Phase 2 Trial Shows Promise for Regorafenib in Pretreated Biliary Tract Cancer

In this multi-institutional study, regorafenib demonstrated modest clinical efficacy in heavily pretreated patients with biliary tract cancer.

A multi-institutional phase 2 trial published in Cancer found that regorafenib (Stivarga) demonstrated modest clinical efficacy in heavily pretreated patients with biliary tract cancer (BTC).

However, researchers indicated that further assessment of biomarkers is warranted to identify which patients with BTC may benefit from regorafenib.

“In our study, we explored the efficacy of regorafenib in refractory BTC on the basis of the hypothesis that regorafenib would inhibit multiple pathways, including angiogenic receptors (VEGFR1, VEGFR2, VEGFR3, and TIE2) and stromal factors receptors (PDGFR-β and FGFR1), which play significant roles in the tumorigenesis, progression, and metastasis of BTC,” wrote the authors.

Patients with BTC who had progressed on at least 1 line of systemic therapy were administered regorafenib at 160 mg daily for 21 days on and 7 days off. Overall, 39 patients were enrolled between June 2014 and October 2017 from 3 different institutions and 33 were evaluable for efficacy.

The primary endpoint of the study was overall survival (OS) at 6 months. Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), and objective response rates.

Notably, 30 patients discontinued treatment due to radiological or clinical disease progression, 8 patients discontinued due to an adverse event (AE), and 1 patient discontinued due to consent withdrawal. The median duration of treatment was 2.1 months (range, 0.5-20.6 months). Dose modifications were required in 19 of the 39 patients (48.7%) because of AEs.

The median PFS and OS were 3.7 and 5.4 months, respectively, with survival rates of 46.2% at 6 months, 35.9% at 12 months, and 25.6% at 18 months for the intention-to-treat population. For the 33 evaluable patients who received regorafenib for at least 3 weeks, the median PFS and OS were 3.9 and 6.7 months, respectively, with survival rates of 51.5% at 6 months, 39.4% at 12 months, and 27.3% at 18 months. The objective response rate was 9.1%, and the disease control rate was 63.6%.

The most common AE was fatigue (59%), followed by hypertension (53.8%), aspartate aminotransferase (51.3%)/alanine aminotransferase (43.6%) increases, thrombocytopenia (38.5%), hand-foot skin reactions (35.9%), anemia (30.8%), and nausea (30.8%). Moreover, 28 patients (71.8%) experienced grade 3-4 adverse AEs including hypertension (30.8%), fatigue (10.3%), aspartate aminotransferase (10.3%)/alanine aminotransferase (10.3%) elevations, and hand-foot skin reactions (10.3%). There were no treatment-related deaths.

“Recently, the Regorafenib Dose Optimisation Study (ReDOS) has demonstrated that a weekly dose-escalation strategy from 80 to 160 mg is as effective as the standard dose of 160 mg with a lower incidence of adverse events in refractory, metastatic colorectal cancer, and this suggests that the dose-escalation strategy be considered to decrease significant adverse events, improve drug compliance, and minimize dose interruptions while maintaining efficacy when clinical studies of regorafenib are designed in the future,” the authors explained.

Importantly, of 23 cytokines analyzed in the plasma of 29 patients, elevated baseline vascular endothelial growth factor D (VEGF-D) was associated with shorter PFS, whereas elevated baseline interleukin 6 (IL-6) and glycoprotein 130 (GP130) were associated with shorter OS.

“In all cases, each biomarker was a negative prognostic marker, which indicated that higher levels of each marker led to an increase in the hazard for either outcome,” the authors wrote.

However, due to the limited number of patients and heterogenous groups of BTC included in this study, the investigators recommended that this data be considered exploratory and hypothesis generating.


Kim RD, Sanoff HK, Poklepovic AS, et al. A Multi-Institutional Phase 2 Trial of Regorafenib in Refractory Advanced Biliary Tract Cancer. Cancer. doi: 10.1002/cncr.32964.

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