Multicenter phase III randomized study
of cisplatin and etoposide
with or without bevacizumab
as first-line treatment in extensive stage
(ED) small cell lung cancer (SCLC)
Dr. Andrea Ardizzoni, Dr. Marcello Tiseo
Small Cell Lung Cancer: highlights
• Decreased incidence (from 20% to 12%)
• Revised histological classification (SCLC vs mixed
SCLC-LC, WHO 2004)
• Stage migration (< LD due to improved PET and brain
MRI staging)
• Cisplatin or carboplatin + etoposide (PE) remains the
standard of care
• 25 years of evaluating various CT cocktails have failed
to produce a survival benefit over PE
• Decreased scientific interest (orphan disease)
Ardizzoni and Tiseo, Educational Book ASCO 2007
Why this trial in SCLC?
• PE has reached an efficacy pleateu
• New treatement with molecular targeted agents are
necessary
• No other ongoing or planned investigator-initiated
randomized trials for first-line in Italy
• SCLC is believed an ideal model for testing antiangiogenic drugs
• The anti-angiogenic approach has allowed a
significant step forward in other malignancies (colorectal, breast, renal cancer and NSCLC)
Angiogenesis and SCLC
• High vascularization by microvessel density count
• Increased levels of serum VEGF have been reported
in SCLC patients
• SCLC express functional VEGFR-2 and VEGFR-3
• High serum and tumor levels of VEGF have been
associated with poorer survival in some but not all
studies
• Serum VEGF levels may or may not correlate with
extent of disease or response to chemotherapy
Lucchi Eur J Cardio-Thoracic Surg 2002; Stefanou D Histol Histopathol 2004
Tanno S Lung Cancer 2004; Tas F Cancer Investigation 2006
Bevacizumab in Extensive Stage SCLC
ECOG 3501
Cisplatin 60 mg/m2, D1
Etoposide 120 mg/m2, D1-3
Bevacizumab 15 mg/kg, D1
Q 21 days x 4 cycles
Bevacizumab
15 mg/kg D1 q 3 weeks
until PD
Horn et al, J Clin Oncol 2009
CALGB 30306
Cisplatin 30 mg/m2, D1, 8
Irinotecan 65 mg/m2, D1, 8
Bevacizumab 15 mg/kg, D1
Q 21 days X 4 – 6 cycles
Ready et al, J Clin Oncol 2011
Phase II Trials of Bevacizumab in ED-SCLC
ECOG 3501: 65 pts
CALGB 30306: 72 pts
Median Survival 11.6 months
OS
PFS
6 month PFS: 30.2%
Median PFS: 7 months
12-months 43.8%
1° Endpoint: 6 month PFS increased from 16% to 33% 1° Endpoint: to differentiate between 50 and
65% 12-months survival rates
mPFS from 2.3 to 3.8 months
Bevacizumab in Extensive Stage SCLC
Randomized Phase II SALUTE trial
Cisplatin 75 mg/m2, D1
or Carboplatin AUC 5, D1
Etoposide 100 mg/m2, D1-3
Bevacizumab 15 mg/kg, D1
or Placebo
Q 21 days x 4 cycles
Bevacizumab 15 mg/kg, D1
or Placebo
q 3 weeks until PD
End-point primario: PFS (HR: 0.70)
Spigel et al, J Clin Oncol 2011
Bevacizumab in Extensive Stage SCLC
Randomized Phase II SALUTE trial
Spigel et al, J Clin Oncol 2011
Bevacizumab in Extensive Stage SCLC
Randomized Phase II SALUTE trial
Spigel et al, J Clin Oncol 2011
7505: Randomized phase II-III study of bevacizumab in combination with
chemotherapy in previously untreated extensive small-cell lung cancer: Results
from the IFCT-0802 trial – Pujol J-L et al
• Study objective
– Phase II study to assess the efficacy and safety of adding bevacizumab to first-line
standard CT in extensive disease SCLC
Key patient
inclusion criteria
• Extensive
disease SCLC
• ECOG PS 0–2
• Age ≤75 years
• Weight loss
<10%
2 x induction
cycles of CT
(cisplatin+
etoposide) or
(cisplatin+
cyclophosphamide
+epidoxorubicin+
etoposide)
(n=147)
4 x cycles of CT
(n=37)
R
1:1
PD
Stratification
• ECOG PS, liver metastases, gender,
induction CT, centre
4 x cycles of CT +
bevacizumab 7.5 mg/kg
q3w
(n=37)
Primary endpoint
Secondary endpoints
• Response rate 2 cycles after randomisation
• PFS, OS, biomarkers, safety and QoL
PD
• Patients
–
Median number of CT cycles was 6 in both treatment arms
Pujol et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7505)
7505: Randomized phase II-III study of bevacizumab in combination with
chemotherapy in previously untreated extensive small-cell lung cancer: Results
from the IFCT-0802 trial – Pujol J-L et al
• Key results
– Survival was unchanged by the addition of bevacizumab
OS
CT alone (n=37)
mOS = 13.3
(95% CI 9.8, 16.6)
Probability of survival
1.0
0.8
0.4
CT plus bevacizumab (n=37)
mOS = 11.1
(95% CI 8.7, 14.0)
0.2
HR for CT alone = 0.80
(95% CI 0.50, 1.28)
0.6
0.0
0
6
12
18
24
30
Months after randomisation
• Conclusions
– The addition of bevacizumab to CT did not improve survival in patients with extensivestage SCLC
– Phase III study has been cancelled
Pujol et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7505)
Bevacizumab in Extensive Stage SCLC
SAFETY
• ECOG Trial: The most common adverse event was
neutropenia (57.8%). Only 1 had grade 3 pulmonary
hemorrhage
• CALGB Trial: There were three grade 5 adverse events
(congestive heart failure, pneumonitis/pulmonary
infiltrates, and CNS hemorrhage/bleeding); there was
no greater than grade 2 haemoptysis
• LUN90 Trial: No patients experienced grade 3 or 4
bleeding (including haemoptysis) or stroke
• SALUTE Trial: The most common grade 3-5 AEs were
neutropenia, pneumonia, dyspnea, thrombocytopenia,
and hypertension; there was a greater incidence in the
BV group. Any grade haemoptysis: 2% for PBO vs 4%
for BV
Bevacizumab in Extensive Stage SCLC
Arruolare le malattie centrali
• Criteri di inclusione/esclusione dei 4
studi di fase II (esclusione solo in
caso di emoftoe)
• Dati di tossicità dei 4 studi di fase II
• NSCLC: fattore predittivo del rischio
di emorragia polmonare
rappresentato dall’escavazione
• Dati di safety dello studio GOIRC
GOIRC TRIAL (progetto AIFA 2006)



