About Kim Margolin, MD, FACP, FASCO, author of In Plain English articles
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When, How, and Where Melanoma Spreads Part I
When and How Melanoma Spreads to the Brain, and How it is Treated Part II
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The Results of DreamSeq
Tumor-Infiltrating Lymphocyte (“TIL”) Therapy for Advanced Melanoma
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Dr. Margolin is the Medical Director of the SJCI Melanoma Program at Saint 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.
Dr. Margolin has co-led the Cytokine Working Group and the Cancer Immunotherapy Trials Network, participated in SWOG’s Melanoma Committee, and served ASCO and the Society for Immunotherapy of Cancer in many capacities. She has served on the FDA’s Oncology Drugs Advisory Committee and has been on two advisory committees to the European Organization for the Research and Treatment of Cancer.
Among her research interests are brain metastasis in melanoma and immunotherapy of skin cancers. Dr. Margolin will collaborate with surgeons and laboratory investigators at Saint John’s and will lead the institute’s efforts in melanoma/skin cancer clinical trials.
Dr. Margolin collaborates with AIM at Melanoma to write our "In Plain English” articles that provide timely updates on new developments for patients, caregivers, and other individuals with an interest in medical advances in melanoma.
Kim Margolin, M D , FACP, FASCO PART I
(originally published on May 25, 2022)
The vast majority of people diagnosed with cutaneous melanoma are cured by one or two small surgical procedures done by the dermatologist and surgical oncologist. The dermatologist who suspects melanoma usually performs a shave biopsy that scoops out the suspicious spot, and if it turns out to be melanoma based on the pathologist’s reading under the microscope, sends the patient to the surgeon. The surgeon then cuts a wider swath around the scar to be sure that any remaining tumor is removed and that the margins of melanoma-free tissue around the tumor are adequate (the thicker the original melanoma was, the wider is this swath of tissue). This procedure is called a wide local excision (WLE). Since most melanomas are shallow at the time of discovery and do not involve any lymph nodes or other tissues (see below), this pair of procedures will cure most patients.
A minority of those diagnosed with melanoma will have metastasis— meaning the melanoma will have spread to nearby skin or lymph nodes (local metastasis/Stage III melanoma), or it will have spread to distant visceral sites, such as the liver, lung, bones, or brain (distant metastasis/Stage IV melanoma). At the time of the WLE, these patients’ metastasis may already be discoverable through diagnostic imaging or further biopsy, or the cancer cells may be in the process of spreading and not yet detectable on a physical examination or by a scan.
Melanoma spreads through the lymphatics
—tiny invisible vessels that normally carry white blood cells through the body—and this route usually takes melanoma cells to lymph nodes and skin It also spreads through the blood vessels, which accounts for spread to the visceral sites (liver, lung, bones, brain) Melanomas can spread through both avenues, but certain types of melanoma are less likely to spread through lymphatics and more likely to spread through the bloodstream, such as mucosal melanoma (arising in mucous membranes internally) or uveal melanoma (from the pigmented cells of the eye)
For patients with an elevated risk of recurrence (the melanoma coming back) or with cancerous lymph nodes, the usual treatment recommendation is postoperative adjuvant therapy (additional treatment given after the primary treatment), using immunotherapy drugs or, if BRAF mutation found, targeted therapies, to lower the chance of recurrence either locally near the primary site, regionally in the node site, or at a distance
When a melanoma primary tumor and/or the patient have certain risk characteristics (more on this subject, below), the patient may undergo diagnostic imaging to assess whether there is distant spread This imaging will reveal if there are tumors in the visceral sites The patient may also undergo a sentinel lymph node biopsy (SLNB) at the time of the WLE In this operation, one or a small number of lymph nodes are removed to assess whether they contain tumor cells—whether there is local spread
The biological basis of melanoma’s spread from a primary lesion with no lethal potential to a metastatic tumor (a cancer that has spread) with potentially fatal consequences has generated innumerable research projects and corresponding articles in the medical literature Nevertheless, the precise prognostic (predictive) and metastasis-determining elements in each individual’s melanoma are not possible to identify at this time. We have only statistical data to use, and that is hard to apply to individual patients In other words, we don’t know by looking at your melanoma whether it will spread or not.
A technically-detailed explanation of what is known and how it is used in the current development of clinical research to understand risk for melanoma patients is beyond the scope of this article, but most of the factors currently used are unfortunately very low-technology Certain characteristics of the tumor seen under the microscope can indicate risk, such as the melanoma’s thickness (sometimes called Breslow’s depth) and whether the melanoma is ulcerated (the top layer of skin is not intact) Scans and imaging are used to assess whether a melanoma has already spread to distant sites And clinical assessments such as whether lymph nodes are “palpable” (swollen and able to be felt) are indications of risk
The dreaded occurrence of metastatic melanoma, which can have more than a 50% mortality rate, may be found in the regional lymph nodes by the patient or the physician or may be detected on a surveillance scan or ultrasound Patients can also have small deposits of melanoma in the skin near the original malignant lesion (which is called satellite recurrence) or along the route of travel between the primary and its draining lymph nodes (which is called in-transit metastasis). Patients almost always undergo a biopsy at one or more sites when there is a suspicion of melanoma spread, because the management and the prognostic implications of recurrence and spread are of the utmost importance.
