gi slide deck 2018 - esdo: home...irinotecan gej gastro-oesophageal junction gi gastrointestinal...
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Supported by Eli Lilly and Company.
Eli Lilly and Company has not influenced the content of this publication
20th World Congress on Gastrointestinal Cancer 20–23 June 2018 | Barcelona, Spain
GI SLIDE DECK 2018 Selected abstracts from:
Letter from ESDO
DEAR COLLEAGUES
It is our pleasure to present this ESDO slide set which has been designed to highlight and summarise
key findings in digestive cancers from the major congresses in 2018. This slide set specifically focuses
on the 20th World Congress on Gastrointestinal Cancer and is available in English, French,
Japanese and Chinese.
The area of clinical research in oncology is a challenging and ever changing environment. Within this
environment, we all value access to scientific data and research which helps to educate and inspire
further advancements in our roles as scientists, clinicians and educators. I hope you find this review of
the latest developments in digestive cancers of benefit to you in your practice. If you would like to share
your thoughts with us we would welcome your comments. Please send any correspondence to
Finally, we are also very grateful to Lilly Oncology for their financial, administrative and logistical support
in the realisation of this activity.
Yours sincerely,
Eric Van Cutsem Ulrich Güller
Thomas Seufferlein Thomas Grünberger
Côme Lepage Tamara Matysiak-Budnik
Wolff Schmiegel Jaroslaw Regula
Phillippe Rougier (hon.) Jean-Luc Van Laethem
(ESDO Governing Board)
ESDO Medical Oncology Slide Deck
Editors 2018
BIOMARKERS
Prof Eric Van Cutsem Digestive Oncology, University Hospitals, Leuven, Belgium
Prof Thomas Seufferlein Clinic of Internal Medicine I, University of Ulm, Ulm, Germany
COLORECTAL CANCERS
Prof Eric Van Cutsem Digestive Oncology, University Hospitals, Leuven, Belgium
Prof Wolff Schmiegel Department of Medicine, Ruhr University, Bochum, Germany
Prof Thomas Gruenberger Department of Surgery, Kaiser-Franz-Josef Hospital, Vienna, Austria
Prof Jaroslaw Regula Department of Gastroenterology and Hepatology, Institute of Oncology, Warsaw, Poland
PANCREATIC CANCER AND HEPATOBILIARY TUMOURS
Prof Jean-Luc Van Laethem Digestive Oncology, Erasme University Hospital, Brussels, Belgium
Prof Thomas Seufferlein Clinic of Internal Medicine I, University of Ulm, Ulm, Germany
Prof Ulrich Güller Medical Oncology & Hematology, Kantonsspital St Gallen, St Gallen, Switzerland
GASTRO-OESOPHAGEAL AND NEUROENDOCRINE TUMOURS
Prof Côme Lepage University Hospital & INSERM, Dijon, France
Prof Tamara Matysiak Hepato-Gastroenterology & Digestive Oncology, Institute of Digestive Diseases,
Nantes, France
Glossary
1/2/3L first/second/third line
5FU 5-fluorouracil
AE adverse event
AFP alpha-fetoprotein
ALP alkaline phosphatase
ALT alanine aminotransferase
AST aspartate aminotransferase
BCLC Barcelona clinic liver cancer
BICR blinded-independent central review
bid twice daily
BOR best overall response
BSC best supportive care
CI confidence interval
CPS combined positive score
CR complete response
CRC colorectal cancer
CT chemotherapy
ctDNA circulating tumour DNA
DCR disease control rate
DFS disease-free survival
dMMR deficient mismatch repair
(m)DoR (median) duration of response
ECOG Eastern Cooperative Oncology Group
EGFR epidermal growth factor receptor
ESCC oesophageal squamous cell cancer
ESMO European Society of Medical
Oncology
FAS full analysis set
FOLFIRINOX leucovorin + 5-fluorouracil + irinotecan
+ oxaliplatin
FOLFOX leucovorin + 5-fluorouracil +
oxaliplatin
(m)FOLFOXIRI (modified) leucovorin +
5-fluorouracil + oxaliplatin +
irinotecan
GEJ gastro-oesophageal junction
GI gastrointestinal
GIST gastrointestinal stromal tumour
HBV hepatitis B virus
HCC hepatocellular carcinoma
HCV hepatitis C virus
HIF-1α hypoxia-inducible factor-1α
HR hazard ratio
IHC immunohistochemistry
IQR interquartile range
ITT intent-to-treat
iv intravenous
KM Kaplan-Meier
LV leucovorin
mAb monoclonal antibody
mCRC metastatic colorectal cancer
met metastasis
mPDAC metastatic pancreatic ductal
adenocarcinoma
MSI(-H) (high) microsatellite instability
Mut mutant
NA not available
NE not evaluable
NR not reached
OR odds ratio
ORR overall/objective response rate
(m)OS (median) overall survival
PCR polymerase chain reaction
PD progressive disease
PD-L1 programmed death-ligand 1
PI3KCA phosphatidylinositol 3-kinase
(m)PFS (median) progression-free survival
PPES palmar-plantar erythrodysesthesia
syndrome
PR partial response
PS performance status
q(2/3/4/6)w every (2/3/4/6) week(s)
QoL quality of life
R randomised
RCT randomised controlled trial
RECIST Response Evaluation Criteria In
Solid Tumors
RT radiotherapy
SAE serious adverse event
SD stable disease
Tid three times daily
TRAE treatment-related adverse event
TRK tropomyosin receptor kinase
TRR tumour resection rate
TTP time-to-progression
(m)TTR (median) time-to-response
tx treatment
VEGF vascular endothelial growth factor
WT wild-type
Contents
• Cancers of the oesophagus and stomach 6
• Cancers of the pancreas, small bowel and hepatobiliary tract 15
– Pancreatic cancer 16
– Hepatocellular carcinoma 21
• Cancers of the colon, rectum and anus 30
Note: To jump to a section, right click on the number and ‘Open Hyperlink’
CANCERS OF THE
OESOPHAGUS AND STOMACH
LBA-002: Overall survival results from a phase III trial of trifluridine/tipiracil
vs. placebo in patients with metastatic gastric cancer refractory to standard
therapies (TAGS) – Tabernero J, et al
Tabernero J, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-002
Study objective
• To assess the efficacy and safety of trifluridine/tipiracil vs. placebo in patients with
metastatic gastric cancer refractory to standard therapies (TAS-102 trial)
*35 mg/m2 bid orally D1–5, 8–12 of each 28-day cycle
PRIMARY ENDPOINT
• OS
SECONDARY ENDPOINTS
• PFS, ORR, DCR, QoL, time to ECOG PS ≥2,
safety
R
2:1
PD
Stratification
• ECOG PS (0 vs. 1)
• Region (Japan vs. rest of world)
• Prior ramucirumab (Y/N)
Trifluridine/tipiracil* +
BSC
(n=337)
Key patient inclusion criteria
• ≥2 prior regimens
• Refractory to last prior
therapy
• Age ≥18 years (≥20 years in
Japan)
• ECOG PS 0–1
(n=507) PD
Placebo + BSC
(n=170)
LBA-002: Overall survival results from a phase III trial of trifluridine/tipiracil
vs. placebo in patients with metastatic gastric cancer refractory to standard
therapies (TAGS) – Tabernero J, et al
Tabernero J, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-002
Key results
*Stratified log-rank test
Trifluridine/tipiracil
(n=337)
Placebo
(n=170)
Events, n (%) 244 (72) 140 (82)
Median, months 5.7 3.6
HR (95%CI) 0.69 (0.56, 0.85)
1-sided p-value* 0.0003
OS
, %
Time, months
100
80
60
40
20
0
0
337
170
2
282
131
No. at risk
Trifluridine/tipiracil
Placebo
1
328
158
3
240
101
4
201
71
5
161
60
6
124
47
7
102
40
8
80
34
9
66
29
10
51
17
11
40
12
12
31
10
13
22
9
14
16
7
15
11
5
16
9
2
17
7
2
18
7
0
19
7
0
20
4
0
21
4
0
22
4
0
23
3
0
24
1
0
25
0
0
12-month OS: 21%
12-month OS: 13%
Trifluridine/tipiracil
Placebo
Primary endpoint – OS
LBA-002: Overall survival results from a phase III trial of trifluridine/tipiracil
vs. placebo in patients with metastatic gastric cancer refractory to standard
therapies (TAGS) – Tabernero J, et al
Tabernero J, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-002
Key results (cont.)
