presentación de powerpoint · bilcap: study design open-label, randomized, controlled phase iii...
TRANSCRIPT
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Biliary Tract Cancers
Miguel Navarro
Salamanca
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BTCs are quite challenging to treat
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BTCs Background
• Uncommon.
• Increasing incidence and mortality globally.
• Most patient are diagnosed with no resecable disease.
• Associated with poor outcomes.
• Need of new drugs.
Khan SA, et al. J Hepatol. 2012;56:848-854.
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Biliary tract cancers are a diverse set of neoplasms arising from the biliary tract epithelium ….
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Why doesn´t one size fits all?
Valle et al. Cancer Discovery.2017
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Why doesn´t one size fits all?
Valle et al. Cancer Discovery.2017
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Why doesn´t one size fits all?Such differences are worth taking into account at time of
treatment planning, research, and clinical trial design.
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Surgery• Biliary tract cancers usually
present at an advanced stage, and only approximately 20% of tumors are considered resectable.
• Surgery is the primary curative treatment option for early-stage biliary tract cancer.
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Adjuvant therapy• Need for effective adjuvant therapy.
• Older randomised studies were not sufficiently statistically powered to define a standard of care.
• Meta-analysis (of mostly retrospective data) has suggested improved overall survival with adjuvant treatment.
Takada T, et al. Cancer 2002; 95: 1685–95.
Neoptolemos JP,et al.JAMA 2012; 308: 147–56
Horgan AM, et al. J Clin Oncol 2012; 30: 1934–40.
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Adjuvant therapyTwo recent randomisedstudies did NOT show a significant benefit of:
• gemcitabine
• gemcitabine plus oxaliplatin (GEMOX regimen)
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Adjuvant therapy
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BILCAP: Study DesignOpen-label, randomized, controlled phase III trial
Primrose JN , et al. ASCO 2017. Abstract 4006.
▪ Primary endpoint: OS
▪ Secondary endpoints: RFS, toxicity, QoL, health economics
Capecitabine 1250 mg/m2 BID
Days 1-14 of 21-day cycle for 8 cycles
(n = 223)
Observation
(n = 224)
Histologically confirmed
biliary tract cancer*; radical
and macroscopically
complete surgery; ECOG
PS ≤ 2; no previous
chemotherapy or
radiotherapy for biliary
tract cancer
(N = 447)
Primary
analysis after
minimum 2-yr
follow-up
Resection
*Included: intrahepatic CC, hilar CC, muscle-invasive gallbladder cancer, and lower common bile duct CC
Excluded: pancreatic, ampullary, mucosal (T1a) gallbladder cancers; incomplete recovery from prior surgery
Stratified by surgical center,
R0 vs R1 resection, ECOG PS
753 patients were screened across 44 UK centres between 2006 and 2014
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BILCAP: Study Design
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BILCAP: Compliance
Primrose JN , et al. ASCO 2017. Abstract 4006..
Median capecitabine dose: 1250 mg/m2 BID (IQR: 1061-1250 mg/m2)
01 50 100 15
020
0
22
3
2
4
6
8
Cycle
s o
f C
ap
ecitab
ine (
n)
Pts (n)
122 (55%) pts in the capecitabine
arm received 8 cycles
10 (< 5%) pts
received 0 cycles
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BILCAP: OS
Primrose JN , et al. ASCO 2017. Abstract 4006..
ITT Population
Treatment Median OS, Mos (95% CI)
HR (95% CI)
Capecitabine 51.1 (34.6-59.1) 0.81 (0.63-1.04)P = .097Observation 36.4 (29.7-44.5)
Treatment Median OS, Mos (95% CI)
HR (95% CI)
Capecitabine 52.7 (40.3-NR) 0.75 (0.58-0.97)P = .028Observation 36.1 (29.6-44.2)
Per Protocol Population
> 80% pts followed-up for 36 mos
0
25
50
75
100
Pts
Aliv
e (
%)
0 12 24 36 48 60Mos Since Randomization
0
25
50
75
100
Pts
Aliv
e (
%)
0 12 24 36 48 60Mos Since Randomization
Unfortunately, the study did not meet its primary endpoint
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BILCAP: OS
Primrose JN , et al. ASCO 2017. Abstract 4006..
