SUMMARY: The FDA on October 13, 2023, approved Nivolumab (OPDIVO®) for the adjuvant treatment of completely resected Stage IIB/C melanoma in patients 12 years and older. The American Cancer Society’s estimates that for 2023, about 97,610 new cases of melanoma of the skin will be diagnosed in the United States and 7,990 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma.
Patients with resected Stage IIB/C disease comprise a significant group of patients at significant risk of recurrence. Patients with Stage IIB disease have primary tumors that are more than 2 mm and 4 mm or less in thickness with ulceration (T3b) or more than 4 mm in thickness without ulceration (T4a). Patients with Stage IIC disease have primary tumors more than 4 mm in thickness with ulceration (T4b). Although Stage II melanoma is less advanced than Stage III, the 5-year risk of recurrence in patients with stage IIB or Stage IIC disease without adjuvant therapy is approximately 35% and 50% respectively. The 5-year Melanoma-Specific Survival (MSS) rates for patients with Stage IIB/IIC disease are similar to those for Stage IIIA, Stage IIIB and Stage IIIC disease.
Immune Checkpoint Inhibitors are the standard of care adjuvant treatment for high-risk, resected, Stage III melanoma. In the KEYNOTE-054 trial, the 5-year Relapse Free Survival (RFS) with adjuvant Pembrolizumab was 55.4% versus 38.3% with placebo, in patients with completely resected, Stage IIIA (more than 1 mm lymph node metastasis), IIIB or IIIC Melanoma. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab versus 41.2% for ipilimumab among patients with resected Stage IIIB/C and IV melanoma.
CHECKMATE-76K is an ongoing, randomized, double-blind, Phase III study conducted to evaluate the efficacy of Nivolumab versus placebo as adjuvant treatment for patients with resected Stage IIB/C melanoma. In this study, 790 eligible patients were randomized (2:1) to Nivolumab 480 mg (N=526) or placebo (N=264) by IV infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable toxicity. Patient characteristics at baseline were well balanced between treatment groups and 50.5% had nodular melanoma, 39% had Stage IIC disease and patients were stratified by tumor category. The Primary endpoint was investigator-assessed Recurrence-Free Survival (RFS). Secondary endpoints included Distant Metastasis-Free Survival (DMFS) and Safety.
At a minimum follow up of 7.8 months, CheckMate 76K met its primary endpoint and Nivolumab significantly improved RFS versus placebo. Nivolumab demonstrated a 58% reduction in the risk of recurrence or death versus placebo in patients with resected stage IIB/C melanoma (HR = 0.42; P < 0.0001). The 12-month RFS was 89.0% for nivolumab and 79.4% for placebo. The benefit with nivolumab over placebo was observed across all pre-specified subgroups, including all disease Stages and T-category subgroups. Adjuvant Nivolumab demonstrated significant benefit in those with stage IIC disease, head and neck primaries or nodular disease, who are all considered to be at a higher absolute recurrence risk. Additionally, there was a clinically meaningful improvement in the Distant Metastasis-Free Survival with Nivolumab versus placebo (HR = 0.47). Further, a lower proportion of patients treated with nivolumab had multiple lesions detected at first recurrence versus those treated with placebo (3.4% versus 9.1%). Adverse events were similar to that observed in patients with resected stage III or stage IV disease and similar to the established anti-PD-1 monotherapy profile.
It was concluded that adjuvant Nivolumab significantly improved Relapse Free Survival as well as Distant Metastasis-Free Survival in patients with resected Stage IIB/C melanoma and this clinical benefit was observed across disease subgroups, including all T categories.
Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Kirkwood, J.M., Del Vecchio, M., Weber, J. et al. Nat Med (2023). https://doi.org/10.1038/s41591-023-02583-2
