POST-IASLC: First-line of advanced NSCLC
Cesare Gridelli
Division of Medical Oncology
“S.G. Moscati” Hospital – Avellino (Italy)
cgridelli@libero.it
Safety and Resource Use in PRONOUNCE: A randomized, phase
3, open-label study of pemetrexed plus carboplatin with
maintenance pemetrexed (PemC) compared to paclitaxel plus
carboplatin plus bevacizumab with maintenance bevacizumab
(PCB) in patients with advanced non-squamous (NS) non-smallcell lung cancer (NSCLC)
Authors: 1Helen J Ross, 2, 3David R Spigel, 4Robert W Weaver, 5Ramaswamy Govindan,
6Viran R Holden, 7Naveed M Chowhan, 8Thaddeus Beck, 9David M Waterhouse,
10Manuel R Modiano, 11Vijay P Rao, 12Katherine B Winfree, 12Symantha A
Melemed, 12Jingyi Liu, 12Andrew G Koustenis, 12Susan C Guba, 12Waldo I Ortuzar,
12Coleman K Obasaju, 13Ralph Zinner
Affiliations: 1Mayo Clinic, Scottsdale, AZ; 2,3Tennessee Oncology, Nashville, TN; Sarah Cannon Research Institute,
Nashville, TN; 4Florida Cancer Specialists, Fort Myers, FL; 5Washington University Medical Center, St. Louis, MO;
6Mercy Clinic Cancer and Hematology, Springfield, MO; 7Floyd Memorial Cancer Center of Indiana, New Albany, IN;
8Highlands Oncology Group, Fayetteville, AR; 9Oncology Hematology Care Inc., Blue Ash, OH; 10ACRC/Arizona Clinical
Research Center, Arizona Oncology, Tucson, AZ; 11Mid Dakota Clinic Hematology and Oncology, Bismarck, ND; 12Eli
Lilly and Company, Indianapolis, IN; 13University of Texas MD Anderson Cancer Center, Houston, TX
PRONOUNCE: Study Design
 Randomized, open-label, phase III superiority study conducted in US
 Pemetrexed 500 mg/m2, Carboplatin AUC 6 (Pem+Cb)
 Paclitaxel 200 mg/m2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev)
Induction Phase
q21d, 4 cycles
Maintenance Phase
q21d until PD
Bev-Eligible Population
Pemetrexed
Inclusion:
- Chemo-naïve patients
- PS 0/1
- Stage IV, nonsquam
- Stable treated CNS mets
(folic acid & vitamin B12)
+ Carboplatin
R
1:1
Exclusion:
- Uncontrolled effusions
(folic acid & vitamin B12)
180 patients each
Paclitaxel
+ Carboplatin
+ Bevacizumab
Stratified for:
PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b)
Zinner R et al, ASCO 2013
Pemetrexed
Bevacizumab
Primary Endpoint: G4PFS
100
Pem+Cb:
-------- Pac+Cb+Bev:
P ro p o rtio n
80
median G4PFS = 3.9 (mo)
median G4PFS = 2.9 (mo)
Log-rank p-value = 0.176
HR (90% CI)
= 0.85 (0.70, 1.04)
60
40
20
0
0
3
6
9
12
15
18
21
24
27
M o n th s
Patients at Risk
Pem+Cb
182
87
44
26
14
7
5
3
1
0
Pac+Cb+Bev
179
75
33
17
9
3
0
0
0
0
Zinner R et al, ASCO 2013
Secondary Endpoint: OS
Pem+Cb:
median OS = 10.5 (mo)
--------- Pac+Cb+Bev: median OS = 11.7 (mo)
100
Log-rank p-value = 0.615
HR (95% CI)
= 1.07 (0.83, 1.36)
Pem+Cb
Pac+Cb+Bev
N = 182
N = 179
%
%
1-Year
43.7
48.8
P ro p o rtio n
80
60
2-Year
40
18.0
17.6
20
0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
M o n th s
Patients at Risk
Pem+Cb
182
Pac+Cb+Bev 179
156
151
125
121
102
96
Zinner R et al, ASCO 2013
72
73
48
59
33
38
20
28
11
10
11
3
5
1
5
1
5
0
5
0
5
0
42
Drug related Treatment Emergent Adverse Events (TEAEs)
A. Toxicities that differed by treatment
PemC
PCB
Anemia
P<0.001
PemC
PCB
Thrombocytopenia
Hypotension
PemC
PCB
Thrombosis
PemC
PCB
P<0.006
P<0.105
P<0.003
PemC
PCB
Musculoskeletal
Pain - Extremity
P<0.033
PemC
PCB
Joint
Pain
P<0.001
PemC
PCB
Hemorrhage
Pulm, Up Resp/Nose
Hypertension
Diarrhea
Number of Patients
P<0.001
PemC
PCB
P<0.001
PemC
PCB
P<0.07
0
10
20
30
40
50
60
70
80
The number of patients experiencing adverse events is on the x-axis with the event type on the y-axis. Color indicates grade with
grade 3, and
grade 4; See table 5 below for detailed data.
