Dabrafenib/Trametinib Shows Promising Activity in BRAF V600E–Mutated Biliary Tract Cancer

The combination therapy of dabrafenib (Tafinlar) and trametinib (Mekinist) recently demonstrated encouraging activity and a manageable safety profile in patients with BRAF V600E–mutated biliary tract cancer, according to results from the ROAR basket trial (NCT02034110) published in Lancet Oncology.¹

After a median follow-up of 10 months, an investigator-assessed overall response was reported in 51% (n = 22) of the 43 patients evaluable for analysis in the biliary tract cancer cohort of the study (95% CI, 36-67). An independent reviewer-assessed overall response was observed in 47% (n = 20) of patients (95% CI, 31-62).

Of the 22 patients with an investigator-assessed overall response, 67% were still responsive to treatment at 6 months (95% CI, 43-83), 36% at 12 months (95% CI, 17-57), and 13% at 24 months (95% CI, 2-33). Notably, 59% (n = 13) of the 22 patients had ongoing responses beyond 6 months, 7 had ongoing responses beyond 12 months, and 2 had ongoing responses at the time of data cutoff. Moreover, investigators observed a median duration of response DOR) of 9 months (95% CI, 6-14) in the 22 patients who experienced an investigator-assessed overall response.

The investigator-assessed progression-free survival (PFS) rate with the combination was 63% at 6 months (95% CI, 47-76), 30% at 12 months (95% CI, 16-45), and 8% at 24 months (95% CI, 2-22). Specifically, the median PFS per investigator assessment for patients on dabrafenib/trametinib was 9 months (95% CI, 5-10). The overall survival (OS) rate with the combination was 84% at 6 months (95% CI, 69-92), 56% at 12 months (95% CI, 38-71), and 36% at 24 months (95% CI, 19-53). Additionally, the median OS with the doublet was 14 months (95% CI, 10-33).

“In this study, we saw that the dabrafenib and trametinib combination demonstrates clinical benefit and should be considered as a therapeutic option for these patients,” Vivek Subbiah, MD, an associate professor of Investigational Cancer Therapeutics with the University of Texas MD Anderson Cancer Center and a lead author on the study, stated in a press release.² “These findings also reinforce the need for routine testing of BRAF mutations in patients with biliary tract cancers. As we move forward with precision oncology, we’re seeing that alterations present in these rare cancers are actionable and the patients do benefit from targeted therapies.”

Biliary tract cancer is an aggressive disease that is often diagnosed at an advanced stage with a 5-year survival rate of 18%. As the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have shown activity in several BRAF V600E–mutated cancers, investigators sought to further analyze the safety and efficacy of the combination as part of the ROAR basket trial in several BRAF V600E–mutated cancers, including biliary tract cancer.

The ongoing, phase 2, open-label, single-arm, multicenter ROAR trial was conducted across 19 different clinical sites throughout Europe and North America. In order to eligible for enrollment on the biliary tract cancer cohort of the trial, patients needed to be 18 years of age or older with a BRAF V600E–mutated histologically or cytologically confirmed unresectable, metastatic, locally advanced, or recurrent biliary tract or gallbladder adenocarcinoma with no other standard options available. Moreover, patients had to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 to 2, and acceptable baseline organ function. Patients must have progressed on or shown intolerance to a gemcitabine-based treatment regimen.

BRAF V600E mutations were identified through locally approved assays at each individual testing site or with the THxID-BRAF kit at the designated central reference laboratory. Once the mutation was confirmed, participants were given 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily until intolerable toxicity, progressive disease, death, or treatment discontinuation for any other reason. Throughout the study, patients were assessed with a computed tomography (CT) scan every 8 weeks during the first 48 weeks on study treatment, followed by once every 12 weeks thereafter.

The primary end point of the study was ORR, defined as either a complete or partial response per RECIST v1.1 criteria and assessed via the investigator and independent central review. Key secondary end points included PFS, DOR, OS, and safety.

The median duration of exposure to the combination regimen was 8 months. With regard to safety, the most common all-cause grade 3 or 4 adverse effect (AE) reported with the treatment was increased γ-glutamyltransferase, which was reported in 12% of patients (n = 5). Thirty-five percent (n = 15) of patients had AEs that resulted in dose reduction, 56% (n = 24) experienced toxicities that led to dose interruption, and 22% (n = 1) presented with sepsis which lead to permanent treatment discontinuation.

Serious AEs were observed in 40% (n = 40) of participants, and 21% (n = 9) experienced serious AEs determined to be related to the study treatment. The most frequently reported serious treatment-related AE was pyrexia (grade 1-2: 60%; n = 26; grade 3: 7%; n = 3) followed by nausea (grade 1-2: 42%; n = 18) and vomiting (grade 1-2: 33%; n =14; grade 3: 2%; n = 1). No treatment-related deaths reported on this trial.

“The trajectory of cholangiocarcinoma is changing rapidly,” Milind Javle, MD, a professor of Gastrointestinal Medical Oncology with MD Anderson Cancer Center and a co-author on the study, added in a press release. “Targeted therapy has made meaningful inroads, and this study is an excellent example of that. This is an important development for patients with cholangiocarcinoma and BRAF V600E mutations, who often have limited treatment options.”

Earlier results from this cohort presented during the 2019 Gastrointestinal Cancers Symposium showed that the BRAF/MEK combination elicited an overall response rate of 42% per investigator assessment, a median PFS of 9.2 months (95% CI, 5.4-10.1), and a median OS of 11.7 months (95% CI, 7.5-17.7).³

The combination therapy of trametinib and dabrafenib was previously granted an accelerated approval by the FDA in January of 2014 for the treatment of BRAF V600E– or V600K–mutated unresectable or metastatic melanoma.

References

1. Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. doi:10.1016/S1470-2045(20)30321-1
2. Targeted therapy combination effective for patients with advanced cholangiocarcinoma and BRAF mutations. News release. MD Anderson Cancer Center. August 17, 2020. Accessed August 17, 2020.
3. Wainberg ZA, Lassen UN, Elez E, et al. 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. J Clin Oncol. 2019;37(suppl 4):187. doi:10.1200/JCO.2019.37.4_suppl.187