phase 3 trial of everolimus in previously treated patients with advanced gastric cancer: granite-1...
TRANSCRIPT
Phase 3 Trial of Everolimus in Previously Treated Patients With
Advanced Gastric Cancer: GRANITE-1
Eric Van Cutsem*,
K. H. Yeh, Y. J. Bang, L. Shen, J. A. Ajani, Y. X. Bai, H. C. Chung, H. M. Pan, K. Chin, K. Muro, Y.
H. Kim, H. Smith, C. Constantini, S. Rizvi, T. Sahmoud, A. Ohtsu
On behalf of the GRANITE-1 Investigators
* University Hospital Leuven/Belgium
Presented at the 2012 Gastrointestinal Cancers Symposium. 1
Background
• Gastric cancer is aggressive and difficult to treat1
• 5-year survival rate for advanced, metastatic disease is <5%2,3
• After failure of first-line chemotherapy, available treatment options provide minimal benefit and are associated with considerable toxicity1,4,5
2
1Catalano V et al. Crit Rev Hematol Oncol. 2009;71:127-34; 2American Cancer Society. Cancer Facts & Figures 2011; 3Matsuda T et al. Jpn J Clin Oncol. 2011;41:40-51; 4Wagner AD et al. Cochrane Database Syst Rev. 2010;CD004064; 5Field K et al. Drugs. 2008;68:299-317.
PI3K/Akt/mTOR Pathway in Gastric Cancer
• The PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, is dysregulated in 50%-60% of gastric cancers1-3
• Everolimus, an oral mTOR inhibitor, showed efficacy in preclinical models of gastric cancer1,4-6
3
mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.
1Xu DZ et al. BMC Cancer. 2010;10:536; 2Lang SA et al. Cancer. 2007;120:1803-10; 3Yu G et al. Clin Cancer Res. 2009;15:1821-29; 4Taguchi F et al. Invest New Drugs. 2011;29:1198-205; 5Cejka D et al. Anticancer Res. 2008;28:3901-08; 6Jaeger-Lansky A et al. Cancer Biol Ther. 2010;9:919-27; 7Doi T et al. J Clin Oncol. 2010;28:1904-1910.
• In a phase 2 study of 53 patients with previously treated advanced gastric cancer, everolimus showed promising efficacy and acceptable tolerability7
Phase 3 GRANITE-1 Study Design
4
Everolimus 10 mg PO daily
+ BSC*(n = 439)
Placebo PO daily+
BSC(n = 217)
SC
RE
EN
Treatment until disease progression
or intolerable
toxicity
• Stratification by region: Asia vs rest of world• Stratification by number of lines of previous
systemic chemotherapy (1 vs 2)
Safety follow-up: EOT + 28 d
Survival follow-up: every 3 mo
RA
ND
OM
IZE
(N =
656
)
BSC, best supportive care; EOT, end of treatment; PO, orally.
ClinicalTrials.gov identifier: NCT00879333.
2
1
Eligibility Criteria
5
• >2 previous systemic therapies for advanced disease
• Anticancer therapy within 3 weeks* or major surgery within 2 weeks of randomization
• Chronic treatment with steroids or immunosuppressive agents
• Enteral feeding
• CNS metastases
• Any severe/uncontrolled medical condition
• Age ≥18 years
• Confirmed gastric adenocarcinoma
– GEJ adenocarcinomas permitted if the majority involved the stomach
• Documented progression after 1 or 2 lines of previous systemic chemotherapy
• ECOG performance status ≤2
• Adequate bone marrow, renal, and hepatic function
Key Inclusion Criteria Key Exclusion Criteria
*Fluoropyrimidine monotherapy was permitted up to 2 weeks before randomization.
CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction.
Study Endpoints
• Primary: OS• Secondary
– PFS– ORR*– AEs as assessed by NCI CTCAE, version 3.0– Time to definitive deterioration of ECOG PS– Time to definitive 5% deterioration in the global health
status/quality of life scale of the EORTC QLQ-C30 questionnaire
• Exploratory– Correlation between biomarkers and clinical endpoints
6
*ORR: overall response rate according to RECIST, version 1.0.
