HEAD AND NECK CANCER - OncologyPRO · HEAD AND NECK CANCER: ... larynx and pharynx) TCGA, Nature...
Transcript of HEAD AND NECK CANCER - OncologyPRO · HEAD AND NECK CANCER: ... larynx and pharynx) TCGA, Nature...
HEAD AND NECK CANCER: STATE OF THE ART
Jean-Pascal Machiels
Department of medical oncology
Institut Roi Albert II
Cliniques universitaires Saint-Luc
Université catholique de Louvain, Brussels, Belgium
I
DISCLOSURE
Advisory board: Nanobiotix, MSD, Boerhinger-Ingelheim, Debio, Astra-Zeneca
Research grant: Novartis, Bayer, Janssen
Squamous cell carcinoma of the head and neck
The seventh most common form of cancer
600 000 cases per year worldwide
Human Papillomavirus (HPV+)
(oropharynx)
Alcohol & tabacco(oral cavity, larynx and pharynx)
TCGA, Nature 2015
Genetic alterations in squamous cell carcinoma
RTOG 0129 TROG 02.02
0102030405060708090
100
% sur
vivi
ng
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0Years from RT
p16 posp16 neg
HR = 0.36, P = 0.0042-y OS: 74% & 91%
.125.25.5 1 2 4Hazard ratio 95% CI
Overall survival by HPV status
Ang KK NEJM 2015Rischin JCO 2010
RTOG 0129 TROG 02.02
0102030405060708090
100
% sur
vivi
ng
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0Years from RT
p16 posp16 neg
HR = 0.36, P = 0.0042-y OS: 74% & 91%
.125.25.5 1 2 4Hazard ratio 95% CI
Overall survival by HPV status
• p16 is a good surrogate marker of HPV infection in oropharyngeal cancer
• Diagnosis and prognosis value of p16 outside the oropharynx is controversial
Different curative treatments depending on disease stage and location
Stage 1-2: - One single treatment modality: surgery or radiotherapy
Stage 3-4: - Multimodal treatment including surgery and/or (chemo)radiation
One third will present recurrent or metastatic disease
Squamous cell carcinoma of the head and neck
Treatment of locally advanced disease (stage 3-4)
Chemoradiation followed by neck dissection in case of suspected residual disease in the regional lymph node
Surgery followed by radiation therapy or chemoradiation(preferred approach for oral cavity)
Cooper et al. NEJM 2004Bernier et al, NEJM 2004
RTOG EORTC
Post-operative chemoradiation
Cooper et al. NEJM 2004Bernier et al, NEJM 2004
RTOG EORTC
Post-operative chemoradiation
Indications to add chemotherapy (high dose cisplatin) to RT post-operatively:
- Positive margins
- Extracapsular spread extension (lymph node)
Presentation outline
Organ preservation for locally advanced disease
Primary tumor site: specific considerations
Recurrent and/or metastatic disease
How to improve outcome
Treatment of locally advanced disease
The role of chemotherapy
The role of anti-EGFR monoclonal antibodies
esmo.org
META-ANALYSIS OF CHEMOTHERAPY IN HEAD AND NECK
CANCER (MACH-NC): AN UPDATE ON 100 RANDOMIZED
TRIALS AND 19,248 PATIENTS
