Inmunotherapy in head and neck cancer

1. Cancer de
Cabeza y Cuello
(Nuevas fronteras )
Dr. Luis Miguel Zetina Toache
Oncología Medica

3. NUEVOS ENFOQUES
(Cirugía +/- RT+/-QT+/-MabEGFR)
- Cirugía Robótica
- RT Protones
- Biología Tumoral (HPV-16 /PDL1/TIL/TMB)
- Perfilamiento Genómico (NGS)
- Inmunoterapia (Nivo-Pembro)
- Multidisciplinario

4. 60
Nivolumab in HPV Positive vs HPV Negative Patients
Ferris. Oral Oncol. 2018;81:45. Slide credit: clinicaloptions.com
HPV positive HPV negative
HPV positive Median OS
(95% CI), mo
HR
(95% CI)
Nivolumab (n = 64) 9.1 (6.5-11.8) 0.60
(0.37-0.97)
IC (n = 29) 4.4 (3.0-9.8)
HPV negative Median OS
(95% CI), mo
HR
(95% CI)
Nivolumab (n = 56) 7.7 (4.8-13.0) 0.59
(0.38-0.92)
IC (n = 37) 6.5 (3.9-8.7)
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
50
Mos
39
0 3 6 9 12 15 18 21 24 27 30 33 36
OS
(%)
100
90
80
70
40
30
20
10
0
Nivo
IC
Nivo
IC

5. 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.

6. PD-L1 Expression on Tumor and Tumor-infiltrating
Lymphocytes
Chow. J Clin Oncol. 2016;34:3838. Slide credit: clinicaloptions.com
PD-L1 Status Tumor and Immune Cells Tumor Cells Only
Nonresponders,
n
Responders, n Response, %
(95% CI)
Nonresponders,
n
Responders, n Response, %
(95% CI)
Negative (< 1%) 24 1 4 (0.1 to 20) 36 7 16 (7 to 31)
Positive (≥ 1%) 84 23 22 (14 to 31) 72 17 19 (12 to 29)
Score < 1%
Score ≥ 1%
Days
400
0 100 200 300
PFS
(probability)
1.0
0.8
0.6
0.4
0.2
0
Score < 1%
Score ≥ 1%
Days
400
0 100 200 300
OS
(probability)
1.0
0.8
0.6
0.4
0.2
0

7. YI-85
Mutational Load and GEP-Associated Best Overall
Response: HPV/EBV—Whole Exome Sequencing
 ML and GEP weakly correlated, remained significant predictors in adjusted multivariate model
‒ (ML, P = .0349; GEP, P = .0056)
 Strongest response with high ML or GEP, particularly with both
Haddad. ASCO 2017. Abstract 6009.
Not PR or CR
PR or CR
3000
1000
300
100
30
10
WESNSML
(log
scale)
18-Gene Inflammation Signature
-0.8 -0.6 -0.4 -0.2 0 0.2 0.4
All patients, r = 0.17; P = .1633
PR/CR, r = 0.029; P = .9276
Not PR/CR, r = 0.077; P = .5647
 ML high and low: ≥ and < 86
 GEP high and low: ≥ and < -0.318
50
40
30
20
10
0
Response
(%)
20
31
6
27
0
40
5
0
All
Patients
ML
High
ML
Low
GEP
High
GEP
Low
ML High
& GEP
High
ML Low
or GEP
Low
ML Low
& GEP
Low
n/N
95% CI
21/107
(12.6-28.4)
12/39
(17-48)
2/33
(0.7-20.0)
14/52
(16-41)
0/20
(0-17)
12/30
(23-59)
2/42
(0.6-16.0)
0/11
(0-28)
Slide credit: clinicaloptions.com

8. Evolving Treatment Paradigm:
(One Drug Fits All)
• Standard has been to treat cancers based on the organ of origin
• Example: head and neck cancer and breast cancer are treated differently
• Emerging paradigm also considers genomic factors that transcend
tissue type
• Example: head and neck cancer and breast cancer with the same molecular
alteration may be treated with the same targeted drug
Adapted from slide by Stacy Gray, MD

