Molecular Testing in Stage III Melanoma

Axel Hauschild, MD: Hello. My name is Axel Hauschild. I’m a dermatology-oncologist from the University of Kiel in northern Germany, and it’s my great pleasure to welcome you to the ESMO [European Society of Medical Oncology Congress] wrap-up on melanoma. It’s also my great pleasure to introduce my cochairman, professor Dirk Schadendorf. He is the chief of the department of dermatology at the University of Essen in Germany, which is approximately 400 miles away from my town. Hi, Dirk. How are you?

Dirk Schadendorf, MD: Hi, Axel. Good to see you.

Axel Hauschild, MD: Thank you. We want to discuss in this format for OncLive®, and we have prepared a number of questions regarding the updates from ASCO [American Society of Clinical Oncology Annual Meeting] and ESMO. My first question goes to Dirk on the molecular testing for stage III melanoma. Dirk, what is the importance of BRAF testing in this setting?

Dirk Schadendorf, MD: It’s part of the work-up of a patient. If a patient is entering a treatment decision, BRAF status is known. It’s standard of care now that patients, starting in stage III at the latest, have the information of BRAF status, because that opens an avenue for adjuvant treatment in that setting.

Axel Hauschild, MD: Are you making any decisions of the BRAF mutational status for neoadjuvant settings?

Dirk Schadendorf, MD: That’s a good point. Adjuvant treatment has been improved in Europe and across the globe since 2 years ago. It’s been a standard of care, including dabrafenib and trametinib. In the adjuvant setting it’s stage III disease, but the neoadjuvant setting is still experimental. There is a lot of excitement in the neoadjuvant field, but the most exciting clinical studies in the neoadjuvant field are checkpoint inhibition, a combination of checkpoint inhibitors. In the past there have been also targeted approaches in the neoadjuvant setting in nonoperable disease, but right now the enthusiasm is being mostly focused on nivolumab-ipilimumab in that setting.

Axel Hauschild, MD: We need to say that at least in Germany, it’s not standard of care to use the neoadjuvant drugs at the moment. For the adjuvant setting, we are very happy in Germany that we have dabrafenib and trametinib approved for the BRAF mutations, and for all comers, the PD-1 antibodies, pembrolizumab and nivolumab. And they are reimbursed in Germany, which is a very fortunate situation.

Dirk Schadendorf, MD: If you rephrase—if you’re a little more flexible with the term neoadjuvant—it’s also tumor reduction. And targeted agents are perfect tools if a patient is BRAF mutant, obviously, to try to get a quick and reliable response and trying to reduce tumor mass. In certain circumstances that could also open the way for surgery or other ablative treatment strategy, so if you would define that as neoadjuvant, it’s part also of the community treatment strategies we could apply nowadays.

Axel Hauschild, MD: Thank you very much for clarifying, Dirk. Another question is on the routine testing of PD ligand 1 and 2 mutation burden. Is this belonging to your panel of biomarkers? Would you test them as routine, and how is the situation in Germany in general?

Dirk Schadendorf, MD:PD-1 ligand expression is standard of care in various tumors and disease entities. It’s established usually in the pathology. It’s part of the label, for example, in lung cancer. We also know that the PD-1 ligand status in melanoma is of relevance in timing the prognostic value off checkpoint blockade; however, it’s not part of the label. It’s not required to test, and in most of the centers across the board, not a routine tool to be analyzed as part of the routine work-up to make treatment decisions. Particularly in the academic centers, it’s being frequently used as a research tool for analysis. I don’t know how you do it in your center, Axel. A number of centers are doing that but not making treatment decisions at the final point.

Axel Hauschild, MD: It’s true because the adjuvant trials are not making a difference at the moment for PD ligand 1 high and low expressers, and their efficacy seems to be the same. There is no significant difference. I completely agree with you, and the tumor mutation burden is still even more experimental than PD ligand 1 testing. It’s more far away from being used in the routine, correct? Is it not?

Dirk Schadendorf, MD: Yes. We are hunting for biomarkers or selection criteria for the last 5 or 6 years, with the first success of checkpoint blockade, and PD-1 ligand expression was the first marker. Tumor mutational burden was the next. We also have emerging discussion on, for example, inflammatory gene signatures as another tool of probably. And this entire discussion is fueled by the cancer immunogram put forward by Christian Blank and the Amsterdam group trying to explain which patients are really responding to checkpoint blockade. Actually, if we are trying to dig deeper, for example, also for palliative therapy, we see it’s the same group of patients who show these inflammatory gene signatures who are showing also PD-1 ligand and other factors, which obviously identify a patient group that is particularly sensitive to the new drugs we have available, including targeted drugs, surprisingly.

Transcript Edited for Clarity