In BRAF-Mutated Advanced Melanoma, Range of First-line Choices Brings Hope, Questions

Patients with BRAF-V600 mutated metastatic melanoma have new treatment options to consider, but scientists are still waiting on additional data to help choose which first-line treatments are best for which patients.

A wave of new treatment strategies and therapeutic agents has transformed the prognosis for patients with BRAF-V600 mutation-positive metastatic melanoma, yet this new era has also created a need for better guidelines to help select the best treatment for each individual patient.

In a recent review article published in Cancer Treatment Reviews, corresponding author Giuseppe Curigliano, MD, PhD, of the European Institute of Oncology and the University of Milan, and colleagues, summarized the latest research and its implications for patients.

Curigliano and colleagues began by walking through the list of available therapies. A trio of BRAF/MEK inhibitor combinations have already been approved by the FDA. In addition, the agency has approved immune checkpoint inhibitors, and the combination treatment of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with untreated disease.

One newer approach has been to combine immune-checkpoint inhibitors with targeted agents, such as the triplet combination of atezolizumab (Tecentriq), vemurafenib (Zelboraf), and cobimetinib (Cotellic).

With so many options available, patients have a number of choices to make, and the authors make clear that those choices must be highly tailored to each patient’s particular case.

“Experts recommend the tailoring of therapy on each patient, considering patient’s clinical characteristics (e.g., LDH level, organs involved, performance status, tumor burden, disease progression kinetics), comorbidities and patient’s preferences,” Curigliano and colleagues wrote. “Moreover, they emphasize the evaluation of the urgency of a short-term benefit versus the possibility to wait for a long-term benefit.”

Patients whose disease is neither progressing rapidly nor threatening vital organs could be good candidates for frontline immunotherapy. However, targeted therapy is preferable in cases where an immediate benefit is important. Whether patients with rapidly evolving tumors are suitable for a triplet therapy remains an open question, the authors wrote, arguing that further analysis is needed to understand the answer.

At present, these decisions must be made in the absence of known biomarkers to suggest a preferable treatment for each patient. However, there is hope that investigators might soon uncover better data to more precisely target treatment options.

The authors said a number of trials are already underway to explore treatment strategies and combinations. They listed 8 ongoing trials, ranging from phase 1 to phase 3, of treatment options, many of which are still recruiting patients. These trials could hold important insights not only into the best treatment options, but also into how physicians can best balance quality of life, adverse events, and clinical benefit.

“Looking at the present and near future of front-line treatment of BRAF G600E melanoma, there is a kaleidoscope of new opportunities arising for metastatic patients,” the authors concluded.

Yet, the authors said the benefits of those newly available therapies cannot be fully realized without a better understanding of which patients are most likely to benefit from which frontline therapy.

“So far, the combination of immunotherapy and [targeted therapy] has shown some promising effects, but it is paramount to individuate characteristics of patients predicting a better response compared with actual standard of care,” they wrote.

When choosing a first-line treatment in this patient group, the investigators said a one-size-fits-all approach will not work.


Giugliano F, Crimini E, Tarantino P, et al. First line treatment of BRAF mutated advanced melanoma: Does one size fit all?.Cancer Treat Rev. 2021;99:102253. doi:10.1016/j.ctrv.2021.102253

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