Por Kim Margolin, M.D., FACP, FASCO
Understanding the principles adjuvant therapy for adult cancers so we can apply this understanding to neoadjuvant therapy
Until the modern era of cancer immunotherapy—which really began in 2011 with the first approval of ipilimumab (Yervoy) for unresectable (inoperable) Stage III or Stage IV, or what is called “advanced,” melanoma—we were taught by the giants of immunology who worked in experimental animal cancers that it was almost impossible to cure an animal once the cancer had grown to the point of detection. Thus, when the cancer was easy to feel or see, or there was evidence that the animal was sick, such as weight loss, slowed movements or ruffled fur, the cancer was too advanced for any treatment to save the animal from death. However, other experiments showed that it was sometimes possible to cure animals that had very little cancer in the body. Many animal cancer experiments featured a so-called three-day model and ten-day model, where three and ten referred to the number of days that had passed after the researcher had injected tumor cells into the animal or had implanted an experimental tumor and then removed it surgically at different sizes of growth. The upshot of these experiments was that effective treatments could eradicate the few cancer cells present in the three-day model or early after transplantation of the experimental tumor, while the animal would more likely die despite therapy in the ten-day model or following more delayed removal of the implanted experimental tumor.
In the previous era of highly toxic and not very active anticancer drugs (before 2011), the treatment of most human cancers was similarly not expected to cure patients with advanced disease. However, based on encouraging results showing early treatment capable of curing a fraction of the animals, investigators and clinicians became enthusiastic about the idea of eradicating micrometastases (single cells or small groups of tumor cells that could grow back into detectable tumors near the original surgical site or at a distance) following surgery, in hopes that the risk of relapse and death could be lowered or eliminated. This type of postoperative treatment was termed “adjuvant therapy,” referring to something that adds to the benefit of surgery.
The above theory was hard to prove, because it is impossible to detect the effects of adjuvant therapy in an individual patient who may or may not have micrometastases after surgery and whose micrometastases—if they are present—may or may not be sensitive to the adjuvant therapy used. It is critical to recognize that the likelihood of benefit from post-surgical adjuvant therapy depends entirely on two factors: 1) does the individual patient have micrometastases capable of growing as incurable, detectable, advanced tumor, and 2) are the micrometastases highly sensitive to the killing effects of the adjuvant therapy (and, of course, is the adjuvant therapy safe and tolerable). Because of the invisibility of micrometastases, the only way to accurately assess the benefit of adjuvant therapy, given the two principles above, is to compare one adjuvant approach with another. If, at the time of the trial, there is no proven, approved adjuvant therapy, it is appropriate for the comparison group to receive NO therapy—sometimes, if the side effects and risks of the drug being tested are also common, everyday events, it may be necessary to use a placebo—an inactive substance packaged up to be indistinguishable by the patient, treating doctor(s), and dispensing pharmacy and medical staff, if given in clinic. Patients must receive very thorough explanations of the rationale for placebo, if used, as there are many bad associations with placebos, and regardless of the lack of sufficient data about a given drug, many patients are strongly opposed to being assigned at random to receive no active therapy. Fortunately, most cancers now have at least one drug approved for adjuvant therapy, so that drug becomes the comparator, or control group, instead of placebo or close observation. Another requirement of sound study design is that patients assigned to both groups undergo the same types of testing (exam, scans, labs) at the same time points in the study in order to be rigorously comparable.
This concept of basing adjuvant therapy trials on successful drugs for patients with an advanced case of the same cancer has been widely used and has led to many approvals for adjuvant therapy in adult cancers. Indeed, the most common cancers (lung, breast, colorectal), which are also responsible for the highest number of deaths from cancer, have approved adjuvant therapies that increase the time it takes to relapse and, in some cases, increase the average lifespan of patients who receive these drugs following surgical removal of the primary tumor.