Pierre Blanchard, Cécile Landais, Claire Petit, Qiang Zhang, Vincent Gregoire, Jeffrey Tobias, Barbara Burtness,
Maria Grazia Ghi, François Janot, Jens Overgaard, Gregory Wolf, Freddi Lewin, Ricardo Hitt, Renzo Corvo, Volker
Budach, Andrea Trotty, Catherine Fortpied, Allan Hackshaw, Jean Bourhis, Jean-Pierre Pignon
on behalf of the MACH-NC Collaborative Group
Meta-Analysis of Chemotherapy in Head & Neck Cancer
MACH-NC
20,092 patients and 13,904 deaths (69%)
LRT+CT
LRT
0
20
40
60
80
100
Time from randomisation (years)
0 1 2 3 4 5 6 7 8 9 10 11 12
Su
rviv
al(%
)
Absolute difference
at 5 years [95% CI]:
+4.2% [+2.8 ; +5.6]
49.6
31.5
19.7
21.9
35.7
53.6Absolute difference
at 10 years [95% CI]:
+2.2% [+0.7 ; +3.7]
Radiotherapy versus radiotherapy + chemotherapy
Bourhis J et al. ESMO 2016
Concomitant CT – median follow-up: 9.1 years
HR=0.83 [0.79;0.87], p<0.0001
Induction CT – median follow-up: 5.7 years
HR=0.97 [0.91;1.03], p=0.30
LRT+CTLRT
0
20
40
60
80
100
Time from randomisation (years)
0 1 2 3 4 5 6 7 8 9 10 11 12
Su
rviv
al(%
)
Absolute difference
at 5 years [95% CI]:
+6.5% [+4.6 ; +8.4]
44.9
27.0
17.1
51.8
33.5
20.5
Absolute difference
at 10 years [95% CI]:
+3.4% [+1.6 ; +5.2]
LRT+CTLRT
Su
rviv
al (%
)
0
20
40
60
80
100
Time from randomisation (years)
0 1 2 3 4 5 6 7 8 9 10 11 12
Absolute difference
at 5 years [95% CI]:
+1.8% [-0.7 ; +4.3]
33.4
31.619.8
18.9
50.8
50.1
Absolute difference
at 10 years [95% CI]:
+0.9% [-2.3 ; +4.1]
Concomitant chemotherapy gives the higher benefit
Bourhis J et al. ESMO 2016
AgeInteraction: p=0.14
Trend: p=0.06
Performance StatusInteraction: p=0.55
Trend: p=0.07
Performed on concomitant and recent trials only (at most 30 trials and 6,591 patients)
0.5 1.5
< 50 0.81 [0.72;0.90]
Age (years) HR [95% CI]
LRT+CT better
|
LRT better
50-59 0.79 [0.71;0.87]
60-69 0.88 [0.79;0.98]
≥ 70 1.00 [0.81;1.23]
0.5 1.5
PS 0 0.83 [0.76;0.91]
Performance
Status HR [95% CI]
LRT+CT better | LRT better
PS 1 0.81 [0.73;0.89]
PS ≥ 2 0.93 [0.73;1.19]
Subgroup analyses: overall survival
Bourhis J et al. ESMO 2016
Poly chemotherapy
No. deaths / No. patients
LRT+CT LRT O-E Variance HR [95% CI]
LRT+CT better | LRT better
5-FU and platin 864/1,234 941/1,230 -96.8 441.3 0.80 [0.73;0.88]
5-FU or platin 407/497 451/551 -27.4 210.1 0.88 [0.77;1.00]
Neither 5-FU nor platin 125/145 138/157 -25.1 59.1 0.65 [0.51;0.84]
Subtotal 1,396/1,876 1,530/1,938 -149.2 710.5 0.81 [0.75;0.87]
Mono chemotherapy
Mono Cisplatin 1,114/1,573 1,137/1,492 -138.6 534.8 0.77 [0.71;0.84]
Mono Other 1,319/1,833 1,351/1,847 -72.6 653.1 0.89 [0.83;0.97]
Subtotal 2,433/3,406 2,488/3,339 -211.2 1,187.9 0.84 [0.79;0.89]
Total 3,829/5,282 4,018/5,277 -360.4 1,898.4 0.83 [0.79;0.87]
p < 0.0001
0.2 2.01.0Test for heterogeneity p = 0.03 ; I² = 64%
Test for interaction p = 0.50
Interaction
p = 0.13
Interaction
p = 0.01
Which chemotherapy should we used (concomitant trials) ?
