Neoadjuvant Strategies in Melanoma

Transcript:Keith T. Flaherty, MD: Before we move fully over the fence into unresectable metastatic disease, where there’s a lot of discussion to have, Jonathan, there’s been a lot of chatter in the academic community in the melanoma field regarding the neoadjuvant concept. For doctors in the community, this is not breast cancer, right? So, true neoadjuvant therapy, with a primary tumor in place, is not the idea. It’s typically more for patients with bulky nodal disease, and so on.

I would, at least for today’s discussion, not use the term neoadjuvant, but maybe use presurgical therapy. I know your group’s been very active on that topic, both in research and, to some degree, in clinical practice. I’d love to hear your thoughts on BRAF inhibitor—based therapy, immune checkpoint inhibitors, T-VEC, in that population. You have a patient in front of you who you think surgery is possible, but you feel as though you might be able to minimize morbidity of surgery with an up-front presurgical approach. Walk us through how you think about that.

Jonathan S. Zager, MD: If you’re borderline resectable, or maybe unresectable but we think we can get you to that point, usually we first assess for a BRAF mutation. And I think that’s our agent of choice at that time because it has its quickest onset of action, BRAF plus or minus MEK, to get you to the resectable stage. If the patient is not BRAF-mutated, then we usually go on to an immunotherapy, for the same principles, to try to get them to a resectable stage. All the tumor doesn’t have to go away; it just has to make surgery easier for the surgeon and for the patient. Again, thinking about the functional and cosmetic defects that we’re going to make.

And then as far as T-VEC is concerned, there’s a current clinical trial using neoadjuvant T-VEC followed by surgery, versus surgery alone, and we’re currently participating within that trial at Moffitt, as well. T-VEC I’ve been using for a lot of patients with stage 3b, 3c, particularly the patients who don’t want to go on systemic therapy, their BRAF wild-type, that may not want the possible toxicity of immunotherapy. It’s very well tolerated, it’s very easily given. And about one-third of the patients are doing quite well on it and with a good response, and it really doesn’t burn any bridges. So, if it doesn’t work, we can go ahead and start giving the heavier hitters, the systemic immunotherapies. And I think that’s part of the theme here that you’re talking about. Why use adjuvant therapy in some cases when we have good therapies if the patient does recur with system disease? I think a lot of the thought process is, if it doesn’t burn any bridges, we still have plenty of powerful therapies in the future—but it’s helping some patients.

Keith T. Flaherty, MD: And what kind of time window are you talking about? So, in terms of duration of exposure for T-VEC or BRAF inhibitor—based therapy, what number of weeks or months are you aiming for?

Jonathan S. Zager, MD: For the systemic BRAF and immunotherapy in a presurgical setting, we look at 4 to 6 months of therapy and then bring them to surgery. For T-VEC, the average length of T-VEC time to response is about 4 months. If they’re not responding by about 4 to 6 months, then that’s probably not the appropriate therapy for them. And it’s not uncommon, just like with some of the immunotherapies, to see a disease burden grow while on therapy for the first couple of rounds of T-VEC. Georgina, you know this, as well, from some of your trials that they presented yesterday in the poster—that some of this disease can grow and then will eventually respond.

Jason J. Luke, MD: And that’s really an important clinical point if you’re taking care of a patient, especially because I find in my practice the patients who actually have the most difficult psychological/emotional component to their disease is if they can see the cancer. If they have cancer all through their body but they can’t see it, it’s less stressful than if it’s a mass here. So, if you’re treating a patient and it’s still getting bigger, you need to really counsel them that we understand and that this is part of the process, because that’s where you can really start to lose people.

Jonathan S. Zager, MD: I tell them that up front. I say, “This might get worse before it starts to get better,” especially if we’re doing an immunotherapy neoadjuvant approach or T-VEC.

Transcript Edited for Clarity