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

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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)

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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

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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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