Metastatic melanoma

Abstract

W.V. is a 39-year-old Caucasian male who, on July 4, 2017, presented with right arm numbness while running a 10-K race. Magnetic resonance imaging (MRI) of the brain revealed a 3-cm, peripherally enhanced mass (Fig. 1), and computed tomography (CT) with contrast of the chest, abdomen, and pelvis revealed subcentimeter (2-4 mm) pulmonary nodules with no other sites of disease. On July 7, 2017, he underwent craniotomy with resection of a parietal tumor. Frozen section was initially suspicious for primary glioma; however, final pathology showed metastatic melanoma that was positive for S100, MITF, and SOX10 by immunohistochemistry. There was no history of prior melanoma or nonmelanoma skin cancers, and no primary tumor was identified on a total body skin examination. In addition, a standard comprehensive examination for mucosal, ocular, and other occult sources was performed, and no definitive primary was identified. The tumor was positive for the BRAF V600E mutation by next-generation sequencing. The patient subsequently underwent radiation to the postoperative bed, receiving 30 grays (Gy) in 5 fractions. In August 2017, the patient began systemic therapy with ipilimumab 3 mg and nivolumab 1 mg/kg. He received 2 doses of therapy, which was then discontinued because of the development of colitis. After a 6-week course of steroids, he was initiated on maintenance nivolumab at 480 mg intravenously every 4 weeks. He received 1 year of nivolumab without complication. CT scans of the body and MRI scans of the brain remained stable during this time. For surveillance and to monitor tumor response to treatment, CT scans were used rather than positron emission tomography (PET)/CT scans because the small pulmonary nodules were below the limits of PET detection and were better imaged by dedicated CT scans. One month after the completion of nivolumab, CT scans showed enlargement of a left upper lobe pulmonary nodule, and the patient subsequently underwent video-assisted thoracoscopic surgery wedge resection. Pathology showed metastatic melanoma 1 cm in size. It was noted on pathology that 15% of nucleated cells in the periphery and 5% of cells in the center were CD8-positive lymphocytes. Although the significance of this observation is unclear, preliminary data demonstrate better outcomes for patients who have increased CD8 infiltration of their melanoma.1 After he underwent video-assisted thoracoscopic surgery resection, the patient was followed with active surveillance. In August 2019, slow but steady growth was noted in the subcentimeter pulmonary nodules over an approximately 18-month period. All nodules had grown by approximately 2 to 3 mm, with the largest measuring 1 cm. After discussion with the patient, he was started on encorafenib and binimetinib on October 1, 2019. At the time of publication, the patient was tolerating treatment without complications and has had a near complete response to treatment. At presentation, this is a young male with stage IV, BRAF-mutated melanoma to the brain from an unknown primary. The first branching point of discussion is whether this is an adjuvant, resected, stage IV melanoma versus an active melanoma with lung metastases. Approved therapies for adjuvant, fully resected melanoma include single-agent, anti–PD-1 agents (nivolumab; pembrolizumab) or BRAF and MEK inhibitors (dabrafenib and trametinib). It should be noted that the numbers of patients with resected brain metastases in adjuvant trials are limited, although some trials have included patients with resected stage IV disease. For active stage IV disease, approved therapies include nivolumab or pembrolizumab as a single agent, anti–PD-1 therapies, combination CTLA-4 and PD-1 antibodies (ipilimumab and nivolumab), as well as BRAF and MEK inhibitors (dabrafenib and trametinib, or encorafenib and binimetinib, or vemurafenib and cobimetinib). Subcentimeter lung nodules are difficult to interpret—they are too small to biopsy or to be detected by PET/CT. The patient did not have prior imaging studies to compare, nor did he have any obvious reasons for having multiple lung nodules (ie, prior infections, smoking, active asthma). Given the brain lesion and the number of nodules, we were highly suspicious that the patient had active, stage IV disease; therefore, we elected to proceed with therapeutic options for active disease. The second point of decision making is whether to pursue immunotherapy or targeted therapy with BRAF/MEK inhibitors. Key clinical factors for decision making include age and performance status, the presence or absence of brain metastases, and medical comorbidities (history of transplantation or autoimmune disease). Patient input into this decision making is critical because the side-effect profiles of both options are quite different. In addition, one should consider the patient's symptomatology from cancer and overall disease burden. The rapid responses and high response rate of targeted therapy often lead clinicians to choose BRAF and MEK inhibitor therapy in patients with symptomatic disease. At the time of diagnosis, this patient had an excellent performance status of 0. He had no known medical problems before the diagnosis but, upon imaging to evaluate for other sites of disease, it was noted that he had radiologic features of ankylosing spondylosis, although he was largely asymptomatic. Given imaging findings that were suspicious for ankylosing spondylosis, the patient was evaluated by a rheumatologist, who confirmed the diagnosis. However, because of this diagnosis and because the patient did not have technically measurable disease according to Response Evaluation Criteria in Solid Tumors, he did not qualify for the treatment-naive trials available at that time. From our standpoint, this fact and the presence of brain metastases were key in choosing a systemic treatment. Single-agent anti–PD-1 drugs, combination immunotherapy, as well as dabrafenib and trametinib have data showing activity in central nervous system (CNS) disease. Ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg have shown equivalent intracranial and extracranial responses in patients with asymptomatic brain metastases who were not receiving systemic steroids.2 Long and colleagues also demonstrated a high response rate for this combination, with a 46% intracranial response rate.3 Updated data from the 204 study4 also demonstrated durable responses intracranially from combination immunotherapy. Single-agent pembrolizumab showed an objective response rate of 25% in melanoma brain metastases.5, 6 Single-agent nivolumab showed an intracranial response rate of 20%.3 From these early and small studies, one can conclude that immunotherapy has activity in controlling CNS metastases of melanoma and that combination therapy has a higher activity rate in the CNS than single-agent therapy. Dabrafenib and trametinib also demonstrated activity in the CNS in the Dabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation (COMBI-MD) study.7 Although that study demonstrated a high intracranial response rate for dabrafenib and trametinib of 58%, the duration of response was quite limited, with a median progression-free survival of 6.5 months in patients with previously untreated, asymptomatic brain disease. As a result, in patients with a good performance status, with no urgent symptomatology, without contraindications, and without trial options, immunotherapy is our preferred initial approach. Although all CNS data are from studies with relatively small numbers of patients, there is still strong evidence that both immunotherapy therapy and targeted therapy can control CNS disease. On the basis of the data we have to date, the highest response rate is with either ipilimumab and nivolumab or dabrafenib and trametinib. Given the durability seen in updates from the CheckMate 204 study (An Investigational Immunotherapy Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread to the Brain, Treated With Nivolumab in Combination With Ipilimumab, Followed by Nivolumab by Itself), it appears that combined ipilimumab and nivolumab may also have the best durability of response in this population. This was the primary reason to choose this therapy for our young, healthy, asymptomatic patient. This choice also comes with great toxicity risk, which was discussed in detail with the patient to ensure that the decision for a treatment with high toxicities was congruent with the patient's goals of treatment. Key factors to discuss with patients are the permanence of some of the immunotherapy toxicities, the risk of hospitalization, as well as the risk of rare but very serious complications. For younger patients, fertility should also be discussed, although there are few data on how long-term fertility is affected by immunotherapy. For combined ipilimumab and nivolumab, the risk of grade 3 and 4 toxicities is approximately 50%, with 20% of patients requiring hospitalization. The endocrinopathies will likely be permanent, lifelong conditions of which all patients should be aware and include thyroid dysfunction, hypophysitis, adrenal insufficiency, and (rarely) type 1 diabetes. More common toxicities that may require a 4-week to 8-week course of high-dose steroids are pneumonitis, colitis, and hepatitis. Rash and pruritus are common, although severe cases are rare. Cardiac complications such as myocarditis are rare but can be fatal. In addition, neurologic complications must be taken seriously, as myasthenia gravis, peripheral neuropathy, and Guillain-Barre have been reported.8, 9 It is essential to educate patients and caregivers about how to recognize symptoms and the need to contact their health care provider early in course of symptoms. Teaching by a team is most effective (using nursing staff and pharmacists, if possible) to provide a broad, patient-focused education about immune-related adverse events (Table 1). After progression on immunotherapy with an increase in the number of lung nodules, the patient was initiated on encorafenib and binimentinib. There are 3 combination BRAF/MEK inhibitors on the market currently (dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimentinib). There is no known, definitive efficacy advantage to using one combination over another, although no trials have compared these drugs head-to-head. Side-effect profiles do vary, with a higher incidence of fevers using combined dabrafenib and trametinib and a higher incidence of rashes using combined vemurafenib and cobimetinib compared with encorafenib and binimentib. Encorafenib and binimetinib can be taken with food, which may be more convenient for patients and thus was chosen for this patient. The follow-up regarding our patient's tolerance of therapy and response to treatment was not yet available at the time of this publication. In between laboratory work, clinic, and treatment appointments, nurses are frequently on the front lines when it comes to patient communication and initial contact. Telehealth nursing as well as communication