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Vía Biliar, actualización
Angela Lamarca MD, PhD, MSc
Consultant Medical Oncologist
Honorary Senior Lecturer
The Christie NHS Foundation Trust University of Manchester
Manchester, United Kingdom
#SEOM20
Disclosures
• Receipt of honoraria or consultation fees: Eisai, Nutricia, Ipsen, Roche, QED
• Participation in company sponsored speaker bureau: Pfizer, Ipsen, Merck, Incyte
• Travel, education funding: Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, Mylan, Celgene, Abbott, Bayer
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Biliary Tract Cancer (BTC) – Heterogeneous
Lamarca Current Med Chem 2020
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BTCs – Epidemiology
• Rare cancers
– Incidence:
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Management Overview
Lamarca Cancer Treat Rev 2018
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Management Overview
Lamarca Cancer Treat Rev 2018
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Adjuvant treatment – BilCap
• Randomised phase III: Capecitabine vs Observation (n=447)
• Primary end-point: OS (pre-planned sensitivity analysis)
Primrose Lancet Oncol 2019
Benefit
Capecitabine considered
standard of care for resected GBC
and CC (adjuvant)
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Management Overview
Lamarca Cancer Treat Rev 2018
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First-line – ABC-02
• First-line advanced BTC; CisGem vs Gem; n=410
• Primary end-point: OS stablished new standard of care
Valle NEJM 2010
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Management Overview
Lamarca Cancer Treat Rev 2018
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% o
f p
atie
nts
aliv
e
100
Months from randomization 0
80
60
40
20
0
12 15 18 21 24 27 30
Number at risk ASC alone
ASC + mFOLFOX
3 6 9
81 81
66 64
28 41
14 29
9 21
7 9
5 6
3 4
1 3
1 2
1 0
OS by trial arm
*Adjusted for platinum sensitivity, albumin and stage.
Lamarca A. ASCO 2019.
Arm A
(ASC alone)
Arm B
(ASC +
mFOLFOX)
Adjusted* Hazard Ratio 0.69 (95% CI, 0.50-0.97)
P=0.031
Median OS 5.3 months 6.2 months
6-month survival rate 35.5% 50.6%
12-month survival rate 11.4% 25.9%
FOLFOX improved OS after
progression to CisGem with:
• A clinically meaningful reduction in risk of
death (HR, 0.69 [95% CI, 0.50-0.97;
P=0.031])
• Survival with active symptom control was
greater than anticipated (5.3 vs 4 months)
• A clinically meaningful increase in OS rate:
at 6 months (+15%)
at 12 months (+15%)
Primary End Point: OS (ITT)
mPFS: 4 months; PR: 5%
FOLFOX + ASC new standard of care
Second Line – FOLFOX (ABC-06)
#SEOM20
https://www.google.com/url?sa=i&url=https://www.davidritchieandsons.co.uk/whats-new-in-aviemore/&psig=AOvVaw3hGFIWevzgiycEJnVwjeTm&ust=1601748337454000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCOi7o9e_luwCFQAAAAAdAAAAABAE
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Updates in Biliary Tract Cancer
1. Adjuvant setting
2. First-line chemotherapy
3. Second-line treatment and new therapies
4. Precision Medicine: targeted therapies
5. Immunotherapy
#SEOM20
Adjuvant: Gem-based vs Observation
Edeline et al, ESMO 2020
• Individual-patient data; Meta-analysis (BCAT + PRODIGE-12)
Lack of benefit from gemcitabine-based strategies (Pending results from ACTICCA-1 trial)
Capecitabine remains SOC
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Adjuvant treatment – Future steps
Edeline ESMO 2017; Primrose ASCO 2017; Ebata Br J Surg 2018
Study [clinicaltrials.gov ID]
n Population Arms Status
PRODIGE12 | France [NCT01313377]
190 Cholangio and GB Observation vs. GemOx
BilCap | UK [NCT00363584]
