Role of systemic therapy in management of laryngeal carcinoma

MohammedFathyBayomy
AssistantLecturer
ofClinicalOncology
ZagazigUniversity
ZUCOD
13 February
2018
Role Of Systemic
Therapy In Management
Of Laryngeal Carcinoma
1

‫عهد‬
‫جديد‬
‫فكر‬
‫جديد‬
Welcome
ZU
Creativity
Distinction
Labor
New
era
New
Thought
‫وسهال‬ ‫أهال‬
2

ZUCOD
I haven’t any thing to disclose.
Disclosur
e
3

ZUCOD
This presentation will include a discussion of off-
label treatment , investigational agents not
approved by the FDA, and data were presented in
abstract form. These data should be considered
preliminary until published in a peer- reviewed
journal.
4

Agenda
Introduction
Chemotherapy
Targeted Therapy
Immunotherapy
Home message
ZUCOD
5

Positive Therapeutic Ratio (Gain)
Maximal probability
of tumor control
Minimal
(reasonably acceptable)
frequency of complications
(sequelae of therapy)
Therapeutic Ratio ZUCOD
7

D isea se
control
Im prov e
Overall
S urv iv a l
Ma inta in
f unction of
orga n
Good/Excellent
a esthetic
outcom e
Minim a l a dv erse
ef f ects/ toxicity
Goals
of
treatment
Ma inta in/
Im p ro v e
Qua lity o f
Lif e ( Qo L)
Goals of treatment ZUCOD
8

Systemic
Therapy
Targeted
Therapy
Immunotherapy
Chemotherapy
Systemic Therapy ZUCOD
9

Induction 
RT
A
B
C
D
Systemic
Therapy
Sittings
Concurrent
Induction 
Concurrent
Palliative
Systemic Therapy Sittings ZUCOD
10

Agenda
Introduction
Chemotherapy
ZUCOD
11

ZUCODCommonly Used Chemotherapeutic Agents
Class Agents Mechanism of action Clearance Toxicity
Platinum agents Cisplatin DNA adduct formation Renal Nausea
Carboplatin Nephrotoxicity
Ototoxicity
Neurotoxicity
Myelosuppression
Antifolates Methotrexate Depletion of precursors for purine Renal Myelosuppression
synthesis Gastrointestinal toxicity
Antimetabolites 5-Fluorouracil Depletion of precursors for DNA synthesis Renal Gastrointestinal toxicity
Incorporation into RNA (inactive drug) Myelosuppression
Taxanes Paclitaxel Mitotic arrest by microtubule Hepatobiliary Hypersensitivity
Docetaxel stabilization Peripheral neuropathy
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
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Multimodality treatment approaches using
Chemotherapy
Approach Definition
Induction chemotherapy The use of chemotherapy prior to definitive locoregional
management
Adjuvant chemotherapy The use of chemotherapy after definitive locoregional management
Concurrent chemoradiotherapy
Definitive chemoradiotherapy The use of concomitant chemotherapy and radiation as definitive
management
Adjuvant chemoradiotherapy The use of concomitant chemotherapy and radiation after definitive
locoregional management
Sequential treatment The use of induction chemotherapy followed by definitive
concomitant chemotherapy and radiation
13

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Randomized Larynx Preservation
Trial Designs and Outcomes
Forastiere AA et al, JCO. 2015; 33(29): 3262-3268.
Study
N
(period)
Site Stage Treatment
Response of
ICT
Larynx Preservation Overall Survival
VALCSG 332 Larynx III (57%) 3-year, 5-year
(1985- SG (63%) IV (43%) a) TL RT NA NA 56% 45%
Phase III 1988) G (37%) b) PF x 3  RT 85% CR+PR 3-year, 62% 53% 42%
RTOG 547 Larynx III (64%) 5-year 10-year 5-year 10-year
91-11 (1992- SG (69%) IV (36%) a) PF x 3  RT 85% CR+PR 71% 68% 58% 39%
Phase III 2000) G (31%) b) RT + P NA 84% 82% 55% 28%
c) RT NA 66% 64% 54% 32%
EORTC 450 Larynx (48%) II (4%) 3-year 3-year
24954-22950 (1996- Hypopharynx (52%) III (39%) a) PF x 4  RT 89% CR+PR 40% 62.2%
Phase III 2004) IV (58%) b) PF alternating/RT NA 45% 64.8%
GORTEC 213 Larynx (46%) III .002 3-year 3-year
2000-01 (2000 Hypopharynx (54%) IV a) PF x 3  RT 59.2% CR+PR 57.5% P= .03 60%
Phase III -2005) b) TPF x 3  RT 80% CR+PR 70.3% 60%
EORTC 202 Hypopharynx II (7%) 3-year 10-year 3-year 10-year
24891 (1986 III (57%) a) TLP  RT NA NA NA 43% 14%
Phase III -1993) IV (37%) b) PF x 3  RT 54% CR 42% 27% 57% 13%
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Definitive Concurrent
Chemoradiation Trials
Study N F/U (years) CT
OS
RT
(control arm)
RT+CT
(experimental arm)
P-value
French trial 226 3 Carbo+5FU 31% 51% 0.002
German trial 270 3 Cis+5FU+LV 24% 48% <0.003
Duke U 116 5 Cis+5FU 28% 42% 0.05
Intergroup 199 3 Cis 23% 37% 0.01
Greek 83 3 Cis 18% 52% <0.001
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Adjuvant Concurrent
Chemoradiation Trials
Study High risk N
F/U
(mon)
RT Endpoint
RT
(control arm)
RT+CT
(experimental arm)
P-value
RTOG 95-01 ≥2+ve LN 459 46 60-66Gy LRC (%) 70% 81% 0.01
ECE DFS (%) 25% 33% 0.04
+ve margin OS (%) 38% 45% 0.19
EORTC 22931 N2-3 350 60 66Gy LRC (%) 69% 82% 0.007
ECE DFS (%) 36% 47% 0.04
+ve margin OS (%) 40% 53% 0.002
Bachaud ECE 83 60 >60Gy LRC (%) 55% 70% 0.05
DFS (%) 23% 45% <0.02
OS (%) 13% 36% <0.01
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Randomized Trials of PF ±
Taxanes
Induction Therapy Trials
Study Eligible N Endpoint
PF
(control arm)
T + PF
(experimental arm)
HR P-value
Spanish Stage III 382 ORR/CR (%) 68%/14% 80%/33% <0.001
Hitt Stage IV TTP (median) 12mon 20mon 0.006
2005 OS (median/2years) 37mon (61%) 43mon (66%) 0.67 0.035
TAX323 Unresectable 358 ORR/CR (%) 54%/6.6% 68%/8.5% 0.006
Vermorken L/HP PFS (median/3years) 8mon/14% 11mon/17% 0.72 0.007
2007 OS (median/3years) 14.2mon/18% 18.6mon/24% 0.71 0.005
GORTC L/HP 205 ORR/CR (%) 60%/30% 82%/43% 0.001
Pointreau II-IV PFS (3years) 44% 58% 0.11
2009 OS (3years) 60% 60% 0.57
LP (3years) 41.1% 63.2% 0.036
TAX324 Stage III 501 ORR/CR (%) 64%/15% 72%/17%
Posner Stage IV PFS (median/2years) 13mon/42% 36mon/53% 0.71 0.004
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Phase III Sequential Chemoradiation
Trials in Unresectable Carcinoma
Study Eligible N Endpoint
PF
(control arm)
T + PF
(experimental arm)
HR P-value
Spanish* Stage III 382 ORR/CR (%) 68%/14% 80%/33% <0.001
Hitt Stage IV TTP (median) 12mon 20mon 0.006
TAX323 Unresectable 358 ORR/CR (%) 54%/6.6% 68%/8.5% 0.006
Vermorken L/HP PFS (median/3years) 8mon/14% 11mon/17% 0.72 0.007
2007 OS (median/3years) 14.2mon/18% 18.6mon/24% 0.71 0.005
Spanish 439 TTF (median) 5mon 12.5mon 0.0001
Hitt
2009
TAX324 Stage III 501 ORR/CR (%) 64%/15% 72%/17%
Posner Stage IV PFS (median/2years) 13mon/42% 36mon/53% 0.71 0.004
* Paclitaxel used instead of docetaxel.
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Meta-analysis of Chemotherapy in HNC
(MACH-NC)
Pignon JP, et al. Lancet. 2000; 355:949.
Plan of analysis
• 65 randomized trials (1965-
1993).
• n = 10,850 (exclude NPC
trials)
26 trial of Concomitant
Chemoradiation
(n=3727)
31 trial of Induction
Chemotherapy 
Radiotherapy (n=5269)
8 trial of Adjuvant
Chemoradiation
(n=1854)Median F/U of 6
years
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Outcome of H&N
(MACH-NC)
Sitting Trials N RR Risk reduction P-value
Absolute benefit
(5-years) %
Chemotherapy 65 10,850 0.89* 11% <0.0001 +4%
Concomitant 26 3,727 0.81 19% <0.0001 +8%
Induction 31 5,269 0.95 5% 0.10 +2%
PF 15 2487 0.01 +5%
Other 16 2782 0.91 0
Adjuvant 8 1,854 0.98 2% 0.74 +1%
* ORR
Pignon JP, et al. Lancet. 2000; 355:949.
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Outcome of Larynx in 2011 update of 93 trial (n =17,346)
(MACH-NC)
Sitting N RR Risk reduction P-value
Absolute benefit
(5-years) %
Chemotherapy 3216 0.87 13% <0.05
Concomitant 0.80 29% <0.05 +5.4%
Induction 1.00 0% >0.05 +3.8%
Adjuvant 1.05 -5% >0.05 +0.1%
Blanchard P, et al. Radiother Oncol 2011; 100(1):33-40.
21

