WHAT IS NEW IN BILE DUCT CANCER IN THE LAST 12 MONTHS?€¦ · WHAT IS NEW IN BILE DUCT CANCER IN...

WHAT IS NEW IN BILE DUCT CANCER IN THE LAST 12 MONTHS?Juan W ValleUniversity of Manchester / The ChristieManchester, UK21 June 2018

1 Bañales et al Nat Rev Gastroenterol Hepatol 2016;13;261, 2 Hundall & Schaffer Clin Epidemiol 2014 6;99

Cholangiocarcinoma1 Gallbladder cancer2

BILIARY TRACT CANCER | A GLOBAL CHALLENGE

Adjuvant Phase III BCAT study

Advanced disease Phase III FUGA-BT study Randomised phase II: addition of MEKi (BIL-MEK) New promising agents/combinations

Understanding biology and actionable sub-groups International Cancer Genome Consortium Single target and multiple target studies

NEW DATA IN THE PAST 12 MONTHS

ADJUVANTResectable disease

BCAT | BILE DUCT CANCER ADJUVANT TRIAL

Ebata et al Br J Surg 2018; 105: 192–202

Extrahepatic CCA (perihilar and distal CCA)≤10 weeks post-opAge ≥20PS 0-1

225 patients recruited from 48 Japanese hospitals

1o endpoint | OS2o endpoints | RFS, subgroup analysis, toxicity

observation

gemcitabine [6 cycles]

1 : 1

Stratification:R0 vs. R1N0 vs. N1PrimaryCentre

HR 0.85Power 80%Two-sided-α 5%N=300 for 189 eventsInterim analysis (200 patients)

BCAT | BILE DUCT CANCER ADJUVANT TRIAL

Relapse-free survival Overall survival (1o endpoint)

HR 1.01 (95%CI 0.70-1.45; p=0.964)HR 0.93 (95%CI 0.66-1.32; p=0.693)

No subgroup benefitted (N0/1; R0/1)5YS better than anticipated (50% vs 30%)

ADJUVANT CHEMOTHERAPY | RANDOMISED TRIALS

1. Ebata et al Br J Surg 2018; 2. Edeline et al (ASCO-GI) J Clin Oncol 2017;35:suppl 4S: abstr 225; updated ESMO 2017 LBA29; 3. Primrose et al (ASCO 2017) J Clin Oncol 35 (15) 4006

BCAT1

• RFS: HR=0.93 [0.66-1.32], p=0.693• OS: HR= 1.01 [0.70-1.45], p=0.964

BILCAP3

• RFS: HR=0.93 [0.66-1.32], p=0.693• OS: HR= 0.81 [0.63-1.04], p=0.097• OS: HR 0.70 [0.55-0.91], p=0.007*

* pre-planned sensitivity analysis

PRODIGE 122

• RFS: HR=0.88 [0.62-1.25], p=0.47*• OS: HR= 1.08 [0.70-1.66], p=0.74

*co-primary endpoint: QoL

BilCap study | improved overall survival in per-protocol analysis*

*Benefit seen in per-protocol analysis population onlyBenefit seen following sensitivity analysis (LN status, disease grade, gender): HR 0.70 (95% CI 0.55-0.91) p=0.007

ADJUVANT CHEMOTHERAPY RCTs

Primrose et al ASCO 2017; J Clin Oncol 35, suppl; abstr 4006

ADJUVANT CHEMOTHERAPY | SUMMARY OF RANDOMISED TRIALS

Study [clinicaltrials.gov ID]

N Population Arms vs. Status

PRODIGE12 | France[NCT01313377]

190 Cholangio & GB Observation GemOx No benefit

BilCap | UK[NCT00363584]

360 Cholangio & GB Observation Capecitabine Improved survival**pre-specified sensitivity analysis

BCAT| Japan[UMIN000000820]

300 EH-Cholangio Observation Gemcitabine No benefit

ASCOT| Japan[UMIN000011688] JCOG1202

350440 Cholangio & GB Observation S1 Recruiting

ACTICCA-1 | Germany[NCT02170090]

