Adjuvant temozolomide plus cisplatin versus high-dose interferon alpha-2b in resected mucosal melanoma: A randomized, multicenter, controlled, phase III trial.
Authors: Lian Bin , Cui Chuanliang , Si Lu , Yang Yue , Wu Di , Li Ke , Wang Xuan , Chi Zhihong , Sheng Xinan , Mao Lili , Tang Bixia , Yan Xieqiao , Li Siming , Bai Xue , Zhou Li , Guo Jun 
Published: June 2022

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Background: Mucosal melanoma (MuM) is a rare cancer with an extremely poor prognosis and no established standard adjuvant therapy. A phase II trial showed promising outcomes with adjuvant temozolomide plus cisplatin (Chemo) versus high-dose interferon alpha-2b (HDI) in resected mucosal melanoma. We conducted the phase III trial to definitively compare these two treatments. Methods: In this multicenter, randomized, controlled, phase III trial, patients with pathologically confirmed stage I-III mucosal melanoma who had undergone complete resection were stratified by primary site (head and neck vs. non-head and neck) and disease stage (I/II vs. III) and randomized 1:1 to receive Chemo (temozolomide 200 mg/m2/day orally on days 1 to 5 plus cisplatin 75 mg/m2 i.v. on days 1-3, repeated every 3 weeks for six cycles) or HDI (15×106 U/m2/day i.v on days 1 to 5 each week for 4 weeks followed by 9×106 U three times per week for 48 weeks). Postoperative radiotherapy was recommended for head and neck MuM patients, with a total dose of 65-70 Gy/30-35 fx to GTV and 60 Gy/30 Fx to CTV. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), and safety. The protocol was registered at ClinicalTrials.gov (NCT03435302). Results: Between Feb 2014 and Jun 2016, 204 patients were randomized to treatment (Chemo group: n = 103, HDI group: n = 101). Baseline characteristics were generally well balanced between the two groups. Anatomic site of head and neck, gastrointestinal, gynecological were 38.8% vs 49.5%, 35.9% vs 22.8%, 25.2% vs 27.7% in Chemo and HDI group, respectively. Stage of I/II, III were 68.9% vs 73.3%, 31.1% vs 26.7% in Chemo and HDI group, respectively. CKIT, BRAF, NRAS Mutation were 7.0% vs 8.2%, 5.0% vs 8.2%, 13.4% vs 15.8% in Chemo and HDI group, respectively. In the ITT population, At a median follow-up of 64.8 months, patients receiving Chemo had a higher median RFS (15.5 vs. 9.9 months; HR = 0.622; 95% CI, 0.463 to 0.836; P = 0.001), DMFS (19.5 vs. 12.7 months; HR = 0.705; 95% CI, 0.518 to 0.959; P = 0.025) and OS (38.2 vs. 33.5 months; HR = 0.832; 95% CI, 0.598 to 1.155; P = 0.270) versus the HDI group. A subgroup analysis revealed consistent improvements in RFS, DMFS and OS with Chemo versus HDI across multiple subgroups. Toxicities were generally mild to moderate in both groups. The most common adverse events were fatigue, anorexia, nausea/vomiting, leukopenia, Neutropenia, hepatotoxicity, fever and anemia, 23 patients (22.3%) in Chemo group and 57 patients (56.4%) in HDI group had a grade 3 or 4 adverse events. Conclusions: Adjuvant temozolomide plus cisplatin led to a significantly lower risk of relapse and distant metastasis in patients with resected mucosal melanoma versus high-dose IFN-a2b and was generally well tolerated. Clinical trial information: NCT03435302.