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Induction
Chemotherapy
22

ZUCODRTOG 68-01
Fazekas JT, Int J Radiat Oncol Biol Phys. 1980 ;6(5):533-
Study Design
638 Patients
• H & N carcinoma.
• SGL: 12%.
• Squamous carcinoma.
• Previously untreated.
• Stage III or IV.
R
Radiation therapy
(5500 to 8000 cGy)
n = 326
Induction
Chemotherapy (MTX)*
n = 312
Radiation therapy
(5500 to 8000 cGy)
* MTX 25 mg every third day for five
doses
John T Fazekas, MD
23

ZUCODRTOG 68-01
Outcome
Primary site
RT
Median OS
MTX RT
Median OS
P-value
Oral cavity 11.8 mon 12.4 mon >0.05
Oropharynx 13.6 mon 13.1 mon >0.05
SGL 17.2 mon 19.2 mon >0.05
Hypopharynx 9.7 mon 13.4 mon >0.05
24

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This study taught
us• Minimal gain, induction methotrexate should not be used
RTOG 68-01
25

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Department of
Veterans Affairs Larynx
trialStudy Design
332 Patients
• Laryngeal carcinoma.
• Resectable.
Laryngectomy
N = 166
Induction chemotherapy
(Cis+5fu)* x 2 cycles
N = 166
(Cis+5fu)* x 1 more cycle
Salvage
Laryngectomy
Radiation therapy
(5400 cGy ± 1000 cGy)
Radiation therapy
(6600 to 7600 cGy)
Radiation therapy
(5400 cGy ± 1000 cGy)
Wolf GT, et al. N Engl J Med. 1991 ;24(24):1685-
R
Responders
Non-responders
Salvage
Laryngectomy
Residual disease
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000
mg/m2 D1 to D5 (CIV) repeat cycle on days
22 & 43.
Median F/U of 33 months Gregory T Wolf, MD
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Wolf GT, et al. N Engl J Med. 1991 ;24(24):1685-90.
Baseline Demographics
Department of
trial
Characteristics
All patients
(n = 332)
No. (%)
Surgery
(n = 166)
No. (%)
Chemotherapy
(n = 166)
No. (%)
Stage
III 188 (56.6%) 95 (57.2%) 93 (56%)
IV 144 (43.4%) 71 (42.8%) 73 (44%)
Tumor class
T1-2 31 (9.3%) 15 (9%) 16 (9.6%)
T3 216 (65.1%) 109 (65.7%) 107 (64.5%)
T4 85 (25.6) 42 (25.3%) 43 (25.9%)
Node class
N0 180 (54.2%) 94 (56.6%) 86 (51.8%)
N1 60 (18.1%) 26 (15.7%) 34 (20.5%)
N2 37 (11.1%) 21 (12.7%) 16 (9.6%)
N3 55 (16.6%) 25 (15.1%) 30 (18.1%)
Characteristics
All patients
(n = 332)
No. (%)
Surgery
(n = 166)
No. (%)
Chemotherapy
(n = 166)
No. (%)
Site
Glottic 124 (37.3%) 63 (38%) 61 (36.7%)
Supraglottic 208 (62.7%) 103 (62%) 105 (63.3%)
Cartilage inv. 30 (9%) 13 (7.8%) 17 (10.2%)
Fixed vocal cords 188 (56.6%) 98 (59%) 90 (54.2%)
PS (Karnofsky)
<80% 79 (23.8%) 40 (24.1%) 39 (23.5%)
≥80% 253 (76.2%) 126 (75.9%) 127 (76.5%)
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Disease Free
Survival
Department of
trial
P = 0.1195
64%
2-year Larynx Preservation Rate = 64%
Overall Survival
68%
P = 0.9846
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Department of
trial
Site of Recurrence
Surgery
(n = 166)
No. (%)
Chemotherapy
(n = 166)
No. (%)
p-value
All 42 (25%) 52 (31%)
Primary 4 (2%) 20 (12%) 0.0005
Regional 9 (5%) 14 (8%)
Distant 29 (17%) 18 (11%) 0.016
Site of Recurrence (pattern of failure)
Causes of Death
Cause of death
Surgery
(n = 166)
No. (%)
Chemotherapy
(n = 166)
No. (%)
All 58 (35%) 65 (39%)
Cancer 38 (23%) 42 (25%)
Complication of therapy 4 (2%) 4 (2%)
Other 14 (8%) 13 (8%)
Unknown 2 (1%) 6 (4%)
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This study taught
us
Department of
trial
• The efficacy of chemotherapy followed by radiotherapy (with surgical
salvage) was similar to that of surgery followed by radiotherapy and
offered the added benefit of laryngeal preservation in two thirds of
patients treated by this approach.
• The higher rate of local recurrence indicates that more effective local
therapy is needed to improve rates of larynx preservation.
Chemotherapy regimens that achieve higher rates of complete
response, newer schemes of radiation fractionation, or other
combinations of radiation and chemotherapy may prove beneficial in
this regard.
30

ZUCODEORTC 24891
Study Design
202 Patients
• Pyriform fossa & AE fold
carcinoma.
• Stage II or IV (Non N2c).
• Resectable.
Total Laryngectomy + partial
pharyngectomy + neck
dissection
N =
N =
Total Laryngectomy +
partial pharyngectomy +
neck dissection
Radiation therapy
(5000 to 7000 cGy)
Radiation therapy
(7000 cGy)
Radiation therapy
(5000 to 7000 cGy)
R
PR
SD or PD
Total Laryngectomy +
partial pharyngectomy +
neck dissection
PDCR
22 & 43.
Median follow-up of 51 months
Lefebvre JL, et al. J Natl Cancer Inst. 1996
CR
Jean-Louis Lefebvre, MD
31

