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What’s New In UGI Tract Cancers?
David H. Ilson, M.D., Ph.D.
Attending Physician
Memorial Sloan-Kettering Cancer Center
New York
Disclosure
Research Support– Genentech
– Bristol Myers Squibb / Imclone
– Sanofi-Aventis
– Bayer
Esophageal and Gastric CarcinomaUS Incidence in 2013
39,590 new cases– Gastric: 21,600 (54%)
– Esophagus: 17,900 (46%)
Decline in Gastric Cancer Incidence
Increase in Esophageal , GE JX, cardia adeno
OS improvement, 1975-77, 1984-86, 1999-2006– Gastric: 16% 18% 27%
– Esophageal: 5% 10% 19%
Siegel et al, CA 63: 11-30; 2013
Gastric and Esophageal Cancer RNA expression signatures
Shah M A et al. Clin Cancer Res 2011;17:2693-2701
©2011 by American Association for Cancer Research
Diffuse Cancer
Intestinal Cancer
GEJ Cancer
Intestinal Cancer
GEJ Cancer Diffuse Cancer
Esoph and GEJ:
Preop therapy for T2-3 or N+
EMR for T1a
Surgery for T1b
Esophageal and GEJ Adenoca: Consensus on Adjuvant Therapy
T2-3 or N+: Something more than surgery alone should be done
Preop chemo ECF, CF improves overall survival in some but not all trials
– MAGIC (ECF): 13% ↑ OS at 5 yr (esophageal and GEJ 25% pts)
– FFCD / FNLC (CF): 14% ↑ OS at 5 yr (esophageal and GEJ cancer, 180 pts) same as MAGIC, no epirubicin
Cunningham NEJM 355: 11; 2006 ,Ychou J Clin Oncol 29: 1715; 2011,
Esophageal Adenocarcinoma: Consensus on Adjuvant Therapy
Trials focusing purely on esophageal and GE junction cancers
Preop chemo CF failed:
– MRC 0E0-2 (CF): 800 pts, adeno and squam
5 year update: 6% ↑OS
Impacted only on rate of R0 resection
– U.S. INT 113 (CF): 450 pts, adeno and squam
No impact on OS or rate of R0 resection
– EORTC 40954 (CF): 70 pts, adeno
No impact on OS
Allum J Clin Oncol 2009, Kelsen NEJM 1998, Schuhmacher J Clin Oncol 28: 5210; 2010
Preop Chemo vs Surgery Alone: 2062 patients, 10 Trials
HR favoring Chemo 0.87 (p = 0.005)
Squamous: HR 0.92 (p = 0.18)
Adeno: HR 0.83 (p = 0.01)
Sjoquist Lancet Oncol 12: 681; 2011
Van Hagen et al NEJM 366: 2074; 2012
Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29
Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy
Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE)
1111
CROSS: Major Results• EUS staged patients• T3N0-1 75%, median age 60• 74% Adenocarcinoma• 93% received all courses chemotherapy
– 23% had > = grade 3 toxicity from pre-op therapy• Post-operative morbidity and mortality almost identical
(mortality 3.7-3.8%)
Resection rate and resection margins
Resection rate of all randomized patients
Surgery alone CRT + surgery
186/188 (99%) 168/178 (95%)
Resection margins
Surgery alone CRT + surgery
R0 111/161 (69%) 148/161 (92%)
p<0.002
R0 = no tumor within 1 mm of the resection marginsCROSS study
12
Overall Survival Improved with Chemo RT + Surgery
• 5-year survival 47% versus 34%
• Median survival 49.4 versus 24 months, HR 0.66, p = 0.003)
•Squamous HR 0.453
•Adeno HR 0.732
• Squamous path CR 49%, Adeno 23% (p = 0.008)
Preop Chemo RT vs Surgery Alone: 1932 patients, 13 trials
HR favoring Chemo RT 0.78 (p < 0.0001)
Squamous HR 0.8 (p = 0.004)
Adeno HR 0.75 ( p = 0.02)
Sjoquist Lancet Oncol 12: 681; 2011
Esophageal Cancer: Preop Chemo, RT, or Both? Conclusions
Esophageal, GEJ Adeno– Preop ECF Chemo improves survival and is feasible– Preop RT + Chemo: superior OS, more path CR’s
