoplasm-related pain, which is adequately controlled
with analgesics and mild dyspnea
CPS 80, TMB ≥10
What would you do next?
Joon’s Journey
Case Study 2: Joon (cont.)
a. Do not offer immunotherapy due to history of latent TB and
autoimmune disease (bullous pemphigoid)
b. Offer pembrolizumab monotherapy given CPS >1 and TMB ≥10
c. Offer pembrolizumab + chemotherapy
d. Clinical trial
e. Best supportive care only/hospice
What Are Joon’s Options?
What are her options?
Case Study 2: Joon (cont.)
a. Do not offer immunotherapy due to history of latent TB and
autoimmune disease (bullous pemphigoid)
b. Offer pembrolizumab monotherapy given CPS >1 and TMB
≥10
c. Offer pembrolizumab + chemotherapy
d. Clinical trial
e. Best supportive care only/hospice
What Are Joon’s Options?
What are her options?
Case Study 2: Joon (cont.)
After an extensive discussion regarding goals of care, Joon opts
for pembrolizumab monotherapy
She receives pembrolizumab 200 mg IV every 3 weeks
After 3 cycles, imaging reveals a CR. However, after 6 cycles she
has frank disease progression
A right-sided pleural mass has now developed with adjacent
chest wall destruction. She also has progressive mediastinal
adenopathy
IV = intravenous. CR = complete response.
Joon’s Journey
Case Study 2: Joon (cont.)
Neoplasm-related symptoms are tolerable
Mild skin flares on immunotherapy effectively managed with
dupilumab (derm involved)
What would you do next?
Joon’s Journey
derm = dermatology.
Case Study 2: Joon (cont.)
a. Offer pembrolizumab + cytotoxic chemotherapy
b. Offer cytotoxic chemotherapy or targeted therapy alone
c. Clinical trial
d. Best supportive care only/hospice
What are Joon’s Options?
What are her options?
Case Study 2: Joon (cont.)
a. Offer pembrolizumab + cytotoxic chemotherapy
b. Offer cytotoxic chemotherapy or targeted therapy alone
c. Clinical trial
d. Best supportive care only/hospice
What are Joon’s Options?
What are her options?
Case Study 2: Joon (cont.)
Joon enrolls on a clinical trial involving pembrolizumab 200 mg
IV every 3 weeks and cetuximab 400 mg/m2 loading dose
followed by 250 mg/m2 weekly (21-day cycle)
She obtains a sustained partial response on this regimen for 2
years, prior to developing disease progression (bilateral dermal
neck metastases) requiring her to come off trial
Neoplasm-related symptoms are tolerable
Mild skin flares while on immunotherapy still effectively
managed with dupilumab
Joon’s Journey
Case Study 2: Joon (cont.)
a. Offer pembrolizumab + cytotoxic chemotherapy
b. Offer cytotoxic chemotherapy or targeted therapy alone
c. Clinical trial
d. Palliative RT to the dermal disease + systemic therapy
e. Best supportive care only/hospice
What are Joon’s Options?
What are her options?
Case Study 2: Joon (cont.)
a. Offer pembrolizumab + cytotoxic chemotherapy
b. Offer cytotoxic chemotherapy or targeted therapy alone
c. Clinical trial
d. Palliative RT to the dermal disease + systemic therapy
e. Best supportive care only/hospice
What are Joon’s Options?
What are her options?
Case Study 2: Joon (cont.)
Joon is offered palliative RT to the dermal disease. She also opts
to start pembrolizumab 200 mg IV plus carboplatin AUC 5 every
3 weeks
Carboplatin was discontinued after 5 cycles due to hematologic
toxicity. She is currently without measurable disease and remains
on pembrolizumab monotherapy. She is in screening for trials
and targeted therapies (multiple mutations on profiling) in the
event of disease progression
She’s been on various lines of systemic therapy for R/M HNSCC
for ~4 years with good QOL
Joon’s Journey
Key Takeaways
Head and neck cancer is increasing globally due to multiple risk
factors (viral etiologies, modifiable social risks, environmental
pollutants, genetics)
In the R/M setting, PD-L1/CPS and TMB are predictive biomarkers
for HNSCC
Clinical trials should be offered for R/M HNSCC when available
Standard first-line treatment for R/M HNSCC includes
pembrolizumab monotherapy for CPS ≥1, or
pembrolizumab/platinum/5-FU regardless of CPS
Key Takeaways (cont.)
Subsequent lines of therapy may include pembrolizumab or nivolumab
monotherapy (if not previously used) or anti-PD-1 plus EGFR inhibition
Staying vigilant and monitoring for the development of immune-
related AEs is critical, with most AEs developing within the first 6
months of therapy and occurring even up to 1 year after treatment
completion
Early integration of multidisciplinary supportive care services, regular
oncologic surveillance, and monitoring of physical and psychological
long-term and late side effects of treatment are important to optimize
survivorship
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New Insights for Improved Outcomes in Recurrent HNSCC

  • 1. Recurrent and Metastatic HNSCC: New Insights and Real-World Evidence for Improved Patient Outcomes Assuntina G. Sacco, MD Associate Professor of Internal Medicine, Division of Hematology/Oncology Medical Director of UCSDH Infusion Services Head and Neck Disease Team Leader, Gleiberman Head and Neck Cancer Center UC San Diego Health, Moores Cancer Center
  • 2. Disclosures Advisory board/panel: Bicara Consultant: First Thought Grants/research support: Bicara, Merck, Nektar i3 Health has mitigated all relevant financial relationships
  • 3. Learning Objectives HNSCC = head and neck squamous cell carcinoma. Distinguish histopathological, molecular, and clinical biomarkers that can inform prognosis and management of HNSCC Incorporate emerging efficacy and safety data on novel immune checkpoint inhibitors into personalized care plans for patients with advanced recurrent/metastatic HNSCC Apply strategies to prevent and mitigate immune-mediated adverse events Evaluate supportive care measures that can help optimize survivorship care in patients who have received treatment for advanced recurrent/metastatic HNSCC
  • 4. Outline HNSCC epidemiology and clinical burden Diagnosis, staging, risk assessment Mechanisms of immune escape and implications for immunotherapy Novel immune checkpoint inhibitors for recurrent/metastatic (R/M) HNSCC: Guideline recommendations Insights from recent trials Real-world evidence Monitoring and managing immune-related adverse events Supportive care measures to optimize survivorship Case studies in R/M HNSCC
  • 6. Global HNSCC Incidence Rate: 2020 GLOBOCAN = Global Cancer Observatory; HPV = human papillomavirus; EBV = Epstein-Barr virus. Graphic generated at gco.iarc.fr/today. Johnson et al, 2020. HNSCC is the sixth most common cancer worldwide By 2030, GLOBOCAN estimates HNSCC incidence will increase by 30% (1.08 million new cases per year) Increasing rates of HPV-related oropharyngeal cancer in US and Western Europe Higher HNSCC prevalence in Southeast Asia and Australia attributable to consumption of carcinogen-containing products and EBV Estimated age-standardized incidence rates (world) in 2020: hypopharynx, larynx, lip, oral cavity, nasopharynx, oropharynx (both sexes, all ages)
