Avances en el tratamiento

del cáncer hepatobiliar

Advances in the treatement
of hepatobiliary cancer
Michel DUCREUX
Gustave Roussy Cancer Campus
Paris-Saclay University
 NIFE trial : Nal-IRI + 5FU/FA vs GemCis 1st line
cholangiocarcinoma (CCK)
• Nal-IRI (liposomal irinotecan) and GI cancers:
• NAPOLI-1: Phase III L2 advanced pancreatic cancer:
• Nal-IRI + 5FU/FA > 5FU/FA (Lancet 2016)
• NIFTY: Phase IIR L2 advanced intrahepatic CCK:
• Nal-IRI + 5FU/FA > 5FU/FA (corean population, ASCO® 2021)

• NIFE trial : phase IIR L1 CCK

• GEMCIS : mPFS 8 months; mOS 12 months, ABC-02 (N Engl J Med 2010)

Nal-IRI + 5FU/FA versus GEMCIS first line advanced CCK

L. Perkhofer et al. ESMO® 2021, Abs # LBA10

 NIFE trial : Nal-IRI + 5FU/FA vs GemCis 1st line
cholangiocarcinoma
Design

Inclusion criteria Arm A n=46

Nal-IRI 70mg/m2 D1
• intra-/extrahepatic CCK 5-FU 2400mg/m2 D1-2 Main endpoint:
• No previous treatment Folinic acid 400mg/m2 J1
• PFS at 4 Months
• ECOG PS 0-1 Cycle every 2 weeks
• Measurable disease
• RECIST v1.1 R Secondary endpoints:
1:1
• PFS, OS
Stratification Arm B n=46 • ORR (RECIST v1.1)
• Intra vs extra CCK
Cisplatin 25mg/m2 D1,D8 • Tolerance (CTC-AE)
Gemcitabine 1000mg/m2 D1,D8
• ECOG PS 0 vs. 1 • QoL
Cycle every 3 weeks
• Sex M vs F

L. Perkhofer et al. ESMO® 2021, Abs # LBA10

 NIFE trial : Nal-IRI + 5FU/FA vs GemCis 1st line
cholangiocarcinoma
Flow chart
Arm A Arm B
01/2018 – 09/2020 Patients characteristics Nal-IRI/5-FU/FA Gem/Cis
93 patients (n=49) n(%) (n=42) n(%)
Screened and randomized
Men 28 (57.1) 25 (59.5)
21 German centers Women 21 (42.9) 17 (40.5)

49 patients 44 patients Age, median, years (range) 65.0 (33-82) 65.5 (46-83)
Arm A Arm B
Nal-IRI / 5-FU/FA Gem/Cis ECOG 0 28 (57.1) 28 (66.7)
ECOG 1 21 (42.9) 14 (33.3)

2 excluded Intrahepatic CCK (iCCK) 34 (69.4) 32 (76.2)

(protocol violation) Extrahepatic CCK (eCCK) 15 (30.6) 10 (23.8)

Well differentiated (G1) 3 (6.1) 0

Moderately differentiated (G2) 22 (44.9) 16 (38.1)
49 patients 42 patients Poorly differentiated (G3) 5 (10.2) 8 (19.0)

ITT
Arm A Arm B Undifferentiated (G4) 1 (2.0) 0
Nal-IRI / 5-FU/FA Gem/Cis Unspecified (Gx) 18 (36.7) 18 (42.9)

Previous treatement, n (%)

Surgery 11 (22.4) 12 (28.6)
Adjuvant CT 1 (2.0) 2 (4.8)
Adjuvant RTCT 2 (4.1) 0

L. Perkhofer et al. ESMO® 2021, Abs # LBA10

 NIFE trial : Nal-IRI + 5FU/FA vs GemCis 1st line
cholangiocarcinoma
⚫ Tolerance
→ Arm A : more GI toxicity
→ Arm B : more haematological toxicity

Arm A Arm B
Grade 3-4 side effects Nal-Iri/5-FU/FA Gem/Cis
(n=49) (n=42)

Anemia 4.1% 26.2%

Neutropenia 10.2% 21.4%
Thrombocytopenia 2.0% 9.5%
Mucositis 2.0% 0%
Diarrhea 22.4% 2.4%
Nausea 12.2% 0%
Fatigue 4.1% 2.4%
Duration of treatment (months) 5.8 5.5