• The most common haematological laboratory abnormality observed in patients treated with
trifluridine/tipiracil (n=328)* was grade 3/4 neutropenia (38%) compared with none in the
placebo arm
– In 2% of patients treated with trifluridine/tipiracil, grade ≥3 febrile neutropenia was
reported
*Treated patients with ≥1 baseline measurement
AEs, % Trifluridine/tipiracil
(n=355)
Placebo
(n=168)
Any AE 97 93
Grade ≥3 AEs 80 58
AEs leading to discontinuation 13 17
TRAEs 81 57
Treatment-related death 0.3 0.6
LBA-002: Overall survival results from a phase III trial of trifluridine/tipiracil
vs. placebo in patients with metastatic gastric cancer refractory to standard
therapies (TAGS) – Tabernero J, et al
Tabernero J, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-002
Conclusions
• In heavily pre-treated patients with metastatic gastric cancer, trifluridine/tipiracil
was associated with a clinically meaningful and statistically significant
improvement in survival vs. placebo
• No new safety signals were noted and the safety profile was consistent with that
previously seen in other patient populations
O-010: Cisplatin/5-fluorouracil +/- panitumumab for patients with non-
resectable, advanced or metastatic esophageal squamous cell cancer:
A randomized phase III AIO/EORTC trial with an extensive biomarker
program – Moehler M, et al
Study objective
• To assess the efficacy and safety of cisplatin + 5FU with or without panitumumab in
patients with ESCC in an AIO/EORTC study*
*Study stopped early due to futility and potential safety concerns; †panitumumab 9 mg/kg D1 of each cycle prior to CT q3w; ‡cisplatin
100 mg/m2 iv infusion over 2 hours D1 + 5FU 1000 mg/m2 iv infusion
over 24 hours D1–4 q3w
Moehler M, et al. Ann Oncol 2018;29(suppl 5):abstr O-010
ENDPOINTS
• BOR, OS, PFS and safety
R
1:1
PD
Panitumumab† +
cisplatin + 5FU‡
(n=73) Key patient inclusion criteria
• Unresectable locally
advanced or metastatic
ESCC
• ECOG PS 0–1
(n=146) PD
Cisplatin + 5FU‡
(n=73)
O-010: Cisplatin/5-fluorouracil +/- panitumumab for patients with non-
resectable, advanced or metastatic esophageal squamous cell cancer:
A randomized phase III AIO/EORTC trial with an extensive biomarker
program – Moehler M, et al
Key results
Moehler M, et al. Ann Oncol 2018;29(suppl 5):abstr O-010
PFS
PFS, days
1.0
No. at risk
Su
rviv
al p
rob
ab
ility
0.8
0.6
0.4
0.2
0.0
0
68
68
49
39
200
29
22
15
12
5
3
600
4
2
3
1
mPFS 5.3 vs. 5.8 months
HR 1.21 (95%CI 0.85, 1.73); p=0.29
Cisplatin + 5FU + panitumumab
Cisplatin + 5FU
400
7
8
800
2
0
OS
OS, days
1.0
No. at risk S
urv
iva
l p
rob
ab
ility
0.8
0.6
0.4
0.2
0.0
0
72
73
64
49
250
22
24
12
9
750
9
2
mOS 9.4 vs. 10.2 months
HR 1.17 (95%CI 0.79, 1.75); p=0.43
Cisplatin + 5FU + panitumumab
Cisplatin + 5FU
500
15
14
8
1
46
42
6
1
1000
2
0
1
0
1250
0
0
31
30
O-010: Cisplatin/5-fluorouracil +/- panitumumab for patients with non-
resectable, advanced or metastatic esophageal squamous cell cancer:
A randomized phase III AIO/EORTC trial with an extensive biomarker
program – Moehler M, et al
Key results (cont.)
• Panitumumab + cisplatin + 5FU demonstrated a trend for improved OS in patients who
were EGFR-positive compared with cisplatin + 5FU alone
• An improved PFS was observed in patients with low vs. high serum EGFR or HIF-1α
(p=0.014 and p=0.109, respectively)
Moehler M, et al. Ann Oncol 2018;29(suppl 5):abstr O-010
Su
rviv
al p
rob
ab
ility
Time, days
1.0
0.8
0.6
0.4
0.2
0.0
0 200 400 600
CFP arm EGFR
Negative/weak
Moderate/strong
Censored
Serum EGFR
Low serum marker
High serum marker
Censored
Su
rviv
al p
rob
ab
ility
Time, days
1.0
0.8
0.6
0.4
0.2
0.0
0 200 400 600 800 1000
OS PFS
O-010: Cisplatin/5-fluorouracil +/- panitumumab for patients with non-
resectable, advanced or metastatic esophageal squamous cell cancer:
A randomized phase III AIO/EORTC trial with an extensive biomarker
program – Moehler M, et al
Key results (cont.)
• At least one SAE was observed in 83.3% vs. 78.6% of patients in the panitumumab +
cisplatin + 5FU vs. cisplatin + 5FU arms, respectively
• The most common grade ≥3 AEs were low neutrophils (21% vs. 24%) and anaemia (13%
vs. 16%) in panitumumab + cisplatin + 5FU vs. cisplatin + 5FU arms, respectively
Conclusions
• In patients with locally advanced or metastatic ESCC, the addition of panitumumab
to cisplatin and 5FU was not associated with improved OS compared with cisplatin
+ 5FU alone
• EGFR-1, HIF-1α and serum EGFR under EGFR-1 inhibition may be potential
biomarkers in locally advanced or metastatic ESCC
Moehler M, et al. Ann Oncol 2018;29(suppl 5):abstr O-010
CANCERS OF THE PANCREAS,
SMALL BOWEL AND
HEPATOBILIARY TRACT
PANCREATIC CANCER
O-002: Geographic variation in systemic treatment of metastatic pancreatic
adenocarcinoma (mPAC) patients in real world across Europe
– Taieb J, et al
Taieb J, et al. Ann Oncol 2018;29(suppl 5):abstr O-002 *Between July 2014 and January 2016
Study objective
• To investigate the geographical variations in treatment selection in European patients from
9 different countries who completed 1L treatment for metastatic pancreatic cancer
• A retrospective electronic chart review based on data gathered from patient records
• The following information was obtained:
– General disease information and patient characteristics
– Disease characteristics at diagnosis
– Initial treatment for pancreatic cancer
– Details of 1L, 2L and 3L treatment
2L treatment
started/completed
(n=1666)
PD
Key patient inclusion criteria
• Metastatic pancreatic cancer
• Completed 1L treatment*
• ≥18 years
(n=2565)
O-002: Geographic variation in systemic treatment of metastatic pancreatic
adenocarcinoma (mPAC) patients in real world across Europe
– Taieb J, et al
Taieb J, et al. Ann Oncol 2018;29(suppl 5):abstr O-002
Key results
1L treatment selection
0
10
20
30
40
50
60
France Germany Italy Spain UK
(m)FOLFIRINOX Gemcitabine + nab-paclitaxel
Gemcitabine monotherapy Other gemcitabine-based therapies
5FU + oxaliplatin 5FU + irinotecan
5FU monotherapy Other
% p
atie
nts
O-002: Geographic variation in systemic treatment of metastatic pancreatic
adenocarcinoma (mPAC) patients in real world across Europe
– Taieb J, et al
Taieb J, et al. Ann Oncol 2018;29(suppl 5):abstr O-002
Key results (cont.)
2L treatment selection
0
10
20
30
40
50
60
France Germany Italy Spain UK
(m)FOLFIRINOX Gemcitabine + nab-paclitaxel
Gemcitabine monotherapy Other gemcitabine-based therapies
5FU + oxaliplatin 5FU + irinotecan
5FU monotherapy Other
% p
atie
nts
O-002: Geographic variation in systemic treatment of metastatic pancreatic
adenocarcinoma (mPAC) patients in real world across Europe
– Taieb J, et al
Taieb J, et al. Ann Oncol 2018;29(suppl 5):abstr O-002
Conclusions
• In European patients with metastatic pancreatic cancer the 1L treatment selection
was broadly consistent with ESMO recommendations
– There was variation between countries in the relative proportion of different
treatments used
– 1L treatment choice depended on local reimbursement status and the patient’s
condition
• 2L treatment selection varied widely between countries
– 2L choice was dependent on 1L treatment and local reimbursement policies
• At the time of the study, there were no approved 2L treatments for patients with
metastatic pancreatic cancer
HEPATOCELLULAR CARCINOMA
LBA-001: Ramucirumab as second-line treatment in patients with advanced
hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP)
following first-line sorafenib: Pooled efficacy and safety across two global
randomized phase 3 studies (REACH-2 and REACH) – Zhu A, et al
Zhu A, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-001
Study objective
• To assess the benefit of ramucirumab in patients with advanced HCC and baseline AFP
≥400 ng/mL in a pooled analysis of the phase III REACH and REACH-2 studies
R†
PD/
toxicity
Stratification of pooled analysis
• Study: REACH vs. REACH-2
Ramucirumab
8 mg/kg iv q2w + BSC
(n=316)
Key patient inclusion criteria
for REACH and REACH-2 studies
• Advanced HCC
• BCLC stage B or C
• Prior sorafenib
• Child-Pugh A
• ECOG PS 0–1
• REACH-2: Baseline AFP* ≥400 ng/mL
(n=542)
PRIMARY ENDPOINT (BOTH STUDIES)
• OS
SECONDARY ENDPOINTS (BOTH STUDIES)
• PFS, ORR, safety, patient-reported outcomes
Placebo + BSC
(n=226)
PD/
toxicity
*Patients with AFP ≥400 ng/mL selected for both studies in
the pooled analysis; †1:1 (REACH) or 2:1 (REACH-2)
LBA-001: Ramucirumab as second-line treatment in patients with advanced
hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP)
following first-line sorafenib: Pooled efficacy and safety across two global
randomized phase 3 studies (REACH-2 and REACH) – Zhu A, et al
Zhu A, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-001
Key results
Ramucirumab
(n=316)
Placebo
(n=226) Difference p-value
Death, n (%) 246 (77.8) 190 (84.1)
Median, months 8.1 5.0 3.1
HR (95%CI) 0.694 (0.571, 0.842) 0.0002
No heterogeneity in
treatment effect observed
across both studies
A random effect frailty
model after adjusting for
study (as random effect)
produced a similar
treatment result
(HR 0.689; p=0.0002)
Time, months
Ramucirumab
Censored
OS
, %
100
80
60
40
20
0 0
316
226
Ramucirumab
Placebo
Censored
No. at risk 3
265
166
6
186
94
9
133
64
12
91
37
15
59
26
18
38
12
21
22
5
24
8
3
27
2
1
30
1
0
33
1
0
36
1
0
39
0
0
LBA-001: Ramucirumab as second-line treatment in patients with advanced
hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP)
following first-line sorafenib: Pooled efficacy and safety across two global
randomized phase 3 studies (REACH-2 and REACH) – Zhu A, et al
Zhu A, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-001
Key results (cont.)