  • 7. HNSCC Risk Factors E-cigarettes = electric cigarettes. Johnson et al, 2020. Tobacco Alcohol Viral etiologies HPV 16 (some 18), EBV Aging Poor oral hygiene Diets lacking vegetables Exposure to environmental pollutants (organic/inorganic chemicals, particulate matter) Areca nut (betel quid, betel leaf, slaked lime and/or tobacco, spices) Fanconi anemia (500-700–fold increased HNSCC risk, primarily oral cavity) E-cigarettes? Unclear at this time
  • 8. Slowly Moving the Survival Needle aDifference between values in 1992-1996 and those in 2002-2006. bP value for trend 1992-1996 to 2002-2006. PE = probable error; SE = standard error. Pulte & Brenner, 2010; Chaturvedi et al, 2011. Modest improvement in survival 55% (1992-1996)  66% (2002-2006) Sub-analysis (not shown) indicated overall improvement except for larynx subsite and age >75 HPV-associated HNSCC, in part, is driving improved prognosis 5-Year Relative Survival Rate by Period Analysis Location 1982-1986 PE (SE) 1987-1991 PE (SE) 1992-1996 PE (SE) 1997-2001 PE (SE) 2002-2006 PE (SE) Differencea P valueb All 52.7 (0.5) 53.2 (0.5) 54.7 (0.5) 58.6 (0.5) 65.9 (0.5) +11.2 <0.0001 Lip 92.5 (1.3) 95.6 (1.4) 95.5 (1.4) 90.9 (1.5) 97.4 (1.7) +1.9 0.5 Tongue 45.2 (1.2) 48.1 (1.2) 50.5 (1.2) 55.6 (1.1) 64.9 (1.0) +14.4 <0.0001 Oral cavity 53.6 (1.0) 52.6 (1.0) 51.1 (1.0) 56.6 (1.1) 62.9 (1.2) +11.8 <0.0001 Nasopharynx 47.1 (2.2) 47.6 (2.1) 53.8 (2.1) 58.3 (1.9) 62.3 (1.9) +8.3 0.002 Tonsil 39.7 (1.7) 41.8 (1.7) 47.6 (1.7) 56.5 (1.5) 69.8 (1.3) +22.2 <0.0001 Oropharynx 26.2 (2.9) 23.4 (2.6) 33.3 (3.2) 37.8 (3.1) 42.2 (3.1) +8.9 0.2 Hypopharynx 24.2 (1.4) 26.2 (1.5) 29.8 (1.6) 29.7 (1.6) 33.8 (2.0) +4.0 0.3 Larynx 66.8 (0.8) 66.3 (0.8) 64.9 (0.9) 64.3 (0.9) 66.8 (0.9) +1.9 0.2
  • 9. HNSCC Survivors Have Second Highest Rate of Suicide Osazuwa-Peters et al, 2018. Multiple sources of unique distress Persistent, late treatment effects Functional/esthetic compromise Dysgeusia, dysphagia, xerostomia Ototoxicity, neuropathy Depression Pain and substance abuse Financial toxicity/inability to return to work 86.4 63.4 23.6 17.4 0 20 40 60 80 100 Pancreatic Cancer Head and Neck Cancer Survivors of Other Cancers General US Population Rate per 100,000 person-years Rate per 100,000 person years
  • 11. Diagnosis: Clinical Presentation p16 = protein 16; CN = cranial nerve. Johnson et al, 2020; Bean et al, 2019. Male-to-female predominance irrespective of etiology Median age at diagnosis: 50s for EBV/HPV–mediated HNSCC, 60s for HPV-negative HNSCC Majority of patients present with locally advanced disease 10% have distant disease at initial presentation Common presenting symptoms by subsite Oral cavity: non-healing sore/ulcer Oropharynx/hypopharynx: p16-negative: dysphagia, odynophagia, otalgia p16-positive: asymptomatic primary tumor, painless level II neck mass Larynx: voice change/hoarseness, dyspnea/airway compromise EBV-positive nasopharynx: neck mass, epistaxis, unilateral nasal obstruction, hearing loss, CN palsies
  • 12. Staging Evaluations DL = direct laryngoscope; FNA = fine needle aspirate; IHC = immunohistochemistry; ISH = in situ hybridization; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography. Johnson et al, 2020. Physical exam Complete head and neck exam with direct inspection of oral cavity, fiberoptic nasopharyngolaryngoscopy as indicated Panendoscopy under anesthesia including DL, esophagoscopy, bronchoscopy for tobacco-related, non-viral HNSCC to rule out second primary Pathology Biopsy of the primary tumor and/or neck mass (FNA for the latter) Excisional node biopsy is not recommended unless FNA is persistently non-diagnostic, primary site not identified or lymphoma suspected HPV testing (p16 IHC and/or HPV ISH) for all oropharynx and unknown primaries Imaging Cross-sectional imaging of head/neck with diagnostic CT or MRI CT chest to rule out distant disease PET/CT preferred for distant metastatic workup for locally advanced or locoregionally advanced disease
  • 13. Staging and Risk Assessment AJCC = American Joint Committee on Cancer; T = tumor; N = node; M = metastasis; DNA = deoxyribose nucleic acid. Johnson et al, 2020; Amin et al, 2017. AJCC 8th Edition 3 important changes to improve hazard discrimination/outcome prediction Addition of depth of invasion to T stage in oral cavity tumors Addition of extranodal extension to N stage in non-viral HNSCC Codification of novel staging system for HPV-positive HNSCC Revision of nodal staging led to stage migration stage III-IVA  stage I-II Only M1 disease is now classified as stage IV Do not “under-treat” stage I-II as this still includes locoregionally advanced disease requiring multimodality therapy Does not account for tobacco use (important modifier of prognosis) Nasopharynx cancer staging still based on anatomy Future editions may include nomograms incorporating plasma EBV DNA
  • 14. Mechanisms of Immune Escape and Implications for Immunotherapy
  • 15. Immune Escape Mechanisms As a Guide for Cancer Immunotherapy PD-L1 = programmed death ligand 1. Beatty et al, 2015.
  • 16. Key Immune Checkpoint Targets For Cancer Immunotherapy APC = antigen-presenting cell; CD = cluster of differentiation; SIRP = signal regulatory protein; TIM3 = T cell immunoglobulin and mucin domain 3; NICD = NAD+-induced cell death; CTLA-4 = cytotoxic T-lymphocyte–associated protein 4; A2AD = adenosine A2A receptor; PD-1 = programmed cell death protein 1; TIGIT = T-cell immunoreceptor with immunoglobulin and ITIM domains; NK = natural killer; LAG3 = lymphocyte activation gene 3; TIGIT = T cell immunoreceptor with immunoglobulin and ITIM domain; MHC = major histocompatibility complex; HLA = human leukocyte antigen; SS = single-stranded; PARP = poly-ADP-ribose polymerase. Dutta et al, 2023.
  • 17. The Immunotherapy Ride CAR T = chimeric antigen receptor T cell; IL-2 = interleukin-2; I/O = immuno-oncology; IDO = indoleamine 2,3-dioxygenase; GITR = glucocorticoid-induced tumor necrosis factor receptor. Sell, 2017; Zhang & Zhang, 2020; NCI, 2022; Van den Eynde et al 2020; Buzzatti et al, 2019; Chauvin & Zarour, 2020; Huo et al, 2022; Tumor immunosurveillance Thomas & Burnet (1957) Benefit of high-dose IL-2 (1985) Skepticism around I/O First cancer vaccine (2010) Sipuleucel-T Reported failures with IDO, GITR, others (2017-2019) Anti-TIGIT (2020) Anti-LAG3 (2021) Trough of disillusionment Trough of disillusionment Slope of enlightenment Peak of inflated expectations IL-2 approved (1992) First anti-CTLA-4 (2011) First anti–PD-1 (2012-2014) First anti–CTLA-4 & –PD-1 combo (2015) First CAR T (2017) Nivolumab Pembrolizumab Ipilimumab Tisagenlecleucel Aldesleukin Excitement Time (not drawn to scale)
  • 18. Predictive Biomarkers of Checkpoint Inhibitors TMB = tumor mutational burden; DDR = DNA damage response; dMMR = deficient mismatch repair; MSI = microsatellite instability; IFN = interferon; KRAS = Kirsten ras oncogene homolog; TME = tumor microenvironment; TAM = tumor-associated macrophage; TIL = tumor-infilitrating lymphocytes; TCR = T-cell receptor; CTC = circulating tumor cells; ctDNA = circulating tumor DNA; irAE = immune-related adverse event. Bai et al, 2020.