L. Perkhofer et al. ESMO® 2021, Abs # LBA10

 NIFE trial : Nal-IRI + 5FU/FA vs GemCis 1st line
cholangiocarcinoma
Progression-free survival (main endpoint)
PFS
PFS 4 months Median PFS, mo OR
(IC-95%)
Arm A : 51.0%
100 5.98
Nal-Iri/5-FU/FA (IC 90% 24.5%
(2.37-9.59)
(n=49) 0.4145, 0.605)
Arm B : Gem/Cis 6.87
80 59.5% 11.9%
⚫ OR rate arm A vs B : 24.5 vs
(n=42) (2.46-7.82)
PFS (%)

60
11.9%
40

20

0
0 6 12 18 24 30
Time (months)
49 19 11 3 1 0
42 23 3 1 0 0

L. Perkhofer et al. ESMO® 2021, Abs # LBA10

 NIFE trial : Nal-IRI + 5FU/FA vs GemCis 1st line
cholangiocarcinoma
PFS iCCK vs eCCK (prespecified analysis)
iCCK eCCK
mPFS mOS mPFS mOS
100 iCCK 100 eCCK
(mo, IC 95%) (mo, IC 95%) (mo, IC 95%) (mo, IC 95%)
Arm A (n=34) 3.45 14.19 Arm A (n=34) 9.59 18.23
80 Nal-Iri/5-FU/FA (2.10-6.05) (7.69-21.85) 80 Nal-Iri/5-FU/FA (1.94-15.67) (8.67-30.95)
Arm B (n=32) 7.72 16.36 Arm B (n=32) 1.76 6.34
Gem/Cis (6.05-9.46) (7.46-19.91) Gem/Cis (0.16-6.87) (0.16-NR)
60 60
PFS (%)

PFS (%)
40 40

20 20

0 0
0 6 12 18 24 30 0 6 12 18 24
Time (Months) Time (months)
34 10 7 2 1 0 15 9 4 1 0
32 21 3 1 0 0 10 2 0 0 0
Test for heterogeneity (Cox regression) : PFS p=0,0018; OS p=0,0519

Interest of 5FU/Nal-IRI in first-line treatment of advanced CCK,

especially for extrahepatic forms. To be confirmed

L. Perkhofer et al. ESMO® 2021, Abs # LBA10

 IMMUTACE : Chemoembolisation +
Nivolumab in advanced HCC
• Immunotherapy in HCC:
• L1 : IMBRAVE 150 Atezolizumab + Bevacizumab >> sorafénib (NEJM 2020),
• Atezo +Bevacizumab = new standard of care in first line treatment of advanced
HCC
• Trans-arterial chemoembolistaion (TACE) = gold standard treatement for
intermediate-stage HCC
• median survival < 20 months in unselected series
• Rationale for the combination of TACE and immunotherapy:
• production of neoantigens secondary to TACE?
Single arm phase II, evaluation of TACE + nivolumab in intermediate
stage HCC

A. Vogel et al. ESMO® 2021, Abs # LBA37

 IMMUTACE : Chemoembolisation +
Nivolumab in advanced HCC
Phase II single arm: Primary endpoint: objective response rate of at least 55% (mRECIST)

Chemoembol 1
Histologically confirmed intermediate stage HCC, age ≥18 years,
NIVO
Population
Limited extrahepatic extension allowed; ECOG ≤2, Child-Pugh A

Chemoembol 2 Main endpoint OR rate > 55% (power = 80%; actual beta 0.17)

NIVO Secondary endpoints PFS, TFS, QoL, and tolerance

Number of patients 49

CR/PR/SD 1st PD = PFS

Possible new local YES

NIVO therapy? Local TT* NIVO 2nd PD TFS = PFS

NO
*3rd CEL, ablative therapy, surgery
1st PD TFS = PFS TFS : time to failure strategy

A. Vogel et al. ESMO® 2021, Abs # LBA37

 IMMUTACE : Chemoembolisation +
Nivolumab in advanced HCC
Patients characteristics

N=49 N=49

Age, median (range) 66 (42-83) Tumor size in cm,

3 (0.6-147)
median (range)

