1
First interim results of GIDEON:oncologists and non-oncologists
appear to use sorafenib differently
Alan P Venook, MD
University of California, San Francisco, USA
R Lencioni, JA Marrero, M Kudo, K Nakajima, F Cihon, SL Ye
2
ASCO conflict of interestdisclosure for Alan P Venook
• Consultant or advisory role
– Yes, NCCN
• Stock ownership and/or employment
– No
• Honoraria received
– No
• Research funding received
– Yes, Bayer, Onyx, Genentech, Novartis, Roche, Pfizer, NCCN
• Expert testimony
– No
• Other remuneration
– No
3
Introduction
• Sorafenib is the only systemic therapy indicatedto treat HCC
– In two Phase III studies (SHARP and Asia-Pacific), sorafenib significantly improved OS in patients with HCC
– Survival was distinctly different across regions
• The ongoing GIDEON registry study aims to evaluate the use of sorafenib in clinical practice conditions
• GIDEON goal is to recruit ~3000 patients from >400 sites in >40 countries
HCC, hepatocellular carcinoma; OS, overall survival
4
SHARP: OS
Adapted from Llovet JM et al. N Engl J Med 2008; 359: 378-390
Months since randomization
Pro
bab
ilit
y o
f su
rviv
al
0
0.25
0.50
0.75
1.00 SorafenibMedian: 10.7 months (95% CI: 9.4-13.3)
SorafenibMedian: 10.7 months (95% CI: 9.4-13.3)
PlaceboMedian: 7.9 months(95% CI: 6.8-9.1)
PlaceboMedian: 7.9 months(95% CI: 6.8-9.1)
HR (S/P): 0.69(95% CI: 0.55-0.87)
p<0.001
HR (S/P): 0.69(95% CI: 0.55-0.87)
p<0.001
SorafenibPatients at risk
Placebo
0
299303
1
290295
2
270272
3
249243
4
234217
5
213189
6
200174
7
172143
8
140108
9
11183
10
8969
11
6847
12
4831
13
3723
14
2414
15
76
16
13
17
00
5
Asia-Pacific: OSS
urv
ival
pro
bab
ilit
y
HR (S/P): 0.68(95% CI: 0.50-0.93)
p=0.014
0.25
0.50
0.75
1.00
0
Months since randomization0
15076
2
13462
4
10341
8
5323
10
3215
12
219
14
155
16
134
20
10
22
00
SorafenibPatients at risk
Placebo7826
6
41
18
Adapted from Cheng AL et al. Lancet Oncol 2009; 10: 25-34Adapted from Cheng AL et al. Lancet Oncol 2009; 10: 25-34
PlaceboMedian: 4.2 months (95% CI: 3.7-5.5)
PlaceboMedian: 4.2 months (95% CI: 3.7-5.5)
SorafenibMedian: 6.5 months (95% CI: 5.6-7.6)
SorafenibMedian: 6.5 months (95% CI: 5.6-7.6)
6
SHARP10.7 months
7.9 months
Asia-Pacific: OSS
urv
ival
pro
bab
ilit
y
HR (S/P): 0.68 (95% CI: 0.50-0.93)
p=0.014
0.25
0.50
0.75
1.00
0
Adapted from Cheng AL et al. Lancet Oncol 2009; 10: 25-34Adapted from Cheng AL et al. Lancet Oncol 2009; 10: 25-34
SorafenibMedian: 6.5 months (95% CI: 5.6-7.6)
SorafenibMedian: 6.5 months (95% CI: 5.6-7.6)
PlaceboMedian: 4.2 months (95% CI: 3.7-5.5)
PlaceboMedian: 4.2 months (95% CI: 3.7-5.5)
Months since randomization0
15076
2
13462
4
10341
8
5323
10
3215
12
219
14
155
16
134
20
10
22
00
SorafenibPatients at risk
Placebo7826
6
41
18
7
Asia-Pacific Liver Cancer Study and SHARP:baseline patient characteristics
Asia-Pacific(n=226)
SHARP(n=602)
Median age (range), years 51 (23-86) 67 (21-89)Hepatitis virus status (HBV/HCV), % 73/8 18/28Sex (male), % 85 87ECOG PS (0/1/2), % 26/69/5 54/38/8Macroscopic vascular invasion, % 35 38Extra-hepatic spread, % 69 51BCLC stage (B/C), % 4/96 17/82
No. of tumor sites, %
1 11 44 2 35 31 3 20 12 ≥4 35 13
Sites of disease, %
Lung 50 21 Lymph node 32 26BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status
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The GIDEON registry study
• The primary objective is to evaluate the safety of sorafenib in patients with HCC under real-life practice conditions
• GIDEON should:
– provide information on treatment patterns and outcomes for patients with HCC
– provide data on patients who would not have been eligible for sorafenib clinical trials
– enable a greater understanding of practice in the real-world setting
• GIDEON may:
– help explain differences in outcome by region
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GIDEON first interim analysis
• The first interim analysis was planned when ~500 patients had been followed for ≥4 months
• There were no pre-specified interventions
• Data were collected prior to the start of sorafenib treatment, then patients who received sorafenib were followed up as per physicians’ usual practice
