Nivolumab (Opvido®) (Melanoma)
Posted: Tuesday, March 20, 2018
‘Taking the Brakes Off’ the Immune System
Melanoma is among the cancers that evade immune destruction in part by suppressing the immune response.1 Strategies that restore innate antitumor activity—effectively “taking the brakes off” the immune system—include agents that block signaling through the programmed cell death protein 1 (PD-1) receptor on the surface of T cells. These immune checkpoint inhibitors have become an important part of the antimelanoma treatment armamentarium,2 contributing to a dramatic improvement in outcomes over the past few decades.
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.3 It was first approved by the U.S. Food and Drug Administration (FDA) for treatment of unresectable and metastatic melanoma and more recently for adjuvant use in early melanoma with lymph node involvement.4 In the advanced-disease setting, nivolumab is sometimes combined with ipilimumab (Yervoy), another immune checkpoint inhibitor with a different mechanism of action. Ipilimumab binds to cytotoxic T-lymphocyte antigen 4 (CTLA-4) and blocks the interaction of CTLA-4 with its ligands, CD80/CD86, augmenting T-cell activation and proliferation.5 Combination therapy with nivolumab and ipilimumab demonstrated a longer overall survival in patients with advanced melanoma.6
In the setting of unresectable or metastatic melanoma, single-agent nivolumab tends to be most efficacious in patients without rapid disease progression, with a normal lactate dehydrogenase level and with stage M1a or M1b disease, according to Jeffrey S. Weber, MD, PhD, Deputy Director and Laura and Isaac Perlmutter Cancer Center Professor of Medicine NYU, Langone Medical Center, New York. Other patients with rapidly growing disease or high tumor burden may not derive as much benefit and “remain the major unmet need,” he said. (Also, because it takes time to mount an immune response, targeted therapy with agents that block the activity of the BRAF protein may be preferred for patients with a BRAF V600–activating mutation who need a rapid response.2)
Tumor levels of PD-L1 are prognostic but not reliably predictive for nivolumab benefit in melanoma, Dr. Weber commented. “In my view, PD-L1 testing is only useful in the metastatic setting,” he elaborated, as the benefit of the combination of ipilimumab and nivolumab appears to be restricted to the PD-L1–negative population. 7
Patients are typically given 240 mg of nivolumab every 2 weeks, but larger doses can be given less frequently, reducing the infusion burden, according to Dr. Weber, who has used the drug for about a decade and in roughly 500 patients with melanoma, initially in clinical trials and then in clinical practice. “I was one of the early investigators to use it every 3 weeks and then every 4 weeks, and it works well. I don’t think it really changes the side-effect profile to give 360 mg every 3 weeks or 480 mg every 4 weeks.” In early March 2018, the FDA approved the use of nivolumab at a fixed dose of 480 mg intravenously every 4 weeks in patients with advanced or resected disease; 360 mg every 3 weeks remains off label.
Strategies to Optimize Efficacy
Given nivolumab’s mechanism of action, one strategy for optimizing outcomes is avoiding immunosuppression as much as possible. “It’s probably a bad idea to preventively use steroids or to use them when you don’t really need to,” Dr. Weber said. “Unless patients have developed immune-related adverse events, you are not going to need steroids, and they won’t help.”
In addition, some simple upfront counseling may help maximize the duration of therapy by mitigating factors that can add to toxicity. “We tell patients to stay away from alcohol, since it’s a hepatotoxin, as potentially is nivolumab. And we tell patients to avoid really spicy foods, because the last thing you want to do is to inflame your GI tract at a time when you are taking a drug that could also inflame the GI tract,” he explained.
Sequencing and Combining Therapies
When it comes to sequential immunotherapy in patients with unresectable or metastatic melanoma, his usual practice is to give single-agent nivolumab first and then ipilimumab second if there is disease progression, Dr. Weber said, as this sequence yields better outcomes than the reverse.8 In patients with untreated metastatic melanoma, nivolumab monotherapy and nivolumab/ipilimumab combination therapy yield longer progression-free survival than ipilimumab monotherapy.7,9 But oncologists using the combination should be prepared for an increase in toxicity over that seen with nivolumab alone.
Common, generally mild adverse effects of nivolumab include fatigue, diarrhea, rash, and musculoskeletal pain, among others.8-10 More serious immune-mediated adverse effects, which are typically less common, include diarrhea/colitis, rash, hepatitis, endocrinopathy, and pneumonitis, among others.
“I think the most important thing about nivolumab is it’s very well tolerated. Our patients on nivolumab go to work and lead normal lives,” Dr. Weber reported. “As I tell them, the likelihood of having any severe, really limiting side effect is [typically] 10% or less.”