  • 19. Novel Immune Checkpoint Inhibitors for R/M HNSCC: Guideline recommendations Insights from recent trials Real-world evidence Monitoring and managing immune-related adverse events
  • 20. NCCN Guideline Recommendations: Version 1.2023 Principles of Systemic Therapy for Non-Nasopharyngeal Cancers: Oral Cavity (Including Mucosal Lip), Oropharynx, Hypopharynx, Glottic Larynx, Supraglottic Larynx, Ethmoid Sinus, Maxillary Sinus, and Occult Primary Recurrent, Unresectable, or Metastatic Disease (No Surgery or Radiotherapy Option) Preferred Regimens First Linea • Pembrolizumab/platinum (cisplatin or carboplatin)/5- fluorouracil (FU) (category 1) • Pembrolizumab (for tumors that express PD-L1 with CPS ≥1) (category 1) Subsequent Line (If Not Previously Used) • Nivolumab (if disease progression on/after platinum therapy) (category 1) • Pembrolizumab (if disease progression on/after platinum therapy) (category 1) Other Recommended Regimens (First and Subsequent Line) Combination Regimens • Cetuximab/platinum (cisplatin or carboplatin)/5-FU (category 1) • Cisplatin/cetuximab • Cisplatin or carboplatin/docetaxel or paclitaxel • Cisplatin/5-FU • Cisplatin or carboplatin/docetaxel/cetuximab • Cisplatin or carboplatin/paclitaxel/cetuximab • Pembrolizumab/platinum (cisplatin or carboplatin)/docetaxel • Pembrolizumab/platinum (cisplatin or carboplatin)/paclitaxel (category 2B) Single Agents • Cisplatin • Carboplatin • Paclitaxel • Docetaxel • 5-FU • Methotrexate • Cetuximab • Capecitabine • Afatinib (subsequent line only, if disease progression on/after platinum therapy) (category 2B) Useful in Certain Circumstances (First and Subsequent Line) • Squamous cell carcinoma • Cetuximab/nivolumab • Cetuximab/pembrolizumab (category 2B) • For select ethmoid/maxillary sinus cancers (ie, small cell, SNEC, high- grade olfactory esthesioneuroblastoma, SNUC with neuroendocrine features) • Cisplatin/etoposide or carboplatin/etoposide • Cyclophosphamide/doxorubin/ vincristine (category 2B) • Pembrolizumab (for MSI-H, dMMR, or TMB-H [≥10 mut/Mb] tumors) • Cisplatin/pemetrexed (for PS 0-1) (category 2B) • Gemcitabine/paclitaxel aIf not previously used, these regimens may be considered in subsequent-line therapy as other recommended regimens. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN = National Comprehensive Cancer Network; 5FU = fluorouracil; SNEC = sinonasal neuroendocrine carcinoma; SNUC = sinonasal undifferentiated carcinoma; MSI-H = MSI–high; TMB-H = TMB–high; mut = mutations; PS = performance status. NCCN, 2022b.
  • 21. CheckMate-141: Nivolumab for Recurrent HNSCC Q2W = every 2 weeks. Ferris et al, 2016. Study Design Platinum-refractory head and neck squamous cell carcinoma (N=361) Investigator’s choice: cetuximab OR docetaxel OR methotrexate Nivolumab 3 mg/kg Q2W Randomizatio n 2:1 Primary end point • Overall survival Secondary end points • Progression-free survival • Response rate • Toxicity • Safety
  • 22. CheckMate-141: Nivolumab for Recurrent HNSCC (cont.) CI = confidence interval; mo = month. Ferris et al, 2016. Overall and Progression-Free Survival Primary Analysis
  • 23. OS = overall survival; ORR = overall response rate; PFS = progression free survival; AE = adverse event. Ferris et al, 2016; Ferris et al, 2018. For patients who progress following platinum-based therapy for R/M HNSCC, nivolumab is superior to standard second-line therapy Improved OS (median 7.5 vs 5.1 months) Improved ORR (13.3% vs 5.8%) Similar PFS (median 2.3 vs 2.0 months) Fewer Grade 3 or 4 AEs (13.1% vs 35.1%) Most frequent AEs with nivolumab: Fatigue, nausea, rash, decreased appetite, and pruritus Trend towards benefit regardless of PD-L1 or p16 status and maintained at 2-year follow-up FDA approved in 2016 for use in previously treated R/M HNSCC Conclusions CheckMate-141: Nivolumab for Recurrent HNSCC (cont.)
  • 24. KEYNOTE-040: Pembrolizumab Q3W = every 3 weeks. Cohen et al, 2019. Platinum refractory head and neck squamous cell carcinoma (N=247) Investigator’s choice: cetuximab OR docetaxel OR methotrexate Pembrolizumab 200 mg IV Q3W Randomizatio n 1:1 Primary end point • Overall survival Study Design: Recurrent or Metastatic HNSCC
  • 25. KEYNOTE-040: Pembrolizumab (cont.) TRAE = treatment-related adverse event; HR = hazard ratio. Cohen et al, 2019. Numerically improved overall survival with pembrolizumab: 8.4 vs 6.9 months Fewer grade ≥3 TRAEs with pembrolizumab Most common TRAE with pembrolizumab was hypothyroidism (13%) FDA-approved in 2016 for platinum refractory R/M HNSCC Recurrent or Metastatic HNSCC
  • 26. KEYNOTE-048: Pembrolizumab SCC = squamous cell carcinoma; ECOG = Eastern Cooperative Oncology Group; TPS = tumor proportional score; pembro = pembrolizumab; AUC = area under the curve; QOL = quality of life ; Q1W = every 1 week. Burtness et al, 2019. Study Design: Recurrent or Metastatic HNSCC 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 Pembro Pembro plus chemo EXTREME Primary end points: overall survival, PFS Secondary end points: safety, tolerability, objective response, QOL
  • 27. KEYNOTE-048: Pembrolizumab (cont.) RR = response rate. Burtness et al, 2019. Overall Survival: PD-L1 CPS ≥20 43% of patients in this category With pembro vs EXTREME: Improved OS: 14.9 vs 10.7 months Lower RR: 23% vs 36% With pembro/chemo vs EXTREME: Improved OS: 14.7 vs 11.0 months Similar RR: 43% vs 38% Overall survival (%) Overall survival (%)
  • 28. KEYNOTE-048: Pembrolizumab (cont.) Burtness et al, 2019. 85% of patients in this category With pembro vs EXTREME: Improved OS: 12.3 vs 10.3 months Lower RR: 19% vs 35% With pembro/chemo vs EXTREME: Improved OS: 13.6 vs 10.4 months Same RR: 36% Overall Survival: PD-L1 CPS ≥1 Overall survival (%) Overall survival (%)
  • 29. Burtness et al, 2019. With pembro vs EXTREME: Similar OS: 11.6 vs 10.7 months Lower RR: 17% vs 36% With pembro/chemo vs EXTREME: Improved OS: 13.0 vs 10.7 months Same RR: 36% Overall Survival: Total Population KEYNOTE-048: Pembrolizumab (cont.) Overall survival (%) Overall survival (%)
  • 30. KEYNOTE-048: Pembrolizumab (cont.) EMA = European Medicines Agency. EMA, 2022. Not included in peer-reviewed publication Available in submission to the EMA (see link below) https://www.ema.europa.eu/en/documents/variation- report/keytruda-h-c-3820-ii-0065-epar-assessment-report- variation_en.pdf For patients with CPS ≥1 but <20: No OS improvement with pembrolizumab monotherapy vs EXTREME (10.8 vs 10.1 months, HR 0.86, 95% CI 0.66-1.12) Improvement in overall survival with pembro/chemo vs EXTREME (12.7 vs 9.9 months, HR 0.71, 95% CI 0.54-0.94) What About Overall Survival for CPS ≥1 but <20?
  • 31. EMA, 2022. Not included in peer reviewed publication Available in submission to the EMA (see link below) https://www.ema.europa.eu/en/documents/variation- report/keytruda-h-c-3820-ii-0065-epar-assessment-report- variation_en.pdf For patients with CPS < 1: No overall survival improvement with pembrolizumab monotherapy vs EXTREME (7.9 vs 11.3 months, HR 1.51, 95% CI 0.96-2.37) No overall survival improvement with pembro/chemo vs EXTREME (11.3 vs 10.7 months, HR 1.21, 95% CI 0.76-1.94) What About Overall Survival for CPS <1? KEYNOTE-048: Pembrolizumab (cont.)