Esophageal Squamous– RT + Chemo:
As primary therapy without surgery is preferred Surgery after chemo RT: in selected patients
Improved local control no improvement in survival
PET Scan Directed Therapy Trial Design: CALGB 80803
T3/4 or N1 Esophageal
Adenoca
PET/CT: Induction Chemo: FOLFOX6
or Carbo/Pacliotaxel
PET-responders: ≥ 35% SUV decrease: continue
same chemo + concurrent RT (5040cGy in 180cGy fx)
PET Scan day 29-35
Surgical resection 6 weeks post-RT
PET- nonresponders: < 35% SUV decrease:
Cross over to alternate chemo + RT (5040cGy in
180cGy fx)
Hypothesis: changing chemo in PET non responding patients will improve pCR
during chemo + RT
Optimal Surgery for Gastric Cancer? D2 resection is the standard of care in Asia
Increasingly in the West D2 resection is considered the standard
Update of Dutch D1 vs D2 resection at 15 years supports D2:
Songun I et al Lancet Oncol 11: 439; 2010
Adjuvant Therapy in Gastric Cancer Improves OS Post op RT + chemo (U.S.), less than a D1-2 resection
– 5FU-LV + RT, INT 116:
10% 5 yr OS, HR 0.65
Pre and post op chemo (U.K.) without RT
– ECF, MAGIC:
13% 5 yr OS, HR 0.75
Post op chemo (Asia): 2 trials, 2000 pts, D2 resection, no RT
– S-1 (Oral 5-FU), ACTS-GC:
13% 5 yr OS, HR 0.67 (2011 update)
– Post op Cape-Oxali , CLASSIC Trial:
14% 3 yr DFS, HR 0.56
Survival improvements with all approaches similar, modest
Cunningham NEJM 355: 11; 2006 Sasako JCO 29: 4387; 2011 Bang Lancet 379: 315-321; 2012 Macdonald NEJM 345:725; 2001
Surgically (D2) resected Stage II, IIIA, or IIIB GC, 6 weeks prior to randomization
No prior chemotherapy or
radiotherapy
n=1035
Capecitabine: 1,000mg/m2 bid, d1–14, q3wOxaliplatin: 130mg/m2, d1, q3w
RANDO MIZATION
1:1†
n=520
n=515
• Primary endpoint: 3-year DFS‡
• Secondary endpoints: overall survival and safety profile
†Stratified by stage and country with age, sex, and nodal status as covariates‡GASTRIC project: 3-year DFS and 5-year overall survival are strongly associated, Burzykowski et al. ASCO 2009
CLASSIC study design
8 cycles of XELOX (6 months)
Observation: No adjuvant therapy
Bang Lancet 379: 315-321; 2012
Primary endpoint (3-year DFS) met at interim analysis
ITT population; DFS = disease-free survivalMedian follow-up 34.4 months (range 16–51)
1.0
0.0
0.2
0.4
0.6
0.8
3-year DFS
74%
60%
HR=0.56 (95% CI 0.44–0.72)P<0.0001
Time (months)
Observation, n=515
XELOX, n=520
520 410 333 246 166 74 30 10443515 352 286 209 147 58 22 6414
XELOXObservation
No. left
0 6 12 18 24 30 36 42 48
Bang Lancet 379: 3150321; 2012
3-year DFS by stratification factors
Category Subgroup n HR estimate
Sex FemaleMale
304731
0.810.49
Age group, years
<65≥65
766269
0.630.46
All All 1,035 0.58
Nodal status
N0N1/2
103932
0.830.56
Stage of disease
Stage IIStage IIIAStage IIIB
515377143
0.550.560.57
HR (95% CI)
210.60.40.2
ITT population
European / Asian Gastric Adjuvant Trials: Is RT required post op?
CRITICS Trial (NL): randomization + / - RT– Preop ECX– D1 resection– Post op chemo + / - RT
Korea ARTIST trial: chemo + / - RT (JCO 2011)– D2 resection– Post op Cape/Cis x 6 mos– + / - Post op RT– 5% increase in 3 yr DFS, N+– Repeat trial planned targeting N+ pts
TROG (Australia): Preop ECF + / - Preop RT– Esophageal and gastric, 750 pts
Advanced Gastric Cancer Chemotherapy: What regimen to use?
