cancer de cabeza y cuello

1. ExpressPoints: Clinical Application of New Advances
in the Treatment of Head and Neck Cancer
Supported by educational grants from Bayer HealthCare Pharmaceuticals, Inc.
and Merck Sharp & Dohme Corp.

2. About These Slides
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Slide credit: clinicaloptions.com

3. Faculty
Aarti Bhatia, MD, MPH
Assistant Professor of Medicine
Division of Medical Oncology
Department of Internal Medicine
Yale University School of Medicine
New Haven, Connecticut
Barbara Burtness, MD
Professor of Medicine
Yale University School of Medicine
Co-Leader, Developmental Therapeutics
Program
Yale Cancer Center
New Haven, Connecticut
Elisabeth King, RN, FNP, AGN, AOCNP
Executive Director
Genomics and Precision Medicine
City of Hope
Duarte, California
Dan P. Zandberg, MD
Associate Professor of Medicine
Director, Head and Neck and Thyroid
Cancer Disease Sections
Division of Hematology/Oncology
Medical Oncology Co-leader, Head and
Neck Cancer Program
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania

4. Faculty Disclosures
Aarti Bhatia, MD, MPH, has no relevant conflicts of interest to report.
Barbara Burtness, MD, has disclosed that she has received consulting fees from
Aduro, ALX Oncology, Celgene, Chemotherapy Advisory,
Cue Biopharma, Debio Pharm, GlaxoSmithKline, IO Biotech, Kura, MacroGenics,
Maverick, Merck, Nanobiotix, and Rakuten.
Elisabeth King, RN, FNP, AGN, AOCNP, has no relevant conflicts of interest to report.
Dan P. Zandberg, MD, has disclosed that he has received funds for research support
paid to his institution from Aduro, Astellas, AstraZeneca, Bristol-Myers Squibb,
GlaxoSmithKline, Lilly, MacroGenics, Merck, and Verastem, and consulting fees from
Blueprint.

5. HNSCC Prognosis and TILs
1. Duray. Clin Dev Immunol. 2010;2010:701657. 2. Russell. Head Neck Oncol. 2013;5:24. 3. Keck. Clin
Cancer Res. 2015;21:870. 4. Vanneman. Nat Rev Cancer. 2012;12:237. 5. Jie. Cancer Res. 2015;75:2200.
Negative Outcomes
Positive Outcomes
 Treg tumor infiltration  higher rates
of metastasis, poor prognosis1,5
 Tumor-associated macrophages 
angiogenesis and tumor progression1
 Macrophage infiltration of primary
tumor  metastasis1
 Tumor-infiltrating CD4+ and CD8+
T-cells  good prognosis1,2
 CD8+ T-cell infiltration seen in both
HPV+ and HPV- tumors2,3
 Decreased myeloid cell infiltration 
reduced rates of metastasis4
 Infiltrating Langerhans cells  better
prognosis1
Slide credit: clinicaloptions.com

6. 50
PD-L1 Expression in HNSCC
Agent Population ORR Median OS Significant OS
Pembrolizumab Total 17% 11.6 No
CPS > 1 19% 12.3 Yes
CPS > 20 21% 14.9 Yes
Chemo + Pembro Total 36% 13 Yes
CPS > 1 36% 13.6 Yes
CPS > 20 43% 14.7 Yes
Checkmate 141: Platinum Failure[1]
KEYNOTE 048: Frontline Therapy[2]
Slide credit: clinicaloptions.com
Mos
39
0 3 6 9 12 15 18 21 24 27 30 33 36
OS
(%)
100
90
80
70
60
40
30
20
10
0
50
Mos
39
0 3 6 9 12 15 18 21 24 27 30 33 36
OS
(%)
100
90
80
70
60
40
30
20
10
0
PD-L1 expressors PD-L1 non-expressors
24.0%
18.5% 13.7%
Nivo
IC
26.2%
20.7%
11.2%
Nivo
IC
PD-L1 expressors Median OS
(95% CI), mo
HR
(95% CI)
Nivolumab (n = 96) 8.2 (6.7-9.5) 0.55
(0.39-0.78)
IC* (n = 63) 4.7 (3.8-6.2)
PD-L1 non-
expressors
Median OS
(95% CI), mo
HR
(95% CI)
Nivolumab (n = 76) 6.5 (4.4-11.7) 0.73
(0.49-1.09)
IC (n = 40) 5.5 (3.7-8.5)
1. Ferris. Oral Oncol. 2018;81:45. 2. Burtness. Lancet. 2019;394:1915.
*IC = investigator’s choice.