ZUCODEORTC 24891
Outcome after 4 years
Parameters ICT  RT Surgery HR (95% CI) p-value
Larynx preservation
Three-year 42%
Four-year 35%
Overall survival
Median (months) 44 25 0.86 >0.05
Three-year 38% 33%
Distant metastasis
Three-year 25% 36% 0.041
Local recurrence
Three-year 17% 12%
Regional recurrence
Three-year 23% 19%
Outcome after 10 years
Parameters ICT  RT Surgery HR (95% CI) p-value
Larynx preservation
Five-year 22%
Ten-year 9%*
Overall survival
Five-year 13% 14%
Progression Free Survival
Five-year 32% 26% >0.05
* 69% survivors.
32

ZUCOD
This study taught
us
• Similar survival curves with larynx preservation as with conventional
total laryngectomy, with 2/3 survivors retaining their larynx.
EORTC 24891
• Induction chemotherapy reduce risk of distant metastasis.
33

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Study Design
68 Patients
• Resectable.
Laryngectomy
N = 32
N = 36
Salvage
Laryngectomy
Radiation therapy
(5000 cGy to 7000 cGy)
Radiation therapy
(6500 to 7000 cGy)
N = 15
Radiation therapy
(5000 cGy to 7000 cGy)
R
No progression
22 & 43.
GETTEC trial
Richard JM, et al. Oral Oncol. 1998;34:224–8
Prematurely closed due to a
poor accrual
> 80% response
Progression
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Outcome
Parameters ICT  RT Surgery p-value
Larynx preservation
Two-year 42%
Overall survival
Two-year 69% 84% 0.006
GETTEC trial
Richard JM, et al. Oral Oncol. 1998;34:224–8
35

ZUCODTAX323 (EORTC 24971)
Vermorken JB, et al, N Engl J Med 2007; 357:1695–1704.
Study Design
358 Patients
• Unresectable.
R
(PF)* x 4 cycles
N = 177
(TPF)‡ x 4 cycles
N = 181
Radiation therapy
CF, AF or HF
Neck Dissection
Radiation therapy
CF, AF or HF
Neck Dissection
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000 mg/m2 D1 to
D5 (CIV) repeat cycle 3weeks.
‡ Docetaxel 75 mg/m2 D1 + Cisplatin 75 mg/m2 D1 + Fluorouracil 750 mg/m2 D1 to
D5 (CIV) repeat cycle every 3 weeks
Stratify:-
• Primary site.
• Institution.
Jan B Vermorken, MD
36

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Outcome
Parameters
TPF
(n = 177)
PF
(n = 181)
HR (95% CI) p-value
Progression-free survival
Median (months) 11.0 8.2 0.72 (0.57-0.91) 0.007
One-year 48% 31%
Two-year 25% 20%
Three-year 17% 14%
Overall survival
Median (months) 18.8 14.5 0.73 (0.56-0.94) 0.02
One-year 72% 55%
Two-year 43% 32%
Three-year 37% 26%
Response after induction CT
Overall 68% 54% 0.006
Complete response 8.5% 6.6%
Partial response 59.3% 47%
Response after RT
Overall 72% 59% 0.006
Partial response 39% 38.7%
Duration of response (months) 15.4 11.6 0.74 (0.53-1.03) 0.08
TAX323 (EORTC 24971)
37

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Progression Free Survival (PFS)
17% 14% P = 0.007
Overall Survival (OS)
37%
26% P = 0.02
38

ZUCOD
This study taught
us
• The efficacy of adding docetaxel to PF as TPF demonstrated superior
response rate , increased 3-year PFS and increased 3-year OS.
• Patients who received TPF had less grades 3-4 toxicity and fewer toxic
deaths compared with those receiving PF, due to the reduced doses of
platinum and 5FU in the TPF regimen.
39

ZUCODGORTEC 2000-01 trial
Pointreau Y, et al. J Natl Cancer Inst. 2009; 101(7):498-506
Study Design
213 Patients
• Larynx & Hypopharynx
carcinoma.
• T2-4, N0-3.
• Resectable.
R
(CF)* x 3 cycles ± 1 more
N = 103
(TCF)‡ x 3 cycles ± 1 more
N = 110
Radiation therapy
(7000 cGy)
Radiation therapy
(7000 cGy)
* Cisplatin 100 mg/m2 D1 +
Fluorouracil 1000 mg/m2
D1 to D5 (CIV) repeat
cycle 3weeks.
‡ Paclitaxel 175 mg/m2 D1 +
Cisplatin 75 mg/m2 D1 +
Fluorouracil 750 mg/m2 D1 to
D5 (CIV) repeat cycle every
3 weeks
Median F/U of 3 years
≥ 50% response
≥ 50% response
< 50% response
Salvage
Laryngectomy
< 50% response
Radiation therapy
(5400 cGy ± 1000 cGy)
• Primary endpoint: 3-year laryngeal preservation.
• Secondary endpoint: Overall survival, Response to ICT, DFS,
Toxicity.
Yoann Pointreau, MD
40

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Outcome
Parameters
TPF
(n = 106)
PF
(n = 99)
p-value
Larynx preservation rate
Three-year 63.2% 41.1% <0.05
Three-year 60% 60% 0.57
Overall response rate 82.8% 60.8% 0.0013
Partial response 39.4% 30.4%
Three-year 58% 44% 0.11
Adverse events (>grade III)
Alopecia 19% 2.1% 0.002
Mucositis 5.1% 9.2% 0.04
Neutropenia 56.5% 35.4% 0.03
Febrile neutropenia 2.1% 6.9% 0.045
Thrombocytopenia 2.1% 6.5% 0.2
Anemia 6.2% 7.3% 0.3
GORTEC 2000-01 trial
Pointreau Y, et al. J Natl Cancer Inst. 2009; 101(7):498-506
41

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Long term Outcome
Janoray G, et al. J Natl Cancer Inst. 2016;108(4)
Parameters
TPF
(n = 106)
PF
(n = 99)
HR (95%CI) p-value
Larynx preservation
Five-years 74% 58.1% 1.94 (1.14-3.30)
Ten-years 70.3% 46.5% 1.93 (1.11-3.27) 0.01
Five-years 50.9% 41.9% 1.08 (0.71-1.63)
Ten-years 30.2% 23.5% 1.07 (0.74-1.57) 0.28
LDEFS
Five-years 67.2% 46.5% 1.82 (1.14-2.91)
Ten-years 63.7% 37.2% 1.82 (1.14-2.90) 0.001
DFS
Five-years 42.4% 31.4% 1.37 (0.94-2.01)
Ten-years 25% 18.7% 1.30 (0.91-1.86) 0.21
LRC
Five-years 46.6% 36.3% 1.15 (0.78-1.70)
Ten-years 27.9% 20.8% 1.16 (0.81-1.67) 0.18
Guillaume Janoray, MD
42

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Larynx preservation rate
Larynx dysfunction-free survival (LDEFS)
43

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Locoregional control (LRC)
44

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Disease Free Survival (DFS)
45

ZUCODConclusions for Induction
Chemotherapy
• The addition of induction chemotherapy for larynx preservation did
not compromise the survival when compared with upfront surgery.
• None of the different induction chemotherapy regimens (PF or TPF)
has been able to improve survival in larynx preservation programs.
• Induction chemotherapy did not compromise subsequent treatment
(either salvage surgery of definitive irradiation) in terms of tolerance
or of efficacy.
46