Ramucirumab
(n=316)
Placebo
(n=226) p-value
PFS
Median, months 2.8 1.5
HR (95%CI) 0.572 (0.472, 0.694) <0.0001
ORR, n (%) [95%CI] 17 (5.4) [2.9, 7.9] 2 (0.9) [0.0, 2.1] 0.0064
DCR, n (%) [95%CI] 178 (56.3) [50.9, 61.8] 84 (37.2) [30.9, 43.5] <0.001
LBA-001: Ramucirumab as second-line treatment in patients with advanced
hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP)
following first-line sorafenib: Pooled efficacy and safety across two global
randomized phase 3 studies (REACH-2 and REACH) – Zhu A, et al
Zhu A, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-001
Key results (cont.)
Conclusions
• In patients with advanced HCC and baseline AFP ≥400 ng/mL, ramucirumab
improved OS vs. placebo in a pooled analysis of the REACH and REACH-2 studies
• Ramucirumab was well tolerated, with a safety profile consistent with other
ramucirumab monotherapy studies
• In patients with HCC and elevated AFP who have received prior sorafenib treatment,
ramucirumab is potentially an important new treatment option
Grade >3 AEs of special interest
occurring in ≥3% of patients, n (%)
Ramucirumab
(n=316)
Placebo
(n=223)
Liver injury/failure 63 (19.9) 59 (26.5)
Ascites 15 (4.7) 9 (4.0)
Bleeding/haemorrhage events 15 (4.7) 15 (6.7)
GI haemorrhage events 11 (3.5) 12 (5.4)
Hypertension 40 (12.7) 8 (3.6)
O-011: Assessment of tumor response, AFP response, and time to
progression in the phase 3 CELESTIAL trial of cabozantinib versus placebo
in advanced hepatocellular carcinoma (HCC) – Merle P, et al
Study objective
• To assess the tumour response, AFP response and TTP in patients with advanced HCC
receiving cabozantinib vs. placebo in the CELESTIAL trial
*Primary (OS) and secondary (PFS, ORR and safety)
endpoints presented previously
Merle P, et al. Ann Oncol 2018;29(suppl 5):abstr O-011
EXPLORATORY ENDPOINTS*
• Tumour response, AFP response, TTP
R
2:1
PD/
toxicity
Stratification
• Disease aetiology (HBV, HCV, other)
• Region (Asia, other)
• Presence of macrovascular invasion and/or
extra-hepatic spread of disease (Y/N)
Cabozantinib
60 mg/day oral
(n=470)
Key patient inclusion criteria
• Advanced HCC
• Child-Pugh A
• Prior sorafenib
• ≤2 systemic regimens and
progressed following ≥1
• ECOG PS ≤1
(n=760)
Placebo
(n=237)
PD/
toxicity
O-011: Assessment of tumor response, AFP response, and time to
progression in the phase 3 CELESTIAL trial of cabozantinib versus placebo
in advanced hepatocellular carcinoma (HCC) – Merle P, et al
Key results
Merle P, et al. Ann Oncol 2018;29(suppl 5):abstr O-011
Cabozantinib (n=388)
Best %
change fro
m b
aselin
e
100
75
50
20
0
–30
–50
–75
–100
47% any reduction
Placebo (n=205) 100
75
50
20
0
–30
–50
–75
–100
11% any reduction
18
25 24
22
1
8
4
7
0
5
10
15
20
25
30
Cabozantinib Placebo
ITT
patients
with ≥
50%
reduction in A
FP
<20 ng/mL
Baseline AFP category
≥20 ng/mL <400 ng/mL ≥400 ng/mL
ITT patients, n
AFP-evaluable patients, n
139
112
77
66
331
261
160
126
278
221
136
119
192
152
101
73
Best % change from baseline in sum of diameters AFP response
O-011: Assessment of tumor response, AFP response, and time to
progression in the phase 3 CELESTIAL trial of cabozantinib versus placebo
in advanced hepatocellular carcinoma (HCC) – Merle P, et al
Key results (cont.)
• Dose reductions occurred in 62% and 13% of patients in the cabozantinib and placebo
arms, respectively
• Discontinuations due to TRAEs occurred in 16% and 3% of patients in the cabozantinib
and placebo arms, respectively
Merle P, et al. Ann Oncol 2018;29(suppl 5):abstr O-011
Median TTP,
months (95%CI)
No. of
events
Cabozantinib (n=470) 5.4 (4.0, 5.6) 323
Placebo (n=237) 1.9 (1.9, 1.9) 200
Pro
ba
bili
ty o
f T
TP
1.0
0.8
0.6
0.4
0.2
0.0
0
470
237
3
251
65
6
127
19
9
78
13
12
38
5
15
14
2
18
10
2
21
3
2
24
3
1
HR 0.41 (95%CI 0.34, 0.49)
No. at risk
Cabozantinib
Placebo
Time, months
TTP
O-011: Assessment of tumor response, AFP response, and time to
progression in the phase 3 CELESTIAL trial of cabozantinib versus placebo
in advanced hepatocellular carcinoma (HCC) – Merle P, et al
Results (cont.)
Conclusions
• In patients with advanced HCC, cabozantinib demonstrated greater reductions in
target lesions than placebo
• In patients with elevated AFP at baseline, reductions of ≥50% in AFP were observed
in a quarter of those in the cabozantinib arm
• Cabozantinib was also associated with improved TTP compared with placebo
Merle P, et al. Ann Oncol 2018;29(suppl 5):abstr O-011
Grade 3 AEs occurring in ≥5% in
cabozantinib arm, %
Cabozantinib
(n=467)
Placebo
(n=237)
Diarrhoea 10 2
Decreased appetite 6 <1
Hand-foot syndrome 17 0
Fatigue 10 4
Hypertension 16 2
AST increased 11 6
Asthenia 7 2
CANCERS OF THE COLON,
RECTUM AND ANUS
LBA-004: Efficacy and safety results from IMblaze370, a randomized
phase III study comparing atezolizumab plus cobimetinib and atezolizumab
monotherapy vs. regorafenib in chemotherapy-refractory metastatic
colorectal cancer – Bendell J, et al
Study objective
• To assess the efficacy and safety of atezolizumab + cobimetinib vs. atezolizumab alone
vs. regorafenib in patients with chemotherapy refractory mCRC in the IMblaze370 study
Bendell J, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-004
PRIMARY ENDPOINT
• OS for atezolizumab + cobimetinib or
atezolizumab vs. regorafenib
SECONDARY ENDPOINTS
• PFS, ORR, DoR
R
2:1:1
Lo
ss o
f cli
nic
al b
en
efi
t
Stratification
• Extended RAS mutation status (≥50% of patients in each arm)
• Time since diagnosis of first metastasis (<18 vs. ≥18 months)
Regorafenib 160 mg oral 21/7 days
(n=90)
Atezolizumab 840 mg iv q2w +
cobimetinib 60 mg oral 21/7 days
(n=183)
Key patient inclusion criteria
• Unresectable locally
advanced or metastatic
CRC
• ≥2 prior regimens of
cytotoxic chemotherapy
• MSI-H capped at 5%
• ECOG PS 0–1
(n=363)
Atezolizumab 1200 mg iv q3w
(n=90)
LBA-004: Efficacy and safety results from IMblaze370, a randomized
phase III study comparing atezolizumab plus cobimetinib and atezolizumab
monotherapy vs. regorafenib in chemotherapy-refractory metastatic
colorectal cancer – Bendell J, et al
Key results
OS
HRs are from stratified log-rank tests. Data cut-off:
March 9, 2018. *For descriptive purposes only
Bendell J, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-004
Time, months No. at risk
Atezolizumab + cobimetinib
Atezolizumab
Regorafenib
Ove
rall
su
rviv
al, %
100
80
60
40
20
0
0
183
90
90
3
150
73
67
6
110
51
52
12
63
22
30
9
83
34
40
15
28
9
9
18
3
21
Atezolizumab
+ cobimetinib
(n=183)
Atezolizumab
(n=90)
Regorafenib
(n=90)
Median OS,
mo (95%CI)
8.9
(7.00, 10.61)
7.1
(6.05, 10.05)
8.5
(6.41, 10.71)
HR vs. rego
(95%CI)
1.00
(0.73, 1.38)
1.19
(0.83, 1.71) NA
p-value 0.9871 0.3360* NA
12-mo OS, % 38.5 27.2 36.6
Atezolizumab + cobimetinib
Atezolizumab
Regorafenib
LBA-004: Efficacy and safety results from IMblaze370, a randomized
phase III study comparing atezolizumab plus cobimetinib and atezolizumab
monotherapy vs. regorafenib in chemotherapy-refractory metastatic
colorectal cancer – Bendell J, et al
Key results (cont.)
