Nivolumab

Adrenal insufficiency may occur; may require hormone replacement therapy and/or corticosteroid therapy. The median time to onset across several clinical trials was 3 to 4.3 months (range: 15 days to 21 months). In studies, the median duration of high-dose systemic corticosteroid therapy was 9 to 11 days (range: 1 day to 2.7 months). Monitor for signs/symptoms of adrenal insufficiency both during and after treatment. Administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent followed by a taper) for severe (grade 3) or life-threatening (grade 4) adrenal insufficiency. Withhold nivolumab for moderate (grade 2) and permanently discontinue for severe (grade 3) or life-threatening (grade 4) toxicity.

Immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been observed in patients receiving nivolumab; some cases have been fatal. The median time to onset of immune-mediated rash ranged was 18 days to 2.8 months (range: 1 day to 25.8 months) after nivolumab initiation. Withhold treatment for signs or symptoms of SJS or TEN and refer to specialist for assessment and treatment; discontinue permanently if confirmed. Withhold treatment for grade 3 rash and permanently discontinue for life-threatening (grade 4) rash and administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent followed by a taper) for severe (grade 3) or life-threatening (grade 4) immune-mediated rash. High-dose systemic corticosteroids (followed by a corticosteroid taper) were administered to some patients for a median duration of 12 to 14 days (range: 1 day to 9 months); topical corticosteroids were also used to manage dermatologic toxicity. Complete resolution occurred in nearly half of patients; some patient experienced recurrence with rechallenge.

Type 1 diabetes mellitus may occur, including cases of diabetic ketoacidosis. The median time to onset was 2.5 to 4.4 months (range: 15 days to 22 months). Monitor for hyperglycemia. Withhold nivolumab for severe (grade 3) hyperglycemia until blood sugar has been appropriately controlled. Permanently discontinue for life-threatening (grade 4) hyperglycemia.

Immune-mediated encephalitis (without clear etiology) may occur. Withhold nivolumab for new-onset moderate to severe neurologic signs/symptoms; evaluate to rule out other neurologic causes or infection. Evaluate with neurology consultation, brain MRI, and lumbar puncture. For confirmed immune-mediated encephalitis felt to be caused by nivolumab (if other etiologies are ruled out), administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent), followed by a corticosteroid taper. Permanently discontinue nivolumab if immune-mediated encephalitis occurs.

Diarrhea or colitis occurred commonly in patients receiving nivolumab (some cases were fatal). Immune-mediated colitis (defined as no other clear etiology and requiring corticosteroid use), including cases of grades 2 and 3 colitis, occurred in some patients. The median time to onset of colitis was 1.6 to 5.3 months (range: 2 days to 21 months) from nivolumab initiation; some cases developed after nivolumab was discontinued for other reasons. In studies, the median duration of high-dose systemic corticosteroid therapy was 23 days to 1.1 months (range: 1 day to 12 months). Most patients with grade 2 or 3 immune-related colitis had complete resolution (improvement to grade 0); after resolution, nivolumab was reinitiated in some patients without recurrence, although was permanently discontinued in other patients. Monitor for signs and symptoms of colitis. May require treatment interruption, corticosteroid therapy, and/or permanent discontinuation. Severe colitis (grade 3) or life-threatening colitis (grade 4) should be managed with corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. Moderate colitis (grade 2) of >5 days duration should be managed with corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent) followed by a corticosteroid taper; may increase to prednisone 1 to 2 mg/kg daily (or equivalent) if colitis worsens or does not improve despite corticosteroid therapy. Some cases required the addition of infliximab to cort

