Aprile
2011
News of the year: impact on clinical practice
Piano Generale di Emergenza
Presidio Ospedaliero di Livorno
Viale Alfieri 36 Federico Cappuzzo
Istituto Toscano Tumori
Ospedale Civile
Livorno-Italy
D.Lgs del 9 aprile 2008 n. 81 – Titolo I – Sezione VI
Gestione delle emergenze
Istituto Toscano Tumori –Livorno, Italy
LACE Meta-analysis: Survival Curves
100
Chemotherapy
No chemotherapy
Absolute difference
Survival (%)
80
at 3 years:
at 5 years:
3.9% + 1.5%
5.3% + 1.6%
61.0
60
57.1
40
48.8
43.5
20
0
0
1
2
3
4
5
>6
Time from randomization (Years)
Istituto Toscano Tumori –Livorno, Italy
Randomized phase III trial of customized adjuvant chemotherapy (CT) according BRCA-1 expression levels in patients with node positive resected Non-Small Cell Lung Cancer
(NSCLC)<br /> SCAT :A Spanish Lung Cancer Group trial <br />
Massuti B, et al. ASCO 2015
Istituto Toscano Tumori –Livorno, Italy
Slide 5
Massuti B, et al. ASCO 2015
Istituto Toscano Tumori –Livorno, Italy
Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT)
Massuti B, et al. ASCO 2015
Istituto Toscano Tumori –Livorno, Italy
Results/1 (cut-off March 15th 2015): Overall survival
Massuti B, et al. ASCO 2015
Istituto Toscano Tumori –Livorno, Italy
ITACA Adjuvant Trial Pharmacogenomic
Taxanes
High
Profile 4
Control
TS
High
ERCC1
Low
Pem
Low
Profile 3
High
Profile 2
Control
Cis/Gem
Control
TS
Cis/Pem
Low
Profile 1
Control
Control = Investigators’ choice; Primary end-point =overall survival; Sample size =700
patients
Istituto Toscano Tumori –Livorno, Italy
Phase III trial of carbo-paclitaxel +/bevacizumab in metastatic NSCLC: OS
12 mo.
24 mo.
bevacizumab + CP
52%
22%
CP
44%
17%
1.0
Probability
0.8
HR: 0.77 (0.65, 0.93)
0.6
p= 0.007
0.4
Medians: 10.2, 12.5
0.2
0
0
6
12
18
24
30
36
Months
Sandler A, NEJM 2006
Istituto Toscano Tumori –Livorno, Italy
Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab
in resected non-small cell lung cancer (NSCLC): Results of E1505
1.0
1.0
Overall Survival
Disease Free Survival
OS hazard ratio (B:A): 0.99
0.4
0.6
0.8
DFS hazard ratio (B:A): 0.98
95% CI: (0.84-1.14)
p=0.75
0.2
Disease-Free Survival Probability
0.6
0.4
0.2
Chemo (208 events/ 749 cases)
Chemo + Bevacizumab (204 events/ 752 cases)
Chemo (338 events/ 749 cases)
Chemo + Bevacizumab (334 events/ 752 cases)
0.0
0.0
Overall Survival Probability
0.8
95% CI: (0.81-1.21)
p=0.93
0
12
24
36
48
60
Months from Registration
72
84
0
12
24
36
48
60
72
84
Months from Registration
. Wakelee H, et al WCLC 2015
Istituto Toscano Tumori – Livorno, Italy
RADIANT trial design
Tumor samples
EGFR IHC+ and/or EGFR FISH+
Stage
IB–IIIA
NSCLC
Complete
surgical
resection
No adjuvant
chemotherapy
Up to 4 cycles of
platinum-based
doublet
90 d
180 d
(N=973) Randomization
stratified by:
histology, stage, prior
adjuvant chemo, EGFR
FISH status, smoking
status, country
(n=623)
Erlotinib
150mg/day
2:1
2-yr treatment period
(n=350)
Placebo
• Radiology assessment: every 3 months on treatment and yearly during long-term follow up
• Primary endpoint: DFS
• Secondary endpoints: Overall survival (OS); DFS and OS in patients with del19/L858R (EGFR M+)
Kelly K, JCO 2015
Istituto Toscano Tumori – Livorno, Italy
RADIANT: DFS and OS in the whole study
population
DFS
OS
Placebo
Erlotinib
Erlotinib
Placebo
Kelly K, JCO 2015
Istituto Toscano Tumori – Livorno, Italy
RADIANT: DFS and OS in EGFR mut+
DFS
OS
Placebo
Erlotinib
Erlotinib
Placebo
Stage Ib-IIa: 59.8% versus 39% in erlotinib arm versus placebo arm
