Hoofd en halstumoren

Systemische therapieën

Alumni 9 oktober 2019

Sylvie Rottey / Medische Oncologie

Lokaal gevorderde ziekte

Concomitant chemoradiation for locally advanced disease= primary chemoradiation

Meta-analysis :

> 10 000 pts5 year survival benefit after 5 years : 8%

To be considered as a standard :cisplatin 100 mg/m² day 1,22,43

Pignon et al. Lancet 2000

WHICH chemo?

Pignon et al. Radiotherapy and Oncology 92 (2009) 4–14

CDDP monotherapy:

11% benefit

Anti-EGFR (“bio-radiotherapy”)

cetuximab + RT: Bonner, NEJM 2006

Chemoradiotherapy : beware of toxicity

Cisplatin weekly or 3-weekly?

Most recommended and first data: 3 weekly 100 mg/m²

Routine practice: CDDP weekly 30-40 mg/m², also in trials

2018 1st RCT comparing weekly 30mg/m² vs 3 weekly 1

1 Noronha V, J Clin Oncol 2018; 36:1064-1072

N=300

Stage III-IV

93%

adjuvant

cis 30mg/m² Q1w + RT

Cis 100 mg/m² Q3w + RT

R

A

N

D

O

M

I

Z

E

Primary endpoint:

Non-inferiority weekly on LRC at

2yr

Secondary: PFS, OS, compliance,

toxicity

2yr LRC 73,1% vs 58,5%

HR 1,76 (1,11-2,79)

Absolute difference 14,6%

Cisplatin weekly or 3-weekly?

Trial failed to demonstrate non-inferiority

Trend towards better PFS and OS for 3-weekly but non-significant

Grade 3-4 toxicity

ASCO&NCCN: 3 weekly as preference (if eligible)

Cumulative dose at least 200mg/m²

Non-eligible: No consensus on other dosing schedules

Noronha V, J Clin Oncol 2018; 36:1064-

1072

3weekly weekly P

mucositis 17,3% 17,4% ,901

Infection 33,6% 19,3% ,019

Deafness 12,8% 4,7% ,016

Hyponatremia 49,7% 22,7% <,001

Febrile neutropenia 4,7% 0,7% ,019

ANY 84,6% 71,6% ,006

Hospitalization 31,1% 13,3% <0,001

Adjuvant/ postop treatment for locally advanced disease

Risk factors for relapse/distant failure 1

Extracapsular extension or soft tissue extension

oral cavity tumor

R1 surgical margins

perineural / lymfovascular invasion

>1 neck nodes. >1 node level

node size >3cm

>6 week interval between surgery and RT

Recurrent tumor

Tumor invasion depth >5mm

T3 or T4 lesion1 Peters, IJROB 1993)

2 Bernier, Head and Neck 2005

Lokaal gerecidiveerde of gemetastaseerde

ziekte

Chemotherapy

Prognostic factors in patients with recurrent or metastatic SCCHN treated with cisplatin-based chemotherapy in two phase III trials (E1393 and E1395)

• 0-2 unfavorable prognostic factors: median OS = one year.

• 3-5 unfavorable prognostic factors: median OS = six months (p < 0.0001)

Prognosis locally recurrent / metastatic disease

Prognostic factors for poor survival in the

multivariate analysis (n=399)

p

Weight loss > 5% 0.0004

ECOG 1 vs 0 0.0016

Well and moderate differentiation 0.028

Primary tumor oral cavity or hypopharynx 0.011

Prior radiation therapy <0.0001

Argiris et al Cancer 2004

Other prognostic factors included:

- comorbidity

- ongoing tobacco and alcohol use

- hypercalcemia

- response to prior treatment

- social support

Colevas AD, JCO, 2006

Prognosis locally recurrent / metastatic disease

Single-agent response rate

Response rate (%)

Cisplatin 14-41%

Carboplatin 20-30%

Oxaliplatin 10%

Methotrexate 8-77%

5-Fluorouracil 15%

Capecitabine 8%

Docetaxel 21-42%

Paclitaxel 13-40%

Chemotherapy for locally recurrent/ metastatic disease

• One trial:

• BSC (n=26) versus bleomycin (n=22) versus cisplatin (n=38) versus cisplatin plus bleomycin (n=30).

• The conclusions were

• cisplatin improved survival compared with BSC by 10 weeks

• cisplatin was better than bleomycin or methotrexate

• cisplatin monotherapy (median survival: 160 days) was at least as effective as the platinum-based combinations.