OS in key subgroups
Bendell J, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-004
Subgroup
≥65 years
<65 years
White
Non-white
ECOG PS 0
ECOG PS 1
<18 mo since 1st met diagnosis
≥18 mo since 1st met diagnosis
>3 prior tx in met setting
≤3 prior tx in met setting
Left sided tumour
Right sided tumour
RAS mutant
RAS wild-type
MSI high
MSI stable/low
PD-L1 high
PD-L1 low
ITT
Favours atezolizumab + cobimetinib
0.2 1 2
Favours regorafenib Hazard ratio*
n
86
187
223
39
133
140
83
190
70
203
148
72
148
104
3
250
110
124
273
HR
1.50
0.84
1.24
0.40
1.13
0.85
1.15
0.95
1.58
0.86
0.97
0.77
0.81
1.39
NE
1.01
0.80
1.26
1.01
*Unstratified
LBA-004: Efficacy and safety results from IMblaze370, a randomized
phase III study comparing atezolizumab plus cobimetinib and atezolizumab
monotherapy vs. regorafenib in chemotherapy-refractory metastatic
colorectal cancer – Bendell J, et al
Key results (cont.)
PFS
Bendell J, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-004
Time, months No. at risk
Atezolizumab + cobimetinib
Atezolizumab
Regorafenib
Pro
gre
ssio
n-f
ree s
urv
iva
l p
rob
ab
ility
, %
100
80
60
40
20
0
0
183
90
90
3
49
22
33
6
18
7
13
12
6
1
5
9
11
1
7
15
1
18
Atezolizumab
+ cobimetinib
(n=183)
Atezolizumab
(n=90)
Regorafenib
(n=90)
Median PFS,
mo (95%CI)
1.9
(1.87, 1.97)
1.9
(1.91, 2.10)
2.0
(1.87, 3.61)
HR vs. rego
(95%CI)
1.25
(0.94, 1.65)
1.39
(1.00, 1.94) NA
Atezolizumab + cobimetinib
Atezolizumab
Regorafenib
LBA-004: Efficacy and safety results from IMblaze370, a randomized
phase III study comparing atezolizumab plus cobimetinib and atezolizumab
monotherapy vs. regorafenib in chemotherapy-refractory metastatic
colorectal cancer – Bendell J, et al
Key results (cont.)
Conclusions
• In patients with chemotherapy refractory mCRC neither atezolizumab + cobimetinib
or atezolizumab alone improved OS compared with regorafenib
• The safety profile of atezolizumab + cobimetinib was similar to the safety profiles of
the individual agents
Bendell J, et al. Ann Oncol 2018;29(suppl 5):abstr LBA-004
AEs, n (%) Atezolizumab +
cobimetinib (n=179)
Atezolizumab
(n=90)
Regorafenib
(n=80)
TRAEs
Grade 3–4
Grade 5
170 (95)
80 (45)
2 (1)
49 (54)
9 (10)
0
77 (96)
39 (49)
1 (1)
SAEs
Treatment related
71 (40)
46 (26)
15 (17)
7 (8)
18 (23)
9 (11)
Leading to withdrawal 37 (21) 4 (4) 7 (9)
Leading to dose interruption
or modification
109 (61) 18 (20) 55 (69)
O-012: Safety and effectiveness of regorafenib in patients with metastatic
colorectal cancer (mCRC) in routine clinical practice: Final analysis from
prospective, observational CORRELATE study – Ducreux M, et al
Ducreux M, et al. Ann Oncol 2018;29(suppl 5):abstr O-012
Study objectives
• To assess the efficacy and safety of regorafenib in patients with mCRC in the real-world
CORRELATE study
PRIMARY ENDPOINT
• Safety
SECONDARY ENDPOINTS
• OS, PFS
Regorafenib at
discretion of physician
according to local
approved label
PD
Key patient inclusion criteria
• mCRC
• Previously treated with other
approved therapies
• Physician’s decision to treat
with regorafenib
(n=1037)
O-012: Safety and effectiveness of regorafenib in patients with metastatic
colorectal cancer (mCRC) in routine clinical practice: Final analysis from
prospective, observational CORRELATE study – Ducreux M, et al
Ducreux M, et al. Ann Oncol 2018;29(suppl 5):abstr O-012
Key results
• Drug-related grade ≥3 AEs occurring >5% of patients in included: fatigue (9%), hand-foot
skin reaction (7%) and hypertension (6%)
AE, n (%) Regardless of relation to drug Drug related
Any
Grade 3
Grade 4
Grade 5
990 (95)
426 (41)
41 (4)
175 (17)
830 (80)
338 (33)
22 (2)
10 (1)
SAEs 443 (43) 116 (11)
Leading to treatment discontinuation 330 (32) 163 (16)
Leading to dose reduction 266 (26) 251 (24)
Leading to treatment interruption 439 (42) 319 (31)
O-012: Safety and effectiveness of regorafenib in patients with metastatic
colorectal cancer (mCRC) in routine clinical practice: Final analysis from
prospective, observational CORRELATE study – Ducreux M, et al
Ducreux M, et al. Ann Oncol 2018;29(suppl 5):abstr O-012
Key results (cont.)
Pro
ba
bili
ty o
f O
S
Time, months
1.0
0.8
0.6
0.4
0.2
0.0
0
1037
6
586
12
210
18
50
24
18
42 30
5
36
2
Overall survival
Median 7.6 months (95%CI 7.1, 8.2)
3-month estimate: 82%
6-month estimate: 60%
1-year estimate: 33.8%
Pro
ba
bili
ty o
f P
FS
Time, months
1.0
0.8
0.6
0.4
0.2
0.0
0
1037
3
417
6
167
9
59
12
31
27 15
12
18
4
Progression-free survival
Median 2.8 months (95%CI 2.6, 2.8)
3-month estimate: 43%
6-month estimate: 15%
21
2
24
1
Censored Censored
No. at risk No. at risk
O-012: Safety and effectiveness of regorafenib in patients with metastatic
colorectal cancer (mCRC) in routine clinical practice: Final analysis from
prospective, observational CORRELATE study – Ducreux M, et al
Ducreux M, et al. Ann Oncol 2018;29(suppl 5):abstr O-012
Conclusions
• In patients with mCRC, regorafenib demonstrated a safety profile that was similar to
previous findings
• Nearly 50% of the patients initiated regorafenib at a lower dose than the
recommended 160 mg/day
• Survival rates with regorafenib were comparable to those seen in previous phase III
clinical trials even with flexible dosing
O-013: Safety and efficacy of trifluridine/tipiracil in previously treated
metastatic colorectal cancer (mCRC): Preliminary results from the
phase IIIb, international, open-label, early-access PRECONNECT study
– Falcone A, et al
Study objective
• To assess the efficacy and safety of trifluridine/tipiracil in previously treated patients with
mCRC in the open-label, early access PRECONNECT study (preliminary data reported)
Falcone A, et al. Ann Oncol 2018;29(suppl 5):abstr O-013
ENDPOINTS
• Safety, PFS, ORR, DCR, time to deterioration to ECOG PS ≥2, QoL
Trifluridine/tipiracil
35 mg/m2 oral bid
D1–5, 8–12
of 28-day cycle
PD/
toxicity
Key patient inclusion criteria
• mCRC
• ≥2 prior chemotherapy regimens
• Refractory, intolerant or unsuitable
for fluoropyrimidine, irinotecan,
oxaliplatin, anti-VEGF or anti-EGFR
for RAS WT
• ECOG PS 0–1
(n=462)
O-013: Safety and efficacy of trifluridine/tipiracil in previously treated
metastatic colorectal cancer (mCRC): Preliminary results from the
phase IIIb, international, open-label, early-access PRECONNECT study
– Falcone A, et al
Key results
PFS
Falcone A, et al. Ann Oncol 2018;29(suppl 5):abstr O-013
Eve
nt fr
ee
, %
Time from start of treatment, months
100
80
60
40
20
0
0
462
2
295
4
130
6
62
12
0
8
23
10
5 No. at risk
mPFS 2.8 months (95%CI 2.7, 3.3)
ORR 2.4% (95%CI 1.2, 4.2)
DCR 36.8% (95%CI 32.4, 41.4)
O-013: Safety and efficacy of trifluridine/tipiracil in previously treated
metastatic colorectal cancer (mCRC): Preliminary results from the
phase IIIb, international, open-label, early-access PRECONNECT study
– Falcone A, et al
Key results (cont.)
Deterioration in ECOG PS – time to ECOG PS ≥2
Falcone A, et al. Ann Oncol 2018;29(suppl 5):abstr O-013
Eve
nt fr
ee
, %
Time from start of treatment, months
100
80
60
40
20
0.0
0
432
2
263
4
129
6
53
12
0
8
15
10
4 No. at risk
Median time to first ECOG PS deterioration
8.7 months (range 0.2–11.0)
O-013: Safety and efficacy of trifluridine/tipiracil in previously treated
metastatic colorectal cancer (mCRC): Preliminary results from the
phase IIIb, international, open-label, early-access PRECONNECT study
– Falcone A, et al
Key results (cont.)
