WHAT IS NEW IN BILE DUCT CANCER IN THE LAST 12 MONTHS?

Transcription

1 WHAT IS NEW IN BILE DUCT CANCER IN THE LAST 12 MONTHS? Juan W Valle University of Manchester / The Christie Manchester, UK 21 June 2018

2 BILIARY TRACT CANCER A GLOBAL CHALLENGE Cholangiocarcinoma 1 Gallbladder cancer 2 1 Bañales et al Nat Rev Gastroenterol Hepatol 2016;13;261, 2 Hundall & Schaffer Clin Epidemiol ;99

3 NEW DATA IN THE PAST 12 MONTHS 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

4 ADJUVANT Resectable disease

5 BCAT BILE DUCT CANCER ADJUVANT TRIAL Extrahepatic CCA (perihilar and distal CCA) 10 weeks post-op Age 20 PS : 1 Stratification: R0 vs. R1 N0 vs. N1 Primary Centre observation gemcitabine [6 cycles] 1 o endpoint OS 2 o endpoints RFS, subgroup analysis, toxicity HR 0.85 Power 80% Two-sided-α 5% N=300 for 189 events Interim analysis (200 patients) 225 patients recruited from 48 Japanese hospitals Ebata et al Br J Surg 2018; 105:

6 BCAT BILE DUCT CANCER ADJUVANT TRIAL Relapse-free survival Overall survival (1 o endpoint) HR 0.93 (95%CI ; p=0.693) HR 1.01 (95%CI ; p=0.964) No subgroup benefitted (N0/1; R0/1) 5YS better than anticipated (50% vs 30%)

7 ADJUVANT CHEMOTHERAPY RANDOMISED TRIALS BCAT 1 PRODIGE 12 2 BILCAP 3 RFS: HR=0.93 [ ], p=0.693 OS: HR= 1.01 [ ], p=0.964 RFS: HR=0.88 [ ], p=0.47* OS: HR= 1.08 [ ], p=0.74 *co-primary endpoint: QoL RFS: HR=0.93 [ ], p=0.693 OS: HR= 0.81 [ ], p=0.097 OS: HR 0.70 [ ], p=0.007* * pre-planned sensitivity analysis 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

8 ADJUVANT CHEMOTHERAPY RCTs BilCap study improved overall survival in per-protocol analysis* *Benefit seen in per-protocol analysis population only Benefit seen following sensitivity analysis (LN status, disease grade, gender): HR 0.70 (95% CI ) p=0.007 Primrose et al ASCO 2017; J Clin Oncol 35, suppl; abstr 4006

9 ADJUVANT CHEMOTHERAPY SUMMARY OF RANDOMISED TRIALS Study [clinicaltrials.gov ID] PRODIGE12 France [NCT ] N Population Arms vs. Status 190 Cholangio & GB Observation GemOx No benefit BilCap UK [NCT ] 360 Cholangio & GB Observation Capecitabine Improved survival* *pre-specified sensitivity analysis BCAT Japan [UMIN ] ASCOT Japan [UMIN ] JCOG1202 ACTICCA-1 Germany [NCT ] 300 EH-Cholangio Observation Gemcitabine No benefit Cholangio & GB Observation S1 Recruiting 781 Cholangio & GB Observation Capecitabine CisGem Design revised

10 DIFFERENCES IN STUDY POPULATION BCAT 1 PRODIGE 2 BILCAP 3 icca (%) hcca (%) dcca (%) GBC (%) 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

11 DIFFERENCES IN STUDY POPULATION BCAT 1 PRODIGE 2 BILCAP 3 icca (%) hcca (%) dcca (%) GBC (%) N0 / N1 (%) 65 / / / 47 (6% unknown) R0 / R1 (%) 89 / / / 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

12 DIFFERENCES IN STUDY POPULATION BCAT 1 PRODIGE 2 BILCAP 3 icca (%) hcca (%) dcca (%) GBC (%) N0 / N1 (%) 65 / / / 47 (6% unknown) R0 / R1 (%) 89 / / / 38 Experimental arm Control arm (mo) 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

13 Phase II, multi-centre EHCC or GBCA after radical resection, pt2-4 or N1 or R1 SWOG 0809 STUDY Gem-Cap (4 cycles, q3w), then CRT 45Gy/25 fractions to LN bed and 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) Inclusion of radiotherapy question in R1 disease Ben-Josef et al J Clin Oncol 2015;33(24)2617

