Continuing Melanoma Research: Why, How, What?

This transcript has been edited for clarity. 

Hello, everybody. It’s a pleasure for me to be here today and to have the chance to collaborate with Medscape in this quite interesting series about melanoma. For this first video, I want to introduce myself and let you know a little bit about my passion for melanoma investigation, and also why this is important to continue speaking about in the next couple of years. 

You can see my background in this slide and also my contact information. Feel free to contact me after this talk if you have any questions or any aspects that you would like to learn a little bit more in detail. These are my disclosures.

Before I start to talk a little bit about clinical data and clinical science, I would like to share with you this concept that is called the golden circle. Basically, it says that if you want to make a difference, but on the other side, if you want to keep yourself motivated in the long run, your most important question is your “why.”

Why are you doing whatever you want to do — clinical investigation, another type of research, clinical activity, and so on? Once you answer this question, then you can answer the questions on how and what in an easier way, but also in a way that keeps you motivated in the long run. Wherever you are in terms of your career, this is something that you probably would like to do for a long time.

If you have any doubts about what you are doing and if you are doing it correctly, then you just need to go back to your why question. I find this quite supportive from a clinical perspective and also from an investigator’s perspective because sometimes we lose sight of what we are doing. If we remember our why, then it’s easier to go back. 

To start, why are we discussing skin cancers, but mostly melanoma? The reason is that, despite some awareness that is available and is known about skin cancers and also the risk factors associated with melanoma and skin melanoma, the reality is that, indeed, the number of new cases of melanoma that will be diagnosed will continue to increase. 

This is a work that we published a couple of years ago that shows exactly this —that the number of new cases will continue to rise. It is true that the majority of them will be diagnosed in an early setting and mostly treated with surgery, but some of them will, at some time, require some systemic therapy or some other therapy besides the initial surgical therapy. 

For the “how” question, I think those who never read The Emperor of All Maladies: A Biography of Cancer should try to buy it and read it because it puts into perspective the way that clinical investigation or investigation in cancer has been done in the past century and how things evolved in the way that we see it now.

If you’ve read it before, remember that there was a mention of the backbone of chemotherapy that was given for pretty much all solid tumors. Then it was adding some therapies, whatever those therapies were, to this backbone of chemotherapy. 

My impression nowadays is that we have this programmed cell death protein 1 (PD-1) backbone therapy that we are using pretty much in all the settings and in almost all tumor types. Then we are adding to this PD-1 backbone therapy in the hope that we are producing better outcomes for our patients. In some cases, this is true. In other cases, we are adding toxicity similar to the backbone of chemotherapy that we had before. 

I think it’s also important that we think a little bit outside of the box and what we can offer to our patients besides this chemotherapy or beside the PD-1 backbone that we have now and the way that we combine it. 

The question of “what” is clear for melanoma, and the “what” is the number of therapies that we have been producing or that have become available in the past, I would say, 20 years. These go by immunotherapy — immune checkpoint–based therapy — but also targeted therapy.

During my next videos, we will look into more detail about these two therapies and what we can offer to these patients in different settings. 

Starting with immune checkpoint inhibitors, the investigations and the outcomes in identifying and also being able to use immune checkpoint as a therapy for solid tumors, particularly for melanoma, led to two of the investigators receiving the Nobel Prize. 

This is one of the first papers that was published about the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) immune checkpoint inhibitor that we use pretty much every day in our clinics for patients with stage IV melanoma. The paper was published in 2003, so more than 20 years ago. It was a phase 1 study, first in humans, with the primary endpoint of safety. 

When we look at safety nowadays, we are knowledgeable about the type of immune-mediated adverse events that patients can have when they receive this therapy, but at the time this was published, these new adverse events were completely different from the adverse events that we were used to when we treated the patients with chemotherapy. I can imagine that it was not easy to convince people to invest in such a trial that had such different adverse events and in some cases severe adverse events.

Think about whether you would fund a phase 2/phase 3 trial using this molecule. I would say that, with these data, the majority of us would say that they would not fund these kinds of trials, which would all be wrong, as you know by now, because these are the outcomes of melanoma-specific survival using PD-1 and CTLA-4 as monotherapy or in combination.

We have now 10 years of melanoma-specific survival data showing the fantastic difference between what we had before in terms of survival outcomes and what we have now because these two therapies are available, not just for melanoma but for other solid tumors as well.

For targeted therapy, these are impressive images that were published almost two decades ago as well, the first time that the BRAF inhibitor was used in patients that had a BRAF-mutated tumor. You can see that the effect is quite fast. The patients respond very fast, but we also see a recurrence that comes fast after starting therapy, especially monotherapy.

Later on, we were able to identify other parts of the mitogen-activated protein (MAP) kinase pathway that could be inhibited. Now, we use mostly targeted therapy as a combined therapy. We also have data for almost 7 years of survival from patients treated with targeted therapy and patients who have melanoma.

Although in the beginning, we had a very brief overview or selection of what exactly these types of therapies can provide to our patients, the reality is that if we keep ourselves true to our “why,” it might be that, in the near future, we can actually provide such outcomes for our patients if we continue to ask the right questions and keep on the right path. 

I’m looking forward to continuing to have these discussions with you in the future. Thank you very much.