18
Chemoradiation versus accelerated radiotherapy
Bourhis et al. Lancet Oncology 2012
19
Chemoradiation versus accelerated radiotherapy
Bourhis et al. Lancet Oncology 2012
Key messages• Standard of care = Concomitant chemoradiation
with high dose cisplatin (100 mg/m2)
• Chemotherapy is needed even if « better » radiation is used
Treatment of locally advanced disease
The role of chemotherapy
The role of anti-EGFR monoclonal antibodies
Ang, K. K. et al. Cancer Res 2002;62:7350-7356
Copyright ©2002 American Association for Cancer Research
EGFR expression and prognosis
Ang et al. Cancer Res 2002
Months
Cetuximab + RT
(n=211)
Ove
rall
su
rviv
al (%
)
100
80
60
40
20
0
0 10 20 30 40 50 60 70
RT (n=213)29.3 49.0
Hazard ratio = 0.74 (95% CI: 0.57–0.97)
Log-rank p=0.03
Bonner J, et al. N Engl J Med 2006;354:567–578
Radiotherapy +/- cetuximab: stage 3 and 4
Bonner, Lancet Oncology 2010
Bonner, Lancet Oncology 2010Rosenthal, ASCO 2014
3-y Loco-regional control p16+ oropharynx p16- oropharynx
RT + Cetuximab 87% (HR:0.31) 32% (HR: 0.78)
RT 65% 20%
Benefit of cetuximab may be more pronounced in p16+ patients
Cetuximab improves overall survival
24
Chemoradiation versus chemoradiation plus cetuximab
Ang et al. JCO 2014
Concert 1: chemoradiation vs chemoradiation plus panitumumab
Concert 2: Chemoradiation vs radiotherapy plus panitumumab
Mesia et al, Lancet Oncology 2015Giralt et al , Lancet Oncology 2015
Panitumumab and chemoradiation
Concert 1: chemoradiation vs chemoradiation plus panitumumab
Concert 2: Chemoradiation vs radiotherapy plus panitumumab
Mesia et al, Lancet Oncology 2015Giralt et al , Lancet Oncology 2015
Panitumumab and chemoradiation
2-Y
survival
Chemoradiation RT+ panitumumab
71% 63%
Accelerated Radiation (70 Gy in 6 weeks)
Panitumumab 9 mg/kg one week before RT and on days 15 and 36N=160
Conventional Radiation (70 Gy in 7 weeks)
Cisplatin 100 mg/m2 Day 1, 22, 43N=160
NCIC CTG HN6Stage III/IV
L Siu et al. ASCO 2015
Primary endpoint = PFS
Panitumumab +RT vs chemoradiation
L Siu et al. ASCO 2015
This supports the investigation of treatment de-escalation in
favorable HPV positive by replacing chemotherapy with anti-EGFR
mAbs
CONCERT 2 NCIC trial
p16+ = 20% p16+ = 75%
This supports the investigation of treatment de-escalation in
favorable HPV positive by replacing chemotherapy with anti-EGFR
mAbs
CONCERT 2 NCIC trial
p16+ = 20% p16+ = 75%
Key messages
• Standard of care = Concomitant chemoradiation
• Alternative = Radiotherapy + cetuximab
• Radiotherapy + cetuximab is a candidate to de-
intensification in HPV + oropharynx cancer
• No benefit of adding cetuximab to chemoradiation
Presentation outline
Organ preservation for locally advanced disease
Primary tumor site: specific considerations
Recurrent and/or metastatic disease
How to improve outcome
Primary tumor site: specific considerations
Oropharyngeal cancer
Oral cavity
Larynx preservation
Incidence rates for overall oropharyngeal
cancer, during 1988 to 2004 in Hawaii,
Iowa, and Los Angeles
Oropharyngeal cancer incidence
Anil K, JCO 2011
HPV and head and neck cancer
Ang et al, NEJM 2010
Oropharyngeal cancer: prognosis
≈88% at 5y
≈65% at 5y
≈38% at 5y
Ang et al, NEJM 2010
Oropharyngeal cancer: prognosis
Shao Hui Huang et al. JCO 2015;33:836-845
©2015 by American Society of Clinical Oncology
T4 or N3 disease
Huang et al JCO 2015
HPV positive oropharyngeal cancer: prognosis
38
TNM p16+ oropharyngeal cancer, 8th edition
Lydiatt et al. CA Cancer J Clin 2017
TNM p16 + oropharyngeal cancer, 8th edition
Lydiatt et al. CA Cancer J Clin 2017