Oxali:
EOX or EOF
Cape:
ECX or EOX
XP FLO FUFIRI S-1 Cis
DCF ECF
Pts 489 513 160 109 170 305 221 126
%RR 44% 45% 41% 34% 32% 54% 36% 45%
TTP, mos 6.7 6.5 5.6 5.5 5.0 6.0 5.6 7.4
OS, mos 10.9 10.4 10.5 10.7 9.0 13.0 9.2 8.9
Second Line Chemo: Gastric Cancer
RANDOMIZATIONStratified by
Institution, PS 0-1/2, target lesion -/+
IRI150 mg/m2 d1, 15 q4w
weekly Paclitaxel80 mg/m2 d1, 8, 15 q4w
AGC refractory to prior FP confirmed by imagingAge 20-75, PS 0-2, No history of CPT-11 or Taxane
Ueda et al Proc ASCO 2012
Overall SurvivalP
rob
abili
ty (
%)
0 6 12 18 24 30 360
50
100
8.49.5
(Months)
108111
8075
3629
1010
23
01
wPTXIRI
Number at risk
01
IRI
wPTX
n
111
108
Median
8.4M
9.5M
P
0.38
HR (95% CI)
1.13 (0.86-1.49)
Log-rank test
FAS
Progression Free Survival
0 3 6 9 12 15 18 21 240
50
100
(Months)
Pro
bab
ility
(%
)
2.33.6
108111
6646
1618
98
36
22
wPTXIRI
Number at risk
21
00
00
IRI
wPTX
n
111
108
Median
2.3M
3.6M
P
0.33
HR (95% CI)
1.14 (0.88-1.49)
Log-rank test
FAS
Response Rate
n CR PR SD PD NE CR+PR P
wPTX 91 0 19 38 32 2 21% 0.24
IRI 88 1 11 28 45 3 14%
Fisher’s exact testRECIST 1.0
Second Line Chemotherapy post Platin + 5-FU: Further support for Taxanes
Cougar Trial-02 (U.K.) (GI Symposium 2013)
– 168 pts with gastric and GEJ cancer
– BSC vs docetaxel 75 mg/m2 every 3 weeks
– OS improved from 3.6 5.2 months (HR 0.67, p = 0.01)
– Responses in 7% of patients
Kang (JCO): 202 pts with gastric cancer
– Docetaxel 60 mg/m2 or irinotecan 150 mg/m2 every 3 weeks vs BSC
– OS improved from 3.8 5.3 months (HR 0.657, p = 0.007)
– RR 10% irinotecan, 17% for docetaxel
Ford et al GI Symposium 2013 Kang JCO 30: 1513-1518/ 2012
Kaplan-Meier estimates for overall survival in randomly assigned patients.
Kang J H et al. JCO 2012;30:1513-1518
©2012 by American Society of Clinical Oncology
Molecular Targets: Gastric Cancer KRAS mutation: < 5-10%
BRAF mutation: < 5%
EGFr over expression: 50-80%– EGFr mutation: < 5%
CMET: < 10%, IHC + 40%
HER2 over expression: 10-25%– TOGA: Trastuzumab + chemo improves OS in HER2+
Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006 Gold GI CA
Symp 2008 Abs 96
ToGA trial design
HER2-positiveadvanced GC
(n=584)
5-FU or capecitabinea + cisplatin(n=290)
R
aChosen at investigator’s discretion GEJ, gastroesophageal junction
5-FU or capecitabinea + cisplatin
+ trastuzumab(n=294) Stratification factors
− advanced vs metastatic − GC vs GEJ− measurable vs non-measurable− ECOG PS 0-1 vs 2− capecitabine vs 5-FU
Phase III, randomized, open-label, international, multicenter study
1Bang et al; Abstract 4556, ASCO 2009
3807 patients screened1
810 HER2-positive (22.1%)
Primary end point: OS
Time (months)
294290
277266
246223
209185
173143
147117
11390
9064
7147
5632
4324
3016
2114
137
126
65
40
10
00
No. at risk
11.1 13.8
0.00.10.20.30.40.50.60.70.80.91.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Event
FC + TFC
Events
167182
HR
0.74
95% CI
0.60, 0.91
p value
0.0046
MedianOS
13.811.1
T, trastuzumab
113
OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)
1.0
0.8
