vía biliar, actualización lamarca.pdfvía biliar, actualización angela lamarca md, phd, msc...

#SEOM20

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

#SEOM20

Biliary Tract Cancer (BTC) – Heterogeneous

Lamarca Current Med Chem 2020

#SEOM20

BTCs – Epidemiology

• Rare cancers

– Incidence:

#SEOM20

Management Overview

Lamarca Cancer Treat Rev 2018

#SEOM20

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)

#SEOM20

Management Overview


#SEOM20

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

#SEOM20

Management Overview


#SEOM20

% 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

#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

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

#SEOM20

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

#SEOM20


1. Adjuvant setting




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?

#SEOM20

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

#SEOM20


1. Adjuvant setting




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)

#SEOM20

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?)

#SEOM20

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

#SEOM20

Second-line trials: ABC-06 vs others

Adapted from Lamarca et al, Annals of Oncol 2020

1.- Study outcomes

#SEOM20

Second-line trials: ABC-06 vs others

Adapted from Lamarca et al, Annals of Oncol 2020

2.- Patient characteristics

#SEOM20


1. Adjuvant setting




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


#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.

-100

-80

-60

-40

-20

0

20

40

60

Bes

t P

erce

nta

ge

Ch

ang

e F

rom

Bas

elin

e

in T

arg

et L

esio

n S

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…


#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


1. Adjuvant setting




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)

#SEOM20

MSI-high/MMR-def

#SEOM20

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

#SEOM20

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

[email protected]

Thank you for your attention
mailto:[email protected]

vía biliar, actualización lamarca.pdfvía biliar, actualización angela lamarca md, phd, msc...

Documents