through patient portals are increasingly common forms of patient-to-clinician toxicity reporting.10 Patients may also present in person via walk-in nursing appointments. This patient's preferred method of communication has been through portal messages. Education has been provided to the patient regarding contact through the portal occurring during business hours only, and he knows that any urgent concerns after hours or over the weekend should not be sent electronically. The patient initially started treatment with combination ipilimumab 3 mg/kg and nivolumab 1 mg/kg. Before any patient's first dose of immunotherapy, nursing has the opportunity to stress both the side effects most frequently seen as well as those that pose the highest clinical risk to patients, regardless of how commonly they occur. With all immunotherapies, but with this combination in particular, the nursing team should spend a significant part of direct patient education focused on immunotherapy-induced colitis. Not only is this a frequently reported toxicity, but, untreated, this can lead to hospitalization, perforation of the bowel, and sepsis.11 The nurse can present information early on to prevent later complications of colitis and stress the importance of early reporting of diarrhea to the clinical team. This patient was provided this education and reached out through the patient portal when the first episodes of diarrhea occurred. In many oncology patients who are receiving chemotherapy or other forms of treatment, diarrhea protocols may differ. With immunotherapy, our approach to assessing patients with diarrhea leads to early diagnosis of autoimmune colitis. Similar assessment questions should be used, including focus on consistency (diarrhea, by definition, is liquid-like) and frequency. In addition, the nurse should establish the patient's baseline before the change in bowel movements. Like with chemotherapy-induced diarrhea, infectious causes should be ruled out, so the provider may order stool studies while simultaneously addressing the possibility of colitis. Immunotherapy-induced colitis may come on quickly with frequent bowel movements, but it can also start with abdominal cramping or “churning.” These early signs can often predict the start of diarrhea shortly thereafter. To manage this patient's diarrhea, loperamide in combination with budesonide was prescribed initially. However, the diarrhea continued, and, at the beginning of October 2017, the patient was prescribed high-dose steroids at 1 mg/kg. With persistent colitis, the team expects a longer steroid course as well as a slow taper once the colitis is on its way out. Nursing should educate the patient about prophylactic medications that should be taken alongside a longer term steroid course: an antibiotic, antiviral, and antifungal. With this patient, additional written information was sent through the portal, which can help patients recall conversations held in clinic. The portal message reads “…we will call in an antibiotic (Bactrim [sulfamethoxazle and trimethoprim]; Sun Pharmaceutical Industries Ltd), antiviral (acyclovir), and antifungal (fluconazole) to protect you while we suppress your immune system with the steroids. This is a standard practice that we do to prevent any microorganisms that might take advantage while we use the steroid to bring down your heightened immune system. Rather than a treatment, this is a preventative measure.” This explanation can assist in medication compliance, so that the patient understands what each medication is and why it was prescribed. In addition, the provider team will likely prescribe a proton-pump inhibitor in anticipation of acid reflux caused by the high-dose steroids. In this patient's case, the colitis responded to the steroids. However, it is important to educate patients on next steps should the steroids not work. Some patients require infliximab infusions for immunotherapy-induced colitis that is nonresponsive to point to stress is the importance of reporting any symptoms while a patient high-dose steroids. This is for colitis as well as any other autoimmune toxicity requiring a course of high-dose steroids. to adrenal upon to a should be as the patient to education should be provided on the possibility of the need for a upon the steroid the is the provider will order this to whether the patient has adrenal This patient reported and other symptoms in a was at that time to out adrenal and, the were For care that do not with immunotherapy, one of the most important is to that standard protocols for chemotherapy patients often do not Immunotherapy causes side effects that should be to prevent on the front lines a in the and of immunotherapy-induced for the of metastatic melanoma are on the of disease. For patients with and metastases, surgery should be as an This is a in the treatment patients with metastatic disease were started on systemic therapy. In included the need to for diagnosis and that provided More and more data are that the of surgery for patients with and metastatic from the adjuvant clinical trials showing significant in overall survival with systemic therapies after complete resection. There are no clinical trials the of surgery compared with treatment using systemic However, trials and data that surgery may provide a over systemic therapy, or at compared with systemic therapy In study patients with resected metastases were followed the and survival were and that patients with stage IV disease who are to surgery have a survival advantage