future directions in the management of advanced btcs...a complete failure of “targeted...

Future directions in the management

of advanced BTCs

Michel Ducreux, MD, PhD

➔DisclosureParticipation to advisory boards:

ROCHE

MERCK SERONO

AMGEN

NOVARTIS

SANOFI

BAYER

SIRTEX

LILLY

SERVIER

Speaker in symposiums:ROCHE

MERCK SERONO

NOVARTIS

SANOFI

LILLY

TERUMO

Research funding:ROCHE

MERCK SERONO

PFIZER

My wife is the Head of The Oncology Business Unit in Sandoz Company

➔Biliary tract cancer: epidemiology

3

BTC = Intrahepatic BTC

Mortality rates

In the US

Gallbladder & extahepatic BTC

new cases = 10,910, Deaths =

3,700

➔A complex carcinogenesis

IntrahepaticCholangiocarcinoma

Labib L et al. BMC Cancer 2019;19:185

➔ A complete failure of “targeted

therapies”

Meta-analysis Gemox + …

Cai W et al. J Cancer 2018;9:1476-85

➔ A biologically heterogeneous disease

➔ Common somatic alterations in biliary tract

cancer

Harris WP et al. Semin Oncol 2018;45:116-23

➔ A biologically heterogeneous disease

➔ A step forward: MOSCATO 1 screening

molecular program

Massard C Cancer Discov 2017;7:586-95

Verlingue L et al. Eur J Cancer 2017;87:122-30

➔Flow chart

➔ Alterations in biliary tract cancer: MOSCATO trial


➔Results for efficacy


➔Exemple…

➔ PFS ratio was 2.1 (versus 1.3 in

MOSCATO main endpoint)

14

Overall survival…

Verlingue L Eur J Cancer 2017;87:122-30

➔ US Multicenter genomic profiling

Javle M et al. Cancer 2016;122:3838-47

• 185 – 236 gene panels; IHC (n = 224), EHC (n=42), GB (n=55). Commonly mutated genes:

• IHC: TP53 (27%), CDKN2A/B (27%), KRAS (22%), ARIDIA (18%), IDH1 (16%)

• EHC: TP53 (40%), CDKN2A/B (17%), KRAS (42%), SMAD4 (21%)

• GB: TP53 (59%), CDKN2A/B (19%), ARIDIA (13%), ERBB2 (16%)

➔ The proof of concept: in all-comers,

Tribimetinib (anti-MEK) is not working

20 refractory patients (1 line: 12, 2 lines: 8)

• 40% gallbladder

• 25% intrahepatic

• 30% bile duct, 5% ampulla of Vater

• No OR, stable disease: 65%

• Median PFS: 10.6 weeks

• One-year overall survival: 20%

Conclusion: Prolonged PFS was observed in one patient having a

specific biological pattern

Ikeda M et al. Cancer Science 2018;109:215-224

➔ Targeted therapy and targeted population…BGJ398

(infigratinib) in patients with FGFR-altered advanced

cholangiocarcinomaBGJ398: Pan FGFR MKI

61 patients

– ECOG PS 1 or 2

• Prior antineoplastic regimens:

– Median: 2, Range: 1 - > 4

• FGFR status

– FGFR1 amplified: 1

– FGFR2• Amplified 3• Mutated 8• Fusion 48

– FGFR3 amplified: 4

Javle M et al. J Clin Oncol 2017;36:276-82

➔ IDH1-3 in intra-hepatic cholangiocarcinoma

• Mutant IDH inhibitorsare tested

• The mutant forms of IDH1/2 catalyse the non-reversible accumulation of 2-hydroxyglutarate (2HG)

• Enasidenib, Ivosidenib(AG-120), on-going phase III

Delahousse J et al. Eur J Cancer 2018; 90:83-91

➔ IDH1 mutations in cholangiocarcinoma:

systematic review

• 45 publications

• 5393 patients

• IDH1 mutation found in :

– 13.1% IHC

– 0.8% EHC

• Higher in non Asian

centers compared to Asian

centers: 16.5% vs 8.8%

• No prognostic impact

Boscoe AN et al. J Gsatronintest Oncol 2019;10:751-65

➔ Phase I study of AG-120, an IDH1 mutant enzyme inhibitor:

Results from the cholangiocarcinoma dose escalation and

expansion cohorts

• 73 pts with mIDH1 CC

• Median number of prior therapies = 2 (range 1–5),

• ECOG 0–1 = 26/47.

• No dose-limiting toxicities.

• 6% (n = 4) PR and 56% (n = 40) stable disease.

• PFS rate at 6 months was 40%

• 8 pts have been treated with AG-120 for ≥1 year.

