TY - JOUR
T1 - Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR)
T2 - a phase 2, open-label, single-arm, multicentre basket trial
AU - Subbiah, Vivek
AU - Lassen, Ulrik
AU - Élez, Elena
AU - Italiano, Antoine
AU - Curigliano, Giuseppe
AU - Javle, Milind
AU - de Braud, Filippo
AU - Prager, Gerald W.
AU - Greil, Richard
AU - Stein, Alexander
AU - Fasolo, Angelica
AU - Schellens, Jan H.M.
AU - Wen, Patrick Y.
AU - Viele, Kert
AU - Boran, Aislyn D.
AU - Gasal, Eduard
AU - Burgess, Paul
AU - Ilankumaran, Palanichamy
AU - Wainberg, Zev A.
N1 - Funding Information:
This study was sponsored by GlaxoSmithKline and Novartis. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health (NIH) Cancer Center Support ( grant CA016672 ). The University of Texas MD Anderson Cancer Center clinical trials programme is supported in part by Cancer Prevention Research Institute of Texas ( grant RP110584 ) and National Center for Advancing Translational Sciences ( grant UL1 TR000371 ; Center for Clinical and Translational Sciences). VS is supported by the NIH National Cancer Institute ( grant 1R01CA242845-01A1 ). We thank the patients and their families for their participation, and the investigators and site staff for their contributions. We acknowledge James Garrett and Kitty Wan for their contributions to statistical biomarker analysis; Catarina Campbell and Mukta Joshi for their contributions to the DNA sequencing analysis; and Navigate BioPharma for their contributions to the Nanostring nCounter gene expression analysis. We thank Julie O'Grady and Philip Sjostedt (The Medicine Group, New Hope, PA, USA) for providing medical writing support, which was funded by Novartis in accordance with current Good Publication Practice guidelines.
Funding Information:
The ROAR basket trial was originally designed and sponsored by GlaxoSmithKline, with input from a steering committee; the current sponsor of the trial is Novartis Pharmaceuticals. Data collection and data analysis were initially done by GlaxoSmithKline before responsibility was assumed by Novartis. Data interpretation was done by all authors, including employees of Novartis. Medical writing support was funded by Novartis. All authors had full access to study data and share final responsibility for the content of the report and the decision to submit for publication.
Funding Information:
This study was sponsored by GlaxoSmithKline and Novartis. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health (NIH) Cancer Center Support (grant CA016672). The University of Texas MD Anderson Cancer Center clinical trials programme is supported in part by Cancer Prevention Research Institute of Texas (grant RP110584) and National Center for Advancing Translational Sciences (grant UL1 TR000371; Center for Clinical and Translational Sciences). VS is supported by the NIH National Cancer Institute (grant 1R01CA242845-01A1). We thank the patients and their families for their participation, and the investigators and site staff for their contributions. We acknowledge James Garrett and Kitty Wan for their contributions to statistical biomarker analysis; Catarina Campbell and Mukta Joshi for their contributions to the DNA sequencing analysis; and Navigate BioPharma for their contributions to the Nanostring nCounter gene expression analysis. We thank Julie O'Grady and Philip Sjostedt (The Medicine Group, New Hope, PA, USA) for providing medical writing support, which was funded by Novartis in accordance with current Good Publication Practice guidelines.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/9
Y1 - 2020/9
N2 - Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting. Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6–15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36–67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31–62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. Funding: GlaxoSmithKline and Novartis.
AB - Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting. Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6–15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36–67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31–62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. Funding: GlaxoSmithKline and Novartis.
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U2 - 10.1016/S1470-2045(20)30321-1
DO - 10.1016/S1470-2045(20)30321-1
M3 - Article
C2 - 32818466
AN - SCOPUS:85090023259
SN - 1470-2045
VL - 21
SP - 1234
EP - 1243
JO - The lancet oncology
JF - The lancet oncology
IS - 9
ER -