ITT Population
Treatment Median OS, Mos (95% CI)
HR (95% CI)
Capecitabine 51.1 (34.6-59.1) 0.81 (0.63-1.04)P = .097Observation 36.4 (29.7-44.5)
Sensitivity analyses adjusting for further prognostic factors (gender, nodal status, disease grade) HR 0.70 (95% CI: 0.55-0.91; P = .007)
Treatment Median OS, Mos (95% CI)
HR (95% CI)
Capecitabine 52.7 (40.3-NR) 0.75 (0.58-0.97)P = .028Observation 36.1 (29.6-44.2)
Per Protocol Population
> 80% pts followed-up for 36 mos
0
25
50
75
100
Pts
Aliv
e (
%)
0 12 24 36 48 60Mos Since Randomization
0
25
50
75
100
Pts
Aliv
e (
%)
0 12 24 36 48 60Mos Since Randomization
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Adjuvant therapy
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Adjuvant therapy
BILCAP investigators unilaterally decide to ABANDON STATISTICAL SIGNIFICANCE, claiming a p=0.09 is practice changing!! Vinay Prasad
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Adjuvant therapy: Why doesn´t one size fits all?
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Adjuvant therapy.
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Adjuvant therapy. Future
A trial of chemotherapy after surgery for cancer of the bile duct or gallbladder (ACTICCA-1)
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Advanced disease: Liver-directed therapy
• Selected patients may be suitable for liver-directed therapy
(e.g., radioembolization or external beam radiation):
✓ Pending confirmation of benefit in randomized studies.
• Liver Transplant remains controversial in this setting.
Bourien H et al. European Journal of Nuclear Medicine and Molecular Imaging, 2019.
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Advanced or Metastatic disease therapy
• Unfortunately, most patients present with advanced or metastatic disease, when systemic chemotherapy is the only treatment option.
• Due to the paucity of effective treatments, BTCs have a dismal prognosis
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SG:11.7 Vs 8.1m
SLP:8 Vs 5m
6 meses
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Gemcitabine, cisplatin plus S-1 (GCS) versus gemcitabine, cisplatin (GC) foradvanced biliary tract cancer (KHBO1401-MITSUBA) – Sakai
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Nab-paclitaxel plus gemcitabine-cisplatin in patients with biliary tractcancers
• Open-label, single-arm, phase 2 trial
• Gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles.
• Dose reduction to G/C/N (in mg/m2) at 800/25/100.
Shroff RT, et al.JAMA Oncology.2019.
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Advanced or Metastatic disease therapy• There is no standard second-line
therapy.
• Fluoropyrimidines are frequently used in clinical practice.
• ABC-06 randomized Phase III clinical study is analyzing the role of chemotherapy FOLFOX in this setting vs symptomatic management.
• Study positive (ASCO 2019)
Active symptom control alone or with mFOLFOX chemotherapy for locally advanced/metastatic biliary tract cancers;2014. Available from: https://ClinicalTrials.gov/show/NCT01926236.
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Significant potential targetable pathways
Valle et al. Cancer Management and Research 2019
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Metastatic disease therapy
No agent has shown to be effective for advanced biliary tract cancer.
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Metastatic disease therapy
SWOG S1310: Randomized phase II trial of single agent MEK inhibitor trametinib vs. 5-fluorouracil or capecitabine in refractory advanced biliary cancer.
• First prospective randomized study of a targeted agent versus chemotherapy for the second line treatment of BC.
• In this unselected population, the lack of response to trametinib resulted in early closure.
• The PFS and OS for trametinib were inferior to 5FU.
Kim RD, McDonough SL, El-Khoueiry AB, et al. SWOG S1310. J Clinl Oncol.2017;35(15_suppl):4016.
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Genomic Landscape BTC
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A number of genetic mutations have been identified in patients with BTC that open the possibility of targeted treatment for this patient population....
Valle et al. Cancer Discovery.2017
"Cholangiocarcinoma has a number of actionable mutations; probably more than any other gastrointestinal cancer¨
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New Horizon on Targets• IDH-1 Mutation
• FGFR fusion rearrangements
• BRAF
• Other targets:
• HER2 Neu alterations
• NTRK
• DNA alterations
• Inmunotherapy
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IDH-1 mutation• Somatic mutations with in the
conserved active site of isocitratedehydrogenase (IDH) 1 and 2 occur in multiple tumors:
• Glioma
• Acute myeloid leukemia (AML)
• Chondrosarcoma
• Cholangiocarcinoma (20-25% iCCA)
• Mutation results in acumulation in
• 2-hydroxyglutarate (oncomet)
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IDH-1 mutation: AG-120AG-120: Ivosidenib (Tibsovo®)
• IDH1 inhibitor
• Small molecule
• Oral
• Reversible
• Approved in AML
• Promising results of the Phase I study of anIDH1 inhibitor, AG-120, in 76 patients with previously treated advanced BTC.
• Ivosidenib was given at 500 mg once daily in the dose-expansion cohort.
