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