compared with patients who metastatic disease during long-term follow-up on underwent surgery as part of their treatment. The median survival for patients who underwent surgery for metastatic melanoma was months compared with months for those who did not Although some surgery in more patients, the survival with surgery in these studies for more trials surgery versus systemic therapy. study is an trial patients who have stage and IV on and to therapy with pembrolizumab versus All patients adjuvant the primary is This trial not only will evaluate the of therapy in the metastatic but also likely will provide the most definitive data to on the of surgery for patients with metastatic melanoma in the of effective systemic this trial patients with CNS metastases, and very few of the patients in the previously trials included these Given that CNS metastases a it is to surgery only for patients with CNS metastases who are in need of diagnosis or In this patient with systemic metastases, including brain and surgery an part in the treatment The initial the diagnosis of and because there was no evidence of significant disease the brain at presentation, the patient underwent adjuvant radiation and systemic therapy. there to be progression of disease in the surgery the of diagnosis of and therapeutic resection. of all and known disease the patient to systemic therapy for a of time. This the need to in every of the care for patients with stage IV melanoma for melanoma metastases, is an standard of the patient had a the was for a radiation dose of 30 in 5 (Fig. In this young patient, the radiation dose was chosen to the risk for side radiation was not to the for because it has not been shown to for these MRI were not definitive and the patient did not have a diagnosis of the on the brain lesion was As was for in our trial compared biopsy followed by versus followed by in for a single to the brain and that median survival from to the rate from down to 20% the time to neurologic from to and from to resection of approximately and those that are neurologic symptoms to mass is also demonstrated that the of radiation after surgery for a single brain control of the tumor and additional from in the The of after surgery was This was to only with the of also the of additional brain metastases from down to but, as noted is with significant and thus is not a preferred approach. patients to plus versus There was no in between the 2 without was the toxicity of This was demonstrated by in a study that patients who had brain metastases to with or without the of trial demonstrated that the of without and postoperative were used to for total resection of the brain and for radiation The MRI is 2 to 4 after the postoperative have in and be to the radiation scans. One important when is the of radiation with systemic therapy. may with immunotherapy agents as well as BRAF therefore, of radiation at the time should be through In our case, we elected to proceed with radiation and therapy the time with the that the combination be on that included a small number of This that the combination of and therapies response and tumor through trials in melanoma should immunotherapy combination that include For our patients who are receiving anti–PD-1 therapy, we have the practice of There are some data from our that that the of anti–PD-1 therapy and appears to be trial of and which is the of this combination, is to have some preliminary from that trial by the of the use of and there are and this should be on a For BRAF inhibitor therapy, we have using and therapy because of concerns about increased have therapy from 1 to 3 before and then it from 1 to 3 after the completion of first with in the of 2017, was and about which the of a melanoma diagnosis to a person with 2 small and a and all of that into when the treatment with all of its and also into if had into a with the diagnosis, been sent and to in had 6 to 9 months to we are over months into this of have been if there was a of how the key of and out on both the provider and patient The of stress this for all of the has been did not how of as complications that to be of have been if there was a of how the key of and out on both the provider and patient of these to the systemic that from health care and patients not their we are provided with and but it down to conversations of importance that should have had later in the are essential to the care of patients with metastatic Before the of systemic therapies for surgery and radiation remained the standard of surgery and radiation have taken on and the of systemic therapy with these must be discussed by a team. The patient's medical presentation, and should be in making the final treatment Nursing staff is essential to ensure that the patient understands of the of care and to complications in a with the patient, the medical team can ensure that patients with melanoma have the best in this that are to most patients with melanoma include the patient's performance status, of disease in the brain other sites of systemic and BRAF that affected the patient's course included the development of toxicity from the initial treatment, which a course of steroids. surveillance of the patient the of disease, while both provided a diagnosis and therapeutic and trial options are both noted in this as is the evidence decision making by the team. provided for clinical trials and to radiation and immunotherapy from and from and from and during the of the and no

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