Sometimes even a patient with melanoma that has spread can be cured with surgery Surgery is feasible when the number of metastatic sites is limited (generally no more than two to three separate sites) and can be safely resected (removed) by the surgical oncologist Customarily, just as for patients with initial high risk of recurrence, patients who undergo surgery for limited metastatic melanoma will also be treated with postoperative adjuvant therapy, using immunotherapy drugs or, if BRAF mutation is found, targeted therapies
Patients who cannot be cured with more surgery, and whose disease must be treated with systemic therapy (oral targeted drugs or intravenous immunotherapy), will be discussed in the rest of this article
It is important to remember that you cannot die from melanoma unless it has invaded the body and spread to other sites; in other words, you can only die from Stage III or Stage IV melanoma And although Stage III itself is rarely lethal, it is possible to succumb to regional metastatic melanoma if the cancerous lymph node(s) cannot be removed safely and if the disease does not respond to therapy Nodal masses tend to start as small lesions that generally don’t cause lethal compression of a critical structure or other complications like hemorrhage or infection Nevertheless, with unrelenting growth, such tumors can grow and cause these complications as well as becoming necrotic (dead tumor tissue) with resulting pain, infection, compression of a critical structure (for example, the ureters, which can lead to kidney failure) and blood clots Besides targeted therapy and immunotherapy, a Stage III patient or a patient with in-transit metastases may be treated with intra-tumoral injections of an inactivated herpesvirus that has been engineered to produce in the tumor a substance that attracts immune cells capable of recognizing and killing tumor Sometimes the immune reaction resulting from injecting tumors with this virus (TVEC, Imlygic) is so potent that the immune cells can travel to other sites in the body and kill tumors that were not directly injected
In thinking about how metastatic melanoma can have lethal consequences when it has spread to more distant parts of the body, nearly anything can happen, as melanoma is remarkable in its ability to spread to and establish fatal metastases in just about any part of the body For example, when melanoma spreads to the liver or lungs, those organs fill up with tumors that eventually block their normal function, which is ultimately fatal to the patient unless one of the systemic therapies can reduce or eliminate those tumors
Melanoma is also the tumor type with the highest propensity to travel to the brain, where it can cause bleeding, inflammation and pressure on normal structures that result in neurologic deficits In fact, the single most common site of metastases with lethal outcomes in melanoma patients is the brain This lethality is in part because the best available therapies for brain metastases—surgery and stereotactic radiotherapy (which delivers very high doses of radiation focused on single, small lesions)—are both limited in the number and size of lesions that can be treated, and these therapies do not prevent the occurrence of new lesions in new sites within the brain Additionally, whole brain radiation, while useful for selected other malignancies, does not work against brain metastases of melanoma, because the amount of radiation that can be given to the whole brain is insufficient to kill melanoma cells, since they are relatively resistant to radiation Systemic immunotherapy and targeted therapy are not sufficiently effective in patients who have neurologic symptoms and swelling around the brain lesions, because these patients are treated with steroids to reduce the inflammation, but the steroids reduce the activity of the drugs The topic of managing patients with melanoma and brain metastases will be covered in greater detail in part two of this two-part series on metastatic melanoma.
The era of successful treatment of metastatic melanoma started with the testing of ipilimumab (Yervoy) in the early 2000s and its approval by the FDA in 2011 for advanced melanoma. Between 22 and 25% of patients who have taken ipilimumab, depending on the mixture of prognostic factors, appear to be cured, and this form of therapy requires only four treatments in three months While ipilimumab is not accompanied by the typical side effects and risks of chemotherapy like hair loss, nausea, and low blood counts, it can cause side effects related to generalized stimulation of the immune system that results in an attack on normal tissues, a complication that in turn requires immunosuppressive treatment The successful treatment era continued in 2014 and 2015 when the FDA approved two new forms of immunotherapy related to ipilimumab but possessing greater potency and fewer risks and side effects When these two drugs—pembrolizumab (Keytruda) and nivolumab (Opdivo)—are used singly, the response rate for melanoma patients is in the 35-40% range, and around 70% of those patients who go into remission appear to have long-term control of metastatic melanoma without relapse When one of the latter drugs is combined with ipilimumab, the highest durable response rates ever reported—around 55%–can be expected for metastatic melanoma patients, and the cure rate may be as high as 40-45% with these drugs We don’t always use the word “ cure ” with certainty, since the drugs are still relatively new, and there remains the possibility of late relapse even in patients who appear to be relapse-free for several years following the completion of therapy New drugs related to these agents (other forms of what we call “immune checkpoint blockade”) are under development and appear very promising—for example, a combination blend of nivolumab (Opdivo) and the newest drug relatlimab has been approved as Opdualag for metastatic melanoma, with a better response rate than nivolumab and a substantially reduced toxicity compared with ipilimumab plus nivolumab In addition, completely new designs for the treatment of advanced melanoma and other malignancies are also being investigated.
