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Immunotherapy Combinations Coming to the Forefront in Melanoma

Laura Panjwani
Published: Thursday, Apr 07, 2016

Jason J. Luke, MD, FACP

Jason J. Luke, MD, FACP

PD-1/PD-L1 should be the backbone of melanoma treatment for many patients, says Jason Luke, MD, an assistant professor of Medicine at the University of Chicago Medicine.

“PD-1/PD-L1 inhibition has now become the foundation of therapy in melanoma and, eventually, it will likely be in all of cancer," he says. "Adding PD-1 to almost anything is likely to make it better.”

Luke believes that, in the near future, most patients will receive immunotherapy combination regimens. However, he adds that a lot of questions need to be answered first.

In an interview with OncLive, Luke explains that, in order for immunotherapy combinations to make it to prime time, T-cell inflammation will need to be more considered when selecting treatments.

He also discusses why adjustments to the FDA approved immunotherapy combination of ipilimumab (Yervoy) and nivolumab (Opdivo) are needed, and why finding a tolerable and effective BRAF-targeted/immunotherapy combination is challenging—but significant.

OncLive: How often are you utilizing ipilimumab/nivolumab?

Luke: First, I think it is really important to point out that the only survival data we have right now is for PD-1 monotherapy. We do not have survival data for any combinations yet.

In clinical practice, I like to start with PD-1 monotherapy, because I think the toxicity profile of the combination is problematic. That being said, there are situations where I think that it is justified to risk a higher side-effect profile in order to get more benefit.

One example of a situation where I would consider using the combination includes a younger patient with widespread metastatic disease who just wants the maximum treatment.

Also, I would consider it for a patient who has brain metastases where I am concerned that, if we don’t get a response fast, we will lose the potential to give immunotherapy completely.

A third example is when a patient presents with bone-predominant disease. Anecdotally, I think PD-1 monotherapy, in those patients, is less effective so I would be more inclined to give the combination.

I tend to lean toward using the combination less, except for those patients who I would deem “high risk” by clinical factors.

In melanoma, we give a full dose of ipilimumab with a lower dose of nivolumab. That causes some good effects, but it also causes a lot of side effects. The question is, “If we used a lower dose of ipilimumab and a higher dose of nivolumab, could we get the same benefit without all of the limiting side effects?”

They are doing this in lung cancer, kidney cancer, and other tumor types; they are using the same 2 agents with different doses. Merck has done a clinical trial of pembrolizumab (Keytruda) with ipilimumab, but they used a low dose of ipilimumab. Their data actually looked really good.

I am going to launch a clinical trial in which we are going to treat patients who received PD-1 as a single agent who progress with the combination of pembrolizumab plus ipilimumab at a low dose. We want to determine if the combination is just as good in second-line as first-line, because then we can avoid exposing the patients to the side effects until we know that they need them.

Will the use of immunotherapy combinations become more commonplace in the near future? What is on the horizon?

The future will include combinations with a PD-1 agent as a backbone for all patients. I see combinations splitting into 2 camps.

PD-1 is not a great marker to tell us about the underlying biology of a tumor. Basically, we need to know if immune cells have gotten into the cancer or not. We call this either a T-cell inflamed tumor or a non–T-cell inflamed tumor. The inflamed tumors are usually PD-L1–positive, where PD-1 monotherapy works really well. That is the space where we should think about combinations that go after other inflammatory markers, such as IDO inhibitors, or other immune checkpoints on T cells such as LAG-3 or TIM-3.

On the other hand, there are patients with non–T-cell inflamed tumors, which are going to be PD-L1–negative. These are tumors that don’t have any T cells in the tumor yet. If you give PD-1, it will not work because of the lack of T cells. Therefore, we need to do something to make the T-cells go there. That is where the ipilimumab (Yervoy) and nivolumab (Opdivo) combinations have some activity.

We know that CTLA-4 agents, such as ipilimumab, can actually make some of the immune cells go to the tumor. We could also use oncolytic viruses, including talimogene laherparepvec (T-VEC; Imlygic), plus PD-1. This might work well because the virus infecting the tumor cell can actually induce the T cells. There are other combinations that we could do to induce T cells, including giving a BRAF inhibitor with PD-1 or radiation with PD-1.




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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
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