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Expert Addresses Sequencing and Resistance With Immunotherapy in Melanoma

Laura Panjwani
Published: Thursday, Jun 09, 2016

Keith Flaherty, MD

Keith Flaherty, MD

Choosing between immunotherapy and targeted therapy in the frontline setting for patients with BRAF-mutated melanoma does not have to be a guessing game, according to Keith T. Flaherty, MD.

“Because we don’t do any testing of PD-L1 or anything else right now, selecting the best frontline treatment can feel like a coin toss,” says Flaherty, director of Developmental Therapeutics at the Cancer Center of Massachusetts General Hospital. “However, we almost have the evidence in front of us—even with PD-L1 alone—to say that it doesn’t have to be a coin toss. “We can actually inform that discussion in a pretty compelling fashion.”

Flaherty is one of several contributors to “The State of Melanoma: Challenges and Opportunities,” a paper published in Pigment Cell & Melanoma Research by the Melanoma Research Foundation.

The paper outlines some of the biggest challenges in melanoma, as well as opportunities for improvement across the treatment landscape.

The first step to making those improvements is to translate the science into clinical practice, says Flaherty, by properly sequencing immunotherapies and targeted therapies, especially in BRAF-mutant patients. Additional steps include investigating the value of PD-L1 testing and the causes of immunotherapy resistance. In an interview with OncLive, Flaherty discusses these and other topics regarding immunotherapy in melanoma.

OncLive: For metastatic BRAF-positive patients, what factors are considered in determining whether they should receive immunotherapy or targeted therapy in the first-line setting?

Flaherty: We don’t have any exact science for how to choose between targeted therapy and immunotherapy and, even in the immunotherapy space, we are still not in the position to triage patients between single-agent and combination immunotherapy.

We are still in an environment where people consider things as simple as disease burden, the pace and amount of metastatic disease, and the presence of symptoms as factors in deciding between immunotherapy and targeted therapy. These are factors that, as disease aggressiveness and disease burden increases, the balance is tipped toward targeted therapy for BRAF-mutated disease.

This is attractive because there is very high confidence that, with targeted therapies, you are going to get short-term disease control and symptom improvement and calm the situation down. However, with immunotherapy—and even combination immunotherapy—that confidence is notably less.

Those types of comparative statements are a little bit dangerous, because we have not actually had a head-to-head comparative trial; however, we have comparative data sets. We can look at multiple large clinical trials and try to determine how patients with high-disease burden do on this therapy versus how did they do on another therapy in another trial, and use that to help make decisions.

There is an obviousness of that statement that it has, in some way, almost led to conclusions by some that targeted therapies are for patients with high-disease burden and immunotherapies are for patients with low-disease burden. That is a ridiculous conclusion to come to. I say that because, if you look at the data on all of our therapies, they all work better in low-disease burden patients than they do in high-disease burden patients.

That is true for targeted therapies and for immunotherapies. I would argue that the issue about choosing between the 2 is most pressing in patients with low-disease burden, because that is the group that has the greatest likelihood of long-term benefit, whether they receive targeted therapy or immunotherapy.

We are very poor right now, in terms of translating science into clinical practice to make a treatment selection. Many people who lack real insight into how to do it, just say, “OK, well I am going to start with immunotherapy first. Then, if patients fail the immunotherapy, I will move to targeted therapy.”

That might sound good, but the problem is that—for all of our therapies—if you hold them until a later-line setting, they won’t work as well. Therefore, the likelihood that someone is going to get a durable benefit is going to be lower. To put a patient through a course or 2 of ineffective treatment and then finally put them on a treatment that they are going to respond to in third-line, their likelihood of responding is less.

Could PD-L1 or other molecular testing help oncologists decide between targeted therapies and immunotherapies?

When you focus on PD-1/PD-L1 antibodies specifically, there is no question that PD-L1 expression on tumor cells themselves actually gives you a good bit of information. It is just a good bit of information that we are currently ignoring.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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