head and neck cancer -...

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


+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


0 1 2 3 4 5 6 7 8 9 10 11 12

Su

rviv

al(%

)

Absolute difference


+6.5% [+4.6 ; +8.4]

44.9

27.0

17.1

51.8

33.5

20.5

Absolute difference


+3.4% [+1.6 ; +5.2]

LRT+CTLRT

Su

rviv

al (%

)

0

20

40

60

80

100


0 1 2 3 4 5 6 7 8 9 10 11 12

Absolute difference


+1.8% [-0.7 ; +4.3]

33.4

31.619.8

18.9

50.8

50.1

Absolute difference


+0.9% [-2.3 ; +4.1]

Concomitant chemotherapy gives the higher benefit


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


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


Organ preservation for locally advanced disease





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


T4 or N3 = stage III

T3 or N2 = stage II

• 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



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



Key messages

• Elective neck dissection

• New TNM classification



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


Organe preservation for locally advanced disease




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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|

|

|

||

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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

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24

|| |

||

| |

|||| || ||| || ||

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|

|

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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



(Phase 1b)

Unselected for PD-L1 132 Overall: 18%

HPV- : 14%

HPV+: 32%

PD-L1 +: 22%

8 months



(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


Organe preservation for locally advanced disease




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

[email protected]

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