Presentation and management of nivolumab (Opdivo®)-induced pneumonitis

By: Shireen Farzadeh, PharmD Candidate c/o 2019

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Nivolumab (Opdivo®) is a monoclonal antibody that blocks programmed death receptor-1 (PD-1). PD-1 plays an important role in the immune checkpoint cascade. It is indicated for the treatment of melanoma, renal cell carcinoma, non-small cell and small cell lung cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, urothelial carcinoma, colorectal cancer, and classical Hodgkin’s lymphoma. Nivolumab has been associated with the occurrence pneumonitis, an immune-mediated reaction.^1,2 Signs and symptoms of pneumonitis include cough, chest pain, and shortness of breath.¹ Pneumonitis is identified on computed tomography (CT) imaging with focal or diffuse inflammation of lung tissue.³ It can occur anytime, but commonly manifests a few months after initiation of treatment.² Aside from a CT scan, pneumonitis can be also be identified via chest x-ray or pulse oximetry. Diagnostic work-up, depending on the severity of the pneumonitis, can also include nasal swabs as well as cultures and sensitivities of sputum, blood, and urine samples.³

 

In two studies, the incidence of pneumonitis in patients who received nivolumab was approximately three percent, 1/1994 patients and 4/117 patients, respectively.^1,4 In a case report, a patient presented with fever and cough after three doses of nivolumab.⁵ The patient’s CT imaging was consistent with aspiration pneumonia. After four days of broad-spectrum antibiotic use, the patient developed ground-glass opacities (GGO). After receiving corticosteroids, the patient’s GGO disappeared.⁵

 

Management of pneumonitis depends on 4 grades of toxicity – G1 (asymptomatic), G2 (symptomatic), G3 (severe symptoms), and G4 (life-threatening). For G1, nivolumab should first be held (not administered). Afterwards, if there is radiographic evidence of improvement or resolution, it may be resumed. If there is no improvement, pneumonitis should be treated as G2, in which nivolumab should be held until it resolves to G1 or less. Prednisone 1 to 2 mg/kg/day can be given with a taper of 5 to 10 mg/week over 4 to 6 weeks. Empirical antibiotics may be prescribed as well. If there is no improvement after 48 to 72 hours of prednisone, the pneumonitis should be treated as G3. In G3 and G4 pneumonitis, nivolumab is recommended to be permanently discontinued. Empiric antibiotics are recommended as well as methylprednisolone IV 1 to 2 mg/kg/day, which should be tapered over 4 to 6 weeks. If the pneumonitis does not improve after 48 hours, infliximab (Remicade®) 5mg/kg, mycophenolate mofetil (CellCept®) IV 1g twice a day, IV immunoglobulin for 5 days, or cyclophosphamide (Cytoxan®) may be added to the regimen.³

 

Pharmacists play an important role on the healthcare team in managing patients with immune-mediated pneumonitis by ensuring that patients are appropriately monitored and managed. Unfortunately, there is no method for patients to prevent immune-mediated pneumonitis.^2,3 However, pharmacists can play a vital role in counseling patients on the tapering directions and the anticipated adverse effects of corticosteroids for treatment of their immune-mediated pneumonitis. They can also help patients who are receiving corticosteroid doses equivalent to or greater than 16 mg of prednisone for 8 weeks. These patients are at a greater risk of developing pneumoncystis pneumonia and pharmacists can recommend prophylactic agents to their doctors. The first-line medication for prophylaxis of pneumocystis pneumonia is oral sulfamethoxazole and trimethoprim (Bactrim®) (See Table 1). Other prophylactic agents include dapsone (Aczone®), dapsone plus pyrimethamine (Daraprim®) and leucovorin (Wellcovorin®), pentamidine (Pentam®), and atovaquone (Mepron®).⁶ Pharmacists can educate patients and healthcare professionals in an interdisciplinary team that despite cases of nivolumab induced pneumonitis, nivolumab has an acceptable long-term safety profile and that the benefits with respect to indicated cancers’ survival rates outweigh the risks of acquiring pneumonitis.⁷

SOURCES:

1. OPDIVO® (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; Revised Aug 2018.
2. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy:ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi: 10.1093/annonc/mdx225. Accessed 09/16/2018.
3. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768. doi: 10.1200/JCO.2017.77.6385. Accessed 09/16/2018.
4. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257-265. doi:10.1016/S1470-2045(15)70054-9. Accessed 09/16/2018.
5. Tada K, Kurihara Y, Myojo T, et al. Case report of nivolumab-related pneumonitis. Immunotherapy. 2017;9(4):313-318. doi: 10.2217/imt-2016-0129. Accessed 09/16/2018.
6. Thomas CF Jr, Limper AH. Pneumocystis pneumonia. N Engl J Med. 2004;350(24):2487. doi: 10.1056/NEJMra032588. Accessed 09/16/2018.
7. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020-1030. doi: 10.1200/JCO.2013.53.0105. Accessed 09/16/2018.