FDA Approves Nivolumab for Fully Fixed Stage IIB/C Melanoma

FDA Approves Nivolumab for Fully Fixed Stage IIB/C Melanoma

metastatic subcutaneous melanoma

Image courtesy of DermNetZ

Treatment for patients with melanoma is undergoing a paradigm shift. In October 2023, the FDA approved nivolumab (Opdivo; Bristol Myers Squibb) for patients 12 years of age and older with completely resected stage IIB/C melanoma.1 This recent approval is considered a groundbreaking development for patients with advanced melanoma.

Wide local excision of advanced melanoma is one of the primary ways to clear a tumor.2,3 There is a risk of microscopic invasion of cancer cells with this surgery, and there may be a risk of disease recurrence, but adjuvant therapy can help reduce the risk.2 Although preferences vary between practices and academic institutions, clinicians generally recommend that patients with stage II melanoma have a sentinel lymph node biopsy to assess for lymph node involvement.4 If the results of the lymph node biopsy indicate cancer in the sentinel node (stage III), a lymph node dissection is then performed. Additional treatment with immune checkpoint inhibitors or targeted therapy drugs may also be recommended to prevent recurrence.

Immunotherapy has improved treatment options for patients with advanced melanoma, including PD-1 checkpoint inhibitors such as nivolumab. Nivolumab was originally approved to treat patients with advanced melanoma and was found to have increased efficacy with ipilimumab (Yervoy), which targets CTLA-4 to activate the immune system.5 To be eligible under the initial FDA approval, patients had to be 12 years of age and older and have metastatic or benign melanoma.1 It has also been included as an adjuvant treatment option for patients 12 years of age or older who have completely resected stage III or IV melanoma.1

Sponsored by Bristol Myers Squibb, the CheckMate-76K phase 3 trial (NCT04099251) studied the efficacy of adjuvant immunotherapy nivolumab vs placebo in participants after complete resection of stage IIB/C melanoma with no evidence of disease.6,7 Before random assignment, participants had to undergo complete resection of their stage IIB/C melanoma, have a pathology excision report showing negative surgical margins, and have negative sentinel lymph node results. ​​​​Participants received 480 mg of intravenous nivolumab on the first day of each 4-week treatment cycle. Treatment was discontinued if the melanoma relapsed or progressed, the patient had completed 12 months of treatment, the patient withdrew consent, or there was unacceptable toxicity. For recurrence-free survival, nivolumab reduced the risk of disease or death versus placebo by 58%.7 The most common adverse reactions were pruritus, diarrhea, arthralgias, rash, and fatigue.7 Nivolumab has a manageable adverse effect profile compared to other conventional cancer treatments.7

Now that nivolumab has been approved by the FDA to treat patients with completely resected stage IIB/C melanoma, it will play an even bigger role in the treatment of melanoma. In 2021, the FDA approved pembrolizumab (Keytruda; Merck) for a similar indication in patients with stage IIB/C melanoma.8 Mohammed M. Milhem, MBBS, said, “It’s good that they included [patients 12 years and older]. Pembrolizumab was approved a while back and we have been using it for the past 2 years…. This is not a new signal in this current space.” Milhem is the Holden Chair of Experimental Therapeutics; director of the Division of Hematology, Oncology, and Blood & Marrow Transplantation; and clinical professor of internal medicine at the University of Iowa in Iowa City.

An advantage of nivolumab over pembrolizumab is that it can be given every 4 weeks as adjuvant therapy compared to every 3 weeks for pembrolizumab.6,9 Making 2 agents available for the same indication will increase access and availability of these medications for patients with advanced melanoma. Even with the challenge of treating this aggressive disease, nivolumab will now provide a new opportunity for improved quality of life and increased longevity in patients with completely resected stage IIB/C melanoma.

Nicole Negbenebor, MDis a Mohs micrographic surgery and discrete oncology fellow in the Department of Dermatology at the University of Iowa in Iowa City.


1. The US Food and Drug Administration approves Opdivo (nivolumab) as adjuvant treatment for eligible patients with completely resected stage IIB or stage IIC melanoma. Bristol Myers Squibb. News release. October 13, 2023. Accessed October 23, 2023. https://news.bms.com/news/corporate-financial/2023/US-Food-and-Drug-Administration-Approves-Opdivonivolumab-as-Adjuvant- Treatment-for-Eligible-Patients-for-Fully-Protected-Stage-IIB-or-Stage-IIC-Melanoma1/default.aspx

2. Treatment of melanoma, according to the stage. American Cancer Society. Updated March 22, 2022. Accessed October 23, 2023. https://www.cancer.org/cancer/types/melanoma-skin-cancer/treating/by-stage.html

3. Di Raimondo C, Lozzi F, Di Domenico PP, Campione E, Bianchi L. Diagnosis and management of cutaneous metastases from melanoma. Int J Mol Sci. 2023; 24(19): 14535. doi:10.3390/ijms241914535

4. Wong SL, Balch CM, Hurley P, et al; American Society of Clinical Oncology; Society of Surgical Oncology. Sentinel lymph node biopsy for melanoma: A joint clinical practice guideline of the American Society of Clinical Oncology and the Society of Surgical Oncology. Ann Surg Oncol. 2012; 19(11):3313-3324. doi:10.1245/s10434-012-2475-3

5. Toor K, Middleton MR, Chan K, Amadi A, Moshyk A, Kotapati S. Comparative efficacy and safety of adjuvant nivolumab versus other treatments in adults with resected melanoma: a systematic review of the literature and network meta-analysis. BMC Cancer. 2021; 21(1):3. doi:10.1186/s12885-020-07538-1

6. Long GV, Del Vecchio M, Weber J, et al. Adjuvant therapy with nivolumab versus placebo in patients with resected stage IIB/C melanoma (CheckMate 76K). Presented at: Society for Research on Melanoma International Conference 2022; October 17-20, 2022; Edinburgh, Scotland.

7. Kirkwood J, Del Vecchio M, Weber J, et al. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nat Med. Published online October 16, 2023. doi:10.1038/s41591-023-02583-2

8. Zhang S, Bensimon AG, Xu R, et al. Cost-effectiveness analysis of pembrolizumab as adjuvant treatment of resected IIB or IIC melanoma in the United States. Adv Ther. 2023; 40(7):3038-3055. doi:10.1007/s12325-023-02525-x

9. Rutkowski P, Czarnecka AM. Pembrolizumab for adjuvant treatment of IIB or IIC melanoma. Expert Rev Anticancer Ther. 2023; 23(9):897-902. doi: 10.1080/14737140.2023.2247565

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