Treatment of metastatic melanoma that carries a mutation of the oncogene (cancer gene) BRAF has been addressed in a prior In Plain English (January 2021) Of note is that patients with metastatic melanoma who are treated with one of the pairs of targeted oral drugs designed to block the BRAF pathway have an extremely high rate of remission, in the 70-80% range, with additional patients having minor tumor regressions However, these drugs have almost no cure potential, as resistance emerges during therapy after an average duration of one year, and subsequent therapy is rarely effective Targeted therapy is generally not favored as the first treatment for metastatic melanoma and is usually reserved for patients who do not achieve longterm remission from immunotherapy The concept of sequencing targeted therapy and immunotherapy for advanced melanoma was studied in an important randomized trial and summarized in the January 2022 article In Plain English. One exception is patients who have underlying autoimmune diseases that might be exacerbated by the immunotherapy given for melanoma; these patients are generally given targeted drugs as first therapy Another exception are patients with autoimmune diseases who are dependent on immunosuppressive drugs that lower their responsiveness to melanoma immunotherapy; these patients, if their melanoma has a BRAF mutation, are also generally treated with targeted agents as first therapy
Chemotherapy, more correctly termed “cytotoxic chemotherapy” to distinguish it from targeted drugs, can induce remissions and sometimes even cures in many other cancers, but cytotoxic agents are rarely used and essentially never provide long-term remissions in melanoma patients Chemotherapy drugs generally work by direct interference with a critical pathway in malignant cells that provides susceptibility to the drug or a combination of drugs Most chemotherapies are not specific to the cancer but have general applicability to many different tumor types Melanoma does not appear to have sufficient susceptibilities to any cytotoxic agents and has only one pathway that can be blocked by BRAF-pathway treatments
We will finish with a few words about the rare melanoma subsets Acral melanoma arises on a patient’s palms, soles, and finger/toenail areas Acral melanoma has different mutation patterns from common cutaneous melanoma and is less responsive than cutaneous melanoma to the immunotherapies discussed above However, there are currently no drugs specifically used for patients with acral melanoma, and acral melanoma rarely has BRAF mutations to target, so immunotherapy is the most likely choice of treatment, despite its lack of efficacy Mucosal melanoma, arising in any of the mucous membranes of the body (mouth, nose, gastrointestinal tract, anus, and vagina), is even more resistant than acral melanoma to the drugs used for cutaneous melanoma and similarly lacks the “druggable” mutations required for targeted therapy Uveal melanoma, arising in the pigmented tissues of the eyes, tends to metastasize almost exclusively to the liver and is almost uniformly resistant to immunotherapy We now have a treatment called Terentius (Kimmtrak) for selected patients with metastatic uveal melanoma, a complex drug in which one end attaches to the tumor cell and the other end stimulates the T lymphocytes responsible for immune killing of the melanoma cells This is a rare melanoma type, and the drug is available to only half of the patients and has a lot of side effects, but it is a good start in the desperate area of finding a treatment for this highly resistant subtype of melanoma. Research continues in this area
As noted at the beginning of this article, the vast majority of cutaneous melanoma patients will be cured through the process of biopsy and WLE, so metastasis in melanoma can be considered rare, fortunately. But rare is a relative term. Nearly 100,000 cases of invasive melanoma are estimated to be diagnosed in 2022, and in the same year, 7650 patients will succumb to metastatic melanoma Many patients will be treated with targeted therapies, immunotherapies, or other treatments, and after treatment, a substantial number will be considered melanoma-free But robust research continues in an attempt to find active and safe treatments for the remaining metastatic melanoma patients who do not respond to treatment, or whose response to treatment is not durable
(originally published on May 25, 2022)
Of all the kinds of cancer in adults, the one with the highest likelihood of spreading to the brain is melanoma Two other types of cancer are somewhat less likely to involve the brain— lung and breast cancer—but because they are so much more common in the general population, the prevalence of patients with brain metastases from lung cancer and breast cancer is higher than that of melanoma
Unfortunately, melanoma is distinguished as being relatively resistant to radiation therapy, especially compared with breast cancer and lung cancers, which are often treated successfully with various forms of radiation Thus, melanoma has unique challenges that have led to unique solutions, which are finally starting to show success and pave the way for new investigations
The major route of spread for any tumor going to the brain is through the bloodstream Lymphatic vessels, while important in some forms of tumor spread, do not carry cancer cells into the brain While it may be more common for cancers that involve the lungs to spread to the brain (considering that essentially all blood that goes to the brain and all other organs and parts of the body must also pass through the lungs in order to fill with oxygen), involvement of the brain is by no means dependent on spread to the lungs—unless the cancer is microscopically involving the lungs and not detectible by the usual scans.