0.6
0.4
0.2
0.0
363432302826242220181614121086420
Time (months)
11.8 16.0
FC + T
FC
Events
120136
HR
0.65
95% CI
0.51, 0.83
MedianOS
16.011.8
Event
0.1
0.3
0.5
0.7
0.9
218 198
40
53
124
2011
228 218
196 170
170 141
142 112
12296
10075
8453
6539
5128
10
00
No. at risk
3920
2813
Secondary end point: tumor response rate
2.4%5.4%
32.1%
41.8%
34.5%
47.3%
Intent to treat
ORR= CR + PRCR, complete response; PR, partial response
p=0.0599
p=0.0145
F+C + trastuzumab
F+C
p=0.0017Patients (%)
CR PR ORR
Secondary end point: PFS
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Event
294290
258238
201182
14199
9562
6033
4117
287
215
133
93
82
62
61
61
40
20
00
5.5 6.7
No. at risk
0.00.10.20.30.40.50.60.70.80.91.0
Time (months)
FC + TFC
Events
226235
HR
0.71
95% CI
0.59, 0.85
p value
0.0002
MedianPFS
6.75.5
Targeted Agents Phase III: HER2: Met Disease
LOGIC: Cape-Ox + / - Lapatinib (HER2+)
TYTAN: Paclitaxel + / - Lapatinib (HER2+)– Second Line
– PFS and Survival Benefit in subset of patients IHC 3+ for lapatinib
OS 7.6 14.0 months, HR 0.59, p = 0.0176
Bang et al GI Cancers Symposium 2013 Abstract 11
HER 2 Directed Therapy
Trials in development– First Line: Capecitabine-Cisplatin -
Trastuzumab + / - Pertuzumab
– Second line: Paclitaxel vs TDM-1
– Second line MSKCC: Afatinib single agent
RTOG 1010: Phase II Study of Neoadjuvant Trastuzumab and Chemoradiation for
Esophageal Adenocarcinoma (Siewert I, II)
‘
CHEMORADIATIONCHEMORADIATION
HER-2 (+)(FISH)
HER-2 (+)(FISH)
TRASTUZUMAB+
CHEMORADIATION
TRASTUZUMAB+
CHEMORADIATION
SURGERYSURGERY
SURGERY+
TRASTUZUMAB (1 YR)
SURGERY+
TRASTUZUMAB (1 YR)
HER-2 (-)(FISH)
HER-2 (-)(FISH)
ALTERNATIVE STUDIES
ALTERNATIVE STUDIES
Chemoradiation: 5-FU + Oxaliplatin, RT 5040 cGy SurgeryMaintenance trastuzumab post op Sample Size = 130 Her-2 (+) Pts, Increase 3-Yr Survival from 30% to 50%. 520+ pts to be screened
Targeted Agents Phase III: Met Disease
Granite: BSC vs Everolimus
– Negative for OS, but improved PFS
Second Line: Paclitaxel + / - Everolimus
REAL 3: ECX + / - Panitumumab (U.K.)
– Negative: Panitumumab had inferior outcomes
EXPAND: Cape-Cis + / Cetuximab (E.U.)
– Negative: Cetuximab trended inferior
SCOPE-1: Cape-Cis-RT + / - Cetuximab as definitive chemo + RT, esophageal and GEJ
– (U.K.) Negative trial, inferior outcomes with cetuximab
COG: BSC vs Gefitinib (U.K.): Negative trial for OS
REAL3 Trial Design
Arm A: EOC
Arm B: mEOC-P
RUntreated advanced adenocarcinoma or
undifferentiated carcinoma of the oesophagus, OGJ or stomach
• EOC (Arm A):– Epirubicin 50mg/m2 IV D1– Oxaliplatin 130mg/m2 IV D1– Capecitabine 1250mg/m2/day PO
in two divided doses D1-21
• mEOC-P (Arm B)1:
– Epirubicin 50mg/m2 IV D1– Oxaliplatin 100mg/m2 IV D1– Capecitabine 1000mg/m2/day PO
in two divided doses D1-21– Panitumumab 9mg/kg IV D1
1. Okines et al, JCO 2010
Primary Endpoint – OS
349275EOC238278EOC-P
Number at risk
0
20
40
60
80
100
0 12 24 36
Months from Randomisation
Pro
bab
ility
of
Su
rviv
al (
%)
EOCEOC-P
Median OS(95% CI)
% alive at 1 year(95% CI)
11.3m (9.6 – 13.0) 46% (38% - 54%)