7. Selected Ongoing Phase II/III Immunotherapy Trials in HNSCC
Trial Treatment Population N Intervention
KEYNOTE-412[1] Locally advanced HNSCC (HPV+ for select
stages/primary sites)
780
Pembrolizumab + cis + RT vs placebo + cis + RT
REACH[2] Stage III/IVb HNSCC 707
Avelumab + cis + RT vs cis + RT
Avelumab + cetuximab + RT vs cis + RT
IMSTAR-HN[3] Stage III/IV p16- OPC, L, HP, OC 276
Neoadjuvant nivolumab, surgery, and adj CRT +
adj nivolumab ± ipi vs SoC surgery + CRT
KEYNOTE-689[4] Resectable stage III/IVa L, HP, OC, p16-OPC
Stage III p16+ OPC
704* Pembrolizumab before surgery/with adj CRT vs surgery
IMvoke010[5] Locally advanced HNSCC treated with
curative-intent therapy
400* Atezolizumab vs placebo after CRT
HN004[6] Cisplatin-unfit locally advanced HNSCC 474*
Durvalumab + RT vs cetuximab + RT in cis-ineligible
patients
KEYCHAIN[7] Locally advanced p16+ OPC, L, OC 114* Cis + RT vs pembrolizumab + RT
EA3161[8] High-risk HPV-associated disease 744* Maint. nivolumab or observation after 1 yr of cis + RT
1. NCT03040999. 2. NCT02999087. 3. NCT03700905. 4. NCT03765918.
5. NCT03452137. 6. NCT03258554. 7. NCT03383094. 8. NCT03811015. Slide credit: clinicaloptions.com
*Recruiting patients as of April 2021.

8. If not vigilant, may result in more serious
immune-related AEs
Pulmonary
 Pneumonitis (< 5% incidence)
Neurologic
 Neuropathy
 Guillain-Barre
 Myasthenia gravis–like
syndrome
Hepatic
 Hepatitis,
autoimmune
Gastrointestinal
 Colitis
Endocrine
 Hypo- or hyperthyroidism
 Adrenal insufficiency
 Hypophysitis
Eye
 Uveitis
 Iritis
Renal
 Nephritis
Skin
 Dermatitis exfoliative
 Vitiligo
 Alopecia
Immune-Related Adverse Events Can Affect Any Organ
System
Cardiac
 Myocarditis
Brigden. Oncology Exchange. 2016;15:10-14. Slide credit: clinicaloptions.com

9. Time of Onset and Toxicity Grade of Immune-Related
Adverse Events in Patients Receiving PD-L1 Antibodies
Martins. Nat Rev Clin Oncol. 2019:16;563.
Colitis
Endocrinopathy
Nephritis
Liver toxicity
Skin, rash or pruritis
Pneumonitis
Toxicity
grade
Duration of Treatment (Wks)
4 6 8 10 12 14 > 30
Slide credit: clinicaloptions.com

10. General Guidelines for Management of
Immune-Related AEs
 Grade 1: asymptomatic to mild
symptoms
‒ Observation
‒ Intervention not needed
 Grade 2: moderate symptoms
‒ Local or noninvasive intervention
indicated
‒ Withhold drug, consider re-dose if toxicity
resolves to grade ≤ 1
‒ Low-dose corticosteroids likely needed
‒ May be able to continue treatment
 Grade 3: medically significant but not
immediately life-threatening
‒ Stop immunotherapy immediately
‒ Hospitalization indicated
‒ High-dose steroids indicated
‒ Slow steroid taper over ≥ 1 mo once
toxicity resolves to grade ≤ 1
 Grade 4: life-threatening consequences
‒ Urgent intervention
‒ Permanently discontinue treatment
CTCAE v5.0. November 2017. Atezolizumab adverse reaction management brochure.
Nivolumab adverse reaction management guide. Pembrolizumab adverse reaction management guide. Slide credit: clinicaloptions.com

11. TRK Fusions Are Found Across Diverse Cancer Types
In Both Adults and Children
Cocco E. Nat Rev Clin Oncol, 2018. Amatu. ESMO Open. 2016;1:e000023. Urano. Hum Pathol. 2015;46:94. Knezevich. Nat Gen. 1998;18:184.
Watanabe. Cancer Genet Cytogenet. 2002;136:10. Hyman. ASCO 2017. Abstr LBA2501. Gatalica. AACR-NCI-EORTC 2017. Abstr A047.
Brain cancers (glioma, GBM, astrocytoma)
Thyroid cancer
Salivary cancer (MASC)
Lung cancer
Secretory breast cancer
Pancreatic
Cholangiocarcinoma
GIST
Colon
Melanoma
Sarcoma (multiple subtypes)
Gliomas
Infantile fibrosarcoma
Thyroid/papillary thyroid cancer
Congenital nephroma
Spitzoid tumors
Sarcoma (multiple subtypes)
Common cancer with low incidence (< 5%)
of TRK fusions
Common cancer with moderately low
incidence (5% - 25%) of TRK fusions
Rare cancer with high incidence (> 90%) of
TRK fusions
NTRK and TRK fusions are rare events:
0.2% found in screening >11,000 patients with tumors of all types
Slide credit: clinicaloptions.com
Thyroid/papillary thyroid cancer
Spitzoid tumors