90
grade 1,
P-values result from Fisher’s exact tests in numbers of patients experiencing adverse events by treatment . There was a significantly higher occurrence of anemia and
thrombocytopenia in patients treated with PemC. Thrombosis, musculoskeletal pain and joint pain, hemorrhage and hypertension occur significantly more in patients treated
with PCB.
100
grade 2,
Drug related Treatment Emergent Adverse Events (TEAEs)
B. Toxicities considered most important to patients
Fatigue
Nausea
PemC
P<0.064
PCB
PemC
P<0.011
PCB
PemC
Vomiting
PCB
P<0.587
**Febrile PemC
Neutropenia PCB
P<0.058
PemC
Alopecia
PCB
P<0.001
PemC
Sensory
Neuropathy PCB
P<0.001
PemC
Neutropenia
PCB
P<0.001
0
10
20
30
40
50
60
70
80
90
100
Number of patients
P-values result from Fisher’s exact tests in numbers of patients experiencing adverse events by treatment. Significantly more patients treated with PemC experience fatigue and nausea. Febrile
neutropenia, alopecia, sensory neuropathy and neutropenia occur significantly more often in patients treated with PCB. **Febrile neutropenia and neutropenia not usually reported because lab
tests are required.
Concomitant medications by treatment
180
Number of patients
160
PemC
PCB
p=0.355
140
p=0.574
120
p=0.323
100
80
60
p<0.001
p=0.005
40
20
0
PemC
PCB
Patients ≥1
Medication
171
166
Analgesic-antiinflammatory
152
153
Antiemetic
Antibiotic
ESA
G-CSF
110
101
91
98
34
12
29
50
*On therapy or within 30 days of discontinuation; No statistical comparison of the total number of patients on ≥1 medication between
treatments. PemC, pemetrexed plus carboplatin followed by maintenance pemetrexed; PCB, paclitaxel plus carboplatin plus bevacizumab
followed by maintenance bevacizumab; ESA, erythropoietic stimulating agent; G-CSF, Granulocyte colony stimulating factor
Resource Utilization
PemC
PCB
N = 171
N = 166
p-value
0.7 hours
4 - 5 hours
N/A
Packed red blood cells
59 (34.5)
19 (11.4)
<0.001
Platelets
10 (5.8)
7 (4.2)
0.621
59 (34.5)
53 (31.9)
0.645
8.2 (6.79)
8.8 (7.33)
0.682
Concomitant medications, G-CSF
29 (17.0)
50 (30.1)
0.005
Erythropoietic stimulating agents
34 (19.9)
12 (7.2)
<0.001
Parameter, n (%)*
Chemotherapy infusion time per protocol
Patients with transfusion
Any Hospitalization
Number of days, mean (StdDev)
Conclusions
■ Toxicity of PemC and PCB were consistent with previous reports.
■ Mild to moderate nausea was more common for patients treated with PemC.
■ Alopecia, infection and neuropathy were more common for patients treated with
PCB.
■ Hospitalizations did not differ between treatment arms.
■ ESA and RBC transfusions were more common for patients treated with PemC.
■ G-CSF use was more common for patients treated with PCB.