Conclusion
• In previously treated patients with mCRC, this preliminary data demonstrated that
trifluridine/tipiracil had a safety profile similar to previous findings and was
efficacious with improvements in time to deterioration of ECOG PS and PFS
Falcone A, et al. Ann Oncol 2018;29(suppl 5):abstr O-013
Grade ≥3 AEs occurring in >2%, n (%) Regardless of relation to drug
Haematological
Neutropenia
Anaemia
182 (39.3)
55 (11.8)
Non-haematological
Diarrhoea
Fatigue
Asthenia
24 (5.2)
15 (3.2)
12 (2.6)
O-014: Regorafenib dose optimization study (reDOS): Randomized phase II
trial to evaluate escalating dosing strategy and pre-emptive topical steroids
for regorafenib in refractory metastatic colorectal cancer (mCRC) –
An ACCRU network study – Bekaii-Saab T, et al
Study objective
• To determine the optimal dose of regorafenib to enable maintenance of benefits and
improve tolerability in patients with refractory mCRC in the ReDOS study
*Cycle 1 week 1 80 mg, week 2 120 mg and week 3 160 mg
Bekaii-Saab T, et al. Ann Oncol 2018;29(suppl 5):abstr O-014
PRIMARY ENDPOINT
• Proportion of patients who completed 2
cycles and cold initiate cycle 3
SECONDARY ENDPOINTS
• OS, PFS, TTP
R
1:1:1:1
Arm B1: Regorafenib 160 mg/day oral
21 days + pre-emptive strategy for PPES
Arm A1: Regorafenib start low* +
pre-emptive strategy for PPES Key patient inclusion criteria
• Refractory mCRC
• Failure of all standard iv
regimens including
appropriate biologics
• No prior regorafenib
• ECOG PS 0–1
(n=363)
Arm A2: Regorafenib start low* +
reactive strategy for PPES
Arm B2: Regorafenib 160 mg/day oral
21 days + reactive strategy for PPES
O-014: Regorafenib dose optimization study (reDOS): Randomized phase II
trial to evaluate escalating dosing strategy and pre-emptive topical steroids
for regorafenib in refractory metastatic colorectal cancer (mCRC) –
An ACCRU network study – Bekaii-Saab T, et al
Key results
Proportion of patients starting cycle 3
*Fisher’s exact test (1-sided)
Bekaii-Saab T, et al. Ann Oncol 2018;29(suppl 5):abstr O-014
43
24
0
10
20
30
40
50
Pe
rce
nta
ge
of p
atie
nts
Escalating
dose
Standard
dose
35% PD
47% PD
p=0.0281*
O-014: Regorafenib dose optimization study (reDOS): Randomized phase II
trial to evaluate escalating dosing strategy and pre-emptive topical steroids
for regorafenib in refractory metastatic colorectal cancer (mCRC) –
An ACCRU network study – Bekaii-Saab T, et al
Key results (cont.)
Bekaii-Saab T, et al. Ann Oncol 2018;29(suppl 5):abstr O-014
Events/
total
Median
(95%CI)
Time
period KM estimate
(95%CI) HR (95%CI)
Arm A 29/54 9.0 (6.8, 13.4) 6 months
12 months
66.5 (53.8, 82.2)
34.4 (21.5, 55.2) 0.65 (0.39, 1.08)
Arm B 34/62 5.9 (5.3, 12.4) 6 months
12 months
49.8 (37.2, 66.8)
26.7 (14.0, 51.1) Reference
OS PFS
Pe
rcen
tage w
ith
ou
t e
ve
nt
Time from randomisation, months
100
80
60
40
20
0
0 6 12 18 24
Log-rank p-value 0.0943
Censor
Pe
rcen
tage w
ith
ou
t e
ve
nt
Time from randomisation, months
100
80
60
40
20
0
0 6 12 18 24
Log-rank p-value 0.5534
Censor
Events/
total
Median
(95%CI)
Time
period KM estimate
(95%CI) HR (95%CI)
Arm A 45/54 2.5 (1.9, 4.0) 6 months
12 months
12.2 (5.4, 27.5)
2.4 (0.4, 16.9) 0.89 (0.59, 1.33)
Arm B 50/62 2.0 (1.8, 2.4) 6 months
12 months
11.8 (5.2, 26.6)
5.9 (1.6, 21.0) Reference
O-014: Regorafenib dose optimization study (reDOS): Randomized phase II
trial to evaluate escalating dosing strategy and pre-emptive topical steroids
for regorafenib in refractory metastatic colorectal cancer (mCRC) –
An ACCRU network study – Bekaii-Saab T, et al
Key results (cont.)
Conclusion
• In patients with refractory mCRC, using an escalating dosing strategy for
regorafenib was superior to the standard dosing strategy and may provide a new
optimal dosing strategy
Bekaii-Saab T, et al. Ann Oncol 2018;29(suppl 5):abstr O-014
AEs occurring in ≥5%, n (%) Escalating dose (n=54) Standard dose (n=82)
Grade 3 Grade 4 Grade 3 Grade 4
Fatigue 7 (13.0) 0 11 (17.7) 0
PPES 8 (14.8) 0 10 (16.1) 0
Abdominal pain 9 (16.7) 0 4 (6.5) 0
Hypertension 4 (7.4) 0 9 (14.5) 0
Hyponatremia 2 (3.7) 1 (1.9) 4 (6.5) 1 (1.6)
Bilirubin increased 2 (3.7) 0 5 (8.1) 0
ALP increased 3 (5.6) 0 1 (1.6) 1 (1.6)
AST increased 1 (1.9) 0 4 (6.5) 0
Dehydration 0 0 5 (8.1) 0
Lymphocyte count decreased 4 (7.4) 0 0 0
O-016: First-line FOLFOX plus panitumumab followed by 5-FU/LV plus
panitumumab or single-agent panitumumab as maintenance therapy in
patients with RAS wild-type metastatic colorectal cancer (mCRC): The
VALENTINO study – Pietrantonio F, et al
Pietrantonio F, et al. Ann Oncol 2018;29(suppl 5):abstr O-016
Study objective
• To assess the efficacy and safety of FOLFOX + panitumumab followed by 5FU/leucovorin
+ panitumumab as maintenance therapy in patients with RAS WT mCRC in the
VALENTINO study
*Oxaliplatin 85 mg/m2 D1 + LV 200 mg/m2 D1,2 + 5FU bolus
400 mg/m2 D1,2 + 5FU pvi 600 mg/m2 D1,2 q14; †6 mg/kg
D1 q14; ‡LV 200 mg/m2 D1,2 + 5FU bolus 400 mg/m2 D1,2 +
5FU pvi 600 mg/m2 D1,2 q14
R
1:1
PD
/to
xic
ity/
co
nsen
t w
ith
dra
wal
Stratification
• Centre, prior adjuvant (Y/N), No. metastatic sites (1/>1)
FOLFOX-4* up
to 8 cycles +
panitumumab†
(n=117)
Key patient inclusion criteria
• Unresectable mCRC
• RAS WT
• No prior treatment
(n=224)
FOLFOX-4* up
to 8 cycles +
panitumumab†
(n=112)
PRIMARY ENDPOINT
• 10-month PFS rate
SECONDARY ENDPOINTS
• Safety, PFS by tumour sidedness
5FU/leucovorin‡
+ panitumumab†
Panitumumab†
Induction Maintenance
O-016: First-line FOLFOX plus panitumumab followed by 5-FU/LV plus
panitumumab or single-agent panitumumab as maintenance therapy in
patients with RAS wild-type metastatic colorectal cancer (mCRC): The
VALENTINO study – Pietrantonio F, et al
Pietrantonio F, et al. Ann Oncol 2018;29(suppl 5):abstr O-016
Key results
PFS
HR 1.55 (95%CI 1.09, 2.20); p=0.011
10-month PFS Median PFS
Rate, % 95%CI Mo 95%CI
Arm A
(5FU/LV +
panitumumab)
62.8 54.0, 73.1 13.0 10.5, 16.0
Arm B
(panitumumab) 52.8 43.4, 64.3 10.2 8.9, 12.2
PF
S
Time, months
1.0
0.8
0.6
0.4
0.2
0.0
0
117
112
2
109
104
4
98
93
6
86
75
8
70
52
20
7
3
No. at risk
Panitumumab +
5FU/LV
Panitumumab
10
52
39
12
42
23
14
29
13
16
19
6
18
14
4
Panitumumab + 5FU/LV
Panitumumab
Median follow-up 13.8 months (IQR 8.6–18.3)
O-016: First-line FOLFOX plus panitumumab followed by 5-FU/LV plus
panitumumab or single-agent panitumumab as maintenance therapy in
patients with RAS wild-type metastatic colorectal cancer (mCRC): The
VALENTINO study – Pietrantonio F, et al
Pietrantonio F, et al. Ann Oncol 2018;29(suppl 5):abstr O-016
Key results (cont.)