14 ADVANCED Non-resectable and metastatic

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

16 CIS-GEM ONLY THE FIRST STEP ON THE LADDER 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 trial 3 (randomized phase II selection study of gemcitabine plus S-1 (GS) vs. S-1): GS had improved 1YS 52.90% vs % Acceptable toxicity profile OS 12.5 months 1 Okusaka 2010 Br J Cancer, 2 Valle 2014 Ann Oncol; 3 Morizane Cancer Sci 2013;104:

17 Randomized phase III study of gemcitabine plus S-1 combination therapy versus gemcitabine plus cisplatin combination therapy in advanced biliary tract cancer (JCOG1113) Recurrent/Unresectable biliary tract cancer (IHBD, EHBD, GB, AV) Randomisation Adjustment factors Primary tumor (GB vs. others) History of primary tumor resection (yes/no) Institution FUGA-BT GEM+CDDP Hepatobiliary and Pancreatic Oncology Group of Japan Clinical Oncology Group (JCOG), Japan GEM:1000 mg/m 2 d1, 8 + CDDP: 25 mg/m 2 d1, 8; repeated every 3 wks Cisplatin was administered up to 16 times (total 400 mg/m 2 ), thereafter GEM monotherapy was continued GEM+S1 GEM:1000 Presented mg/m 2 By d1, Makoto 8 + Ueno, S-1: 60, MD 80, 100 mg/body/day d1-14; repeated every 3 wks Morizane et al ASCO-GI 2018: abstr 205; Ueno et al ASCO 2018 abstr 4014

18 Primary analysis Overall survival FUGA-BT %1 year OS (95% CI) Median OS (95% CI) GC N= % (50.6%-65.2%) 13.4 months ( ) GS N= % (51.6%-66.0%) 15.1 months ( ) HR ) : 0.945, 90% CI p for non-inferiority = < 0.05 Hepatobiliary and Pancreatic Oncology Group of Japan Clinical Oncology Group (JCOG), Japan Morizane et al ASCO-GI 2018: abstr 205; Ueno et al ASCO 2018 abstr 4014

19 Exploratory subgroup analysis FUGA-BT Hepatobiliary and Pancreatic Oncology Group of Japan Clinical Oncology Group (JCOG), Japan Morizane et al ASCO-GI 2018: abstr 205; Ueno et al ASCO 2018 abstr 4014

20 Authors Summary GC/GS Primary endpoint Median OS: 13.4 /15.1 months FUGA-BT Primary Met non-inferiority demonstrated HR (90% CI: ), p= Secondary endpoint Median PFS: 5.8 / 6.8 months GS better RR: 32.4 / 29.8% GC better AE: Both regimens are tolerable Comparable Clinically significant AE: 35.1 / 29.9% GS better SAE: TRD 3 / 0 GS better %Planned dose: GEM:75.7% / CDDP:76.7% GEM:76.2% / S-1:75.3% Comparable Hydration GC require, GS not require GS convenient Gem-S1 is non-inferior to Cis/Gem in Japanese patients Morizane et al ASCO-GI 2018: abstr 205; Ueno et al ASCO 2018 abstr 4014

21 BIL-MEK STUDY BACKGROUND BTC frequently demonstrates upregulation of RAS/RAF/MEK/ERK pathway Selumetinib (ARRY , 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 rate 1 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

22 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

23 BIL-MEK STUDY EFFICACY Primary Endpoint: Median % change in measurable disease at 10 weeks Arm A Continuous Selumetinib + CisGem Arm B Sequential Selumetinib + CisGem Arm C CisGem Alone % change in measurable tumor at 10 weeks 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% * Denotes patients non-evaluable due to lack of 10 week study imaging Kruskal-Wallis p=0.73 Doherty et al ASCO 2018

24 Secondary Endpoints: PFS, OS BIL-MEK STUDY EFFICACY Doherty et al ASCO 2018

25 DEVELOPMENTS IN CHEMOTHERAPY Acelarin first-in-class nucleotide analogue hent1 independent transport no metabolism by cytidine deaminase (reduced toxic metabolites) achieves higher intracellular levels of dfdctp than gemcitabine 1 hent1, human equilibrative nucleoside transporter-1; CDA, cytidine deaminase; dck, deoxycytidine kinase; dfdc, Acelarin ABC-08 study 2 Phase IB study acelarin and cisplatin in BTC gemcitabine; dfdu, ifluorodeoxyuridine 1 Blagden et al J Clin Oncol 33, 2015 (suppl; abstr 2547); 2 ClinicalTrials.gov NCT

26 ABC-08 1 DEVELOPMENTS IN CHEMOTHERAPY NUC-1031 at 625 mg/m 2 + cisplatin at 25 mg/m 2 is an attractive and effective combination for treatment of patients with advanced/metastatic biliary tract cancer 1 ClinicalTrials.gov NCT ; 2 McNamara et al ASCO-GI 2018 (abstr TPS544)