ToPPS : phase II randomized trial on
advanced NSCLC patients with PS 2
Previously
untreated, stage
IIIb, IV nonsquamous NSCLC
Primary endpoint: PFS
R
A
N
D
O
M
I
S
E
D
PEMETREXED
CARBOPLATIN +
PEMETREXED
CBDCA +
PEMETREXED +
BEVACIZUMAB
15mg/kg
Primary endpoint:
PFSand Sarah Cannon Cancer Center
Mount Sinai,
Lilenbaum R et al, WLCC 2013
Bevacizumab
PD
Efficacy (N=163)
Best Response
Randomized Pts)
Arm 1
(N=48)
Arm 2
(N=59)
Arm 3
(N=56)
CR
PR
SD
PD
UE
Haven’t reached 1st restaging
0
7 (14.6%)
22 (45.8%)
13 (27.1%)
6 (12.5%)
0
0
15 (25.4%)
22 (37.3%)
10 (16.9%)
10 (16.9%)
2 (3.4%)
1 (1.8%)
21 (37.5%)
18 (32.1%)
7 (12.5%)
8 (14.3%)
1 (1.8%)
Overall Response Rate (All
Randomized Pts)
Proportion (P)
Exact Confidence Limits
95% LCL
95%UCL
Arm 1
(N=48)
0.1458
Arm 2
(N=59)
0.2542
Arm 3
(N=56)
0.3929
0.0607
0.2776
0.1498
0.3844
0.2650
0.5325
Overall Response Rate (All
Evaluable Pts)
Proportion (P)
Exact Confidence Limits
95% LCL
95%UCL
Arm 1
(N=42)
0.1667
Arm 2
(N=47)
0.3191
Arm 3
(N=47)
0.4681
0.0607
0.2776
0.1498
0.3844
0.2650
0.5325
(All
Progression Free Survival
Median PFS (95% CI)
12-month PFS (95% CI)
13
Arm 1 (N=48)
Pem Only
2.6 (1.5, 5.1)
0.05 (0.01, 0.16)
Arm 2 (N=59)
Pem + Bev
3.5 (2.4, 5.1)
0.10 (0.03, 0.22)
Arm 3 (N=56)
Pem + Bev+ Carbo
4.1 (3.0, 6.4)
0.16 (0.06, 0.29)
Overall Survival
Median OS (95% CI)
14
12-month PFS (95% CI)
Arm 1 (N=48)
Arm 2 (N=59)
Arm 3 (N=56)
Pem Only
Pem + Bev
Pem + Bev+ Carbo
7.6 (3.0, 10.7)
8.7 (5.0, 11.3)
8.8 (5.4, 13.4)
0.28 (0.15, 0.43)
0. 36 (0.23, 0.50)
0.44 (0.29, 0.58)
Adverse Events
Hematologic
ANEMIA
LEUKOPENIA
THROMBOCYTOPENIA
NEUTROPENIA
Non-Hematologic
FATIGUE
NAUSEA
CONSTIPATION
ANOREXIA
DYSPNEA
THROMBOCYTOPENIA
EDEMA PERIPHERAL
COUGH
DEHYDRATION
ASTHENIA
VOMITING
DIARRHEA
WEIGHT DECREASED
PNEUMONIA
EPISTAXIS
PROTEINURIA
BACK PAIN
INSOMNIA
PYREXIA
RASH
ABDOMINAL PAIN
CHEST PAIN
HEADACHE
HYPERTENSION
DIZZINESS
HYPERGLYCEMIA
ARTHRALGIA
CELLULITIS
DYSGEUSIA
PAIN IN EXTREMITY
Grade 1
Arm 1 (N=48)
Grade 2
Grade 3
7 (14.6%)
2 (4.2%)
9 (18.8%)
1 (2.1%)
6 (12.5%)
2 (4.2%)
1 (2.1%)
2 (4.2%)
6 (12.5%)
8 (16.7%)
7 (14.6%)
7 (14.6%)
4 (8.3%)
9 (18.8%)
6 (12.5%)
4 (8.3%)
2 (4.2%)
1 (2.1%)
6 (12.5%)
5 (10.4%)
3 (6.3%)
14 (29.2%)
9 (18.8%)
3 (6.3%)
6 (12.5%)
6 (12.5%)
1 (2.1%)
4 (8.3%)
9 (18.8%)
1 (2.1%)
2 (4.2%)
1 (2.1%)
3 (6.3%)
Grade 1
Arm 2 (N=56)
Grade 2
Grade 3
4 (8.3%)
1 (2.1%)
1 (2.1%)
1 (2.1%)
8 (14.8%)
5 (9.3%)
1 (1.9%)
4 (7.4%)
1 (1.9%)
1 (1.9%)
3 (6.3%)
8 (14.8%)
3 (5.5%)
7 (13.0%)
2 (3.7%)
10 (18.5%)
13 (24.1%)
9 (16.6%)
11 (20.3%)
6 (11.1%)
7 (13.0%)
8 (14.8%)
11 (20.3%)
