IMMUNOTERAPIA E TUMORI TESTA COLLO:
Selezione dei pazienti,
compliance e qualità di vita
Paolo Bossi
Head and Neck Medical Oncology Unit Istituto Nazionale Tumori Milan, Italy
AGENDA
Stato dell’arte: da qui si parte!
Fattori predittivi o prognostici di risposta
Importanza della qualità di vita nella scelta del trattamento e come obiettivo della terapia
Una finestra aperta sulle «pt’s preferences»
STATE OF THE ART:
IMMUNOTHERAPY
IN REC/MET HN CANCER
TRIALS OF IMMUNOTHERAPY IN
REC/MET HN CANCER
THE IMPORTANCE OF BEING
PREDICTIVE
7
PREDICTOR OF RESPONSE TO IMMUNOTHERAPY
CLINICAL ASPECTS Site of
metastasis
Prior therapies GRim-Score Smoking status
Antibiotic use HPV status
GENOMICS Mutational Load
Predisposing mutations Type of mutations
EPIGENOME Methylation of DNA-repair gene
AZA-Induced immune
phenotype
TRANSCRIPTOMICS Inflamed subtypes
Blood-based expession signature
PROTEOMICS PD-L1
PD-L2
STRUCTURE Microbiome MICROENVIRONMENT
Myeloid immunosupp infiltrates
8
PREDICTOR APPLIED TO
HEAD AND NECK CANCER
Peripheral blood lymphocytes
(PBL)
Mutational Load
Inflammatory GEP
PD-L1 on tumour cells and immune
cells PD-L2
Previous therapies Modulators of
Tregs and NK cells
HPV status
9
Predictors of outcome with immunotx
HPV STATUS
PRIOR CETUXIMAB EXPOSURE
0 3 6 9 12 15 18 21 24 27
Months
Nivo 147 102 77 56 44 17 0
IC 74 57 32 22 17
26
7 2
5 2 No. of patients at risk
0 1
0 0
10 20 30 40 50 60 70 80 90 100
OS (%)
12-mo OS = 31.3%
18-mo OS = 19.4%
Nivo IC 25.4%
8.8%
Patients with prior cetuximab exposure
Patients without prior cetuximab exposure
0 3 6 9 12 15 18 21 24 27
Months
Nivo 93 67 55 42 32 10
IC 47 31 19 10 5
19
2 2
7 1 No. of patients at risk
2 0
0 0 0
10 20 30 40 50 60 70 80 90 100
OS (%) 12-mo OS =
38.5%
18-mo OS = 24.9%
Nivo
IC 11.0%
NA
Median OS, mo (95% CI)
HR (95% CI)
Nivo (n = 147) 7.1 (4.9, 8.7)
0.84 (0.62, 1.15)
IC (n = 74) 5.1 (4.0, 6.8)
Median OS, mo (95% CI)
HR (95% CI)
Nivo (n = 93) 8.2 (5.4, 9.9)
0.52 (0.35, 0.77)
IC (n = 47) 4.9 (3.1, 6.5)
OS by subgroup and prior cetuximab exposure
Nivo IC
Nivo IC
HPV status Positive Negative Unknown PD-L1 expression
≥ 1%
< 1%
Not quantifiable Only 1 prior line of therapy
n
36 33 78
52 50 45 44
n
18 20 36
40 20 14 23 Median
OS, mo
8.2 7.5 6.1
8.0 4.9 8.7 8.0
Median OS, mo
6.0 4.8 5.1
4.7 5.1 5.9 6.2
Hazard ratio (95% Cl)
1.16 (0.61, 2.19) 0.63 (0.34, 1.18) 0.89 (0.57, 1.37)
0.66 (0.41, 1.05) 1.14 (0.64, 2.03) 0.84 (0.44, 1.63) 0.88 (0.51, 1.54)
Favors Nivo
Hazard ratio (95% Cl)
Hazard ratio (95% Cl) Favors IC
HPV status Positive Negative Unknown PD-L1 expression
≥ 1%
< 1%
Not quantifiable Only 1 prior line of therapy
n
27 22 44
36 23 34 62
n
11 17 19
21 18 8 35
Hazard ratio (95% Cl)
0.30 (0.13, 0.69) 0.66 (0.32, 1.38) 0.57 (0.32, 1.01)
0.33 (0.18, 0.61) 0.41 (0.20, 0.86) 1.00 (0.41, 2.44) 0.60 (0.38, 0.96)
0.25
0.125 0.5 1 2 4
Patients without prior cetuximab exposure
0.125 0.25 0.5 1 2 4
Median OS, mo
15.6 8.3 5.4
8.3 12.9
4.4 7.8
Median OS, mo
3.1 7.4 4.1
4.0 7.0 5.4 4.9
Favors Nivo Favors IC
Patients with prior cetuximab exposure
Patients without prior cetuximab exposure
PD-L1 EXPRESSION
PD-L1 EXPRESSION
Keynote 012 trial - Pembrolizumab
PD-L1 EXPRESSION
Timepoints!
