Transcript Avastin In Lung (AVAiL) Study Results LCC Meeting – Feb 19th

Results of Docetaxel Plus Oxaliplatin (DOCOX)
+/- Cetuximab in Patients with Metastatic
Gastric and/or Gastroesophageal
Junction Adenocarcinoma:
Results of a Randomized Phase II Study
Donald Richards, MD, PhD1,2; Darren M. Kocs,MD1,3;
Alexander I. Spira, MD1,4; A. David McCollum, MD1,5;
Kristi Boehm, MS1; Feng Zhan, PhD1; Lina Asmar, PhD1
1US
Oncology Research, LLC, The Woodlands, TX; 2Tyler Cancer
Center, Tyler, TX; 3Texas Oncology, PA, Round Rock, TX;
4Virginia Cancer Specialists, PC , Fairfax, VA;
5Baylor-Charles Sammons Cancer Center, Dallas, TX
ASCO, 2011
Abstract
Background
Advanced adenocarcinoma of the gastroesophageal
junction and adenocarcinoma of the stomach are
standardly treated by combination chemotherapy
resulting in minimal improvements in survival. This
noncomparative study evaluated the value of adding
cetuximab (C) to combination chemotherapy.
2
Abstract Continued
Methods
•
Primary objective - Progression-free survival (PFS).
•
Secondary objectives: 1-yr survival, response rate, time to response
(TTR), duration of response (DOR), correlation of KRAS type of
mutation to response, safety.
•
Treatment:
- Arm 1: DOCOX=docetaxel 60 mg/m2 + oxaliplatin 130 mg/m2 on Day
1 of each 21-day cycle.
- Arm 2: DOCOX+C = DOCOX with C 400 mg/m2 first dose then 250
mg/m2 weekly
• Inclusion: stage IV adenocarcinoma of the GEJ/stomach; measurable
disease; ECOG 0-2; and normal renal, hepatic, and marrow function.
• Exclusion: Prior Tx other than adjuvant radiation with 5-FU/leucovorin.
• Tissue was collected to correlate responses with KRAS status.
3
Abstract Continued
Results
• 150 pts enrolled; 75/arm.
• Demographics Arm 1/2: male 79%/80%, median age 61.7/64.0 yrs;
disease site: gastric 44%/41%, GEJ 51%/55%, both 5%/4%;
95%/96% had surgery, and 7%/5% had radiation.
• Response rates/arm: 26.5%/34.7%. Median PFS: 4.2/5.1 mo (95% C.I.
3.0-5.4 - 4.3-5.9); 1-yr survival: 39.7%/32.4%; median overall
survival: 9.0/9.4 mo; median TTR: 1.3/1.4 mo, and median DOR:
7.3/7.2 mo.
• AEs: Most frequent Grade 3-4 treatment-related AEs (%) included
neutropenia (48.5/43.1), diarrhea (11.8/16.7), febrile neutropenia
(13.2/18.1), fatigue (11.8/15.3). Discontinuation due to AEs
21/35 or progressive disease 37/31. AEs were mainly GI,
hematologic, or neuropathic.
• KRAS:Both treatment regimens seem to be more effective in the wild
type KRAS than in the mutated type.
4
Abstract Continued
Conclusions
• The addition of C to DOCOX may improve RR minimally
• No significant improvement in PFS, OS, or 1-yr survival
• C did not produce clinically significant benefit when added to the
backbone of DOCOX.
• Toxicities were consistent with the known safety profiles of the
study drugs.
• Treatment regimens were more effective in wild type than in
mutated KRAS
This research was supported, in part, by grants from sanofi-aventis,
Bridgewater, NJ, and Lilly/ImClone, Indianapolis, IN.
5
Study Objectives
Primary Objective
• To determine the progression-free survival produced by the combination
of docetaxel (Taxotere) + oxaliplatin (Eloxatin) (Arm 1 - DOCOX)
versus DOCOX + cetuximab (ERBITUX) (Arm 2 - DOCOX+C)
Secondary Objectives
• 1-year survival
• Response rate (CR+PR)
• Time to response
• Duration of response (DOR)
• Correlation of KRAS mutation type (mutant vs wild) to response
(in patients with available tissue)
• Toxicity
6
Treatment Schedule
Arm 1
Day
1
8
15
22
Taxotere
DOCOX
60 mg/m2
Eloxatin
130 mg/m2
Rest
Rest
Day 1 of next cycle
Rest
Rest
Arm 2
Day
1
8
15
22
Taxotere
Eloxatin
DOCOX+C
60 mg/m2 130 mg/m2
Rest
Rest
Rest
Rest
Day 1 of next cycle
Erbitux
400 mg/m2*
(250 mg/m2)
250 mg/m2
250 mg/m2
7
Treatment Schedule Continued
• *400 mg/m2 on Day 1 of Cycle 1 only; 250 mg/m2 for all
other doses.
