SAN FRANCISCO — Biliary tract cancers (BTCs) are rare, aggressive malignancies that generally have a poor prognosis, and are usually treated with chemotherapy.
A new study shows that in a subgroup of these patients, individuals who have tumors with BRAF V600E mutations, treatment with a combination of targeted agents showed promising activity.
The combination of drugs used — the BRAF kinase inhibitor dabrafenib (Tafinlar, Novartis) and the MEK inhibitor trametinib (Mekinist, Novartis), is already approved for use in melanoma with BRAF V600 mutations.
Results of this drug combination in patients with BRAF-mutated biliary tract cancer, a cohort within the larger ROAR basket trial, were presented here at the Gastrointestinal Cancers Symposium (GICS) 2019.
There was an overall response rate (ORR) of 42%, and at data cutoff, 5 of 14 responses are ongoing, and seven patients had a response lasting 6 months or longer, said lead author Zev Wainberg, MD, codirector of the GI Oncology Program at the University of California, Los Angeles.
Median progression-free survival was 9.2 months and median overall survival was 11.7 months.
"Dabrafenib plus trametinib demonstrated clinical benefit in patients with BRAF mutant BTC and should be considered a meaningful therapeutic option for these patients," Wainberg told the audience.
"The efficacy observed in this population of patients with advanced disease is comparable with that of first-line chemotherapy with gemcitabine and cisplatin," he said.
These results "represent the first prospectively analyzed cohort of patients with BRAF V600E-mutated BTC treated with a combination of BRAF and MEK inhibition," he added.
Biliary Tract Cancer
Historically, the 5-year overall survival in biliary tract cancer patients is about 15%, but recurrence rates and prognosis may differ between extrahepatic and intrahepatic disease, explained Wainberg. The current standard of care includes resection and chemotherapy with gemcitabine and cisplatin. This regimen is associated with a progression free survival of 8 months and an overall survival of 11.7 months, which is similar to the results seen in this study with targeted agents, he commented.
Multiple mutations have been identified in association with biliary cancer, including BRAF in about 5% of overall tumors, and this "opens the possibility for targeted therapy in this population," he said. "BRAF mutations may be enriched in intrahepatic BTC," he added.
Potential Therapeutic Option
The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has already demonstrated efficacy in other BRAF V600E cancers, including metastatic melanoma and melanoma in the adjuvant setting; non-small cell lung cancer; and anaplastic thyroid cancer.
The results in BRAF-mutated biliary tract cancer presented at this meeting come from a larger study, the ROAR basket trial conducted in patients with nine different types of rare tumors, all with BRAF V600E mutations.
The results come from a cohort of 35 patients with BRAF-mutated biliary tract cancer, of whom 74% had stage IV disease at enrollment, and 80% had received two or more lines of prior systemic therapy.
Patients received dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily, and treatment was continued until unacceptable toxicity, disease progression, or death. The primary endpoint was investigator-assessed ORR and secondary endpoints included progression free survival, duration of response (DOR), overall survival, and safety.
The median exposure to the combination therapy was 6 months (range 2-32 months), and 86% of the cohort remained on therapy for more than 3 months.
The median duration of follow-up was 8 months, and the ORR was 42% by investigator assessment and 36% by independent review (all partial responses). Stable disease was achieved by 45% of patients by investigator assessment and 39% by independent review.
A genetic analysis was also performed, using targeted next-generation sequencing on 16 tissue samples collected at baseline. Copy-number variant (CNV) analysis showed that a loss of CDKN2A/B was the most common finding, identified in 6 of 11 (55%) patients with any CNV. But overall, Wainberg noted that the mutational burden was low, consistent with other reports in this tumor type.
In addition, biomarker analyses showed that this was a "heterogeneous genetic landscape," and suggested that there was a higher baseline expression of MAPK pathway genes among patients who did not respond to the therapy.
There were no new safety signals noted during the study period. The most commonly reported treatment-related adverse events were pyrexia (40%); rash (29%); nausea, diarrhea, and fatigue (23% each); and chills (20%). Sepsis led to the death of two patients, but it was not considered to be treatment related.
"BRAF V600 is one of several actionable driver mutations in this disease and should be considered for routine testing in patients with BTCs," Wainberg concluded.
Efficacy Results "Incredibly Impressive"
In a discussion of the paper, Heinz-Josef Lenz, MD, Professor of Medicine and Preventive Medicine at the University of Southern California Keck School of Medicine in Los Angeles, stated that the efficacy results were "incredibly impressive."
"I think it's very important — most of these patients were heavily pretreated, two or more lines," he said. "And this is the effect. I don't think I need to convince you that this treatment is very effective."
Lenz emphasized that both the survival and progression-free survival curves were "incredible," but in biliary cancer there are many identified and actionable mutations. "And it depends not only on doing next-genome sequencing, as we know it's dependent on the location," he said, pointing out the intrahepatic and extrahepatic biliary cancers are different diseases.
He also noted that tools such as a liquid biopsy will be able to guide treatment decisions in the future and stressed the importance of incorporating whole-genome sequencing and other types of molecular profiling into practice.
Integrating next-generation sequencing into clinical practice "should be done in order to identify these incredible, well-categorized subgroups," Lenz said. "I think we should consider expanding whole exome [sequencing] and whole genome sequencing to identify novel pathways, novel genes, novel action and mutations, and using RNA to better understand the dynamics and the activity of these pathways."
"We need more needles in the haystack to find [in order] to have more successful treatment," he added. "There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments. The key is that you need to do the testing in order to really find and identify the most successful treatments for our patients."
The study was supported by Novartis. Wainberg disclosed relationships with Aduro Biotech, Array BioPharma, Bristol-Myers Squibb, Five Prime Therapeutics, Genentech, Lilly, Merck, Merck KGaA, Novartis, Sirtex Medical, Pfizer, and Plexxikon. Lenz disclosed relationships with Bayer, Boehringer Ingelheim, Merck Serono, Roche, and Pfizer.
Gastrointestinal Cancers Symposium (GICS) 2019: Abstract 187. Presented January 18, 2019.
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Cite this: 'Impressive' Activity with BRAF/MEK Inhibitors in Biliary Cancer - Medscape - Jan 24, 2019.