By Kim Margolin, M.D.

In this chapter of “In Plain English,” we will describe the concept of neo-adjuvant therapy.

Certain terms are used to describe the order of therapies given to cancer patients. In the context of melanoma, neo-adjuvant means treatment that is given prior to surgery, and adjuvant means treatment that is given after surgery. In both neo-adjuvant and adjuvant therapy, the treatments are systemic, which means the treatments are able to travel throughout the body to reach all potential sites of tumor. In melanoma, we use the terms adjuvant and neo-adjuvant primarily in Stage III disease. Traditionally, Stage III melanoma has been treated with adjuvant therapy: After finding cancerous lymph node(s), surgery is performed to remove those node(s), and then a systemic treatment is used to attempt to kill any tumor cells that may remain in the body. But researchers are wondering if neo-adjuvant treatment might be a better approach. With neo-adjuvant therapy, after finding cancerous lymph node(s), the patient would be treated with systemic therapy in an attempt to shrink or eliminate the existing tumor, and then surgery would be performed to remove all known/remaining tumor.

What are the limitations of the way adjuvant therapy is currently given to patients with melanoma in the lymph nodes after surgical removal of the involved lymph nodes?

• All patients get extensive surgery, consisting of removal of a large number of lymph nodes in addition to the clinically-enlarged node
• All patients get a full year of postoperative systemic therapy unless they develop excessive toxicity or relapse during the year of treatment
• There is very little information currently available regarding which patients will benefit and, importantly, which patients will NOT benefit from traditional adjuvant therapy
• For patients with melanoma carrying a BRAF mutation, it is not clear whether to use BRAF-targeting drugs (given orally) or immunotherapy drugs (given intravenously) for the best outcomes with the least amount of toxicity
• Most importantly, none of these treatments is good enough at reducing the chance of relapse (return of the melanoma in either the nearby tissues or in other organs) or the chance of death from recurrent melanoma, as they still leave around 40% of patients to relapse and die from this disease at some point following their treatment.

Neo-adjuvant therapy—again, treatment that is given prior to surgery—addresses many of the limitations listed above. Giving treatment prior to surgery can also help us to further improve our understanding of the way drugs work and the characteristics of each patient and tumor that might allow better outcomes of treatment and reduce their toxicities and risks.

What are the additional reasons for studying neoadjuvant treatment?

When the tumor (again, usually referring to the lymph nodes containing melanoma, at a size that is removable by surgery) has been surgically removed, only microscopic traces of tumor or even single cancer cells can remain, but the immune system may not be able to recognize those cells as foreign and therefore won’t fight to destroy them.   However, when the palpable (big enough to feel) tumor has not yet been removed, it may provide many more foreign cells to be recognized by the immune system, which may trigger an immune response not only against that tumor but also against microscopic seeds of melanoma that may be circulating and starting to grow in other areas.  Regardless of whether traditional adjuvant therapy or the newer approach of neo-adjuvant therapy is used, it is critical that the treatment be capable of killing tumor cells wherever they might exist in the body, because it is these stray tumor cells that can ultimately form Stage IV disease.

Another very important reason to consider neoadjuvant treatment is medical research that can be done at the time of the surgical procedure that follows neoadjuvant treatment.  For patients whose tumor shrinks, the tumor cells that may remain at the time of surgery can be studied in the laboratory to discover characteristics associated with tumor reduction.  For patients whose tumor grows or remains stable during neo-adjuvant treatment, the tumor cells and the surrounding cells of the tumor’s “environment” can be studied to discover characteristics associated with resistance.  Investigators have already shown in melanoma—as well as in other tumor types—that patients whose tumor cells disappear altogether during neo-adjuvant treatment have a much more favorable outcome and hardly ever relapse.  On the other hand, those patients who don’t have such a dramatic response to neo-adjuvant therapy (meaning that there are still plenty of tumor cells remaining, detectable by the pathologist under the microscope) have a higher chance to relapse in the future.  It is likely that information from this kind of analysis will provide insight into which patients will benefit the most from specific treatments and which patients may not.  For those who are predicted to benefit, it may be possible to shorten the treatment time and reduce side effects and expense.  For those who are predicted to do less well, it may be possible to find other treatments that would work better, some of which may involve enrollment in clinical trials.  Forgoing ineffective treatments avoids unnecessary side effects and expenses.