Many laboratories and scientists are working on understanding the biological underpinnings of melanoma cells that cause them to go to the brain, settle there, and thrive. Those patients with advanced melanoma who have brain metastases often die of complications in the brain Probably the most common complication that leads to the patient’s death from melanoma in the brain is bleeding and/or swelling, which cause loss of critical brain functions Melanoma has a particularly rich blood supply, and these vessels are very fragile and bleed easily, even spontaneously without injury or other causes such as anticoagulation or low platelet count
Melanoma in the brain is often surrounded by swelling (edema), which can require large doses of steroids to reduce the edema and alleviate symptoms such as headache or neurologic deficits. Steroids don’t always work; and furthermore, steroid therapy can be complicated by muscle weakness, opportunistic infections (the ones that take advantage of a suppressed immune system), diabetes, or psychotic behavior Sometimes control of swelling can be achieved by treatment with drugs that reduce blood vessel growth or leakiness, such as bevacizumab (Avastin), an antibody that is also used in combination treatments for other kinds of tumors
Ideally, the deep causes of melanoma spreading to the brain will be unraveled by laboratory scientists, and it will be possible to identify patients at high risk for this complication long before it occurs By understanding these factors, it may become possible to intervene in ways that are not currently available and thus move towards preventing brain metastasis altogether
We already have a large body of literature (published reports from clinical and laboratory science) that tries to explain the brain-seeking behavior of metastatic melanoma. However, many reports focus on just a single or limited number of characteristics that increase the risk of brain metastasis, and we know that the story is far more complex and cannot be explained by studies of single or very few factors Like so many other phenomena in cancer, it is likely that understanding the likelihood of developing brain metastases will require a complex map or algorithm that integrates multiple independent or partiallyconnected factors and then tests them in animals and then people
Many laboratories and scientists are working on understanding the biological underpinnings of melanoma cells that cause them to go to the brain, settle there, and thrive.
A BRIEF DISCUSSION OF HOW MELANOMA IS UNIQUE AND HOW IT GETS INTO THE BRAIN
The best way to detect any abnormality in the brain is almost always the MRI, which stands for magnetic resonance imaging In fact, the imaging device is a very strong magnet that does not cause any radiation exposure, and for the most part, the intravenous contrast material that is injected in order to best delineate all of the brain structures is nontoxic Brain MRIs very clearly demonstrate the normal brain tissue and a vast number of types of abnormalities that range from blood vessel alterations to infections to benign tumors to malignancies, either primary brain tumors or metastases from cancers starting outside of the brain (like melanoma)
Because melanoma usually spreads to the brain only after it has already been detected in other areas outside of the brain, it is rarely necessary to prove by biopsy that a spot showing up on MRI scan is indeed melanoma However, there are some exceptions: For example, rare patients have a lesion (spot) in the brain without evidence of spread from a prior melanoma to any other part of the body Since those patients would not be getting regular scans, they often get diagnosed with a suspicious lesion as a result of going to their doctor with a new neurologic symptom. Even rarer, but at least as important, is a patient who never had any history of melanoma but turns up with a symptomatic brain lesion that requires biopsy for diagnosis as well as sometimes surgery to relieve the neurologic deficit (loss of function). Brain surgery is always done exceedingly carefully to avoid removing any normal brain tissue—and the resulting positive margins (lines where the neurosurgeon has cut to remove the tumor) are generally treated after surgical recovery with a form of intensified but highly localized radiation that is described below
The most common presentation of melanoma metastatic to the brain has evolved from the evaluation of a patient with a new neurologic symptom or finding on exam to identification of patients on routine brain MRIs that are done as part of their staging evaluation (assessing how far melanoma has spread by doing scans such as CT or PET-CT of the body). This may occur at the time of initial staging or may occur after the patient has failed to achieve long-term benefit from his/her first treatment for advanced melanoma and is about to switch to a later line of therapy
Melanoma has long been considered a radiationresistant malignancy, and nowhere is this more critical than in the brain, where a growing tumor poses life-threatening consequences. Radiation oncologists used to rely on radiation of the entire brain, which had been used successfully for other malignancies due to their sensitivity to radiation and the resistance of normal brain to radiation Radiating the entire brain could address the grim fact that whenever there is one or a small number of brain metastases, almost inevitably more lesions will follow The field changed dramatically in the 1990s with the advent of stereotactic radiation or radiosurgery (SRS), a method of directing multiple radiation beams into a single tumor, delivering a very large dose to a small spot, and sparing the surrounding tissue
Several lesions can be irradiated at the same time, and the procedure can be repeated for new lesions, up to a certain point that is determined by the number, size, and location of metastases. And like traditional radiation, it is possible to safely combine SRS to the brain with other forms of therapy, particularly immunotherapy [note—when SRS is given to patients receiving molecularly targeted drugs for melanoma—see In Plain English: What is a “Triplet,” and Why Does it Matter in Melanoma?—it is recommended that the targeted agents be withheld for a few days to avoid excessive toxicity to the surrounding tissues]
Until 2011, with the approval of the first effective immunotherapy and the first targeted drug against melanoma carrying a BRAF mutation, treatment of the brain was limited to radiation, and the only systemic therapies were chemotherapy agents which had substantial toxicities and almost no activity Occasional patients derive benefit from temozolomide, a mild chemotherapy used for primary brain tumors that crosses the physiologic barrier between blood and brain but has very low activity against melanoma In 2012, the first reports came out that demonstrated activity for ipilimumab (Yervoy) against both brain and non-brain metastases in melanoma, and several years later, reports of pembrolizumab (Keytruda) and then the combination of ipilimumab and nivolumab (Opdivo) for patients with melanoma and brain metastases were published The bottom line with these studies was that, for the most part, patients in good shape without symptoms from their brain metastases and without a dependence on steroids could have the same probability of benefiting from immunotherapy in the brain as they did in the body, and the rate of benefit was the same as for patients without brain metastases at all. For patients with neurologic symptoms and/or dependence on steroid therapy, the rate of response to immunotherapy has been much lower, and this situation remains as a serious unmet need for melanoma patients with brain metastases.
