Weber Evaluates the Role of Neoadjuvant and Adjuvant Immunotherapy in Melanoma

Jeffrey S. Weber, MD, PhD

The use of immunotherapy has improved the treatment landscape of melanoma, including checkpoint inhibitors like ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda). Combinations with these therapies and other agents are also promising for the treatment of patients with melanoma, but the role of neoadjuvant therapy remains under investigation.

Patients with melanoma undergoing surgery can receive adjuvant therapy, but in an effort to improve the survival and outcomes of these patients, investigators are evaluating the potential role of neoadjuvant therapy prior to surgery. For example, the ongoing phase II SWOG S1801 clinical trial is comparing neoadjuvant pembrolizumab versus adjuvant pembrolizumab in patients with high-risk stage III to IV resectable melanoma (NCT03698019).

In the adjuvant setting, the checkpoint inhibitors appear to prolong survival, particularly among patients with resectable, high-risk disease. However, clinical trials comparing neoadjuvant therapy before surgery with adjuvant therapy to follow-up versus surgery and adjuvant therapy alone are necessary to determine the benefit of neoadjuvant therapy and what patients in particular would do well with less therapy versus more.

In an interview with Targeted Oncology, Jeffrey S. Weber, MD, PhD, deputy director and co-director of the melanoma program, Laura and Isaac Perlmutter Professor of Oncology, Department of Medicine, NYU Langone’s Perlmutter Cancer Center, discussed the role of neoadjuvant and adjuvant therapy for the treatment of patients with melanoma. He also highlighted the role of immunotherapy, as well as other types of therapy, in this treatment landscape.

TARGETED ONCOLOGY: What advances have we seen with immunotherapy in melanoma?

Weber: Immunotherapy for melanoma has a long history, but it has only been in the last 10 years that we have had newly approved checkpoint inhibitors in melanoma that prolong survival in patients with metastatic disease. Over the last couple of years now, it has become obvious that when you use these checkpoint inhibitors, like ipilimumab, pembrolizumab, and nivolumab, as adjuvant therapy in patients with resected high-risk disease, it prolongs survival for those patients. We will get our first survival data on the use of nivolumab as adjuvant therapy probably by the end of this year.

TARGETED ONCOLOGY: What are modern perspectives of adjuvant therapy in melanoma?

Weber: The big controversies are not just adjuvant. I should mention that it is both neoadjuvant and adjuvant. At the [16th Annual International Symposium on Melanoma and Other Cutaneous Malignancies, we debated whether neoadjuvant was superior to adjuvant or vice versa, and it is probably not the right question. It should be whether adjuvant is as good as neoadjuvant therapy and if you need neoadjuvant therapy.

The idea of neoadjuvant therapy is when you have a patient with palpable melanoma nodal disease, and those are stage IIIB, IIC, or even IIID patients at high risk for relapse. Do we give these patients several cycles of ipilimumab or nivolumab prior to trying to have surgery or do you have surgery and give either nivolumab and pembrolizumab or ipilimumab and nivolumab? The idea is that if you give the ipilimumab and nivolumab prior to surgery, the presence of the tumor will somehow allow that immunotherapy to work better. That is a theoretical concern. It is something that probably happens in mouse models. It is not clear overall that you are better off seeing that happen in patients.

The definitive trial would be neoadjuvant therapy, surgery, adjuvant therapy versus just surgery, and adjuvant therapy alone. It is of some interest, as in breast cancer, when you develop a pathologic complete response (pCR) to immunotherapy given as neoadjuvant therapy for melanoma, those patients will probably do well for a long period of time, but it is not that 100% of them aren’t going to relapse. These are only the patients who would probably do well with adjuvant therapy. Neoadjuvant therapy is a hot ticket, but it probably will work to simply select out the patients that you can give less therapy to rather than more. If you do not have a pCR, those is probably the patients who need additional adjuvant therapy.

TARGETED ONCOLOGY: Could you discuss the use of other types of therapy for melanoma?

Weber: I think that targeted therapies will now have to target other molecules. We will be looking at antibody-drug conjugates (ADCs) and adoptive cell therapy, and I think we will hear the initial tumor-infiltrating lymphocyte (TIL) results.

TIL is a field I have been intimately involved in since 1988 when I was a fellow at the National Cancer Institute, and we treated the first TIL patient. The idea of TILs is that it is an adoptive cell therapy where it can be effective in an area of unmet need. The area of unmet need is the patient with BRAF wild-type who has been through ipilimumab and nivolumab, then what do you do? There is no clear-cut established pathway for those patients. If that patient has been through ipilimumab, nivolumab, and a BRAF/MEK inhibitor, then what do you do? TIL is appropriately being developed in a phase II study in this area of unmet need. I think the response rates and duration of response will, I hope, put TIL in a good position to be approved and become a new member of our armamentarium.

There is a space for TIL therapy in these refractory patients. I hope we will be able to see new immunotherapies, new ADCs, and maybe new targeted therapies, all of which I think are immunological in nature anyway. Hopefully, these therapies will again prolong survival even more than we have seen with immunotherapy in melanoma.

TARGETED ONCOLOGY: What is your overall takeaway?

Weber: The overall takeaway is we are doing extraordinarily well with patients with melanoma. We have multiple tools in our toolbox to put patients into remission and that adjuvant and neoadjuvant therapy will make things even better, but by no means have we resolved the melanoma problem. Approximately half of the melanoma patients who are treated with frontline therapy are going to need other therapy, so it is not as if we have found the cure for all patients who have metastatic melanoma. Of those who are treated with adjuvant or neoadjuvant therapy, approximately a third of them will still relapse and will need further treatment. The main message is we have good news, but we haven’t resolved this problem yet.