2 (3.7%)
2 (3.7%)
6 (11.1%)
5 (9.3%)
7 (13.0%)
15 (27.8%)
5 (9.3%)
9 (16.6%)
12 (22.2%)
8 (14.8%)
1 (1.9%)
3 (5.5%)
2 (3.7%)
5 (9.3%)
6 (11.1%)
3 (5.5%)
1 (1.9%)
2 (3.7%)
4 (7.4%)
1 (1.9%)
7 (13.0%)
5 (9.3%)
3 (5.5%)
1 (1.9%)
3 (5.5%)
2 (3.7%)
10 (18.5%)
2 (3.7%)
3 (5.5%)
1 (2.1%)
1 (2.1%)
1 (2.1%)
2 (4.2%)
4 (8.3%)
1 (2.1%)
1 (2.1%)
7 (14.6%)
2 (4.2%)
3 (6.3%)
3 (6.3%)
10 (20.8%)
4 (8.3%)
2 (4.2%)
1 (2.1%)
1 (2.1%)
3 (6.3%)
6 (12.5%)
2 (4.2%)
1 (2.1%)
2 (4.2%)
1 (2.1%)
2 (4.2%)
1 (2.1%)
2 (4.2%)
4 (8.3%)
2 (4.2%)
URINARY TRACT INFECTION 1 (2.1%)
DEPRESSION
1 (2.1%)
ANXIETY
CONFUSIONAL STATE
DYSPHONIA
MUCOSAL INFLAMMATION
VISUAL IMPAIRMENT
COPD
10 (20.8%)
3 (6.3%)
4 (8.3%)
3 (6.3%)
2 (4.2%)
3 (6.3%)
Grade 4
1 (2.1%)
3 (6.3%)
1 (2.1%)
3 (6.3%)
1 (2.1%)
2 (4.2%)
1 (2.1%)
1 (2.1%)
2 (3.7%)
3 (5.5%)
1 (1.9%)
3 (5.5%)
7 (13.0%)
2 (3.7%)
5 (9.3%)
1 (1.9%)
5 (9.3%)
1 (2.1%)
2 (3.7%)
5 (9.3%)
2 (3.7%)
1 (1.9%)
1 (1.9%)
3 (5.5%)
4 (7.4%)
2 (3.7%)
3 (5.5%)
3 (5.5%)
1 (1.9%)
Grade 4
3 (5.8%)
7 (13.5%)
11 (21.2%)
3 (5.8%)
15 (28.8%)
2 (3.8%)
2 (3.8%)
6 (11.5%)
4 (7.7%)
3 (5.8%)
7 (13.5%)
7 (13.5%)
1 (1.9%)
1 (1.9%)
3 (5.8%)
2 (3.8%)
7 (13.5%)
19 (36.5%)
12 (23.1%)
6 (11.5%)
12 (23.1%)
4 (7.7%)
7 (13.5%)
7 (13.5%)
8 (15.4%)
2 (3.8%)
5 (9.6%)
1 (1.9%)
4 (7.7%)
7 (13.5%)
12 (23.1%)
2 (3.8%)
11 (21.2%)
7 (13.5%)
12 (23.1%)
5 (9.6%)
1 (1.9%)
6 (11.5%)
7 (13.5%)
8 (15.4%)
9 (17.3%)
1 (1.9%)
2 (3.8%)
2 (3.8%)
4 (7.7%)
2 (3.8%)
4 (7.4%)
2 (3.7%)
1 (1.9%)
1 (1.9%)
2 (3.7%)
2 (3.7%)
1 (1.9%)
4 (7.4%)
3 (5.5%)
1 (1.9%)
2 (3.7%)
2 (3.7%)
2 (3.7%)
2 (3.7%)
* All Adverse Events per CTCAE version 4 occuring in >5% of the total treated patient population
2 (3.8%)
1 (1.9%)
2 (3.8%)
2 (3.8%)
2 (3.8%)
1 (1.9%)
3 (5.8%)
1 (1.9%)
1 (1.9%)
2 (3.7%)
2 (4.2%)
Arm 3 (N=52)
Grade 2
Grade 3
9 (16.6%)
1 (1.9%)
2 (4.2%)
2 (4.2%)
Grade 1
2 (3.7%)
1 (1.9%)
5 (9.3%)
2 (3.7%)
1 (1.9%)
1 (1.9%)
1 (1.9%)
1 (1.9%)
2 (3.7%)
4 (8.3%)
2 (4.2%)
1 (2.1%)
3 (6.3%)
5 (10.4%)
2 (4.2%)
4 (7.4%)
3 (5.5%)
1 (1.9%)
Grade 4
1 (1.9%)
2 (3.8%)
3 (5.8%)
2 (3.8%)
4 (7.7%)
4 (7.7%)
1 (1.9%)
1 (1.9%)
5 (9.6%)
7 (13.5%)
3 (5.8%)
1 (1.9%)
4 (7.7%)
1 (1.9%)
1 (1.9%)
3 (5.8%)
2 (3.8%)
1 (1.9%)
4 (7.7%)
2 (3.8%)
3 (5.8%)
2 (3.8%)
1 (1.9%)
3 (5.8%)
1 (1.9%)
2 (3.8%)
3 (5.8%)
2 (3.8%)
1 (1.9%)
1 (1.9%)
1 (1.9%)
2 (3.8%)
2 (3.8%)
1 (1.9%)
1 (1.9%)
1 (1.9%)
6 (11.5%)
3 (5.8%)
1 (1.9%)
1 (1.9%)
1 (1.9%)
2 (3.8%)
4 (7.7%)
3 (5.8%)
3 (5.8%)
1 (1.9%)
2 (3.8%)
1 (1.9%)
Conclusions
•
This is the largest prospective trial of bevacizumab in poor
performance status patients with advanced NSCLC.
