Dr Ricard Mesía
Institut Català d’Oncologia - Badalona
MESA VIII: CÁNCER DE CABEZA Y CUELLO
“La inmunoterapia: cambio de paradigma en primera línea de cáncer de cabeza y cuello”.
R/M treatment evolution in SCCHN.
The 80sThe 70s The 90s 2 Last decadeThe 2000sMonoCT:Bleomicine CisplatinMethotrexateFUVincasMTX
PoliCT:PF vs PTTaxol Taxotere PoliCT+Cetuximab:
EXTREMEERBITAX
Checkmate 141
Keynote 040
2016 2017 2018
Keynote 048
Immunotherapy ageTarget ageChemotherapy ageOnly locally age
2019
Eagle
A new paradigm
20 años 20 años 10 años
CheckMate 141: Platino refractarios
R2:1
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
Key eligibility criteria
• R/M HNSCC of the oral cavity, pharynx,
or larynx
• Progression on or within 6 months of
last dose of platinum-based therapy
• Irrespective of no. of prior lines of
therapy
• Documentation of p16 to determine
HPV status (oropharyngeal)
• Regardless of PD-L1 statusa
Stratification factor
• Prior cetuximab treatment
Ferris RL, et al. N Engl J Med 2016;375:1856–1867.
Median OS, mo (95% CI)
HR(97.73% CI)
p-value
7.5 (5.5, 9.1) 0.70 (0.51, 0.96)
0.01015.1 (4.0, 6.0)
Nivolumab in 1st line R/M
4
CONSIDERATIONS to 1st line:
We don’t treat these patients with monoCT
No data according to PDL1
We don’t know important information:
- Progression to radical treatment vsrecurrence <6m.- Speed of progression: Symptoms, Risk of fast PROG
After CheckMate 141 – How do the clinical practice guidelines vary?
R/M1 disease: 1st line: EXTREME vs Nivolumab
Progression to CDDP <3 months ............................. 1st line nivolumab?
Especially bad prognosis
ERBITAX, carbo-taxol (first 3 months)
Progression to CDDP > 3m <6 months ............................. 1st line nivolumab?
- Try EXTREME-Carboplatin? (last 3 months)
NIVOLUMAB INDICATION: A greater number of deaths have been observed during the first 3 months in the nivolumab group compared to that of DOCETAXEL.Factors associated with early death: functional status (ECOG> 0), fast progression to previous Platinum treatment, and high tumor burden.
Patientselection
Avoid hyperprogression / fast progression !!!!
Immunoterapia en HNSCC - Platino refractariaKEYNOTE-040– Fase 3: Pembrolizumab vs Eleccion Investigador
Cohen EZ et al. Lancet 2019. 2019 12;393:156-167
KEYNOTE-040
Cohen E et al. Lancet 2019. 2019 12;393:156-167
Burtness B, Lancet 2019
OS, P vs E,
• ESMO-18
Events HR (95% CI) P
Pembro alone 62% 0.61 (0.45-0.83) 0.0007
EXTREME 78%
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
12-mo rate
56.9%
44.9%24-mo rate
38.3%
22.1%
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 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
126 102 77 60 50 44 36 21 4 0 0
110 91 60 40 26 19 11 4 1 0 0
Median (95% CI)
14.7 mo (10.3-19.3)
11.0 mo (9.2-13.0)
OS, P+C vs E,
ASCO-19
Events HR (95% CI) P
Pembro + Chemo 67% 0.60 (0.45-0.82)
0.0004a
EXTREME 89%
12-mo rate
57.1%
46.1%
24-mo rate
35.4%
19.4%36-mo rate
33.2%
8.0%
Great!!l
36 m rate:CT alone
6.9% EXTREME:
8%
Argiris A Cancer 2004Vermorken JASCO 2014
Burtness B, Lancet 2019
CPS >20 population
Median (95% CI)
14.9 mo (11.6-21.5)
10.7 mo (8.8-12.8)
Pembro mono* (n=133)EXTREME (n=122)
Median OS, months 14.9 (11.6–21.5)10.7 (8.8–12.8)
Pembro mono* (n=257)
EXTREME (n=255)
Median OS, months (95% CI)
12.3 (10.8–14.9)
10.3 (9.0–11.5)
CPS ≥20
00
10
20
30
40
50
60
70
80
90
100
Percen
t su
rviv
al
(%
)
5 10 15 20 25 30 35 40
Months
133 106 85 65 47 24 11 2 0122 100 64 42 22 12 5 0 0
No. at risk
12-month rate56.9%44.9%
24-month rate38.3%22.1%
p=0.0007
Total events62%
78%
12-month rate51.0%43.6%
24-month rate30.2%18.6%
Percen
t su
rviv
al
(%
)
00
5 10 15 20 25 30 35 40
Months
257 196 152 110 74 34 17 2 0
10
20
30
40
50
60
70
80
90
No. at risk
100
255 207 131 89 47 21 9 1 0
CPS ≥1
p=0.0086
Total events69%
81%
HR: 0.61 (0.45-0.83)HR: 0.78 (0.64-0.96)
What is the incluence of CPS>20 in CPS 1-19?
