Long-term outcomes of sequential chemotherapy in epithelioid sarcoma.

Our study was carried out to define the efficacy of treatment with sequential chemotherapy lines in patients with epithelioid sarcoma (ES) at referral centres for sarcoma. From 1998 to 2023, 22 patients with ES were treated with chemotherapy and included in the analysis. The median age at the start of palliative treatment was 35 (20-68). The median follow-up was 22.1 months. In the first line, 13 patients (59%) received anthracycline-based chemotherapy and 6 (27%) high-dose ifosfamide. One patient (4.5%) achieved PR, 15 (68%) SD, and 6 (32%) PD as the best response. The median progression-free survival (PFS) in the first line was 6.4 months (95% CI: 3.02-12.9), but 9.7 months (95% CI: 4.37-NR) for chemotherapy based on anthracycline, indicating a more favourable PFS (p = 0.027). Twenty (90%) patients received second-line treatment, and eleven received third-line chemotherapy. The median OS from the start of first-line palliative chemotherapy was 22.1 months (95% CI: 10.5-41.4) and 14.7 months from the beginning of the second line. Perioperatively, patients pretreated with anthracycline had a median PFS of 2.9 months in the M1 setting. Second-line long-time responses were achieved with pazopanib or vincristine with actinomycin D. Despite chemoresistance, an advantage associated with anthracycline-based chemotherapy was confirmed in the ES cohort. Poor responses underscore the need for further research on targeted therapies for ES. Second-line chemotherapy or clinical trials should be offered to all eligible patients.

Real-world outcomes of metastatic clear cell sarcoma sequential chemotherapy.

Clear cell sarcoma is an ultra-rare chemoresistant subtype of soft tissue sarcoma. This retrospective analysis aimed to clarify the efficacy of palliative chemotherapy in CCS by assessing response rates, progression-free survival (PFS), and overall survival (OS) at a referral center. A retrospective analysis of palliative treatment was conducted on patients with CCS treated at the sarcoma unit from 1997 to 2023. Treatment responses were assessed using RECIST criteria, and the Kaplan-Meier method was used to calculate PFS and OS. The analysis covered 23 CCS chemotherapy-treated patients with 11 (47.8%) men. The median age at the palliative treatment start was 32 years (range 18-59). The median follow-up was 8.2 months. Four patients were referred to our centre for M1 disease, and 6 received perioperative chemotherapy and progressed during follow-up. In the first line, 14 patients received anthracycline-based chemotherapy (60.9%), five were treated with ifosfamide (HD-IFO), and four received other regimens. One patient (4.3%) achieved partial response (PR), and 12 patients (52.2%) achieved stable disease (SD) as the best response. Median PFS in 1 line was 2.79 months (95% CI: 2.04-8.38), and 1.76 months (95% CI: 0.72-6.97) in the second line. The median OS from first-line palliative chemotherapy was 8.2 months (95% CI: 6.2-14), and the second-line palliative chemotherapy mOS was 4.6 months (95% CI: 3.9-NA). Perioperatively anthracycline-pretreated worsened patients' median PFS in the M1 setting. Poor responses to conventional chemotherapy were observed in CCS, indicating a need for further clinical trials in this indication.

Long-term efficacy of neoadjuvant-adjuvant targeted therapy in borderline resectable stage IIIB-D and IV melanoma.

BACKGROUND: Neoadjuvant-adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. METHODS: Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. RESULTS: Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near-complete response. In the whole group, median recurrence-free survival was 19.4 months and median distant metastasis-free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near-pCR median recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR) = 0.37 (p = .005) for RFS and HR = 0.33 (p = .002) for DMFS. After median follow-up of 52.5 months, median progression-free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time-to-treatment-failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near-pCR (HR = 0.45; p = .022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near-pCR and pathological partial response/pathological nonresponse, respectively. CONCLUSIONS: The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. PLAIN LANGUAGE SUMMARY: Our study presents a large comprehensive analysis of neoadjuvant-adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma. Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection. After median follow-up of 52.5 months, median progression-free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near-complete pathological response-and together they had median recurrence-free survival and distant metastasis-free survival significantly longer than in patients with pathological partial response or nonresponse. Complete/near-complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence-free, including distant metastasis-free, survival in these patients.

Preoperative-postoperative immunotherapy as treatment of borderline resectable and oligoprogressive stage III B-D and IV melanoma.

