Clinical relevance and actionability of BRAF alterations in advanced biliary tract cancer: Preliminary results from the multicenter B-REAL study

In advanced Biliary Tract Cancers (aBTCs), RAF alterations define a rare subset of patients (pts) and may predict response to inhibition of the BRAF/MEK/ERK signaling pathway. BRAF mutations are grouped in activating RAS-independent mutations (muts) signaling as monomers (class I) or as dimers (class II) and in RAS-dependent mutations with impaired kinase activity or kinase-dead (class III). Moreover, BRAF+MEK inhibitors have been FDA-approved for pts affected by BRAFV600E (class I) mutated aBTC, but real-word data on their efficacy are still lacking.

The B-REAL study aims at evaluating 1) the molecular landscape of BRAF-altered aBTC, 2) the clinical characteristics of aBTC pts with BRAF alterations, and 3) the prognostic and predictive impact of BRAF alterations in pts treated with first-line chemotherapy and targeted therapy. To date, data of advanced BTCs pts treated at five Italian referral centers with available BRAF status were collected. Clinical characteristics and outcomes from standard therapy and BRAF+MEK inhibitors of patients with BRAF class I vs BRAF class II-III vs BRAF wild-type (WT) were compared.

Out of 764 pts screened, 628 pts with available clinical data and BRAF status were here included, with 413 (66%) affected by intrahepatic (iCCA), 124 (20%) by extrahepatic cholangiocarcinoma and 84 (13%) by gallbladder carcinoma. BRAF alterations were found in 29 (4.6%) pts, with 15 (2.4%) BRAFV600E class I muts and 14 (2.2%) BRAFnot-V600E muts (2 class II, 9 class III and 3 of unknown significance); BRAF alterations were mostly found in iCCA (87% of BRAFV600E and 57% of BRAFnot-V600E). Patients with BRAF class I muts were younger (p=0.007) and more frequently females (p= 0.044), compared to class II-III muts and WT cases. No significant difference between BRAF WT, BRAF class I and class II-III muts pts was highlighted in terms of overall survival (OS, 17.4 vs 16.1 vs 13.2 months, p=0.831) and progression-free survival (PFS) to first-line chemotherapy (3.9 vs 5.0 vs 6.0 months, p=0.632). Nine patients with aBTC BRAFV600E mutated were treated with BRAF+/-MEK inhibitors, with a median PFS of 7.3 months (95%CI 4.5-NA) and OS of 9.4 months (95%CI 8.2-NA).

Our study confirms that BRAF is a relevant biomarker for aBTC. Clinically meaningful activity of BRAF+/-MEK inhibition for BRAFV600E mutated aBTC is confirmed, while more studies are needed for a comprehensive understanding of the molecular and clinical characteristics of class II-III BRAF mutated BTC, which may support future development of RAF-directed strategies.

The authors.

Has not received any funding.

M. Niger: Honoraria (self): Editorial collaboration: Incyte, Servier, Medpoint SRL, Sandoz, Speaker: Incyte; Advisory / Consultancy: Incyte, Servier, Taiho, Astrazeneca; Travel / Accommodation / Expenses: Astrazeneca. L. Rimassa: Honoraria (self): Lecture fees: Bayer, Eisai, Gilead, Incyte, Ipsen, Merck Serono, Roche, Sanofi, Servier; Advisory / Consultancy: AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; Research grant / Funding (institution): Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks; Travel / Accommodation / Expenses: AstraZeneca. F. de Braud: Honoraria (self): BMS; Nadirex; Dephaforum; Accmed; Ambrosetti; Sanofi; Pierre Fabre; , Mattioli 1885; Effetti; MCCann Health; ESO; Fare Comunicazione; MSD; Itanet ; , IQVIA ; Advisory / Consultancy: Sanofi; BMS; Taiho; Pierre Fabre; Mattioli 1885; MCCann Health; MSD; Accmed; Incyte; Speaker Bureau / Expert testimony: Motore Sanità; Nadirex; Dephaforum; Accmed; Ambrosetti; VMLY&R; Effetti; , Aiom; ESO; Events; Fare Comunicazione; Itanet; Nadirex; BMS; Travel / Accommodation / Expenses: SID; ESO. All other authors have declared no conflicts of interest.