Expert Discusses Long-Term Dabrafenib/Trametinib Data in Melanoma

Georgina Long, MD

At the 2017 ASCO Annual Meeting, investigators reported 5-year follow-up data from a phase II study of dabrafenib (Tafinlar) plus trametinib (Mekinist) in patients with BRAF V600-mutant unresectable or metastatic melanoma.

The results are the longest follow-up for any randomized trial examining combination treatment with a BRAF inhibitor plus a MEK inhibitor. Patients in the study had unresectable stage IIIC or IV BRAF V600E/K-mutant melanoma, an ECOG performance score of 0 or 1, and prior treatment with at most 1 line of chemotherapy.

In an even distribution, patients were randomized to 150 mg of dabrafenib twice daily alone (n = 54) or in combination with either 2 mg of trametinib daily (n = 54) or 1 mg of trametinib daily (n = 54). Forty-five patients initially receiving single-agent dabrafenib crossed over to receive the combination.

In patients receiving dabrafenib plus 2 mg of trametinib, the 5-year overall survival (OS) rate was 28% with a median OS of 25 months (95% CI, 17.5-36.5), and the 5-year progression-free survival (PFS) rate was 13% with a median PFS of 9.4 months (95% CI, 8.6-16.6). Among patients with a baseline LDH ≤ upper limit of normal (ULN) and <3 sites of metastases, the 5-year OS rate was 51%.

Among patients receiving dabrafenib plus 1 mg of trametinib, the 5-year OS rate was 33% with a median OS of 22.5 months (95% CI, 14.2-42.3), and the 5-year PFS rate was 9% with a median PFS of 9.2 months (95% CI, 6.4-11.0).

The single-agent dabrafenib cohort had a 5-year OS rate of 21% with a median OS of 20.2 months (95% CI, 14.5-27.1), and the 5-year PFS rate was 3% with a median PFS of 5.8 months (95% CI, 4.6-7.4). Among patients with a baseline LDH ≤ ULN and <3 sites of metastases, the 5-year OS rate was 31%.

OncLive: Could you provide an overview of this long-term follow-up?

Lead study investigator Georgina V. Long, BSc, PhD, MBBS, clinical researcher at the Melanoma Institute Australia and Westmead Hospital in Sydney, reflected on these data in an interview with OncLive.Long: For the dabrafenib and trametinib phase I/II study, we are now reporting the 5-year PFS and OS. Overall, 13% of patients are progression-free at 5 years, which is pretty significant. When we turn to the OS, we know that about 28% of patients are still alive at 5 years. If we look at the subgroup that have less than 3 metastatic sites and a normal LDH at best line, the figures are even better. We have an OS of 51%...so pretty significant—that is more than half of the patients with lower burden of disease and lower LDH alive at 5 years having been treated with dabrafenib/trametinib. These are actually the same subset of patients that do very well long term on immunotherapy, as well.

What about brain metastases with this population?

What is the most important thing that community oncologists should know about this combination?

How have you seen this combination affect practice?

We need to wait until we see the phase III, [because] this is a small study. We are talking a small number of patient—54 patients. So, now we need to see the 5-year results or the pooled analysis of the phase III studies. The brain metastases, again, very interesting data, very highly active in brain metastases. However, patients do progress. This is a very poor prognostic group with brain metastases. What we see is a response rate in the brain of 58%, however the PFS at 12 months is 17%. So highly active, good short-term control, but we aren’t seeing the longevity of control in the brain that we’d like to see. Although, nearly 20% are still fine and progression-free at 12 months, now that is taking patients with the V600E mutation, asymptomatic, untreated brain metastases at baseline. Basically, its toxicity, and side effects, like fever. Do not dose reduce—you are better off using steroids to control the fevers in the first few months and then taper slowly, or some intermittent dosing&mdash;but do not dose reduce to manage fever.I mean, it’s been unbelievable. Patients 5 or 8 years ago would only survive 9 months. With all the therapies that we are using now—targeted and immunotherapy&mdash;we think we are curing some and patients are living a long time, which is where we want to be.

Long GV, Eroglu Z, Infante JR, et al. Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600—mutant unresectable or metastatic melanoma (MM). J Clin Oncol 35, 2017 (suppl; abstr 9505).