Kelly K, JCO 2015
Istituto Toscano Tumori – Livorno, Italy
Take home message degli studi di terapia
adiuvante
1. La chemioterapia basata sul platino rimane lo standard
terapeutico adiuvante nei pazienti con carcinoma polmonare
resecato
2. La farmacogenomica non aiuta ad ottimizzare I risultati della
terapia adiuvante (in attesa dello studio ITACA)
3. L’aggiunta del bevacizumab alla chemioterapia adiuvante
non migliora la sopravvivenza dei pazienti
4. Nessun farmaco biologico è attualmente indicato come
terapia precauzionale neppure in pazienti selezionati
(esempio EGFR-TKIs nei pazienti con mutazione di EGFR)
Istituto Toscano Tumori –Livorno, Italy
Locally advanced (stage III) NSCLC:
a heterogeneous group
potentially resectable
some IIIA-N2
some T4-N0/1
Induction chemo
 surgery
Induction CTRT
 surgery
“surgical multimodality”
unresectable
bulky IIIA-N2
most IIIB
• Radiotherapy
• Systemic therapy
“non-surgical multimodality”
Vansteenkiste ERS 2008
Istituto Toscano Tumori –Livorno, Italy
Concurrent versus sequential chemoradiation:
metaanalysis of survival
Auperin et al J Clin Oncol 2010; 28:2181
Istituto Toscano Tumori –Livorno, Italy
Final overall survival results of the phase III PROCLAIM trial: Pemetrexed, cisplatin or etoposide, cisplatin plus thoracic radiation therapy followed by consolidation cytotoxic
chemotherapy in locally advanced nonsquamous non-small cell lung cancer
Senan S, et al. ASCO 2015
Istituto Toscano Tumori –Livorno, Italy
PROCLAIM: Study Design
Senan S, et al. ASCO 2015
Istituto Toscano Tumori –Livorno, Italy
Slide 11
Senan S, et al. ASCO 2015
Istituto Toscano Tumori –Livorno, Italy
Slide 17
Senan S, et al. ASCO 2015
Istituto Toscano Tumori –Livorno, Italy
OS with CDDP-VP16 versus CBDCA-Paclitaxel
concomitant with RT
Santana-Davila et al. JCO 2014
Istituto Toscano Tumori –Livorno, Italy
Take home message degli studi sul trattamento
della malattia localmente avanzata
1. La chemioradioterapia concomitante è lo standard
terapeutico per la malattia localmente avanzata non
resecabile
2. La chemioterapia con platino-Vepesid rimane una valida
opzione in concomitanza con la radioterapia
3. La tossicità può essere ridotta utilizzando platinopemetrexed ma
–
Solo nei non squamosi
–
Con aumento dei costi
–
Carbo-taxolo valida alternativa low-cost
Istituto Toscano Tumori –Livorno, Italy
Pembrolizumab (MK-3475) in Patients With Extensive-Stage Small Cell Lung Cancer: Preliminary Safety and Efficacy <br />Results from KEYNOTE-028
Istituto Toscano Tumori – Livorno, Italy
Change From Baseline in Tumor Size <br />(RECIST v1.1, Investigator Review)
Ott P, et al. ASCO 2015
Istituto Toscano Tumori – Livorno, Italy
Phase I/II Study (CheckMate 032) of Nivolumab<br />With or Without Ipilimumab for Treatment of Recurrent Small Cell Lung Cancer (SCLC)
Presented By Scott Antonia at 2015 ASCO Annual Meeting
CheckMate 032 Study Design
Scott A, et al. ASCO 2015
Istituto Toscano Tumori – Livorno, Italy
Summary of Clinical Activity
Scott A, et al. ASCO 2015
Istituto Toscano Tumori – Livorno, Italy
Tumor Responses (PD-L1 expression)
Scott A, et al. ASCO 2015
Istituto Toscano Tumori – Livorno, Italy
Overall Survival
Scott A, et al. ASCO 2015
Istituto Toscano Tumori – Livorno, Italy
Phase I Study of a delta-like protein 3 (DLL3)Targeted Antibody Drug Conjugate Rovalpituzumab
in SCLC
●
DLL3, is a protein encoded by the DLL3 gene
●
This gene encodes a member of the delta protein ligand family.
