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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