Randomized trials chemotherapy versus BSC

Campbell JB et al Acta Otolaryngol 1987Morton et al Cancer Chemother Pharmacol.1985

Randomized trials mono vs polychemotherapy

Jacobs et al JCO 2002, Clavel et al Ann Oncol 1994, Forastiere et al JCO 1992

Regimens NORR(%)

Median survival(months)

Cisplatin/5-FU

vs

Cisplatin

vs

5-FU

249 32%

17%

13%

5.5

5

6.1

Cisplatin/methotrexate/

bleomycine/vincristine

vs

Cisplatin/5-FU

vs

Cisplatin

382 34%

31%

15%

8.2

6.2

5.3

• Median survival of patients is 6-8 months

• No strong evidence that chemotherapy prolongs survival

• Polychemotherapy versus monochemotherapy:

- Higher response rate- More toxic- No improvement in survival

• Cisplatin /5-FU

• Cisplatin /paclitaxel

• Methotrexate (40 mg/m2/every week)

Chemotherapy: conclusions

Copyright © American Society of Clinical Oncology

Dannenberg, A. J. et al. J Clin Oncol; 23:254-266 2005

Anti EGFR / MABs

Tumor cell cytoplasmic membrane

Monoclonal

AntibodiesCetuximab

Panitumumab

Zalutumumab

Tyrosine kinase

InhibitorsGefitinib (EGFR)

Erlotinib (EGFR)

Lapatinib (EGFR + HER2)Afatinib, dacomitinib (pan-HER)

Tumor proliferation

EGF receptor

HER1 or EGFR targeting

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

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

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

Vermorken et al, NEJM 2008

Extreme trial

These regimenscan be TOXIC

Study N Regimens Median

PFS

Median

Survival

VermorkenNEJM 2008

220

222

Platin/5-Fluorouracil versus

Platin/5-FU/cetuximab

3.3 months*

5.6 months*

7.4 months*

10.1 months*

VermorkenLancet Oncol2013

330

327

Cisplatin/5-Fluorouracil versus

Cisplatin/5-FU/panitumumab

4.6 months*

5.8 months*

9 months

11.1 months

Recurrent/metastatic: first-line

* Statistically significant

Recurrent first-line

Lokaal gerecidiveerde of gemetastaseerde

ziekte

Immunotherapy

Courtesy of P. Coulie and S. LucasInstitut de Duve, UCLOUVAIN

Non-synonymous mutations result in amino acid change in a protein that can be recognizedby T-cells

Vogelstein et al. Science 2013

Antigens resulting from mutations

MHC TCR

B7 CD28

Activation signals

B7CD28

Antibody

Inhibitory signals

MHCTCR

PD-L1PD-1

Antibody Antibody

Negative signals

TCR = T-cell receptor; PD-L1 = programmed death-ligand 1.

Ribas A. N Engl J Med. 2012;366:2517‒2519.

Priming phase Effector phase

Dendriticcell

T cell

Lymphnode

Peripheraltissue

T cell Tumorcell

CTLA-4

Design N

Nivolumab(Checkmate 141)

Phase III 361

Pembrolizumab(Keynote-040)

Phase III 495

Durvalumab(Hawk)

Single arm 111

Atezolizumab Single arm 32

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

Gillison & Ferris ASCO 2017

27

240 169 132 98 76 45 27 12 3

121 88 51 32 22 9 4 3 0

Months

0 3 6 9 12 15 18 21 24

OS

(%)

0

10

20

30

40

50

60

70

80

100

90

Nivo

IC

No. of patients at risk

19.7%

34.0%21.5%

8.3%

Nivolumab

Investigator’s choice

0

0

18-mo OS =

Median OS,

mo (95% CI)

HR

(95% CI) P value

Nivolumab (n = 240) 7.7 (5.7, 8.8) 0.71

(0.55, 0.90)0.0048

Investigator’s choice (n = 121) 5.1 (4.0, 6.2)

Overall survival

Gillison & Ferris ASCO 2017

27

240 169 132 98 76 45 27 12 3

121 88 51 32 22 9 4 3 0

Months

0 3 6 9 12 15 18 21 24

OS

(%)

0

10

20

30

40

50

60

70

80

100

90

Nivo

IC

No. of patients at risk

19.7%

34.0%21.5%

8.3%

Nivolumab

Investigator’s choice

0

0

18-mo OS =

Median OS,

mo (95% CI)

HR

(95% CI) P value

Nivolumab (n = 240) 7.7 (5.7, 8.8) 0.71

(0.55, 0.90)0.0048

Investigator’s choice (n = 121) 5.1 (4.0, 6.2)

Overall survival

Gillison & Ferris ASCO 2017

PLATEAU

Event

Nivolumab

(n = 236)