•
All three regimens were safe and well-tolerated.
•
ORRs with Pem/Bev +/- Cb were encouraging and comparable
to historical outcomes in patients with better performance
status.
Efficacy and Safety of Paclitaxel and Carboplatin
With Bevacizumab for the
First-Line Treatment of Patients With
Nonsquamous Non–Small Cell Lung Cancer:
Analyses Based on Age in the Phase 3 E4599 and
PointBreak Trials
CJ Langer,1 MA Socinski,2 JD Patel,3 AB Sandler,4
JH Schiller,5 L Leon,4 SJ Hazard,4 SS Ramalingam6
1Abramson
Cancer Center, University of Pennsylvania, Philadelphia, PA;
2University of Pittsburgh Medical Center, UPMC Cancer Pavilion, Pittsburgh, PA;
3Feinberg School of Medicine, Northwestern University, Chicago, IL; 4Genentech,
Inc., South San Francisco, CA; 5Harold C. Simmons Cancer Center, University of
Texas Southwestern, Dallas, TX; 6Winship Cancer Institute of Emory University,
Atlanta, GA
Outcomes for Elderly A-NSCLC Pts (28%)treated with
bevacizumab + carboplatin and paclitaxel
Retrospective Analysis of ECOG 4599 Trial
S Ramalingam et al, JCO 2008
The PointBreak Study
Randomized Phase III Trial
Non squam
NSCLC
St IIIB
wet/IV
ECOG PS 0-1
N. Pts: 900
Pr Obj: = OS
CBDCA+ PEM+
BEV x 4
PEM + BEV
Until TOX or PD
R
CBDCA+TAX+
BEV X 4
BEV
until TOX or PD
PointBreak: OS from Randomization (ITT)
Pac+Cb+Bev
13.4
1 .0
OS median (mo)
12.6
0 .9
HR (95% CI); P value
1.00 (0.86, 1.16); P=0.949
Survival rate (%)
1-year
2-year
52.7
24.4
0 .8
S u rvival P ro b ab ility
Pem+Cb+Bev
0 .7
54.1
21.2
0 .6
0 .5
0 .4
0 .3
0 .2
0 .1
0 .0
0
3
6
9
12
15
18
21
24
27
T im e fro m In d u c tio n (M o n th s )
Censoring rate for Pem+Cb+Bev was 27.8%; for Pac+Cb+Bev was 27.2%
30
33
36
39
Elderly Results:
OS in the Pooled Population
Unadjusted Kaplan–Meier estimates for OS among pts (A) <75 yrs and (B) ≥75 yrs receiving PC +
Bev in the pooled population of E4599 and PointBreak relative to pts receiving PC alone in E4599
Proportion Surviving
A. <75 years
HR (95% CI)=0.76 (0.66–0.87)
Log-rank P <.001
0
Pts at risk
n=
n=
Median OS in pts <75 yrs was 13.4 months
with PC + Bev vs 10.2 months with PC (HR,
0.78; 95% CI, 0.68–0.89 )
PC + Bev
PC alone
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
787
401
3
708
352
6
611
288
9
512
218
12
404
169
331
125
15
239
94
18
21 24 27 30
Time (months)
162
61
104
32
67
15
39
9
19
7
33
7
5
36
6
4
39
42
0
1
0
1
2
1
45
48
Proportion Surviving
B. ≥75 years
HR (95% CI)=1.1 (0.74–1.6)
Log-rank P =.652
0
Pts at risk
n=
n=
Median OS in pts ≥75 yrs was 9.6 months
with PC + Bev vs 13.0 months with PC (HR,
1.05; 95% CI, 0.70–1.57)
PC + Bev
PC alone
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
114
43
3
99
37
6
79
30
9
56
24
12
43
21
31
15
15
21
10
18
13
5
21 24 27 30
Time (months)
9
4
6
2
3
0
2
0
33
1
0
36
1
0
1
0
39
42
1
0
1
0
45
48
Bev, bevacizumab; CI, confidence interval; E4599, Eastern Cooperative Oncology Group 4599; HR, hazard ratio; OS, overall survival; PC, paclitaxel + carboplatin.
