TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer

Ferraro, Danielle; Goldstein, David; O’Connell, Rachel; Zalcberg, John; Sjoquist, Katrin Marie; Tebbutt, Niall C.; Grimison, Peter; McLachlan, Sue‐Anne; Lipton, Lara; Vasey, P.; Gebski, Val; Aiken, Chris; Cronk, Michelle F.; Ng, Siobhan; Karapetis, Christos S.; Shannon, Jenny

doi:10.1007/s00280-016-3089-4

Cited by 16 publications

(11 citation statements)

References 19 publications

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“…(76) KRAS mutations are known to preclude any therapeutic benefit from anti-EGFR therapies in other cancers, but only two studies have suggested this effect in CCA for erlotinib and panitumumab. (77,78) The recent development of a patientderived xenograft model of iCCA bearing the most frequent KRAS mutation (G12D) should provide answers on the role of this mutation in anti-EGFR treatment efficacy. (68) Secondary resistance appears under long-term anti-EGFR treatment.…”

Section: Resistance Mechanisms To Anti-erbb Therapiesmentioning

confidence: 99%

Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

2017

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The ErbB/HER family comprises four distinct tyrosine kinase receptors, EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/ HER3, and ErbB4/HER4, which trigger intracellular signals at the origin of essential cellular functions, including differentiation, proliferation, survival, and migration. Epithelial cells, named cholangiocytes, that line intrahepatic and extrahepatic bile ducts, contribute substantially to biliary secretory functions and bile transport. Although ErbB receptors have been widely studied in cholangiocarcinoma (CCA), a malignancy of the biliary tract, knowledge of these receptors in biliary epithelium physiology and in non-malignant cholangiopathies is far from complete. Current knowledge suggests a role for epidermal growth factor receptor (EGFR) in cholangiocyte specification and proliferation, and in hepatocyte transdifferentiation into cholangiocytes during liver regeneration to restore biliary epithelium integrity. High expression and activation of EGFR and/or ErbB2 were recently demonstrated in biliary lithiasis and primary sclerosing cholangitis, two cholangiopathies regarded as risk factors for CCA. In CCA, ErbB receptors are frequently overexpressed, leading to tumor progression and low prognosis. Anti-ErbB therapies were efficient only in preclinical trials and have suggested the existence of resistance mechanisms with the need to identify predictive factors of therapy response. This review aims to compile the current knowledge on the functions of ErbB receptors in physiology and physiopathology of the biliary epithelium. (HEPATOLOGY 2017; 00:000-000). ErbB/HER FamilyThe ErbB family of receptor tyrosine kinases comprises epidermal growth factor (EGF) receptor (EGFR; ErbB1/HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4; Fig. 1). These plasma membrane receptors are composed of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with a conserved tyrosine kinase (TK) domain, with the exception of ErbB3 which holds an inactive TK domain. They bind specific ligands belonging to the EGF family, with the exception of ErbB2 which has no known ligand. Thus, ErbB2 and ErbB3 are activated through heterodimerization with other family members. ErbB ligands are produced as transmembrane precursors and processed

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Section: Resistance Mechanisms To Anti-erbb Therapiesmentioning

confidence: 99%

Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

2017

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“…A recent phase II trial stratified BTC patients based on KRAS status, but failed to demonstrate that KRAS status predicted the population most likely to benefit from anti-EGFR therapy (45). Furthermore, two biomarker-driven trials that was restricted to KRAS wild-type patients failed to show a clinically significant improvement in PFS or OS using panitumumab combined with chemotherapy (46,47). These studies call into question the utility of KRAS status as a clinically relevant biomarker predictive of EGFR therapy response in BTC, as opposed to colon cancer.…”

Section: Egfrmentioning

confidence: 99%

“…These studies call into question the utility of KRAS status as a clinically relevant biomarker predictive of EGFR therapy response in BTC, as opposed to colon cancer. The relative importance of mutations in other EGFR pathway genes, such as BRAF, are being investigated as mechanisms of resistance to anti-EGFR agents (47,48).…”