9. Select Validated Biomarkers and Associated
Approved Therapies Across Solid Tumors
Slide credit: clinicaloptions.com
Tumor Type Molecular Testing Commonly Used (Associated Targeted Agents)
Bladder cancer PD-L1 (pembrolizumab, atezolizumab); FGFR (erdafitinib)
Breast cancer
HER2 (trastuzumab, pertuzumab, T-DM1, T-DXd, lapatinib neratinib, tucatinib);
BRCA1/2 (olaparib, talazoparib); PIK3CA (alpelisib); PD-L1 (atezolizumab)
Cervical cancer PD-L1 (pembrolizumab)
Colorectal cancer
BRAF V600E (dabrafenib/trametinib + cetuximab or panitumumab, encorafenib + cetuximab or panitumumab ±
binimetinib); HER2 (trastuzumab, pertuzumab)
Gastric/GEJ/esophageal PD-L1 (pembrolizumab); HER2 (trastuzumab)
Head and neck cancer PD-L1 (pembrolizumab and nivolumab)
Lung cancer
PD-L1 (pembrolizumab); EGFR (afatinib, dacomitinib, erlotinib, gefitinib, osimertinib);
ALK (alectinib, brigatinib, crizotinib, ceritinib, lorlatinib); ROS1 (crizotinib, entrectinib, lorlatinib);
BRAF V600E (dabrafenib/trametinib); METex14 (tepotinib, capmatinib, crizotinib); RET (selpercatinib)
Melanoma BRAF V600 (dabrafenib/trametinib, encorafenib/binimetinib, vemurafenib/cobimetinib)
Ovarian cancer BRCA1/2 (olaparib, rucaparib); HRD, including BRCA1/2 (niraparib)
Pancreatic cancer BRCA1/2 (olaparib); EGFR (erlotinib)
Tumor agnostic MSI-H/dMMR (pembrolizumab; nivolumab ± ipilimumab); NTRK (larotrectinib, entrectinib)
Bedard. Lancet. 2020;395;1078.

10. 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.

11. Ascierto. J Mol Diagn. 2019;21:756. Slide credit: clinicaloptions.com
Tissue Journey: Biopsy to Analysis
DNA
Preliminary
diagnosis
Extraction Analysis
Morphologic
assessment
Biopsy methods and specimen processing
 Surgeons
 Pathologists
 Allied health professionals
 Clinical informaticians
 Patients
 Pathologists
 Laboratory staff
 Clinical informaticians
 Bioinformaticians
Key personnel Key personnel
 Resection
 Excision
 Small tissue biopsies
Assessment methods
 PCR
 Cancer gene panels
 MSI
 WES
 WGS
 Targeted mutations
 RT-qPCR
 Gene expression panels
 RNA-seq
 Proteomics
 FACS
 Data analytics
Parallel diagnostics
 IHC (eg, PD-L1,
dMMR)
 ISH/FISH
Histology
Cytology
Non–cell
block slide
LIQUID
CYTOLOGY
TISSUE
 Fine-needle aspiration
 Exfoliative cytology
(cells shed from body surfaces)
• Urine
• Ascitic fluid
• Pleural fluid
• Sputum
• Cerebrospinal fluid
• Residual supernatant
 Liquid biopsies
• Blood
• Cyst fluid
RNA
Protein
FFPE block
FFPE block

20. EXTREME Chemotherapy* + Cetuximab: OS
Vermorken. NEJM. 2008;359:1116.
HR: 0.80 (95% CI: 0.64-0.99; P = .04)
Chemotherapy + cetuximab (n = 222)
Chemotherapy (n = 220)
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24
Probability
of
OS
Median OS:
10.1 mos
Median OS:
7.4 mos
+ 2.7 mos
Mos
Slide credit: clinicaloptions.com
*Cisplatin or carboplatin.