Conclusions
• This exploratory, pooled analysis of pt data from the E4599
and PointBreak studies demonstrated a statistically significant and
clinically meaningful OS and PFS benefit with the addition of Bev to PC
for all pts <75 yrs of age
• No significant PFS or OS benefit was observed for pts ≥75 yrs of age
receiving PC + Bev compared with PC alone
– Incidence of grade 5 events was 8% vs 2% for PC + Bev vs PC
– However, the small number of pts in this subgroup (n=157) may not
allow firm conclusions to be made
• Outside of a clinical trial, clinicians must use careful judgment
when administering Bev to pts ≥75 yrs with advanced NSCLC
The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80
Expression Customization (BREC) randomized phase III
trial of customized chemotherapy in advanced non-small-cell
lung cancer (NSCLC) patients with wild-type epidermal
growth factor receptor (EGFR) (NCT00617656/GECPBREC)
Rafael Rosell1, Teresa Moran1, manuel A. Cobo Dols2, Manuel Domine3, Maria Sanchez-Ronco4, Isabel Bover5,
Mariano Provencio6, Bartomeu Massuti7, Alain Vergnenegre8, Guillermo Lopez-Vivanco9, Gilles Robinet10, Amelia
Insa11, Margarita Majem12, Ramon De Las Peñas13, Maria Angeles Sala14, Dolores Isla15, Nathalie Baize16, Javier
Garde17, Imane Chaib1, Carlos Camps18
1Catalan
Institute Of Oncology, Badalona/SPAIN, 2HRU Carlos Haya, Malaga/SPAIN, 3Fundacion Jiménez-Díaz, Madrid/SPAIN,
of Alcala de Henares, Madrid/SPAIN, 5Hospital Son Llatzer, Palma De Mallorca/SPAIN, 6Hospital Puerta de Hierro,
Madrid/SPAIN, 7Hospital General de Alicante, Alicante/SPAIN, 8Centre Hospitalier Universitaire de LIMOGES, Limoges/FRANCE,
9Hospital de Cruces de Barakaldo, Vizcaya/SPAIN, 10Hôpital Morvan, Brest/FRANCE, 11Hospital Clínico Universitario, Valencia/SPAIN,
12Hospital de Sant Pau, Barcelona/SPAIN, 13Hospital de Castellon, Castellon/SPAIN, 14Hospital de Basurto, Bilbao/SPAIN, 15Hospital
Lozano Blesa, Zaragoza/SPAIN, 16Hôpital de l'Archet, Nize/FRANCE, 17Hospital Arnau de Vilanova, Valencia/SPAIN, 18Hospital Clínico
Universitario de Valencia, Valencia/SPAIN
4University
BREC (BRCA1 RAP80 Expression Customization)
CONTROL
Advanced
NSCLC
Docetaxel/Cis
1:1
EXPERIMENTAL
T1 RAP80
(T1-T3 BRCA1)
T2-T3 RAP80 (T1T2 BRCA1)
T2-T3 RAP80
(T3 BRCA1)
Presented by: Rafael Rosell
25
Gem/Cis
Docetaxel/Cis
Docetaxel
PFS in control arm and in the experimental groups
Control Arm (n=142): 5.5 months ( 95% CI 5.08-5.91)
Experimental Group 1 (n=45): 5.4 months ( 95% CI 5.08-5.77)
Experimental Group 2 (n=49): 5.5 months ( 95% CI 3.83-7.16)
Experimental Group 3 (n=43): 2.5 months ( 95% CI 1.16-3.84)
2·5
Patients at risk
5·4
5·5
5·5
Control
Exp. Group 3
Exp. Group 1
Exp. Group 2
OS in control arm and in the experimental groups
Control Arm (n=142): 12.66 months ( 95% CI 10.07-15.26)
Experimental Group 1 (n=45): 7.7 months ( 95% CI 3.85-11.55)
Experimental Group 2 (n=49): 11.3 months ( 95% CI 7.66-14.84)
Experimental Group 3 (n=43): 7.3 months ( 95% CI 5.36-9.11)
Exp. Group 2
7·2
7·7
12·7
Exp. Group 3
Control
Exp. Group 1
11·3
Patients at risk
27
Response by treatment arm
Control Arm
Response Rate: 42%
Experimental Arm
Response Rate: 31% ( p: 0.35)
- Group 1: 34%
- Group 2: 40%
- Group 3: 18%
Conclusions
• Prespecified interim analysis of the BREC trial showed a
detrimental effect in the experimental arm.
