Clinical Outcomes of Dacarbazine After Failure of Immune Checkpoint Inhibitors: A Case Study of 15 Japanese Patients With Malignant Melanoma

Immune checkpoint inhibitors (ICIs) have become the standard systemic treatment for advanced malignant melanoma (MM); however, > 50% of Asian patients do not respond to ICIs [1]. Dacarbazine, the previous standard treatment, remains occasionally used. However, there are few reports on the efficacy of dacarbazine after ICI treatment in Asian patients. Here, we report the clinical outcome of dacarbazine after ICI failure in Japanese patients with MM at our institution. Our retrospective study included 15 patients who received dacarbazine (220 mg/m2/day×3 day Q4W) after tumor progression with anti-PD-1 antibody (PD-1) monotherapy or PD-1 plus anti-CLTA-4 antibody combination therapy for stage IV MM between January 2021 and August 2025. Treatment response was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were calculated from dacarbazine initiation. Patient characteristics and treatment outcomes are summarized in Table 1. Subtypes included cutaneous, acral, mucosal (four patients each), uveal (n = 2), and unknown (n = 1). Dacarbazine was administered as a second- (n = 9) or subsequent-line (n = 6) treatment. No serious adverse events related to dacarbazine were observed. No objective responses were observed; stable disease (SD) in one patient and progressive disease (PD) in 14 patients. The median PFS and OS with dacarbazine were 2.1 and 7.5 months, respectively. Among the eight patients who did not respond to dacarbazine, subsequent rechallenge with PD-1 monotherapy resulted in no objective response. A large multicenter study in Caucasians evaluated the efficacy of chemotherapy after ICI treatment in 463 patients with metastatic MM [2]. Among 118 patients who received dacarbazine, the ORR was only 10% (median PFS; 2.7 months). Other cytotoxic agents showed similar limited effects; therefore, chemotherapy should not be chosen automatically after ICI failure. This is consistent with the European consensus guidelines for metastatic MM [3]. Our results align with these findings; the limited efficacy in our cohort may be further explained by the high proportion of acral/mucosal subtypes (53%) and elevated LDH levels (67%), both of which are poor prognostic factors. Chemotherapy may be necessary in reversing resistance to PD-1 inhibitors [2, 4]. However, none of the eight cases in this study, including those who initially responded to ICI, responded to PD-1 rechallenge. This outcome is consistent with that of previous studies conducted in Western populations [2]. Conversely, there is a report that four Japanese patients with MM were treated with dacarbazine after failure of nivolumab and rechallenged with pembrolizumab, with two achieving a partial response [4]. This discrepancy may stem from differences in disease burden or the immunosuppressive tumor microenvironment inherent in advanced acral and mucosal melanomas. Further case studies are needed to determine the impact of dacarbazine on ICI rechallenge. This study is the largest case series of dacarbazine treatment after ICI failure in Japanese patients with MM. Similar to findings in Western countries, dacarbazine demonstrated poor clinical benefit in Japanese patients after immunotherapy failure, both in terms of direct tumor control and as a pretreatment to restore sensitivity for ICI rechallenge. Further retrospective and prospective studies with larger sample sizes are warranted. The authors have nothing to report. This study was reviewed and approved by the Ethics Committee of Shizuoka Cancer Center (2025/11/10): approval #J2025-148. The requirement for informed consent was waived by the Ethics Committee of Shizuoka Cancer Center due to the retrospective nature of this study. Information regarding the study was disclosed via a notice board within the institution to provide patients with an opportunity to opt out. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.