Will Immunotherapy or Targeted Therapy Take the Lead in Melanoma?

Michael Atkins, MD

With immunotherapies showing significant promise in melanoma in both frontline and adjuvant settings, the role for targeted therapies has become less clear, says Michael Atkins, MD, deputy director and professor at Lombardi Comprehensive Cancer Center, Georgetown University.

Numerous questions remain. Should BRAF-mutant patients receive targeted agents or immunotherapies first? What is the ideal adjuvant treatment option? What role will immunotherapy combinations or targeted therapy/immunotherapy combinations play?

Clinical trials, including the EA6134 trial, lead by Atkins, are attempting to answer these questions and more. The ongoing, randomized phase III EA6134 trial is investigating dabrafenib (Tafinlar) and trametinib (Mekinist) followed by ipilimumab (Yervoy) and nivolumab (Opdivo) compared with ipilimumab and nivolumab followed by dabrafenib and trametinib in patients with stage III/IV BRAF V600 melanoma.

OncLive: How do immunotherapy and targeted therapy compare as frontline treatment for metastatic disease?

In an interview with OncLive, Atkins discusses his views on the potential of immunotherapy versus targeted therapy in melanoma, what research has shown so far, and what could be on horizon for both classes of drugs going forward.Atkins: Immunotherapy accomplishes what the patients want, which is an agent that produces complete responses, so they can stop the treatment and their response is maintained. They want treatment-free survival. You don’t see that with targeted therapy, except in a rare patient population.

With targeted therapies, patients basically have to stay on the drugs forever and, at some point, they stop working. If we want to get a patient to a situation where they are cured and back to their normal life, immunotherapy is probably the best way to do that.

There is some data to suggest, at least with ipilimumab and single-agent anti—PD-1 therapies, that they don’t work as well in patients who have progressed after a BRAF inhibitor as they do in treatment-naïve patients. By giving a BRAF inhibitor first, oncologists may be compromising their patients’ ability to get a complete response.

On the other hand, to balance it out, I think that the combination of nivolumab plus ipilimumab is active enough that it probably works just as well in patients who have progressed after a BRAF inhibitor, particularly if the BRAF inhibitor has reduced the tumor and put the patient into a better state. If the therapy has stopped and the immunotherapy is then given, it may give a good, if not a better, result in that setting.

Are there patients who may benefit more from immunotherapy versus targeted therapies?

In the context of combination immunotherapy, it may not be as critical to start with immunotherapy instead of a BRAF inhibitor. That is particularly true in patients who are sick in the hospital, symptomatic from their disease, and need something that is going to work immediately. You may not be able to start the immunotherapy in that setting and be as confident that the patient will get better.We don’t know. We are going to address that in our cooperative group trial, which will compare BRAF inhibitor therapy upfront followed by combination immunotherapy versus the converse sequence. Hopefully, we will have enough patients enrolled in that trial that we will be able to sort out which patients do better with which approach.

I have my own feelings about this. Clearly, there are some patients who would not be eligible for that trial because they are too sick; those patients should probably receive BRAF inhibitors first.

However, for patients who fall into the eligibility of that trial, meaning performance status 0 to 1 and LDH levels less than 10 times the upper limit of normal, it is an open question that should be answered in the trial.

What role do you envision for immunotherapy in the adjuvant setting?

What adjuvant treatment options are currently available for patients with melanoma?

There will also be opportunities to sort that out by looking at the tumors of the patient population that can get either therapy in the trial. By looking at mutational profiles and immune response profiles in the tumor microenvironment, we are going to try and tease out, beyond clinical grounds, which patients should get which therapies.There are 5 trials that we are waiting on information from: 2 ipilimumab trials and 3 anti—PD-1 trials. When we have all those trial results, which we should hopefully have by 2020, we should be able to have a rational discussion about a good adjuvant therapy. If the anti–PD-1 agents are as good in the adjuvant setting as we anticipate they will be, it is likely that those will become the adjuvant treatments of choice.There is no real optimal adjuvant therapy, at this point. There is no treatment that is without controversy and achieves what we want, which is efficacy in terms of not only progression-free or relapse-free survival, but also overall survival. It also needs to have an acceptable toxicity level that one would feel comfortable giving to patients who would most likely already be cured of their disease by surgery.