  • 32. EMA, 2022. Conclusions: Pembro Plus Platinum and 5-FU vs EXTREME KEYNOTE-048: Pembrolizumab (cont.) Superior OS for pembro/chemo in the PD-L1 CPS ≥20 and CPS ≥1 and total populations Longer duration of response for pembro/chemo Overall, comparable safety profiles for pembro/chemo and EXTREME Most common AEs: Anemia (58.3% vs 46.7%) Nausea (51.1% vs 51.2%) Constipation (37% vs 33.1%) Fatigue (34.4% vs 35.5%) Neutropenia (33.7% vs 32.8%) Vomiting (32.6% vs 27.9%) Mucosal inflammation (30.8% vs 28.2%) Higher incidence of hypothyroidism, anemia, and blood creatinine increase with pembro/chemo
  • 33. EMA, 2022; Burtness et al, 2019. Conclusions: Pembrolizumab Monotherapy vs EXTREME KEYNOTE-048: Pembrolizumab (cont.) Superior OS for pembro in the CPS ≥20 and CPS ≥1 populations Noninferior OS for pembro in the total population Substantially longer duration of response for pembro Favorable safety profile for pembro vs EXTREME Most common AEs: Fatigue (28% vs 36%) Anemia (21% vs 47%) Constipation (20% vs 33%) Hypothyroidism (18% vs 6%) Nausea (16% vs 51%) Diarrhea (15% vs 34%)
  • 34. Platinum/Taxane/Pembrolizumab SWOG = Southwest Oncology Group. Burtness et al, 2019; Gibson et al, 2005; Samlowski et al, 2007; Dizenis et al, 2022. KEYNOTE-048 supporting platinum + anti–PD-1 as backbone (Burtness et al, Lancet 2019) E1395 phase 3 randomized cooperative group trial showing no statistically significant difference in response or survival with cisplatin/paclitaxel vs cisplatin/5-FU (Gibson et al, JCO 2005) SWOG phase 2 study showing activity/safety of carboplatin/docetaxel (Samlowski et al, Cancer Invest 2007) Phase 4 KEYNOTE-B10 trial (ESMO 2022, proffered paper) Rationale for Swapping out 5-FU in Favor of Taxane
  • 35. KEYNOTE-B10: Pembro/Carboplatin/Paclitaxel BICR = blinded independent central review. Dzienis et al, 2022. Study Design, Phase 4 Trial Key Eligibility Criteria • 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
  • 36. KEYNOTE-B10: Pembro/Carbo/Paclitaxel (cont.) 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; DOR = duration of response. Dzienis et al, 2022. Most common any grade TRAEs: neutropenia (57%), anemia (43%), fatigue (40%) ORR and DOR per RECIST v1.1 by BICR 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)
  • 37. Pembrolizumab/Cetuximab for R/M HNSCC Sacco et al, 2021. Study Design: Open-Label Non-Randomized Phase 2 Trial
  • 38. Pembro/Cetuximab for R/M HNSCC (cont.) Sacco et al, 2021. Response Type N (%) Overall response rate by 6 months 15 (45%) Complete response 1 (3%) Partial response 14 (42.4%) Stable disease 5 (15.2%) Disease control rate 20 (61%) Progressive disease 13 (39.4%) Overall Response Rate and Best Response Overall response rate beyond 6 months was 48% 3 withdrew consent during Cycle 1, per protocol classified as PD HPV-positive patients were less likely to respond (not significant); no association with response and CPS
  • 39. Pembro/Cetuximab for R/M HNSCC (cont.) Sacco et al, 2021. Response Type N (%) Overall response rate by 6 months 15 (45%) Complete response 1 (3%) Partial response 14 (42.4%) Stable disease 5 (15.2%) Disease control rate 20 (61%) Progressive disease 13 (39.4%) Overall Response Rate and Best Response Overall response rate beyond 6 months was 48% 3 withdrew consent during Cycle 1, per protocol classified as PD HPV-positive patients were less likely to respond (not significant); no association with response and CPS
  • 40. Pembro/Cetuximab for R/M HNSCC (cont.) IQR = interquartile range. Sacco et al, 2021. Outcomes Over Time John T Response Type Median Duration in Months Complete or partial 13.1 (95% CI: 6.5-NR) Stable disease 8.9 (95% CI: 4.0-NR) Median duration of follow-up: 7.3 months (IQR 3.9-10.9)
  • 41. Pembro/Cetuximab for R/M HNSCC (cont.) Sacco et al, 2021. Overall Survival and Progression-free Survival John T Median OS: 18.4 months (95% CI: 11 months - NR) Median PFS: 6.5 months (95% CI: 2.1 months - NR) No difference in OS or PFS based on HPV status or CPS (not powered to assess); data not shown
  • 42. Pembro/Cetuximab for R/M HNSCC (cont.) Sacco et al, 2021. Treatment-Related Adverse Events John T Most common grade ≥3 TRAE was oral mucositis Grade 1-2 Grade 3 Grade 4 Grade 5 Rash acneiform 25 (76%) 2 (6%) 0 0 Hypomagnesaemia 11 (33%) 2 (6%) 0 0 Dry skin 11 (33%) 0 0 0 Increase in aspartate aminotransferase 9 (27%) 0 0 0 Nausea 8 (24%) 0 0 0 Fatigue 7 (21%) 1 (3%) 0 0 Vomiting 6 (18%) 0 0 0 Increase in alanine aminotransferase 6 (18%) 0 0 0 Increase in alkaline phosphatase 6 (18%) 0 0 0 Skin and subcutaneous tissue disorders (others) 6 (18%) 0 0 0 Hypothyroidism 5 (15%) 0 0 0 Paronychia 5 (15%) 0 0 0 Diarrhea 4 (12%) 1 (3%) 0 0 Mucositis oral 4 (12%) 3 (9%) 0 0 Pruritus 4 (12%) 0 0 0 Colitis 0 2 (6%) 0 0 Acidosis 0 1 (3%) 0 0 Laryngeal oedema 0 1 (3%) 0 0 Sepsis 0 0 1 (3%) 0
  • 43. Nivolumab Plus Cetuximab TTMV = tumor tissue–modified viral. Chung et al, 2022. Median OS in previously treated R/M HNSCC = 11.4 months, with 1-year OS 50% Median OS in first-line R/M HNSCC = 20.2 months, with 1-year OS 66% In the total population: p16-negative patients had higher response rate but no survival advantage Higher PD-L1 score was associated with higher response rate and longer OS p16-positive patients with lower median TTMV DNA counts had higher RR and longer OS Grade ≥3 TRAE: hypophosphatemia (5%), skin- and nail-related (14%), hypomagnesemia (5%) Grade 3 irAE: fatigue (5%) Phase 2 Trial for R/M HNSCC (Treatment-Exposed or -Naive) Key Eligibility Criteria • SCC of oral cavity, oropharynx, paranasal sinuses, nasal cavity, larynx, hypopharynx • HPV p16-positive unknown primary in cervical node • Incurable R/M HNSCC Nivolumab 240 mg Q2W Cetuximab 500 mg/m2 Q2W Lead in cetuximab cycle followed by 24 Cycles Primary end point • Overall response rate N=95
  • 44. CheckMate 651: Ipi/Nivo vs EXTREME aInitial cetuximab dose of 400 mg/m2 once only, then cetuximab 250 mg/m2 Q1W plus cisplatin 100 mg/m2 or carboplatin AUC 5 on Day 1, plus fluorouracil 1,000 mg/m2/day for 4 days for 6 cycles (Q3W). bCetuximab 250 mg/m2 Q1W; Ipi = ipilimumab; nivo = nivolumab; BICR = blinded independent review committee. Haddad et al, 2023. Study Design Key Eligibility Criteria • R/M HNSCC (oral cavity, oropharynx, hypopharynx, or larynx) • No prior treatment for R/M disease • Prior chemotherapy for locally advanced disease permitted if progression-free ≥6 months post- treatment Stratification • p16 status in oropharynx • Tumor PD-L1 status (<1% vs ≥1%) • Prior chemotherapy (yes vs no) Nivo 3 mg/kg Q2W Ipi 1 mg/kg Q6W EXTREME Regimena Cetuximab plus cisplatin/carboplatin plus 5-FU Q3W for 6 cycles followed by cetuximabb monotherapy Q1W Primary End Points • OS in all randomized • OS in PD-L1 CPS ≥20 Secondary End Points • OS in PD-L1 CPS ≥1 • PFS by BICR (all randomized, PD-L1 CPS ≥20) • ORR/DOR by BICR (all randomized, PD-L1 CPS ≥20) Exploratory End Points • PFS and ORR/DOR in PD-L1 CPS ≥1 • Patient-reported outcomes • Safety Until disease progression, unacceptable toxicity, or 2 years for nivo plus ipi R A N D O M I Z E 1:1 N=947