“I make sure that patients know the key is good communication between the patient and the care team,” he added. At his institution, all patients are given counseling and printed information about side effects before receiving nivolumab. “We always encourage them, when they are not sure about calling, to err on the side of calling. Any protocol patients on any complex regimen have my cell phone number, and they all have my e-mail address.”
Patients are instructed to notify the team immediately if they experience fever higher than 100.5˚F; diarrhea more than once a day; bloody stool; profound fatigue; or bloody, green or yellow sputum—possible indicators of adverse effects that can become life-threatening. “Those are the things we need to hear about as soon as they happen,” Dr. Weber stressed. Other possible adverse events include changes in urine or vision, shortness of breath, and muscle weakness.10
Educating patients is key to the safe use of nivolumab in melanoma, according to Jeannie Warner, RN, OCN, Clinical Nurse Coordinator in the Melanoma and Renal Cell Cancer Clinics at Seattle Cancer Care Alliance. She has a formal education session with patients and family members a week or two before or the day of starting therapy.
“My approach is first to see if they’ve had friends or family members who have had cancer treatment before and find out what kind of treatment it was, because the next thing I talk about with them is the difference between chemotherapy and immunotherapy,” explained Ms. Warner, who has been an oncology and hospice nurse for 23 years and has worked with patients receiving immunotherapy for more than 1 year. She said she shares with them that this type of immunotherapy is typically well tolerated, “that they shouldn’t expect to lose their hair, have nausea every day, be at higher risk of infection, or miss a lot of work while they are on treatment. I try to wipe the slate clean, so they don’t have any preexisting ideas about what to expect.”
She next discusses with patients how “taking the brakes off” the immune system allows it to better target the cancer but also can lead to inflammation in healthy organs. She also reviews how that may manifest. “I go head to toe with them, letting them know it can impact anything in their body. I separate the common side effects, which are fairly minimal, from the uncommon but more serious adverse effects,” she elaborated.
Patients are instructed to call any time side effects begin to affect their daily living and immediately if they experience any symptoms of more serious adverse effects. “I make the point that they are never bothering us. I tell them, this is what we do, this is what we like to do, and we want to keep you on treatment. So the sooner we know about things, the sooner we can help mitigate side effects and continue your treatment.”
During her patient education session, Ms. Warner uses a simple handout about nivolumab from her institution’s electronic medical record. “I like to keep it to 2 to 3 pages so patients aren’t overwhelmed. I give it to them and highlight the things I am talking about. I always make sure they see both the common side effects and the symptoms of [an adverse immune reaction] that has gone too far, and when to call their doctor 24-7.”
She also gives the patient a wallet card that lists the patient’s name and the physician’s name and 24-7 contact number; it also instructs emergency staff not to start treatment before contacting the physician. “We want to be really careful that they are not, for example, thinking the patient is on chemotherapy and working them up for infection when they could have some flu-like symptoms that may be related to the treatment itself,” she explained.
Assessing Adverse Effects
“Because we give nivolumab every 2 weeks, our protocol is that patients must see a provider (physician or physician assistant) or a nurse every time they are here for infusion, for a review,” Ms. Warner said. If patients develop side effects, she typically has an in-person visit or phone call with them at least every week. “I basically do a head-to-toe assessment for side effects every time I talk with a patient,” she said. These measures help to identify subtle, but potentially important signs of immune-mediated side effects.
“It takes quite a bit of teasing out with patients to see whether a symptom is related to the immunotherapy or something else.”
It takes quite a bit of teasing out with patients to see whether a symptom is related to the immunotherapy or something else.
Routine laboratory monitoring typically detects certain more serious adverse effects before patients become symptomatic. For example, thyroid function tests every 4 to 6 weeks generally detect thyroid dysfunction early, and liver function tests every 2 to 3 weeks usually identify hepatitis early.10
Preventing and Managing Common Adverse Effects
Dry Skin and Rash: Ms. Warner recommends that patients start using a moisturizer when they start nivolumab. “I ask them to use a good-quality emollient moisturizer on their whole body twice a day. We want to prevent dry skin and rash from becoming so bothersome they think about stopping treatment,” she explained. More severe dermatologic adverse effects may require steroids or antihistamines; more information on treating dry skin and rash is available in the NCCN Guidelines for Management of Immunotherapy-Related Toxicities.10
Constipation: Patients who experience mild constipation may be started on a stool softener protocol. “But we mostly talk about calling as soon as they see changes in bowel habits, so we can work with them on a specific bowel program. We don’t want them self-treating constipation or the next thing you know, they are on multiple laxatives and we didn’t know about it. What they may really be experiencing are immune-mediated side effects,” Ms. Warner said.