• Cycles continued until disease progression or intolerable
toxicity.
• Pts were followed for 2 years.
8
Patient Characteristics (ITT Population)
Sex (n[%])
Race (n[%])
Age at Registration (yr)
Baseline ECOG (n [%])
Stage at Diagnosis (n [%])
Histopathologic Grade (n[%])
Site of Primary Disease (n [%])
Female
Male
Caucasian
Black
Hispanic
Asian
Hawaiian
Other
Median
(Min, Max)
0
1
2
I
II/IIA/IIB
III/IIIA/IIIB
IV/IVA/IVB
Unknown
G1 (Well differentiated)
G2 (Moderately differentiated)
G3 (Poorly differentiated)
G4 (Undifferentiated)
GX/Unknown
Gastric Adenocarcinoma
Body
Fundus
Pyl Antrum
Gastroesophageal Junction
Both
DOCOX
N=75
16 (21.3)
59 (78.7)
62 (82.7)
5 (6.7)
5 (6.7)
3 (4.0)
0
0
61.7
(25.2, 82.2)
26 (34.7)
42 (56.0)
7 (9.3)
1 (1.3)
4 (5.3)
3 (4.0)
62 (82.7)
5 (6.7)
DOCOX+C
N=75
15 (20.0)
60 (80.0)
56 (74.7)
7 (9.3)
9 (12.0)
1 (1.3)
1 (1.3)
1 (1.3)
64.0
(25.2, 83.7)
33 (44.0)
33 (44.0)
9 (12.0)
1 (1.3)
5 (6.7)
3 (4.0)
55 (73.3)
11 (14.7)
1 (1.3)
24 (32.0)
38 (50.7)
2 (2.7)
10 (13.3)
33 (44.0)
22
6
5
38 (50.7)
4 (5.3)
4 (5.3)
20 (26.7)
41 (54.7)
0
10 (13.3)
31 (41.3)
14
7
10
41 (54.7)
3 (4.0)
9
Results
Survival (ITT Population)
DOCOX DOCOX+C
N=75
N=75
Estimated PFS at 1 year
12.5%
4.8%
Estimated OS at 1 year
39.7%
32.4%
10
Results Continued
Kaplan-Meier Curves of Progression-Free Survival
(PFS) (ITT Population)
1.0
0.9
0.8
Median PFS
Estimated PFS Rate
0.7
DOCOX
DOCOX+C
0.6
4.2
5.1
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
Month
11
Results Continued
Kaplan-Meier Curves of Overall Survival (OS)
(ITT Population)
1.0
0.9
0.8
Estimated OS Rate
0.7
Median OS
0.6
DOCOX
DOCOX+C
9.0
9.4
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
Month
12
Responses
Responses
(Evaluable Population)*
Overall Response
CR+PR
Median TTR (Months)
All CR+PR pts
DOCOX
N=68
DOCOX+C
N=72
18
(26.5%)
25
(34.7%)
1.3
1.4
Median DOR (Months)
All CR+PR pts
7.3
7.2
*ITT population minus 7/3 pts found either ineligible after
randomization or not treated
13
Responses Continued
Kaplan-Meier Curves of Duration of Response (DOR)
(Evaluable Population)
1.0
0.9
0.8
Estimated DOR Rate
0.7
DOCOX
DOCOX+C
0.6
Median DOR
7.3
0.5
7.2
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
Month
14
Treatment-Related AEs
Most Frequent Grade 3-4 Treatment-Related
Adverse Events
DOCOX
DOCOX+C
N (%)*
N (%)*
Neutropenia
33 (48.5)
31 (43.1)
Febrile Neutropenia
9 (13.2)
13 (18.1)
Diarrhea
8 (11.8)
12 (16.7)
Fatigue
8 (11.8)
11 (15.3)
Leukopenia
5 (7.4)
10 (13.9)
Dehydration
4 (5.9)
7 (9.7)
Hypokalemia
2 (2.9)
3 (4.2)
General Weakness
2 (2.9)
3 (4.2)
*Pts received at least 1 dose of study drug.
15
KRAS Analysis
Best Overall Responses by KRAS Status
KRAS
Best
Response
Wild Type
DOCOX
N=68
DOCOX+C
N=72
CR
PR
SD
PD
NE
0
4
9
1
0
0
9
5
1
0
Mutated
CR
PR
SD
PD
NE
0
1
0
0
0
0
1
1
0
0
(Unknown)
CR
PR
SD
PD
NE
Pending
1
12
20
12
7
1
2
13
24
3
19
3
16
Conclusions
• Addition of C to DOCOX may improve RR minimally.
• There appears to be no significant improvement in
PFS, OS, or 1-year survival.
• C did not produce a clinically significant benefit when
added to DOCOX.
• Toxicities were consistent with the known safety
profiles of the study drug.
• DOCOX and DOCOX+C seem to have a greater effect
in patients with wild-type versus mutated-type KRAS.
17