CIBLES THÉRAPEUTIQUESEN CANCER ORLJean-Pascal Machiels
Department of medical oncology
Institut Roi Albert II
Cliniques universitaires Saint-Luc
Université catholique de Louvain, Brussels, Belgium
I
• Seventh most common malignancy
o 35% > 65 years
o 15% > 75 years
• Risk factors
o Alcohol & tobacco(oral cavity, larynx and pharynx)
o Human Papillomavirus (HPV+) (oropharynx)
Squamous cell carcinoma of the head and neck
• Standard of care
• Data in elderly
• 80-90 % cure rate in early stage (stage I/II)
o Surgery
oRadiation
• 50% cure rate in locally advanced stage (stage III/IV) with multimodal treatment
o Surgery followed by chemo(radiation)
oChemoradiation
• Recurrent/metastatic SCCHN (median survival: 10-15 months)
oCisplatin + 5FU + Cetuximab
oAnti-PD1 compounds: pembrolizumab or nivolumab
Squamous cell carcinoma of the head and neck
Inactivated in 90%
Mutated
in 70%
HPV negative
Leemans R et al, Nature Reviews 2011
HPV positive
Leemans R et al, Nature Reviews 2011
HER family• EGFR amplification/mutation in
15%• ERBB2 amplification/mutation
in 5%
FGFR pathway• FGFR1 amplification in 10%
HPV neg disease• FGFR3 mutations in up to
10% HPV pos disease
PI3K pathway• PIK3CA mutation/amplification in
up to 56% HPV positive SCCHN• PTEN loss in up to 12%
Cell cycle alteration• CCND1 amplification in 30%
DNA repair mechanism• Deficit in homologuous
recombination
Actionable genomic alterations
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
Platin/5-FU vs platin/5-FU plus cetuximab
Vermorken et al, NEJM, 2008
Platin/5-FU vs platin/5-FU plus cetuximab
Vermorken et al, NEJM, 2008
R
1:1:1
• FIRST-LINE R/M disease incurable by local therapies
Pembrolizumab
Pembrolizumab +Carboplatin or Cisplatin + 5-FU
Cetuximab +Carboplatin or
Cisplatin + 5-FU
N=882
Phase 3 Keynote 048
Burtness et al, ESMO 2018
HR (95% CI) P
Pembro alone 0.61 (0.45-0.83) 0.0007
EXTREME
Median (95% CI)
14.9 mo (11.6-21.5)
10.7 mo (8.8-12.8)
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
M o n th s
OS
, %
N o . a t R is k
133 106 85 65 24
122 100 64 42 12
47
22
0
0
11
5
2
0
Pembrolizumab improves OS in PD-L1 expressing tumors
Burtness et al, ESMO 2018
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
M o n th s
OS
, %
N o . a t R is k
281 227 169 122 40
278 227 147 100 20
75
51
0
0
10
5
1
1
HR (95% CI) P
Pembro + Chemo 0.77 (0.63-0.93)
0.0034
EXTREME
Median (95% CI)
13.0 mo (10.9-14.7)
10.7 mo (9.3-11.7)
CT + Pembrolizumab improves OS in the whole population
Burtness et al, ESMO 2018
• Standard of care
• Data in elderly
• No treatment guidelines
• Survival rate seems to be lower
Age 5-year suvival rate
< 44 years 56%
65-74 years 38%
> 75 years 34%
Gata et al, Eur J Cancer 2015
Concomitant CT – median follow-up: 9.1 years
HR=0.83 [0.79;0.87], p<0.0001
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]
Concomitant chemoradiation in locally-advanced disease
Bourhis et al, ESMO 2016
AgeInteraction: p=0.14
Trend: p=0.06
Performance StatusInteraction: p=0.55
Trend: p=0.07
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]
Bourhis et al, ESMO 2016
Sub-group analyses
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
Bonner et al, Lancet Oncology 2010
Radiotherapy +/- cetuximab
Bonner et al, Lancet Oncology 2010
Subgroups ORR Median suvival (days)
All patients 13% 178
< 65 years 13% 174
> 65 years 13% 193.5
Vermorken et al, J Clin oncol 2007
Single-agent cetuximab in recurrent/metastatic disease
Safety was not analyzed
Cetuximab + chemotherapy in recurrent/metastatic disease
Vermorken et al, N Engl Med 2008
Afatinib versus methotrexate in recurrent/metastatic disease
Clement P et al, Ann Oncol 2017
< 65 years > 65 years
• Retrospective trials in 4 French centers
• Eligible patients:
• Patients treated with immune checkpoint inhibitors
• Recurrent/metastatic head and neck cancer
• Data available
Immune checkpoint inhibitors in elderly (> 70 years)
Even C et al, ASCO 2019
• N=226
• 67 patients > 70 years
Immune checkpoint inhibitors in elderly (> 70 years)
Even C et al, ASCO 2019
Immune checkpoint inhibitors in elderly (> 70 years)
ORR PFS
>70 years 13% 2.7 months
< 70 years 23% 1.9 months
Even C et al, ASCO 2019
ORR > 70 years: 13% vs 23%
Median OS: 8.7 vs 9.7 months
No significant differences in immune related AEs
< 70 ans 91 décès / 161 ptsOS médiane (mois) 7,7 [5,6-9,5]≥ 70 ans 22 décès / 38 ptsOS médiane (mois) 7,0 [4,7-NR]
Patients < 70 ans
Patients ≥ 70 ans
Etude TOPNIVO
Even et al, ASCO 2019
Courtesy Pr. Guigay
ELAN-ONCOVAL-Geriatric assessment
Mertens et al, ESMO 2017
Courtesy Pr. Guigay
EGE : – Autonomie : ADL (Activity of Daily Living)
– Chute et support monopodal
– Cognitif : MMSE (Mini Mental State)
– Humeur : GDS 4 (Geriatric Depression Scale)
– Comorbidités : Charlson
Test G8 EGE
Sensibilité 91 % 95 %
Spécificité 30 % 60 %
FIT 29%UNFIT 71%
Mertens et al, ASCO 2019
GOLD standard: Comprehensive geriatric assessment (Gériatre)
EGE élaboré par le groupe GERICO
ELAN-Geriatric evaluation (N=613)
Courtesy Pr. Guigay
