Metastatic subcutaneous melanoma
Image courtesy of DermNetZ
A paradigm shift is occurring in the treatment of patients with melanoma. 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.one This latest approval is considered a breakthrough for patients with advanced melanoma.
Wide local excision of advanced melanoma is one of the primary ways to remove the tumor.2,3 This surgery carries a risk of microscopic invasion of cancer cells and there may be a risk of disease recurrence, but adjuvant therapy can help reduce this risk.2 Although preferences vary among practices and academic institutions, clinicians generally recommend that patients with stage II melanoma undergo sentinel lymph node biopsy to evaluate lymph node involvement.4 If lymph node biopsy results show that the cancer is in the sentinel node (stage III), lymph node dissection is performed. Additional treatment with immune checkpoint inhibitors or targeted therapy drugs may also be recommended to prevent relapse.
Immunotherapies, including PD-1 checkpoint inhibitors such as nivolumab, have improved treatment options for patients with advanced melanoma. Nivolumab was initially approved for the treatment of patients with advanced melanoma, and increased efficacy was found 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 or older and have metastatic or unresectable melanoma.one It was also included as an adjuvant treatment option for patients 12 years of age and older with completely resected stage III or IV melanoma.one
The phase 3 CheckMate-76K study (NCT04099251), sponsored by Bristol Myers Squibb, investigated the effectiveness of nivolumab adjuvant immunotherapy versus placebo in participants after complete resection of stage IIB/C melanoma without evidence of disease.6.7 Before random assignment, participants were required to undergo complete resection of stage IIB/C melanomas, have a pathology excision report showing negative surgical margins, and have negative sentinel lymph node results. Participants received nivolumab 480 mg intravenously on the first day of each 4-week treatment cycle. Treatment was discontinued in case of recurrence or progression of melanoma, if the patient had completed 12 months of treatment, if the patient had withdrawn consent, or if unacceptable toxicity was present. For relapse-free survival, nivolumab reduced the risk of disease relapse or death by 58% compared to placebo.7 The most adverse reactions included itching, 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 have an even greater role in melanoma treatment. 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 this [patients 12 years and older]. Pembrolizumab was approved a while ago and we have been using it for the last 2 years…. “This is not a new indicator in the current field.” Milhem is Holden Chair of Experimental Therapeutics; Director of the Department of Hematology, Oncology and Blood and 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 administered every 4 weeks as adjuvant therapy, rather than every 3 weeks for pembrolizumab.6.9 Having 2 agents available for the same indication will increase access and availability of these drugs for patients with advanced melanoma. Despite the challenge of treating this aggressive disease, nivolumab will now provide a new opportunity to improve quality of life and increase longevity in patients with completely resected stage IIB/C melanoma.
Nicole Negbenebor, MDHe is a specialist in Mohs micrographic surgery and cutaneous oncology at the University of Iowa Department of Dermatology in Iowa City.
References
1. The U.S. Food and Drug Administration approved Opdivo (nivolumab) as adjuvant therapy for eligible patients with completely resected stage IIB or stage IIC melanoma. BristolMyers Squibb. Newsletter. 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-Melanom1/default.aspx
2. Treatment of melanoma by stages. American Cancer Society. Updated March 22, 2022. Access date: 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 treatment of cutaneous metastases from melanoma. International J Mol Science. 2023;24(19):14535. doi:10.3390/ijms241914535
4. Wong SL, Balch CM, Hurley P, et al; American Society of Clinical Oncology; Surgical Oncology Association. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. 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 effectiveness and safety of adjuvant 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. Long GV, Del Vecchio M, Weber J, et al. Adjuvant treatment with nivolumab versus placebo in patients with resected stage IIB/C melanoma (CheckMate 76K). Presented at: Melanoma Research Association 2022 International Congress; 17-20 October 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 study. NatMed. 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. Advertise. 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