360 Cholangio and GB Observation vs.
Capecitabine
BCAT| Japan [UMIN000000820]
300 Cholangio Observation vs. Gem
JCOG1202 | Japan [UMIN000011688]
350 Cholangio and GB Observation vs. S1 Results awaited
ACTICCA-1 | Germany [NCT02170090]
440 Cholangio and GB Observation vs. CisGem Capecitabine
Recruiting patients
No benefit
Benefit
No benefit
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Updates in Biliary Tract Cancer
1. Adjuvant setting
2. First-line chemotherapy
3. Second-line treatment and new therapies
4. Precision Medicine: targeted therapies
5. Immunotherapy
#SEOM20
KHBO1401-MITSUBA: CisGem vs CisGem + S1
Sakai et al, ESMO 2018
• Randomised phase III study; n= 246; 1st-line setting
• Primary end-point: OS
• mOS: 13.5 vs 12.6 ( HR 0.79
(95% CI 0.60-0.99); p-value 0.046)
• mPFS 7.4 vs 5.5 (HR 0.75 (95% CI 0.58-0.97); p-value 0.0015)
• ORR 41.5% vs 15%
Benefit in ORR>PFS? Down-staging strategy?
#SEOM20
CisGem + NabPaclitaxel (GAP)
Shroff et al, JAMA Oncol 2020
• Phase II study; n=60
• Primary end-point: PFS
• 63% iCCA, 15% eCCA, 22%
GBC • mPFS 11.8 months • ORR 45%; DCR 84% • mOS: 19.2 months
Phase III trial required to
compare to CisGem (SWOG 1815)
Down-staging strategy?
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AMEBICA: mFOLFIRINOX VS CisGem
Phelip et al, ESMO 2020
• Randomised phase II study; n=190; 1st-line
• Randomly assigned (1:1) to either mFOLFIRINOX or CisGem (x6 months)
• Primary end-point: PFS-rate at 6 months
Cisplatin and gemcitabine remains standard-of-care first-line
#SEOM20
Tailoring chemotherapy options: DDR
Xiao et al, ESMO 2020; Chae EJC 2019; Lamarca et al, JCM 2020.
• Deficiency of DNA Damage Repair mechanism (dDDR) is present in ~15-20% of BTC.
• Platinum-based chemotherapy may achieve increased response rate in the presence of dDDR
• Impact on PFS/OS
Longer OS: prognostic factor
Longer PFS: prognostic factor
Discrepant results between studies
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Updates in Biliary Tract Cancer
1. Adjuvant setting
2. First-line chemotherapy
3. Second-line treatment and new therapies
4. Precision Medicine: targeted therapies
5. Immunotherapy
#SEOM20
NUC-1031: “protected” gemcitabine
McNamarca et al, ESMO 2018; Knox et al, ESMO 2020
• Pro-Tide transformation of gemcitabine overcome resistance mechanisms
• ABC-08 clinical trial (Phase Ib) – Encouraging efficacy: ORR, durable responses – Well tolerated
Phase III Nutide-121 trial ongoing: 1st
line setting (CisGem vs Cis-Nuc-1031)
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Etoposide toniribate (EDO-S7.1)
Belkouz et al ASCO 2019 abstract 4086; Pape et al, ASCO-GI 2019 abstract 264; Pape et al, ESMO 2019 abstract 724P
• Activated (hydrolysed by carboxylesterase) at the tumour
site, to produce activated etoposide (inhibits
topoisomerase II DNA damage apoptosis)
• Phase II: EDO-S7.1 vs BSC; cross over allowed; n=19 (9
vs10)
• DCR 55.6% vs 20%; PFS 103 days vs 39 days
• After cross over: risk of progression was reduced
Phase III planned (1st line?)