Investigator’s Choice

(n = 111)

Any grade

n (%)

Grade 3–4

n (%)

Any grade

n (%)

Grade 3–4

n (%)

Anya 139 (58.9) 31 (13.1) 86 (77.5) 39 (35.1)

Fatigue 33 (14.0) 5 (2.1) 19 (17.1) 3 (2.7)

Nausea 20 (8.5) 0 23 (20.7) 1 (0.9)

Diarrhea 16 (6.8) 0 15 (13.5) 2 (1.8)

Anemia 12 (5.1) 3 (1.3) 18 (16.2) 5 (4.5)

Asthenia 10 (4.2) 1 (0.4) 16 (14.4) 2 (1.8)

Mucosal inflammation 3 (1.3) 0 14 (12.6) 2 (1.8)

Alopecia 0 0 14 (12.6) 3 (2.7)aOne Grade 5 event (hypercalcemia) in the nivolumab arm and one Grade 5 event (lung infection) in the investigator’s choice arm were reported. A second death occurred in the nivolumab arm subsequent to pneumonitis.

Treatment-related AEs in > 10% of patients

Event

Nivolumab

(n = 236)

Investigator’s Choice

(n = 111)

Any grade

n (%)

Grade 3–4

n (%)

Any grade

n (%)

Grade 3–4

n (%)

Skin 37 (15.7) 0 14 (12.6) 2 (1.8)

Endocrine 18 (7.6) 1 (0.4) 1 (0.9) 0

Gastrointestinal 16 (6.8) 0 16 (14.4) 2 (1.8)

Hepatic 5 (2.1) 2 (0.8) 4 (3.6) 1 (0.9)

Pulmonary 5 (2.1) 2 (0.8) 1 (0.9) 0

Hypersensitivity/Infusion reaction 3 (1.3) 0 2 (1.8) 1 (0.9)

Renal 1 (0.4) 0 2 (1.8) 1 (0.9)Select AEs: AEs with potential immunologic etiology that requires monitoring/intervention

Immune-related AEs

-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

Mean

Ch

an

ge F

rom

Baselin

e (

95%

CI)

Nivolumab Investigator's choice

EORTC QLQ-H&N35 symptom burden

Key Eligibility Criteria

• SCC of the oral cavity, pharynx, or

larynx

• PD after platinum-containing regimen

• ECOG PS 0 or 1

Pembrolizumab

200 mg IV Q3W

for 2 y

Methotrexate 40 mg/m2 QWd

OR

Docetaxel 75 mg/m2 Q3WOR

Cetuximab 250 mg/m2 QWe

R

1:1

PRIMARY ENDPOINT: Overall survival

N=495

Cohen et al. Lancet. In Press

Phase 3 Keynote 040 study design

37.3%

27.2%

Overall survival (IIT population)

Soulieres et al. AACR 2018

R

• FIRST-LINE R/M disease incurable by local therapies

Pembrolizumab

Cetuximab +Carboplatin or

Cisplatin + 5-FU

CPS > 20

CPS > 1

THE BENEFIT IS CLINICALY RELEVANT IN CPS > 20

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

Stage III/IV SCCHN

Chemoradiation

Chemoradiation +/- Anti-PD1/PD-L1

R

Chemoradiation +/- Immune checkpoint

Primary consentandscreeningeligibility

Biopsy (sequencing oftargeted genes andIHC)

Biomarker-driven cohortsImmunotherapy cohorts

B1:p16negandEGFRamp/mutorPTENhighorHER2 amp/mut

B2:p16negandcetuximab naive

B3:p16negandCCND1amp

B4:p16negand‘platinum-sensitive'

B5:p16posoropharyngeal cancer

B6:FGFR1-3mRNAoverexpression

Afatinib

Physician’s choice

Afatinib

Palbociclib

Physician’s choice

Physician’s choice

Niraparib

Niraparib

Rogaratinib

Cohort I1

Monalizumab +Durvalumab

Physician’s choiceCohort I2

Monalizumab

Recurrent/metastatic SCCHNprogressiveafter platinum-based therapy

R/2:1

R/2:1

R/2:1

R/2:1

EORTC-HNCG-1559 TRIAL (UPSTREAM)

HER pathway

Cell cycle

DNA repair

FGFR pathway

Immunotherapy

Functie

Afdeling of dienst

Universitair Ziekenhuis Gent

C. Heymanslaan 10 | B 9000 Gent

T +32 (0)9 332 21 11

E info@uzgent.be

www.uzgent.be

Volg ons op

SYLVIE ROTTEY

Medical Oncology

Head and neck cancer