Melanoma Coverage from Every Angle

Nivolumab (Opvido®) in Melanoma

Updated: Wednesday, December 11, 2019
Posted: Tuesday, March 20, 2018

Since the original Spotlight on the use of nivolumab in the management of cutaneous melanoma was posted, many new data have emerged. In particular, recent evidence from the Checkmate 067 study published in The New England Journal of Medicine indicated that long-term survival at 5 years was better in patients with advanced cutaneous melanoma who received nivolumab plus ipilimumab or nivolumab alone compared with those who received ipilimumab alone.1 Indeed, James Larkin, PhD, of the Royal Marsden NHS Foundation Trust in London, and colleagues reported the median overall survival was longer than 60.0 months (median not reached), 36.9 months, and 19.9 months in the nivolumab-plus-ipilimumab group, the nivolumab group, and the ipilimumab group, respectively.

CheckMate 511 Study

Among patients with advanced cutaneous melanoma in the CheckMate 511 phase IIIb/IV trial, increasing the nivolumab dose to 3 mg/kg and decreasing the ipilimumab dose to 1 mg/kg led to a better safety profile without compromising progression free survival or overall survival.2 This dosing modification, recently published in the Journal of Clinical Oncology, may offer patients with advanced melanoma a safer combination regimen of nivolumab and ipilimumab.

The CheckMate 511 trial included 360 adult patients with treatment-naive, unresectable stage III or IV cutaneous melanoma. Patients were randomly assigned to treatment with either the standard U.S. Food and Drug Administration (FDA)-approved dosing of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg or the alternative dosing of nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg once every 3 weeks for four doses. The primary trial endpoint was incidence of treatment-related grade 3 to 5 adverse events.

Metastatic Uveal Melanoma

Notably, new data are emerging on the combination of nivolumab plus ipilimumab for the management of metastatic uveal melanoma, a condition that is difficult to treat. It accounts for up to 5% of all melanoma cases in the United States and is the most common primary intraocular malignant tumor in adults.

A phase II study was conducted ( identifier NCT01585194)3 in patients with metastatic disease; 19 patients completed all four cycles of the combination regimen (1 mg/kg of nivolumab; 3 mg/kg of ipilimumab). Preliminary results reported at the annual meeting of the American Society of Clinical Oncology in 2019 showed that most patients in the study experienced treatment-related adverse events, and just fewer than half had grade 3 or 4 effects, with 10 patients leaving the study due to adverse events. The median duration of follow-up was 60.5 weeks; the median progression-free survival was 26 weeks, and overall survival exceeded 1 year (83 weeks or 1.6 years). The 1-year overall survival was 62%.

The combination of ipilimumab and nivolumab is included as a systemic therapy option in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Uveal Melanoma; however, it is not preferred over the other options listed.4

Precautions Associated With Nivolumab Therapy

Clinicians should be aware of potential immune-mediated conditions associated with nivolumab therapy. They include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and renal dysfunction, among others.5

[Editor’s Note: These precautions are based on the FDA-approved labeling for nivolumab.5 The NCCN Guidelines for Management of Immunotherapy-Related Toxicities include additional recommendations for managing potential immune-mediated conditions associated with nivolumab therapy.6]

Pneumonitis: Patients should be assessed for symptoms of immune-related pneumonitis and may be monitored radiographically. Corticosteroids should be administered for grade 2 or more severe pneumonitis. Clinicians should permanently discontinue nivolumab for grade 3 or 4 adverse events and should withhold the drug until resolution for grade 2 adverse events.5

Colitis: Patients should be monitored for signs and symptoms of immune-related colitis. Corticosteroids are recommended for grade 2 (of more than 5 days’ duration), 3, or 4 colitis. Nivolumab should be withheld for grade 2 or 3 colitis and permanently discontinued for grade 4 or recurrent colitis upon reinitiation of nivolumab.5

Hepatitis: Patients’ liver function should be evaluated prior to and periodically during treatment. Corticosteroids should be administered for grade 2 or greater transaminase elevations, according to the FDA labeling.5 The NCCN Guidelines for Management of Immunotherapy-Related Toxicities recommend considering steroids for grade 2 elevations and administering steroids for grade 3 or 4 elevations.6 Nivolumab should be withheld for moderate (grade 2) and permanently discontinued for severe (grade 3) or life-threatening (grade 4) immune-mediated hepatitis.5

Endocrinopathies: Nivolumab may cause adrenal insufficiency, autoimmune thyroid disorders, hypophysitis, and type 1 diabetes mellitus. FDA labeling suggests hormone replacement as clinically indicated and corticosteroids should be administered for grade 2 or greater hypophysitis.5 The NCCN Guidelines also include recommendations for each type of endocrinopathy.6

Nephritis/renal dysfunction: Serum creatinine levels should be assessed prior to and periodically during treatment. Nivolumab therapy should be withheld for grade 2 or 3 nephritis and corticosteroids administered. Permanently discontinue nivolumab therapy for grade 4 increased serum creatinine levels.5

[Editor’s Note: At the end of this update, see Commentary by Michael A. Postow, MD, JNCCN 360 Co-Site Editor in Melanoma, about the use of nivolumab in the treatment of melanoma in 2019.]



  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381:1535–1546.
  2. Lebbé C, Meyer N, Mortier L, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J Clin Oncol 2019;37:867–875.
  3. Pelster M, Gruschkus SK, Bassett R, et al. Phase II study of ipilimumab and nivolumab in metastatic uveal melanoma. J Clin Oncol 2019;37:15 (suppl). Abstract 9522.
  4. Coit DG, Thompson JA, Albertini MR, et al. NCCN Clinical Practice Guidelines: Uveal Melanoma. Version 1.2019. Accessed December 3, 2019. To view the most recent version, visit
  5. Bristol-Myers Squibb Company. Opdivo (nivolumab). Full prescribing information. Revised September 2019. Available at Accessed November 6, 2019.
  6. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Clinical Practice Guidelines: Management of Immunotherapy-Related Toxicities. Version 2.2019. Accessed December 3, 2019. To view the most recent version, visit


Commentary by Melanoma Co-Site Editor for JNCCN 360

Michael A. Postow, MD

Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York


As longer-term data mature, nivolumab continues to demonstrate remarkable promise for patients with advanced cutaneous melanoma. The main question in treating patients with unresectable stage III or IV melanoma is who should receive drugs like nivolumab (or pembrolizumab) alone and who should be treated with the more aggressive combination of nivolumab plus ipilimumab. Given the potential adverse effects of the nivolumab-plus-ipilimumab combination, physicians should select patients carefully, with consideration given to patients’ ability to tolerate side effects and likelihood to communicate with their treatment team through side effect management. In certain populations, such as patients with melanoma brain metastases, the nivolumab-plus-ipilimumab combination has shown particularly high promise and should be strongly considered as the treatment of choice.

In addition to its use in the unresectable stage III/IV setting, immune checkpoint inhibitors, such as nivolumab and pembrolizumab, have also been shown to improve recurrence-free survival in the adjuvant setting after resection of high-risk melanoma. The main question from those studies is whether these agents also improve overall survival. We eagerly await forthcoming data from ongoing clinical trials.



Dr. Postow has received clinical research support from or served on a data safety monitoring board for Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation, Array BioPharma, Infinity Pharmaceuticals, and Rgenix and has served on a scientific advisory board or as a consultant or expert witness for Bristol-Myers Squibb Company, Array BioPharma, Merck & Co., Incyte Corporation, and NewLink Genetics.

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