Dacarbazine in the management of metastatic melanoma in the era of immune checkpoint therapy: a valid option or obsolete?

Abstract

Despite the dramatic improvement in both overall survival (OS) and progression-free survival (PFS) in patients with metastatic melanoma treated with immune checkpoint inhibitors, up to 60% will develop treatment resistance and 50% will die from their disease. Therefore, although dacarbazine is no longer a mainstay of modern melanoma management, we examined the extent to, and in which context, it may still play a role. A retrospective analysis of electronic medical records of patients who had received dacarbazine treatment between October 2014 and October 2021, following innate or acquired resistance to immune checkpoint inhibitors, was performed to determine PFS and OS and examine tolerability. Nine patients with locally advanced (n = 1) or metastatic melanoma (n = 8) were identified (average age: 74 years, 4 males and 5 females). The number of cycles of dacarbazine ranged from 2 to 45 (mean = 12). One-third of patients developed a complete (n = 2) or partial (n = 1) response, two-thirds did not respond to treatment. The median PFS time was 90 days. Common adverse events included blood dyscrasias; one patient developed a grade 3 hepatitis, although it was unclear if this was due to the chemotherapy or the preceding combined immunotherapy. Dacarbazine may still be a valid option in the setting of treatment for refractory, relapsed, or progressive disease. Future studies should focus on the immunomodulatory effects of dacarbazine on the tumor microenvironment, which could be harnessed to potentially restore sensitivity to immune checkpoint-based therapy.

The role of dacarbazine and temozolomide therapy after treatment with immune checkpoint inhibitors in malignant melanoma patients: A case series and meta‐analysis

“…Among these, 13 studies were excluded because they failed to meet the inclusion criteria. After the selection process, seven studies were included in the meta‐analysis, all case series (Bouchereau et al., 2021; Gaughan & Horton, 2022; Goldinger et al., 2022; Karachaliou et al., 2020; Klee et al., 2022; Mangin et al., 2021). Study characteristics are summarized in Table 3.…”

“…For instance, Klee et al. described two patients (from a cohort of nine) with complete response to DTIC after CPI therapy, who were alive at last follow‐up at 35 months and 85 months, respectively (Klee et al., 2022). Karachaliou et al.…”

“…The question arises whether CPI treatment could induce persisting alterations in the immune system and the tumor microenvironment that affects response to DTIC and TMZ in later lines of treatment. The existing studies evaluating treatment with DTIC and TMZ after CPI therapy are scarce and show conflicting results (Bouchereau et al., 2021; Gaughan & Horton, 2022; Goldinger et al., 2022; Karachaliou et al., 2020; Klee et al., 2022; Mangin et al., 2021; Weber et al., 2015). Although some of them are based on large screened patient cohorts, the absolute number of patients who have received TMZ or DTIC after a prior treatment with a CPI is relatively low per study.…”