781 Cholangio & GB ObservationCapecitabine CisGem Design revised

DIFFERENCES IN STUDY POPULATIONBCAT1 PRODIGE2 BILCAP3

iCCA (%) - 44 19hCCA (%) 45 8 29dCCA (%) 55 28 35GBC (%) - 20 18



iCCA (%) - 44 19hCCA (%) 45 8 29dCCA (%) 55 28 35GBC (%) - 20 18N0 / N1 (%) 65 / 35 63 / 37 47 / 47

(6% unknown)

R0 / R1 (%) 89 / 11 87 / 13 62 / 38



iCCA (%) - 44 19hCCA (%) 45 8 29dCCA (%) 55 28 35GBC (%) - 20 18N0 / N1 (%) 65 / 35 63 / 37 47 / 47

(6% unknown)

R0 / R1 (%) 89 / 11 87 / 13 62 / 38Experimental arm 62.3 75.8 52.7Control arm (mo) 63.8 50.8 36.1


Phase II, multi-centre• EHCC or GBCA after radical resection, pT2-4 or N1 or R1

• Gem-Cap (4 cycles, q3w), then CRT 45Gy/25 fractions to LN bed and 54-59 Gy tumour boost + capecitabine as sensitizer

• 79 eligible patients− R0 (n= 54); R1 (n=25)− EHCC 68%; GBCA, 32%− 86% completed, acceptable toxicity− 2-year DFS 52% (met threshold of activity)

Ben-Josef et al J Clin Oncol 2015;33(24)2617

SWOG 0809 STUDY

Inclusion of radiotherapy question – in R1 disease

ADVANCEDNon-resectable and metastatic

1. Valle et al Ann Oncol 2016;27(suppl5):v28-v37; 2. Valle 2010 New Eng J Med

ESMO GUIDELINES1

In Japan: cisplatin & gemcitabine (CisGem) improves survival (over Gem alone)

• BT-22 (n=84): OS 11.2 months 1

• Meta-analysis with ABC-02 (n=493) OS 11.6 months 2

JCOG0805 trial3 (randomized phase II selection study of gemcitabine plus S-1 (GS) vs. S-1):

• GS had improved 1YS 52.90% vs. 40.00%

• Acceptable toxicity profile

• OS 12.5 months

1 Okusaka 2010 Br J Cancer, 2 Valle 2014 Ann Oncol; 3Morizane Cancer Sci 2013;104: 1211–1216

CIS-GEM | ONLY THE “FIRST STEP” ON THE LADDER

Randomized phase III study of gemcitabine plus S-1 combination therapy versus gemcitabine plus cisplatin combination therapy in advanced biliary tract cancer (JCOG1113)

Hepatobiliary and Pancreatic Oncology Group of Japan Clinical Oncology Group (JCOG), Japan

Presented By Makoto Ueno, MD

FUGA-BT

Morizane et al ASCO-GI 2018: abstr 205; Ueno et al ASCO 2018 abstr 4014

GEM:1000 mg/m2 d1, 8 + CDDP: 25 mg/m2

d1, 8; repeated every 3 wks

Cisplatin was administered up to 16 times (total 400 mg/m2), thereafter GEM monotherapy was continued

GEM+CDDP GEM+S1GEM:1000 mg/m2 d1, 8 + S-1: 60, 80, 100 mg/body/day d1-14; repeated every 3 wks

Adjustment factors• Primary tumor (GB vs. others)• History of primary tumor resection (yes/no)• Institution

Recurrent/Unresectable biliary tract cancer (IHBD, EHBD, GB, AV)

Randomisation

Primary analysis| Overall survival


FUGA-BT

GCN=175

GSN=179

%1 year OS(95% CI)

58.3%（50.6%－65.2%）

59.2%（51.6%－66.0%）

Median OS(95% CI)

13.4 months(12.4-15.5)

15.1 months(12.2-16.4)

HR✝): 0.945, 90% CI 0.777-1.149p for non-inferiority = 0.0459 < 0.05


Exploratory subgroup analysis


FUGA-BT


GC/GS• Primary endpoint

Median OS: 13.4 /15.1 months HR 0.945 (90% CI: 0.777-1.149), p=0.0459

• Secondary endpoint Median PFS: 5.8 / 6.8 months RR: 32.4 / 29.8% AE: Both regimens are tolerable Clinically significant AE: 35.1 / 29.9% SAE: TRD 3 / 0 %Planned dose: GEM:75.7% / CDDP:76.7%