Lowery MA et al. Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: results from thecholangiocarcinoma dose escalation and expansion cohorts. ASCO Annual Meeting 2017, Poster 4015
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IDH-1 mutation: AG-120
It is estimated to be completed in August 2020.
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IDH-1 mutation: AG-120
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FGFR 2 fusions: • FGFR genetic aberrations
occur in several of cancers, most notably bile duct cancers and urothelial carcinoma.
• Recurrent FGFR2 fusions in 11% to 45% of patients with ICC.
• Tested in multiple trials.
• Prognostic
Jain et al. JCO Precis oncol Jan 17, 2018
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FGFR 2 fusions: BGJ398 (infigratinib)
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FGFR 2 fusions: BGJ398 (infigratinib)• Phase 3 Study of BGJ398 (Oral Infigratinib) in First Line
Cholangiocarcinoma With FGFR2 Gene Fusions/Translocations.
Primary objective is to demonstrate non-inferiority (NI) of treatment with infigratinibversus gemcitabine with cisplatin based oncentrally assessed progression-free survival (PFS)
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FGFR 2 fusions: TAS 120
Meric-Bernstam F, et al. Ann Oncol. 2018;29 (suppl 5; abstr O-001).
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BRAF
• BRAF mutations in 5% to 7% of patients with BTC.
• may be enriched in intrahepatic BTC
• The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has demonstrated efficacy in BRAFV600E–mutated cancers:• metastatic melanoma and melanoma in the adjuvant setting
• non-small cell lung carcinoma
• anaplastic thyroid cancer
Ahn DH, et al. J Gastrointest Oncol. 2017;8(2):293-301. SchrocJain A, et al. Curr Treat Options in Oncol. 2016;17(11):58. Long GV, et al. Lancet. 2015;386(9992):444-451.Planchard D, et al. Lancet Oncol. 2016;17(7):984-993.Subbiah V, et al. J Clin Oncol 2018;36:7-13k AB, et al. JAMA. 2017;3(11):1546-1553.
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BRAF kinase inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist)
Wainberg ZA, et al. J Clin Oncol 2019;37(Suppl):Abstr 187
80% of patients received ≥ 2 lines of prior systemic therapy
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BRAF kinase inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib(Mekinist)
Wainberg ZA, et al. J Clin Oncol 2019;37(Suppl):Abstr 187
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Other targets: HER-2
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Other targets: NTRK
1. Vaishnavi A, et al. Cancer Discov. 2015;5:25-34.2. Amatu A, et al. ESMO Open. 2016
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Cut-off date: 31 May 2018Note: Patients (n=6) without matched pre/post therapy scans were excluded from the plot
CI: confidence interval; CRC: colorectal cancer; MASC: mammary analogue secretory carcinoma; NSCLC: non-small cell lung cancer
Other targets: NTRK
0
-30
-50
-90
Bes
t %
ch
ang
e fr
om
bas
elin
e
15
-80
-70
-60
-40
-20
-10
20
30
40
-100
50
CRCNSCLCSarcoma
Neuroendocrine tumours
PancreaticThyroidMASC Breast
CholangiocarcinomaGynaecological
NTRK+ patients (n=54)
ORR (95% CI) 57.4% (43.2–70.8)
SD 9 (16.7)
PD 4 (7.4)
Non-CR/PD, missing or unevaluable
10 (18.5)
Results per Blinded Independent Central Review (BICR)
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Inmunotherapy
• Microsatellite instability predict response to immunotherapy.
• About 3% of CCA patients have microsatellite instability and have had positive long-term results with checkpoint inhibitors
Le DT, et al. Science. 2017;357:409-413.
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Inmunotherapy
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Key points
• Adjuvant :
• Bilcap/SWOG 0809
• Locally advanced:
• Role of liver directed therapies?
• 1 line:
• ABC-02: SOC/ Triplets?
• 2 line:
• ABC-06: New SOC with FOLFOX? (Asco 2019)
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Key points• IDH1 Mutations:
• Results of ClarIDHy positive.• Others agents in studies.
• FGFR2 Fusions:• Multiple drugs / Promising ORR / Phase III vs CT
• BRAF: • Lower frequency / Meaningful therapeutic option (Should be
considered for routine testing).
• Inmunotherapy:• Microsatellite instability• Role for IO combinations?
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Difficulties?
• Availability of tissue
• Simple arm studies
• Next-generation sequencing into clinical practice???
• Role of resistance.
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Conclusion
• BTCs are quite challenging to treat
• Treatment paradigm for patients with advanced BTC is evolving.
• For BTCs PatientsMutations Matter.