Burtness B, Lancet 2019
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 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
242 197 144 109 84 70 52 29 5 0 0
235 191 122 83 54 35 17 5 1 0 0
OS, P+C vs E, CPS ≥1 Population
Median (95% CI)
13.6 mo (10.7-15.5)
10.4 mo (9.1-11.7)
12-mo rate
55.0%
43.5% 24-mo rate
30.8%
16.8%36-mo rate
25.6%
6.5%
Events HR (95% CI) P
Pembro + Chemo 73% 0.65 (0.53-0.80)
<0.0001a
EXTREME 91%
ASCO-19
How influence CPS >20
Burtness B, Lancet 2019
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
PF
S,
%
N o . a t R is k
1 2 6 6 5 3 7 2 5 8
1 1 0 5 3 1 5 6 2
1 4
4
0
0
3
0
0
0
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
PF
S,
%
N o . a t R is k
2 4 2 1 1 7 5 4 3 6 1 1
2 3 5 1 0 9 3 2 1 6 5
2 1
1 1
0
0
3
1
0
0
PFS, P+C vs E, Events HR (95% CI)
P + C 81% 0.73a
(0.55–0.97)
E 92%
CPS ≥20 CPS ≥1
Median (95% CI)
5.8 mo (4.7-7.6)
5.2 mo (4.8-6.2)
12-mo rate
23.5%
10.8%
24-mo rate
14.7%
3.3%
Events
HR (95% CI)
P + C
85% 0.82b
(0.67–1.00)
E 92%
Median (95% CI)
5.0 mo (4.7-6.2)
5.0 mo (4.8-5.8)
12-mo rate
19.2%
10.7%24-mo rate
11.1%
4.0%
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
PF
S,
%
N o . a t R is k
1 3 3 4 5 3 2 2 8 8
1 2 2 5 8 1 8 8 3
1 7
6
0
0
6
1
1
0
Events HR (95% CI) P
Pembro 86% 0.99 (0.75-1.29)
0.5
EXTREME 91%
Median (95% CI)
3.4 mo (3.2-3.8)
5.0 mo (4.8-6.2)
12-mo rate
22.9%
12.4%
24-mo rate
14.9%
4.8%
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
PF
S,
%
N o . a t R is k
2 5 7 8 0 5 4 4 3 9
2 5 5 1 1 9 3 7 2 0 8
2 3
1 5
0
0
7
4
1
0
Events HR (95% CI)
Pembro 88% 1.16 (0.96-1.39)
EXTREME 91%
Median (95% CI)
3.2 mo (2.2-3.4)
5.0 mo (4.8-5.8)
12-mo rate
19.6%
11.9%
24-mo rate
11.2%
5.4%
PFS, P vs E,
• ESMO-18
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 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
On
go
ing
Re
sp
on
se
, %
N o . a t r is k
88 56 28 21 19 13 7 2 0 0 0
84 31 9 7 5 5 4 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 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
On
go
ing
Re
sp
on
se
, %
N o . a t r is k
54 37 20 16 15 11 7 2 0 0 0
42 15 4 2 2 2 2 0 0 0 0
Response Summary, P+C vs EConfirmed Response, n (%)
P + CN = 126
EN = 110
ORR 54 (42.9) 42 (38.2)
CR 12 (9.5) 4 (3.6)
PR 42 (33.3) 38 (34.5)
SD 29 (23.0) 38 (34.5)
PD 19 (15.1) 9 (8.2)
Non-CR/non-PDa 4 (3.2) 5 (4.5)
Not evaluable or assessedb 20 (15.9) 16 (14.5)
CPS ≥20 CPS ≥1
Duration of response, median (range)P + C: 7.1 mo (2.1+ to 39.0+)E: 4.2 mo (1.2+ to 31.5+)
Confirmed Response, n (%)
P + CN = 242
EN = 235
ORR 88 (36.4) 84 (35.7)
CR 16 (6.6) 7 (3.0)
PR 72 (29.8) 77 (32.8)
SD 64 (26.4) 77 (32.8)
PD 42 (17.4) 29 (12.3)
Non-CR/non-PDa 11 (4.5) 9 (3.8)
Not evaluable or assessedb 37 (15.3) 36 (15.3)
Duration of response, median (range)P + C: 6.7 mo (1.6+ to 39.0+)E: 4.3 mo (1.2+ to 31.5+)
ASCO-19
What happen?
