Treatment Goals and Patient Decisions in Melanoma

Axel Hauschild, MD, PhD: Dirk, you were one of the coauthors for the cure-rate model paper, which has been released in the Journal of Clinical Oncology. There is a report on a 17% improvement of cure. Are you touching the “C” word with your patients if you treat in the adjuvant setting? Is your goal to cure the patient, or just to prolong the relapse-free survival? This is a major difference in the discussions with patients.

Dirk Schadendorf, MD: That’s an interesting point, Axel, because when I’m giving presentations on adjuvant therapy, I always like to start in my introduction and discuss this with my audience of colleagues: “What is the treatment goal I want to reach?” This is so that I’m clear, and when I’m clear, I’m able to talk to my patient.

The treatment goal might be quite different if I’m talking to a person who is, let’s say 35 years old, or a patient who is 75. I think that, if I’m able to control the disease for 10 years in the patient who is 75, the patient might die from other disease without having a relapse, and that is often fine for them and their family.

If the patient is 35, and I’m gaining 10 years, that’s also a good result, but it’s obviously not sufficient because I want to have more. I want to have control for decades in order to achieve a cure.

I think about aggressiveness and willingness to accept toxicity, and what you want to achieve might be quite different in terms of age as well as comorbidities, preferences, and characteristics the patient might have.

Axel Hauschild, MD, PhD: This leads us to the next important question: the selection criteria. If you have a BRAF-mutated patient, let’s say it’s 60-year-old male, and you have the choice of a BRAF-directed treated with dabrafenib/trametinib, or you can give one of the 2 PD-1 antibodies that are approved in this setting. What would you recommend to the 60-year-old patient without significant comorbidities?

Dirk Schadendorf, MD: It’s very much dependent on additional tumor characteristics, for example. Would the patient fall into the IIIA category more, or according to the new specifications, would the patient fall more into the IIIC or IIID categories, which gives us a certain likelihood on the chances that this patient will relapse and how quickly this relapse would occur.

In patients who are more in stage IIIC or IIID, I would definitely have a tendency to use and recommend targeted therapy. In stage IIIA, the patient has more options. 

That’s one thing in terms of tumor control while on treatment, but there are other options that are playing into this discussion. This is the adverse effect profile of the drugs. We have learned that in the COMBI-AD study, the discontinuation rate was quite high for dabrafenib/trametinib, 25%, which is surprisingly high. We see the algorithms and the discontinuation rates in the metastatic setting, which is roughly 50% of that.

With the results now of the high clinical efficacy and the good management algorithms for using dabrafenib/trametinib in our setting, the patient is experiencing these adverse effects, but it’s manageable. It’s usually pyrexia, which you can easily control by pausing for a day or two, and you can educate your patient on that. Most of the adverse effects with targeted therapy are reversible, and that’s one of the messages one has to give to the patient. 

That’s slightly different with a checkpoint blockade. The toxicity profile, the acute toxicity, is usually much safer. This is also reflected by the discontinuation rate, which is in the range between 10% and 15% for checkpoint blockade. On the other hand, there are some rare adverse effects that are irreversible, and odds are that these could have a strong effect on the patient’s quality of life, and these include endocrine toxicities, including rare cases of diabetes, autoimmune and neurological complications, and impacts on cardiac functionalities.

Here again, we are back to young patients, old patients, and patients with comorbidities. If you consider treating a patient who is in their 30s, and you are creating these irreversible adverse effects, then that’s a problem. And I think there’s another argument. 

If you look at the studies, particularly the placebo-controlled studies like COMBI-AD and KEYNOTE-054, these are perfect examples, now that we have the long-term follow-up of these clinical trials. We see that even in stage III, roughly one-third of the patients would not need adjuvant treatment at all. After 5 years, there is no relapse, so surgery would be sufficient. But we are not able to identify these patients early enough, so we are overtreating at least one-third of the patients. 

If we would induce toxicity in these patients that is irreversible, that’s very difficult to justify. You have to have a risk-benefit discussion with the patient on that.

Axel Hauschild, MD, PhD: Dirk, we need to discuss this another time because gene expression profiling of primary tumors could eventually lead to the selection of good and less-good patients, and there are other markers under discussion, but all of this is experimental at this point. 

Transcript Edited for Clarity