GEM:76.2% / S-1:75.3%• Hydration GC require, GS not require GS convenient

GS betterGC better

GS betterGS better

Primary Metnon-inferiority demonstrated

Comparable

Comparable

FUGA-BT

Gem-S1 is non-inferior to Cis/Gem in Japanese patients

Authors’Summary


BIL-MEK STUDY | BACKGROUND

BTC frequently demonstrates upregulation of RAS/RAF/MEK/ERK pathway

Selumetinib (ARRY-142886, AZD6244) is an oral inhibitor of MEK1/2

Selumetinib exhibited synergistic preclinical activity with gemcitabine (used sequentially)

A phase II trial of selumetinib in advanced BTC demonstrated safety at a dose of 100mg BID, with 12% response rate1

A phase 1b study of CisGem with selumetinib recommended a phase 2 dose of 75mg BID (ABC-04) 2

1. Bekai-Saab, et al. JCO 2011; 2. Bridgewater, et al. BMC Cancer 2016

BIL-MEK STUDY | SCHEMA

**Selumetinib dose was reduced from 75 mg to 50 mg BID March 2016 by protocol amendment

Doherty et al ASCO 2018

Arm AContinuous Selumetinib + CisGem

Arm BSequential Selumetinib + CisGem

Arm CCisGem Alone

Median change at 10 wk-12.4%

ORR 35.7%

Median change at 10 wk-15%

ORR 33.3%

Median change at 10 wk-11.6%

ORR 29.4%

Kruskal-Wallis p=0.73

% c

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* Denotes patients non-evaluable due to lack of 10 week study imaging

Primary Endpoint: Median % change in measurable disease at 10 weeks

BIL-MEK STUDY | EFFICACY


Secondary Endpoints: PFS, OS

BIL-MEK STUDY | EFFICACY


1 Blagden et al J Clin Oncol 33, 2015 (suppl; abstr 2547); 2 ClinicalTrials.gov | NCT02351765

first-in-class nucleotide analogue hENT1 independent transportno metabolism by cytidine deaminase (reduced toxic metabolites) achieves higher intracellular levels of dFdCTP than gemcitabine1

Phase IB study | acelarin and cisplatin in BTChENT1, human equilibrative nucleoside transporter-1; CDA,

cytidine deaminase; dCK, deoxycytidine kinase; dFdC,

gemcitabine; dFdU, ifluorodeoxyuridine

DEVELOPMENTS IN CHEMOTHERAPYAcelarin

Acelarin | ABC-08 study2

1 ClinicalTrials.gov | NCT02351765; 2 McNamara et al ASCO-GI 2018 (abstr TPS544)

DEVELOPMENTS IN CHEMOTHERAPYABC-081

NUC-1031 at 625 mg/m2 + cisplatin at 25 mg/m2 is an attractive and effective combination for treatment of patients with advanced/metastatic biliary tract cancer

Gem/Cis/nab-paclitaxel1

[NCT02392637]USA (MDA and Mayo)Single-arm, phase II; n=61

GCN regimen

1Shroff et al ASCO 2017 J Clin Oncol 35, 2017 (suppl; abstr 4018); 2 Shroff et al ASCO-GI 2018 (abstr 350)

Schedule | gemcitabine 800mg/m2 + cisplatin 25 mg/m2 + nab-paclitaxel 100 mg/m2 ; D1,8 q21d

Promising early data1

- median PFS (1o endpoint): 11.8 months- response rate: 28.8%- median OS: 18.8 months

DEVELOPMENTS IN CHEMOTHERAPY

Updated analysis2

- median PFS: 11.4 months (95% CI: 6.1-16.1)- response rate: 39%.- median OS: 19.2 months (95%CI: 13.6-NA) Phase III study

planned (vs. CisGem)

UNDERSTANDING BIOLOGY AND ACTIONABLE SUB-GROUPS

IMPROVING OUR UNDERSTANDING OF THE GENETIC ENVIRONMENT OF BTC

Intrahepatic cholangiocarcinoma CCA has a different profile to extrahepatic CCA or GBC 1,2

Opisthorchis viverrini (liver-fluke)*-associated CCA (TP53 mutations) is different from non-liver fluke associated CCA (BAP1, IDH1 and IDH2 mutations)3

