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.

Treatment of Locally Advanced Merkel Cell Carcinoma-A Multi-Center Study.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a high risk of recurrence and poor prognosis. The treatment of locally advanced disease involves surgery and radiotherapy. To analyze real-life treatment patterns and clinical outcomes, we conducted a retrospective analysis of data from 161 MCC patients treated with curative intent in four oncological centers in Poland. The median age at diagnosis was 72 years (30-94); 49.7% were male. Lymph node (LN) involvement at diagnosis was found in 26.9% of patients. Sentinel lymph node biopsy (SLNB) was performed in 36.5% of patients (positive in 10.5%), and 51.9% of patients received perioperative treatment. The relapse rate was 38.3%. With the median follow-up of 2.3 years, the median disease-free survival (DFS) was not reached, and the 1-year rate was 65%. The negative independent risk factors for DFS were male gender, metastases in LN at diagnosis, no SLNB in patients without clinical nodal metastases, and no perioperative radiotherapy. The estimated median overall survival (OS) was 6.9 years (95% CI 4.64-9.15). The negative independent risk factors for OS were male gender, age above 70, metastases in LN at diagnosis, and no SLNB in patients without clinical nodal metastases. Our results confirm that the MCC treatment should be conducted in an experienced multidisciplinary team; however, the outcomes are still unsatisfactory.

Efficacy of immunotherapy beyond RECIST progression in advanced melanoma: a real-world evidence.

Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST 1.1 defined progression. The clinical concept of treating selected patients (pts) beyond disease progression (PD) is supported by so-called pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond (RECIST) progression (TBP) in advanced melanoma patients. Of 584 subsequent melanoma pts analyzed 77 (13.2%) received TBP. In this cohort, the median time to first PD (TTFP) was 5.29 months (m), while time to second PD (TTSP)-8.02 m. On TBP 23.4% pts achieved an objective response (OR), and next 42.9%-stabilization of the disease (SD). 1st PD was reported most often as the development of a new lesion or increase (> 20%) of the diameter of three or more targets. In about 50% second PD was observed as an increase in the diameter of different targets that in 1st PD. Multimodal treatment resulted in 9.82 m TTSP, while ITH alone-4.93 m (p = 0.128). An oligoprogressive pattern of first PD was associated with longer TTSP (HR 0.55, 95% CI: 0.32-0.94). Median OS after first PD was 28.75 months and correlated with OR during TBP (HR 0.18, 95% CI: 0.004-0.76). Selected clinically fit melanoma patients, despite evidence of first radiographic progression, may benefit from continued treatment with PD-1 checkpoint inhibitors, but the findings should be validated in larger prospective trials. Multidisciplinary treatment should be offered to advanced melanoma patients, including radiosurgery or stereotactic radiotherapy of single loci progressing during immunotherapy.

First-line treatment of advanced/metastatic melanoma with anti-PD-1 antibodies: multicenter experience in Poland.

Aim: To evaluate treatment results in advanced/metastatic melanoma patients treated with anti-PD-1 immunotherapy in routine practice in oncology centers in Poland. Methods: Multicenter retrospective analysis included 499 patients with unresectable/metastatic (stage IIIC-IV) melanoma treated with anti-PD-1 in first-line therapy. Results: Estimated median overall survival (OS) and progression-free survival (PFS) were 19.9 and 7.9 months, respectively. Multivariate analysis confirmed that ECOG 0, no brain metastases, normal lactate dehydrogenase level and occurrence of immune-related adverse events (irAEs) were statistically significantly associated with improved OS and PFS. Any irAE occurred in 24% of patients. Grade 3 or Grade 4 irAEs occurred in 6% of patients. Conclusion: Analysis revealed a slightly worse OS in real-world treatment in comparison to clinical trials (KEYNOTE-006 and CheckMate 066). Polish population treatment results are similar to other studies of real-world data. PFS and ORR are similar in our research and clinical trials.

Sensors to Detect Sarin Simulant.

This work presents a literature review concerning the construction, properties and application of different sensors used to detect dimethyl methylphonate (DMMP), which is the simulant of sarin. Sensors sensitive to mass are described, together with such sensors as: SAW, QCM, MEMS, also chemical capacitors, semiconductors, and field effect transistors.

Efficacy of Neoadjuvant Targeted Therapy for Borderline Resectable III B-D or IV Stage BRAF V600 Mutation-Positive Melanoma.

Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment as it is for sarcoma, breast, rectal, esophageal, or gastric cancers. Patients with locoregional recurrence after initial surgery and those with advanced regional lymphatic metastases are at a high risk of relapse and melanoma-related death. There is an unmet clinical need to improve the outcomes for such patients. Patients with resectable bulky stage III or resectable stage IV histologically confirmed melanoma were enrolled and received standard-dose BRAFi/MEKi for at least 12 weeks before feasible resection of the pre-therapy target and then received at least for the next 40 weeks further BRAFi/MEKi. Of these patients, 37 were treated with dabrafenib and trametinib, three were treated with vemurafenib and cobimetinib, five with vemurafenib, and one with dabrafenib alone. All patients underwent surgery with 78% microscopically margin-negative resection (R0) resection. Ten patients achieved a complete pathological response. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median disease free survival and progression free survival were significantly longer than in patients with a minor pathological response. No patient discontinued neoadjuvant BRAFi/MEKi due to toxicity. BRAFi/MEKi pre-treatment did not result in any new specific complications of surgery. Fourteen patients experienced disease recurrence or progression during post-operative treatment. We confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of melanoma. Pathological response to neoadjuvant treatment may be considered as a surrogate biomarker of disease recurrence.