AE, adverse event NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; RECIST, Response Evaluation Criteria In Solid Tumors.
Statistical Considerations
• Between-group OS comparison performed using stratified log-rank test at overall one-sided 2.5% level, stratified by protocol stratification factors
• Single interim analysis planned after 60% of required deaths observed– At time of interim analysis (cut-off date of Jan 31, 2011), IDMC
recommended continuing study without any changes
• Sample size calculation– Considering randomization scheme and planned interim analysis,
estimated that 526 deaths would give study 90% power to detect a 26% difference in the risk of death, corresponding to prolongation in OS from 4.0 months with placebo to 5.4 months with everolimus
– Assuming uniform patient accrual over 2 years, 6 months of follow-up, and 5% loss to follow-up, determined that 633 patients needed to be enrolled
• Hierarchical testing strategy– Formal statistical significance for PFS could be declared only if between-
group difference in OS statistically significant
7
Patient Disposition
8
Patients randomly assigned (N = 656)
Everolimus + BSC (n = 439) Placebo + BSC (n = 217)
Ongoing (n = 11; 2.5%)Discontinued treatment (n = 428; 97.5%)
– Disease progression (n = 292; 66.5%)– AEs (n = 94; 21.4%)– Abnormal laboratory values (n = 1; 0.2%)– Withdrew consent (n = 20; 4.6%)– Administrative problems (n = 2; 0.5%)– Death NOS (n = 16; 3.6%)– Lost to follow-up (n = 2; 0.5%)– Protocol deviation (n = 1; 0.2%)
Ongoing (n = 0; 0%)Discontinued treatment (n = 217; 100%)
– Disease progression (n = 169; 77.9%)– AEs (n = 34; 15.7%)– Abnormal laboratory values (n = 0; 0%)– Withdrew consent (n = 7; 3.2%)– Administrative problems (n = 0; 0%)– Death NOS (n = 5; 2.3%)– Lost to follow-up (n = 1; 0.5%) – Protocol deviation (n = 1; 0.5%)
Full analysis set (n = 439)Safety set (n = 437)
Full analysis set (n = 217)Safety set (n = 215)
NOS, not otherwise specified.
GRANITE-1: Participating Countries
9
Baseline Demographics and Disease Characteristics (FAS)
10
Everolimus + BSC (n = 439)
Placebo + BSC (n = 217)
Age, yrs, median (range) 62.0 (20.0-86.0) 62.0 (26.0-88.0)
Age <65 yrs 260 (59.2) 129 (59.4)
Male, n (%) 322 (73.3) 161 (74.2)
Race, n (%)
Caucasian 166 (37.8) 75 (34.6)
Asian 251 (57.2) 126 (58.1)
Other 22 (5.0) 16 (7.4)
Region, n (%)
Asia 243 (55.4) 120 (55.3)
Rest of world 196 (44.6) 97 (44.7)
ECOG performance status, n (%)
0 144 (32.8) 70 (32.3)
1 269 (61.3) 120 (55.3)
2 25 (5.7) 27 (12.4)
FAS, full analysis set.