ZUCODPros and Cons of Induction
Chemotherapy
• Improve distant control.
• Organ preservation.
• Higher rate of loco-regional failure.
Pros Cons
47

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Induction
Chemotherapy
Concurrent
Chemotherapy
48

ZUCODRTOG 91-11: Larynx Preservation
Trial
Forastiere AA, etal, N Engl J Med 2003; 349:2091–2098
Study Design
• Primary endpoint: preservation of the
larynx.
• Secondary endpoint: locoregional
547 Patients
• Squamous carcinoma
• Stage III-IV.
• Resectable.
R
N = 180
Responders Induction chemotherapy
Radiation therapy
(7000 cGy)
Non-responders
Salvage
Laryngectomy
Radiation therapy +
Chemotherapy (Cis)‡
N = 182
Radiation therapy
(7000 cGy)
N = 185 Radiation therapy
(5000 to 7000 cGy)
D5 (CIV) repeat cycle on days 22 & 43.
‡ Cisplatin 100 mg/m2 D1, 22, 43 of RT
Stratify:-
• Location: glottic vs supra.
• T stage: T2 vs T3mobile vs
T3fixed vs T4.
• N stage: N0+N1 vs N2+N3.
Arlene A Forastiere, MD
49

ZUCOD
Characteristics
RT+CT
(n = 172)
No. (%)
CT  RT
(n = 173)
No. (%)
RT
(n = 173)
No. (%)
Stage
III 115 (67%) 111 (64%) 111 (64%)
IV 57 (33%) 62 (36%) 62 (36%)
Tumor class
T2 21 (12%) 19 (11%) 20 (12%)
T3 134 (78%) 136 (78%) 137 (79%)
T4 17 (10%) 18 (10%) 16 (9%)
Node class
N0 86 (50%) 87 (50%) 87 (50%)
N1 39 (23%) 38 (22%) 32 (18%)
N2 43 (25%) 45 26%) 52 (31%)
N3 4 (2%) 3 (2%) 2 (1%)
Characteristics
RT+CT
(n = 172)
No. (%)
CT  RT
(n = 173)
No. (%)
RT
(n = 173)
No. (%)
Site
Glottic 58 (34%) 55 (32%) 49 (28%)
Supraglottic 114 (66%) 118 (68%) 124 (72%)
Fixed vocal cords 82 (48%) 82 (47%) 76 (44%)
PS (Karnofsky)
<80% 7 (4%) 12 (7%) 13 (8%)
≥80% 165 (96%) 161 (93%) 160 (92%)
Age
<60 years 83 (48%) 91 (53%) 89 (51%)
≥60 years 89 (52%) 82 (47%) 84 (49%)
Sex
Male 137 (80%) 131 (76%) 133 (77%)
Female 35 (20%) 42 (24%) 40 (23%)
RTOG 91-11: Larynx Preservation
Trial
50

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Trial
Preservation of the Larynx
88%
75%
70%
P = 0.005
P = 0.27
P < 0.001
Locoregional Control
78%
61%
56%
P = 0.003
P = 0.16
P < 0.001
51

Toxic effect
Radiotherapy with concurrent
cisplatin (N = 171)
Cisplatin plus Fluorouracil
Followed by Radiotherapy
Radiotherapy alone
(N = 171)
Chemotherapy Period
(N = 168)
Radiotherapy period
(N = 156)
grade 3 grade 4 total grade 3 grade 4 total grade 3 grade 4 total grade 3 grade 4 total
Hematologic 64 17 81 (47%) 43 44 87 (52%) 13 10 23 (15%) 3 2 5 (3%)
Infection 7 0 7 (4%) 4 5 9 (5%) 2 0 2 (1%) 2 0 2(1%)
Mucositis
Stomatitis 64 9 73 (43%) 27 7 34 (20%) 36 2 38 (24%) 40 1 41 (24%)
Pharyngeal or
esophageal
60 0 60 (35%) - - - 30 0 30 (19%) 32 0 32 (19%)
Laryngeal 29 2 31 (18%) - - - 20 1 21 (13%) 23 5 28 (16%)
Dermatologic 10 2 12 (7%) - - - 16 0 16 (10%) 15 0 15 (9%)
Nausea or
vomiting
28 7 35 (20%) 20 3 23 (14%) 0 0 0 0 0 0
Renal or
genitourinary
6 1 7 (4%) 3 0 3 (2%) 2 0 2(1%) 0 0 0
Neurologic 8 1 9 (5%) 5 1 6 (4%) 0 0 0 0 0 0
Other 58 11 69 (40%) 20 7 27 (16) 16 2 18 (12%) 9 1 10 (6%)
Overall maximal 99 32 131 (77%) 62 49 111 (66%) 66 13 79 (51%) 71 9 80 (47%)
ZUCOD
Forastiere AA, et al, N Engl J Med 2003; 349:2091–2098
Trial
Toxicity profile
52

Trial
10 years Outcome
Forastiere AA, etal, J Clin Oncol. 2013 ;31(7):845-52
53
Parameters
Radiotherapy with concurrent
cisplatin (N = 171)
Cisplatin plus Fluorouracil
Followed by Radiotherapy (N=172)
Radiotherapy alone
(N=171)
Laryngectomy-free survival
5 years 47.0% 44.1% 34.0%
10 years 23.5% 28.9% 17.2%
Larynx preservation
5 years 83.6%* 70.8% 65.8%
10 years 81.7%* 67.5% 63.8%
Local control
5 years 71.1%* 58.2% 53.6%
10 years 69.2%* 53.7% 50.1%
Locoregional control
5 years 67.7%* 54.8% 51.2%
10 years 65.3%* 48.9% 47.2%
Distant control
5 years 86.4% 85.3% 78.0%
10 years 83.9% 83.4% 76.0%
Disease-free survival
5 years 38.0% 37.7% 28.0%
10 years 21.6% 20.4% 14.8%
Overall survival
5 years 55.1% 58.1% 53.8%
10 years 27.5% 38.8% 31.5%

Trial
Larynx preservation Laryngectomy-free survival
Forastiere AA, etal, J Clin Oncol. 2013 Mar 1;31(7):845-52
54

Trial
Locoregional control Overall Survival
Forastiere AA, etal, J Clin Oncol. 2013 Mar 1;31(7):845-52
55

ZUCOD
This study taught
us
• Preservation of the larynx significantly favored concurrent therapy.
• No improvement in overall survival with addition of chemotherapy to
radiotherapy.
Trial
• Locoregional control significantly favored concurrent therapy.
56

ZUCODFrench Trial: Definitive Chemoradiation
Prades JM, et al. Acta Otolaryngol. 2009 ;15:1-6.
Study Design
75 Patients
• Pyriform fossa
carcinoma.
• Squamous carcinoma
• Stage T3 N0-3.
• Resectable.
R
CR or PR Radiation therapy
(7000 cGy)
SD or PD
Salvage
Laryngectomy
Radiation therapy
(7000 cGy)
+ Chemotherapy (Cis)‡
Radiation therapy
(5000 to 7000 cGy)
D5 (CIV) repeat cycle every 3weeks.
‡ Cisplatin 100 mg/m2 D1, 22, 43 of RT
Median F/U 2 years
Jean M Prades, MD
57

ZUCOD
Parameters Concurrent Induction p-value
Larynx preservation
Two-year 92% 68% <0.05
Overall survival
Two-year 47% 51% >0.05
Event Free Survival
Two-year 36% 41% >0.05
Local control
Two-year 81% 62% <0.05
Distant metastasis
Two-year 38% 19% <0.05
Any toxicity 76% 71% >0.05
Outcome
French Trial: Definitive Chemoradiation
58