T4 or N3 = stage III
T3 or N2 = stage II
Lydiatt et al. CA Cancer J Clin 2017
• De-intensification of systemic therapy
- Cetuximab versus cisplatin (RTOG1016, TROG1201, De-escalate)
• De-intensification of radiation therapy
- Surgery to select for de-intensification of radiation (ECOG331, ADEPT)
- Induction chemotherapy to select for de-intensification of radiation (ECO1308, Quarterback study)
De-intensification in oropharyngeal cancer
• De-intensification of systemic therapy
- Cetuximab versus cisplatin (RTOG1016, TROG1201, De-escalate)
• De-intensification of radiation therapy
- Surgery to select for de-intensification of radiation (ECOG331, ADEPT)
- Induction chemotherapy to select for de-intensification of radiation (ECO1308, Quarterback study)
De-intensification in oropharyngeal cancer
Key messages
• New TNM classification
• De-intensication strategies are explored BUT
are not standard of care today
Primary tumor site: specific considerations
Oropharyngeal cancer
Oral cavity
Larynx preservation
Therapeutic neck dissection
N=298
Elective neck dissection (ipsilateral, level I-III)
N=298cT1-2, cN0Oral cavity
D’Cruz et al. ASCO 2015D’Cruz et al, NEJM 2015
Primary endpoint = Overall survival
Elective versus therapeutic neck dissection in oral cavity
D’Cruz et al. ASCO 2015D’Cruz et al, NEJM 2015
Overall survival Disease-free survival
Elective versus therapeutic neck dissection in oral cavity
Depth of invasion
TNM oral cancer, 8th edition
Lydiatt et al. CA Cancer J Clin 2017
TNM oral cancer, 8th edition
Lydiatt et al. CA Cancer J Clin 2017
TNM oral cancer, 8th edition
Key messages
• Elective neck dissection
• New TNM classification
Primary tumor site: specific considerations
Oropharyngeal cancer
Oral cavity
Larynx preservation
Better Larynx preservation and locoregional controlwith CRT
RTOG larynx preservation study
Forastiere et al. JCO 2013
Similar survivalbetween induction and chemoradiation
RTOG larynx preservation study
Forastiere et al. JCO 2013
TPF improves overall survival(as compared to PF : updated data from 6 randomized trials)Meta-Analysis of Chemotherapy
in Head & Neck Cancer
MACH-NC
TPF
PF
Surv
ival
(%
)
0
20
40
60
80
100
Time from randomisation (Years)
0 1 2 3 4 5 6 7 8
100
78.2
59.5
51.7
4542.4
39.4 37.7 32.7
100
71.6
52.2
44.7
38.835
32.829
26.3
Absolute difference at 5 years ± SD: 7.4 ± 2.59p = 0.0002
Blanchard, Bourhis JCO 2013 Blanchard et al. JCO 2013
Presentation outline
Organe preservation for locally advanced disease
Primary tumor site: specific considerations
Recurrent and/or metastatic disease
How to improve outcome
©2014 by American Society of Clinical Oncology
p16 and recurrent disease
Fakhry et al. JCO 2014
55
Locoregional relapse Distant metastases
Salvage surgery No salvage surgery
p16 and recurrent disease
Fakhry et al. JCO 2014
Recurrent disease: diagnosis
Amenable to curative treatment
- Pathology- HPV
YES
NO
- Surgery: lung nodules- (Re)-Irradiation- Local salvage surgery
-- Symptoms- Disease burden- Comorbidities and PS- Prognosis (HPV)- Patient wishes
Systemic treatment
NO YES
Best supportive careBest supportive care Systemic treatment
- Platin/5-FU/cetuximab- Clinical trial
Monotherapy
PS 0-1 PS 2
R
Platinum-5FU
Platinum-5FU + cetuximab Cetuximab monotherapy6 chemotherapy cycles until PD or toxicity
Primary endpoint: survival
N= 442
EXTREME Trial: first line palliative treatment
Standard-of-care in first-line metastatic/recurrent setting
Platinum/5-FU/cetuximab
Vermorken et al. NEJM 2008
Vermorken JB et al. New Eng J Med, 2008;359:1116-27.