22. Cohen. Lancet. 2019;393:156.
Patients with SCC of oral cavity, oropharynx,
hypopharynx, or larynx, and:
 recurrent disease or PD 3-6 mos after
multimodal tx with platinum or PD after
platinum-based tx for RM HNSCC
 ≤ 2 prior tx for RM HNSCC
 known p16 status with oropharynx disease
 ECOG PS 0/1
(N = 495)
Pembrolizumab 200 mg IV Q3W
(n = 247)
Standard of Care*
(n = 248)
Stratified by ECOG PS (0 vs 1),
p16 status (pos vs neg),
PD-L1 TPS (≥ 50% vs < 50%) 2 yrs
*Investigator’s choice of methotrexate 40 mg/m2/wk (in absence of toxicity could increase to 60 mg/m2),
docetaxel 75 mg/m2 Q3W, or cetuximab loading dose of 400 mg/m2 followed by 250 mg/m2/wk.
Until confirmed PD
(crossover not allowed)
Slide credit: clinicaloptions.com
KEYNOTE-040: Pembrolizumab vs Standard of Care in
Recurrent/Metastatic HNSCC
 Primary endpoint: OS in ITT population
 Secondary endpoints: OS in PD-L1–positive subgroups, PFS, ORR, DoR,
safety, tolerability

23. KEYNOTE-040: OS by PD-L1 Expression
Cohen. Lancet. 2019;393:156.
Patients at Risk, n Mos
OS
(%)
Median OS, Mos (95% CI)
8.7 (6.9-11.4)
7.1 (5.7-8.6)
P Value*
.0078
HR (95% CI)
0.75
(0.59-0.95)
*Nominal 1-sided P value from log-rank test, stratified by randomization stratification factors.
0 5 10 25
0
20
40
60
100
196
191
131
113
87
63
43
28
80
15 20
14
8
2
1
Pembro
SOC
30
0
0
12
PD-L1 CPS ≥ 1
Events, n
137
157
40.1%
Patients at Risk, n Mos
OS
(%)
Median OS, Mos (95% CI)
11.6 (8.3-19.5)
7.9 (4.8-9.3)
P Value*
.0017
HR (95% CI)
0.54
(0.35-0.82)
0 5 10 25
0
20
40
60
100
64
65
49
38
35
22
19
9
80
15 20
7
2
1
0
Pembro
SOC
30
0
0
12
PD-L1 TPS ≥ 50%
Events, n
41
55
46.6%
26.7% 25.8%
Slide credit: clinicaloptions.com

24. Pembrolizumab 200 mg Q3W
for up to 35 cycles
Cetuximab 250 mg/m2 Q1W‡ +
Carboplatin AUC 5 OR
Cisplatin 100 mg/m2 +
5-FU 1000 mg/m2/day for
4 days for 6 cycles (each 3 wk)
Cetuximab
250 mg/m2 Q1W
Stratification Factors
 PD-L1 expression*
(TPS ≥ 50% vs < 50%)
 p16 status in oropharynx
(positive vs negative)
 ECOG PS (0 vs 1)
*Assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent) †Assessed using the CINtec p16 Histology
assay (Ventana); cutpoint for positivity: 70%. ‡Following a loading dose of 400 mg/m2.
Pembrolizumab 200 mg +
Carboplatin AUC 5 OR
Cisplatin 100 mg/m2 +
5-FU 1000 mg/m2/day for
4 days for 6 cycles (each 3 wk)
Pembrolizumab
200 mg Q3W
for up to
35 cycles total
Key Eligibility Criteria
 SCC of the oropharynx, oral cavity,
hypopharynx, or larynx
 R/M disease incurable by local
therapies
 ECOG PS 0 or 1
 Tissue sample for PD-L1
assessment*
 Known p16 status in the
oropharynx†
Pembrolizumab
Monotherapy
Pembrolizumab
+ Chemotherapy
EXTREME
Slide credit: clinicaloptions.com
KEYNOTE-048: Study Design
R
1:1:1
Burtness. Lancet. 2019;394:1915.

25. Events HR (95% CI) P
Pembro alone 62% 0.61
(0.45-0.83)
.0007
EXTREME 78%
Slide credit: clinicaloptions.com
KEYNOTE-048: OS (CPS ≥ 20) for Pembrolizumab vs
EXTREME CPS, CPS: combined positive score
Median OS, Mos (95% CI)
14.9 (11.6-21.5)
10.7 (8.8-12.8)
12-mo rate
56.9%
44.9% 24-mo rate
38.3%
22.1%
0 5 10 15 20 25 30 35 40
0
20
40
60
80
100
Mos
Patients at Risk, n
133 106 85 65 24
122 100 64 42 12
47
22
0
0
11
5
2
0
OS
(%)
Burtness. Lancet. 2019;394:1915. Burtness. ESMO 2018. LBA8_PR.