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Regorafenib; REACHIN trial
Demols et al, Annals of Oncol 2020
• Randomised (regorafenib vs placebo) phase II study; n=66; second-line and beyond
• No PR/CR; DCR (70% vs 33%) • PFS (primary end-point): 3 months vs
1.5 months (HR 0.49 (95% CI 0.29-0.814; p-value 0.004)
• OS: 5.3 months vs 5.1 months (p-value 0.28)
Further trials required
Progression-free survival
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Second-line trials: ABC-06 vs others
Adapted from Lamarca et al, Annals of Oncol 2020
1.- Study outcomes
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Second-line trials: ABC-06 vs others
Adapted from Lamarca et al, Annals of Oncol 2020
2.- Patient characteristics
#SEOM20
Updates in Biliary Tract Cancer
1. Adjuvant setting
2. First-line chemotherapy
3. Second-line treatment and new therapies
4. Precision Medicine: targeted therapies
5. Immunotherapy
#SEOM20
Biliary Tract Cancer (BTC) – Heterogeneous
Lamarca et al Journal of Hepatol 2020
Most promising data: IDH and FGFR (iCCA)
#SEOM20
iCCA: Precision medicine
• BTC (iCCA)-specific – IDH-1 mutations
– FGFR2 fusions
• Disease-agnostic – NTRK fusions
– MMR-deficiency
– BRAF mutations
Lamarca et al Journal of Hepatol 2020
#SEOM20
AG-120 (Ivosidenib) is a first-in-class, potent, oral inhibitor of the mutant IDH1 enzyme
n=186
2:1 R
AG-120 n=124
Placebo n=62
Cross-over to AG-120
on disease progression
Phase III study, second/third-line, placebo- controlled (ClarIDHy) [NCT02989857]
Targeting IDH-1 in CCA
Abou-Alfa et al Lancet Oncol 2020; OS: overall survival; PFS: progression-free survival
• mPFS (months): 2.7 (Ivosidenib) vs 1.4 (placebo); HR 0.37 (95% CI 0.25-0.54)
• 6 months PFS rate: 32% vs 0%; at 12 months 22% vs 0%
• mOS (months; adjusted for cross-over): 10.8 vs 6 months (9.7 months un-adjusted)
#SEOM20
FGFR inhibitors in CCA
FGFR inhibitor Company ORR Current status
Infigratinib; BGJ3981,2
Novartis/QED
26.9% PROOF trial: 1st line CisGem vs Infigratinib [NCT03773302]; FGFR2 fusions
Derazantinib; ARQ 0873
Arqule/ Basilea
20.7% Ongoing phase II (iCCA) [NCT03230318]; FGFR2 fusions
Pemigatinib; INCB548284
Incyte 35.5% (FGFR2 fusion
FIGHT-302 trial: 1st line CisGem vs Pemigatinib [NCT03656536]; FGFR2 fusions
Futibatinib TAS-1205
Taiho 37.3% (FGFR2 fusion)
Phase II study (iCCA cohort) [NCT02052778]; FGFR2 fusions
Infigratinib; BGJ3981,2
Derazantinib; ARQ 0873
Pemigatinib; INCB548284
Futibatinib TAS-1205,6
1. Javle M et al. J Clin Oncol. 2017;36:276–82; 2. Javle M, et al. Poster presentation at ESMO 2018. LBA28; 3. Mazzaferro V, et al. Br J Cancer. 2018;120:165–71; 4. Vogel A, et al. Oral presentation at ESMO 2019. LBA40; 5. Tran B, et al. Oral presentation at ESMO-Asia 2018. Abstract 1550. 6. Bridgewater et al, ESMO 2020 ePoster #54P.