27 DEVELOPMENTS IN CHEMOTHERAPY GCN regimen Gem/Cis/nab-paclitaxel 1 [NCT ] USA (MDA and Mayo) Single-arm, phase II; n=61 Schedule gemcitabine 800mg/m 2 + cisplatin 25 mg/m 2 + nab-paclitaxel 100 mg/m 2 ; D1,8 q21d Promising early data 1 - median PFS (1 o endpoint): 11.8 months - response rate: 28.8% - median OS: 18.8 months Updated analysis 2 - median PFS: 11.4 months (95% CI: ) - response rate: 39%. - median OS: 19.2 months (95%CI: 13.6-NA) Phase III study planned (vs. CisGem) 1 Shroff et al ASCO 2017 J Clin Oncol 35, 2017 (suppl; abstr 4018); 2 Shroff et al ASCO-GI 2018 (abstr 350)

28 UNDERSTANDING BIOLOGY AND ACTIONABLE SUB-GROUPS

29 IMPROVING OUR UNDERSTANDING OF THE GENETIC ENVIRONMENT OF BTC Intrahepatic cholangiocarcinoma CCA has a different profile to extrahepatic CCA or GBC 1,2 Table adapted from 1 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 subclass 4 1 Ross (ASCO GI) J Clin Oncol 33, 2015 (suppl 3; abstr 231); 2 Borger 2011 Oncologist 17(1):72; 3 Chan-on 2013 Nat Genet 45(12):1474; 4 Sia 2015 Nat Commun 6:6087

30 IMPROVING OUR UNDERSTANDING OF THE GENETIC ENVIRONMENT OF BTC Up to 70% of IH-CCA patients have an actionable mutation 1 IDH-1 mutations and FGFR fusion rearrangements have emerged as potential therapeutic targets 1 Sia 2015 Nat Commun 6:6087

31 IMPROVING OUR UNDERSTANDING OF THE GENETIC ENVIRONMENT OF BTC 1 Jasakul et al Cancer Discov 2017;7(10);

32 IMPROVING OUR UNDERSTANDING OF THE GENETIC ENVIRONMENT OF BTC 1 Jasakul et al Cancer Discov 2017;7(10);

33 IDH-1 MUTATION IS DRUGGABLE Phase I study: cholangiocarcinoma (CCA), chondrosarcoma, glioma, others [NCT ] CCA cohort 1 : n=73 [dose escalation (n=24); doseexpansion 500 mg QD (n=49)] No DLTs; drug-related AEs: fatigue, nausea, diarrhoea, vomiting Activity: median PFS 3.8 months 6-month PFS: 38.5% 12-month PFS: 20.7% RR 5% (4 PRs) OS data not mature R n=186 Phase III study, second-line, placebocontrolled (ClarIDHy) [NCT ] 2:1 AG-120 n=124 Placebo n=62 Cross-over to AG-120 on disease progression AG-120 is a first-in-class, potent, oral inhibitor of the mutant IDH1 enzyme 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)

34 FGFR AS A POTENTIAL TARGET IN INTRAHEPATIC CHOLANGIOCARCINOMA Fibroblast Growth Factor Receptor Turner & Gross 2010 Nat Rev Cancer

35 BJG398 Phase II trial TARGETING FGFR IN THE CLINIC Key inclusion criteria Advanced or metastatic CC FGFR2 fusion or other genetic alterations in FGFR Progression following prior cytotoxic therapy BGJ mg daily Days 1-21, every 28 days Treatment until disease progression, unacceptable toxicity, withdrawal of informed consent, or death 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) Javle et al J Clin Oncol 2017 [Nov 28, Epub ahead of print]

36 TARGETING FGFR IN THE CLINIC BJG398 Phase II trial Median 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]

37 MOSCATO STUDY MOSCATO study 1035 patients 1 prior systemic treatment ECOG PS 0-1 At least one tumour site accessible to biopsy Multiple high-throughput molecular analysis BTC n=43 Evaluable n=34 Druggable alteration n=23 Treated n=18 ORR 33% DCR 88% Median OS 17 mo vs. 5 mo, [HR 0.29; 95% CI, ; p< 0.008). Verlingue et al Eur J Cancer 2017;87:122e130

38 TARGETS UNDER EVALUATION Valle et al Cancer Discovery Cancer Discov; 2017;7(9);

39 NEW DATA IN THE PAST 12 MONTHS SUMMARY 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

40 THANK YOU