ALT, AST, alkaline phosphatase, and total bilirubin elevations have occurred in nivolumab-treated patients. Immune-mediated hepatitis (defined as no other clear etiology and requiring corticosteroid use) occurred in patients receiving nivolumab; most cases included grade 2 and grade 3 hepatitis, although grade 4 toxicity also occurred. The median time to onset was 2.1 to 3.3 months (range: 6 days to 11 months) after nivolumab initiation. Immune-mediated hepatitis was managed with high-dose systemic corticosteroids; in some cases, mycophenolate was added to corticosteroid therapy. In studies, the median duration of high-dose systemic corticosteroid therapy was 23 days to 1.1 months (range: 1 day to 13.2 months). Immune-mediated hepatitis resolved and did not recur with continued corticosteroid use in some patients, although some patients experienced recurrence and permanently discontinued treatment. When used in combination with ipilimumab, a majority of patients had complete resolution of hepatitis after completion of steroid therapy, and some patients had recurrence or worsening hepatitis when nivolumab and ipilimumab were restarted. Monitor liver function at baseline and periodically for changes. In patients without hepatocellular carcinoma (HCC), initiate corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent for grade 2 or prednisone 1 to 2 mg/kg daily or equivalent followed by a corticosteroid taper for grade 3 or 4) transaminase elevations (with or without total

Hypophysitis may occur; some patients developed grades 1, 2, or 3 toxicity. Most patients received corticosteroids; combination therapy was restarted for the majority of the patients without worsening hypophysitis (several patients continued on corticosteroid therapy). The median time to onset was 2.7 to 4.9 months (range: from 27 days to 11 months). Monitor for signs/symptoms of hypophysitis. Administer hormone replacement therapy as clinically indicated and corticosteroids (prednisone 1 mg/kg/day or equivalent followed by a taper) for grade 2 or higher toxicity. In studies, the median duration of high-dose systemic corticosteroid therapy was 14 to 19 days (range: 1 day to 2 months). Withhold nivolumab for moderate (grade 2) or severe (grade 3) and permanently discontinue treatment for life-threatening (grade 4) hypophysitis.

Infusion-related reactions have occurred with both single-agent nivolumab and when used in combination with ipilimumab; severe reactions, although rare, were observed when given as a single agent. Monitor closely; discontinue for severe or life-threatening reactions. Mild or moderate reactions may be managed by interrupting or decreasing the infusion rate. A pharmacokinetic study that looked at the safety of a shortened nivolumab infusion time found similar incidences of infusion-related reactions when nivolumab was administered over 60 or 30 minutes. Small percentages of patients receiving the 60-minute or 30-minute infusion experienced reactions within 48 hours of infusion, which resulted in dose delay, permanent discontinuation, or withholding of nivolumab (0.5% and 1.4%, respectively).

Renal dysfunction has occurred with nivolumab therapy. Immune-mediated nephritis (defined as renal dysfunction or ≥ grade 2 creatinine elevations with no other clear etiology and requiring corticosteroid use) or autoimmune nephritis may occur with nivolumab treatment. The median time to onset was 2.7 to 4.6 months (range: 9 days to 12.3 months). For single-agent nivolumab, all patients received high-dose systemic corticosteroids (at least 40 mg prednisone or equivalent per day) for a median duration of 3 weeks (range: 1 day to 15.4 months); complete resolution occurred in about one-half of patients, with no recurrence upon rechallenge. When used in combination with ipilimumab, two-thirds of patients received high-dose systemic corticosteroids (at least 40 mg prednisone or equivalent per day) for a median duration of 2 weeks (range: 1 day to 1.1 months); complete resolution occurred in all patients, some patients resumed combination therapy with no recurrence. Monitor serum creatinine at baseline and periodically during treatment. Initiate corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper for life-threatening (grade 4) serum creatinine elevation and permanently discontinue nivolumab. Withhold treatment for moderate (grade 2) and severe (grade 3) creatinine elevations and administer corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent) followed by a corticosteroid taper; if toxicity worsens or does not improve, increase t

Uveitis and iritis have been reported. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving nivolumab (as a single agent and in combination with ipilimumab) and may require systemic corticosteroids to reduce the risk of permanent vision loss.