  • 45. CheckMate 651: Ipi/Nivo vs EXTREME (cont.) a95% CI: 12.1-15.8 (nivo + ipi) and 12.6-15.2 (EXTREME). b95% CI: 13.8-22.0 (nivo + ipi) and 12.3-16.0 (EXTREME). cConfidence intervals are adjusted based on the final α levels for each primary end point. Haddad et al, 2023. Primary End Points: Overall Survival Minimum follow-up: 27.3 months
  • 46. CheckMate 651: Ipi/Nivo vs EXTREME (cont.) aPer BICR. B95% CI: 3.1-6.9 (nivo + ipi) and 5.6-8.7 (EXTREME). C95% CI: 12.1-not reported (NR) (nivo + ipi) and 5.6-10.1 (EXTREME). Haddad et al, 2023. Efficacy of Ipi/Nivo vs EXTREME in CPS ≥20 Population Minimum follow-up: 27.3 months
  • 47. CheckMate 651: Ipi/Nivo vs EXTREME (cont.) Haddad et al, 2023. Incidence of TRAEs in All Treated Patients Most common any-grade TRAEs were fatigue (18.2%), pruritus (15.0%), and hypothyroidism (14.1%) with ipi/nivo and nausea (44.7%), rash (38.3%), and anemia (34.9%) with EXTREME Most common any-grade IrAEs with ipi/nivo were hypothyroidism/thyroiditis (16.0%), rash (12.6%), and hyperthyroidism (6.8%) Ipi/Nivo (n=468) EXTREME (n=441) Any Grade Grade 3/4 Any Grade Grade 3/4 Any TRAEs 338 (72.2%) 132 (28.2%) 430 (97.5%) 312 (70.7%) TRAEs leading to discontinuation of any component of the regimen 58 (12.4%) 45 (9.6%) 57 (12.9%) 39 (8.8%) Serious TRAEs 74 (15.8%) 57 (12.2%) 122 (27.7%) 105 (23.8%) Treatment-related deaths 6 (1.3%) 8 (1.8%)
  • 48. Real-World Evidence of First-Line Pembrolizumab rwOS = real-world OS. Black et al, 2022. Retrospective cohort (Flatiron database in the US) from 2019-2021 of R/M HNSCC patients receiving first-line therapy Pembro monotherapy: n= 337 Pembro + chemo: n=176 Median rwOS consistent with KEYNOTE-048 Higher survival rates at 24 months compared with KEYNOTE-048 Age and ECOG were independent predictors In a secondary analysis, comparable treatment duration noted when trial- matched for ECOG PS 0-1
  • 49. Real-World Evidence of Second-Line Nivolumab Rajappa et al, 2022. Despite fairly comparable outcomes to clinical trials (cannot make direct comparisons given nuances of the patient populations), global access to immunotherapy remains problematic In India, only 0.25% of the patient population had access in 2016 compared with 7.3% in 2019
  • 50. Staying Vigilant Martins et al, 2019. Kinetics of irAEs with anti–PD-1/PD-L1 Agents
  • 51. GI (n = 56; 14%) 10.1 (0.1-122.1) N=406 Patients From Updated Results of Phase 3 CheckMate 025 Trial (Nivolumab for Renal Cancer) n, %: AE incidence. n, %: pts whose AE resolved. Time to Onset Time to Resolution From Start of AE Wks 0 50 10 0 15 0 20 0 Skin (n = 107; 26%) 8.4 (0.1-100.1) Renal (n = 28; 7%) 10.6 (4.0-79.1) Endocrine (n = 41; 10%) 16.4 (2.1-112.3) Pulmonary (n = 18; 4%) 17.4 (1.9-73.0) Wks 7.86 (0.1-132.1+) GI (n = 47; 84%) NR (1.9- 141.9+) Endocrine (n = 15; 37%) 26.14 (0.6-109.1+) Renal (n = 17; 63%) Hepatic (n = 45; 11%) 7.3 (2.0-71.1) 0 50 10 0 15 0 20 0 8.0 (1.6-127.1+) Hepatic (n = 37; 84%) 16.0 (0.1-156.6+) Skin (n = 83; 78%) 5.57 (1.3-96.1+) Pulmonary (n = 16; 89%) Median Time to Onset and Resolution GI = gastrointestinal. Plimack et al, 2016; Motzer et al, 2020. Treatment-Related AEs of Any Grade
  • 52. Managing irAEs: General Principles CTCAE = Common Terminology Criteria for Adverse Events; G = grade; ICI = immune checkpoint inhibitor. Martins et al, 2019; Owen et al, 2021; NCCN, 2023a. Educate patients on what to look out for Generally develop within first 6 months, but can also have late onset of up to 1 year after treatment If you have a high suspicion, grade the toxicity per CTCAE v5.0 G1: continue ICI with close monitoring G2: typically hold ICI and consider steroids G3: hold ICI and administer steroids G4: permanently discontinue ICI and administer steroids
  • 53. Managing irAEs: General Principles (cont.) Martins et al, 2019; NCCN, 2023a. Not responding to steroids? Consider additional immunosuppression Colitis: infliximab, vedolizumab Pneumonitis: infliximab, mycophenolate Hepatitis: mycophenolate/azathioprine/tacrolimus NCCN supportive care guidelines: management of immunotherapy-related toxicities is a helpful resource Rechallenge? Depends on the health risk of the toxicity, steroid responsiveness/resolution, patient goals
  • 54. Managing irAEs: General Principles (cont.) Martins et al, 2019. Nervous system • Encephalitis • Meningitis • Polyneuropathy • Guillain-Barré syndrome • Subacute inflammatory neuropathies Eyes • Uveitis • Sjogren syndrome • Conjunctivitis and/or blepharitis • Episcleritis and/or scleritis • Retinitis Lungs • Pneumonitis • Pleuritis • Sarcoid-like granulomatosis Skin • Skin rash • Pruritus • Vitiligo • Psoriasis • Stevens- Johnson syndrome • DRESS Blood • Anemia • Neutropenia • Thrombocytopenia • Thrombotic microangiopathy • Acquired hemophilia • Vasculitis Gastrointestinal • Colitis • Enteritis • Gastritis Joints and muscles • Arthralgia • Arthritis • Myositis • Dermatomyositis Kidneys • Interstitial nephritis • Glomerulonephritis Pancreas • Pancreatitis • Autoimmune diabetes Heart • Myocarditis • Pericarditis Adrenal glands • Adrenalitis Liver • Hepatitis Pituitary • Hypophysitis Thyroid • Thyroiditi s
  • 55. irAEs with Pembrolizumab: KEYNOTE-048 HD = high-dose; IO = immuno-oncology. Burtness et al, 2018.
  • 56. Treatment-Related Adverse Events: Summary Tahara et al, 2022.
  • 57. 0 1 2 3 4 # of AEs Reported Attributable Toxicity (Grade ≥3) for Pembro/Cetux Cetux = cetuximab. Sacco et al, 2020.
  • 58. Supportive Care Measures to Optimize Survivorship
  • 59. It Starts With Embracing Survivorship at Diagnosis Adapted from the National Coalition for Cancer Survivorship. An individual is considered a cancer survivor from the time of diagnosis, through the balance of his or her life Family members, friends, and caregivers are also impacted by the survivorship experience and are therefore included in this definition Prevention Detection Diagnosis Treatment Survivorship
  • 60. Reactivity Often Drives Supportive Care Referrals Images courtesy of Assuntina Sacco, MD.