INTRODUCTION: Perioperative therapy has gained significant importance in patients with advanced melanoma. Currently, there is little data on the routine use of preoperative immunotherapy in metastatic melanoma outside clinical trials. This study aimed to evaluate the effectiveness of preoperative treatment in patients with borderline resectable stage III or IV melanoma as well as in oligoprogressing stage IV cases; the secondary aim is to describe the safety of surgery after immunotherapy. MATERIALS AND METHODS: Since 1/Jan/2016 seventeen patients were treated with curative intent neoadjuvant immunotherapy, surgery, and adjuvant immunotherapy, while nineteen patients were operated due to oligoprogression while treted with immunotherapy. Survival was analyzed using the Kaplan-Meier method and association between variables was tested using the chi-squared test. RESULTS: R0 resection was achieved in 76.5 % of cases after neoadjuvant immunotherapy. 24 % of patients achieved objective RECIST response and 35 % complete or major pathological response. At the median follow-up time of 51.4 months, 64.7 % of patients were free of PD after perioperative treatment, while 3-year RFS and OS rates were 68 % and 80.9 %, respectively. R0 resection was achieved in 73.7 % of oligo-progressing nodules. The median time to PD on immunotherapy after the first oligoprogression was 10.3 months. Immunotherapy did not result in any unexpected surgical complications. No patient died during preoperative treatment due to immunotherapy toxicity or disease progression. CONCLUSIONS: We confirmed treatment safety and long-term disease control after perioperative immunotherapy. Patients with borderline resectable melanoma should be referred to reference centers using neoadjuvant immunotherapy.

Modern Approach to Melanoma Adjuvant Treatment with Anti-PD1 Immune Check Point Inhibitors or BRAF/MEK Targeted Therapy: Multicenter Real-World Report.

BACKGROUND: The landscape of melanoma management changed as randomized trials have launched adjuvant treatment. MATERIALS AND METHODS: An analysis of data on 248 consecutive melanoma stage III and IV patients given adjuvant therapy in eight centers (February 2019 to January 2021) was conducted. RESULTS: The analyzed cohort comprised 147 melanoma patients given anti-PD1 (33% nivolumab, 26% pembrolizumab), and 101 (41%) were given dabrafenib plus trametinib (DT). The 2-year overall survival (OS), relapse-free survival (RFS), and distant-metastases-free survival (DMFS) rates were 86.7%, 61.4%, and 70.2%, respectively. The disease stage affected only the RFS rate; for stage IV, it was 52.2% (95% CI: 33.4-81.5%) vs. 62.5% (95% CI: 52.3-74.8%) for IIIA-D, p = 0.0033. The type of lymph node surgery before adjuvant therapy did not influence the outcomes. Completion of lymph node dissection cessation after positive SLNB did not affect the results in terms of RFS or OS. Treatment-related adverse events (TRAE) were associated with longer 24-month RFS, with a rate of 68.7% (55.5-84.9%) for TRAE vs. 56.6% (45.8-70%) without TRAE, p = 0.0031. For TRAE of grade ≥ 3, a significant decline in OS to 60.6% (26.9-100%; p = 0.004) was observed. CONCLUSIONS: Melanoma adjuvant therapy with anti-PD1 or DT outside clinical trials appears to be effective and comparable with the results of registration studies. Our data support a de-escalating surgery approach in melanoma treatment.

Myocarditis Induced by Immunotherapy in Metastatic Melanoma-Review of Literature and Current Guidelines.

Immunotherapy is a widely used treatment modality in oncology. Immune checkpoint inhibitors, as a part of immunotherapy, caused a revolution in oncology, especially in melanoma therapy, due to the significant prolongation of patients' overall survival. These drugs act by activation of inhibited immune responses of T lymphocytes against cancer cells. The mechanism responsible for the therapy's high efficacy is also involved in immune tolerance of the patient's own tissues. The administration of ICI therapy to a patient can cause severe immune reactions against non-neoplastic cells. Among them, cardiotoxicity seems most important due to the high mortality rate. In this article, we present the history of a 79 year-old patient diagnosed with melanoma who died due to myocarditis induced by ICI therapy, despite the fast administration of recommended immunosuppressive therapy, as an illustration of possible adverse events of ICI. Additionally, we summarize the mechanism, risk factors, biomarkers, and clinical data from currently published guidelines and studies about ICI-related myocarditis. The fast recognition of this fatal adverse effect of therapy may accelerate the rapid introduction of treatment and improve patients' outcomes.