Lowery MA et al. J Clin Oncol 2017;35(suppl 5):abs 4015

➔ ClarIDHy: Study design and endpoints

➔ ClarDHy: PFS by Independent review

committee

Abou-Alfa GK et al. ESMO 2019 plenary session

➔ Efficacy across all subgroups


➔ Toxicity


➔HER as a target: MyPathway

• Open-label, multicenter, phase IIA

study

• Refractory HER2 metastatic biliary

cancer (FISH, or IHC)

• Standard doses of pertuzumab +

trastuzumab

• 11 patients

– HER2-amplified/overexpressed, n = 8

– HER2-mutated, n = 3

HER2-amplified/overexpressed

(n = 8)

HER2-mutated(n = 3)

Median age, y (range) 61 (45–77) 57 (56–67)

Female 5 (62.5) 1 (33.3)

ECOG score, n (%)

0 3 (37.5) 1 (33.3)

1 4 (50.0) 2 (66.7)

2 1 (12.5) 0

Median number of prior regimens, n (range)

2.5 (1–4) 2 (2–3)

Median time on treatment, m (range)

4.2 (1.4–5.8) 2.8 (1.5–2.9)

Overall response ratea, n (%)

3 (37.5) 1b (33.3)

Clinical benefit ratec, n (%)

6 (75.0) 1b (33.3)

Duration of PR, m 0.7, 2.8, 2.8 0.1

Median PFS, m (95% CI) 4.2 (1.2–5.4) 2.8 (1.4–2.8)

aComplete response (CR) + PR. bPatient had an extracellular HER2 mutation (D277Y). cCR + PR + SD for > 4 months.

Javle ML J Clin Oncol 2017;(4_suppl):Abs 402

➔Mutations BRAF-V600E

• Phase II, open-label trial

• BRAF V600E mutations in 9 rare tumor types, including

BTC, received D (150 mg BID) + T (2 mg QD)

• Metastatic cancer and had been treated with ≥ 1 prior

systemic therapy

Wainberg et al ASCO 2019

489 cholangiocarcinoma from 10 countries

Cancer Discov. 2017; 7(10): 1116–1135

➔ TCGA: different prognostic groups

Another tool for selction of the

patients??

UK: J Bridgewater, ABC10France: D Malka• Evaluate the role of

personalized medicine in thesepatients

• Molecular screening

➔ Another way: Biologically driven trials

IMMUNOTHERAPY

➔ Pembrolizumab and refractory bile ducts

cancers• Multicentric single arm phase II trial:

– pembrolizumab (200 mg IV/3 weeks)

• Inclusion criteria:

– Cholangiocarcinoma with progressive disease after at least one line of

treatment (59% ≧ 2 lines)

– ECOG PS 0-1

– Tissue sample available for PDL1 IHC evaluation.

• Endpoints

– Main endpoint: Objective response rate

– Secondary : PFS, OS, Tolerance

M. Ueno et al. - ESMO® 2018 - Abs. 625 PD

Population

N=104PLD1+

N = 61

PLD1-

N = 34

Objective response 5.8% 6.6% 2.9%

Partial response 6 (6%) 4 (7%) 1 (3%)

Stabilisation 17 (16%) 6 (10%) 11 (32%)

Progression 65 (63%) 44 (72%1) 17 (50%)

PFS 2 1.9 2.1

OS 9.1

→ Median duration of response: not reached

➔ Pembrolizumab and refractory bile ducts

cancers

M. Ueno et al. - ESMO® 2018 - Abs. 625 PD

➔ Immunotherapy: durvalumab +

tremelimumab

Bile duct cancers (n=12)

OR 1 (8.3%)

SD 5 (41.7%)

PD 5 (41.7%)

PFS 3.1 months

OS 5.45 months

Charalampos S et al GI ASCO 2019 abs 316

Side effects, Grade > 3: 14%

➔Nivolumab + GemCis…

• 30 patients with metastatic cholangioK (all types)

• Chemotherapy naive

• Objective response rate: 37%

• Median overall survival: 15.4 months

• Median progression-free survival: 4.2 months

?????????

Ueno M et al. Lancet Gastroenterol Hepatol 2019;4:611-21

➔Conclusion

• Among GI cancers bile duct tumours are probably the best

candidates for personalized medicine

• Druggable targets have already been identified

– IDH1 for intrahepatic cholangiocarcinoma

– FGFR fusion for intrahepatic cholangiocarcinoma

– HER2, PI3K for gallbladder carcinoma

– HER2 for extrahepatic cholangiocarcinoma

• Positive results on some of those targets

– FGFR, BRAF, HER2..

• Global Biologically-driven trials are on-going

• Role of immunotherapy: to bedefined…. (sub-group of patients???)

➔Back to ESMO guidelines

Valle J et al. AnnOncol 2016;27(Suppl 5):v28-v37

FOLFOX

Ivodisenib for mIDH BTC

Molecular testing is mandatory especially for IHC

future directions in the management of advanced btcs...a complete failure of “targeted...

Documents