• BREC trial was prematurely closed
• Interaction between PS and treatment arm.
– Favorable non- significant effect for the experimental arm among patients
with ECOG PS 0
– Significant increased risk of death in the experiental ar in atients with
ECOG PS1
• We are currently examining alternative biomarkers that could
elucidate DNA repair mechanisms.
First-line erlotinib versus cisplatin/gemcitabine (GP) in patients
with advanced EGFR mutation-positive non-small-cell lung cancer
(NSCLC): phase 3,
open-label, ENSURE study
Yi-long Wu,1 Chong-Kin Liam,2 Caicun Zhou,3 Gang Wu,4 Xiaoqing Liu,5 Zhaoyang Zhong,6 Shun Lu,7 Ying
Cheng,8 Baohui Han,7 Lei Chen,9 Yunzhong Zhu,10 Shukui Qin,11
Cheng Huang,12 Hongming Pan,13 Houjie
Liang,14 Enxiao Li,15 Soon Hin How,16
Guoliang Jiang,17 Marie Cherry Lynn Fernando,18 Meng Chen,19
Yunxia Zuo,19 Guia Ladrera20
1Guangdong
Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangdong, China; 2Department of Medicine,
Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 3Department of Oncology, Affiliated Shanghai Pulmonary Hospital of Tongji University,
Shanghai, China; 4Cancer Centre of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 5Internal
Medicine Tumor Department, 307 Hospital of the Academy of Military Medical Sciences, Beijing, China; 6Cancer Centre, Research Institute of Surgery, Daping
Hospital, Third Military Medical University, Chongqing, China; 7Department of Lung Cancer, Shanghai Chest Hospital, Shanghai, China; 8Jilin Cancer Hospital,
Changchun, China; 9Medical Oncology Department, Cancer Hospital of Shantou University Medical College, Shantou, China; 10Lung Cancer Department,
Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China; 11Nanjing Bayi Hospital, Nanjing, China; 12Fujian Provincial Tumor Hospital,
Fujian, China; 13Department of Oncology, Sir Run Run Shaw Hospital, Hangzhou, China; 14Affiliated Xinan Hospital of Third Military Medical University,
Chongqing, China; 15First Affiliated Hospital, Medical School Xi’an Jiaotong University, Xi’an, China; 16Hospital Tengku Ampuan Afzan, Kuantan, Malaysia;
17Cancer Hospital, Fudan University, Shanghai, China; 18Manila Doctors Hospital, Manila, the Philippines; 19Roche (China) Holding Ltd; 20Lung Center of the
Philippines, Quezon City, Philippines
Kaplan–Meier curves for
PFS assessed by IRC
ORR and DCR results
•
OS data were still immature at the latest data cut-off
•
ORR and DCR for the interim and updated analyses are shown
EGFR mutation
subgroup analysis
•
Meaningful treatment benefit was observed in both EGFR mutation type subgroups (exon 19 deletions and
exon 21 L858R mutations), and was more marked in the exon 19 deletion subgroup
AEs of special interest
Conclusions
• These analyses demonstrate that erlotinib provides statistically
significant and clinically meaningful improvement in investigatorassessed PFS, which was corroborated by IRC assessment,
compared with GP in Asian patients with EGFR mutation-positive
NSCLC
• Primary efficacy results were also supported by secondary
endpoints including ORR and DCR, with no new safety concerns
compared with previous studies of erlotinib
• These results support the data from other first-line studies in
Asian populations, showing that erlotinib provides a PFS benefit
over chemotherapy in this patient subgroup with EGFR mutationpositive NSCLC1,2
1. Zhou C, et al. Lancet Oncol 2011