• 511 patients enrolled (140 sites)
• 479 patients (safety population) reported here
– Results of preplanned subgroup analyses are included
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GIDEON: first interim analysisdistribution of patientsa by region
aIn the safety population (N=479)
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Table 1. Patients by region and specialty
Hep/GIn (%)
Med Oncn (%)
Surgeryn (%)
Othera
n (%)
Asia-Pacific, n=167 88 (53) 58 (35) 6 (4) 14 (8)
Europe, n=143 93 (65) 40 (28) 2 (1) 4 (3)
USA, n=116 39 (34) 62 (53) 10 (9) 2 (2)
Latin America, n=32 18 (56) 8 (25) 6 (19) 0
Japan, n=21 10 (48) 0 11 (52) 0
Total,b N=479 248 (52) 168 (35) 35 (7) 20 (4)
aOther includes radiology, anesthesiology, and traditional Chinese medicine
bIncludes all specialties; missing data not tabulated
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Child-Pugh: classificationseverity of liver disease
Pugh RN et al. Br J Surg 1973; 60: 646-649; Lucey MR et al. Liver Transpl Surg 1997; 3: 628-637
Measure 1 point 2 points 3 points
Bilirubin (mg/dL) <2.0 2.0-3.0 >3.0
Albumin (g/dL) >3.5 2.8-3.5 <2.8
Prothrombin time (sec) <4.0 4.0-6.0 >6.0
Ascites None Slight Moderate
Encephalopathy (grade) None I-II III-IV
Grade Total points Surgical risk 2-year survival
A (Well-compensated disease)
5-6 Good 85%
B (Significant functional compromise)
7-9 Moderate 60%
C(Decompensated disease)
10-15 Poor 35%
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Table 2. Selected patient baselinedisease characteristics by specialty
Hep/GI(n=248)
Med Onc(n=168)
Surgery(n=35)
Totala
(N=479)
BCLC, n (%) Stage C 129 (52) 98 (58) 9 (26) 253 (53)
TNM, n (%) Stage IV
69 (28) 78 (46) 10 (29) 167 (35)
Child-Pugh, n (%) A (5-6) B (7-9)
149 (60)80 (32)
91 (54)34 (20)
17 (49)16 (46)
278 (58)134 (28)
Vascular invasion,n (%) 75 (30) 20 (12) 9 (26) 107 (22)
Extra-hepatic spread, n (%) 73 (29) 77 (46) 10 (29) 170 (35)
TNM, tumor nodes metastasis aIncludes all specialties
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Results: variations in patientcharacteristics by specialty
• Most common treating physician specialty by region:
– Med Onc in USA
– Hep/GI in Asia-Pacific, Europe, and Latin America
• Patients with more advanced disease (BCLC and TNM) and extra-hepatic spread were most often treated byMed Oncs compared with Hep/GIs
• The largest proportion of patients with Child-Pugh B status(80 of 134 patients; 60%) were treated by Hep/GIs
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Table 3. Summary of sorafenibdaily dose by specialty and region
Median daily dose, mg Hep/GI Med Onc Surgery Totala
Asia-Pacific, n=142b 800.0 502.0 616.0 710.0
Europe, n=93b 774.0 800.0 575.0 779.0
USA, n=96b 606.0 533.0 586.0 563.5
Latin America, n=19b 743.0 800.0 800.0 800.0
Japan, n=17b 542.0 NA 521.0 521.0
NA, no specialists in regionaIncludes all specialties; missing data not tabulated; b Missing data not tabulated
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Initial sorafenib dose level of 800 mg, n (%)a Hep/GI Med Onc Surgery Totalb
Asia-Pacific, n=167 82 (93) 33 (57) 5 (83) 133 (80)
Europe, n=143 71 (76) 36 (90) 0 114 (80)
USA, n=116 28 (72) 32 (52) 5 (50) 69 (59)
Latin America, n=32 17 (94) 8 (100) 6 (100) 31 (97)
Japan, n=21 8 (80) NA 8 (73) 16 (76)
Table 4. Summary of initial sorafenibdose level by specialty and region
NA, no specialists in regionaDenominator for % based on number of patients by specialty in each region; bIncludes all specialties
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Table 5. Summary of sorafenibadministration by specialty
Hep/GI(n=248)
Med Onc(n=168)
Surgery(n=35)
Totala
(N=479)
Treatment duration ≤4 weeks, n (%)
53 (21) 40 (24) 9 (26) 106 (22)
aIncludes all specialties; bMissing data not tabulated
Median daily dose,b mg 773.5 570.0 596.0 692.0
Initial sorafenib dose 800 mg, n (%)
206 (83) 109 (65) 24 (69) 363 (76)
Patients with dose interruptions, n (%)
60 (24) 40 (24) 11 (31) 117 (24)
Patients with dose increase, n (%)
35 (14) 33 (20) 6 (17) 80 (17)