Patients at Risk Survival Time [Months]CTX onlyCET + CTX
220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3
HR (95%CI): 0.797 (0.644, 0.986)
Strat. log-rank test: 0.0362
CTX only
Cetuximab + CTX
Su
rviv
al P
rob
ab
ilit
y
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24
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10.1
mo7.4
mo
Patients at Risk Survival Time [Months]CTX onlyCET + CTX
220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3
HR (95%CI): 0.797 (0.644, 0.986)
Strat. log-rank test: 0.0362
CTX only
Cetuximab + CTX
Su
rviv
al P
rob
ab
ilit
y
0.0
0.1
0.2
0.3
0.4
0.5
0.6
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0.8
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10.1
mo7.4
mo
Platinum/5-FU/cetuximab
Study N Regimens ORR Median PFS Median Survival
Stewart JCO 2009
161
158
167
Methotrexateversus
Gefitinib 250 mg/dayversusGefitinib 500 mg/day
3.9%
2.7%
7.6%
NA 5.6 months
6 months
6.7 months
ArgirisJCO 2009
136
134
Docetaxel + placeboversus
Docetaxel + gefitinib
6.2%
12.5%
NA 6 months
7.3 months
MachielsLancet Oncol2011
95
191
BSC or methotrexateversus
Zalutumumab
1.1%
6.3%
8.4 weeks
9.9 weeks*
5.2 months
6.7 months
* Statistically significant
All trials with anti-EGFR failed in second-line
60Seront and Machiels, ESMO Texbook 2016
Nivolumab 3 mg/kg IV Q2W
Investigator’s Choice
• Methotrexate 40 mg/m² IV
weekly
• Docetaxel 30 mg/m² IV
weekly
• Cetuximab 400 mg/m² IV
once, then 250 mg/m²
weekly
R
2:1
Key Eligibility Criteria• R/M SCCHN of the oral
cavity, pharynx, or larynx
• Progression on or within 6
months of last dose of
platinum-based therapy
• Irrespective of number of
prior lines of therapy
• Documentation of p16 to
determine HPV status
(oropharyngeal cancer only)
• Regardless of PD-L1 status
Stratification factor• Prior cetuximab treatment
Primary endpoint• OS
Other endpoints• PFS
• ORR
• Safety
• DOR
• Biomarkers
• Patient-reported
quality of life
Clinicaltrials.gov NCT02105636
Phase 3 Checkmate 141 study design
0 3 6 9 12 15 18
Median OS, mo
(95% CI)
HR
(97.73% CI)p-value
Nivolumab (n = 240) 7.5 (5.5–9.1) 0.70
(0.51–0.96)0.0101
Investigator’s Choice (n = 121) 5.1 (4.0–6.0)
Months
Nivolumab240 167 109 52 24 7 0
Investigator’sChoice 121 87 42 17 5 1
No. at Risk
0
0
10
20
30
40
50
60
70
80
90
100
Ove
rall
Surv
ival
(% o
f p
atie
nts
)
1-year OS rate (95% CI)36.0% (28.5–43.4)
16.6% (8.6–26.8)
Overall survival
-30
-20
-10
0
10
20
30
9 15 9 15 9 15
MID
MID
Social Contact ProblemsSensory ProblemsPain
Week
P = 0.001P = 0.258P = 0.012 P < 0.001P < 0.001 P = 0.022
Bett
er
Wo
rse
Me
an
Ch
an
ge
Fro
m B
ase
lin
e (
95%
CI)
Nivolumab Investigator's choice
EORTC QLQ-H&N35 symptom burden
Harrington K ESMO 2016
Design Population N ORR % Survival
Nivolumab(Checkmate 141)
Anti-PD-1 Phase III Progressive disease with six
months of platinum therapy
361 7.5 vs 5.1 months
PD-L1+
