Efficacy and safety of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated biliary tract cancer (BTC): A cohort of the ROAR basket trial.

Abstract

187 Background: BTCs are rare, aggressive malignancies with poor prognoses. Treatment options and outcomes after first-line therapy are not well defined. Median progression-free survival (PFS) in second-line BTC is < 5 mo. Combined BRAF + MEK inhibition is efficacious in BRAF V600–mutated anaplastic thyroid cancer, melanoma, and lung cancer, but less so in BRAF V600E-mutated colorectal cancer. Activating BRAF V600E mutations have been reported in 0% to 20% of BTCs; thus, D (BRAF inhibitor) + T (MEK inhibitor) was evaluated as a treatment for pts with BRAF V600E–mutated BTC in the ROAR basket trial. Methods: In this phase II, open-label trial, pts with BRAF V600E mutations in 9 rare tumor types, including BTC, received D (150 mg BID) + T (2 mg QD) until unacceptable toxicity, disease progression, or death. Eligible pts had advanced or metastatic cancer and had been treated with ≥ 1 prior systemic therapy. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), PFS, overall survival (OS), biomarker correlates, and safety. Results: Thirty-three pts with BTC had enrolled at data cutoff (January 3, 2018). BRAF V600E mutations were centrally confirmed in 30 of 33 pts with BTC (91%). Median age was 58 y, and 78% had received ≥ 2 prior lines of systemic therapy. 32 of 33 pts with BTC were evaluable. Investigator-assessed ORR was 41% (13/32; 95% CI, 24%-59%), with 6 of 13 responses ongoing at data cutoff, 7 of 13 pts (54%) had a DOR ≥ 6 mo. Median PFS was 7.2 mo (95% CI, 4.6-10.1 mo), and median OS was 11.3 mo (95% CI, 7.3-17.6 mo). Grade 3/4 adverse events in ≥ 3 pts were increased γ-glutamyltransferase (n = 3 [9%]) and decreased white blood cell count (n = 3 pts [9%]). Biomarker analyses demonstrate a heterogeneous genetic landscape, and suggest a higher baseline expression of MAPK pathway genes in the pts who did not respond to D + T. Conclusions: D + T demonstrated promising efficacy in pts with BTC, with a favorable safety profile. These pts should be considered for BRAF mutation analysis, and D + T should be considered for pts with BRAF V600E-mutated BTC. Clinical trial information: NCT02034110.

Emerging Targeted and Immunotherapies in Cholangiocarcinoma

“…The first reports with the combination of dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) was presented by Wainberg et al, reporting outcomes from the biliary tract cohort of the phase II ROAR basket trial. The data revealed a 41% response rate in BRAFV600E mutated biliary tract cancers treated with dabrafenib and trametinib and stable disease as best response in another 45% of patients 17. The median progression-free survival in this study was 9.2 months and median overall survival was 11.7 months, which is comparable to outcomes with standard of care first-line chemotherapy.…”

Systemic therapies for intrahepatic cholangiocarcinoma

“…In a basket trial of rare tumours, including CCA harbouring RAF V600E mutations, the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib resulted in a response rate of 42% per investigator assessment in 35 patients with CCA. 41 The median PFS by investigator assessment was 9.2 months, and the median OS was 11.7 months in this cohort. Mutations in the following genes have been identified but have proven difficult to target: PRKACA, PRKACB, ELF3, ARID1A, ARID1B and BAP1.…”

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

“…In two independent reports, the combination of Dabrafenib and Trametinib showed durable clinical responses [55,56]. Finally, the preliminary results of a basket trial involving patients with BRAF mutation showed, in a cohort of pretreated biliary tract cancer, a response rate of 42% with a median overall survival of 11.7 months [57].…”