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Nivolumab: Mechanism of Action, Adverse Effects, Contraindications and Dosage

Mechanism of Action of Nivolumab

Nivolumab is a monoclonal antibody directed against the programmed cell death–1 (PD-1) receptor. By inhibiting this immune checkpoint, nivolumab enhances T-cell–mediated immunity against advanced cancer.

Treatment of Advanced Renal Cell Carcinoma with Nivolumab

Nivolumab is approved for first-line therapy of metastatic renal cell carcinoma in combination with cabozantinib (all risk groups) and in combination with ipilimumab for patients with poor prognosis. Nivolumab is also approved as second-line therapy.

• First-line therapy of metastatic renal cell carcinoma with Nivolumab and cabozantinib: In the CheckMate-9ER trial, the combination improved progression-free survival (17 vs. 8 months; HR 0.51), overall response rate (56% vs. 27%), complete response (8% vs. 5%), and overall survival (HR 0.60) versus sunitinib, with benefit across all risk groups (Choueiri et al., 2021).
• First-line therapy of metastatic renal cell carcinoma with Nivolumab and ipilimumab: In CheckMate-214, the combination showed superior progression-free and overall survival compared with sunitinib in first-line therapy for patients with intermediate and poor risk (overall survival 56 vs. 38 months at 5-year follow-up). The regimen also demonstrated strong activity in sarcomatoid renal cell carcinoma (Albiges et al., 2020).
• Second-line therapy of metastatic renal cell carcinoma with Nivolumab monotherapy: As second-line therapy after tyrosine kinase inhibitor failure, nivolumab improved progression-free survival, response rate (CR + PR: 25% vs. 5%), and overall survival (25 vs. 20 months) versus everolimus, with fewer adverse effects (Motzer et al., 2015).

Treatment of Advanced Urothelial Carcinoma with Nivolumab

Nivolumab is approved as first-line therapy of metastatic urothelial (bladder) carcinoma in combination with Cisplatin-Gemcitabine chemotherapy, for second-line therapy of metastatic urothelial carcinoma after platinum-containing chemotherapy and for adjuvant therapy after cystectomy.

• First-line therapy of metastatic urothelial (bladder) carcinoma with Nivolumab and cisplatin-gemcitabine chemotherapy (GC+N): The combination GC+N was tested in a phase III trial (CheckMate 901) as first-line therapy against GC (Heijden et al., 2023): Overall survival 22 vs. 19 months, complete remission 22% vs. 12%, grade 3–5 adverse events were 62% vs. 52%.
• Second-line therapy of metastatic urothelial (bladder) carcinoma with nivolumab after progression with platinum-based chemotherapy: objective response rate 20–26%, with median overall survival 9–10 months (Sharma et al., 2016; Sharma et al., 2017).
• Adjuvant therapy after cystectomy: In patients at high risk of recurrence (pT3–4 or pN+), nivolumab improved disease-free survival after cystectomy: 21 months (nivolumab) vs. 11 months (placebo) (Bajorin et al., 2021). In Europe, approval was restricted to patients with tumor-cell PD-L1 expression ≥1%.

Pharmacokinetics of Nivolumab

Administer by intravenous infusion over 30–60 min. The elimination half-life is approximately 26 days. Catabolic protein metabolism mediates clearance.

Adverse Effects of Nivolumab

Nivolumab is associated with immune-mediated adverse events that may occur up to five months after the last dose. Depending on severity, clinicians should hold or discontinue pembrolizumab and initiate corticosteroids (typically methylprednisolone 1–3 mg/kg/day), followed by an appropriate taper. See the section on adverse effects of immune checkpoint inhibition for each organ system.

Contraindications to Nivolumab

Loss of clinical benefit or unequivocal disease progression; grade 4 immune-mediated adverse events; persistent grade 2/3 adverse events despite treatment interruption and corticosteroids. Pregnancy and lactation.

Drug Interactions with Nivolumab

Systemic corticosteroids and other immunosuppressants may blunt nivolumab’s pharmacodynamic activity and should be avoided unless clinically necessary to manage immune-mediated toxicity. Live vaccines are generally not recommended during treatment.

There is a complex interplay between the gut microbiome and the activity of immune checkpoint inhibitors. Exposure to systemic antibiotics around the start of therapy has been associated in multiple observational studies with reduced efficacy of checkpoint inhibitors.

Dosing of Nivolumab Monotherapy

Administer 240 mg every two weeks as a short infusion (about 30 minutes) or 480 mg every four weeks as a short infusion (about 60 minutes, depending on institutional practice).

Dosing of Nivolumab in Combination with Ipilimumab

Administer nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg intravenously every three weeks for four cycles. Continue with nivolumab monotherapy afterward using the dosing above.

Monitoring During Therapy with Nivolumab

Before each treatment cycle of nivolumab, assess for symptoms and laboratory abnormalities. Provide thorough patient education and perform targeted review of systems across all organ systems to ensure prompt diagnostics, treatment pause or discontinuation, and timely steroid initiation when indicated.

• Thorough medical history and physical examination: Inspect skin and oral mucosa; auscultate lungs; perform a focused neurologic examination; measure the blood pressure.
• Laboratory monitoring: Complete blood count with differential; electrolytes; liver function tests and bilirubin; lipase; creatine kinase and troponin; coagulation studies; blood glucose; creatinine; TSH and free T4; LDH; CRP.

References

L. Albiges, N. M. Tannir, M. Burotto, D. McDermott, E. R. Plimack, and R. J. Motzer, “Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial.,” ESMO open, vol. 5, no. 6, p. e001079, 2020.

D. F. Bajorin et al., “Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.,” NEJM, vol. 384, no. 22, pp. 2102–2114, 2021, doi: 10.1056/NEJMoa2034442.

Motzer, R. J.; Escudier, B.; McDermott, D. F.; George, S.; Hammers, H. J.; Srinivas, S.; Tykodi, S. S.; Sosman, J. A.; Procopio, G.; Plimack, E. R.; Castellano, D.; Choueiri, T. K.; Gurney, H.; Donskov, F.; Bono, P.; Wagstaff, J.; Gauler, T. C.; Ueda, T.; Tomita, Y.; Schutz, F. A.; Kollmannsberger, C.; Larkin, J.; Ravaud, A.; Simon, J. S.; Xu, L.-A.; Waxman, I. M.; Sharma, P. & CheckMate025 Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.
New Engl J Med 2015, 373, 1803-1813.

Sharma, P.; Callahan, M. K.; Bono, P.; Kim, J.; Spiliopoulou, P.; Calvo, E.; Pillai, R. N.; Ott, P. A.; de Braud, F.; Morse, M.; Le, D. T.; Jaeger, D.; Chan, E.; Harbison, C.; Lin, C.-S.; Tschaika, M.; Azrilevich, A. & Rosenberg, J. E. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.
The Lancet. Oncology, 2016, 17, 1590-1598.

Sharma, P.; Retz, M.; Siefker-Radtke, A.; Baron, A.; Necchi, A.; Bedke, J.; Plimack, E. R.; Vaena, D.; Grimm, M.-O.; Bracarda, S.; Arranz, J. Á.; Pal, S.; Ohyama, C.; Saci, A.; Qu, X.; Lambert, A.; Krishnan, S.; Azrilevich, A. & Galsky, M. D. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial.
The Lancet. Oncology, 2017, 18, 312-322.

  Deutsche Version: Nivolumab

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