Nivolumab may cause immune-mediated pneumonitis (severe pneumonitis or interstitial lung disease); fatal cases have been reported. Immune-mediated pneumonitis is defined as no other clear etiology and requiring corticosteroid use. The median time to onset was 1.6 to 3.5 months (range: 1 day to 22.3 months) across several clinical trials. Some cases developed after nivolumab was discontinued for other reasons. High-dose systemic corticosteroids (followed by a corticosteroid taper) were administered for a median duration of 26 to 30 days (range: 1 day to 11.8 months). Most patients improved to grade 0 or 1; some patients with grade 2 or 3 pneumonitis had complete resolution (after completing corticosteroid therapy) and nivolumab was reinitiated without recurrence in some patients. Monitor for signs (with radiographic imaging) and symptoms of pneumonitis. May require treatment interruption, corticosteroid therapy, and/or permanent discontinuation. Grades 2, 3, or 4 pneumonitis should be managed with corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. Withhold treatment until resolution for moderate (grade 2) immune-mediated pneumonitis; permanently discontinue for severe (grade 3) or life-threatening (grade 4) immune-mediated pneumonitis.

Immune-mediated hyperthyroidism and hypothyroidism/thyroiditis have occurred, mostly grades 1 and 2 hyper-/hypothyroidism (one patient receiving nivolumab in combination with ipilimumab experienced grade 3 autoimmune thyroiditis). The median onset for hyperthyroidism was 23 days to 1.5 months (range: 1 day to 14.2 months); most cases resolved (may require medical management, including corticosteroids and methimazole). Hypothyroidism occurred with a median onset of 2 to 3 months (range: 1 day to 16.6 months). Most patients received subsequent nivolumab (with or without ipilimumab) treatment while continuing thyroid replacement therapy. Monitor thyroid function at baseline and for changes periodically during treatment (in one study, patients were evaluated at baseline, treatment day 1, and every 6 weeks). Isolated hypothyroidism may be managed with hormone replacement therapy; initiate medical management (eg, methimazole) to control hyperthyroidism.

Other clinically relevant and potentially fatal immune-mediated disorders may occur; may develop after discontinuation of nivolumab. Immune-mediated adverse reactions observed included facial/abducens nerve paresis, autoimmune neuropathy, demyelination, duodenitis, gastritis, Guillain-Barré syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), hypopituitarism, motor dysfunction, myasthenic syndrome, myocarditis, myositis, pancreatitis, polymyalgia rheumatica, rhabdomyolysis, sarcoidosis, systemic inflammatory response syndrome, and vasculitis. If an immune-mediated adverse event is suspected, evaluate to exclude other causes. Based on symptom severity, withhold or permanently discontinue nivolumab, administer high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to grade 0 or 1, begin corticosteroid taper (over at least 1 month). After corticosteroid taper is completed and based on the severity of the reaction, may consider reinitiating nivolumab. Disease-related concerns:

Anti-PD-1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. A retrospective study analyzed the safety and efficacy of treatment with anti-PD-1 monoclonal antibodies (eg, nivolumab or pembrolizumab) in melanoma patients with preexisting autoimmune disease or prior significant ipilimumab-mediated adverse immune events. Results showed that while immune toxicities associated with this class of therapy did occur, most reactions were mild and easily manageable, and did not require permanent drug therapy discontinuation. A significant percentage of patients achieved clinical response with anti-PD-1 monoclonal antibody therapy, despite baseline autoimmunity or prior ipilimumab-related adverse events (Menzies 2017).

Patients who received allogeneic hematopoietic stem cell transplant (HSCT) following discontinuation of nivolumab therapy experienced complications (some fatal) including severe or refractory acute graft versus host disease (some cases occurring within 14 days after stem cell infusion), noninfectious febrile syndrome (requiring corticosteroids), lymphocytic encephalitis, viral encephalitis, and sinusoidal obstructive syndrome (SOS; formerly called veno-occlusive disease). These complications may occur despite intervening therapy between nivolumab and HSCT. Monitor closely for early signs/symptoms of transplant-related complications and manage promptly. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.