Diarrhea: Patients with mild diarrhea are often instructed to go on a low-residue, bland-food BRAT (bananas, rice, applesauce, toast) diet. “Generally, diarrhea eventually needs to be treated with steroids, but we don’t jump right to steroids. We might start with the BRAT diet to see if we can get the diarrhea down to just a few stools a day,” she said. Patients are also encouraged to drink a 50-50 sport drink-water combination or broth to replace fluids and electrolytes. “We will sometimes use a little bit of loperamide, but not for more than 24 hours without close follow-up, because it might slow the diarrhea but doesn’t really control what is causing it, the inflammation of the bowel,” she noted. Immunotherapy may need to be held if there is concern for rapid progression.10
Musculoskeletal Pain: Older adults, in particular, may develop or have worsening of joint pain on nivolumab. “Under the physician’s approval, I work with such patients, so they can use ibuprofen or acetaminophen for joint aches and pains,” Ms. Warner said. They may also be referred for physical therapy.
Dose Holds and Treatment Discontinuations
Dose holds are used for certain grade 2 and higher adverse effects of nivolumab, typically with initiation of steroid therapy. “When somebody gets past 12 or 24 weeks, dose holds will often happen, and it’s a way of keeping things going for the patient,” Dr. Weber commented. For example, in a patient with a grade 2 or 3 rash, a dose hold combined with a brief course of steroids often allows subsequent resumption of therapy. “Usually, I will skip a dose and if I see resolution of symptoms to grade 1 or none, I will restart it,” he said. “I don’t think it is a good idea to restart someone in the face of grade 2 symptoms.”
Patience in restarting nivolumab is key, Ms. Warner agreed. “The big tip here is not to push it too hard to restart sooner than needed because that can backfire. You want to make sure there is a slow taper on the steroids. When we taper patients too quickly, they can have a flare again before we are able to restart treatment,” she said. The team also considers the impact of treatment on patients’ daily activities. “We don’t think about restarting nivolumab until the patient has returned to normal for at least a couple of weeks,” she noted.
Decisions to permanently discontinue nivolumab because of toxicity require judgment and consideration of the treatment setting, according to Dr. Weber. “You have to have a different threshold for stopping due to side effects when you are in the adjuvant mode with a patient who has a 50% chance of being cured, versus a patient with metastatic disease,” as the latter patient needs the treatment to survive.
Importance of Multidisciplinary Care
A multidisciplinary approach is critical in the care of patients on immunotherapy, Ms. Warner asserted. “It’s very important to make sure you are using all of the supportive care services available to you. We are lucky to have quite a few supportive services in our organization alone, but the team should also be aware of what’s available for a patient in the community,” she said.
It’s very important to make sure you are using all of the supportive care services available to you.
In addition to oncologists and nurses, important team members include varied specialists, nutritionists, social workers, and physical therapists. She also endorsed enlisting the help of patient navigators and pharmacists. “We rely on our pharmacists to review medications and supplements for all of our new patients, to see if there are any interactions that could affect the effectiveness of the immunotherapy or any contraindications that could harm the patient or increase the dose availability,” she explained.
Dr. Weber’s institution has similarly assembled a virtual clinic of diverse clinicians dedicated to managing immune-related adverse effects of nivolumab and similar agents. “You need to have consultants who are familiar with the side effects and who can provide rapid turnaround,” he recommended.
Jeffrey S. Weber, MD, PhD, has received honoraria, institutional research funding, and travel expenses from Bristol-Myers Squibb and Merck. He also has served as a consultant or advisor to Bristol-Myers Squibb and Merck.
Jeannie Warner, RN, OCN, disclosed no relevant relationships.
- Ko JS. The immunology of melanoma. Clin Lab Med. 2017;37:449–471.
- Coit DG, Thompson JA, Albertini MR, et al. NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 2.2018. Accessed February 27, 2018. To view the most recent version of these guidelines, visit NCCN.org.
- National Cancer Institute. Nivolumab. Available at https://www.cancer.gov/publications/dictionaries/cancer-terms/def/nivolumab. Accessed February 27, 2018.
- Drugs.com. Opdivo approval history. Available at https://www.drugs.com/history/opdivo.html. Accessed February 27, 2018.
- National Cancer Institute. Ipilimumab. Available at https://www.cancer.gov/publications/dictionaries/cancer-drug/def/ipilimumab. Accessed February 27, 2018.
- Wolchok J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377:1345–1356.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23–34.
- Bristol Myers-Squibb Company. Opdivoâ (nivolumab). Full prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s044s045lbl.pdf.Accessed March 1, 2018.
- Weber JS, Gibney G, Sullivan RJ, et al. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol 2016;17:943–955.
- Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities. Version 1.2018. Accessed March 15, 2018. For the most recent version of these guidelines, visit NCCN.org.