Male, n(%) 40 (81,6) No. of nodules*,

3 (1-12)
median (range)
ECOG, n(%) BCLC stage, n(%)
0 42 (85.7) A 9 -18.4)
1 7 (14.3) B 29 (59.2)
Etiology of liver disease, n(%) C 1 (2.0)
Non viral 34 (69.4) Child Pugh, n(%)
HBV 4 (8.2) A 49 (100)
HCV 7 (14.3)
ALBI score
Previous TT, n(%)
1 30 (61.2)
Radiotherapy 1 (2.0)
2 17 (34.7)
Surgery 11 (22.4)
*Based on measurements from central radiologic review

A. Vogel et al. ESMO® 2021, Abs # LBA37

 IMMUTACE : Chemoembolisation +
Nivolumab in advanced HCC
• Tolerance (frequency > 10% of patients)

n=49 n=49
Side effect, n (%) Side effect, n (%)
All Grades Grade > 3 All Grades Grade > 3

Fatigue 15 (30.6) 0 Pruritus 6 (12.2) 1 (2.0)

ASAT increase 12 (24.5) 7 (14.3) GGT increase 6 (12.2) 5 (10.2)

ALAT increase 11 (22.4) 4 (8.2) Anemia 6 (12.2) 0

Pain 10 (20.4) 3 (6.1) Hypothyroidism 5 (10.2) 0

Constipation 8 (16.3) 0 Creatinin increase 5 (10.2) 0

Nausea 7 (14.3) 0 Anorexia 5 (10.2) 0

Hyperthyroidism 7 (14.3) 0

Fever 7 (14.3) 1 (2.0)

Expected toxicity profile

A. Vogel et al. ESMO® 2021, Abs # LBA37

 IMMUTACE : Chemoembolisation +
Nivolumab in advanced HCC
Response
Response rate
100 Progression (PD) Non evaluable
Stable disease(SD) Complete response (CR)
80 Partial response (PR)

60 ORR (mRECIST)
Change of sum of measurements
by mRECIST from baseline (%)

40
Variable Analysis (n=49)
20

0
OR (95% CI), % 71.4 (56.8 – 83.4)
Best response, n
-20 (%)
8 (16.3)
CR
-40 27 (55.1)
PR
2 (4.1)
-60 SD
7 (14.3)
PD
5 (10.2)
-80 Not evaluable

-100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44

Nbre pts

A. Vogel et al. ESMO® 2021, Abs # LBA37

 IMMUTACE : Chemoembolisation +
Nivolumab in advanced HCC
Response rate by subgroup
No. of
Subgroup HR (IC 95%)
patients
All patients 49 71.4 (56.8 - 83.4)
Sex
M 40 (81.6) 82.5 (67.2 - 92.7)
F 9 (18.4) 22.2 (2.8 - 60.0)
ECOG status
0 42 (85.7) 69.0 (52.9 - 82.4)
➢ 0 7 (14.3) 85.7 (42.1 - 99.6)
Child Pugh
A 49 (100) 71.4 (56.7 - 83.4)
ALBI Score
1 30 (61.2) 70.0 (50.6 - 85.3)
2 17 (34.7) 76.5 (50.1 - 93.2)
BCLC
A 9 (18.4) 66.7 (29.9 - 92.5)
B 29 (59.2) 72.4 (52.8 - 87.3)
Etiology of liver disease
Non-viral 34 (69.4) 67.6 (49.5 - 82.6)
HBV 4 (8.2) 75.0 (19.4 - 99.4)
HCV 7 (14.3) 85.7 (42.1 - 99.6)

0 25 50 75 100

A. Vogel et al. ESMO® 2021, Abs # LBA37

 IMMUTACE : Chemoembolisation +
Nivolumab in advanced HCC
Median PFS
*3 mo 6 mo 9 mo 12 mo 15 mo 18 mo
(95% CI) Median
*6 mo 12 mo 18 mo 24 mo 30 mo
PFS OS (IC 95%)

6.14 months
80 52 36 25 15 15 28,32 months
(5.16-7.56) 91 87 72 65 26
(69-92) (37-66) (22-50) (12-39) (4-26) (4-26) (20,60-NE)
41 events (83-99) (76-97) (58-86) (49-81) (0-54)
18 events
100 100
*proportion without event (95%CI) *proportion without event (95%CI)