8.7 vs 4.6 months
Pembrolizumab(Keynote-012)
Anti-PD-1 Single arm
(Phase 1b)
PD-L1 positive 60 Overall: 18%
HPV- : 14%
HPV+: 25%
13 months
Pembrolizumab(Keynote-012)
Anti-PD-1 Single arm
(Phase 1b)
Unselected for PD-L1 132 Overall: 18%
HPV- : 14%
HPV+: 32%
PD-L1 +: 22%
8 months
Pembrolizumab(Keynote-055)
Anti-PD-1 Single arm
(Phase 2)
Unselected for PD-L1, after
progression on platinum and
cetuximab therapy
50 Overall: 18%
Durvalumab(study 1108)
Anti-PD-L1 Single arm Unselected for PD-L1 51 Overall: 12%
PD-L1 +: 25%
Seiwert et al. Lancet Oncol. 2016, Chow et al. J. Clin. Oncol. 2016, Bauml et al. ASCO 2016, Segal ASCO 2015, Gillison, AACR 2016
Targeting the PD-1/PD-L1 pathway
System organ class Event
Durvalumab 10 mg/kg q2w
(N=62)
All grades
n (%)
Grade ≥3†
n (%)
Endocrine Hypothyroidism 2 (3) 0
Gastrointestinal Diarrhoea 5 (8) 0
Investigations Aspartate aminotransferase increased 2 (3) 0
Blood thyroid-stimulating hormone decreased 1 (2) 0
Respiratory Pneumonitis 2 (3) 0
Skin Erythema 3 (5) 0
Pruritus 4 (7) 0
Rash 4 (7) 0
Rash erythematous 2 (3) 1 (2)
Rash generalised 1 (2) 0
Rash maculo-papular 4 (7) 0
Rash pruritic 1 (2) 1 (2)
Selected drug-related AEs of interest
Soulières D et al. Lancet Oncology 2017
Number of patients at risk
79
79
67
68
60
55
54
40
44
30
39
25
26
21
20
14
12
10
7
7
6
4
2
3
Buparlisib
Placebo
Time (months)
100
80
60
40
20
0
Pro
bab
ility
of
ove
rall
surv
ival
(%
) Median OS,
months
Hazard Ratio
(80% CI)*
One-sided
p-value†
Buparlisib (n=79) 10.4 0.72
(0.56–0.92)
(95% CI: 0.49–1.04)
0.041Placebo (n=79) 6.5
12-month OS rate:43% vs 33%
1
3
1
1
0
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Protocol-specified criteria for success were: HR ≤0.77 and posterior probability of (HR <1) >90.0%
BERIL-1: overall survival
Soulières D et al. Lancet Oncology 2017
Number of patients at risk
79
79
67
68
60
55
54
40
44
30
39
25
26
21
20
14
12
10
7
7
6
4
2
3
Buparlisib
Placebo
Time (months)
100
80
60
40
20
0
Pro
bab
ility
of
ove
rall
surv
ival
(%
) Median OS,
months
Hazard Ratio
(80% CI)*
One-sided
p-value†
Buparlisib (n=79) 10.4 0.72
(0.56–0.92)
(95% CI: 0.49–1.04)
0.041Placebo (n=79) 6.5
12-month OS rate:43% vs 33%
1
3
1
1
0
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Protocol-specified criteria for success were: HR ≤0.77 and posterior probability of (HR <1) >90.0%
BERIL-1: overall survival
Key messages
• First-Line: cisplatine/5FU/cetuximab
• Second-line: anti-PD-1/PD-L1 inhibitor
Presentation outline
Organe preservation for locally advanced disease
Primary tumor site: specific considerations
Recurrent and/or metastatic disease
How to improve outcome
Krigsfeld et al. Clin Can Res 2014
Time to move anti-PD-1/PD-L1 in the curative treatment
Chemoradiation versus chemoradiation + anti-PD-1/PD-L1
Chemoradiation versus radiation + anti-PD-1/PD-L1
Adjuvant after surgery or chemoradiation