8.8m (7.7 – 9.8) 33% (26% - 41%)
HR 1.37, p = 0.013
HR 1.37 (95% CI: 1.07 – 1.76)
6 18 30
Based on 251 OS events
Trial Results - PFS
225275EOC024278EOC-P
Number at risk
Median PFS(95% CI)
% alive and progression-free at 1 year(95% CI)
7.4m (6.3 – 8.5) 21% (14% - 27%)
6.0m (5.5 – 6.5) 20% (14% - 26%)
HR 1.22, p = 0.068
0
20
40
60
80
100
0 12 24
Months from Randomisation
Pro
bab
ility
of
Su
rviv
al (
%)
EOCEOC-P HR 1.22 (95% CI: 0.98 – 1.52)
6 18 30
Based on 333 PFS events
Trial Results - RR
• Patients who had not reached 1st response assessment at time of data censoring are excluded (n=61)
Best Response EOC (n=238)
mEOC-P(n=254)
CR 5 (2%) 8 (3%)
PR 95 (40%) 108 (43%)
SD 51 (21%) 46 (18%)
PD 19 (8%) 30 (12%)
Not evaluable 68 (29%) 62 (24%)
ORR 42% 46%
Odds Ratio for Response
1.16(95% CI: 0.81-1.57)
p-value 0.467
Doshi et al Proc ASCO 2012
ECX + / - Rilotumumab in CMET High: RILOMET Trial
VEGF Revisited?
AVAGAST: Cape or 5-FU + cisplatin + / - bevacizumab
– PFS and RR improved
– Non significant increase in OS
Ramucirumab (Fuchs, GI Symposium 2013)
– Humanized antibody blocking VEGFR2
– 355 patients post 5-FU and platin based chemo
– BSC vs Ramucirumab 8 mg/kg IV every 3 weeks
– PFS improved 2.1 3.8 months (HR 0.483, p < 0.0001)
– OS improved 3.8 5.2 months (HR 0.776, p = 0.0473)
– Disease control improved from 23% to 49% (p < 0.0001)
– Essentially no toxicity (rare grade 3/4 hypertension 7.2%)
Fuchs et al GI Symposium 2013
Pancreatic Cancer and HCCUS Incidence in 2013
Pancreatic Cancer– 45,220 cases, 38,460 deaths (85%)
– FOLFIRINOX new standard chemotherapy for good PS pts
Gemcitabine combination therapy for good PS
– Adjuvant gemcitabine + / - RT after resection
HCC and bile duct– 30,640 cases, 21,670 deaths (71%)
– HCC: sorafenib for metastatic disease
– Cholangiocarcinoma: gemcitabine/cisplatin for metastatic disease
Siegel et al, CA 63: 11-30; 2013
Neuhaus, et al. ASCO, 2008 (LBA #4504)
CONKO-001: Efficacy Results
Gemcitabine(N= 179)
Observation (N= 175)
P-value
Median DFS 13.4 mths 6.9 mths < 0.001
Median OS 22.8 mths 20.2 mths 0.005
1-Year OS 72% 72.5% -
3-year OS 36.5% 19.5% -
5-Year OS 21% 9% -
Results ESPAC-3(v2)
• 1,088 pts, 17 countries 1/00- 1/07• 35% R1; 72% node positive; 25% grade III• Median follow up 34.2 months
Neoptolemos, et al. JAMA, 2010
5-FU-LVN= 551
GemcitabineN= 537 Log-rank
Med OS 23 mths 23.6 mths HR= 0.94 (0.81-1.08)p= 0.39
Resected Pancreas CancerN= 952 Gemcitabine
+ Erlotinib x 4
US Intergroup/RTOG 0848
Gemcitabine x 4 cycles
Stratification₋ R0 vs R1 resection; T stage; N(+) vs N(-)
Primary Endpoint: Overall Survival +/- Erlotinib, +/- RTSecondary Endpoints: DFS +/- Erlotinib, +/- RT, toxicityTissue acquistion/ correlative science
RANDOMIZE
2nd Randomization
+/-ChemoRT
Conroy, et al. NEJM, 2011
FOLFIRINOX vs GemcitabineProdige 4- ACCORD 11
Randomization 1: 1Stratification₋ PS: 0-1 vs 2; Primary tumor location, Center
Primary Endpoint: Overall Survival
Untreated Metastatic Panc Adenocarcinoma
ECOG 0-1 Gemcitabine(N = 169)
