Second line treatments in WT
pts: which opportunities with
biologic agents?
Silvia Novello
silvia.novello@unito.it
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Life was so simple back in 2008
Di Maio M, EJC 2010
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
In 2014, “second line therapy” is
no longer as simple
We must now take into consideration:
1.Tumor histology
2.Molecular phenotype (EGFR, ALK, ROS1, etc)
3.Frontline chemo components
4.Maintenance therapy (continuation, switch)
5.Bevacizumab use
6.Others (adequacy of tumor tissue, third party
reimbursement, guidelines, “pathways”, etc)
INDUCTION MAINTENANCE
2 nd LINE
3 rd LINE
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Which is the influence of
Maintenance on 2nd line
PARAMOUNT discontinuation treatment
Di Maio M, JCO 2009
Clinical Lung Cancer 2014
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Second line therapy Outside Clinical Trials (N=464)
De Marinis F et al, Clinical Lung Cancer 2014
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Timing of Biomarker Analyses
(excluded those with no computable timing)
EGFR=37; KRAS=13; Alk=18
De Marinis F et al, Clinical Lung Cancer 2014
[TITLE]
Presented By Yoshio Okano, MD. PhD at 2013 ASCO Annual Meeting
[TITLE]
Okano ASCO 2013
[TITLE]
Presented By Yoshio Okano, MD. PhD at 2013 ASCO Annual Meeting
[TITLE]
Okano ASCO 2013
EGFR Unselected
Kawaguchi JCO 2014
EGFR Wild-Type
Kawaguchi JCO 2014
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
If the selection is (more or less) real from the beginning
OS
PFS
Garasssino M, LO 2013
Zhou et al, WCLC 2013
Zhou et al, WCLC 2013
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Guidelines [ESMO-AIOM]
Zer, JCO 2014
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Zer, JCO 2014
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
How we can select?
PROSE Patient Flow
285 patients randomized
263 included for primary analysis
3 major protocol violations
19 never received therapy
Chemotherapy (129)
VS-G
88 (68%)
VS-P
41 (32%)
Erlotinib (134)
VS-G
96 (72%)
VS-P
38 (28%)
The patient population was 72% male, 63% adenocarcinoma, 14% never smokers,
52% ECOG PS 0, and 41% ECOG PS 1, and was well balanced between arms.
Third-line treatment at progression:
– CT arm: 41% overall (48% VS-G and 27% VS-P)
– ERL arm: 52% overall (56% VS-G and 39% VS-P)
*PCR amplification/Sanger sequencing of common mutations
01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
PROSE in NCCN Guidelines in second line NSCLC
Gregorc V, Novello S, Lazzari C, Lancet Oncology 2014; 15.713-21
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
Gene Methylation
HYPERPLASIA
Mutations
DYSPLASIA
Air Space
Cellular proliferation through independent
growth signaling
Translocations
CARCINOMA
INVASIVE
CARCINOMA
Limitless potential
for replication
Promotion of
survival signals and
evasion of apoptosis
Vascular
recruitment
and endothelial
cell growth
Bronchial Epithelium
Tissue invasion
and metastasis
Adapted from Weinberg RA. Sci Am. 1996;275:62-70.
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
• Ramucirumab (RAM) is a human IgG1 monoclonal
antibody, specifically binding to the extracellular domain of VEGFR-2.
• Two phase III studies in second-line gastric cancer
demonstrated that RAM monotherapy or in combination with
chemotherapy prolongs OS.
– Ramucirumab (CYRAMZATM) monotherapy is approved by the
FDA as second-line treatment of advanced gastric cancer (April
2014).
• Nintedanib is an oral angiokinase inhibitor
targeting VEGFR 1–3, FGFR 1–3, and PDGFR α/β as
well as RET
REVEL: Study Design
1:1
- Stage IV NSCLC
after one platinumbased chemo +/maintenance
- Prior Bev allowed
- All histologies
- PS 0 or 1
R
A
N
D
O
M
I
Z
E
Stratification factors:
•
•
•
•
ECOG PS 0 vs 1
Gender
Prior maintenance
East-Asia vs. ROW
Ramucirumab 10 mg/kg
+
Docetaxel 75 mg/m2 q3wks
N=628
Placebo
+
Docetaxel 75 mg/m2 q3wks
N=625
Treatment
until disease
progression
or
unacceptable
toxicity
Primary endpoint: Overall Survival
Secondary endpoints:
PFS, ORR, safety, patient-reported outcomes
Abbreviations: Bev=bevacizumab; ECOG PS=Eastern Cooperative Oncology Group performance status; ORR=objective response rate;
PFS=progression-free survival; ROW=rest of the world; q3wks=every 3 weeks.
LUME-Lung 1 Study Design
Stage IIIB/IV
or recurrent
NSCLC patients
after 1st line
chemotherapy
(all histologies)
R
A
N
D
O
M
I
Z
E
PD
Placebo BID p.o., D2–21,
+ Docetaxel 75mg/m2 IV, D1,
21-day cycles (n=659)
PD
1:1
N=1314
Stratification:
Nintedanib 200mg BID p.o., D2–21,
+ Docetaxel 75mg/m2 IV, D1,
21-day cycles (n=655)
Number of docetaxel cycles not restricted
Monotherapy allowed after ≥4 cycles of combination therapy
ECOG PS (0 vs 1)
Prior bevacizumab (yes vs no)
Histology (squamous vs nonsquamous)
Brain metastases (yes vs no)
RECK LBA8011, ASCO 2013
Primary end point: PFS
Next analysis step only allowed if PFS confirmed
with all PFS events at time point of OS analysis
REVEL: Patient Disposition
Screened (N=1825)
Excluded (n=572)
Randomized (ITT) Population
N=1253
RAM+DOC (N=628)
Patients not
receiving
treatment (n=4)
wt 33%
mutant 2.4%
unknown 64%
RAM+DOC (N=627)*
PL+DOC (N=625)
31%
wt 31.5%
Patients not
mutant
2.9%
receiving
treatment65%
(n=4)
unknown
PL+DOC (N=618)*
Safety Population
N=1245
Reasons for discontinuation (N=613)
PD
341
Adverse event
94
Subject decision
90
Investigator decision
37
Death due to adverse events
30
Death from study disease
12
Other
9
Reasons for discontinuation (N=611)
PD
429
Adverse event
55
Subject decision
53
Investigator decision
19
Death due to adverse events
31
Death from study disease
14
Other
10
On treatment at data cutoff N=11
On treatment at data cutoff N=10
*Three PL+DOC arm patients were inadvertently treated with RAM and are therefore considered part of the RAM+DOC arm for the safety analyses, but the
PL+DOC arm for the ITT efficacy analysis.
REVEL:Tumor Response by RECIST v1.1
ITT Population, Investigator Assessment
RAM+DOC
N=628
PL+DOC
N=625
3 (0.5)
141 (22.5)
258 (41.1)
128 (20.4)
98 (15.6)
2 (0.3)
83 (13.3)
244 (39.0)
206 (33.0)
90 (14.4)
P-value
Response, n (%)
CR
PR
SD
PD
Unknown/not assessed
ORR (CR+PR), % (95% CI)
22.9 (19.7-26.4) 13.6 (11.0-16.5)
<.001
DCR (CR+PR+SD), % (95% CI)
64.0 (60.1-67.8) 52.6 (48.6-56.6 )
<.001
Abbreviations: CI=confidence interval; CR=complete response; DCR=disease control rate; ITT=intention-to-treat; ORR=objective response rate;
PD=progressive disease; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.
REVEL: Progression-Free Survival
ITT Population, Investigator Assessment
Progression-Free Survival (%)
100
Median (95% CI) Censoring Rate
RAM+DOC
4.5 (4.2-5.4)
11.1%
PL+DOC
3.0 (2.8-3.9)
6.7%
RAM+DOC vs PL+DOC:
Stratified HR (95% CI) = 0.762 (0.677-0.859)
Stratified log-rank P < .0001
80
60
40
20
RAM+DOC
PL+DOC
Censored
0
0
3
6
9
12
15
18
21
24
27
30
33
36
7
4
3
3
3
2
0
0
0
0
0
0
Survival Time (months)
Number at risk
RAM+DOC
PL+DOC
628
625
383
301
204
172
120
95
59
37
38
17
11
9
REVEL: Overall Survival
ITT Population
100
RAM+DOC
PL+DOC
Overall Survival (%)
80
Median (95% CI) Censoring Rate
10.5 (9.5-11.2)
31.8%
9.1 (8.4-10.0)
27.0%
RAM+DOC vs PL+DOC:
Stratified HR (95% CI) = 0.857 (0.751-0.979)
Stratified log-rank P = .0235
60
40
20
RAM+DOC
PL+DOC
Censored
0
0
3
6
9
12
15
18
21
24
27
30
33
36
45
36
23
23
11
9
2
0
0
0
Survival Time (months)
Number at risk
RAM+DOC 628
PL+DOC 625
527
501
415
386
329
306
231
197
156
129
103
86
70
56
Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm
Presented By Maurice Perol at 2014 ASCO Annual Meeting
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
LUME1: PFS
TOTAL population
ADENOCARCINOMA
SQUAMOUS CARCINOMA
Reck M et al, Lancet Oncol 2014
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
LUME1: OS
Adenocarcinoma <9mo
ADENOCARCINOMA
Total population
Reck M et al, Lancet Oncol 2014
UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY
LUME1: Safety
Reck M et al, Lancet Oncol 2014
New Educational Tracks:
Community practices, ,
Nurses, Patient Advocacy,
Palliative care
46
LBA42_PR: Cisplatin plus pemetrexed (CP) versus cisplatin plus gemcitabine
(CG) according to thymidylate synthase expression in non-squamous NSCLC:
A biomarker-stratified randomized phase II trial – Ahn M et al
• Study objective
– To investigate whether thymidylate synthase (TS) expression is a predictive
factor for pemetrexed + cisplatin compared with gemcitabine + cisplatin in
patients with non-squamous NSCLC
Key patient
inclusion criteria
• Non-squamous
NSCLC
TS-negative
(n=160)
R
• ECOG PS 0 or 1
(n=321)
TS-positive
(n=161)
PD
Gemcitabine + cisplatin x6
(n=77)
PD
Pemetrexed + cisplatin x6
(n=79)
PD
Gemcitabine + cisplatin x6
(n=82)
PD
1:1
• Stage IIIB or IV
• Adequate organ
function
Pemetrexed + cisplatin x6
(n=83)
R
1:1
Primary endpoint
Secondary endpoints
• Response rate
• PFS, OS
• Safety
Pemetrexed 500 mg/m2 + cisplatin 70 mg/m2 D1 q3w or
gemcitabine 1000 mg/m2 D1–D8 + cisplatin 70 mg/m2 D1 q3w
Ahn et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA42_PR
LBA42_PR: Cisplatin plus pemetrexed (CP) versus cisplatin plus gemcitabine
(CG) according to thymidylate synthase expression in non-squamous NSCLC:
A biomarker-stratified randomized phase II trial – Ahn M et al
• Key results
– In the TS-negative group, pemetrexed + cisplatin was more efficacious than
gemcitabine + cisplatin, while in the TS-positive group efficacy was similar
between treatments
Objective response rate (%)
60
50
Investigator assessment
Independent assessment
Interaction p=0.0084
Interaction p=0.0077
p=0.0008
p=1.0
p=0.02
p=0.34
48%
47%
40% 39%
40
40%
39%
30
21%
21%
20
10
0
TS (-)
TS (+)
Pemetrexed + cisplatin
TS (-)
Gemcitabine + cisplatin
TS (+)
Ahn et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA42_PR
LBA42_PR: Cisplatin plus pemetrexed (CP) versus cisplatin plus gemcitabine
(CG) according to thymidylate synthase expression in non-squamous NSCLC:
A biomarker-stratified randomized phase II trial – Ahn M et al
• Key results (cont.)