Long Term Results and Prognostic Biomarkers for Anti-PD1 Immunotherapy Used after BRAFi/MEKi Combination in Advanced Cutaneous Melanoma Patients.

(1) Background: BRAFi/MEKi are usually offered as a first line treatment for patients requiring rapid response; with elevated lactate dehydrogenase (LDH) activity, large tumor burden, and with brain metastases. The efficacy of second line therapies after BRAFi/MEKI failure is now well defined. (2) Methods: Patients treated with first line target BRAFi/MEKi therapy (vemurafenib plus cobimetinib, dabrafenib plus trametinib or encorafenib plus binimetinib); and for the second line treatment immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors (nivolumab or pembrolizumab) with at least one cycle of second line were analyzed for survival and prognostic biomarkers. (3) Results: There were no statistically significant differences in ORR between the treatment groups with nivolumab and pembrolizumab, as well as median progression free-survival (PSF) and overall survival (OS) since the initiation of second line therapy; on nivolumab OS was 6.6 months, and on pembrolizumab 5.0 months. The greatest clinical benefit with second line immunotherapy was observed in patients with LDH ≤ ULN and <3 organ sites with metastasis at baseline. Longer OS was also noted in patients with time to PD >6 months in first line (slow progression). (4) Conclusions: Second line anti-PD1 immunotherapy is effective in BRAF-mutated melanoma patients after BRAFi/MEKi therapy failure.

Long-Term Outcomes of Targeted Therapy after First-Line Immunotherapy in BRAF-Mutated Advanced Cutaneous Melanoma Patients-Real-World Evidence.

BACKGROUND: Currently, limited data on targeted therapy and immunotherapy sequencing in patients with BRAF-mutant melanoma is available. Targeted therapy and immunotherapy are expected to be comparable in terms of overall survival (OS) when used as second-line therapies; therefore, understanding the characteristics of patients who completed sequential treatment is needed. METHODS: The primary objective of this study was to analyze the efficacy of BRAFi/MEKi activity as second-line therapy in patients with advanced melanoma. We also aimed to describe the clinical characteristics of patients with advanced melanoma who were treated sequentially with immunotherapy and targeted therapy. We enrolled 97 patients treated between 1st December 2015 and 31st December 2020 with first-line immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors; and for the second-line treatment with at least one cycle of BRAFi/MEKi therapy with follow-up through 31 January 2022. RESULTS: Median OS since first-line treatment initiation was 19.9 months and 12.8 months since initiation of BRAFi/MEKi treatment. All BRAFi/MRKi combinations were similarly effective. Median progression free survival (PFS) was 7.5 months since initiation of any BRAFi/MEKi treatment. CONCLUSIONS: BRAFi/MEKi therapy is effective in the second-line in advanced and metastatic melanoma patients. For the first time, the efficacy of all BRAFi/MEKi combinations as second-line therapy is shown.

The Use of ctDNA for BRAF Mutation Testing in Routine Clinical Practice in Patients with Advanced Melanoma.

Assessment of BRAF mutation status is mandatory in advanced, treatment-naïve melanoma patients. Liquid biopsy can be an alternative in cases with inadequate or unavailable tumor tissue. The aim of our study was to evaluate the clinical utility of plasma circulating tumor DNA analysis for BRAF mutation testing and to assess outcomes of therapy with BRAF/MEK inhibitors initiated based on the liquid biopsy results. This was a retrospective single-center analysis of 46 patients (21 female, 25 male) with advanced melanoma who underwent circulating tumor DNA (ctDNA) BRAF mutation testing. A BRAF mutation was found in 45.7% (21/46) of liquid biopsies and 44.8% (13/29) of tissue samples. In patients with both ctDNA and tissue samples (n = 29), the concordance between the results of both tests was 82.8%. A BRAF mutation was detected in 7/17 (41.2%) patients with only ctDNA analysis. In 18 patients, therapy with BRAF/MEK inhibitors was initiated on the basis of the result of liquid biopsy. The objective response rate was 77.8 %, and the median PFS was 6.0 months. Our study confirms the clinical utility of BRAF mutation detection in plasma ctDNA. This study provides initial real-world data showing that treatment with BRAF/MEK inhibitors could be commenced based on liquid biopsy results.