Patients with metastatic melanoma whose tumor carries the BRAF mutation have only a very small increase in their risk of developing brain metastases, and these patients have been treated with the BRAF-targeted drugs that are detailed in a previous issue of IPE The data for these patients suggests that response in the brain is possible but occurs at a somewhat lower rate than when these drugs are used for patients without brain metastases and that the response to therapy is of shorter duration in the presence of brain metastases Therefore, just as for patients without involvement of the brain, the use of immunotherapy first, even when the melanoma has a BRAF mutation, is recommended (as for the DreamSeq data, see In Plain English: The Results of DreamSeq), particularly in patients without dependence on steroid. For those who require steroid therapy to control swelling around the tumor(s) or neurologic symptoms, the use of SRS and an attempt to wean the patient off of steroid therapy should be attempted prior to immunotherapy.
In conclusion, the prognosis is looking up for patients with melanoma that has spread to the brain, but there remain many unanswered scientific questions and many unmet clinical needs Working in this field has provided many opportunities for the discovery of how melanoma behaves and for the development of new treatment strategies. As new drugs continue to be demonstrated effective in this disease, they are likely to contribute to improved treatment outcomes.
(originally published on January 27, 2022)
Patients with advanced melanoma spread to other organs or grown too large in the lymph nodes to be safely and effectively removed surgically that has a BRAF v600E mutation are most commonly prescribed one of two treatments: immunotherapy or targeted therapy The immunotherapy most commonly given is the combination of a CTLA-4 and PD-1 blockade such as ipilimumab and nivolumab. Targeted therapy consists of inhibitors of two biochemical pathways in melanoma, BRAF and MEK, and there are three choices of such paired inhibitors vemurafenib plus cobimetinib, dabrafenib plus trametinib, and encorafenib plus binimetinib all with about the same efficacy but somewhat different side effects For advanced melanoma patients and their oncologists, one question is critically important: What should be their first treatment, immunotherapy or targeted therapy?
Before now, the answer was unclear. But study results revealed in November 2021 have given us the answer: The best treatment regimen to start with for patients with advanced melanoma whose tumors carry a BRAF v600E mutation is generally a regimen of double immune checkpoint blockade with CTLA-4 and PD-1 antibodies.
Certain patients may be better served by starting with targeted therapies, for example, those with a very high tumor burden who require a quick regression to achieve symptom relief or avoid other disease complications In the rest of this article, we will explain the background, results, conclusions, and controversies about the DreamSeq trial, comparing in a randomized fashion the outcome of patients starting with double immunotherapy to that of patients starting with double targeted agents, both groups crossing over to the other therapy if their disease progressed (grew or cause worsening symptoms) on the first therapy
Certain patients may be better served by starting with targeted therapies, for example, those with a very high tumor burden who require a quick regression to achieve symptom relief or avoid other disease complications In the rest of this article, we will explain the background, results, conclusions, and controversies about the DreamSeq trial, comparing in a randomized fashion the outcome of patients starting with double immunotherapy to that of patients starting with double targeted agents, both groups crossing over to the other therapy if their disease progressed (grew or cause worsening symptoms) on the first therapy
Before we explain the study and the results, let’s revisit the important characteristics of BRAF mutant melanoma and what we know about initial treatment with targeted therapy and initial treatment with immunotherapy.
There are actually several types of BRAF mutation in melanoma and other cancers, but in this article, we will be referring to the most common form of BRAF mutation, termed v600E This mutation leads to the melanoma cell having a hyperactivated BRAF protein that is responsible for much of the melanoma cell’s ability to grow faster, spread through the body, and be more oblivious to normal growthcontrolling pathways in the cell
As with most cancers, there is a subset of patients whose tumors carry a mutation so powerful that it can transform normal cells (in this case mole or pigment cells, called melanocytes) into malignant cells (melanoma) with only a few additional alterations of their genetic material, such as damage from repetitive exposure to the ultraviolet rays in sunlight BRAF v600E is one of these powerful mutations About half of all melanomas that arise on skin surfaces carry the BRAF mutation
There are, however, some serious limitations to the targeted agents: Not only do they have dose-limiting toxicities in a substantial fraction of patients (and it is uncertain whether patients requiring a dose reduction will have the same likelihood of remission as those who can tolerate full dose), but the melanoma becomes resistant to therapy after an average of about a year. Based on retrospective, nonrandomized data, which can have many biases and inaccuracies (see more detailed explanation below), it has been reported that patients whose BRAF mutant melanoma grows back after a remission from targeted therapies and who then receive immunotherapy have a lower rate of remission than if the same immunotherapy drugs were given as first therapy.
