Hoofd en halstumoren...>6 week interval between surgery and RT Recurrent tumor Tumor invasion depth...
Transcript of Hoofd en halstumoren...>6 week interval between surgery and RT Recurrent tumor Tumor invasion depth...
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Hoofd en halstumoren
Systemische therapieën
Alumni 9 oktober 2019
Sylvie Rottey / Medische Oncologie
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Lokaal gevorderde ziekte
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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
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WHICH chemo?
Pignon et al. Radiotherapy and Oncology 92 (2009) 4–14
CDDP monotherapy:
11% benefit
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Anti-EGFR (“bio-radiotherapy”)
cetuximab + RT: Bonner, NEJM 2006
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Chemoradiotherapy : beware of toxicity
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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%
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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
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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
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Lokaal gerecidiveerde of gemetastaseerde
ziekte
Chemotherapy
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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
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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
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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
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• 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
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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
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• 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
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Copyright © American Society of Clinical Oncology
Dannenberg, A. J. et al. J Clin Oncol; 23:254-266 2005
Anti EGFR / MABs
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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
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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
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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
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0.8
0.9
1.0
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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
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10.1
mo7.4
mo
Vermorken et al, NEJM 2008
Extreme trial
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These regimenscan be TOXIC
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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
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Lokaal gerecidiveerde of gemetastaseerde
ziekte
Immunotherapy
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Courtesy of P. Coulie and S. LucasInstitut de Duve, UCLOUVAIN
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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
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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
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Design N
Nivolumab(Checkmate 141)
Phase III 361
Pembrolizumab(Keynote-040)
Phase III 495
Durvalumab(Hawk)
Single arm 111
Atezolizumab Single arm 32
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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
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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
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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
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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
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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
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-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
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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
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37.3%
27.2%
Overall survival (IIT population)
Soulieres et al. AACR 2018
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R
• FIRST-LINE R/M disease incurable by local therapies
Pembrolizumab
Cetuximab +Carboplatin or
Cisplatin + 5-FU
CPS > 20
CPS > 1
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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
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Stage III/IV SCCHN
Chemoradiation
Chemoradiation +/- Anti-PD1/PD-L1
R
Chemoradiation +/- Immune checkpoint
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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
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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