●
This family functions as Notch ligands
●
DLL3 is higly expressed in 70% of SCLC
●
Rova-T is an antibody drug conjugate (ADC) consisting of :
–
An antibody
–
A linker
–
A chemotherapy
Rova-T: Best Response Data in Evaluable SCLC Patients
Be st Re sponse
(RECIST)
0.2 mg/kg q3w and 0.3 mg/kg q6w cohorts (n=53)
80
Expression
60
High
40
Intermedia
te
20
H-Score
SCLC %
180+
70%
90-180
11%
Low
0-90
19%
Unknown
NA
0
-20
-40
-60
-80
DLL3 tested in 48 cases, with 33 cases
with high levels of expression with 34% RR and
31% SD
All patients received the drug as second or third-line
Pietanza C, et al. ECC 2015
Istituto Toscano Tumori – Livorno, Italy
Take home message sul microcitoma
polmonare
1. L’immunoterapia rappresenta una potenziale nuova opzione
terapeutica per il microcitoma polmonare con promettenti dati
preliminari
–
In monoterapia
–
In combinazione con altri immunoterapici
2. Rovalpituzumab ha mostrato di indurre remissione di malattia in
pazienti pretrattati e selezionati per espressione di DLL3
Istituto Toscano Tumori –Livorno, Italy
IFCT MAPS: study design
Scherpereel, et al. WCLC 2015
Istituto Toscano Tumori –Livorno, Italy
IFCT MAPS: OS
1.0
Pemetrexed + cisplatin (n=225)
Pemetrexed + cisplatin + bevacizumab (n=223)
OS estimate
0.8
HR 0.76 (0.61–0.94)
p=0.0127
0.6
0.4
0.2
16.07
0
0
No. at risk
225
223
18.82
10
20
30
Time (months)
40
50
60
166
171
77
91
36
45
16
20
10
8
7
8
Scherpereel, et al. WCLC 2015
Istituto Toscano Tumori –Livorno, Italy
IFCT MAPS: OS by subgroup
All (n=448)
Male (n=338)
Female (n=110)
Age <65.7 years (n=224)
Age ≥65.7 years (n=224)
PS 0/1 (n=433)
PS 2 (n=15)
Epithelioid (n=361)
Sarcomatoid (n=42)
Mixed (n=45)
Smokers (n=254)
Never smokers (n=194)
Platelet <400x109/L (n=336)
Platelet ≥400x109/L (n=111)
Haemoglobin ≤14g/L (n=309)
Haemoglobin >14g/L (n=139)
Leucocytes ≥8.3x109/L (n=191)
Leucocytes <8.3x109/L (n=256)
EORTC good prognosis (n=320)
EORTC poor prognosis (n=128)
0
0.5
Favours triplet
1.0
1.5
Favours doublet
2
Scherpereel, et al. WCLC 2015
Istituto Toscano Tumori –Livorno, Italy
Take home message sul mesotelioma
•
L’aggiunta di bevacizumab all’attuale standard terapeutico di
platino-pemetrexed aumenta la sopravvivenza dei pazienti con
mesotelioma pleurico
•
La riduzione del rischio di morte è rilevante (24%)
•
Il vantaggio in sopravvivenza è presente in tutti i sottogruppi
•
Nuovo standard terapeutico se bevacizumab verrà registrato con
questa indicazione
Istituto Toscano Tumori –Livorno, Italy