Disclosures: GlaxoSmithKline and Novartis funded this study. Subbiah reports grants from AbbVie, Amgen, Bayer, Eli Lilly, Exelixis, Genentech/Roche, GlaxoSmithKline, Novartis, Pfizer, PharmaMar, Takeda and several other pharmaceutical companies. He also reports travel support from ASCO, European Society for Medical Oncology, Incyte, Helsinn, Novartis and PharmaMar, as well as consultant/advisory roles with Eli Lilly, Helsinn, Incyte, Loxo Oncology, MedImmune, Novartis, QED Therapeutics and R-Pharm US. Please see the study for all other authors’ relevant financial disclosures.
August 18, 2020
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Dabrafenib-trametinib combination active in BRAF-mutated biliary tract cancer

Disclosures: GlaxoSmithKline and Novartis funded this study. Subbiah reports grants from AbbVie, Amgen, Bayer, Eli Lilly, Exelixis, Genentech/Roche, GlaxoSmithKline, Novartis, Pfizer, PharmaMar, Takeda and several other pharmaceutical companies. He also reports travel support from ASCO, European Society for Medical Oncology, Incyte, Helsinn, Novartis and PharmaMar, as well as consultant/advisory roles with Eli Lilly, Helsinn, Incyte, Loxo Oncology, MedImmune, Novartis, QED Therapeutics and R-Pharm US. Please see the study for all other authors’ relevant financial disclosures.
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The combination of dabrafenib and trametinib appeared active among patients with BRAF V600E-mutated biliary tract cancer, according to results of an ongoing phase 2 basket trial published in The Lancet Oncology.

Approximately half of patients achieved response, and the combination also exhibited a manageable safety profile.

The combination of dabrafenib and trametinib appeared active among patients with BRAF V600E-mutated biliary tract cancer.

“The results ... [support] the use of this combination therapy as a treatment option for patients with BRAF V600E-mutated biliary tract cancer,” researcher Vivek Subbiah, MD, associate professor in the department of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center, told Healio. “Routine testing for BRAF V600E mutations should be considered [for] all patients with biliary tract cancer.”

BRAF V600 mutations occur in a variety of tumor types.

The combination of the BRAF inhibitor dabrafenib (Tafinlar, Novartis) and the MEK1/2 inhibitor trametinib (Mekinist, Novartis) is standard treatment for patients with melanoma, non-small cell lung cancer or anaplastic thyroid cancer who have underlying BRAF driver mutations.

Effective treatments are urgently needed for patients with cholangiocarcinoma whose disease progresses on gemcitabine-based chemotherapy. Approximately 5% of biliary tract tumors harbor mutations in the BRAF gene, according to study background.

Vivek Subbiah

Subbiah and colleagues are conducting the open-label, single-arm, multicenter Rare Oncology Agnostic Research (ROAR) trial to assess the activity and safety of dabrafenib and trametinib for patients with BRAF V600E-mutated rare cancers.

The trial included a cohort of adults with unresctable, metastatic, locally advanced or recurrent biliary tract cancer. All patients in the biliary tract cancer cohort had ECOG performance status of 0 to 2 and had undergone prior systemic treatment.

“This is a rare subset of a rare disease, and over 600 patients were screened to enroll 43 patients,” Subbiah told Healio.

All patients received dabrafenib dosed at 150 mg twice daily plus trametinib dosed at 2 mg once daily. Treatment continued until disease progression or treatment intolerance.

Overall response rate in the intention-to-treat population served as the primary endpoint.

Researchers performed an interim analysis based on median follow-up of 10 months (interquartile range, 6-15).

At the time of data cutoff, seven patients (16%) remained on treatment. Of the 36 patients who had discontinued treatment, 34 experienced disease progression, one died due to sepsis and one requested to discontinue treatment.

Results showed an investigator-assessed ORR of 51% (95% CI, 36-67) and an independent reviewer-assessed ORR of 47% (95% CI, 31-62).

Among the 22 patients who achieved investigator-assessed response, researchers reported ongoing responses among 67% (95% CI, 43-83) at 6 months, 36% (95% CI, 17-57) at 12 months and 13% (95% CI, 2-33) at 24 months. Median duration of response among those who achieved investigator-assessed response was 9 months (95% CI, 6-14).

Median PFS by investigator assessment was 9 months (95% CI, 5-10), with PFS rates of 63% (95% CI, 47-76) at 6 months, 30% (95% CI, 16-45) at 12 months and 8% (95% CI, 2-22) at 24 months.

Median OS was 14 months (95% CI, 10-33), with OS rates of 84% (95% CI, 69-92) at 6 months, 56% (95% CI, 38-71) at 12 months and 36% (95% CI, 19-53) at 24 months.

The most common grade 3 or higher adverse event was increased gamma-glutamyl transferase (12%). Seventeen patients (40%) experienced serious adverse events and nine (21%) experienced treatment-related serious adverse events, the most common of which was pyrexia (19%).

Researchers reported no treatment-related deaths.

“The safety [of] the combination is now well-established in multiple tumor types, and this study shows that [the] combination is effective in biliary tract cancer,” Subbiah told Healio. “A better understanding of mechanisms of acquired resistance to BRAF inhibitors in biliary tract cancers would guide the development of therapies directed toward further improvement of treatment outcomes for patients with BRAF V600E-mutated biliary tract cancers.”

For more information:

Vivek Subbiah, MD, can be reached at vsubbiah@mdanderson.org.