PFS left-sided primary tumours PFS right-sided primary tumours
PF
S
Time, months
1.0
0.8
0.6
0.4
0.2
0.0
0
98
90
2
93
87
4
84
77
6
74
61
8
61
45
20
7
3
No. at risk
Panitumumab +
5FU/LV
Panitumumab
10
45
36
12
36
21
14
26
12
16
17
6
18
13
4
Panitumumab + 5FU/LV
Panitumumab P
FS
Time, months
1.0
0.8
0.6
0.4
0.2
0.0
0
19
22
2
16
17
4
14
16
6
12
14
8
9
7
20 No. at risk
Panitumumab +
5FU/LV
Panitumumab
10
7
3
12
6
2
14
3
1
16
2
18
1
Panitumumab +
5FU/LV
Panitumumab
10-month PFS Median PFS
n Rate, % 95%CI Months 95%CI
Arm A
(5FU/LV + panitumumab) 98 64.5 55.0, 75.8 13.2 10.7, 16.0
Arm B (panitumumab) 90 63.0 52.7, 75.4 11.6 10.1, 14.5
10-month PFS Median PFS
n Rate, % 95%CI Months 95%CI
Arm A
(5-FU/LV + panitumumab) 19 55.6 37.0, 84.0 10.4 5.9, NA
Arm B (panitumumab) 22 16.2 6.0, 45.2 7.0 5.5, 8.9
O-016: First-line FOLFOX plus panitumumab followed by 5-FU/LV plus
panitumumab or single-agent panitumumab as maintenance therapy in
patients with RAS wild-type metastatic colorectal cancer (mCRC): The
VALENTINO study – Pietrantonio F, et al
Pietrantonio F, et al. Ann Oncol 2018;29(suppl 5):abstr O-016
Key results (cont.)
Conclusions
• In patients with RAS WT mCRC who have received induction therapy with FOLFOX
+ panitumumab, maintenance treatment with 5FU/leucovorin + panitumumab
appears to provide better PFS than maintenance with panitumumab alone
• PFS was poorer in those with right-sided tumours, particularly with maintenance
with panitumumab alone
AEs occurring in ≥10%, %
5FU/leucovorin + panitumumab
(n= 81)
Panitumumab
(n=71)
Any grade Grade ≥3 Any grade Grade ≥3
Stomatitis/oral mucositis 27 6 8 1
Diarrhoea 20 4 10 1
Hand-foot syndrome 14 5 10 1
Peripheral neuropathy 26 - 13 1
Neutropenia 11 3 1 -
Skin rash 54 22 46 14
Paronychia 14 1 6 -
Hypomagnesemia 16 1 17 1
O-017: FOLFOXIRI plus bevacizumab (bev) followed by maintenance with
bev alone or bev plus metronomic chemotherapy (metroCT) in mCRC: final
results of the phase II randomized MOMA trial by GONO – Marmorino F, et al
Study objective
• To assess the efficacy and safety of FOLFOXIRI + bevacizumab followed by bevacizumab
alone or bevacizumab + metronomic chemotherapy as maintenance therapy in patients
with mCRC in the MOMA study
*7.5 m/day q3w; †capecitabine 500 mg tid +
cyclophosphamide 50 mg/day
Marmorino F, et al. Ann Oncol 2018;29(suppl 5):abstr O-017
R
1:1 PD
Stratification
• ECOG PS (0 vs. 1, 2), previous adjuvant chemotherapy
FOLFOXIRI +
bevacizumab*
up to 8 cycles
(n=117)
Key patient inclusion criteria
• Unresectable mCRC
• No prior treatment for
metastatic disease
• ECOG PS 0–2
(n=232)
FOLFOXIRI +
bevacizumab*
up to 8 cycles
(n=115)
PRIMARY ENDPOINT
• PFS
SECONDARY ENDPOINTS
• Safety, PFS by tumour sidedness
Bevacizumab* +
metronomic
chemotherapy†
Bevacizumab*
Induction Maintenance
O-017: FOLFOXIRI plus bevacizumab (bev) followed by maintenance with
bev alone or bev plus metronomic chemotherapy (metroCT) in mCRC: final
results of the phase II randomized MOMA trial by GONO – Marmorino F, et al
Key results
PFS
Marmorino F, et al. Ann Oncol 2018;29(suppl 5):abstr O-017
Events Median, mo 70%CI
Bev arm (n=117) 104 9.4 8.3, 10.6
Bev + metroCT
arm (n=115) 106 10.3 9.1, 11.6
Follow-up, months No. at risk
Maintenance with bev
Maintenance with
bev + metroCT
HR 0.94 (70%CI 0.82, 1.09); p=0.680
Pro
gre
ssio
n-f
ree s
urv
iva
l p
rob
ab
ility
1.0
0.8
0.6
0.4
0.2
0.0
0
117
115
6
100
90
12
40
42
18
25
26
36
8
10
24
16
19
30
12
16
42
6
8
48
4
5
54
3
2
60
1
1
66
0
0
O-017: FOLFOXIRI plus bevacizumab (bev) followed by maintenance with
bev alone or bev plus metronomic chemotherapy (metroCT) in mCRC: final
results of the phase II randomized MOMA trial by GONO – Marmorino F, et al
Key results (cont.)
OS
Marmorino F, et al. Ann Oncol 2018;29(suppl 5):abstr O-017
Events Median, mo 95%CI
Bev arm (n=117) 79 28.0 20.0, 33.6
Bev + metroCT
arm (n=115) 85 22.5 18.4, 25.8
Follow-up, months No. at risk
Maintenance with bev
Maintenance with
bev + metroCT
HR 1.16 (95%CI 0.99, 1.37); p=0.336
Ove
rall
su
rviv
al p
rob
ab
ility
1.0
0.8
0.6
0.4
0.2
0.0
0
117
115
6
111
101
12
89
84
18
75
69
36
29
27
24
60
51
30
50
40
42
16
18
48
10
12
54
6
7
60
3
1
66
0
0
O-017: FOLFOXIRI plus bevacizumab (bev) followed by maintenance with
bev alone or bev plus metronomic chemotherapy (metroCT) in mCRC: final
results of the phase II randomized MOMA trial by GONO – Marmorino F, et al
Key results (cont.)
Conclusions
• In patients with mCRC, after induction therapy with FOLFOXIRI + bevacizumab
adding metronomic chemotherapy to bevacizumab as maintenance therapy did not
improve PFS
• The best maintenance option after a 1L bevacizumab-containing regimen remains
the standard of care fluoropyrimidine + bevacizumab
Marmorino F, et al. Ann Oncol 2018;29(suppl 5):abstr O-017
Grade 3/4 AEs
occurring in ≥5% in
induction phase, %
Bev + metronomic
CT (n=116)
Bev
(n=115)
Vomiting 6.1 0.9
Diarrhoea 15.6 11.1
Neutropenia 50.4 59.5
Febrile neutropenia 8.7 13.8
Asthenia 8.7 12.9
Anorexia 6.1 4.3
Hypertension 1.7 5.2
Venous thrombosis 5.2 1.7
Grade 3/4 AEs in
maintenance
phase, %
Bev +
metronomic
CT (n=78)
Bev
(n=88)
Neutropenia 3.9 0
Hand-foot syndrome 9.1 0
Hypertension 3.9 4.5
O-020: Activity of larotrectinib in patients with TRK fusion GI malignancies
– Nathenson M, et al
Nathenson M, et al. Ann Oncol 2018;29(suppl 5):abstr O-020
Study objective
• To assess the efficacy and safety of larotrectinib (a TRK inhibitor) in patients with TRK
fusion gastrointestinal malignancies pooled data from three trials investigating larotrectinib
in patients with solid tumours
*Colon, GIST, gall bladder, biliary tract, appendix or pancreas
PRIMARY ENDPOINT
• BOR (RECIST v1.1)
SECONDARY ENDPOINTS
• DoR, PFS, safety
Larotrectinib 100 mg
bid q4w
Treatment
beyond PD
permitted if
continuing
benefit
Key patient inclusion criteria
• TRK fusions
• Included in a phase I, phase
I/II(SCOUT) or phase II
basket (NAVIGATE) trial
(n=55; 12 GI malignancies*)
O-020: Activity of larotrectinib in patients with TRK fusion GI malignancies
– Nathenson M, et al
Nathenson M, et al. Ann Oncol 2018;29(suppl 5):abstr O-020
Key results
*One patient initially diagnosed with GIST was determined to
have peri-rectal undifferentiated soft tissue sarcoma
Best overall response Duration of response
Be
st ch
an
ge
fro
m b
ase
line
in ta
rge
t le
sio
ns, %
60
40
20
0
–20
–40
–60
–100
–80
Biliary tract Appendix Colon
Pancreas GIST Gall bladder
Objective response rate (95%CI)
Partial response
Complete response
Stable disease
Progressive disease
67%
7
1
3
1
Overall treatment duration, months
0 3 6 9 12 18 21 24 27
Median time to response = 1.8 months
15
Treatment after progression
Treatment ongoing
First objective response
Complete response
*
O-020: Activity of larotrectinib in patients with TRK fusion GI malignancies
– Nathenson M, et al
Nathenson M, et al. Ann Oncol 2018;29(suppl 5):abstr O-020
Key results (cont.)