206 pts
48 centres
ED
Stratification:
- centre
- PS (0-1 vs 2)
- Gender
- Age
R
R
A
A
N
N
D
D
O
O
M
M
cisplatin (25 mg/m2 d 1-3)
etoposide (100 mg/m2 d 1-3)
every 3 weeks
for a maximum of 6 cycles
End-point primario: OS
(1-year from 40 to 58%)
cisplatin (25 mg/m2 d 1-3)
etoposide (100 mg/m2 d 1-3)
bevacizumab (7.5 mg/kg d 1)
every 3 weeks
Non-PD after 6 cycles will continue bevacizumab
until PD or for a maximum of 18 cycles
Prt FARM6PMFJM
Multicenter phase III randomized study of cisplatin and etoposide with or
without bevacizumab as first-line treatment in extensive stage (ED) small
cell lung cancer (SCLC)
• Studio GOIRC (Gruppo Italiano di Ricerca Clinica)
• Centro coordinatore: Parma-Dr. Andrea Ardizzoni
• Progetto finanziato dall’AIFA (programma di finanziamento della ricerca
indipendente Bando 2006 - area dei farmaci orfani e malattie rare)
• CRO: GB Pharma Services & Consulting Srl
• Fornitura Roche del Bevacizumab:
 103 pazienti al dosaggio di 7.5 mg/kg;
 numero massimo di cicli previsti: 6
 pazienti in risposta o stabili continuano con il mantenimento fino a 18
cicli complessivi
• Obiettivo primario: OS
Prt FARM6PMFJM
Multicenter phase III randomized study of cisplatin and etoposide
with or without bevacizumab as first-line treatment in extensive
stage (ED) small cell lung cancer (SCLC)
• Data scadenza contratto con AIFA: 15-01-2011
• Concesse proroghe, quindi scadenza attuale: 15-04-2015
• Difficile ottenere ulteriori proroghe!
• Scadenza assicurazione: 3.11.2015
• Termine reclutamento: 30.09.2015
• IDMC (analisi ad interim): non ci sono elementi per interrompere lo
studio per futilità, quindi necessario proseguire come previsto dal
protocollo
Prt FARM6PMFJM Accrual 01.10.2015
Totale: 205 pz
Centri aperti: 44
Centri ritirati/chiusi: 10
1° paziente inserito il 16.11.2009 da Ospedale Versilia
205° paziente inserito il 01.10.2015 da Perugia
GOIRC SCLC 1st-line TRIAL Proposal



316 pts
40 centres
ED
Stratification:
- centre
- PS (0-1 vs 2)
- Age
R
A
N
D
O
M
cisplatin (60 mg/m2 d 1)
etoposide (80 mg/m2 d 1-3)
every 3 weeks X 6 courses
cisplatin (60 mg/m2 d 1)
etoposide (80 mg/m2 d 1-3)
every 3 weeks X 6 courses
+ ramucirumab 10 mg/kg q 2wks
until PD
*Assuming a 40% survival at 1 year in
arm A, and a 12% absolute improvement
Non-PD after 6 cycles will continue bevacizumab
in arm B with a HR of 0.70.
until PD or for a maximum of 18 cycles
GOIRC SCLC 2nd-line TRIAL Proposal


65 pts (22 R/
43 S)
20 centres
Stratification:
- Resistant vs
Sensitive
R
R
E
A
G
N
I
D
S
O
T
M
E
R
NabPaclitaxel 100 mg/sqm d 1,
8, 15 q 28
-Primary end-point: Response Rate
-Target RR in RD > 20%
-Target RR in SD > 30%
Non-PD after 6 cycles will continue bevacizumab
until PD or for a maximum of 18 cycles