– Low expression of TS was asssociated with prolonged OS irrespective of
treatment regimen
Median OS
(months)
TS-negative
30.3
TS-positive
15.2
Probability of overall survival
1.0
0.9
0.8
95% CI
p value
26.4, not reached
11.5, 21.0
<0.0001
0.7
HR 0.64, 95% CI 0.45, 0.90
0.6
0.5
0.4
0.3
0.2
0.1
0
0
Number at risk
TS (-)
159
TS (+)
156
10
20
Months
30
116
90
52
31
18
8
• Conclusion
– TS is a predictive and prognostic biomarker
Ahn et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA42_PR
LBA40_PR: TARGET: A randomized, phase II trial comparing vintafolide versus
vintafolide plus docetaxel, versus docetaxel alone in second-line treatment of
folate-receptor-positive non-small cell lung cancer (NSCLC) patients
– Hanna N et al
• Study objective
– To compare vintafolide with vintafolide + docetaxel and docetaxel alone as
second-line treatment in patients with folate-receptor-positive NSCLC
99mTc-etarfolatide
scan
Key patient
inclusion criteria
• Adeno and
squamous
NSCLC
• One prior
chemotherapy
All target
lesions
are FR
positive
R
1:1:1
Arm A: vintafolide 2.5 mg IV
days 1, 4, 8, 11, q3w
(n=63)
PD
Arm B: vintafolide + docetaxel
As per Arm A and Arm C
schedules (n=68)
PD
Arm C: docetaxel 75 mg/m2 IV
day 1 q3w
(n=68)
PD
Stratification
• Time since last chemotherapy (<3 vs. ≥3 months); best response to chemotherapy;
stage IIIB vs. IV; prior EGFR inhibitor treatment (yes vs. no)
Primary endpoint
Secondary endpoints
• PFS
• ORR, DCR, OS
Hanna et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA40_PR
LBA40_PR: TARGET: A randomized, phase II trial comparing vintafolide versus
vintafolide plus docetaxel, versus docetaxel alone in second-line treatment of
folate-receptor-positive non-small cell lung cancer (NSCLC) patients
– Hanna N et al
• Key results
Vintafolide
(n=63)
Vintafolide + docetaxel
(n=68)
Docetaxel
(n=68)
1.6 (1.4, 3.2)
4.2 (2.8, 5.4)
3.3 (1.7, 4.2)
All patients
Median (95% CI) PFS, months
PFS HR (95% CI; vs. docetaxel)*; p value† 1.35 (0.92, 1.96); 0.9421 0.75 (0.52, 1.09); 0.0696
Median (95% CI) OS, months
OS HR (95% CI; vs. docetaxel)*; p value†
8.4 (5.6, 12.3)
11.5 (7.3, 13.4)
8.8 (5.4, 12.6)
1.05 (0.68, 1.61); 0.5818 0.88 (0.58, 1.36); 0.2874
Stratified analysis
All patients
n=63
n=68
PFS HR (95% CI; vs. docetaxel); p value†
1.35 (0.89, 2.04); 0.9266 0.78 (0.52, 1.17); 0.1175
OS HR (95% CI; vs. docetaxel); p value†
0.96 (0.62, 1.50); 0.4396 0.75 (0.48, 1.18); 0.1066
Adenocarcinoma
*Unstratified log-rank; †1-sided
PFS HR (95% CI; vs. docetaxel); p value†
n=41
n=43
Hanna et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA40_PR
1.32 (0.79, 2.21);
0.8590 0.68 (0.41, 1.14); 0.0732
LBA40_PR: TARGET: A randomized, phase II trial comparing vintafolide versus
vintafolide plus docetaxel, versus docetaxel alone in second-line treatment of
folate-receptor-positive non-small cell lung cancer (NSCLC) patients
– Hanna N et al
• Key results (cont.)
– OS
All patients
0.8
0.6
0.4
Patients Events Treatment
0.2
63
40
Vintafolide only
68
41
Vintafolide + docetaxel
68
43
Docetaxel only
Adenocarcinoma
1.0
Probability of overall survival
Probability of overall survival
1.0
0
0.8
0.6
0.4
Patients Events Treatment
0.2
41
25
Vintafolide only
43
21
Vintafolide + docetaxel
49
30
Docetaxel only
0
0
3
6
9
12
Months
15
18
21
0
3
6
9
12
Months
15
18
21
• Conclusions
–
Compared with docetaxel alone, vintafolide + docetaxel provided a non-significant trend in PFS and
OS outcomes
• Outcomes were better in patients with adenocarcinoma
Hanna et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA40_PR