26. Median OS, Mos (95% CI)
12.3 (10.8-14.9)
10.3 (9.0-11.5)
12-mos rate
51.0%
43.6% 24-mos rate
30.2%
18.6%
Slide credit: clinicaloptions.com
Patients at Risk, n
257 196 152 110 34
255 207 131 89 21
74
47
0
0
17
9
2
1
0 5 10 15 20 25 30 35 40
0
20
40
60
80
100
Mos
OS
(%)
Events HR (95% CI) P
Pembro alone 69% 0.78
(0.64-0.96)
.0086
EXTREME 81%
KEYNOTE-048: OS (CPS ≥ 1) for Pembrolizumab vs
EXTREME CPS: combined positive score
Burtness. Lancet. 2019;394:1915. Burtness. ESMO 2018. LBA8_PR.

27. KEYNOTE-048: OS for Pembrolizumab + Chemotherapy vs
EXTREME
Events HR (95% CI) P Value
Pembro + chemo 70% 0.77
(0.63-0.93)
.0034
EXTREME 80%
Median OS, Mos (95% CI)
13.0 (10.9-14.7)
10.7 (9.3-11.7)
12-mos rate
53.0%
43.9% 24-mos rate
29.0%
18.7%
Slide credit: clinicaloptions.com
0 5 10 15 20 25 30 35 40
0
20
40
60
80
100
Mos
Patients at Risk, n
281 227 169 122 40
278 227 147 100 20
75
51
0
0
10
5
1
1
OS
(%)
Burtness. Lancet. 2019;394:1915. Burtness. ESMO 2018. LBA8_PR.

28. KEYNOTE-048: Long-Term OS
OS CPS ≥ 1 CPS ≥ 20
Median, mos (HR; P value) 12.3 vs 10.4 (0.71; .0008) 14.9 vs 10.8 (0.61; .0003)
24-mo OS,% 28.9 vs 17.7 35.3 vs 19.7
48-mo OS, % 16.7 vs 5.9 21.6 vs 8.0
Pembrolizumab vs EXTREME
OS CPS ≥ 1 CPS ≥ 20
Median, mos (HR; P value) 13.6 vs 10.6 (0.64; < .0001) 14.7 vs 11.1 (0.62; .0008)
24-mo OS,% 30.8 vs 17.1 35.4 vs 20.0
48-mo OS, % 21.8 vs 4.1 28.6 vs 6.6
Pembrolizumab Plus Chemotherapy vs EXTREME
Slide credit: clinicaloptions.com
Greil. ESMO 2020. Abstract 915MO.

29. Immune Checkpoint Inhibitors in Head and Neck Cancer
1.. Nivolumab PI. 2. Pembrolizumab PI. 3. Atezolizumab PI. 4. Durvalumab PI. 5. Avelumab PI.
Drug Approved Indication Target
Nivolumab[1] Second line in R/M HNSCC with progression
on/after platinum-based chemotherapy
PD-1
Pembrolizumab[2] Second line in R/M HNSCC with progression
on/after platinum-containing chemotherapy
First line in R/M HNSCC as a single agent in patients with
PD-L1–expressing tumors (CPS ≥ 1) and in combination
with platinum + 5-FU for all patients
PD-1
Atezolizumab[3] Not approved in HNSCC PD-L1
Durvalumab[4] Not approved in HNSCC PD-L1
Avelumab[5] Not approved in HNSCC PD-L1
Slide credit: clinicaloptions.com

30. PRESENTACION DE CASO CLINICO
• Paciente de 73 ańos
• Presenta lesion de rapido crecimiento de 3 meses de evolucion en
borde lateral derecho de lengua
• Biopsia : Carcinoma escamoso de Lengua . Moderadamente
diferenciado.
• RMN: Lesion de 5.3cm. No adenopatia . No se realizo PET CT
• T4N0M0. EC: IVa (JICC 8ta Ed. 2017)
• Tx: Pembrolizumab 200 mgs cada 3 semanas . Taxo/Carbo/5FU x 4

38. INMUNOTERAPIA
(RETOS)
• CONCOMITANTE CON RT
• CONCOMITANTE CON QT
• USO NEO ADYUVANTE
• USO SUBSEQUENTE
• AGENTE UNICO