These reports of lower remission rates to immunotherapy in patients previously exposed to and relapsing on BRAF mutation-targeted therapy come from so-called historical or retrospective series, which are simple reviews of patient charts for their clinical characteristics and their treatment outcomes The problem with retrospective series is that many factors that influence the outcome of therapy (or impact the patient’s prognosis, irrespective of the therapy they get) are not matched up between the groups of patients who started with targeted therapy and those who started with immunotherapy Also, patients may not undergo tumor assessments (scans, physical examinations, laboratory tests) at the same intervals following the start of therapy, so the calculation of how long they were in remission may be influenced by when they are evaluated New sites of metastasis can also occur that shorten a remission and threaten the patient’s survival, such as metastasis to the brain, which isn’t always looked at when other tumor assessments are performed.
For BRAF mutant melanoma there are now one or more drugs, deemed “targeted agents,” that can produce remissions by blocking the action of the abnormally activated protein that results from the powerful mutation These targeted agents are also called BRAF and MEK inhibitors Fortunately, advanced melanoma is uniquely sensitive to the BRAF and MEK drugs
BRAF and MEK inhibitors are given orally every day, and they provide an initially very high remission rate (complete or partial reduction of all of the melanoma masses), reported in the 60%s, with additional patients having less dramatic remissions but experiencing some degree of tumor reduction and symptom relief These drugs also have the very appealing characteristic of inducing rapid remissions, which is a strong advantage for patients with a large tumor burden and symptomatic metastases Often, patients with a high tumor burden, a rapid pace of growth, and symptoms from their cancer are started on targeted drugs because of their rapid onset of action, with relief of symptoms and regression of metastases literally within days to weeks
Immunotherapy using CTLA-4 plus PD-1 blocking antibodies given intravenously is considered to be the optimal treatment for advanced melanoma because it has been shown to provide very long-term remission in those patients who respond well. As with targeted therapy, one limitation is that patients must be able to tolerate the combination, which is likely to cause immune-related inflammation of many different organs It is very difficult to determine in advance which patients will not be able to tolerate this combination, other than those with pre-existing major medical illnesses Even advanced age by itself has not turned out to be a predictor of toxicity or poor outcomes.
Immunotherapy, while providing very long-term remissions in patients who respond well, tends to take longer to start working than targeted therapy, so it has not been as appealing to start with in patients with BRAF mutant advanced melanoma, particularly when it seems to be growing fast However, the retrospective data referred to in the preceding section also showed that despite lower overall remission rates for immunotherapy and slower onset of action, the ultimate benefit of immunotherapy seems to be greater than that of targeted agents, which rarely provide durable remissions or the potential for cure
Targeted Agents: BRAF and MEK Inhibitors
Immunotherapy with CTLA-4 and PD-1 Blockade
It has long been known and accepted that the only way to obtain adequate and balanced data that allow for valid conclusions to be drawn is to perform a prospective, controlled, randomized trial. The definition of these critical terms is that the trial does not involve collecting data obtained in the past from patients who were not enrolled in the trial when they received treatment and underwent tumor assessments (prospective) Rather, patients who provide their informed consent are randomly assigned (by a computer using random number generation) to one of the treatments, and all patients in each treatment group undergo the same treatment, dose, schedule, and tumor assessments and intervals (randomized, controlled) Sometimes factors that might influence the outcome other than the treatment itself such as a blood test reflecting tumor burden or a subtype of melanoma are built into the computerized randomization system to assure that both treatment groups are balanced for such factors (stratified).
Informed consent means that patients in clinical trials must agree to the details of the procedures and are, to the extent possible, informed of the expected risks and benefits of all elements of treatment, whether standard or investigational In some trials, such as the one detailed below, the treatments were both standard (already approved by the U S Food and Drug Administration to treat melanoma), but the trial question was about which regimen, started first, conferred the best survival Patients whose melanoma grew during the first assigned therapy were then crossed over to the opposite therapy as their secondline regimen.
In 2011, Dr Michael Atkins at Georgetown Lombardi Comprehensive Cancer Center, together with selected colleagues in the melanoma field, began what would turn out to be a very long but criticallyimportant quest to define the optimal first-line treatment for patients with advanced melanoma that carried a BRAF mutation.
As the trial was moving towards activation, the field changed dramatically for both BRAF-directed therapy and immunotherapy: In the case of BRAF, it was found that a two-drug combination worked better, because the addition of a MEK inhibitor reinforced the BRAF inhibition and prevented secondary non-melanoma skin cancers that sometimes emerge on BRAF-only treatment. In the case of ipilimumab, the addition of nivolumab provided a far more potent regimen, comparable to the BRAF plus MEK combination Ultimately, the trial of two targeted drugs versus two immunotherapy drugs was opened in July, 2015, and although accrual started slowly, the level of interest in this important question accelerated its momentum By late 2020, the trial’s Data Monitoring Committee deemed the patient number sufficient to answer the question with statistical significance, which means the numbers would not have come out as they did merely by chance
The trial’s results were reported by Dr Atkins in a special ASCO (American Society of Clinical Oncology) session in November, 2021: The survival rates of patients in the two treatment groups were compared at the two-year mark and found to be substantially better for the immunotherapy patients than for the targeted therapy patients (72% versus 52%), thus establishing the superiority of immunotherapy over targeted therapy as the first treatment for patients with advanced melanoma carrying a BRAF mutation
We will look forward to Dr. Atkins publishing his data for the entire scientific and clinical communities in the near future
Many questions remain without complete answers, such as:
Many patients are currently treated with a single immunotherapy drug (PD-1 antibody such as nivolumab or pembrolizumab) rather than two combined immunotherapy drugs (ipilimumab plus nivolumab, as in this study) For these patients, will the effects of immunotherapy using only one drug be as much superior to targeted therapy as immunotherapy with two drugs?
