Changing Course in Treating Advanced Melanoma

Surgery has long been the first course of action in treating advanced melanoma, but recent study findings have turned this approach on its head. Two landmark studies demonstrated that in many cases immunotherapy works remarkably better when administered prior to surgery. These findings are already changing clinical care, particularly in large comprehensive cancer centers like Cleveland Clinic where medical oncologists and surgical oncologists work in partnership.

An intact tumor has more resident tumor infiltrating lymphocytes that can be activated with checkpoint inhibitor therapy. These lymphocytes have the ability to not only attack the primary tumor but also to go after microscopic cancer cells circulating elsewhere in the body.

“We now know that these medications work better in the presence of the existing tumor,” says Cleveland Clinic surgeon Anthony Tufaro, MD. “Heretofore, we thought that we could resect the tumor and then send the patient for adjuvant therapy, but we now see that patients with large tumors, and even metastatic disease, have had a marked response after two rounds of neoadjuvant therapy. So, when we do get them to surgery, there's no viable tumor in the lymph node and even the primary site has markedly improved. That upends the paradigm that surgery is always the first choice.”

Study findings

In two large randomized trials (S1801 and NADINA), neoadjuvant immunotherapy improved outcomes compared to adjuvant immunotherapy, with roughly 50% better event-free survival in patients with stage 3 and 4 melanoma. This research was based on preliminary lab work positing that immunotherapy works better before surgery by activating immune T-cells associated with the tumor, thereby generating memory T-cells that remember a tumor and keep it in check.

“The treatments for melanoma work by re-activating the immune system in the body,” says James M. Isaacs, MD, a hematologist/oncologist at Cleveland Clinic Cancer Institute. “If the tumor is still present at the time the treatment is starting, the immune cells ‘see’ more of the cancer cells. This allows the most potent anti-tumor immune cells to expand and attack the tumor. We also see that these immune cells can remain active in the body for many years, preventing the tumors from recurring.”

The studies demonstrated that when immune therapy treatment was given before surgery, there was a high rate of treatment response. In many cases, the tumor was completely gone at the time of surgical resection. This also translated to better long-term outcomes, with patients who had neoadjuvant therapy having a lower rate of recurrence of melanoma several years later.

Changing clinical care

There is now 10-year data showing that patients with metastatic melanoma who receive immune therapy can achieve durable responses to immune therapy. The hope is to now expand those benefits to patients with earlier stages of melanoma. When immune therapy is given prior to surgery this appears to maximize the long-term benefit of this therapy.

"Every patient understandably wants to have their tumor removed immediately but the reality is, especially with neoadjuvant approaches for immunotherapy, leaving the tumor intact may actually have a long-term benefit," says Cleveland Clinic general surgeon Joseph Skitzki, MD, who worked on several NADINA-related surgical studies. “Immunotherapy also does not seem to interfere with surgical resection. There are no inflammatory or fibrotic reactions, which could impede resection.”

"As surgical oncologists, the most you could hope for was control of local regional disease,” says Dr. Tufaro. “With this new approach, we’re seeing some patients [treated with immunotherapy before surgery] have pathology reports showing no viable tumor in the lymph nodes. That’s a dramatic turn of events.”

Reducing surgical morbidity

There are now trials investigating whether it’s possible to de-escalate surgery after immunotherapy and maintain the same efficacy. “De-escalating surgery – particularly in the liver or lung – is preferable to having a larger visceral resection,” says Dr. Skitzki. “Even in lymph node areas, we could look at removing only the index node if the patient has had a major pathological response. That’s a much less debilitating surgery and decreases the risk of lymphedema.”

Considering neoadjuvant therapy in earlier disease stages

Clinicians are considering the risks and benefits of using neoadjuvant immunotherapy for earlier stages of disease. “We need to consider the risk of recurrence balanced with the risk of toxicity in patients who may or may not necessarily have needed to be exposed to immunotherapy,” says Dr. Skitzki.

“While immunotherapy is fantastic in terms of the side effect profile compared to older chemotherapy treatments, there are some toxicities that can be life altering. Even though they occur in a minority of patients, that's something that needs to be considered when we start taking it to earlier stage disease.”

Currently, Cleveland Clinic researchers are conducting a study of new combination immune therapies as well as neoadjuvant treatment. There is also great interest in studying neoadjuvant immunotherapy for the treatment of multiple types of solid tumors.

Moving forward

Typically when someone is diagnosed with melanoma, they're referred to a local surgeon. However, it’s important for surgeons to know that there are other options, and that the tumor doesn’t necessarily need to be removed immediately. For advanced melanomas, a referral to a center well versed in neoadjuvant approaches would be in the best interest of the patient.

"When patients feel a palpable mass, it's disconcerting and the traditional thinking is to remove it,” says Dr. Tufaro. “With careful counseling and sharing of study data, patients understand how neoadjuvant immunotherapy can result in more favorable outcomes.”

“Neoadjuvant therapy is a major advance in the treatment of melanoma,” says Dr. Isaacs. “It is remarkable that a small change — giving the treatment before surgery rather than only after surgery — has such a large impact. In the future, we aim to develop even more effective therapies. Ideally, therapy will also become more personalized as to which patients should receive certain combinations of treatments.”