Conclusion
• In patients with TRK fusion gastrointestinal malignancies, larotrectinib provided
durable and clinically meaningful responses and was associated with minimal
toxicity with prolonged treatment
Grade 3 TRAEs, %
Increased ALT/AST 5
Dizziness 2
Nausea 2
Anaemia 2
Decreased neutrophil count 2
O-021: Safety and antitumor activity of pembrolizumab in patients with
advanced microsatellite instability–high (MSI-H) colorectal cancer:
KEYNOTE-164 – Le D, et al
Le D, et al. Ann Oncol 2018;29(suppl 5):abstr O-021
Study objective
• To assess the efficacy and safety of pembrolizumab in patients with advanced MSI-H CRC
in the KEYNOTE-164 study
PRIMARY ENDPOINT
• ORR
SECONDARY ENDPOINTS
• DoR, PFS, OS, safety
Pembrolizumab
200 mg q3w
Treatment for
~2 years
(35 cycles)
or until
PD/toxicity/
withdrawal
Key patient inclusion criteria
• Locally advanced, unresectable
or metastatic CRC
• dMMR/MSI-H CRC by
IHC/PCR
• ≥1 prior line of therapy
• ECOG PS 0–1
(n=63)
O-021: Safety and antitumor activity of pembrolizumab in patients with
advanced microsatellite instability–high (MSI-H) colorectal cancer:
KEYNOTE-164 – Le D, et al
Le D, et al. Ann Oncol 2018;29(suppl 5):abstr O-021
Key results Pembrolizumab (n=63)
ORR, n (%) [95%CI] 20 (32) [21, 45]
CR 2 (3) [0, 11]
PR 18 (29) [18,41]
SD 16 (25) [15, 38]
PD 25 (40) [28, 53]
DCR 36 (57) [44, 70]
mTTR, months (range) 3.9 (1.8–10.4)
mDoR, months (range) NR (2.1+–13.2+)
ORR, n/N (%)
BRAF mutated
BRAF WT
1/5 (20)
13/29 (45)
ORR, n/N (%)
KRAS mutated
KRAS WT
8/22 (36)
11/34 (32)
Median duration of follow-up
12.6 months (range 0.1–15.4)
Cha
ng
e fro
m b
ase
line
, %
60
40
20
0
–20
–40
–60
–100
–80
1
2
≥3
Prior lines of therapy
80
100
O-021: Safety and antitumor activity of pembrolizumab in patients with
advanced microsatellite instability–high (MSI-H) colorectal cancer:
KEYNOTE-164 – Le D, et al
Le D, et al. Ann Oncol 2018;29(suppl 5):abstr O-021
Key results (cont.)
Data cut-off: 12 September 2017
PFS OS
Pro
gre
ssio
n-f
ree s
urv
iva
l %
Time, months
100
80
60
40
20
0
0
63
2
47
4
33
6
30
8
24
10
22
14
6
12
21
No. at risk 18
0
16
0
Events,
n (%)
6-month
rate, %
12-month
rate, %
Median, months
(95%CI)
MSI-H CRC 37 (59) 49 41 4.1 (2.1, NR)
Events,
n (%)
6-month
rate, %
12-month
rate, %
Median, months
(95%CI)
MSI-H CRC 16 (25) 84 76 NR (NR, NR)
Ove
rall
su
rviv
al, %
Time, months
100
80
60
40
20
0
0
63
2
60
4
55
6
51
8
48
10
46
14
15
12
43
No. at risk 18
0
16
0
O-021: Safety and antitumor activity of pembrolizumab in patients with
advanced microsatellite instability–high (MSI-H) colorectal cancer:
KEYNOTE-164 – Le D, et al
Le D, et al. Ann Oncol 2018;29(suppl 5):abstr O-021
Key results (cont.)
Conclusion
• In previously treated patients with advanced MSI-H CRC, pembrolizumab
demonstrated durable responses and a safety profile comparable to previous
studies in patients with solid tumours
Grade 1/2
Grade 3/4
Fre
qu
en
cy,
%
0
4
8
12
16
20
O-022: Phase II study evaluating trifluridine/tipiracil+bevacizumab and
capecitabine+bevacizumab in first-line unresectable metastatic colorectal
cancer (mCRC) patients who are non-eligible for intensive therapy
(TASCO1): results of the primary analysis – Van Cutsem E, et al
Study objective
• To assess the efficacy and safety of trifluridine/tipiracil + bevacizumab and capecitabine +
bevacizumab as a 1L therapy for patients with unresectable mCRC who are not eligible for
intensive therapy in the TASCO1 study
Van Cutsem E, et al. Ann Oncol 2018;29(suppl 5):abstr O-022
PRIMARY ENDPOINT
• PFS
SECONDARY ENDPOINTS
• OS, ORR, DCR, safety, QoL
R
PD/
toxicity/
patient
decision
Stratification
• RAS status, ECOG PS, country
Trifluridine/tipiracil 35 mg bid
D1–5, 8–12 +
bevacizumab 5 mg/kg D1,15
q4w (n=77)
Key patient inclusion criteria
• mCRC
• No prior treatment for
metastatic disease
• Not eligible for intensive
therapy according to
investigator’s judgement
• ECOG PS 0–2
(n=153)
Capecitabine 1250 or
1000 mg/m2 bid D1–14 +
bevacizumab 7.5 mg/kg iv D1
q3w (n=76)
PD/
toxicity/
patient
decision
O-022: Phase II study evaluating trifluridine/tipiracil+bevacizumab and
capecitabine+bevacizumab in first-line unresectable metastatic colorectal
cancer (mCRC) patients who are non-eligible for intensive therapy
(TASCO1): results of the primary analysis – Van Cutsem E, et al
Key results
PFS
Van Cutsem E, et al. Ann Oncol 2018;29(suppl 5):abstr O-022
Su
rviv
al p
rob
ab
ility
, %
Time, months
100
80
60
40
20
0
0
0
0
2
12
3
4
23
12
6
30
18
C-B
TT-B
8
37
31
10
43
40
14
51
47
12
49
44
18
52
48
16
52
47
HR 0.71 (95%CI 0.48, 1.06)
9.23 (95%CI 7.59, 11.56) 7.82 (95%CI 5.55, 10.15)
Cumulative
number
of events
Δ = 1.41
Trifluridine/tipiracil + bevacizumab (TT-B)
Capecitabine + bevacizumab (C-B)
O-022: Phase II study evaluating trifluridine/tipiracil+bevacizumab and
capecitabine+bevacizumab in first-line unresectable metastatic colorectal
cancer (mCRC) patients who are non-eligible for intensive therapy
(TASCO1): results of the primary analysis – Van Cutsem E, et al
Key results (cont.)
OS
Van Cutsem E, et al. Ann Oncol 2018;29(suppl 5):abstr O-022
Time, months
100
80
60
40
20
0
0
76
77
2
71
74
4
68
71
6
62
64
No. at risk
C-B
TT-B
8
56
61
10
50
56
14
14
18
12
35
34
18
0
4
16
7
6
HR 0.56 (95%CI 0.32, 0.98)
Trifluridine/tipiracil + bevacizumab (TT-B; 22 events)
Capecitabine + bevacizumab (C-B; 33 events)
18.00 (15.18; NA)
16.16 (12.52; NA)
Δ = 1.84
Su
rviv
al p
rob
ab
ility
, %
O-022: Phase II study evaluating trifluridine/tipiracil+bevacizumab and
capecitabine+bevacizumab in first-line unresectable metastatic colorectal
cancer (mCRC) patients who are non-eligible for intensive therapy
(TASCO1): results of the primary analysis – Van Cutsem E, et al
Key results (cont.)
Conclusions
• In patients with mCRC who were not eligible for intensive therapy,
trifluridine/tipiracil + bevacizumab demonstrated a mPFS of 9.2 months and had an
acceptable safety profile
• Biomarker and QoL analyses are ongoing
Van Cutsem E, et al. Ann Oncol 2018;29(suppl 5):abstr O-022
AEs, n (%) Trifluridine/tipiracil + bevacizumab
(n=77)
Capecitabine + bevacizumab
(n=76)
Any AE 77 (100) 74 (97.4)
SAEs 42 (54.5) 44 (57.9)
Grade ≥3 AEs 68 (88.3) 53 (69.7)
Any TRAEs 75 (97.4) 68 (89.5)
Grade ≥3 TRAEs 60 (77.9) 33 (43.4)
Serious TRAEs 25 (32.5) 17 (22.4)
Leading to withdrawal 31 (40.3) 28 (36.8)
Death during treatment period 4 (5.2) 9 (11.8)
O-024: mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line
treatment in patients with RAS wild- type metastatic colorectal cancer
m(CRC): A randomized phase II VOLFI trial of the AIO (AIO-KRK0109)
– Geissler M, et al
Study objective
• To assess the efficacy and safety of panitumumab + mFOLFOXIRI vs. FOLFOXIRI as 1L
treatment in patients with mCRC
*If resectable: surgery then protocol treatment for up to
12 cycles; if CR/PR/SD after 12 cycles: re-induction
(same combination) recommended on PD Geissler M, et al. Ann Oncol 2018;29(suppl 5):abstr O-024
PRIMARY ENDPOINT
• ORR
SECONDARY ENDPOINTS
• TRR, time-to-relapse, PFS, OS, safety, QoL
R
2:1
PD/
resectability/
maximum
12 cycles*
Stratification
• Cohort 1: Histologically confirmed and definitively
inoperable/unresectable
• Cohort 2: Chance of secondary resection with
curative intent (pre-treatment liver/tumour biopsy)
Panitumumab 6 mg/kg +
mFOLFOXIRI q2w
(n=63) Key patient inclusion criteria
• Unresectable mCRC
• WT RAS
• 1L (1 cycle of FOLFIRINOX
permitted prior to randomisation)
• ECOG PS 0–1
(n=96) FOLFOXIRI q2w
(n=33)
PD/
resectability/
maximum
12 cycles*
O-024: mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line
treatment in patients with RAS wild- type metastatic colorectal cancer
m(CRC): A randomized phase II VOLFI trial of the AIO (AIO-KRK0109)
– Geissler M, et al
Geissler M, et al. Ann Oncol 2018;29(suppl 5):abstr O-024
Panitumumab +
mFOLFOXIRI (n=63)
FOLFOXIRI alone
(n=33)
OR (95%CI);
p-value
ORR, % (95%CI) 87.3 (76.5, 94.4) 60.6 (42.1, 77.1) 4.469 (1.614, 12.376);
0.004
Key results
Panitumumab +
mFOLFOXIRI
FOLFOXIRI
alone OR (95%CI); p-value
ORR by tumour sidedness, %
Left (n=78)
Right (n=18)
90.6
70.0
68.0
37.5
4.518 (1.298, 15.718); 0.02
3.889 (0.543, 27.886); 0.34
ORR by mutation status, %
RAS/BRAF WT (n=60)
BRAF mut (n=16)
86.0
85.7
64.7
22.2
3.364 (0.902, 12.549); 0.08
21.000 (1.504, 293.25); 0.04
O-024: mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line
treatment in patients with RAS wild- type metastatic colorectal cancer
m(CRC): A randomized phase II VOLFI trial of the AIO (AIO-KRK0109)
– Geissler M, et al
Geissler M, et al. Ann Oncol 2018;29(suppl 5):abstr O-024
Key results (cont.)
