Survival of Patients with Metastatic Melanoma Treated with Ipilimumab after PD-1 Inhibitors: A Single-Center Real-World Study.

BACKGROUND: When monotherapy with PD-1 inhibitors in metastatic melanoma fails, there are currently no standard second-line choices. In case of the unavailability of clinical trials, ipilimumab represents a possible alternative treatment. METHODS: We collected data of 44 patients who received ipilimumab after the failure of PD-1 inhibitors from July 2017 to May 2023 at our Institute. Overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) based on BRAF or NRAS mutation status, sex, and the presence of brain metastases were estimated using the Kaplan-Meier method. Cox regression was used to evaluate independence in multivariate analysis. The objective response rate (ORR) was estimated based on RECIST 1.1. RESULTS: Among the 44 patients enrolled in this study, 28 BRAF-wildtype, 9 BRAF-mutated, and 7 NRAS-mutated patients were identified. OS analysis showed a significant difference between wildtype and BRAF- or NRAS-mutated patients: 23.2 months vs 5.3 and 4.59, respectively, p = 0.017. The presence of brain metastases and BRAF or NRAS mutation were independent factors for mortality in multivariate analysis. CONCLUSIONS: In case of failure to enroll patients in innovative clinical trials, second-line ipilimumab still represents an effective therapy in patients with metastatic wildtype melanoma and in the absence of brain metastases.

Weekly carboplatin plus paclitaxel chemotherapy in advanced melanoma patients resistant to anti-PD-1 inhibitors: a retrospective, monocentric experience.

Immunotherapy with anti-PD-1 antibodies significantly improved the prognosis in advanced melanoma patients, but most of them develop primary or secondary resistance to the treatment. In this study, we evaluated efficacy and safety of a chemotherapy regimen with weekly carboplatin plus paclitaxel (wCP) in patients previously treated with anti-PD-1 antibodies. We retrospectively identified 30 patients with advanced melanoma treated at our Institute over the last eight years with wCP. The co-primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). In addition, we evaluated treatment tolerability. For this patient cohort, median PFS and OS were 3.25 and 7.69 months, respectively. All included patients had previously received anti-PD-1 immunotherapy, most of them had ECOG PS 0-1, and only 5 patients had a BRAF V600 mutation. In univariable analysis, we observed shorter OS in patients with > 2 involved metastatic sites, superficial spreading histology, and serum lactate dehydrogenase (LDH) values above the median. Liver metastases were associated with worse outcomes, while radiotherapy treatment of brain metastases was associated with improved OS. However, in a multivariable Cox regression model, only LDH above the median, superficial spreading histology, and female sex were significantly associated with worse OS. We reported grade 3 and 4 treatment-related toxicities in 4 and 0 patients, respectively. In conclusion, chemotherapy with wCP is a valid palliative treatment in advanced melanoma who progressed with anti-PD-1 antibodies.

Case report: Fast disease progression during adjuvant therapy with anti-PD-1 in stage III melanoma patients.

Background: Stage III surgically resected melanoma is a disease at high risk of recurrence. Immune checkpoint inhibitors (ICIs) and the target therapy with BRAF and MEK inhibitors significantly changed the outcome of patients with metastatic melanoma and several studies have also shown their benefit in the adjuvant setting for the delay of recurrence in stage III melanoma patients. Hyperprogression disease was observed as a possible adverse response to immunotherapy in the metastatic setting, suggesting that some patients could face additional risk of progression with ICIs, although no consensus was found for the correct definition of this event. Case presentation: We describe here two cases of rapid multiorgan metastatization during adjuvant immunotherapy in patients with stage III resected melanoma. Even though it would be not accurate to define this syndrome as hyperprogression because of apparent absence of the initial disease in the adjuvant setting, we observed in these two cases the same very rapid progression after first administration of adjuvant ICIs that resulted in death of patients within two months from the starting of treatment. Both patients had NRAS mutated melanoma. Conclusion: There is an urgent need for a better understanding of the causes of these fatal outcomes and for the identification of biomarkers that would allow to select the patients before offering them an adjuvant treatment, reducing the risk of hyperprogression. From these cases, we suggest that it could be useful a particular attention in proposing ICI adjuvant treatment based on the molecular profile.