Variation within tumor tissue
Cutoff…
TC, IC or both?
Sensitivity and specificity are not perfect…
…however… could it be an enrichment factor?
CHALLENGES WITH PD-L1 ASSESSMENT
PD-L2 EXPRESSION
PD-L2 EXPRESSION
PD-L2 EXPRESSION
IFN-γ SIGNATURE
IFN-γ SIGNATURE
IFN-γ SIGNATURE
IFN-γ SIGNATURE
IFN-γ SIGNATURE
ML= tumor antigenicity Infl. GEP = activated T-cells 25
MUTATIONAL LOAD AND inflamed GEP
26
27
28
QUALITA’ DI VITA NEI PZ CON
MALATTIA RECIDIVO-METASTATICA
Qualità di vita:
Mezzo o fine?
QUALITA’ DI VITA come
«MEZZO» per definire PROGNOSI
QUALITA’ DI VITA come
«MEZZO» per definire PROGNOSI
QUALITA’ DI VITA: 1st line setting
QUALITA’ DI VITA: 1st line setting
Non modifiche QoL durante terapia, MA studiato solo timepoint del 3° ciclo
Aggiunta di cetuximab beneficia alcuni domini (social, speech, swallowing, pain) sono
quelli più connessi con la risposta clinica
(aggiunta cet incrementa RR al 36% vs 20%)!
Risposta precoce tipica di chemo+targeted Tx (70-80% entro 2 mesi)
QUALITA’ DI VITA: 1st line setting
Immunoterapia in seconda linea RR 11-13%
Spostamento in prima linea incrementerà RR?
O necessità di combinazione con altra terapia?
E sarà in grado di raggiugere chemo + cet?
Poiché assunto: RR = QoL
QUALITA’ DI VITA: what about
immunoTx in platinum-refractory pts?
Negli studi con pazienti refrattari a platino, non è stato mai evidenziato un trattamento che
abbia portato incremento di qualità di vita, se non in ridotta % di pz e per durata limitata
QUALITA’ DI VITA: what about
immunoTx in platinum-refractory pts?
QUALITA’ DI VITA: what about
immunoTx in platinum-refractory pts?
UTILITA’ SEMPRE MAGGIORE PER QoL
E’ prognostica…
Conosciamo quali domini migliorano con Tp…
Nella value-based assessment di nuovi trattamenti
VERSO LE PT’S PREFERENCES
0 10 20 30 40 50 60 70 80 90 100
Being cured of my cancer
Having no pain
Living as long as possible
Others Survive the
cancer
Expenses covered
Daily life tasks
Speak clearly
Breath well
• List MA, Stracks J, Colangelo L, et al: How Do Head and Neck Cancer Patients Prioritize Treatment Outcomes Before Initiating Treatment? Journal of Clinical Oncology 18:877, 2000
• Tschiesner U, Sabariego C, Linseisen E, et al: Priorities of head and neck cancer patients: a patient survey based on the brief ICF core set for HNC. European Archives of Oto-Rhino-Laryngology 270:3133-3142, 2013 Head & Neck
Cancer Program
Year 2000 Top Priority
Year 2010 Top 5 Priorities
75%
9 % 8%
58%
51% 50%
42% 39%
8%
0 10 20 30 40 50 60 70 80 90 100
Being cured of my cancer
Having no pain
Living as long as possible
Others Survive the
cancer
Expenses covered
Daily life tasks
Speak clearly
Breath well
75%
9 % 8%
58%
51% 50%
42% 39%
8%
25% 42%
Year 2000
Year 2010
VERSO LE PT’S PREFERENCES
IN CONCLUSIONE
Predittori di risposta
PD-L1, HPV, inflammatory signatures tra i più solidi
Non ancora validati e non utilizzati al
momento per la scelta terapeutica (e il
rimborso)
IN CONCLUSIONE
Qualità di Vita
E’ prognostica!
Domini diversi hanno benefici da trattamenti
Elemento per value based choices