2. Goto K, et al. Lung Cancer 2013
Activity of afatinib in uncommon epidermal
growth factor receptor (EGFR) mutations:
Findings from three prospective trials of afatinib
in EGFR mutation-positive lung cancer
J. C.-H. Yang1, L.V. Sequist2, S. L. Geater3, C.-M. Tsai4, T. Mok5, M. H. Schuler6,
N. Yamamoto7, D. Massey8, V. Zazulina8, Yi-Long Wu9
1National
Taiwan University Hospital, Taipei, Taiwan; 2Massachusetts General Hospital, Boston, MA, USA;
of Respiratory and Respiratory Critical Care Medicine, Department of Internal Medicine, Faculty of Medicine,
Prince of Songkla University, Songkhla, Thailand; 4Taipei Veterans General Hospital, Taipei, Taiwan;
5The Chinese University of Hong Kong, Hong Kong; 6West German Cancer Center, University Duisburg-Essen, Essen, Germany; 7Shizuoka Cancer
Center, Shizuoka, Japan; 8Boehringer Ingelheim Limited, Bracknell, UK; 9Guangdong Lung Cancer Institute, Guangdong General Hospital and
Guangdong Academy of Medical Sciences, Guangzhou, China
3Division
EGFR mutation-positive patients in LUX-Lung trials
LUX-Lung 2
LUX-Lung 3
LUX-Lung 6
Phase II
(1 or 2 line)
Phase III
(A vs CisPem)
Phase III
(A vs CisGem)
N=129
N=345
N=364
Del19
n=408
n=52
n=170
n=186
L858R
n=330
n=54
n=138
n=138
Uncommon
n=100
n=23
n=37
n=40
Patients with uncommon mutations treated with afatinib
Uncommon
n=75
3
n=23
n=26
n=26
Objective response and disease control rates
Independent review
Other
n=38
Objective response rate (CR +
PR), n (%)
Median duration of response,
months
(range)
Disease control rate
(CR + PR + SD), n (%)
De novo
T790M
n=14
Exon 20 insertions
n=23
2 (14.3%)
2 (8.7%)
27 (71.1%)
8.2 (4.1–12.4)
7.1 (4.2–10.1)
11.1 (1.3–35.0+)
9 (64.3%)
15 (65.2%)
32 (84.2%)
Progression-free survival and overall survival in patients
Independent review
De novo T790M
n=14
Exon 20 insertions
n=23
Other
n=38
Median PFS, months
(range)
2.9
(0.3−13.8)
2.7
(0.4-11.9)
10.7
(0.0+-35.8+)
Median OS, months
(range)
14.9
(1.5-30.5)
9.4
(0.4-32.2+)
18.6
(0.0+-51.3+)
Conclusions
• Largest prospective dataset in patients with uncommon EGFR
mutations (n=75)
• High heterogeneity within the subgroup with uncommon
EGFR mutations
• Low response rate in patients with exon 20 insertions
and T790M tumours
– Durable tumour control observed in some cases
(PFS up to 13.8 months)
• Activity was observed in other exon 18 (G719X),
20 (S768I) and 21 (L861Q) mutations that are known
to be less responsive to reversible EGFR TKIs
– Activity was in the range of efficacy observed with afatinib in common
EGFR mutations
INDIRECT COMPARISONS OF EFFICACY AND
SAFETY PROFILE OF EGFR TYROSINE
KINASE INHIBITORS AS FIRST-LINE
TREATMENT IN EGFR MUTATED NSCLC
PATIENTS: A SYSTEMATIC REVIEW AND
META-ANALYSIS
Eva Regina Haspinger*, Francesco Agustoni*, Francesco
Gelsomino*, Marina Chiara Garassino*, Valter Torri** and
Michela Cinquini**
* Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
**Laboratorio di Metodologia per la Ricerca Biomedica Dipartimento di Oncologia
"IRCCS - Istituto di Ricerche Farmacologiche Mario Negri"
RESULTS: Relative Risks for PFS
RESULTS: Relative Risks for overall response rate
RESULTS according to AEs (any grade): skin toxicity (panel A),
diarrhea (panel B) and hypertransaminasemia (panel C)
Indirect comparisons among EGFR-TKIs: Panel A (gefitinib vs
erlotinib), panel B (gefitinib vs afatinib), panel C (erlotinib vs afatinib)
Panel A
Panel B
Panel C