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
www.uzgent.be
Volg ons op
SYLVIE ROTTEY
Medical Oncology
Head and neck cancer