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Adjuvant treatment for stage III melanoma in the era of targeted medicine and immunotherapy.

ABSTRACT: The accelerated development in the treatment of metastatic melanoma, both in molecular targeted therapy and immunotherapy, is already starting to impact on adjuvant therapy in stage III melanoma. Following the approval of ipilimumab for adjuvant therapy in melanoma, clinical trials assessing other checkpoint modulators and MAPK pathway inhibitors as adjuvant treatments for melanoma are currently ongoing. As results from these trials mature in the next few years, a change in the landscape of adjuvant treatment for melanoma is expected, resulting in new challenges in treatment decisions such as optimizing patients selection through predictive and prognostic biomarkers, and management of treatment related adverse events, in particular immune related toxicities.

SUBMITTER: Ben-Ami E

PROVIDER: S-EPMC6094670 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Adjuvant treatment for stage III melanoma in the era of targeted medicine and immunotherapy.

Ben-Ami Eytan E Schachter Jacob J

Melanoma management 20160525 2

The accelerated development in the treatment of metastatic melanoma, both in molecular targeted therapy and immunotherapy, is already starting to impact on adjuvant therapy in stage III melanoma. Following the approval of ipilimumab for adjuvant therapy in melanoma, clinical trials assessing other checkpoint modulators and MAPK pathway inhibitors as adjuvant treatments for melanoma are currently ongoing. As results from these trials mature in the next few years, a change in the landscape of adju ...[more]

PMID: 30190882

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Project description:BackgroundOn the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma.MethodsAfter patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety.ResultsAt a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events.ConclusionsAs adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

Project description:BackgroundMelanoma frequently harbors BRAF, NRAS, or KIT mutations which influence both tumor development and treatment strategies. For example, it is still controversial whether adjuvant anti-PD-1 monotherapy or BRAF/MEK inhibitors may better improve the survival for resected BRAF-mutant melanoma. Furthermore, outcomes for melanoma with NRAS and KIT mutation receiving adjuvant immunotherapy remain unclear.MethodsOne hundred seventy-four stage III melanoma patients who underwent radical surgery in Fudan University Shanghai Cancer Center (FUSCC) during January 2017 to December 2021 were included in this real-world study. Patients were followed up until death or May 30th, 2022. Pearson's chi-squared test or Fisher's exact test was performed for univariable analysis of the different category groups. Log-rank analysis was used to identify the prognostic factors for disease-free survival (DFS).ResultsThere were 41 (23.6%) patients with BRAF mutation, 31 (17.8%) with NRAS mutation, 17 (9.8%) with KIT mutation, and 85 (48.9%) wild-type patients without either genomic alteration of those three genes. Most ( n = 118, 67.8%) of them were acral melanoma, while 45 (25.9%) were cutaneous subtype, and 11 were (6.3%) primary unknown. Among them, 115 (66.1%) patients received pembrolizumab or toripalimab monotherapy as adjuvant therapy; 22 (12.6%) patients received high-dose interferon (IFN), and 37 (21.3%) patients were just for observation. There was no statistical difference in clinicopathologic factors between anti-PD-1 group and IFN/OBS group. Of all the enrolled patients, anti-PD-1 group had a better DFS than IFN/OBS group ( p = 0.039). In anti-PD-1 group, patients with BRAF or NRAS mutations had poorer DFS than wild-type group. No survival difference was found among patients harboring different gene mutations in IFN/OBS group. In wild-type patients, anti-PD-1 group had a better DFS than IFN/OBS group ( p = 0.003), while no survival benefits were found for patients with BRAF, NRAS, or KIT mutations.ConclusionAlthough anti-PD-1 adjuvant therapy provides a better DFS in the general population and in wild-type patients, patients with BRAF, KIT or, especially, NRAS mutation may not benefit further from immunotherapy than conventional IFN treatment or observation.

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Adjuvant treatment for stage III melanoma in the era of targeted medicine and immunotherapy.

Publications

Adjuvant treatment for stage III melanoma in the era of targeted medicine and immunotherapy.

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