  • 61. A Missed Opportunity… Silver et al, 2018. >90% did not have an easily identifiable patient-facing link Julie K Silver, Vishwa S Raj, Jack B Fu, Eric M Wisotzky, Sean Robinson Smith, Sasha E Knowlton, and Alexander J Silver
  • 62. Quaternary Care Cancer Center Giuliani et al, 2016. 61% of Patients With at Least 1 Unmet Need Top Unmet Needs Emotional support Help managing side effects Local health care services To feel like I am managing my health together with the medical team To know that all my doctors talk to each other to coordinate my care More accessible parking Help getting life/travel insurance Top 3 Resource Requests Education about cancer prevention (50%) Support/information for caregivers (40%) Health insurance/drug coverage assistance (35%)
  • 63. Proactivity Through Cancer Prehabilitation Silver et al, 2013; Silver et al, 2014. “Occurs between time of diagnosis and the beginning of acute treatment and includes physical and psychological assessments that establish a baseline functional level, identify impairments, and provide interventions that promote physical and psychological health to reduce the incidence and/or severity of future impairments” Survivorship Care Continuum Cancer diagnosis Prehabilitation assessments and interventions Cancer treatment Rehabilitation assessments and interventions
  • 64. Prehabilitation May Improve Health Above Baseline Status Silver, 2015. New Cancer Diagnosis Prehabilitation Assessments Prehabilitation Interventions Acute Cancer Treatments No Physical or Psychological Impairments Psychological Impairments Physical Impairments Referral to Mental Health Services Referral to Rehabilitation Services
  • 65. Survivorship Care Planning CT = computed tomography; ENT = ear, nose, and throat; SLP = speech-language pathologist; PT/OT = physical therapy/occupational therapy. NCCN, 2023b; Cohen et al, 2016. Care of the HNSCC cancer survivor should include the following: Surveillance for HNSCC recurrence Assessment and management of physical and psychological long-term and late side effects of treatment Screening for second primary cancers Colonoscopy, mammogram, low-dose chest CT, skin examination Health promotion Vaccines, exercise, nutrition, sun exposure, tobacco/alcohol cessation, dental cleanings and fluoride applications, swallowing exercises, and neck and shoulder stretching Care coordination Oncology, ENT, radiation oncology, primary care, dentist, SLP, PT/OT, dietician Treatment summary
  • 66. Assessment/Management of Long-Term/Late Effects GERD = gastroesophageal reflux disorder; SPC = salivary pepsin concentration; TSH = thyroid-stimulating hormone. Cohen et al, 2016. Musculoskeletal/neuromuscular Rehabilitation specialists, physical therapists Neuro-stabilizing agents Dysphagia/aspiration/stricture SLP specialists Dilation GERD Prevents healing, risk of HNSCC recurrence/SPC Conservative measures first, then GI Lymphedema Rehab specialist for manual lymphatic drainage ± compression bandaging Hypothyroidism TSH Q6-12 months Fatigue Assess for causative/reversible factors Assess for mood disorder Encourage physical activity Altered or loss of tase Registered dietitian Speech/voice SLP specialists Hearing loss, vertigo, vestibular neuropathy Audiology Sleep disturbance/sleep apnea Sleep study
  • 67. Oral Health ORN = osteoradionecrosis; HNS = head and neck surgeon; HBO = hyperbaric oxygen. Cohen et al, 2016. Surveillance, caries, periodontitis, xerostomia, osteonecrosis, oral infections/candidiasis Close follow-up with the dental professional Avoid tobacco, alcohol, caffeine, spicy/abrasive foods, extreme temperature liquids, sugary gum or soft drinks, acidic or citric liquids Dental prophylaxis, including brushing with remineralizing toothpaste, fluoride Alcohol-free mouth rinses (salt/soda, chlorhexidine, etc) For ORN, conservative measures (eg, antibiotics, chlorhexidine), HNS eval for consideration of HBO or debridement For candidiasis, systemic fluconazole and/or clotrimazole troches Nystatin is administered in suspension with high-sugar solution
  • 68. Mental Health and Well-Being Cohen et al, 2016. Psychosocial effects Altered eating, speech, aesthetics, social disruption, depressive symptoms, general health Social disruption >80% Depressive symptoms >70% Body and self-image Common and often ignored by treating clinicians Distress/depression/anxiety Multiple validated screening tools
  • 69. Addressing Psychosocial Challenges Prompt referrals to social work, palliative care, and mental health colleagues as needed NCCN Distress Thermometer NCCN, 2022a. NCCN Distress Thermometer Distress is an unpleasant experience of a mental, physical, social, or spiritual nature. It can affect the way you think, feel, or act. Distress may make it harder to cope with having cancer, its symptoms, or its treatment. Instructions: Please circle the number (0-10) that best describes how much distress you have been experiencing in the past week, including today. 1. No distress 10. Extreme distress
  • 70. Addressing Psychosocial Challenges (cont.) Problem List for Patients NCCN, 2022a.
  • 71. Post-Treatment Surveillance Recommendations PCP = primary care physician. NCCN, 2022b; NCCN, 2023b. Exam Frequency Provider History and physical including head and neck exam, mirror, and fibrotic evaluation Year 1: every 1-3 months Year 2: every 2-6 months Year 3-5: every 4-8 months >5 years: every 12 months Oncologist/ENT/radiation oncologist TSH Every 6-12 months if neck irradiated Oncologist/PCP Dental evaluation At least every 6 months Dentist Chest CT indicated for patients with significant smoking history Annually Oncologist/PCP Surveillance for depression Every visit Oncologist/PCP Speech, hearing, swallowing evaluation As clinically indicated Speech and language pathology; audiology Nutrition evaluation As clinically indicated Oncologist/PCP/dietician Smoking cessation and alcohol counseling As clinically indicated Oncologist/PCP
  • 72. Case Study 1: Mary Mary is an 89-year-old woman, never-smoker, who initially presented with squamous cell carcinoma of the right inferior maxilla (pT3N0M0) and underwent surgical resection followed by postoperative radiation Three months after radiation, she has nodal disease (biopsy-proven squamous cell carcinoma) Right modified neck dissection was attempted but aborted secondary to disease extent and morbidity Distant metastatic workup was negative
  • 73. Case Study 1: Mary (cont.) ADLs = activities of daily living FAT1 = FAT atypical cadherin 1; TP53 = tumor protein 53; JAK = Janus kinase. Medical history: stroke, renal insufficiency, hearing loss Functional status: ECOG 1; still drives, goes to the gym, volunteers as a nursing home assistant, able to perform ADLs Genomic profiling: Tumor: FAT1, MPL, NOTCH1, TP53 Blood: JAK CPS/PD-L1 testing not performed What would you do next?
  • 74. Case Study 1: Mary (cont.) a. Best supportive care only/hospice b. Pembrolizumab or nivolumab monotherapy c. Clinical trial d. a, b, c are all appropriate What Are Mary’s Options? What are her options?
  • 75. Case Study 1: Mary (cont.) a. Best supportive care only/hospice b. Pembrolizumab or nivolumab monotherapy c. Clinical trial d. a, b, c are all appropriate What Are Mary’s Options? What are her options?
  • 76. Case Study 1: Mary (cont.) Pembrolizumab initiated on 7/15/2016 Complete response noted on imaging Pembrolizumab discontinued on 6/29/2018 after 2 years of treatment No treatment-related toxicities Sustained remission as of last visit on 05/05/23, and she is 96 years young Mary’s Journey
  • 77. Case Study 2: Joon Joon is a 64-year-old woman, never-smoker, initially diagnosed with stage IVA (T4aN0M0) squamous cell carcinoma of the mandible She underwent upfront surgical resection followed by postoperative radiation with cisplatin 100 mg/m2 every 3 weeks due to involved margins Her post-treatment imaging demonstrated interval development of mediastinal adenopathy (biopsy-proven metastatic disease)
  • 78. Case Study 2: Joon (cont.) During this time, she is also diagnosed with latent tuberculosis (TB) and bullous pemphigoid Medical history: otherwise none ECOG: 0 CPS 80, TMB ≥10 What would you do next?
  • 79. Case Study 2: Joon (cont.) a. Palliative radiation to mediastinum b. Consider cytotoxic or targeted therapy c. Give immunotherapy d. Best supportive care/hospice What Are Joon’s Options? What are her options?
  • 80. Case Study 2: Joon (cont.) a. Palliative radiation to mediastinum b. Consider cytotoxic or targeted therapy c. Give immunotherapy d. Best supportive care/hospice What Are Joon’s Options? What are her options?
  • 81. Case Study 2: Joon (cont.) Joon receives palliative RT to the mediastinal disease for disease control while on active therapy for latent tuberculosis, which she completes 8 months later, she develops metastatic right-sided pleural disease She has neoplasm-related pain, which is adequately controlled with analgesics and mild dyspnea CPS 80, TMB ≥10 What would you do next? Joon’s Journey
  • 82. Case Study 2: Joon (cont.) a. Do not offer immunotherapy due to history of latent TB and autoimmune disease (bullous pemphigoid) b. Offer pembrolizumab monotherapy given CPS >1 and TMB ≥10 c. Offer pembrolizumab + chemotherapy d. Clinical trial e. Best supportive care only/hospice What Are Joon’s Options? What are her options?
  • 83. Case Study 2: Joon (cont.) a. Do not offer immunotherapy due to history of latent TB and autoimmune disease (bullous pemphigoid) b. Offer pembrolizumab monotherapy given CPS >1 and TMB ≥10 c. Offer pembrolizumab + chemotherapy d. Clinical trial e. Best supportive care only/hospice What Are Joon’s Options? What are her options?
  • 84. Case Study 2: Joon (cont.) After an extensive discussion regarding goals of care, Joon opts for pembrolizumab monotherapy She receives pembrolizumab 200 mg IV every 3 weeks After 3 cycles, imaging reveals a CR. However, after 6 cycles she has frank disease progression A right-sided pleural mass has now developed with adjacent chest wall destruction. She also has progressive mediastinal adenopathy IV = intravenous. CR = complete response. Joon’s Journey
  • 85. Case Study 2: Joon (cont.) Neoplasm-related symptoms are tolerable Mild skin flares on immunotherapy effectively managed with dupilumab (derm involved) What would you do next? Joon’s Journey derm = dermatology.
  • 86. Case Study 2: Joon (cont.) a. Offer pembrolizumab + cytotoxic chemotherapy b. Offer cytotoxic chemotherapy or targeted therapy alone c. Clinical trial d. Best supportive care only/hospice What are Joon’s Options? What are her options?