Baseline Disease Characteristics (FAS)
11
Everolimus + BSC (n = 439)
Placebo + BSC (n = 217)
Anatomical site, n (%)
Proximal 162 (36.9) 94 (43.3)
Distal 276 (62.9) 123 (56.7)
GEJ involvement, n (%) 118 (26.9) 69 (31.8)
Lauren classification, n (%)
Adenocarcinoma, diffuse 93 (21.2) 37 (17.1)
Adenocarcinoma, intestinal 82 (18.7) 50 (23.0)
Adenocarcinoma, mixed 29 (6.6) 18 (8.3)
Adenocarcinoma, NOS 105 (23.9) 45 (20.7)
Other 129 (29.4) 67 (30.9)
Previous gastrectomy, n (%)
Partial 126 (28.7) 60 (27.6)
Total 97 (22.1) 46 (21.2)
Previous lines of chemotherapy, n (%)
1 210 (47.8) 103 (47.5)
2 229 (52.2) 114 (52.5)
Exposure to Study Treatment (Safety Set)
12
Everolimus + BSC (n = 437)
Placebo + BSC (n = 215)
Duration, wks, median (range) 7.1 (0.1-79.6) 6.4 (0.4-90.9)
Duration, wks, mean (SD) 11.5 (12.09) 8.5 (8.76)
Duration of exposure, wks, n (%)
<4 84 (19.2) 49 (22.8)
4 to <8 163 (37.3) 101 (47.0)
8 to <12 55 (12.6) 23 (10.7)
12 to <16 46 (10.5) 20 (9.3)
16 to <20 26 (5.9) 7 (3.3)
20 to <24 12 (2.7) 3 (1.4)
24 to <28 9 (2.1) 5 (2.3)
28 to <32 7 (1.6) 2 (0.9)
≥32 35 (8.0) 5 (2.3)
Overall Survival (FAS)
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Pro
bab
ilit
y o
f o
vera
ll s
urv
ival
(%
) 100
80
60
40
20
00 2 4 6 8 10 12
Time (months)
14
Censoring TimesEverolimus + BSC (n/N = 352/439)Placebo + BSC (n/N = 180/217)
Kaplan-Meier medians Everolimus + BSC: 5.39 months Placebo + BSC: 4.34 months
Hazard ratio: 0.90 (95% CI, 0.75-1.08)Log-rank P value = 0.1244
No. of patients still at riskTime (months)EverolimusPlacebo
16 18 20 22 24
0 2 4 6 8 10 12 14 16 18 20 22 24
217 172 117 82 60 35 28 16 12 8 4 1 0439 355 253 195 139 87 52 30 13 6 3 1 0
Overall Survival by Stratification Factors (FAS)
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ROW, rest of world.
Priorchemotherapy
Region
Cross-class.of strata
Hazard Ratio(95% CI)
0.80.6Everolimus
10 mg/dPlacebo
In favor of
1.0 1.2 1.4
All (N = 656) 0.90 (0.75-1.08)
2 (n = 343) 0.90 (0.70-1.15)
Asia (n = 363) 0.96 (0.75-1.23)
ROW (n = 293) 0.85 (0.65-1.10)
1 prior chemo & ROW (n = 167) 0.91 (0.64-1.31)
2 prior chemo & ROW (n = 126) 0.74 (0.50-1.09)
1 (n = 313) 0.94 (0.73-1.23)
0.98 (0.71-1.35)2 prior chemo & Asia (n = 217)
0.94 (0.63-1.39)1 prior chemo & Asia (n = 146)
Progression-Free Survival (FAS)
15
Pro
bab
ilit
y o
fp
rog
res
sio
n-f
ree
su
rviv
al (
%)
100
80
60
40
20
00 2 4 6 7 9 10
Time (months)
12
Censoring TimesEverolimus + BSC (n/N = 386/439)Placebo + BSC (n/N = 206/217)
Kaplan-Meier medians Everolimus + BSC: 1.68 months Placebo + BSC: 1.41 months
Hazard ratio: 0.66 (95% CI, 0.56-0.78)Log-rank P value < 0.0001
No. of patients still at riskTime (months)EverolimusPlacebo
14 15 17 21
0 2 4 5 7 9 11 12 14 16 17 20 21
217 55 23 17 7 3 2 2 2 2 2 1 0439 179
1
168367 92
3
28117 60
6
844 37 20
8
627 10
10
213 6 3 2
15
23
13
25 1
19
20
18
21 0 0
18 2019161311851 3
Tumor Response (Patients With Measurable Disease)
16
DCR, disease control rate.