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 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 94 77 55 29 5 0 0
278 227 147 100 66 45 23 6 1 0 0
OS, P+C vs E, Total Population
• aAt IA2 (data cutoff date: Jun 13, 2018): HR 0.77 (95% CI 0.53–0.93). FA (data cutoff date: Feb 25, 2019).
Events HR (95% CI)
Pembro + Chemo 76% 0.72a
(0.60–0.87)EXTREME 89%
Median (95% CI)
13.0 mo (10.9-14.7)
10.7 mo (9.3-11.7)
12-mo rate
53.0%
43.9%24-mo rate
29.4%
18.8%36-mo rate
22.6%
10.0%
ASCO-19
Which is the influence of CPS>20
Overall Survival in Subgroups: P vs E,
D is e a s e s ta tu s
p 1 6 s ta tu s (o ro p h a ry n x )
0 .6 7 (0 .5 0 -0 .9 0 )
R e g io n o f e n ro llm e n t
E C O G P S
0 .1 10 .5
S u b g r o u pN o . o f D e a th s /
N o . o f P a tie n ts H a z a rd R a t io (9 5 % C I)
P e m b ro A lo n e
B e tte r
E X T R E M E
B e tte r
O ve ra ll 1 7 7 /2 5 5
< 6 5 y rs 1 1 9 /1 6 5 0 .6 8 (0 .4 7 -0 .9 7 )
6 5 y rs 5 8 /9 0 0 .7 0 (0 .4 2 -1 .1 8 )
M a le 1 4 8 /2 1 2 0 .6 3 (0 .4 6 -0 .8 8 )
2 9 /4 3 0 .8 0 (0 .3 8 -1 .7 0 )
0 6 7 /1 1 0 1 .0 1 (0 .6 2 -1 .6 3 )
1 1 1 0 /1 4 5 0 .4 8 (0 .3 2 -0 .7 0 )
N o rth A m e rica 4 0 /6 3 1 .0 4 (0 .5 6 -1 .9 4 )
R e s t o f w o r ld 8 0 /1 0 6 0 .3 8 (0 .2 4 -0 .6 1 )
P o s it iv e 2 7 /5 2 0 .9 8 (0 .4 6 -2 .0 9 )
N e g a tive 1 5 0 /2 0 3 0 .5 7 (0 .4 1 -0 .7 9 )
A g e
S e x
2
5 7 /8 6 0 .8 9 (0 .5 3 -1 .4 9 )
S m o k in g s ta tu s
N e v e r 4 7 /6 4 0 .7 9 (0 .4 4 -1 .4 0 )
C u rre n t 2 5 /3 7 0 .6 1 (0 .2 7 -1 .3 7 )
F o rm e r 1 0 4 /1 5 3 0 .6 4 (0 .4 3 -0 .9 4 )
M e ta s ta tic 1 1 4 /1 6 7 0 .6 5 (0 .4 5 -0 .9 5 )
R e c u rre n t 6 2 /8 4 0 .7 6 (0 .4 6 -1 .2 5 )
F e m a le
E u ro p e
Burtness B. Lancet 2019
D is e a s e s ta tu s
p 1 6 s ta tu s (o ro p h a ry n x )
0 .7 6 (0 .6 2 -0 .9 3 )
R e g io n o f e n ro llm e n t
E C O G P S
0 .1 10 .5
S u b g r o u pN o . o f D e a th s /
N o . o f P a tie n ts H a z a rd R a t io (9 5 % C I)
P e m b ro A lo n e
B e tte r
E X T R E M E
B e tte r
O ve ra ll 3 8 3 /5 1 2
< 6 5 y rs 2 4 9 /3 2 9 0 .7 4 (0 .5 7 -0 .9 5 )
6 5 y rs 1 3 4 /1 8 3 0 .8 1 (0 .5 8 -1 .1 4 )
M a le 3 2 0 /4 2 9 0 .7 4 (0 .5 9 -0 .9 2 )
6 3 /8 3 0 .8 9 (0 .5 4 -1 .4 6 )
0 1 4 2 /2 0 5 0 .9 3 (0 .6 7 -1 .2 9 )
