Dabrafenib Plus Trametinib Demonstrates Activity in GI Cancers

Zev A. Wainberg, MD

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) led to encouraging responses in patients with rare, incurable cancer of the digestive tract, according to phase II data presented at the 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.¹

“These are patients with rare, aggressive cancers that have very poor prognoses and for which there are currently limited therapeutic options. These are significant and promising results that provide proof that BRAF is a validated target in patients with [biliary tract cancer],” said Zev A. Wainberg, MD, an associate professor medicine at David Geffen School of Medicine, University of California, Los Angeles, in a news release.

In the single-arm study, 36 patients with biliary tract cancer (BTC) and adenocarcinoma of the small intestine (ASI) were treated with the combination. Patients received oral dabrafenib at 150 mg twice daily and 2 mg of oral trametinib once daily.

All of the patients harbored BRAF V600E mutations, which is identified in a number of malignancies and is in approximately 15% of BTC and ASI cancers. All patients had advanced or metastatic disease and failed multiple lines of prior therapy.

Thirteen of the 32 patients (41%) with BTC and 2 out of the 3 patients (67%) with ASI had tumor shrinkage when treated with the BRAF/MEK inhibitor combination. By November 2018, 6 of the patients with BTC were still responding to treatment at a duration of ≥6 months. Median time to progression was 7.2 months, with some patients maintaining stable disease for more than 1 year. The median overall survival (OS) was 11.3 months, with some patients alive beyond 2 years, said Wainberg.

BTCs and ASIs are rare, occurring in approximately 1 to 2 people per 100,000. These diseases are difficult to detect in their early stages, so the cancer is likely to be metastatic by the time patients are diagnosed. Prognosis is poor, with survival outcomes less than 5 years of diagnosis, said Wainberg.

“There is an urgent unmet need for these patients and we believe these exciting data represent a potential new treatment option for patients with this BRAF mutation,” Wainberg noted.

The combination of dabrafenib and trametinib has shown promise in other cancers, particularly with recent data in thyroid cancer, melanoma, and non—small cell lung cancer (NSCLC).

The FDA initially dabrafenib combined with trametinib as a treatment for patients with unresectable or metastatic melanoma who harbor a BRAF V600E or V600K mutation in January 2014. The combination was approved as an adjuvant treatment for patients with BRAF V600E— or V600K–positive stage III melanoma following complete resection in April 2018.

The adjuvant approval is based on data from the phase III COMBi-AD trial, in which the recurrence-free survival rate at 3 years was 59% for patients who received dabrafenib and trametinib versus 40% for those who were treated with placebo.² Four-year rate was 54% versus 38%, respectively (HR, 0.49; 95% CI, 0.40-0.59). Regarding safety, grade 3/4 adverse events were experienced by 31% of the patients treated with the BRAF and MEK inhibitors, and 26% of the patients had to discontinue therapy.

In June 2017, the FDA approved the combination of dabrafenib and trametinib for patients with BRAF V600—positive advanced or metastatic NSCLC. In the nonrandomized, phase II trial that led to the approval, patients were stratified by no prior treatment (n = 36) and those who had prior lines of therapy (n = 57). At a median follow-up of 9 months, the overall response rates were 61.1% and 63%, respectively. Among patients who responded to treatment, 59% had responses lasting longer than 6 months, although the median duration of response was not reached.³

Most recently, in May 2018, the FDA approved dabrafenib/trametinib for the treatment of patients with unresectable or metastatic BRAF V600E—positive anaplastic thyroid cancer. The approval is based on an open-label trial that accrued patients with rare cancers harboring a BRAF V600E mutation. Among 23 patients evaluable for efficacy, 57% achieved a partial response and 4% reached a complete response. Among the 14 responders, 64% (n = 9) had no significant tumor growth for at least 6 months.⁴

References

1. Wainberg ZA. Patients with rare, incurable digestive tract cancers respond to new drug combination. In: Proceedings from the 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 13-16, 2018; Dublin, Ireland. Abstract 2. https://bit.ly/2Px5aGf.
2. Hauschild A, Dummer R, Schadendorf D, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600—mutant stage III melanoma [published online ahead of print October 22, 2018]. J Clin Oncol. doi: 10.1200/JCO.18.01219.
3. Planchard D, Smit EF, Groen HMJ, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF V600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307-1316. doi: 10.1016/S1470-2045(17)30679-4.
4. Subbiah V, Kreitman RJ, Wainberg AZ, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600—mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36(1):7-13. doi: 10.1200/JCO.2017.73.6785.