12. Slide credit: clinicaloptions.com
Hong. Lancet Oncol. 2020;21:531.
Larotrectinib Meta-Analysis: Efficacy Across Tumor Types
Response NTRK Fusion (n = 153)
ORR, % (95% CI) 79 (72-85)
Best overall response, n (%)
 CR 24 (16)
 PR 97 (63)
 SD 19 (12)
 PD 9 (6)
 Not determined 4 (3)
Change in Tumor Size
*Maximum change in tumor size of 93% tumor
growth
†Patients with brain metastases
‡Patients with a pCR

13. Entrectinib in NTRK Fusion–Positive Solid Tumors:
Individual Patient Responses by Tumor Type
Doebele. Lancet Oncol. 2020;21:271. Slide credit: clinicaloptions.com
0
-30
-50
-90
Best
%
Change
From
Baseline
15
-80
-70
-60
-40
-20
-10
20
30
40
-100
50
CRC
NSCLC
Sarcoma
Neuroendocrine tumors
Pancreatic
Thyroid
MASC Breast
Cholangiocarcinoma
Gynecological
NTRK+ Patients (n = 54)
ORR, % (95% CI) 57.4 (43.2-70.8)
SD 9 (16.7)
PD 4 (7.4)
Non-CR/PD, missing or unevaluable 10 (18.5)
Results per blinded independent central review (BICR)
Cutoff date: May 31, 2018. Note: Patients (n = 6) without matched pre/post therapy scans were excluded from the plot

14. Methods for Detection of TRK Fusions
IHC RT-PCR FISH NGS
Advantages
 Rapid results
 Detects transcribed
and translated
events only
 Low cost as single
test
 Rapid results
 Detects specific fusion
partners
 High sensitivity,
specificity
 Low cost as single test
 Rapid results  Potential for
multiplexed testing
 Less depletion of
tissue
 Fusion partner and
position are
defined
Disadvantages
− Depletion of tissue
− Fusion partner and
position unknown
− Less well-validated
currently
− Limited multiplexing
− Specific primer sets for
each fusion
− Difficult to extract high-
quality RNA from FFPE
− Usually does not detect
novel fusion partners
− Depletion of
tissue
− Fusion partner
and position
unknown
− Can be difficult
to interpret
− Longer wait time
for results
− Cost
Jordan. Cancer Discov. 2017;7:596. Hyman. ASCO 2017. Abstr LBA2501.
Farago. J Thorac Oncol. 2015;10:1670. Hechtman. Am J Surg Pathol. 2017;41:1547. Slide credit: clinicaloptions.com

15. Occasional TRK Inhibition–Mediated Adverse Events
Can Occur
 Retrospective analysis of adverse events in patients with advanced or unresectable
solid tumors treated with a TRK inhibitor (N = 96)
Slide credit: clinicaloptions.com
Liu. Ann Oncol. 2020;S0923-7534(20)39820.
100
80
60
40
20
0
Weight gain Dizziness or ataxia
Patients
(%)
Withdrawal pain Paresthesia
No AE
Grade 1
Grade 2
Grade 3
47%
22% 23%
8%
59%
32%
8%
1%
66%
12% 11% 11%
82%
17%
1%
TRKA Inhibition
1. Neuropathy: sensory or
autonomic
2. Congenital insensitivity
to pain with anhidrosis
TRKB Inhibition
1. Hyperphagia or hyperdipsia
2. Dorsal root neuron loss
3. Nociception and memory
impairment
TRKC Inhibition
1. Proprioception defects
2. Motor neuron afferent
loss

16. Biomarkers and Targeted Drugs in Head and Neck
Cancer
*Guideline-recommended off-label use under certain circumstances.
Biomarker Drug Head and Neck Cancer
PD-L1 Pembrolizumab First line in R/M HNSCC as monotherapy (CPS ≥ 1) and
in combination with chemotherapy
PD-L1 Nivolumab, pembrolizumab Monotherapy in R/M HNSCC with progression on/after
platinum-based chemotherapy
MSI-H Pembrolizumab Monotherapy in R/M HNSCC with progression on/after
prior treatment
TMB-H Pembrolizumab Monotherapy in head and neck cancers with
progression on/after prior treatment
AR + Leuprolide*, bicalutamide* Salivary gland tumors
NTRK gene fusion Larotrectinib, entrectinib Salivary gland tumors
HER2+ Trastuzumab ± pertuzumab or
docetaxel*, TDM-1*
Salivary gland tumors
Slide credit: clinicaloptions.com
Pembrolizumab PI. Nivolumab PI. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Head and Neck Cancers. Version 1.2021.
11/08/2020. Available at: www.NCCN.org. Accessed March 8, 2021.

17. clinicaloptions.com/oncology
clinicaloptions.com/HNSCCTool
Go Online for More CCO
Coverage of Head and Neck Cancer!
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Interactive HNSCC text module of key points
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