80 80

60 60
SSP(%)

SG (%)
40 40

20 20

0 0
0 6 12 18 24 30 0 6 12 18 24 30 36
Time (months) Time (months)

Interesting results. To be confirmed

A. Vogel et al. ESMO® 2021, Abs # LBA37

 ORANGE II Plus : Laparoscopy versus open
surgery for liver surgery

• Surgical resection is the mainstay of curative treatment of liver tumors,

especially malignant ones
• Definition of resectability has evolved in recent years and the laparoscopic
approach to major liver resections is increasingly practiced. Laparoscopy
could be associated with a faster fonctional recovery
• The objective of this study was to evaluate the perioperative and oncologic
outcomes of laparoscopy compared to open surgery

RS. Fichtinger et al., ESMO® 2021, Abs #384O

 ORANGE II Plus : Laparoscopy versus open
surgery for liver surgery
• Randomized, controlled, blind study
• Statistics
• 2 X 125 patients
• 2 days difference, 5 days standard deviation
• Bilateral alpha 4%, power 80%

Primary endpoint:
Laparoscopy • Functional recovery time (FRT)
Inclusion criteria
• Right/left hemi-hepatectomy +/- Secondary endpoints:
controlateral resection (wedge) • Length of stay
• Benign or malignant disease R • Intra-operative data
• BMI 18 - 35 kg/m² 1:1 • Complications
• ASA I-II-II • DFS
• OS
Open surgery • QoL (EORTC QLQ-C30 & LM-21)
• Medico-economic analysis
ᶲMinimised on hemihepatectomy side and surgery center.

RS. Fichtinger et al., ESMO® 2021, Abs #384O

 ORANGE II Plus : Laparoscopy versus open
surgery for liver surgery
Functional recovery time

Expectations / Confidence / Administration / Planning

3-10 days
Length of stay
Surgery

2-8 days 1-2 days

Functional recovery time Extension of time

✓ Tolerance for solid foods Functional recovery Sortie

✓ Discontinuation of infusions
✓ Oral analgesics only
✓ Autonomous mobilization
✓ Normalization of the liver tests
Patient preparation / Surgery / Stress response

RS. Fichtinger et al., ESMO® 2021, Abs #384O

 ORANGE II Plus : Laparoscopy versus open
surgery for liver surgery

RS. Fichtinger et al., ESMO® 2021, Abs #384O

 ORANGE II Plus : Laparoscopy versus open
surgery for liver surgery
Patients characteristics
Laparoscopy Open surgery Laparoscopy Open surgery
(n=166) (n=166) (n=166) (n=166)
Right 105 (63%) 108 (65%)
Age Mean, years (± SD) 61.5 (± 13.5) 62.6 (± 13) Hemi-hepatectomy
Left 61 (37%) 58 (35%)
Gender Woman 67 (40%) 70 (42%) Wedge 26 (16%) 23 (14%)
BMI Median, kg/m2 (IQR) 26 (23 to 29) 25 (22 to 28) Associated procedure RFA 18 (11%) 18 (11%)
Wedge and RFA 6 (4%) 3 (2%)
I 13 (8%) 19 (11%) 30 (18%) 20 (12%)
ASA score II 93 (56%) 91 (55%) Hemangioma 6 (4%) 7 (4%)
III 52 (31%) 52 (31%)
Benign indications Adenoma 6 (4%) 0
Charlson comorbidity index Mean (± standard deviation) 6.3 (± 3.2) 6.2 (± 2.8)
FNH 1 (1%) 2 (1%)
0 121 (73%) 123 (74%)
Other benign 17 (10%) 11 (67%)
1 36 (22%) 40 (24%)
WHO Performance status 136 (81%) 145 (88%)
2 4 (2%) 1 (1%)
3 1 (1%) 0 CRC meetastases 89 (54%) 77 (46%)
Previous abdominal surgery 87 (52%) 90 (55%) Malignant indications HCC 19 (11%) 28 (17%)
Preoperative chemotherapy 53 (32%) 61 (37%) Cholangiocarcinoma 17 (10%) 30 (18%)
Preoperative portal Others malignant 11 (7%) 10 (6%)
16 (10%) 9 (5%)
embolization Unknown diagnosis 0 1 (1%)

