Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion

Abstract

Since the prognosis of advanced cholangiocarcinoma (CCA) remains poor with traditional chemotherapy, attention has shifted to molecularly targeted agents. Results of available clinical studies reveal little or no benefit of using targeted agents in advanced CCA. Limitations of these trials could be the lack of comprehensive molecular and genetic characterization of CCA samples in order to identify potential drug targets. Here we report a case of a 59-year-old female with chemotherapy-refractor, metastatic extrahepatic cholangiocarcinoma (EHCCA). After failure of first-line chemotherapy with cisplatin plus gemcitabine, next generation sequencing (NGS) based tumor molecular profiling was performed on aspiration cytological sample, that revealed BRAF V600E mutation. Multidisciplinary team decided on the initiation of combined treatment with BRAF and MEK inhibitors. Dabrafenib was started orally 150 mg twice a day, adding trametinib 2 mg once a day. Right from the initiation of targeted therapy, significant clinical improvement had been observed. Even though the first restaging computed tomography (CT) scan at 8 weeks revealed spectacular decrease in all metastatic sites, a new hepatic mass of 67 mm × 40 mm was identified and interpreted as new metastatic lesion. As the clinical and radiological response was contradictory, CT-guided biopsy was taken from the hepatic lesion while the therapy was continued on. Histopathologic evaluation excluded the hepatic lesion from being a metastasis, instead described it as a fibrotic, inflammatory lesion.At 12 week, PET CT confirmed further tumor regression with complete regression of the multiple cerebral metastases. The therapy has been extremely well tolerated by the patient. According to our knowledge, this is the first reported case on a successful treatment of EHCCA with the combination of dabrafenib and trametinib. Our case highlights the importance of molecular profiling in CCA, in order to find potential actionable driver mutations for personalised treatment.

Targeting BRAF-Mutant Biliary Tract Cancer: Recent Advances and Future Challenges

“…Sporadic case reports and case series regarding BRAFV600E-mutant BTC patients receiving dabrafenib plus trametinib combination have reported remarkable results, with cases of complete response to BRAFi plus MEKi. 65,66 In particular, Kocsis and colleagues reported the case of a 59-year-old BRAF V600E-mutated eCCA patient reporting complete response after dabrafenib plus trametinib combination treatment. 65 Of note, the included patient-whose disease progressed after first-line chemotherapy with cisplatin plus gemcitabine doublet-was firstly treated with dabrafenib orally 150 mg twice daily with subsequent addition of trametinib 2 mg once a day.…”

“…65,66 In particular, Kocsis and colleagues reported the case of a 59-year-old BRAF V600E-mutated eCCA patient reporting complete response after dabrafenib plus trametinib combination treatment. 65 Of note, the included patient-whose disease progressed after first-line chemotherapy with cisplatin plus gemcitabine doublet-was firstly treated with dabrafenib orally 150 mg twice daily with subsequent addition of trametinib 2 mg once a day. Similarly, Lavingia reported 2 cases of BRAF V600E-mutated iCCA treated with dabrafenib plus trametinib, reporting one complete response and a partial response, confirming the promising activity of dual BRAF and MEK targeting in these patients.…”

Recent Progress in the Systemic Treatment of Advanced/Metastatic Cholangiocarcinoma

“…In addition, several case series have published good tolerability and response to this combination [ 22 , 23 , 24 ] and another phase-2 trial, VE-BASKET, demonstrated single agent efficacy of the BRAF inhibitor, vemurafenib, in BRAF V600E mutant cancers. In this study, a total of 208 patients with 26 different types of cancers were enrolled, including nine CCA patients.…”

Systemic treatment options for advanced biliary tract carcinoma

“…In a phase II basket trial, only one patient out of 12 with iCCA demonstrated a partial response over a year of treatment with vemurafenib [89]. The combination of trametinib and dabrafenib was reported in case studies of advanced BTC with a BRAF V600E mutation and the results showed regression of metastatic lesions [90,91]. In a basket trial of rare tumors, including BTC harbouring BRAF V600E mutations, treatment with dabrafenib and trametinib resulted in an ORR of 42% in 35 patients with BTC [92].…”