4. 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
7. Positive Therapeutic Ratio (Gain)
Maximal probability
of tumor control
Minimal
(reasonably acceptable)
frequency of complications
(sequelae of therapy)
Therapeutic Ratio ZUCOD
7
8. 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
12. 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
12
13. ZUCOD
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
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
13
14. ZUCOD
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%
14
15. ZUCOD
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
15
23. 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
24. ZUCODRTOG 68-01
Fazekas JT, Int J Radiat Oncol Biol Phys. 1980 ;6(5):533-
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
25. ZUCOD
This study taught
us• Minimal gain, induction methotrexate should not be used
RTOG 68-01
Fazekas JT, Int J Radiat Oncol Biol Phys. 1980 ;6(5):533-
25
26. ZUCOD
Department of
Veterans Affairs Larynx
trialStudy Design
332 Patients
• Laryngeal carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Stage III or IV.
• Resectable.
Laryngectomy
N = 166
Induction chemotherapy
(Cis+5fu)* x 2 cycles
N = 166
Induction chemotherapy
(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
26
28. ZUCOD
Disease Free
Survival
Department of
Veterans Affairs Larynx
trial
Wolf GT, et al. N Engl J Med. 1991 ;24(24):1685-90.
P = 0.1195
64%
2-year Larynx Preservation Rate = 64%
Overall Survival
68%
P = 0.9846
28
29. ZUCOD
Department of
Veterans Affairs Larynx
trial
Wolf GT, et al. N Engl J Med. 1991 ;24(24):1685-90.
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%)
29
30. ZUCOD
This study taught
us
Department of
Veterans Affairs Larynx
trial
Wolf GT, et al. N Engl J Med. 1991 ;24(24):1685-90.
• 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
31. ZUCODEORTC 24891
Study Design
202 Patients
• Pyriform fossa & AE fold
carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Stage II or IV (Non N2c).
• Resectable.
Total Laryngectomy + partial
pharyngectomy + neck
dissection
N =
Induction chemotherapy
(Cis+5fu)* x 2 cycles
N =
Induction chemotherapy
(Cis+5fu)* x 1 more cycle
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
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000
mg/m2 D1 to D5 (CIV) repeat cycle on days
22 & 43.
Median follow-up of 51 months
Lefebvre JL, et al. J Natl Cancer Inst. 1996
CR
Jean-Louis Lefebvre, MD
31
32. ZUCODEORTC 24891
Lefebvre JL, et al. J Natl Cancer Inst. 1996
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
33. 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.
Lefebvre JL, et al. J Natl Cancer Inst. 1996
33
34. ZUCOD
Study Design
68 Patients
• Laryngeal carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Stage III or IV.
• Resectable.
Laryngectomy
N = 32
Induction chemotherapy
(Cis+5fu)* x 2 cycles
N = 36
Induction chemotherapy
(Cis+5fu)* x 1 more cycle
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
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000
mg/m2 D1 to D5 (CIV) repeat cycle on days
22 & 43.
GETTEC trial
Richard JM, et al. Oral Oncol. 1998;34:224–8
Prematurely closed due to a
poor accrual
> 80% response
Progression
34
35. ZUCOD
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
36. ZUCODTAX323 (EORTC 24971)
Vermorken JB, et al, N Engl J Med 2007; 357:1695–1704.
Study Design
358 Patients
• H & N carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Unresectable.
R
Induction chemotherapy
(PF)* x 4 cycles
N = 177
Induction chemotherapy
(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.
Median follow-up of 51 months
Jan B Vermorken, MD
36
38. ZUCOD
Vermorken JB, et al, N Engl J Med 2007; 357:1695–1704.
Progression Free Survival (PFS)
17% 14% P = 0.007
Overall Survival (OS)
37%
26% P = 0.02
TAX323 (EORTC 24971)
38
39. 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.
TAX323 (EORTC 24971)
Vermorken JB, et al, N Engl J Med 2007; 357:1695–1704.
39
40. ZUCODGORTEC 2000-01 trial
Pointreau Y, et al. J Natl Cancer Inst. 2009; 101(7):498-506
Study Design
213 Patients
• Larynx & Hypopharynx
carcinoma.
• Squamous carcinoma.
• Previously untreated.
• T2-4, N0-3.
• Resectable.
R
Induction chemotherapy
(CF)* x 3 cycles ± 1 more
N = 103
Induction chemotherapy
(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
46. 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
47. ZUCODPros and Cons of Induction
Chemotherapy
• Improve distant control.
• Organ preservation.