What data are available regarding the benefits of neo-adjuvant immunotherapy for locally-advanced, resectable melanoma?

The most active immunotherapy regimen for melanoma is a combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) which produces clinical remissions (reduction in the size of tumors seen on scans or felt on examination) in nearly 60% of patients with advanced melanoma.  This combination is too toxic to use as adjuvant treatment, but it was studied in the neo-adjuvant setting by a group in the Netherlands, who found that 70% of the patients had a pathologic remission. Pathologic remission is measured by the microscopic assessment of tumor that was surgically removed after immunotherapy—it’s a more rigorous measure of tumor cell killing than physical exam and assessment of scans. Similar results were reported from the MD Anderson Cancer Center, and both groups also found that patients with the greatest degree of tumor shrinkage had the highest number of immune cells entering the tumor.  This observation provided direct visual evidence that activation of the immune system led to tumor regression, and those patients whose tumors showed dramatic regression also lived the longest.

The use of combination ipilimumab and nivolumab is associated with a high rate of toxicity that can be dangerous; it requires extensive specialty management and in rare cases can have a fatal outcome.  However, abbreviated immunotherapy, consisting of only two cycles of ipilimumab and nivolumab, may turn out to have just as much power to shrink melanoma as longer durations of treatment that are associated with a higher risk of such toxicities.  The Dutch group set out to find the sequence with the greatest benefit and the least amount of toxicity.  They started by doing a study in which 86 patients with melanoma that could be surgically removed were assigned at random (like a three-way dice roll) to one of three different regimens containing the same two immunotherapy drugs.  Patients in the first group were treated with two cycles (three weeks apart) of ipilimumab plus nivolumab at the usual doses given to patients with advanced melanoma.  In the second group, the ipilimumab dose was adjusted downward, since it’s the more toxic drug, and the nivolumab dose was adjusted upward, since it’s the less toxic drug.  Patients assigned to the third group received the higher dose of ipilimumab alone for two cycles (three weeks apart) and then received the higher dose of nivolumab alone for two cycles (three weeks apart).  All patients then went on to surgery after recovering from any toxicity experienced with immunotherapy.

The results of this three-way randomized study, called the OPACIN-Neo, were remarkable.  First of all, the remission rates were similar for the two groups receiving combinations of ipilimumab and nivolumab given together, in the range of 77-80%.  The remission rate for group 3 was only slightly lower at 65%.  However, the toxicity rates were much lower in group 2, so group 2 was chosen as the overall best regimen based on high activity against melanoma and best profile of tolerability and safety to the patient.

Many additional insights came from these landmark studies of neo-adjuvant therapy for melanoma.  Most importantly for melanoma patients, long-term follow-up showed that the probability of relapse was extremely low for those patients whose tumors had major pathologic (under the microscope) responses to neo-adjuvant treatment.  In fact, only one patient with a major pathologic response (no remaining melanoma cells or very few detectable melanoma cells on examining under the microscope the surgical specimen that was removed after neo-adjuvant therapy) had relapsed over a period of two years’ follow-up.

What other melanoma treatments may be given as neo-adjuvant therapy, and what is their promise?