1 2 4 1 /3 0 7 0 .6 9 (0 .5 3 -0 .8 9 )
N o rth A m e rica 8 5 /1 2 2 0 .9 1 (0 .6 0 -1 .4 0 )
R e s t o f w o r ld 1 7 5 /2 2 4 0 .7 3 (0 .5 4 -0 .9 8 )
P o s it iv e 6 8 /1 0 9 0 .7 3 (0 .4 5 -1 .1 7 )
N e g a tive 3 1 5 /4 0 3 0 .7 7 (0 .6 2 -0 .9 6 )
A g e
S e x
2
1 2 3 /1 6 6 0 .7 7 (0 .5 3 -1 .1 0 )
S m o k in g s ta tu s
N e v e r 9 3 /1 2 0 0 .7 1 (0 .4 7 -1 .0 7 )
C u rre n t 5 6 /8 0 0 .6 4 (0 .3 7 -1 .0 8 )
F o rm e r 2 3 2 /3 1 0 0 .8 4 (0 .6 5 -1 .0 9 )
M e ta s ta tic 2 5 7 /3 4 7 0 .6 6 (0 .5 2 -0 .8 5 )
R e c u rre n t 1 2 4 /1 5 9 1 .0 4 (0 .7 3 -1 .4 8 )
F e m a le
E u ro p e
CPS ≥20 Population CPS ≥1 Population
ICHNO-2019
How should patients be treated in the 2nd line?
1st-line
Pembrolizumab + CT*
PD2nd-line and beyond
?
Platinum-based CT has already been received in the 1st line1
There is uncertainty regarding the merit of using ICIs in the 2nd line after use in the 1st line2,3
+
1st-line
EXTREME regimen
PD2nd-line and beyond
ICIs
ICIs are an approved and recommended 2nd-line treatment option available to patients who receive the EXTREME regimen in the 1st line1,4–8
ERBITAX
-Patient-PS-Comorbidities
Tumor-TNM (volume)-Speed growth
PD-L1
ROLE OF BIOMARKERS
CPS
How to select
a patient for 1st line?
Clinically validated BMK Emerging
PDL1 Inflamatorybiomarkers
T-cell inflamedgene expression
proflile (GEP)
High microsatelliteinstability (MSI-H)
1% SCCHN
Tumor antigenicity Tumor mutationalburden (TMB)
HPV p16
Patient-PS-Comorbidities
Tumor-TNM (volume)-Speed growth
PD-L1 (CPS)>2020-1<1
PS 0-1
PDL1 CPS>20
Low tumoral burden
EXTREME2 ERBITAX4
No previous systemic treatment or >6 months for the LA diseaseProgression on or within 6 months of last dose of
platinum-based therapy
High tumoral burden
Pembro1 Pembro + PF1
Any PDL1
NIVOLUMAB3
1. Keynote-048, Burtness et al; 2.EXTREME Vermorken et al; 3. Checkmate 141. Ferris et al; 4. ERBITAX Hitt et al.
1st L
2nd L
EC3rd L
PDL1 CPS >1 y < 20 PDL1 CPS <1
Low tumoral burden
High tumoral burdenLow tumoral
burdenTPEX vs
EXTREME2
NIVOLUMAB3
EXTREME1
ERBITAX3
EXTREME1
ERBITAX3NIVOLUMAB3
HPV???
HOW COULD BE THE TREATMENT FROM NOW?
EXTREME vsTPEX2
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