ZUCOD
This study taught
us
• Concurrent chemo-RT superior to induction chemotherapy then
radiotherapy as it improve local control, and preserve more larynx.
• No improvement in overall survival with concurrent use of
chemotherapy
• Concurrent Chemo-RT had less distant control than induction strategy.
French Trial: Definitive Chemoradiation
59

ZUCOD
Conclusions for Concomitant
Chemoradiotherapy
• Concurrent chemoradiotherapy provides the highest larynx
preservation defined as the larynx in place.
• Concurrent chemoradiotherapy generates a substantial acute toxicity.
• Late toxicity after concurrent chemoradiotherapy may compromise
the laryngeal function. It is important to stress that for quality of life
only the preservation of a functioning larynx is meaningful.
• Neither concurrent nor alternating chemoradiotherapy improves
survival.
60

ZUCODPros and Cons of Definitive Chemoradiation
• Improve loco-regional control.
• Facilitates organ preservation.
• Beneficial impact on survival.
• Doubles the rate of sever acute
mucositis.
• Over-treatment based on stage.
• Long term functional deficit in voice
quality, swallowing.
Pros Cons
61

ZUCODRTOG 95-01: Postoperative Chemoradiation
Cooper JS, etal, N Engl J Med 2004; 350:1937–1944
Study Design
• Primary endpoint: Locoregional Control.
• Secondary endpoint: Disease-Free Survival, Overall
Survival.
459 Patients
• Stage III-IV
(Resectable).
• Radical surgery.
• High risk feature:
histologic evidence of 2
or more LN &/or extra-
capsular extension
and/or microscopically
involved resection
margin
R
Radiation therapy
(6600 to 7000 cGy)
+ Chemotherapy (Cis)*
Radiation therapy
(6600 to 7000 cGy)
* Cisplatin 100 mg/m2 D1, 22, 43
of RT.
Median follow-up of 45.9 months
Jay S. Cooper, MD
62

Baseline characteristics
Parameters
CT+RT
(n = 206)
No. (%)
RT
(n = 210)
No. (%)
High risk features
Positive margins 34 (17%) 39 (19%)
≥2 involved nodes or ECE 172 (83%) 171 (81%)
Differentiation of tumor
Low 15 (7%) 15 (7%)
Intermediate 113 (55%) 118 (56%)
High 69 (33%) 72 (34%)
Not stated 9 (4%) 5 (2%)
Site of tumor
Oral cavity 50 (24%) 62 (30%)
Oropharynx 99 (48%) 78 (37%)
Hypopharynx 15 (7%) 26 (12%)
Supraglottic 29 (14%) 32 (15%)
Glottic 11 (5%) 5 (5%)
Subglottic 2 (1%) 1 (<1%)
Parameters
CT+RT
(n = 206)
No. (%)
RT
(n = 210)
No. (%)
Age
18-69 years 195 (95%) 196 (93%)
≥70 years 11 (5%) 14 (7%)
Performance status (KS)
60% 1 (<1%) 6 (3%)
70% 33 (16%) 19 (9%)
80% 56 (27%) 62 (30%)
90% 93 (45%) 95 (45%)
100% 23 (11%) 28 (13%)
Sex
Male 177 (86%) 181 (86%)
Female 29 (14%) 29 (14%)
63

Outcome
Parameters CT+RT RT p-value
Locoregional failure
Three-year 22% 33% 0.01
Disease Free Survival
Three-year 47% 36% 0.04
Overall Survival
Three-year 56% 47% 0.19
Distant metastasis
Three-year 20% 23% 0.46
Toxicity
≥Grade 3 acute toxicity 22% 34% <0.0001
Late toxicity 21% 17% 0.29
Subset
analysis
Ten-year 22.3% 28.8% 0.01
Ten-year 20.1% 19.1% 0.25
Overall Survival
Ten-year 29.1% 27% 0.31
Long term Outcome
(+ve margin &/or ECE)
Ten-year 21% 33.1% 0.02
Ten-year 18.4% 12.3% 0.05
Overall Survival
Ten-year 27.1% 19.6% 0.07
64

ZUCODEORTC 22931: Postoperative
Chemoradiation
Study Design
• Primary endpoint: disease free survival.
• Secondary endpoint: locoregional, Overall survival.
334 Patients
• Stage III-IV
(Resectable).
• Radical surgery.
• High risk feature:
histologic evidence of
extra-capsular spread
positive resection
margins, perineural
involvement, or vascular
tumor embolism.
R
Radiation therapy
(6600 to 7000 cGy)
+ Chemotherapy (Cis)*
Radiation therapy
(6600 cGy)
* Cisplatin 100 mg/m2 D1, 22, 43
of RT.
Bernier J et al, N Engl J Med 2004; 350:1945–1952
Jacques Bernier, MD
65

ZUCOD
Baseline characteristics
Parameters
CT+RT
(n = 167)
No. (%)
RT
(n = 167)
No. (%)
High risk features
Positive margins 52 (31%) 43 (26%)
ECE 102 (61%) 89 (53%)
Perineural invasion 21 (13%) 24 (14%)
Vascular embolism 35 (21%) 31 (19%)
≥2 positive LN 89 (53%) 93 (56%)
Histologic differentiation
Well differentiated 74 (44%) 64 (38%)
Moderately differentiated 60 (36%) 70 (42%)
Poorly differentiated 30 (18%) 32 (19%)
Unknown 3 (2%) 1 (1%)
Primary tumor site
Oral cavity 41 (25%) 46 (28%)
Oropharynx 54 (32%) 47 (28%)
Hypopharynx 34 (20%) 34 (20%)
Larynx 37 (22%) 38 (23%)
Parameters
CT+RT
(n = 167)
No. (%)
RT
(n = 167)
No. (%)
Age
15-50 years 46 (28%) 58 (35%)
51-70 years 121 (72%) 109 (65%)
Sex
Male 153 (92%) 155 (93%)
Female 13 (8%) 12 (7%)
Tumor stage
T1 11 (7%) 16 (10%)
T2 40 (24%) 43 (26%)
T3 44 (26%) 49 (29%)
T4 72 (43%) 57 (34%)
Nodal stage
N0 37 (22%) 42 (25%)
N1 35 (21%) 29 (17%)
N2 83 (50%) 84 (50%)
N3 12 (7%) 12 (7%)
EORTC 22931: Postoperative
Chemoradiation
66

ZUCOD
Outcome
Five-year 18% 31% 0.007
Five-year 47% 36% 0.04
Overall Survival
Five-year 53% 40% 0.02
Distant metastasis
Five-year 21% 24% 0.01
Toxicity
≥Grade 3 acute toxicity 44% 21% 0.001
Late toxicity 38% 41% 0.25
EORTC 22931: Postoperative
Chemoradiation
67

ZUCOD
Combined Analysis of RTOG 95-01
& EORTC 22931
Bernier J , Cooper JS , et al, Head Neck 2005; 27:843–850
Pooled the data sets from RTOG
9501 and EORTC 22931 to analyze
the effect of possible predictors of
benefit from chemotherapy.
ECE and/or microscopically
involved surgical margins were the
only risk factors for which the
influence of concurrent chemo-RT
was significant in both trials.
• ≥2 positive
LN
• Stage III-IV
• OP or OC
with level 4
or 5 LN
• PNI
• Vascular
embolism
• Positive
margin
• ECE
EORTC 22931 RTOG 95-01 68