Patients with dose reduction, n (%)
77 (31) 54 (32) 13 (37) 153 (32)
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Duration of exposure by physicians’ primary specialty: Hep/GI, medical oncology, and surgerya
300
200
100
0Nu
mb
er o
f su
bje
cts
un
der
tre
atm
ent
0 100 200 300 400
Time since start of therapy (days)
Hepatology / gastroenterologyMedical oncologySurgery
n=248
n=168
n=35
aData for radiology (n=6), anesthesiology (n=4), and traditional Chinese medicine (n=10) not shown
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Results: variations in sorafenibusage by specialty and region
• In general, a greater percentage of Hep/GIs initiate sorafenib therapy at 800 mg/day
• Hep/GIs had a higher median daily dose than Med Oncs
• In Europe and Latin America, the median daily dose of sorafenib used by Hep/GIs and Med Oncs was comparable
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Table 6. Safety databy specialty (as reported)
Hep/GI(n=248)
Med Onc(n=168)
Surgery(n=35)
Totala
(N=479)
AEs (all grades) 217 (88) 149 (89) 31 (89) 415 (87)
AEs (grade 3/4) 81 (33) 60 (36) 13 (37) 161 (34)
Drug-related AEs (all grades) 156 (63) 125 (74) 26 (74) 319 (67)
Drug-related AEs (grade 3/4) 49 (20) 41 (24) 13 (37) 109 (23)
SAEsb (all grades) 117 (47) 59 (35) 19 (54) 201 (42)
Drug-related SAEsb (all grades) 28 (11) 14 (8) 8 (23) 51 (11)
AEs resulting in permanent discontinuation of sorafenibc
81 (33) 34 (20) 15 (43) 133 (28)
Deathsd 69 (28) 29 (17) 11 (31) 114 (24)
AE, adverse event; aIncludes all specialties; bSerious AE (SAE) is any AE at any dose resulting in any of the following outomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; medically important event; cAny AE; dTreatment-emergent deaths occurring up to 30 days after last sorafenib dose
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Table 7. Drug-related AEs (all grades) byspecialty (incidence ≥10% in any group)
n (%) Hep/GI(n=248)
Med Onc(n=168)
Surgery(n=35)
Totala
(N=479)
HFSR 56 (23) 51 (30) 10 (29) 124 (26)
Diarrhea 57 (23) 46 (27) 8 (23) 114 (24)
Rash / desquamation 31 (13) 27 (16) 3 (9) 63 (13)
Fatigue 24 (10) 22 (13) 2 (6) 51 (11)
Hypertension 12 (5) 12 (7) 5 (14) 29 (6)
Thrombocytopenia 3 (1) 17 (10) 2 (6) 23 (5)
HFSR, hand-foot skin reactionaIncludes all specialties
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Results: no clinically significant difference in AE profiles across specialties
• Based on reported data, AE profiles across specialties appear to be comparable
• Med Oncs reported fewer SAEs, discontinuations due to any AE, and deaths on treatment
• The most common drug-related AEs were HFSR and diarrhea, irrespective of specialty
• However, follow-up intervals / assessments and dose adjustments were not specified so further analysis of this data will be necessary
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Conclusions
• The first interim analysis of GIDEON suggests differential use of sorafenib depending on physician specialty and region
• No apparent clinically significant differences in the overall AE and drug-related AE profile of sorafenib were seen across specialties in these early analyses
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• In the non-clinical trial setting, what makes dosing of sorafenib different in patients with HCC?
– Patient factors: extent of cancer, liver dysfunction, general condition?
– Physician specialty?
– Physician expectations?
– Patient preference / expectations?
– Regional differences?
Questions
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Questions
• Are these findings real or a reflection of physicians selected to participate in GIDEON?
• Is a registry a ‘real-life’ setting?
• If true, why do Hep/GIs use more sorafenib than Med Oncs?
• More mature data from GIDEON as well as additional studies may be useful in providing further data on sorafenib dosing and ensuringits optimal use
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Acknowledgments
• The study was supported by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals
