Targeted therapy combination effective for patients with advanced cholangiocarcinoma and BRAF mutations
First prospective trial for rare patient population supports dabrafenib
plus trametinib as new treatment option

Date:
August 17, 2020
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
In a Phase II trial a combination targeted therapy achieved a 51%
overall response rate in patients with cholangiocarcinoma and
BRAF V600E mutations. This is the first prospective study for this
group of patients.



FULL STORY ==========================================================================
In a Phase II trial led by researchers at The University of Texas MD
Anderson Cancer Center, the combination of dabrafenib, a BRAF inhibitor,
and trametinib, a MEK inhibitor, achieved a 51% overall response rate
(ORR) in patients with cholangiocarcinoma marked by the BRAF V600E
mutation.


==========================================================================
This trial represents the first prospective study for patients with
BRAF- mutated cholangiocarcinoma, or bile duct cancer, and suggests
this targeted therapy combination could serve as a much-needed treatment
option for patients with treatment-resistant advanced disease. The trial results were published today in Lancet Oncology.

"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 ," said lead author Vivek Subbiah, M.D.,
associate professor of Investigational Cancer Therapeutics. "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." This study is part of an ongoing Phase II, open-label, multicenter trial testing the efficacy and safety of the combination therapy in patients with a variety of BRAF V600E-mutated
rare cancers. The bile duct cohort enrolled 43 patients, all of whom
had received at least one prior line of therapy.

Trial participants were 91% Caucasian, 5% Asian (Japanese heritage), 2%
Asian (East Asian heritage) and 2% white (Arabic/North African). The
median age was 57, with women accounting for 56% and men 44% of
participants.

Bile duct cancer is a rare disease diagnosed in about 8,000 people each
year in the U.S. Most cases are diagnosed at advanced stages, and thus
clinical outcomes are generally poor, with a five-year survival rate below
20%. Standard of care includes surgery, when possible, and chemotherapy.



==========================================================================
In patients with advanced disease, median overall survival with
chemotherapy treatment is less than one year, so there is a significant
unmet need for effective new treatment approaches, explained Subbiah.

Mutations in the BRAF gene are found in 5-7% of those diagnosed with bile
duct cancer, and patients with the BRAF V600E mutation are more likely
to have poor outcomes. Trials with single-agent therapies targeting
BRAF have been effective for treating these patients, but have shown significant toxicities, including secondary malignancies.

However, combining these agents with MEK inhibitors, which act downstream
in the same signaling pathway, have proven effective and are FDA-approved
for use in other cancer types, including melanoma, lung cancer and
anaplastic thyroid cancer. These agents are not currently approved by
the FDA to treat cholangiocarcinoma.

In the current trial, the combination therapy achieved an ORR of 51%
(22 patients) according to investigator assessments. The median duration
of response was 8.7 months, with seven patients seeing an ongoing response beyond 12 months.

Median progression-free survival was 9.1 months and median overall
survival was 13.5 months, with 56.4% and 35.8% of patients still alive
at 12 months and 24 months, respectively.

All patients experienced at least one adverse event, with the most common
being fever, nausea, vomiting, diarrhea and fatigue. Twenty-four patients
(56%) experienced a Grade 3 or 4 adverse event, the most common of which
was an increase in gamma-glutamyltransferase, an enzyme found in the
liver and bile ducts. According to the authors, these side effects were consistent with those seen previously from this combination in other
cancer types.

"The trajectory of cholangiocarcinoma is changing rapidly," said
co-author Milind Javle, M.D., professor of Gastrointestinal Medical
Oncology. "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." This research was supported by GlaxoSmithKline and Novartis. Co-authors from MD Anderson include Milind
Javle, M.D., of Gastrointestinal Medical Oncology.


========================================================================== Story Source: Materials provided by University_of_Texas_M._D._Anderson_Cancer_Center. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Vivek Subbiah, Ulrik Lassen, Elena E'lez, Antoine Italiano, Giuseppe
Curigliano, Milind Javle, Filippo de Braud, Gerald W Prager, Richard
Greil, Alexander Stein, Angelica Fasolo, Jan H M Schellens, Patrick
Y Wen, Kert Viele, Aislyn D Boran, Eduard Gasal, Paul Burgess,
Palanichamy Ilankumaran, Zev A Wainberg. Dabrafenib plus trametinib
in patients with BRAFV600E-mutated biliary tract cancer (ROAR):
a phase 2, open-label, single-arm, multicentre basket trial. The
Lancet Oncology, 2020; DOI: 10.1016/S1470-2045(20)30321-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200817191745.htm

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