Will any of the newer (still experimental) immunotherapy drugs be more effective and less toxic than the currently-approved combination of ipilimumab plus nivolumab?
Is there a way to safely combine or more cleverly sequence the targeted anti- melanoma drugs and the immunotherapy drugs to better exploit the benefits of each class of agent?
Researchers are beginning to answer the second question: There are already very promising data for a new antibody against an immune checkpoint called LAG3, which seems less toxic and at least as effective as the ipilimumab plus nivolumab combination. That combination is likely to be approved by the US FDA soon, which will be encouraging but may raise questions about how it compares with previous regimens And researchers are trying to answer the third question, too: In a prior issue of In Plain English, we discussed combinations of immunotherapy with targeted therapy and the evidence of some superiority of these combinations over targeted therapy alone However, there are substantial toxicities of combining three drugs simultaneously, so few oncologists offer them routinely to these patients There are also plenty of data suggesting that targeted therapy agents can enhance the responsiveness of melanoma cells to immunotherapy, so many investigators are performing clinical trials to probe this question by studying sequences that involve switching from targeted to immunotherapy before the melanoma becomes resistant to targeted therapy.
These are exciting times for melanoma therapy, and it is almost impossible to keep up with the pace of new developments, but we will continue to bring these advances to the melanoma information-seeking public through our In Plain English articles.
The explosion of immunotherapy over the past decade has revolutionized the treatment of melanoma and nearly every other adult type of cancer As a reminder, this form of treatment stimulates the body’s immune system to attack and kill tumor cells
Of all cancers, melanoma has benefited the most from immunotherapy, in large part because the mutations caused by extensive sun damage
lead to changes in the cells that can be recognized by the immune system, particularly after stimulation by immunotherapy Additionally, because melanoma is so resistant to chemotherapy and radiation, the relative benefits of immunotherapy are greater in melanoma patients, since they have few other choices for effective treatments.
B A C K G R O U N D I M M U N O T H E R A P Y O F M E L A N O M A
B Y K I M M A R G O L I N , M . D . , F A C P , F A S C O
TIL cells are tumor-infiltrating lymphocytes Lymphocytes are the white blood cells that are able to recognize and attack malignant cells, especially when they are stimulated with immunotherapy Tumor-infiltrating lymphocyte therapy, known by the simple acronym “TIL,” refers to a treatment that involves extracting T lymphocytes from a patient’s tumor, growing them in special liquid, and giving them back to the patient via intravenous (in the vein through a needle) infusion The factors that determine whether a patient will go into remission from TIL therapy are not well understood, but the number of cells that can be given may be an important factor, so the goal of laboratory expansion of TIL cells is usually several billion cells
The TIL cell approach has been under investigation for nearly 35 years, starting in the mid-1980s in the laboratories at the National Cancer Institute’s Surgery Branch. There, Dr. Steve Rosenberg worked tirelessly and trained dozens of investigators (surgeons, medical oncologists, and laboratory scientists) to develop and improve on methods and outcomes of TIL therapy While much of this research has been preclinical (in animals, where the conditions can be manipulated and the outcomes measured in much shorter timeframes than in people), an extensive series of clinical trials testing the new therapy in people with cancer has provided new insights. These insights include the best ways to obtain the tumor that the cells are taken from, cultivate the TIL cells, select the best cells to give back to the patient, and treat the patient with additional immune system-directed medications to optimize the anti-tumor effects of the TIL cell therapy
W H A T A R E T I L C E L L S ? W H A T I S T I L T H E R A P Y ?
While much of this research has been preclinical (in animals, where the conditions can be manipulated and the outcomes measured in much shorter timeframes than in people), an extensive series of clinical trials—testing the new therapy in people with cancer has provided new insights.