RS. Fichtinger et al., ESMO® 2021, Abs #384O

 ORANGE II Plus : Laparoscopy versus open
surgery for liver surgery
Results
Treatment Duration of operation, median (IQR)
Primary endpoint
Laparoscopy 310 minutes (255 – 379) Estimated difference : 56 minutes, p ≤ 0.001
Critères secondaires
Treatment FRT, median (IQR) Open surgery 254 minutes (194 – 301)
Laparoscopy 4 days (3 – 5)
Treatment Blood loss, median (IQR)
Open surgery 5 days (4 – 6) Laparoscopy 450 mL (300 – 775)
Open surgery 450 mL (300 – 785)

Treatment Conversions
5
Laparoscopy 28 (17%)
-17.5%
Open surgery Not applicable
4
Treatment Complications index, median (IQR)*
Open surgery

Laparoscopy 32 (21-41) p=0,440

Laparoscopy

Open surgery 33 (23-43)

Days

R1 margins OR 1.65 (0.69 – 3.97, p=0.136)

Cancer recurrence OR 0.72 (0.38 – 1.37), p=0.187)

Liver cancer recurence OR 0.67 (0.34 – 1.34), p=0.134)

0
In favor of laparoscopy In favor of open surgery
RS. Fichtinger et al., ESMO® 2021, Abs #384O
 ORANGE II Plus : Laparoscopy versus open
surgery for liver surgery
Time to start adjuvant chemo, 3-year OS
Treatment
mean (+/- SD) 100 HR 1.23 (IC 99% 0.72 to 2.11 , p=0.320)

Laparoscopy 47 days (+/-19)

80

Probability of survial (%)

Open surgery 60 days (+/-17)
60

60
40
13 days

47 20
Open surgery

Estimated difference : -13 days

0
Laparoscopy

(IC 99% -23.1 to -1.8 0 4 8 12 16 20 24 28 32 36

p = 0.003)
Time (months)
Days

136 131 128 120 111 108 99 93 78 67

145 140 135 130 121 116 110 102 98 86

RS. Fichtinger et al., ESMO® 2021, Abs #384O

 ORANGE II Plus : Laparoscopy versus open
surgery for liver surgery
• Laparoscopy for major liver surgery in expert centers allowed to reduce
the time to functional recovery and the length of hospital stay by one day
• with an increased operative time of one hour
• with no difference in perioperative complications rate
• and with earlier initiation of adjuvant chemotherapy
• There was no significant difference in oncologic outcomes, but there was a
tendency for more R1 resections with laparoscopy and survival data were not
mature

Laparoscopy appears to be preferable to open surgery IN EXPERT CENTERS

(learning curve = 55 patients), especially for liver metastases of CRC

RS. Fichtinger et al., ESMO® 2021, Abs #384O

 “Hidden” intrahepatic cholangiocarcinoma (iCCA) among
cancers from unknown primary (CUP). A single center
retrospective study in a tertiary center
• CUP = heterogeneous group of metastatic lesions for which the primary cannot be identified:
• 2% of all cancers and the 6th leading cause of death by cancer in the UK
• Poor prognosis: median OS: 6-9 months
• ORR with first line chemotherapy (platinum based) = approximately 30%, no validated second line
• Molecular profiling to predict organ of origin and guide chemotherapy has not been shown to be clinically effective
(insufficient evidence))

• A significant proportion of CUPs could be iCCA -> 11% of CUPs in this study of 233 patients, and 34% of CUPs with
liver involvement
• Diagnostic diffuclty (no specific IHC…)
• iCCA = diagnostis of exclusion
• Issue : new targeted therapies available for iCCA (iDH1, FGFR fusions…)
• Importance of having molecular analysis..

Consider iCCA for any hepatic CUP with adenocarcinoma-like histology

Then: apply “iCCA-type” molecular profiling for the sessions to allow accss to targeted therapies

A-M Conway et al., ESMO® 2021, Abs #58P → Sommaire

 Conclusion

• No major change in standard of care

• Some hopes concerning:
• Chemotherapy of Cholangiocarcinoma
• Combination of immunotherapy and TACE in hepatocellular carcinoma

• Confirmation:
• Laparoscopic surgery is feasible in liver resection or tumors (but in expert centers)
• We have to propose sequencing in ACUP with liver involvement