Most studies of adjuvant therapy and now neo-adjuvant therapy are based on what we know about the activity and safety of the same drugs when they are given to patients with advanced melanoma (melanoma that has spread to multiple parts of the body, not suitable for being cured with surgery or radiation).  The two most commonly used treatments for advanced melanoma are single immune checkpoint blocking antibodies such as nivolumab (Opdivo) or pembrolizumab (Keytruda).  For patients whose melanoma has a BRAF mutation we can also give one of three orally-administered pairs of drugs that block the BRAF protein and the next biochemical step, called MEK—this form of therapy is generally called “molecularly targeted.”  Both of these approaches have also been tried in the neo-adjuvant setting for patients with surgically-removable melanoma, asking the same questions as detailed above: What percentage of patients have a good regression of the tumor, and what are the microscopic and immunologic characteristics of the remaining tumor when it is removed following treatment?  Small studies have been reported for both of these approaches and suggest that the benefits of giving systemic treatment prior to surgery are also seen with these therapies.

For patients whose melanoma had a BRAF mutation, the molecularly-targeted drugs dabrafenib (Tafinlar) and trametinib (Mekinist) were used as neo-adjuvant therapy.  Fourteen patients were treated and 12 had surgery after eight weeks of neo-adjuvant therapy with these drugs.  Among these 12, a very high percentage of the surgical specimens—58%—showed complete eradication of melanoma cells, and another 17% had partial eradication of tumor cells, while only 25% of the tumors showed poor regression in response to neo-adjuvant therapy.

What is the future of neo-adjuvant therapy for melanoma?

There is now a very large ongoing trial to assess the role of pembrolizumab (Keytruda) given alone as neo-adjuvant treatment of melanoma, compared with traditional adjuvant therapy.  In this trial, which is led by investigators at MD Anderson and the SWOG cooperative clinical trial group, 500 patients will be randomly (like a coin flip) assigned to one of the two treatment groups.  One group of patients will receive three cycles of neo-adjuvant pembrolizumab given every three weeks, followed by surgical removal of the melanoma mass and then another 15 cycles of every-three-week adjuvant pembrolizumab.  The other group of patients will have surgery first, in the traditional way: removal of the palpable tumor plus all of the safely-removed lymph nodes in the nearby lymph node group.  This second group of patients will then receive all 18 doses of adjuvant pembrolizumab, given every three weeks over one year.  At the end of the trial, 250 patients will have been treated in each group, and both groups will finish all aspects of their therapy at a little over a year from the start.  In addition to the clinical outcomes of relapse and death as well as side effects and risks, there will be an extensive set of immunologic and other sophisticated studies that can be done on blood and tissue from tumors removed either before or after immunotherapy.

Neoadjuvant therapy is not yet standard and will need to be validated with studies like the one described above, but the power of this approach appears likely to propel it into more frequent use in the appropriate setting for patients with both melanoma and many other kinds of cancer.  New drugs and combinations are likely to be incorporated into these approaches as well, making the future look even brighter for melanoma patients.

Kim Margolin, M.D.

Dr. Margolin earned her undergraduate degree summa cum laude from the University of California, Los Angeles, graduating Phi Beta Kappa, then went on to receive her medical degree from Stanford University School of Medicine. After an internal medicine residency at Yale-New Haven Hospital in New Haven, CT, Dr. Margolin began her fellowship in hematology/oncology at the University of California, San Diego School of Medicine and completed the fellowship in medical oncology and hematology and bone marrow transplantation at City of Hope. 

Triple board-certified in internal medicine with subspecialties in medical oncology and hematology, Dr. Margolin is a fellow of the American College of Physicians. She is on the editorial board of the Journal of Immunotherapy and is section editor in melanoma for the journal Cancer. Dr. Margolin has chaired numerous institutional committees, professional societies, and advisory boards. She has been the Chair of the Cancer Education Committee and a member of the Nominating Committee of ASCO and previously served as a member of the Oncologic Drug Advisory Committee (ODAC) of the FDA.

Dr. Margolin is also an active member of several foundations and federal grant review committees. Among her 180 peer-reviewed articles, 60 invited reviews or editorials, and 16 book chapters, her most recent work has been in the area of melanoma metastatic to the brain and immunotherapy strategies for melanoma and other skin cancers. Dr. Margolin is frequently invited to present her work at national and international conferences and symposia.