Everolimus + BSC (n = 379)
Placebo + BSC (n = 191)
Best overall response, n (%)
CR 1 (0.3) 0
PR 16 (4.2) 4 (2.1)
SD 147 (38.8) 38 (19.9)
PD 157 (41.4) 119 (62.3)
Unknown 58 (15.3) 30 (15.7)
ORR (CR + PR), n (%) 17 (4.5) 4 (2.1)
DCR (CR + PR + SD), n (%) 164 (43.3) 42 (22.0)
Best Percentage Change From Baseline in Tumor Size
17
Bes
t %
ch
an
ge
fro
m b
asel
ine
(me
asu
rab
le l
esio
ns
)
160%
140%
120%
100%
80%
60%
40%
20%
0%
–20%
–40%
–60%
–80%
–100%
160%
140%
120%
100%
80%
60%
40%
20%
0%
–20%
–40%
–60%
–80%
–100%
Everolimus 10 mg/day (n = 304) Placebo (n = 154)
º No change º No change
Everolimus + BSC (n = 304)
Placebo + BSC (n = 154)
Decrease in best percentage change from baseline, n (%) 115 (37.8) 19 (12.3)
Zero change in best percentage change from baseline, n (%) 16 (5.3) 2 (1.3)
Increase in best percentage change from baseline, n (%) 109 (35.9) 98 (63.6)
Best % change from baseline available but contradicted by overall lesion response of progressive disease, n (%)
64 (21.1) 35 (22.7)
Summary of Adverse Events and Deaths (Safety Set)
Everolimus + BSC
(n = 437)
Placebo + BSC
(n = 215)
Any AE, n (%) 433 (99.1) 208 (96.7)
Any grade 3/4 AE, n (%) 310 (70.9) 115 (53.5)
Any serious AE, n (%) 207 (47.4) 89 (41.4)
AE leading to discontinuation, n (%) 94 (21.5) 34 (15.8)
AE requiring dose interruption/reduction, n (%) 242 (55.4) 46 (21.4)
AE requiring additional therapy, n (%) 395 (90.4) 174 (80.9)
All deaths, n (%) 352 (80.5) 179 (83.3)
On-treatment deaths*, n (%) 88 (20.1) 49 (22.8)
Study indication as primary cause 79 (18.1) 45 (20.9)
Other primary cause 9 (2.1) 4 (1.9)
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*On-treatment deaths are those that occurred during study treatment and up to 28 days after treatment discontinuation.
Most Common All-Cause Adverse Events (Safety Set)
Adverse Event, n (%)
Everolimus + BSC (n = 437)
Placebo + BSC (n = 215)
All grades Grade 3/4 All grades Grade 3/4
Nonhematologic
Decreased appetite 208 (47.6) 48 (11.0) 78 (36.3) 12 (5.6)
Stomatitis 174 (39.8) 20 (4.6) 23 (10.7) 0
Fatigue 150 (34.3) 34 (7.8) 65 (30.2) 11 (5.1)
Nausea 132 (30.2) 16 (3.7) 69 (32.1) 8 (3.7)
Diarrhea 115 (26.3) 15 (3.4) 33 (15.3) 2 (0.9)
Hematologic
Anemia 114 (26.1) 70 (16.0) 42 (19.5) 27 (12.6)
Thrombocytopenia 80 (18.3) 22 (5.0) 5 (2.3) 3 (1.4)
Neutropenia 47 (10.8) 17 (3.9) 6 (2.8) 1 (0.5)
Abnormal biochemistry
Hypokalemia 52 (11.9) 26 (5.9) 9 (4.2) 2 (0.9)
Blood alkaline phosphatase increased 34 (7.8) 20 (4.6) 6 (2.8) 3 (1.4)
Aspartate aminotransferase increased 34 (7.8) 14 (3.2) 8 (3.7) 2 (0.9)
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Conclusions
• Compared with BSC, everolimus did not significantly reduce the risk of death in patients with advanced gastric cancer
• Everolimus did reduce the risk of progression or death compared with BSC
• The safety profile of everolimus was similar to that observed with everolimus in other cancers, with no new safety signals identified
• Biomarker analysis is ongoing
20
Acknowledgements
• The patients participating in this trial and the study investigators
• Independent data monitoring committee– Roberto Labianca (chair)– Ichinosuke Hyodo (member)– Ian Ford (biostatistician)
• The Novartis teams
• Steering committee members– Eric Van Cutsem (co-chair)– Atsushi Ohtsu (co-chair)– Jaffer Ajani– Yung-Jue Bang– Lin Shen– Kun-Huei Yei– Chiara Constantini– Syed Rizvi– Tarek Sahmoud– Heind Smith
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