• Higher rate of loco-regional failure.
Pros Cons
47
51. ZUCOD
Forastiere AA, etal, N Engl J Med 2003; 349:2091–2098
RTOG 91-11: Larynx Preservation
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
55. ZUCODRTOG 91-11: Larynx Preservation
Trial
Locoregional control Overall Survival
Forastiere AA, etal, J Clin Oncol. 2013 Mar 1;31(7):845-52
55
56. ZUCOD
This study taught
us
• Preservation of the larynx significantly favored concurrent therapy.
• No improvement in overall survival with addition of chemotherapy to
radiotherapy.
RTOG 91-11: Larynx Preservation
Trial
Forastiere AA, etal, N Engl J Med 2003; 349:2091–2098
• Locoregional control significantly favored concurrent therapy.
56
57. ZUCODFrench Trial: Definitive Chemoradiation
Prades JM, et al. Acta Otolaryngol. 2009 ;15:1-6.
Study Design
75 Patients
• Pyriform fossa
carcinoma.
• Squamous carcinoma
• Previously untreated.
• Stage T3 N0-3.
• Resectable.
R
Induction chemotherapy
(Cis+5fu)* x 2 cycles
CR or PR Radiation therapy
(7000 cGy)
SD or PD
Salvage
Laryngectomy
Radiation therapy
(7000 cGy)
+ Chemotherapy (Cis)‡
Radiation therapy
(5000 to 7000 cGy)
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000 mg/m2 D1 to
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
59. 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
Prades JM, et al. Acta Otolaryngol. 2009 ;15:1-6.
• Concurrent Chemo-RT had less distant control than induction strategy.
French Trial: Definitive Chemoradiation
59
60. 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
61. 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
62. 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
• H & N carcinoma.
• Squamous carcinoma.
• 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
68. 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
70. ZUCODTAX324 (Dana Farber trial)
Study Design
494 Patients
• H & N carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Unresectable.
R
Induction chemotherapy
(PF)* x 3 cycles
Induction chemotherapy
(TPF)* x 3 cycles
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000 mg/m2 D1 to
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
71. 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)
Posner MR, et al, N Engl J Med 2007; 357:1705–1715.
71
72. 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)
Posner MR, et al, N Engl J Med 2007; 357:1705–1715.
72
73. ZUCOD
Study Design
382 Patients
• H & N carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Locally advanced
• Resectable & unresectable.
R
Induction chemotherapy
(CF)* x 3 cycles ± 1 more
N = 193
Induction chemotherapy
(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) +
Chemotherapy (Cis)‡
Radiation therapy
(7000 cGy) +
Chemotherapy (Cis)‡
Radiation therapy
(7000 cGy) +
Chemotherapy (Cis)‡
Ricardo Hitt, MD
73
74. ZUCOD
Hitt R. et al, J Clin Oncol. 2005;23(34):8636-45.
Spanish Intergroup Trial
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
Overall Survival (OS)
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
75. ZUCOD
This study taught
us
• Induction chemotherapy with PCF was better tolerated and resulted in
a higher CR rate than CF.
Spanish Intergroup Trial
Hitt R. et al, J Clin Oncol. 2005;23(34):8636-45. 75
76. 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
78. ZUCODNew active* agents in R/M
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
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
79. ZUCOD
Single-agent treatment in R/M
(Randomized trials)
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
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
80. ZUCOD
Platinum-based combinations vs. single-
agent chemotherapy (Randomized trials)
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
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
81. ZUCOD
Platinum-Taxanes combinations in R/M: two
vs. three drugs (Randomized trials)
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
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
82. ZUCOD
Second-line treatment in R/M
(Randomized trials)
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
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
90. 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
91. 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
92. 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
93. ZUCODRelevance of Immunotherapies
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
94. ZUCODRelevance of Immunotherapies
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
96. 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
97. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Baseline Demographics
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
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
98. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
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
99. ZUCOD
Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
Maximum percentage change from baseline in target lesions
99
100. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
Progression Free Survival
(PFS)
Overall Survival
(OS)
ZUCOD
Median PFS 2 months Median OS 8 months
100
101. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
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
102. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
PFS by PDL-1 expression
ZUCOD
OS by PDL-1 expression
102
103. 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
104. 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
106. Overall Survival (OS)
CheckMate 141 Trial: Nivolumab
in R/M Head and Neck Carcinoma
Ferris RL, et al. N Engl J Med. 2016;375:1856-1867.
ZUCOD
Progression Free Survival (PFS)
106
107. 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
121. 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