FOLFIRINOX (N = 167)
RANDOMIZE
Gemcitabine
FOLFIRINOX
FOLFIRINOX vs Gemcitabine Overall Survival
Number at riskGemcitabine
FOLFIRINOX
171 134 89 48 28 14 7 6 3 3 2 2 2
171 146 116 81 62 34 20 13 9 5 3 2 2
1 .0 0
0 .7 5
0 .5 0
0 .2 5
0 .0 0
Pro
ba
bilit
y
Mo nths0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3 3 6
Median 11.1 mo
Median 6.8 mo
HR = 0.57P < 0.0001
Conroy, T. NEJM, 2011
FOLFIRINOX vs GemcitabineSecondary Endpoints
Conroy T, et al. NEJM, 2011
FOLFIRINOX(N = 167)
Gemcitabine (N = 169) P-Value
Febrile neutropenia 5.4% 0.6% 0.009
Thrombocytopenia 9.1% 2.4% 0.008
Peripheral neuropathy 9% — 0.001
Vomiting 14.5% 4.7% 0.002
Diarrhea 12.7% 1.2% 0.0001
Filgrastim support 42.5% 5%
Overall response rate 31.6% 9.4% 0.0001
Median PFS 6.4 m 3.3 m 0.0001HR = 0.47
Phase III Nab-Paclitaxel + Gemcitabine vs Gemcitabine (MPACT)
Nab-Paclitaxel + Gemcitabine
N= 431Gemcitabine
N= 430
Median Overall Survival 8.5 mths 6.7 mths
HR 0.72, p= 0.000015
1-Year Survival 35% 22%
Progression-Free Survival 5.5 mths 3.7 mths
Response Rate 23% 7%
Neutropenia (Gd 3-4) 38% 27%
Fatigue (Gd 3-4) 17% 7%
Neuropathy (Gd 3-4) 17% <1%
Von Hoff, D. LBA #148. Gastrointestinal Cancers Symposium, 2013
SCALOP Trial: Unresectable Pancreatic Cancer 114 pts with locally advanced pancreatic
cancer
3 months of weekly gemcitabine 5040 cGy RT +
– Gemcitabine 300 mg/m2 weekly vs
– Capecitabine 830 mg/m2 bid Monday through Friday during RT
More heme (18.4% vs 0%) and non heme toxicity (26.3% vv 11.1%) for gemcitabine
OS superior with capecitabine (13.4 15.2 months (HR 0.50, p = 0.025)
Mukherjee et al GI Cancers Symposium 2013
CMET Targeted Therapy in HCC Tivantinib vs Placebo in HCC (4006)
– CMET TKI
107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib
– 160 mg tivantinib vs placebo
– Cross over permitted at POD
TTP 6.0 to 6.9 weeks (HR 0.64, p = 0.04)
– Effect greatest beyond 8 weeks
OS not different, given cross over (6.2-6.6 months)
CMET IHC low, better prognosis, no benefit from tivantinib
CMET IHC high, OS 3.8 to 7.2 months (HR 0.38, p = 0.01) with tivantinib
Phase III Trial planned in CMET high pts
CMET Targeted Therapy in HCC Cabozantinib vs Placebo in HCC (4007)
– CMET and VEGR2 TKI, most patients failed sorafenib
107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib
– 100 mg cabozantinib, stable disease randomized to placebo or continuation
– Cross over permitted at POD
41 treated, 22 randomized to discontinuation
PFS 4.4 mos, OS 15 mos in all pts
RR 5%, Stable disease 78%
Larger phase II trial planned
CALGB 80802
Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus
placebo can be continued as single agent
Approved circumstances: benefit from therapy and continues to have normal EF on MUGA
Eligibility
Child-Pugh A
ECOG PS: 0, 1, 2
(1:1
) R
and
om
izat
ion
(N~
480-
680)
Period 1 Period 2
Continue until
withdrawal,
PD, or death
6 cycles of:• Doxorubicin 60 mg/m2 IV*
Day 1 in 21-day cycles• Sorafenib 400 mg po bid
6 cycles of:• Sorafenib 400 mg po bid
Sorafenib400 mg po
bid
Sorafenib400 mg po
bid