To date, the patients who have been considered candidates for TIL cell therapy have had metastatic melanoma that has already been treated with standard therapies without achieving a long term remission. This means nearly all patients have already received the small number of standard treatments currently available for advanced melanoma: both of the immune checkpoint blocking antibodies ipilimumab (Yervoy) and nivolumab (Opdivo), or pembrolizumab (Keytruda), and, if the patient’s tumor is positive for the BRAF mutation, one of the three pairs of oral medications that target malignant cells with this mutation Some patients have also received interleukin-2 (IL-2), which stimulates immune cells, causes T lymphocytes to multiply and become activated, and provides a low level of antitumor activity in patients with melanoma However, high doses of IL-2 can also cause a lot of (reversible) side effects and dangers to the patient
The TIL cell regimen begins with patient assessment, making sure that candidates for this therapy have a safely accessible tumor one that can be partially or fully removed with a small surgical procedure Tumors in the brain, the spinal cord, bones, and other less safely accessible locations would not qualify for TIL Patients must also be in generally good medical and physical condition, which means they are judged by their doctor to be healthy enough to get through all phases of the regimen, which is shown in the diagram below and explained in the next section
The next step is extracting and growing the TIL cells from the patient’s tumor and growing them as described above. Then the patient must be prepped for the process of infusion, which currently requires the administration of two chemotherapy drugs over five days. These drugs do not kill melanoma cells but lower the patient’s own lymphocyte count, which the body counters by increasing its levels of growth factors that will stimulate the incoming TIL cells to expand and acquire more anti- melanoma activity After the TIL cells are given, a few doses of IL-2 are administered to keep stimulating and growing the TIL cells inside the body
Other details of TIL cell therapy are similar to any form of combination chemotherapy and immunotherapy with highly potent drugs, including antibiotics, blood transfusions if needed, and very close supervision by doctors and nurses to minimize the risks associated with the cells going in and the side effects of IL-2
Most of the published results of TIL cell therapy for melanoma have come from the National Cancer Institute Surgery Branch mentioned above; additional data are from a small number of cancer centers, mostly in the U S , who participated in multi-site studies of TIL cells for melanoma patients in relapse, with the goal of getting the first TIL therapy approved by the FDA.
The first trial ever to randomize TIL therapy against standard immunotherapy for melanoma patients in first relapse was reported by Haanen et al at the 2022 annual meeting of the European Society of Medical Oncology. In this study, 80 patients with similar characteristics whose melanoma was not controlled with PD-1 antibodies were randomly assigned to receive either ipilimumab or undergo TIL therapy The results strongly favored TIL therapy, which doubled the response rate to approximately 50%, and significantly improved the complete response rate, the average time before tumor growth, and the percentage of patients without tumor growth at six months or longer following the initiation of therapy
Most recently, at the November, 2022 annual meeting of the Society for the Immunotherapy of Cancer, another trial was reported by Sarnaik et al, who led a trial of TIL cell therapy for advanced melanoma patients who had failed to benefit from standard therapy for advanced melanoma In this group of 153 patients, the overall response rate was 31%, with 6% of the patients achieving a complete response and the median (time point at which half the values were longer and half were shorter) duration of response being over two years While this form of therapy has a long way to go in terms of curing patients with melanoma that is resistant to standard therapies, it may find a place earlier in the treatment of patients who are predicted not to achieve long-term benefit from other treatments Studies are ongoing to identify those patients as well as to make the TIL cell therapy less complex and more widely available
While these exciting results for TIL cell therapy as an option and a hope for patients who do not achieve long term benefit from standard immunotherapy are likely to lead to an FDA approval and then further studies to improve TIL therapy even more, there remain many questions and potential obstacles The practical ones concern the exorbitant cost of cell therapy but considering that cell therapy is a “one and done” strategy, it may not prove to be more expensive than less complex treatments The length of time required to prepare the TIL cell product has also gone down as laboratory advances are made currently only about three weeks Access to centers with experience who can perform this therapy may be challenging, but unlike the original form of anti-malignancy cell therapy bone marrow transplantation TIL therapy does not require a donor. More important clinical issues that oncologists and laboratory investigators are still grappling with are the high initial drop-off rate (the trial detailed above actually entered twice as many patients as eventually went on to get treated) and what to do about growing and freezing TIL from patients who may not need them at the time but may need them in the future for possible relapse
Taken together, the pooled results of TIL cell therapy from a number of U S and ex-U S centers as well as the industry-sponsored studies are remarkably good, considering that these studies most often enrolled patients who had exhausted all other therapies with known benefit If patients whose melanomas are resistant to available immunotherapy and targeted therapies can still achieve long-term remissions from another form of immunotherapy like TIL, it is highly likely that we can expect to cure a substantially larger percentage of melanoma patients
The next question to answer is whether we can identify in advance thosepatients who will not benefit from currently available therapies (immunotherapies and targeted therapies) but will benefit from TIL cell therapy and give those patients TIL treatment earlier in their diagnosis and without having to receive the other therapies first Indeed, there are clinical trials looking at this question now While metastatic melanoma is still a very challenging disease to treat, the options are getting better every day, and with the advent of TIL cells and other new immunotherapies, it is likely that an increasing percentage of patients with this disease will have access to therapies that could cure their disease.
Of course, the rising tide lifts all boats. While TIL cell and related strategies are being worked on to improve their outcomes, safety, lower costs and enhance accessibility, other treatments for melanoma and other cancers are also in the works Competition is good, as it brings out the creativity of scientists and the enthusiasm of clinical investigators It is possible that sometime in the near or distant future, TIL cell therapy will have become not only commonplace but maybe even obsolete, moving aside in favor of treatments that are even more effective, safe, cheap and well-tolerated. Look for those advances in coming issues of “In Plain English.”
