The treatment of patients with melanoma is undergoing a paradigm shift. In October 2023, the FDA approved nivolumab (Opdivo; Bristol Myers Squibb) for patients 12 years 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 most important ways to remove a tumor. 2.3 With this surgery there is a risk of microscopic invasion of cancer cells, and there may be a risk of recurrence of the disease, but adjuvant therapy can help reduce the risk. 2 Although preferences vary among practices and academic institutions, physicians commonly recommend that patients with stage II melanoma undergo a sentinel lymph node biopsy to assess lymph node involvement. 4 If the results of the lymph node biopsy show that the cancer is in the sentinel lymph node (stage III), a lymph node dissection is performed. Additional treatment with immune checkpoint inhibitors or targeted therapy medications may also be recommended to prevent recurrence.
Immunotherapies, including PD-1 checkpoint inhibitors such as nivolumab, have improved treatment options for patients with advanced melanoma. Nivolumab was originally approved for the treatment of patients with advanced melanoma and was shown to have increased efficacy with ipilimumab (Yervoy), which targets CTLA-4 to activate the immune system. 5 To qualify for the initial FDA approval, patients had to be 12 years or older and have metastatic or unresectable melanoma. 1 It was also included as an adjunctive treatment option for patients aged 12 years or older with completely resected stage III or IV melanoma. 1
The phase 3 CheckMate-76K trial (NCT04099251), sponsored by Bristol Myers Squibb, studied the effectiveness of adjuvant immunotherapy with nivolumab versus placebo in participants after complete resection of stage IIB/C melanoma without evidence of disease. 6.7 Before randomization, participants were required to undergo complete resection of their stage IIB/C melanoma, submit a pathology excision report with negative surgical margins, and a negative sentinel node result. Participants received 480 mg nivolumab intravenously on the first day of each four-week treatment cycle. Treatment was stopped if there was recurrence or progression of melanoma, the patient had completed 12 months of treatment, the patient had withdrawn consent, or unacceptable toxicity. For recurrence-free survival, nivolumab reduced the risk of disease recurrence or death compared to placebo by 58%. 7 The most common adverse events were pruritus, diarrhea, arthralgia, rash, and fatigue. 7 Nivolumab has a manageable side effect profile compared to other traditional cancer treatments. 7
Now that the FDA has approved nivolumab for the treatment of patients with completely resected stage IIB/C melanoma, it will play an even greater 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 are involved [patients 12 years and older]. Pembrolizumab was approved a while ago and we have been using it for the past 2 years.... This is not a new indication in the current situation." Milhem is the Holden Chair in Experimental Therapeutics; director of the Department of Hematology, Oncology and Blood and Bone Marrow Transplantation; and a clinical professor of internal medicine at the University of Iowa in Iowa City.
An advantage of nivolumab over pembrolizumab is that it can be administered every 4 weeks as adjunctive therapy, as opposed to every 3 weeks for pembrolizumab. 6.9 Having two agents available for the same indication will increase access and availability of these medications for patients with advanced melanoma. Despite the challenge of treating this aggressive disease, nivolumab will now offer a new option for improved quality of life and longevity in patients with completely resected stage IIB/C melanoma.
Nicole Negbenebor, MD is a Mohs Fellow in Micrographic Surgery and Skin Oncology in the Department of Dermatology at the University of Iowa in Iowa City.
References1. The U.S. Food and Drug Administration approves Opdivo (nivolumab) as an adjunctive treatment for eligible patients with completely resected stage IIB or stage IIC melanoma. Bristol Myers Squibb. News item. 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-with-completely-resected-stage-IIB-or-stage-IIC-melanoma1/default.aspx
2. Treatment of melanoma, by 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. The diagnosis and treatment 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 for Clinical Oncology; Society for Surgical Oncology. Sentinel lymph node biopsy for melanoma: 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 adjunctive nivolumab versus other treatments in adults with resected melanoma: a systematic literature review and network meta-analysis. BMC Cancer. 2021;21(1):3. doi:10.1186/s12885-020-07538-1
6. Lange 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 Melanoma Research 2022 International Congress; 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 stage 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 the adjuvant treatment of IIB or IIC melanoma. Expert Rev Anticancer Ther. 2023;23(9):897-902. doi:10.1080/14737140.2023.2247565
