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SAN FRANCISCO -- A precision-medicine treatment strategy showed "impressive" activity in patients with a rare but aggressive biliary tract cancer, according to a study reported here.

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) led to objective responses in about 40% of patients with BRAF-mutated biliary tract cancer. An additional 40-45% of 33 evaluable patients had stable disease.

"Nearly every patient had some tumor reduction," said Zev Wainberg, MD, of the University of California Los Angeles, at the Gastrointestinal Cancers Symposium. "The duration of response at 6 months was 66%. Many of the patients who had stable disease also had durable clinical benefit."

The cohort had a median progression-free survival (PFS) exceeding 9 months and a median overall survival (OS) of almost a year, he added. The safety profile of dabrafenib/trametinib was consistent with previously reported clinical experience.

The results are "incredibly impressive," said Heinz-Josef Lenz, MD, of the University of Southern California Norris Cancer Center in Los Angeles.

"I think it is important to recognize that most of these patients were heavily pretreated," he said. "I don't think I need to convince you that this treatment is very effective."

Given the multiple potentially actionable mutations in biliary tract cancer, the study could represent just the first step toward expanded and more effective treatment options for the aggressive disease, Lenz added. Better understanding of the tumor microenvironment -- particularly signaling between normal tissue, stromal tissue, and tumor tissue -- should provide insights to inform development of new therapeutic strategies.

Biliary tract cancer has a poor prognosis, reflected in a 5-year OS of 15%, Wainberg noted. Standard of care includes resection and gemcitabine (Gemzar)-cisplatin chemotherapy, which has been associated with a PFS of 8 months and an OS of 11.7 months. Rate of recurrence and prognosis may differ between extrahepatic and intrahepatic disease.

Multiple mutations have been identified in association with biliary cancer, including BRAF in about 5% of tumors overall, perhaps more often in intrahepatic tumors, Wainberg continued. Previous studies of dabrafenib/trametinib, which simultaneously inhibits BRAF and MEK, demonstrated activity in several types of cancer associated with the BRAF V600E mutilation , including melanoma, non-small cell lung cancer, and anaplastic thyroid cancer.

Wainberg reported findings from the biliary cancer cohort of phase II , which evaluated the dabrafenib/trametinib combination in multiple types of advanced rare cancer associated with BRAF V600E. The biliary cancer subgroup included 35 patients, most of whom had received two or more prior lines of therapy.

The median duration of exposure to dabrafenib/trametinib was 6 months and ranged to 32 months. All but five patients continued study medication for more than 3 months. The trial had a primary endpoint of investigator-assessed response.

Among 33 evaluable patients, 14 (42%) had partial responses with the combination therapy. An independent review committee concluded that 12 (36%) patients achieved objective responses. An additional 15 patients had stable disease by investigator assessment, 13 by independent review. Both reviews found that four patients had progressive disease as best overall response. Two patients were not evaluable, according to the independent review committee.

About a third of patients received one or more additional treatments after dabrafenib/trametinib, including chemotherapy, surgery, small-molecule inhibitors, immunotherapy, biologic therapy, and radiation therapy.

The biliary cancer cohort had a median PFS of 9.2 months by investigator assessment. Median OS was 11.7 months.

N0 new or unexpected adverse events occurred during treatment with dabrafenib/trametinib. The most commonly reported treatment related adverse events were pyrexia (40%); rash (29%); nausea, diarrhea, and fatigue (23% each); and chills (20%). Adverse events leading to dose reduction occurred in 37% of patients and adverse events leading to dose interruption in 54%. One patient (3%) had an adverse event that led to permanent discontinuation.

Two patients died of sepsis, but neither death was considered treatment related, said Wainberg.

Genetic analysis of tissue samples from 16 patients yielded findings consistent with previously reported observations about the genetic landscape of biliary tract cancer. Tumor mutational burden was low (<6 mut/Mb) in all evaluable patients.

"These results represent the first prospectively analyzed cohort of patients with BRAF V600-mutant biliary tract cancer treated with the combination of BRAF and MEK inhibitors," Wainberg concluded. "Dabrafenib and trametinib demonstrated clinical benefit in patients with BRAF-mutant biliary tract cancer and should be considered a meaningful therapeutic option for these patients. BRAF V600 is an actionable driver mutation and should be considered for routine testing in patients with biliary tract cancer."

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