ZUCOD
Induction
Chemotherapy
Concurrent
Chemotherapy
Induction 
Concurrent
Chemotherapy
69

ZUCODTAX324 (Dana Farber trial)
Study Design
494 Patients
• Unresectable.
R
(PF)* x 3 cycles
(TPF)* x 3 cycles
D5 (CIV) repeat cycle 3weeks.
* Docetaxel 75 mg/m2 D1 + Cisplatin 100 mg/m2 D1 + Fluorouracil 1000 mg/m2 D1
to D5 (CIV) repeat cycle every 3 weeksMedian follow-up of 42 months
Posner MR, et al, N Engl J Med 2007; 357:1705–1715.
Radiation therapy
(7000 cGy) +
Chemotherapy ‡
‡ Carboplatin (AUC 1.5)weekly for 7 weeks. .
Radiation therapy
(7000 cGy) +
Chemotherapy ‡
‡ Carboplatin (AUC 1.5)weekly for 7 weeks. .
Marshall R Posner, MD
70

ZUCOD
Outcome
Parameters
TPF
(n = 255)
PF
(n = 246)
HR (95% CI) p-value
Progression-free survival
Median (months) 36 13 0.71 (0.56-0.90) 0.004
Two-year 53% 42%
Three-year 49% 37%
Overall survival
Median (months) 71 30 0.70 (0.54-0.90) 0.006
Two-year 67% 55%
Three-year 62% 48%
Time to progression
Median (months) NR 14% 0.66 (0.50-0.86) 0.002
Two-year 57% 43%
Three-year 54% 40%
Treatment failure
Any 35% 45% 0.70 (0.53-0.92) 0.01
Locoregional 30% 38% 0.73 (0.54-0.99) 0.04
Distant 5% 9% 0.60 (0.30-1.18) 0.14
Second primary 4% 4%
TAX324 (Dana Farber trial)
71

ZUCOD
This study taught
us
• The efficacy of adding docetaxel to PF as TPF demonstrated,
increased 3-year PFS and increased 3-year OS.
• Patients who received TPF had less local and regional failure.
TAX324 (Dana Farber trial)
72

ZUCOD
Study Design
382 Patients
• Locally advanced
• Resectable & unresectable.
R
(CF)* x 3 cycles ± 1 more
N = 193
(PCF)* x 3 cycles ± 1 more
N = 180
* Cisplatin 100 mg/m2 D1 +
Fluorouracil 1000 mg/m2
D1 to D5 (CIV) repeat
cycle 3weeks.
‡ Cisplatin 100 mg/m2 D1,
22, 43 of RT
* Paclitaxel 175 mg/m2 D1 +
Cisplatin 100 mg/m2 D2 +
Fluorouracil 500 mg/m2 D2 to
D6 (CIV) repeat cycle every
3 weeks.
‡ Cisplatin 100 mg/m2 D1, 22,
43 of RT
CR or PR ≥ 80% response
CR or PR ≥ 80% response
PR < 80% response or SD
Surgery
Neck dissection
PR < 80% response or SD
• Primary endpoint: Response to ICT.
• Secondary endpoint: Overall survival, TTP, Toxicity.
Spanish Intergroup Trial
Hitt R. et al, J Clin Oncol. 2005;23(34):8636-45.
Radiation therapy
(7000 cGy) +
Radiation therapy
(7000 cGy) +
Radiation therapy
(7000 cGy) +
Ricardo Hitt, MD
73

ZUCOD
Hitt R. et al, J Clin Oncol. 2005;23(34):8636-45.
Outcome
Parameters
PCF
(n = 189)
CF
(n = 193)
p-value
Response rate
ORR 80% 68% <0.001
CR 33% 14% <0.001
Time to progression (TTP)
Median (months) 20 12 0.006
Median (months) 43 37 0.06
Median (months) (unresectable ) 36 26 0.04
Toxicity
Intolerable 2% 4% >0.05
Mucositis 16% 53% <0.001
Neutropenia (Febrile) 37% (8%) 36% (5%) >0.05
Alopecia 10% 2% <0.001
Peripheral neuropathy 8% 3% >0.05
Death due to toxicity 2% 4% >0.05
74

ZUCOD
This study taught
us
• Induction chemotherapy with PCF was better tolerated and resulted in
a higher CR rate than CF.
Hitt R. et al, J Clin Oncol. 2005;23(34):8636-45. 75

ZUCOD
Conclusions for Sequential
Chemoradiotherapy
• Sequential chemoradiotherapy is potentially a new option.
• Delivering standard induction chemotherapy followed by the standard
concurrent chemoradiotherapy generates a substantial overall
toxicity..
76

ZUCOD
Induction
Chemotherapy
Concurrent
Chemotherapy
Induction 
Concurrent
Chemotherapy
Palliative
Chemotherapy
77

ZUCODNew active* agents in R/M
Drug Response rates (%)
Edatrexate 6-21%
Pemetrexed 26%
Vinorelbine 6-16%
Irinotecan 21%
Capecitabine 8-24%
Orzel 21%
S-1 27%
Paclitaxel 20-43%
Docetaxel 12-20%
* Activity defined as >15 % responses
78

ZUCOD
Single-agent treatment in R/M
(Randomized trials)
Author (year) No. of patients Drugs randomized Response rate (%) Median OS (months)
Grose (1985) 100 Methotrexate 16% 4.6
Cisplatin 8% 4.1
Hong (1983) 38 Methotrexate 23% 6.1
Cisplatin 29% 6.3
Schomagel (l995) 264 Methotrexate 16% 6.1
Edatrexate 21% 6.1
Vermorken (1999) 95 Methotrexate 16% 6.8
Paclitaxel 3 h (or 24h) 11% (23%) 6.5
Guardiola (2004) 57 Methotrexate 15% 3.9
Docetaxel 27% 3.7
79

ZUCOD
Platinum-based combinations vs. single-
agent chemotherapy (Randomized trials)
Author (year) No. of patients Agents Response rate (%) Median OS (months)
Jacobs (1992) 249 PF 32%* 5.5
P 17% 5.0
F 13% 6.1
Forastiere (1992) 277 PF 32%† 6.6
CF 21% 5.0
M 10% 5.6
Clavel (1994) 382 CABO 34%‡ 8.2
PF 31%§ 6.2
P 15% 5.3
Urba (2012) 795 P + PEM 12.1% 7.3
P + placebo 8% 6.3
P cisplatin, C carboplatin, M methotrexate, B bleomycin, V vincristine, PEM pemetrexed, CABO=P+M + B+V
* p=0.035, † p<0.001, ‡p<0.001, § p=0.003
80

ZUCOD
Platinum-Taxanes combinations in R/M: two
vs. three drugs (Randomized trials)
Paclitaxel Docetaxel
ORR CR ORR CR
Two drugs
Cisplatin 32-39% 0% 33-52% 9-11%
Carboplatin 33-33% 4-8% 25% NR
Three drugs
Cisplatin/5-FU 31-38% 13% 44% 12%
Cisplatin/Ifosfamide 58% 17% ----- -----
Carboplatin/Ifosfamide 59% 17% ----- -----
NR not reported
81

ZUCOD
Second-line treatment in R/M
(Randomized trials)
Author (year) Drug
Prior chemotherapy
for R/M-SCCHN
Median PFS (months) Median OS (months)
Pivot (2001) MTX 62% 1.5 3.7
Stewart (2009) MTX Unclear N/A 6.7
Machiels (2011) BSC (MTX)a 83% (17%)b 1.9 5.2
Numico (2002) Docetaxel 61% 4.0 (TTP) 6.0
Zenda (2007) Docetaxel Unclear 1.7 4.6
Specenier (2011) Docetaxel 77% 1.7 4.1
Argiris (2013) Docetaxel Unclear 2.1 (TTP) 6.0
MTX methotrexate, BSC best supportive care, PFS progression-free survival,
N/A not assessable, TTP time to progression, OS overall survival.
a 78 % of the patients received MTX.
b 17 % of the patients relapsed <6 months after Chemoradiation.
82