  • 87. Case Study 2: Joon (cont.) a. Offer pembrolizumab + cytotoxic chemotherapy b. Offer cytotoxic chemotherapy or targeted therapy alone c. Clinical trial d. Best supportive care only/hospice What are Joon’s Options? What are her options?
  • 88. Case Study 2: Joon (cont.) Joon enrolls on a clinical trial involving pembrolizumab 200 mg IV every 3 weeks and cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly (21-day cycle) She obtains a sustained partial response on this regimen for 2 years, prior to developing disease progression (bilateral dermal neck metastases) requiring her to come off trial Neoplasm-related symptoms are tolerable Mild skin flares while on immunotherapy still effectively managed with dupilumab Joon’s Journey
  • 89. Case Study 2: Joon (cont.) a. Offer pembrolizumab + cytotoxic chemotherapy b. Offer cytotoxic chemotherapy or targeted therapy alone c. Clinical trial d. Palliative RT to the dermal disease + systemic therapy e. Best supportive care only/hospice What are Joon’s Options? What are her options?
  • 90. Case Study 2: Joon (cont.) a. Offer pembrolizumab + cytotoxic chemotherapy b. Offer cytotoxic chemotherapy or targeted therapy alone c. Clinical trial d. Palliative RT to the dermal disease + systemic therapy e. Best supportive care only/hospice What are Joon’s Options? What are her options?
  • 91. Case Study 2: Joon (cont.) Joon is offered palliative RT to the dermal disease. She also opts to start pembrolizumab 200 mg IV plus carboplatin AUC 5 every 3 weeks Carboplatin was discontinued after 5 cycles due to hematologic toxicity. She is currently without measurable disease and remains on pembrolizumab monotherapy. She is in screening for trials and targeted therapies (multiple mutations on profiling) in the event of disease progression She’s been on various lines of systemic therapy for R/M HNSCC for ~4 years with good QOL Joon’s Journey
  • 92. Key Takeaways Head and neck cancer is increasing globally due to multiple risk factors (viral etiologies, modifiable social risks, environmental pollutants, genetics) In the R/M setting, PD-L1/CPS and TMB are predictive biomarkers for HNSCC Clinical trials should be offered for R/M HNSCC when available Standard first-line treatment for R/M HNSCC includes pembrolizumab monotherapy for CPS ≥1, or pembrolizumab/platinum/5-FU regardless of CPS
  • 93. Key Takeaways (cont.) Subsequent lines of therapy may include pembrolizumab or nivolumab monotherapy (if not previously used) or anti-PD-1 plus EGFR inhibition Staying vigilant and monitoring for the development of immune- related AEs is critical, with most AEs developing within the first 6 months of therapy and occurring even up to 1 year after treatment completion Early integration of multidisciplinary supportive care services, regular oncologic surveillance, and monitoring of physical and psychological long-term and late side effects of treatment are important to optimize survivorship
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  • 95. References (cont.) European Medicines Agency (2022). Assessment Report: Keytruda EMA/CHMP/591139/2019/corr. Available at: https://www.ema.europa.eu/en/documents/variation- report/keytruda-h-c-3820-ii-0065-epar-assessment-report-variation_en.pdf Ferris RL, Blumenschein G Jr, Fayette J, et al (2016). Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med, 375(19):1856-1867. DOI:10.1056/NEJMoa1602252 Ferris RL, Blumenschein G Jr, Fayette J, et al (2018). Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long- term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol, 81:45-51. DOI:10.1016/j.oraloncology.2018.04.008 Gibson MK, Li Y, Murphy B, et al (2005). Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol, 23(15):3562-7. DOI:10.1200/JCO.2005.01.057 Giuliani J & Bonetti A (2016). Cisplatin versus cetuximab given concomitantly with radiotherapy in non-resectable head and neck squamous cell carcinoma: an open question. Eur Arch Otorhinolaryngol, 273(1):263-5. DOI:10.1007/s00405-015-3562-4 Haddad RI, Harrington K, Tahara M, et al (2023). Nivolumab plus ipilimumab versus extreme regimen as first-line treatment for recurrent/metastatic squamous cell carcinoma of the head and neck: the final results of CheckMate 651. J Clin Oncol, 41(12):2166-2180. DOI:10.1200/JCO.22.00332 Huo JL, Wang YT, Fu WJ, et al (2022). The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application. Front Immunol, 13:956090. DOI:10.3389/fimmu.2022.956090 Johnson DE, Burtness B, Leemans CR, et al (2020). Head and neck squamous cell carcinoma. Nat Rev Disease Primers, 6:92. DOI:10.1038/s41572-020-00224-3 Martins F, Sofiya L, Sykiotis GP, et al (2019). Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol, 16(9):563-580. DOI:10.1038/s41571-019-0218-0 McDermott DF & Atkins MB (2006). Interleukin-2 therapy of metastatic renal cell carcinoma—predictors of response. Semin Oncol, 33(5):583-587. DOI:10.1053/j.seminoncol.2006.06.004 Motzer RJ, Escudier B, George S, et al (2020). Nivolumab versus everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label phase 3 CheckMate 025 trial. Cancer, 126(18):4156-4167. DOI:10.1002/cncr.33033 National Cancer Institute (2022). CAR T cells: engineering patients’ immune cells to treat their cancers. Available at:https://www.cancer.gov/about-cancer/treatment/research/car- t-cells National Comprehensive Cancer Network (2022a). Clinical Practice Guidelines in Oncolgoy: distress management. Version 2.2023. Available at: https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1431 National Comprehensive Cancer Network (2022b). Clinical Practice Guidelines in Oncology: head and neck cancers. Version 1.2023. Available at: https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1486 https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437
  • 96. References (cont.) National Comprehensive Cancer Network (2023a). Clinical Practice Guidelines in Oncology: management of immunotherapy-related toxicities. Version 1.2023. Available at: https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1486 National Comprehensive Cancer Network (2023b). Clinical Practice Guidelines in Oncology: Survivorship. Available at: https://www.nccn.org/guidelines/guidelines- detail?category=3&id=1466 Osazuwa-Peters N, Simpson MC, Zhao L, et al (2018). Suicide risk among cancer survivors: head and neck versus other cancers. Cancer, 124(20):4072-4079. DOI:10.1002/cncr.31675 Owen CN, Bai X, Quah T, et al (2021). Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma. Ann Oncol, 32(7):917-925. DOI:10.1016/j.annonc.2021.03.204 Plimack ER, Motzer RJ, Escudier B, et al (2016). Two-year efficacy and safety update from the phase III CheckMate 025 study of nivolumab versus everolimus in patients with advanced renal cell carcinoma (aRCC). BJU International (15th International Kidney Cancer Symposium), 118: 11-12. DOI:10.1111/bju.13694 Pulte D & Brenner H (2010). Changes in survival in head and neck cancers in the late 20th and early 21st century: a period analysis. Oncologist, 15(9):994-1001. DOI:10.1634/theoncologist.2009-0289 Rajappa SJ & Pinninti R (2022). Real-world evidence with nivolumab in head-and-neck cancer: Access is key! CRST, 5(3):541-543. DOI:10.4103/crst.crst_264_22 Sacco AG, Chen R, Ghosh D, et al (2020). An open-label, non-randomized, multi-arm phase II trial evaluating pembrolizumab combined with cetuximab in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): updated results of cohort 1 analysis. International Journal of Radiation Oncology Biology Physics, 106(5):1121-1122. DOI:10.1016/j.ijrobp.2019.11.376 Sacco AG, Chen R, Worden FP, et al (2021). Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial. Lancet Oncol, 22(6):883-892. DOI:10.1016/S1470-2045(21)00136-4 Samlowski WE, Moon J, Kuebler JP, et al (2007). Evaluation of the combination of docetaxel/carboplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study. Cancer Invest, 25(3):182-8. DOI:10.1080/07357900701209061 Sell S (2017). Cancer immunotherapy: breakthrough or ”déjà vu, all over again”?. Tumor Biology, 39(6). DOI:10.1177/1010428317707764 Silver (2014). Cancer rehabilitation and prehabilitation may reduce disability and early retirement. Cancer, 120(14):2072-2076. DOI:10.1002/cncr.28713 Silver (2015). Cancer prehabilitation and its role in improving health outcomes and reducing health care costs. Sem Oncol Nursing, 31(1):13-30. Silver JK, Baima J, & Mayer RS (2013). Impairment-driven cancer rehabilitation: an essential component of quality care and survivorship. CA Cancer J Clin, 63(5):295-317. DOI:10.3322/caac.21186 Silver JK, Raj VS, Fu JB, et al (2018). Most national cancer institute-designated cancer center websites do not provide survivors with information about cancer rehabilitation services. J Cancer Educ, 33(5):947-953. DOI:10.1007/s13187-016-1157-4
  • 97. References (cont.) Tahara M, Greil R, Rischin D, et al (2022). Pembrolizumab with or without chemotherapy for first-line treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): 5-year results from KEYNOTE-048 [oral presentation]. ESMO, 33(suppl_7) 295-322. DOI:10.1016/annonc/annonc1056 Van den Eynde BJ, van Baren N & Baurain JF (2020). Is there a clinical future for IDO1 inhibitors after the failure of epacadostat in melanoma?. Ann Rev Cancer Biol, 4:241-256. DOI:10.1146/annurev-cancerbio-030419-033635 Zhang Y & Zhang Z (2020). The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol, 17(8):807-821. DOI:10.1038/s41423-020-0488-6

Editor's Notes

  1. Figure Legend: Immune escape mechanisms in cancer. Clinically apparent tumors must evolve mechanisms to evade immune elimination. During this process, nascent transformed cells may be selected for based on (i) a loss of antigenicity and/or (ii) a loss of immunogenicity. Loss of antigenicity may be achieved through the acquisition of defects in antigen processing and presentation or through the loss of immunogenic tumor antigens leading to a lack of immunogenic peptides presented in the context of a peptide–MHC complex. Although a loss of antigenicity is also associated with a loss of immunogenicity, malignant cells can gain additional immunosuppressive properties, such as expression of PD-L1 or secretion of suppressive cytokines (e.g., IL10 and TGFβ), which further reduces their immunogenicity. (iii) Tumors may also escape immune elimination by orchestrating an immunosuppressive microenvironment. Malignant transformation induced by alterations in oncogenes and tumor-suppressor genes can lead to the recruitment of an immune response that suppresses antitumor immunity.