Cohort 1 Cohort 2
Panitumumab +
FOLFOXIRI (n=63)
FOLFOXIRI alone
(n=33)
HR (95%CI);
p-value
mPFS, months (95%CI) 9.7 (9.0, 11.7) 10.1 (7.8, 12.1) 0.920 (0.584, 1.451);
0.72
FAS
0
10
20
30
40
50
60
70
80
mFOLFOXIRI
+ panitumumab
FOLFOXIRI
OR
R, %
OR 3.625 (1.126, 11.671)
p=0.02
33.3
12.1
R0 62%
R1 19%
Rx 19%
R0 75%
R1 25% n=21
n=4
0
10
20
30
40
50
60
70
80
mFOLFOXIRI
+ panitumumab
FOLFOXIRI
OR
R, %
OR 7.800 (0.419, 145.135)
p=0.08
14.0 0.0
R0 67%
Rx 33%
n=6
0
10
20
30
40
50
60
70
80
mFOLFOXIRI
+ panitumumab
FOLFOXIRI
OR
R, %
OR 5.250 (1.069, 25.789)
p=0.05
75.0
36.4
R0 60%
R1 27%
Rx 13%
R0 75%
R1 25%
n=15
n=4
O-024: mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line
treatment in patients with RAS wild- type metastatic colorectal cancer
m(CRC): A randomized phase II VOLFI trial of the AIO (AIO-KRK0109)
– Geissler M, et al
Key results (cont.)
Conclusions
• In patients with mCRC, 1L treatment with panitumumab + mFOLFOXIRI significantly
improved ORR vs. FOLFOXIRI in the VOLFI trial
• Panitumumab + mFOLFOXIRI resulted in very high resection rates vs. mFOLFOXIRI,
despite the fact that most patients had advanced disease
• Panitumumab + mFOLFOXIRI was associated with relevant, but manageable, GI
toxicity and should only be used in patients with ECOG PS 0–1
Geissler M, et al. Ann Oncol 2018;29(suppl 5):abstr O-024
Non-haematological grade ≥3 AEs
occurring in ≥5% patients, %
Panitumumab + mFOLFOXIRI
(n=64)
FOLFOXIRI alone
(n=33)
Nausea 9.4 -
Vomiting 9.4 3.0
Diarrhoea 25.0 12.1
Stomatitis 9.4 -
Fatigue 7.8 -
Pain 7.8 3.0
Infections 12.5 12.1
O-027: BEACON CRC study safety lead-in: Assessment of the BRAF
inhibitor encorafenib + MEK inhibitor binimetinib + EGFR inhibitor
cetuximab for BRAFV600E mCRC – Van Cutsem E, et al
Study objective
• To assess the efficacy and safety of binimetinib + encorafenib + cetuximab in
patients with BRAF V600E mutant mCRC following completion of a safety lead-in*
*Safety lead-in (n=30): binimetinib 45 mg bid;
encorafenib 300 mg/day; cetuximab 400 mg/m2 (initial)
then 250 mg/m2 qw Van Cutsem E, et al. Ann Oncol 2018;29(suppl 5):abstr O-027
PRIMARY ENDPOINT
• ORR
SECONDARY ENDPOINTS
• OS, PFS, safety
Key patient inclusion criteria
• BRAF V600E mutant mCRC
• Progressed after 1 or 2 previous
regimens
• No prior treatment with RAF, MEK,
EGFR inhibitors or irinotecan
• Eligible for cetuximab
• ECOG PS 0–1
(n=615)
R
1:1:1 PD
Stratification
• BRAF V600E mutation status, ECOG PS, no. of prior regimens (1/2)
FOLFIRI + cetuximab or
irinotecan + cetuximab
(n=205)
Binimetinib +
encorafenib + cetuximab
(n=205)
Encorafenib + cetuximab
(n=205)
O-027: BEACON CRC study safety lead-in: Assessment of the BRAF
inhibitor encorafenib + MEK inhibitor binimetinib + EGFR inhibitor
cetuximab for BRAFV600E mCRC – Van Cutsem E, et al
Confirmed best ORR (assessed per RECIST 1.1) Patients with BRAF V600E mutations (n=29)
ORR (CR + PR), n (%) [95%CI] 14 (48) [29, 67]
CR, n (%) 3 (10)
PR, n (%) 11 (38)
SD, n (%) 13 (45)
PD, n (%) 0 (0)
Not evaluable for response*, n (%) 2 (7)
Key results
Van Cutsem E, et al. Ann Oncol 2018;29(suppl 5):abstr O-027
*Non-responders per ITT analysis; †patients with lymph node
disease with decreases in short axis dimensions consistent with
RECIST 1.1 defined CR; ‡one patient had no baseline sum of
longest diameters and is not presented
100 80 60 40 20
0 -20 -40 -60 -80
-100
26 2 14 13 24 15 22 5† Patients‡
PR (n=11)
CR (n=3)
Be
st ch
an
ge
fro
m
ba
se
line
, %
17 9 8 25 27 4† 6† 1 16 7 28 23 12 19 10 20 21 3 18 11
O-027: BEACON CRC study safety lead-in: Assessment of the BRAF
inhibitor encorafenib + MEK inhibitor binimetinib + EGFR inhibitor
cetuximab for BRAFV600E mCRC – Van Cutsem E, et al
Key results (cont.)
• Median OS was not reached (data fully mature through 12.6 months)
• In patients with 1 and 2 prior regimens mPFS was 8.0 (95%CI 4.0, 9.3) and 8.1 (95%CI
4.1, 10.8) months, respectively Van Cutsem E, et al. Ann Oncol 2018;29(suppl 5):abstr O-027
100
80
60
40
20
0
0 12 15 Time, months
Patients with BRAF
V600E mutation (n=29)
Censored patients
OS
, %
6 9 3 18
29 18 6 25 22 28 0 No. at risk
1-year OS rate: 62% 100
80
60
40
20
0
0 12 Time, months
PF
S, %
6 9 3 15
29 3 17 9 27 No. at risk
mPFS 8.0 months (95%CI 5.6, 9.3)
Patients with BRAF
V600E mutation (n=29)
Censored patients
Survival
rate
1 prior
regimen
2 prior
regimen
6 months 88% 85%
12 months 63% 62%
O-027: BEACON CRC study safety lead-in: Assessment of the BRAF
inhibitor encorafenib + MEK inhibitor binimetinib + EGFR inhibitor
cetuximab for BRAFV600E mCRC – Van Cutsem E, et al
Key results (cont.)
Conclusions
• In patients with BRAF V600E mutant mCRC, binimetinib, encorafenib plus
cetuximab triplet therapy led to improvements in ORR, PFS and OS
• The triplet therapy had an acceptable safety profile with no unexpected toxicities
• Enrolment is ongoing for the BEACON CRC phase III trial
AEs, n (%) Patients (n=30)
Total AEs 30 (100)
Grade 3/4 21 (70)
Leading to discontinuation*† 6 (20)
Leading to dose interruption/change† 5 (17)
On-treatment deaths‡ (including those within 30 days
of stopping study treatment) 5 (17)
Van Cutsem E, et al. Ann Oncol 2018;29(suppl 5):abstr O-027
*Includes increased blood bilirubin (n=1), drug hypersensitivity
(n=1), dyspnoea (n=1), fatigue (n=1), hypersensitivity (n=1),
malaise (n=1) and retinal detachment (n=1); †discontinuation or
dose interruption/change of ≥1 study drug; ‡on-treatment
deaths were due to disease progression