Agenda
Introduction
Chemotherapy
Targeted Therapy
ZUCOD
83

ZUCODPossible Molecular Targets
84

ZUCODEGFR Pathway
85

ZUCOD
EGFR-targeting agents under
clinical investigation
Toxicity
Monoclonal antibodies
Cetuximab Chimeric human-murine IgG1 Skin
Matuzumab Humanized mouse IgG1 Skin
Nimotuzumab Humanized mouse IgG1 Systemic/hemodynamic
Zalutumumab Human IgG1 Skin
Panitumumab Human IgG2 Skin
Tyrosine kinase inhibitors
Gefitinib Reversible EGFR Skin/gastrointestinal (GI)
Erlotinib Reversible EGFR Skin/Gl
Reversible EGFR/ERbB2 Skin/GI/systemic/hepatic
Lapatinib Reversible EGFR/ERbB2 Skin/GI/systemic
Afatinib Irreversible Pan Her (EGFR/Her2/Her4) Skin/GI/systemic
Dacomitinib Irreversible Pan Her (EGFR/Her2/Her4) Skin/oral/G I/systemic
86

ZUCOD
First-line treatment with EGFR
inhibitors (Randomized trials)
Study, author (year) N Regimen Response rate (%) Median PFS (months) Median OS (months)
ECOG 5397 117 P+ Cetuximab 26%* 4.2 9.2
Burtness (2005) P + placebo 10% 2.7 8.0
EXTREME 442 PF1 + Cetuximab 36%* 5.6* 10.1*
Vermorken (2008) PF1 20% 3.3 7.4
SPECTRUM 657 PF2 + panitumumab 36%* 5.8* 11.1
Vermorken (2013) PF2 25% 4.6 9.0
P cisplatin, PF' cisplatin or carboplatin plus 5-fluorouracil, PF2 cisplatin plus 5-fluorouracil, *significant differences, PFS
progression-free survival, OS overall survival
87

ZUCOD
Second line treatment with
EGFR inhibitors (Randomized
trials)
Study, author (year) N Regimen Response rate (%) Median PFS (months) Median OS (months)
IMEX 486 Gefitinib (250 mg) 2.7% ND 5.6
Stewart (2009) Gefitinib (500 mg) 7.6% ND 6.0
MTX 3.9% ND 6.7
ECOG 1302 270 D + Gefitinib 12.5% 3.5 (TTP) 7.3
Argiris (2013) D + placebo 6.2% 2.1 (TTP) 6.0
ZALUTE 286 Z + BSC 6.3% 2.3* 6.7
Machiels (2011) BSC (optional MTX) 1.1% 1.9 5.2
LUX-Head & Neck 1 483 Afatinib 10.2% 2.6* 6.8
Machiels (2015) MTX 5.6% 1.7 6.0
MTX methotrexate, D docetaxel, Z zalutumumab, BSC best supportive care, PFS progression-free survival, ND no data, TTP
time to progression, *significant differences, OS overall survival
88

Agenda
Introduction
Chemotherapy
Targeted Therapy
Immunotherapy
ZUCOD
89

ZUCOD
SCC of Larynx is an
Immunosuppressive Tumor
Freiser ME, et al. Immunol Res. 2013; 57:52-69.
Kang H, et al. Nat Rev Clin Oncol. 2015; 12:11-26.
Immune modulation occurs on multiple levels within the SCC
microenvironment a, b
CD8+ cells: reduced counts; display defects such as low
responsiveness to cytokines and reduced proliferative
ability.
CD+4 cells: Th2 phenotype favored.
TAMs: secrete immunosuppressive molecules, impair CD8+
cells, promote Tregs production.
Soluble factors: cytokine profile includes
immunosuppressive molecules such as TGF-B, VEGF, IL-6
and IL-10, as well as apoptosis-promoting factors that
induce T-cell death.
Tregs: secrete immunosuppressive molecules and induce T-
cell and DC dysfunction.
NK cells: activity is impaired
DC: tumors prevent maturation of DCs, promoting T-cell
dysfunction and promoting Treg production. 90

ZUCODTumor and Immune
Biomarkers
Blank CU, et al. Science. 2016; 352:658-
Biomarkers are being evaluated to predict better outcome to Immuno-oncology
therapy.
Tumor Antigens
• Biomarkers indicative of
hypermutaion and neoantigens may
predict response to IO treatment.
Examples:
-TMB, MSI-high, neoantigens
Tumor Immune Suppression
• Biomarkers that identify tumor
immune system evasion beyond PD-
1/CTLA-4 to inform new IO targets
and rational combinations
Examples:
-Treg, MDSCs, LAG-3
Inflamed Tumor Microenvironment
• Biomarkers (intratumoral or
peritumoral) indicative of an inflamed
phenotype may predict response to
IO treatment.
Examples:
-PD-L1, inflammatory signatures.
Host Environment
• Biomarkers that characterize the
host environment, beyond tumor
microenvironment, mar predict
response to IO treatment.
Examples:
-Microbiome, germline genetics.
91

ZUCODRelevance of Immunotherapies
a. Cooper JS, et al, N Engl J Med 2004; 350:1937–1944, b. Bernier J et al, N Engl J Med 2004; 350:1945–1952, c. Vermorken JB, et al. Ann Oncol.
Unmet medical need for effective systemic therapy.
• In postoperative setting, adding cisplatin to radiation improve disease
control(a) and improve survival by ~10% compared with radiation alone (b).
• In metastatic/recurrent disease, systemic therapy achieve median survival
of <11 mon(C).
• Second-line therapy in fit patients is associated with median survival of <6
mon(C).
• Targeted therapy has been limited by high prevalence of tumor suppressor
mutations.
• Agents that are active in the face of cisplatin-resistance or TS mutation are 92

Existing therapies are highly morbid
• Cisplatin induced renal injury, ototoxicity, and increased risk for non-cancer
mortality.
• Chronic sequelae of radiation include hypothyroidism, swallowing dysfunction,
chronic pain, xerostomia, soft tissue necrosis and osteonecrosis.
• Extensive surgery can be associated with neck and shoulder dysfunction,
pain, dysphagia and feeding tube dependence, risk for postoperative infection
and bleeding and graft failure.
• Psychological sequelae include PTSD-like syndrome, lower likelihood of
returning to work.
93

Have hallmarks of immune tolerance
• Inflamed phenotype with tumor infiltrating lymphocytes and transcription of
interferon response genes.
• Expression of PD-L1 and PD-L2.
• High mutational load.
• Viral antigens in HPV and EBV-driven cancer.
• Neoantigens predicted by mutational profile.
94

ZUCODAnti-PDL-1 and Anti-PD-1
95

Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
• Response assessment: every 8 weeks.
• Primary endpoints: ORR (RECIST v1.1, central imaging vendor),
safety.
• Secondary endpoints: ORR (investigator), PFS, OS, response
duration, ORR in patients who are HPV+‡.† Treatment beyond progression was
allowed.
‡ Initial cohort only.
Study Design
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
Pembrolizumab
200 mg q3w
N = 132
Patients
• R/M HNSCC
• Measurable disease
(RECIST v1.1)
• ECOG PS 0-1
• PD-L+ (initial cohort)
• PD-L1+ or PD-L–
(expansion cohort)
Initial Cohort
Pembrolizumab
10 mg/kg q2w
N = 60
Expansion Cohort
Continue untill:
• 24 month of
treatment†
• PD
• Intolerable toxicity
Combined
analyses of
initial and
expansion
cohorts
ZUCOD
Laura Q.M. Chow, MD
96

