Targeted Combos Improve OS in Melanoma, But Mitigating Toxicities Essential

Danielle Ternyila
Published: Friday, Nov 22, 2019

Adil Daud, MD, a clinical professor in the Department of Medicine (Hematology/Oncology), at the University of California, San Francisco and the director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center

Adil Daud, MD

As more targeted therapies become available, the need for genomic testing in patients with melanoma is amplified, according to Adil Daud, MD. Although a dual targeted therapy approach can lead to survival gains, a management plan must be put in place to combat associated toxicities, he added.

“It’s important to test for BRAF mutations so that you know if someone is a candidate for a BRAF inhibitor or a BRAF/MEK combination therapy,” said Daud, a clinical professor in the Department of Medicine (Hematology/Oncology), at the University of California, San Francisco. “[These tests could also help us determine] what kind of agent to use.”

Patients with BRAF V600-mutant metastatic melanoma have seen promising activity with the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist), according to 5-year data presented at the 2019 ASCO Annual Meeting.

At 5 years, one-third of patients with unresectable or metastatic BRAF V600-mutant disease remained alive following treatment with the combination of the BRAF and MEK inhibitor, according to an analysis of the COMBI-d and COMBI-v trials. Furthermore,19% of patients remained alive without experiencing disease progression. Treatment with the dual targeted therapy led to a 5-year overall survival (OS) rate of 34% in the 563 evaluable patients.

This was the largest data set with the longest follow-up in treatment-naïve patients with BRAF V600-mutant unresectable or metastatic melanoma treated with these targeted therapies, according to Daud.

“In terms of adverse events (AEs), in my clinic, if someone has a history of immune-related AEs or might be at risk of having these complications, that might be the patient population in which I would consider giving dabrafenib and trametinib,” said Daud.

Most patients will develop fever and chills. Doctor-patient communication on these types of complications early on can help prevent events from worsening, according to Daud. For example, it’s important for patients to know that if they develop a fever, they stop taking both drugs immediately until the fever has subsided, he added.

In an interview with OncLive at the 16th International Congress of the Society for Melanoma Research, Daud, who is also the director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center, discussed the role of dabrafenib plus trametinib in patients with advanced melanoma and highlighted other combinations under investigation.

OncLive: Why is testing in patients with stage III melanoma important right now?

Daud: Stage III melanoma spans across a wide variety of different clinical subtypes; that goes all the way from stage IIIA to stage IIIC disease. [Patients] are categorized based on their risk of recurrence, so some are candidates for adjuvant treatment. About 50% of them will have BRAF-mutant disease, and for that category of patients, you could consider BRAF inhibitor therapy.

What role does the combination of dabrafenib and trametinib play in these patients?

There are patients for whom this combination is an appropriate treatment and [even a] preventative treatment. The other option is to use immunotherapy in the same patients. There are pros and cons to using dabrafenib plus trametinib, immunotherapy, or just observing these patients. To some extent, it comes down to whether your patient wants something oral that may have a greater incidence of AEs that are more reversible versus a lower incidence of AEs [that may] be long-lasting and irreversible.

In the case of dabrafenib plus trametinib, we do have mature 5-year OS data at this point in time. For immunotherapies, we have some really exciting relapse-free survival data that is relatively short-term. The issue is just extrapolating that to 5-year OS to see how that translates.

How do you manage the toxicities associated with these agents?

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