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-80
-60
-40
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20
40
60
Bes
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Ch
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rom
Bas
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arg
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esio
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ize
CR (n=3 [2.8%])PR (n=35 [32.7%])
SD (n=50 [46.7%])PD (n=16 [15.0%])Not evaluable*
#SEOM20
FGFR inhibitors in CCA
Confirmatory randomised trials are still
required…
Lamarca et al Journal of Hepatol 2020
#SEOM20
Dabrafenib and trametinib: BRAF V600E-mutated BTC
Subbiah et al, LancetOncol 2020
• Phase II study; n=43
• ORR 51% (95% CI 36-67) – investigator assessed
• ORR 47% (95% CI 31-62) – central review
• Duration of response: 9 months (95% CI 6-14)
• PFS: 9 months (95% CI 5-10) • OS: 14 months (95% CI 10-33)
Promising activity and manageable safety profile.
#SEOM20
Updates in Biliary Tract Cancer
1. Adjuvant setting
2. First-line chemotherapy
3. Second-line treatment and new therapies
4. Precision Medicine: targeted therapies
5. Immunotherapy
#SEOM20
Immunotherapy in iCCA: first steps
• KEYNOTE-028 (n=24) – Pembrolizumab: 4/24 (14%) response rate
• KEYNOTE-158: biliary tract cohort (n=104) – Pembrolizumab monotherapy
– ORR was 5.8%; 6.6% in PD-L1+ patients
– Median PFS 2.0 months (95% CI, 1.9–2.1); 1.9 in PD-L1+ patients
– Median OS 9.1 months (95% CI, 5.6–10.4); 7.2 in PD-L1+ patients
– None were MSI-H
Bang ECC 2015; Ueno ESMO 2018
Alternative approaches (combined with
chemotherapy) are required (clinical trials
ongoing)
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MSI-high/MMR-def
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Immunotherapy (bintrafusp alfa)
Yoo et al, ESMO 2020
• Fusion protein anti TGF-β/PD-L1
• Phase II, monotherapy; 2nd-line setting
– N=30; 13.3% (n=4) of patients had received ≥2 prior anticancer regimens
– GBC (40% [n=12]), iCCA (33.3% [n=10]), eCCA (23.3% [n=7]), and AMP (3.3% [n=1])
#SEOM20
Immunotherapy (+CisGem)
Sahai et al, ASCO 2020; Oh ASCO 2020; Liu et al, ESMO 2020;
• Multiple phase II trials: CisGem+immunotherapy 1st-line setting – BilT-01 (randomised phase II): n=64
• Arm A: CisGem + Nivolumab: PFS 7.4m • Arm B: Nivolumab+ Ipilimumab: PFS 4.1m
– CisGem + Durvalumab +/- Tremelimumab: n=121 • CisGem +DT: ORR 73.3%, PFS 11.9m • CisGem +D: ORR 73.4%, PFS 18.1
– Toripalib (anti PD-1): CisGem+Tol n=34 (all BTC): PR 20.6%; DCR 85.3%; PFS 6.7
• Ongoing phase III randomised studies:
CisGem + Pd-1/PD-L1 inhibitor – TOPAZ-1: durvalumab – Keynote-699: Pembrolizumab – INTR@PID 005: bintrafusp alfa (fusion protein
anti TGF-β/PD-L1)
CisGem + Toripalib
#SEOM20
Immunotherapy (+TKIs)
Zhou ESMO 2020, Lwin ESMO 2020
• Lenvatinib + Toripalib + GemOx – Phase II; iCCA only; 2nd line and beyond – ORR: 80% (1 CR) – 2 pts with lo advanced were resected – Median PFS/OS not reached – Tolerable
• LEAP-005: Lenvatinib + Pembrolizumab – Multicohort study: BTC cohort (n=31); 2nd-line and beyond – ORR: 10% – Median PFS 6.1 months
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Take home messages
Adjuvant: capecitabine remains standard of care
1
First-line: CisGem remains standard of care; +nab-paclitaxel? 2
Second-line: FOLFOX; better treatments required (regorafenib?)
3
Targeted therapies: FGFR and IDH: first-line role? 4
Immunotherapy: + chemotherapy/TKIs 5
#SEOM20
Thank you for your attention
mailto:[email protected]