Inflammatory subclass is different from proliferative subclass4

Table adapted from 1

1Ross (ASCO GI) J Clin Oncol 33, 2015 (suppl 3; abstr 231); 2Borger 2011 Oncologist 17(1):72; 3Chan-on 2013 Nat Genet 45(12):1474; 4Sia 2015 Nat Commun 6:6087

Up to 70% of IH-CCA patients have an actionable mutation1

IDH-1 mutations and FGFR fusion rearrangements have emerged as potential therapeutic targets


1 Sia 2015 Nat Commun 6:6087


1 Jasakul et al Cancer Discov 2017;7(10); 1116–35

IDH-1 MUTATION IS DRUGGABLE

Phase I study: cholangiocarcinoma (CCA), chondrosarcoma, glioma, others [NCT02073994]

CCA cohort1: n=73 [dose escalation (n=24); dose-expansion 500 mg QD (n=49)]

No DLTs; drug-related AEs: fatigue, nausea, diarrhoea, vomiting

Activity: median PFS 3.8 months6-month PFS: 38.5%12-month PFS: 20.7%RR 5% (4 PRs)OS data not mature

1 Lowery et al ASCO 2017 J Clin Oncol 35, 2017 (suppl; abstr 4015); 2 Lowery et al ASCO2017 J Clin Oncol 35 (suppl; abstr TPS4142)

AG-120 is a first-in-class, potent, oral inhibitor of the mutant IDH1 enzyme

n=186

2:1R

AG-120n=124

Placebon=62

Cross-over to AG-120

on disease progression

Phase III study, second-line, placebo-controlled (ClarIDHy) [NCT02989857]

FGFR AS A POTENTIAL TARGET IN INTRAHEPATIC CHOLANGIOCARCINOMA

Fibroblast Growth Factor Receptor

Turner & Gross 2010 Nat Rev Cancer

BJG398 Phase II trial

Javle et al J Clin Oncol 2017 [Nov 28, Epub ahead of print]

BGJ398 125 mg dailyDays 1-21, every 28 days

Treatment until disease progression, unacceptable toxicity, withdrawal of informed consent, or death

Key inclusion criteria• Advanced or metastatic CC• FGFR2 fusion or other genetic alterations in FGFR• Progression following prior cytotoxic therapy

Primary endpoint | RR (RECIST v1.1)Secondary endpoints | PFS, OS, best overall response (BOR), disease control rate (DCR), safety, and pharmacokinetics.

• 47 patients treated

• Majority of patients had ≥2 prior therapies and 11% had at ≥ 4 prior regimens

• FGFR2 fusions/rearrangements were present in 38 patients

• Other FGFR genetic alterations were present in 9 patients;− FGFR2 mutations (n=3) − FGFR2 amplifications (n=4) − FGFR3 amplifications (n=2)

TARGETING FGFR IN THE CLINIC

BJG398 Phase II trialMedian duration of exposure was 188 days (6.2 months)

**All 8 patients with a partial response had an FGFR2 fusion**

Javle et al J Clin Oncol 2017 [Nov 28, Epub ahead of print]

TARGETING FGFR IN THE CLINIC

MOSCATO study | 1035 patients≥1 prior systemic treatmentECOG PS 0-1At least one tumour site accessible to biopsy

Multiple high-throughputmolecular analysis BTC n=43 Evaluable n=34 Druggable alteration n=23 Treated n=18

Verlingue et al Eur J Cancer 2017;87:122e130

MOSCATO STUDY

ORR 33%DCR 88%Median OS 17 mo vs. 5 mo, [HR 0.29; 95% CI, 0.11-0.76; p< 0.008).

Valle et al Cancer Discovery Cancer Discov; 2017;7(9); 943–62.

TARGETS UNDER EVALUATION

Adjuvant Phase III BCAT study – no benefit from adjuvant gemcitabine

Advanced disease Phase III FUGA-BT study – gem/S1 a new option for Japanese patients Randomised phase II (BIL-MEK) – no benefit from adding selumetinib to CisGem New promising agents/combinations – acelarin; gem/nab-pac/cisplatin (early days)

Understanding biology and actionable sub-groups International Cancer Genome Consortium – improved understanding of landscape Single target and multiple target studies – exciting times ahead: targeted therapies,

umbrella studies

NEW DATA IN THE PAST 12 MONTHS | SUMMARY

THANK YOU

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