The landscape of advanced melanoma treatment has witnessed a remarkable transformation with the introduction of targeted therapies and immunotherapies. While immunotherapy has shown great promise in various cancer types, there exist specific scenarios where targeted therapy can outshine immunotherapy. In this article, we delve into the situations where targeted therapy may be the preferred choice for advanced melanoma patients, while also examining the comparative efficacy and potential side effects of these treatment approaches.
Q1: Thank you. And our first question is about based on your extensive research, could you provide some insights on when targeted therapy might outperform immunotherapy in patients with advanced melanoma?
A: It’s a very good question and it’s a tough question because there’s randomized data that suggests that patients do better if they start with immunotherapy than targeted therapy and patients with BRAF mutant melanoma.
However, there are some scenarios where it’s either not practical to start immunotherapy or not possible. One of those scenarios are patients who are on very high dose steroids that commonly will happen in the setting of patients who have substantial brain metastases upon presentation.
The problem with steroids is they’ll make, particularly at high doses, they’ll make the immunotherapy less likely to work. And so in those patients, starting targeted therapy is absolutely going to be better than trying to start immunotherapy.
Another setting where we begin to think about targeted therapy over immunotherapy are patients who have very severe autoimmune disease that’s not well controlled with ongoing immune suppression or who have bad autoimmune disease and are on lots of immune suppression again because immune suppression can make the immunotherapy less likely to work.
If that patient has a BRAF mutation, we might think about starting them on BRAF targeted therapy.
A third scenario is quite similar to that scenario, but instead of autoimmune conditions, it’s actually a solid tumor transplantation.
And in patients who have solid tumor transplantation, they’re on lots of immune suppression and giving immunotherapy not only may not work as well because of the immune suppression, but it also may put the transplant graft at risk. And so, again, if a patient has a trigger, a reaction against their transplant graft, that patient may reject their graft. If that’s a kidney, that’s not great, but they can at least go on dialysis and survive.
If it’s their liver or their heart or their lungs, those patients are very likely to die as a result of the rejection of the graft. So, again, the three scenarios, patients who are in very high doses of steroids in the setting of brain metastases, we tend to use BRAF targeted therapy over immunotherapy if they have a BRAF mutation, patients who are on lots of immune suppression or have uncontrolled autoimmune disease, we tend to offer BRAF targeted therapy over immunotherapy if they have a BRAF mutation and then patients who have a transplant, a solid tumor transplant for fear of one rejection and two concern that the immunotherapy may be less effective in the setting of the immune suppression we tend to favor BRAF target therapy over immunotherapy. When the targeted therapies are more expected, we choose.
Q2: In your studies, you’ve explored the development of novel molecular therapeutic agents for malignant melanoma. How do these targeted therapies compare to immunotherapies in terms of efficacy and potential side effects?
A: Yeah, so they’re very different from a side -effect standpoint. So immune therapy, actually I’ll start with targeted therapy, targeted therapy is very much like any other drug that we tend to think about humans taking.
The drug gets in the system at a high enough level, it causes effects both good and bad. The side effects from drugs tend to continue if you continue the drug. If you stop the drug, the side effects get better within a predictable amount of time as the drug exposure is reducing.
And then you can resume therapy at a lower dose or sometimes you have to stop therapy if the side effect was severe enough. The types of side effects we see also are different, so that’s one the quality of the side effects.
The types of side effects with targeted therapy are much more of the common side effects of sort of toxic agents like they cause stomach upset or diarrhea. They commonly cause rash, tiredness, fatigue, most of these are pills so they can also cause alterations of taste.
That’s the general side effect profile, they’re much more predictable in terms of when the side effects will start and when they’ll go away when you stop the drug and then how likely are to lower the dose and come in with a dose reduction.
With regards to immune therapy, those side effects tend to happen whenever they happen, meaning it’s not quite, they always happen three hours after you take the dose, no. It’s like the cause of the side effects is a reaction that the drugs are having on the T cell, which is the actual drug of our immune therapies.
So whenever those T cells get activated and then released by the relieving of the checkpoints that are placed upon them, that’s when the side effects kick in. So it’s a little less predictable than, say, chemotherapy, where we can know by the minute almost how a patient’s going to feel once they get dose of chemotherapy.
So they happen a little bit, it’s a little seemingly more random when they happen. The side effects are inflammatory in nature, meaning that they occur as a result of immune cells getting into and interacting with the patient.
in a negative way to a tissue. The other issue about that, however, is if you stop the drug, the cells are still there and they’re still activated. The immune system tends to have this feed -forward or positive feedback loop.
So you get inflammation, which gets more inflammation, which gets more inflammation. And so stopping the drug isn’t enough to have the side effect go away. And so very commonly we have to give immune suppression to treat the side effect.
And then deal with that as its own issue with tapering the steroids or whatever immune suppression we end up using. So targeted therapy, much more predictable, much more like most of the drugs we give to patients get better when you stop the drug.
And you tend to be able to come back in with dose reductions if necessary. Immunotherapy, they tend to be a little bit less predictable in terms of timing. They tend to require, if they’re severe enough, immune suppression.
And they also are more likely to be permanent than, say, a targeted therapy toxicity.
