Prospective observational study of the efficacy of nivolumab in Japanese patients with advanced melanoma (CREATIVE study)

Abstract

Background Nivolumab, the anti-programmed cell death protein 1 antibody, has been approved for advanced melanoma, mainly based on evidence from Western countries. The profile of melanoma differs between Caucasian and Asian patients. This study was performed to obtain post-marketing data of nivolumab in Japanese patients with advanced melanoma. Methods This prospective, observational study involved patients with unresectable or metastatic melanoma treated with nivolumab at dosages of 2 mg/kg every 3 weeks or 3 mg/kg every 2 weeks. The primary endpoints were objective response rate and overall survival. The secondary endpoints were progression-free survival and the objective response rate according to immune-related Response Evaluation Criteria in Solid Tumours. Result Among 124 patients analysed, mucosal melanoma was the most common subtype, followed by acral lentiginous, nodular, superficial spreading and lentigo maligna melanoma. Response Evaluation Criteria in Solid Tumours evaluation showed an objective response rate of 17.7%. The median survival time was 15.93 months, and the 1-year overall survival rate was 66%. Outcomes were not significantly different among melanoma subtypes. Better overall survival and/or progression-free survival but not objective response rate were associated with performance status 0, lower levels of lactate dehydrogenase, C-reactive protein and neutrophil-to-lymphocyte ratio. Patients with immune-related adverse events showed a better objective response rate, 3-month landmark overall survival and progression-free survival than patients without immune-related adverse events. Conclusion The objective response rate and median survival time in Japanese patients treated with nivolumab were lower in daily practice than the >30% and >30 months, respectively, seen in global phase III trials. The occurrence of immune-related adverse events may be a predictor for survival and response to treatment with nivolumab.

TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment

“…While acral and mucosal melanomas reportedly have a noninflamed TME with less efficacy of ICIs, [35][36][37] a Japanese prospective observational study has shown that anti-PD-1 Open access mAb exhibits similar efficacy against these types. 34 We analyzed our cohort according to the type and found that the OS of patients with acral or mucosal melanoma was slightly shorter than that of the others (online supplemental figure S5B), which is consistent with previous studies. [35][36][37] Next, we stained the FFPE samples for CD8 and CD155 before ICI treatment (online supplemental figure S6A).…”

“…While acral and mucosal melanomas reportedly have a non-inflamed TME with less efficacy of ICIs, [35][36][37] a Japanese prospective observational study has shown that Open access anti-PD-1 mAb exhibits similar efficacy against types. 34 In our cohort, there was no significant difference in CD8 + T-cell infiltration or CD155 expression among melanoma types. While patients with acral or mucosal melanoma had a slightly shorter OS, multivariate analyses demonstrated that the melanoma type was not a prognostic factor.…”

“…Indeed, a randomized phase 2 trial of combination therapy with anti-PD-L1 mAb and anti-TIGIT mAb has demonstrated favorable efficacy against PD-L1 high lung cancer, which can reflect inflamed TME, 50 and a phase 3 trial is currently ongoing (NCT04294810). Acral and mucosal melanomas are dominant in Japan, 34 and our cohort included a considerable number of these types. While acral and mucosal melanomas reportedly have a non-inflamed TME with less efficacy of ICIs, [35][36][37] a Japanese prospective observational study has shown that Open access anti-PD-1 mAb exhibits similar efficacy against types.…”

“…The PFS of patients receiving ICIs as second-line therapy was significantly shorter than that of patients as firstline therapy, as previously reported 33 (online supplemental figure S5A). In Japan, acral and mucosal types are dominant, 34 and our study also included 81 patients with these types (online supplemental table S2). While acral and mucosal melanomas reportedly have a noninflamed TME with less efficacy of ICIs, [35][36][37] a Japanese prospective observational study has shown that anti-PD-1 Open access mAb exhibits similar efficacy against these types.…”

Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study)

“… 2 , 3 , 4 Notably, advanced MCM (unresectable primary or metastatic) is the most common advanced-stage subtype in Japan, accounting for 28%-38% of all melanoma subtypes at this stage. 5 , 6 , 7 MCM is genetically, molecularly, and clinically different from NACM in that it has distinct oncogenic drivers with a 3%-15% infrequent rate of BRAF V600 mutation, 8 a lower tumor mutational burden, 9 and a highly aggressive phenotype with a poorer prognosis. 10 …”