  2. Key immune checkpoint targets for cancer immunotherapy.. Immune checkpoint inhibitors (ICIs) and their respective ligands are reported in the context of the tumor immune microenvironment (TME). Various immune checkpoint target-mediated interactions between immune cells such as dendritic cells (DC) (serving as APCs), T cells, NK cells, and tumor cells are shown here. Mechanisms of action of all the checkpoint proteins mentioned here have been elaborated in their respective sections in this review. ICIs targeting these immune checkpoints are currently used in clinic or under pre-clinical or clinical investigation. The “?” indicates interactions which are unknown/uncertain. This figure has been created with BioRender.com, access date 22 January 2023. If we need to add more abbreviations here is the link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9952779/
  3. An overview of predictive biomarkers for immune checkpoint inhibitors efficacy. Key elements in predictive biomarker development for the efficacy of immune checkpoint inhibitors therapy are briefly described in the figure, including tumor cells-related biomarkers, tumor immune microenvironment phenotype biomarkers, circulating factors, host-related factors, and immune-related adverse events
  4. Panel A shows the Kaplan–Meier curves for overall survival among all the patients who underwent randomization and were assigned to receive either nivolumab or standard therapy. In the planned interim analysis, the boundary for statistical significance for overall survival required the P value to be less than 0.0227. Panel B shows the Kaplan–Meier curves for progression-free survival among all the patients who underwent randomization. Symbols indicate censored observations. Hazard ratios (and confidence intervals) were computed with the use of a stratified Cox proportional-hazards model, and the P values were from a stratified log-rank test. 
  5. Kaplan-meier estimates of progression-free and overall survival according to the treatment group.
  6. From JITC abstract: A total of 513 patients initiated 1L pembrolizumab therapy, [P (n=337), P+C (n=176)]. The median rwOS was 13.0 months (95%CI 10.0-15.3) for P and 12.8 months (95% CI 9.0-21.1) for P+C (figure 1), consistent with the results of the KEYNOTE-048 trial [P: 11.5 months (10.3 – 13.5) P+C: 13.0 months (10.9 – 14.7)]. Survival rates at 24 months (P: 33.3% (26.2 – 40.6) and P+C: 40.3% (31.3- 49.2) were greater in the real-world compared to KEYNOTE-048. The Cox proportional- hazards model found that older age (>=75 years vs <75) and higher ECOG PS (2+ vs 0-1) were unfavorable predictors of rwOS survival (HR=1.4 , 95% CI 1.03- 1.90, HR: 1.5, 95%C 1.08-2.1). This analysis further showed no significant differences in rwOS between P and P+C populations.
  7. Comprehensive clinical spectrum of immune-related adverse events induced by checkpoint inhibitors.
  8. Comprehensive clinical spectrum of immune-related adverse events induced by checkpoint inhibitors.
  9. Comprehensive clinical spectrum of immune-related adverse events induced by checkpoint inhibitors.
  10. What is your institution’s approach to survivorship care planning? How do you ensure optimal multidisciplinary cooperation? Currently, there are over 400,000 head and neck (H&N) cancer survivors living in the US, accounting for roughly 3% of all cancer survivors. Long-term survival is becoming more common in this population. While H&N cancer survivors may experience many of the same sequelae as other survivors, additional concerns arise as a result of the anatomic location of the disease and area of treatment. Educate patients on signs and symptoms of local recurrence. It’s important to coordinate care between primary care providers and specialists to ensure that all of the survivor's health needs are met.
  11. Given the challenges associated with a diagnosis of head and neck squamous cell carcinoma (HNSCC), how do you ensure that your patients’ educational and psychosocial needs are being met? Patients with head and neck cancer have disproportionately high amounts of emotional distress owing to the possibility of physical disfigurement from disease progression and/or treatment, as well as from impairment of such basic human functions such as eating, speaking, and breathing. Large numbers of patients undergoing radiation therapy (RT) for head and neck cancer have symptoms suggestive of psychosocial distress even before the beginning of treatment. The National Comprehensive Cancer Network (NCCN) issued a consensus statement recommending distress screening and management as a standard of care within oncology health services delivery. Many different tools can be used. The NCCN Distress Thermometer and Problem List is a comprehensive way to identify and address these challenges. This can be completed by a new patient nurse coordinator or practice nurse either before or during a new patient visit. Depending on the problems identified, you can then make a referral to the appropriate subspecialty. In our practice, we rely heavily on our social worker to help us with transportation, etc, as these barriers to care can delay treatment if not addressed promptly. We also rely on palliative care and our psychology/psychiatry colleagues in the community to help us manage complex pain, depression, and anxiety. Knowing who your mental health resources are and how to access them is extremely important. H&N support group is another resource. Education needs: new patient coordinators, handouts on swallowing exercises, neck stretching, oral care
  12. Given the challenges associated with a diagnosis of head and neck squamous cell carcinoma (HNSCC), how do you ensure that your patients’ educational and psychosocial needs are being met? Patients with head and neck cancer have disproportionately high amounts of emotional distress owing to the possibility of physical disfigurement from disease progression and/or treatment, as well as from impairment of such basic human functions such as eating, speaking, and breathing. Large numbers of patients undergoing radiation therapy (RT) for head and neck cancer have symptoms suggestive of psychosocial distress even before the beginning of treatment. The National Comprehensive Cancer Network (NCCN) issued a consensus statement recommending distress screening and management as a standard of care within oncology health services delivery. Many different tools can be used. The NCCN Distress Thermometer and Problem List is a comprehensive way to identify and address these challenges. This can be completed by a new patient nurse coordinator or practice nurse either before or during a new patient visit. Depending on the problems identified, you can then make a referral to the appropriate subspecialty. In our practice, we rely heavily on our social worker to help us with transportation, etc, as these barriers to care can delay treatment if not addressed promptly. We also rely on palliative care and our psychology/psychiatry colleagues in the community to help us manage complex pain, depression, and anxiety. Knowing who your mental health resources are and how to access them is extremely important. H&N support group is another resource. Education needs: new patient coordinators, handouts on swallowing exercises, neck stretching, oral care
  13. There are no clear guidelines for the shared care and comanagement of patients with head and neck cancer (HNC) after the completion of active treatment. The time for optimal transition from oncology to primary care is unknown and should be based on the individual risk profile, the treating clinician's expertise, and resource constraints. While HNC survivors may continue to see the oncology team for follow-up disease surveillance, they should also be seen by the primary care clinician for health maintenance and management of comorbidities that may or may not be related to cancer diagnosis and treatment.