Until the last decade, melanoma was not a part of the adjuvant therapy conversation, because melanoma was almost completely impervious to the various drugs used in the adjuvant setting, which is not surprising, since those drugs were also inactive for patients with advanced melanoma. Nevertheless, desperate diseases [sic] call for desperate measures, and patients with advanced melanoma were among the first to benefit from the new generation of immunotherapies and targeted drugs that were first approved by the FDA in 2011. Once these drugs were shown to be effective in advanced melanoma, researchers began studying whether they would also be effective in the adjuvant setting for patients whose melanoma is removed surgically and who have no evidence of disease but might have micrometastases. And they were! Both immunotherapy—using immune checkpoint blocking antibodies like ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda)—and targeted therapy—using one of the three pairs of oral drugs that are approved for melanoma with a BRAF mutation—can reduce the rate of relapse and prolong the average time to relapse. The standard of care now is to offer adjuvant treatment (drug treatment after surgical removal of detectable melanoma) to Stage III patients, and adjuvant treatment has also been approved for Stage IIB and IIC melanoma. These adjuvant treatments have shown great success in preventing or delaying relapse of melanoma, but their impact on overall lifespan may be less dramatic, since most patients who relapse can then get the same drugs and potentially the same degree of benefit.
Principles and practice of neoadjuvant therapy in melanoma and other cancers
The newest and possibly most beneficial approach—currently undergoing randomized trials—is to give immunotherapy prior to surgery to patients with a single site of melanoma that can be safely removed. This strategy is termed “neoadjuvant” therapy. The number of treatments given before surgery is usually limited to one to three cycles so that the removed tumor can then be studied for microscopic features, but it is likely that some forms of neoadjuvant therapy will be so effective as to make surgery unnecessary some of the time.
Animal studies showed survival (lifespan) benefits to the neoadjuvant approach and opened the field to human patients with various cancer types. While neoadjuvant treatment uses drugs that are already known to be effective against Stage IV melanoma, the drugs are not formally FDA-approved for neoadjuvant treatment, since the drug approvals specify treatment for “advanced (surgically unresectable) melanoma.” Nevertheless, this strategy is already used in other settings and has become part of standard practice for malignancies such as with radiation in patients with rectal cancer (in large part to avoid the need for huge surgeries and colostomy bags), and a similar approval has been given for the most dangerous form of breast cancer using chemotherapy, radiation and immunotherapy. These tumors are particularly amenable to this approach as a result of their moderate sensitivity to chemotherapy and radiation and the decrease in surgical complications and organ dysfunction resulting from surgery on smaller tumors. Further, not only does the neoadjuvant approach reduce local tumor and potentially eliminate the need for surgery or reduce the amount of surgery required, the systemic therapy can also eradicate microscopic metastases at other sites and thus prolong the survival of these patients. As in the postoperative adjuvant treatment setting, the most critical determinant of the benefit from neoadjuvant therapy is the level of antitumor activity of the drug balanced against its toxicities, which could even have an unfavorable impact on surgical risks.
In melanoma, the neoadjuvant approach came as a natural consequence of the emergence of today’s highly-active drugs, particularly immunotherapy agents that can provide durable remissions to a substantial proportion of patients with melanoma. Based on a series of very well-designed trials coming out of the Netherlands, together with recently-published experience at U.S. centers (detailed in the next section), the optimal immunotherapy combinations have been shown to eradicate all pathologic (under the microscope) evidence of melanoma in over half of the patients. Similar but smaller trials of neoadjuvant targeted therapies for patients with BRAF-mutant melanoma showed the expected very high rate of regression, but the role of these therapies in neoadjuvant treatment hasn’t been as well established as immunotherapy.
Because of the limited number of neoadjuvant treatment cycles, most patients still have residual tumor masses at the time of planned surgery; also, because of the experimental nature of this approach, nearly all patients still undergo surgery so the tissue can be studied in detail. Although these dramatic results would suggest the uptake of this approach as standard therapy for all or most patients with a single site of Stage IV melanoma, the proof of benefit remains to be demonstrated in randomized trials that compare neoadjuvant preoperative to adjuvant therapy given postoperatively.