Section: Egfrmentioning

confidence: 99%

Current biologics for treatment of biliary tract cancers

Zhao

Lim

2017

J. Gastrointest. Oncol.

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Biliary tract cancers (BTC) is a group of malignancies that arise from the epithelial cells of the biliary tree. These cancers are typically classified by anatomic site of origin: intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). To date, complete surgical resection remains the mainstay of treatment especially for earlier stage disease. 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. There is a tremendous need to better understand the disease biology, discover new therapies, and improve clinical outcomes for this challenging disease. Next-generation sequencing has produced a more accurate and detailed picture of the molecular signatures in BTCs. The three BTC histologic subtypes are, in fact, quite molecularly distinct.IHCC commonly contain FGFR2 fusions and IDH 1 and 2 mutations, whereas EHCC and GBC tend to carry mutations in EGFR, HER2, and MAPK pathway. In light of this emerging knowledge, clinical trials have become more biomarker-driven, which allows capturing of subsets of patients that are most likely to respond to certain therapies. Many new and promising targeted therapeutics are currently in the pipeline.Here we review the genetic landscape of BTCs while focusing on new molecular targets and targeted therapeutics currently being investigated in biomarker-driven clinical trials.

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“…There have been a couple of attempts at targeting EGFR in cholangiocarcinoma with monoclonal antibodies instead of EGFR tyrosine kinase inhibitors. One such study (BINGO trial) did not show meaningful improvement in survival with cetuximab in combination with gemcitabine and cisplatin as compared to a placebo in cholangiocarcinoma patients, however, a more recent single arm trial (TACTIC trial) that included only KRAS wild type patients showed a response rate of 46% suggesting a more selected population as a better target . We did not include HER1/EGFR expression analysis, however, studies performed with erlotinib prior to our study showed higher EGFR expression in BDC and HCC patients without correlation with erlotinib responsiveness and the study by Lee et al.…”

Section: Discussionmentioning

confidence: 84%

INST OX‐05‐024: first line gemcitabine, oxaliplatin, and erlotinib for primary hepatocellular carcinoma and bile duct cancers: a multicenter Phase II trial

et al. 2017

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Hepatocellular Carcinoma (HCC) incidence is increasing in the USA. Gemcitabine (G) and oxaliplatin (O) are active in HCC and biliary duct cancer (BDC). Erlotinib (E) is an EGFR tyrosine kinase inhibitor (TKI) with known activity against both. We sought to evaluate the efficacy of the combination G+O+E. Patients with either of the two diagnosis were treated in a phase II trial. Simons 2 stage design was used. A disease‐control rate (DCR), complete response (CR) + partial response (PR)+ stable disease (SD) at 24 weeks of ≤20% and >40% (P0 and P1 of 0.2 and 0.4, respectively) were set as undesirable (null) and desirable results. 26 HCC and 7 BDC patients were accrued. In HCC, 1 PR, 10 SD, and 9 PDs were seen. DCR in HCC was 42%. Among seven (7) patients with BDC, one patient was not evaluable; one achieved a long lasting PR, and five patients had SD and DCR was 86%. Median overall survival (OS) times and progression‐free survivals (PFS) were 196 and 149 days in HCC and 238 days and not reached in BDC. PFS at 26 weeks in HCC was 41% and at 21 weeks in BDC was 60%. Grade 3 toxicities in >5% of patients were fatigue (12.9%), neutropenia (9.6%), thrombocytopenia (9.6%), and diarrhea (6.4%). G+O+E exceeded both preset P0a and P1 of the primary objective with a PFS of 41% at 26 weeks for HCC and preliminary BDC data may warrant further investigations.

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TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer

Cited by 16 publications

References 19 publications

Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

Current biologics for treatment of biliary tract cancers

INST OX‐05‐024: first line gemcitabine, oxaliplatin, and erlotinib for primary hepatocellular carcinoma and bile duct cancers: a multicenter Phase II trial

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