A phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT02034110) using a combination of dabrafenib and trametinib in advanced cholangiocarcinoma has shown a positive overall response rate in patients whose tumors have BRAFV600E mutations.

The results from an interim analysis were published in The Lancet Oncology1 with the trial achieving a 51% overall response rate in 43 patients, all of whom had been treated with at least 1 previous line of therapy. Although only 5% to 10% of people with cholangiocarcinoma harbor this specific mutation in their tumor, the study may mean that more people with the disease are eligible for targeted therapies.

“Cholangiocarcinoma is becoming the poster child for precision oncology,” said Vivek Subbiah, MD, associate professor in the department of investigational cancer therapeutics at MD Anderson in Houston, Texas, and senior author of the study. “An EGFR inhibitor was approved early this year, but before that, cholangiocarcinoma didn’t have any specific targeted therapies approved after progressing from standard forms of therapy,” added Dr Subbiah.

The trial reported a median duration of response of 8.7 months with 7 of 42 patients seeing an ongoing response past 12 months. Median overall survival (OS) was 13.5 months, with 56.4% and 35.8% of patients still alive at 12 and 24 months, respectively.


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“The OS is really encouraging for this disease and really shows the power of a targeted therapy approach — we wouldn’t get this high response rate with traditional chemotherapy in the second line,” said Dr Daneng Li, MD, assistant clinical professor and hepatobiliary tumor lead in the department of medical oncology and therapeutics research at City of Hope Comprehensive Cancer Center in Duarte, California.

A recent study showed that OS in advanced cholangiocarcinoma patients treated with FOLFOX chemotherapy (folinic acid, fluorouracil, oxaliplatin) is around 6 months.2

“It is especially impressive if you compare it to traditional second-line chemotherapy. This wasn’t a randomized study to compare targeted therapy, but this data is encouraging for this type of approach over traditional chemotherapy,” said Dr Li.

The study was part of a wider-scale basket trial called ROAR (Rare Oncology Agnostic Research) focusing on patients with rare tumors with BRAFV600E mutations.3 As well as existing approvals for melanoma and non-small cell lung cancer, another arm of the trial showed promising results in anaplastic thyroid cancer, leading to an FDA approval for the drug combination in this context.4

“There is no question that this result is exciting and I’m interested in the longer-term responses,” said Ghassan Abou-Alfa, MD, medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. While there is a small number of patients, “you have to put it in perspective,” said Dr Abou-Alfa. “The rarity of the cancer to begin with means there are only around 40,000 patients in the US every year and the mutation itself is also rare.”

BRAF-targeting therapies have shown some initial promise as single agents in treating cholangiocarcinoma, but toxicities have limited their use. However, the combination showed a reasonable toxicity profile in this study.

“We didn’t have any surprises in terms of the toxicity profile, it is similar to what we see in other types of cancer using these drugs. The combination actually seems to decrease the number of adverse events compared to single agents. The toxicity of this combination is well known and oncologists are familiar with this and are well equipped to take care of these patients,” said Dr Subbiah, who has also authored a review paper on the combination in several different cancer types.5