Current status and future of neoadjuvant therapy for cutaneous melanoma
The most definitive trial, with the largest number of patients and the most commonly-used immunotherapy—pembrolizumab (Keytruda)—for melanoma was reported in the last year and published in the New England Journal of Medicine. Based in part on a very small trial in Philadelphia and subsequent laboratory analyses at UCLA, this randomized study (commonly referred to by its trial number, S1801 ), which was led by Dr. Sapna Patel of M.D. Anderson and chair of the SWOG (U.S. cooperative clinical trials group) melanoma committee, recruited 313 patients with a resectable but bulky single site of melanoma. Most patients had a large single node or group of nodes involved with tumor, and patients were randomly assigned to receive three cycles of neoadjuvant pembrolizumab prior to surgery and 15 more cycles after surgery OR to have surgery first, followed by 18 cycles of traditional postoperative adjuvant pembrolizumab. The trial was completed in record time and demonstrated a large benefit of the neoadjuvant treatment over all-adjuvant treatment in delaying or even preventing relapse. It was too early to know if overall lifespan would also be longer in this group, since measuring overall survival requires a substantial number of patients to have died in each group in order to detect a meaningful difference. Also, despite the seemingly large number of patients—more than 300 total—this trial was designed at a level of precision that would require further validation with an even larger number of patients. Such a trial will most likely be performed soon in order to provide data to the FDA in support of its approval of neoadjuvant therapy for similar patients with resectable melanoma.
Clinical investigators (researchers whose “experiments” consist of patients going on important trials of novel therapies in hopes of improving upon the current standard for their disease) are now excited about several elements in this arena. First of these is the basic science underlying the clinical observations: Using the same drugs that are given to patients with advanced melanoma, who are sometimes biopsied to see if there is evidence of immune attack against melanoma, it has been shown that neoadjuvant therapy can enhance the number and function of the particular immune cells that are inside the tumor and are responsible for killing melanoma cells and producing remissions. It is believed that this phenomenon is responsible for the high rate of complete and near-complete remissions resulting from pre-surgical therapy, which appear to occur more frequently than for advanced melanoma treated with the same drugs. Many researchers are currently working on the detailed mechanism of these effects so that we can understand it better. Secondly, there is a strong chance that some, many, or even all of the patients who go into a complete or near-complete remission—including the absence of any residual alive-appearing melanoma cells under the microscope—may not need any postoperative adjuvant therapy. This question is another one that will need to be answered by well-designed and randomized clinical studies. Finally, the choice of agents to be used in the neoadjuvant setting (and, if necessary, in the postoperative adjuvant setting) will also need to be studied in trials designed to compare the antitumor effects and toxicities of the best-known drug regimens for melanoma.
In conclusion, not only do neoadjuvant studies allow clinicians and researchers to pick the best and safest drugs for inducing remissions in patients with melanoma but they also appear to improve the average time to any relapse that might occur. It is sincerely hoped that this approach will result in lengthening the average survival time and thus enhancing the likelihood of cure for a higher percentage of patients with melanoma than are currently cured without neoadjuvant therapy.
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Dr. Margolin is a Medical Director of the SJCI Melanoma Program, St. John’s Cancer Institute. She worked at City of Hope for 30 years and also held faculty positions at the Seattle Cancer Care Alliance/University of Washington and at Stanford University. Among her academic achievements were long-term leadership of the Cytokine Working Group, leadership involvement in the Cancer Immunotherapy Trials Network, participation in the Southwest Oncology Group’s Melanoma Committee, and many positions in the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer. Dr. Margolin has reviewed grants for many cancer-related nonprofit organizations and governmental agencies. She has also served as a member of the Oncology Drugs Advisory Committee to the FDA, the American Board of Internal Medicine’s Medical Oncology certification committee, and the Scientific Advisory Committee of the European Organization for the Research and Treatment of Cancer.
Dr. Margolin collaborates with AIM at Melanoma to write our In Plain English articles to provide timely updates on new developments for patients, caregivers, and other individuals with an interest in medical advances in melanoma.