Keynote-012 Trial:
Neck Carcinoma
Characteristics All patients (n = 132)
Age, median (range), years 60 (25-84)
Male 110 (83%)
Race
White 95 (72%)
Asian 29 (22%)
Other 8 (6%)
ECOG performance status
0 38 (29%)
1 94 (71%)
Smoking
Smoked 81 (61%)
Sum of target lesions at baseline,
median (range), mm
99 (16-664)
Characteristics All patients (n = 132)
Primary location
Oropharynx 60 (49%)
Oral cavity 17 (13%)
Larynx 16 (12%)
Hypopharynx 12 (9%)
Nasal cavity 8 (6%)
Nasopharynx 5 (4%)
Previous Adj &/or NAT 53 (40%)
No. of previous lines
0 24 (18%)
1 33 (25%)
2 27 (21%)
3 20 (15%)
≥4 28 (21%)
ZUCOD
97

Keynote-012 Trial:
Neck Carcinoma
Characteristics
All patients (n = 132)
No. (%) 95% CI
ORR 24 (18%) 12% to 26%
Best overall response
CR 4 (3%) 1% to 8%
PR 20 (15%) 10% to 22%
SD 26 (20%) 13% to 28%
Non-CR/Non-PD 1 (1%) 0% to 4%
PD 61 (46%) 38% to 55%
NA 18 (14%) 8% to 21%
NE 2 (2%) 0.2% to 5%
Response Rate
ZUCOD
Treatment exposure & Response
Duration
98

ZUCOD
Keynote-012 Trial:
Neck Carcinoma
Maximum percentage change from baseline in target lesions
99

Keynote-012 Trial:
Neck Carcinoma
Progression Free Survival
(PFS)
Overall Survival
(OS)
ZUCOD
Median PFS 2 months Median OS 8 months
100

Keynote-012 Trial:
Neck Carcinoma
Association of efficacy and programmed death-ligand 1 (PD-L1)
expression
ZUCOD
PD-L1 Status Tumor and Immune Cells Tumor Cells Only
Nonresponders
No.
Responders,
No.
Response, %
(95% CI)
Nonresponders,
No.
Responders,
No.
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)
101

Keynote-012 Trial:
Neck Carcinoma
PFS by PDL-1 expression
ZUCOD
OS by PDL-1 expression
102

FDA Approval of Pembrolizumab
in R/M Head and Neck Carcinoma ZUCOD
• On August 5, 2016, U.S. Food and Drug Administration granted accelerated
approval to Pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme
Corp., Kenilworth, NJ)
• For treatment of patients with recurrent or metastatic head and neck
squamous cell carcinoma (HNSCC) with disease progression on or after
platinum‐containing chemotherapy.
• Approval was based on the objective response rate (ORR) and duration of
response (DoR) in a cohort of patients in a nonrandomized multi‐cohort trial
(KEYNOTE‐012) that included 174 patients. 103

CheckMate 141 Trial: Nivolumab
in R/M Head and Neck Carcinoma
Ferris RL, et al. N Engl J Med. 2016;375:1856-1867.
Study Design
ZUCOD
361 patients
• R/M HNSCC of oral cavity,
pharynx, or larynx
• Not amenable to curative
therapy
• Progression on or within 6
mon of last dose of platinum-
based therapy.
• ECOG PS 0-1
• Documentation of p16 to
determine HPV status.
• No active CNS metastasis.
R
2:1
Nivolumab
3 mg/kg IV q2w
Investigator’s Choice
• Methotrexate 40mg/m2
IV weekly
• Docetaxel 30 mg/m2 IV
weekly
• Cetuximab 400 mg/m2
IV once, then 250
mg/m2 weekly
Primary endpoint:-
• OS.
Secondary
endpoint:-
• PFS.
• ORR.
• Safety.
• DoR.
• Biomarkers.
• QoL.
Stratify by previous Cetuximab.
104

Characteristics
Nivolumab
(n = 240)
Investigator
choice (n=121)
ECOG PS
0 49 20.4% 23 19%
1 189 78.8% 94 77.7%
≥2 1 0.4% 3 2.5%
Not reported 1 0.4% 1 0.8%
Prior lines
1 105 43.8% 58 47.9%
2 81 33.8% 45 37.2%
≥3 54 22.5% 18 14.9%
Smoking
Current 191 79.6% 85 70.2%
Never 39 16.3% 31 25.6%
ZUCOD
Characteristics
Nivolumab
(n = 240)
Investigator
choice (n=121)
Site of primary
Larynx 43 14.2% 15 12.4%
Oral cavity 108 45% 67 55.4%
Pharynx 92 38.3% 36 29.8%
Other 6 2.5% 3 2.5%
Context
Adjuvant 37 15.4% 21 17.4%
Neoadjuvant 17 7.1% 16 13.2%
Primary 173 72.1% 83 68.6%
Metastatic 112 46.7% 59 48.8%
Cetuximab
Exposed 150 62.5% 72 59.5%
105

ZUCOD
106

FDA Approval of Nivolumab in
R/M Head and Neck Carcinoma ZUCOD
• On November 10, 2016, U. S. Food and Drug Administration approved Nivolumab
(OPDIVO Injection, Bristol-Myers Squibb Company)
• For the treatment of patients with recurrent or metastatic squamous cell carcinoma
of head and neck (SCCHN) with disease progression on or after a platinum-based
therapy.
• Approval was based on statistically significant and clinically meaningful improvement
in overall survival (OS) in international, multi-center, open-label, randomized trial
(CheckMate 141) that included 361patients.
107

Treatment Beyond
Progression:
CheckMate 141
ZUCOD
108

Treatment Beyond
Progression:
CheckMate 141
ZUCOD
109

TAIC PD-L1 Evaluation:
CheckMate 141 ZUCOD
110

OS by Tumor PD-L1 Expression and
PD-L1-Positive TAIC Abundance ZUCOD
111

OS by Tumor PD-L1 Expression and
PD-L1-Positive TAIC Location ZUCOD
112

Keynote-048: Pembrolizumab in 1st
line treatment ZUCOD
113

EAGLE: Efficacy & Safety of
Durvalumab +/-Tremelimumab vs SOC
in 2nd line
ZUCOD
114

KESTRL: Efficacy & Safety of
Durvalumab +/-Tremelimumab vs SOC
in 1st line
ZUCOD
115

CheckMate 714: Nivolumab+Ipilimumab
vs Nivolumab+Placebo ZUCOD
116

CheckMate 651: Nivolumab+Ipilimumab
vs EXTREME regimen in 1st line ZUCOD
117

MasterKey232: Talimogene
Laherparepvec +Pembrolizumab ZUCOD
118

Javelin Head and Neck 100: Avelumab
vs SOC (CRT) in treatment of LA-
HNSCC
ZUCOD
119

Agenda
Introduction
Chemotherapy
Targeted Therapy
Immunotherapy
Home message
ZUCOD
120

ZUCOD
Not one size fit
allTailoring management strategy according to risk of disease
recurrence, impact of disease on overall survival, and impact
of management on quality of life of your patient.
Take Home Message
121

‫عهد‬
‫جديد‬
‫فكر‬
‫جديد‬
Thank you
ZU
Creativity
Distinction
Labor
New
era
New
Thought
‫لسيادتك‬ ‫شكرا‬‫م‬
122

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