Body mass index (BMI) and outcome of metastatic melanoma patients receiving targeted therapy and immunotherapy: a multicenter international retrospective study.

BACKGROUND: Obesity is a risk factor for malignancy; however, its prognostic role in patients with metastatic melanoma is controversial. We aim to investigate the prognostic role of body mass index (BMI) in patients with metastatic melanoma receiving mitogen-activated pathway kinase inhibitors (MAPKi), immune checkpoint inhibitors (ICIs) alone or their sequence. METHODS: Data on patients with metastatic melanoma receiving ≥1 line of systemic treatment were retrieved from prospectively collected databases. Progression-free survival (PFS) and overall survival (OS) were analyzed by means of multivariable stratified Cox regression models; disease control rate (DCR) was analyzed by multivariable stratified logistic regression models. Subgroup analyzes according to the type of treatments received, and in BRAF-mutated patients were pre-planned. All multivariable models included BMI, age, gender, American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment sequencing strategy as covariates. RESULTS: Between November 2010 and November 2018, 688 patients from three Italian and two Polish centers were enrolled. 379 (57%) patients had M1c/d disease, 273 (41%) were female and the mean BMI was 27.1 (SD=4.9). Considering first-line treatment, 446 patients (66.8%) received ICIs and 222 MAPKi. No impact of BMI on OS was detected either considering the first line of ICIs, or ICIs sequencing (HR=1.02, 95% CI: 0.99 to 1.05, p=0.202, and HR=1.02, 95% CI: 0.99 to 1.04, p=0.237, respectively). A late effect of BMI on OS was found in patients treated with MAPKi: for five units increment, a 51% of risk reduction at 18 months and a 76% of risk reduction at 30 months were observed. No significant effect of BMI on PFS and DCR was found in any of the subgroup analyzes. CONCLUSION: In patients with metastatic melanoma receiving ICIs, there is no impact of BMI on DCR, PFS and OS. The late prognostic effect of BMI in patients treated with MAPKi should be considered hypothesis generating and needs to be further investigated.

Multimodal Treatment of Advanced Mucosal Melanoma in the Era of Modern Immunotherapy.

Mucosal melanoma is a rare disease epidemiologically and molecularly distinct from cutaneous melanoma developing from melanocytes located in mucosal membranes. Little is known about its therapy. In this paper, we aimed to evaluate the results of immunotherapy and radiotherapy in a group of patients with advanced mucosal melanoma, based on the experience of five high-volume centers in Poland and Italy. There were 82 patients (53 female, 29 male) included in this retrospective study. The median age in this group was 67.5 (IQR: 57.25-75.75). All patients received anti-PD1 or anti-CTLA4 antibodies in the first or second line of treatment. Twenty-three patients received radiotherapy during anti-PD1 treatment. In the first-line treatment, the median progression-free survival (PFS) reached six months in the anti-PD1 group, which was statistically better than 3.1 months in the other modalities group (p = 0.004). The median overall survival (OS) was 16.3 months (CI: 12.1-22.3) in the whole cohort. Patients who received radiotherapy (RT) during the anti-PD1 treatment had a median PFS of 8.9 months (CI: 7.4-NA), whereas patients treated with single-modality anti-PD1 therapy had a median PFS of 4.2 months (CI: 3.0-7.8); this difference was statistically significant (p = 0.047). Anti-PD1 antibodies are an effective treatment option in advanced mucosal melanoma (MM). The addition of RT may have been beneficial in the selected subgroup of mucosal melanoma patients.

A durable complete response to immunotherapy in a patient with metastatic alveolar soft part sarcoma.

BACKGROUND: Recent years have brought the dynamic development of a new method of cancer treatment: immunotherapy. Monoclonal antibodies blocking the programmed death receptor 1 (PD-1) are now widely used in the treatment of several malignancies: melanoma, lung, head and neck cancer, among others. The therapeutic benefit of immunotherapy in soft tissue sarcoma (STS) has not yet been proven. The exception is results obtained in the treatment of a rare STS subtype alveolar soft part sarcoma (ASPS). CASE REPORT: We describe a case of a man with a diagnosis of metastatic ASPS in whom the use of immunotherapy with nivolumab resulted in excellent long-term clinical benefit and a pathologically confirmed complete response. CONCLUSION: There are strong indications that immunotherapy may become the next important treatment method of ASPS.

Efficacy of ipilimumab after anti-PD-1 therapy in sequential treatment of metastatic melanoma patients - Real world evidence.

PURPOSE: Immunotherapy has become a standard treatment option for patients with metastatic melanoma, and the use of checkpoint inhibitors significantly improves the treatment outcomes in this group. PATIENTS AND METHODS: A total of 116 patients with metastatic melanoma were enrolled in the study. In the first line, they were treated with an anti-PD-1 inhibitor (nivolumab or pembrolizumab), following which ipilimumab was used as the second-line therapy. RESULTS: BRAF mutation was detected in 12 patients (10%). The median progression-free survival (PFS) of ipilimumab treatment was 2.8 months, the overall survival (OS) was 5.1 months. The rate of 6-month survival was 45%, 1-year survival was 24%, and 2-year survival was 3%. The responses to treatment were: complete response in 2 cases (2%), partial response in 7 cases (6%), stable disease in 39 cases (34%). In multivariate analysis, normal levels of lactate dehydrogenase (LDH) were associated with a longer median OS and PFS (p = 0.02 and p = 0.009, respectively), while 2 or less number of metastatic locations and the presence of BRAF mutations were correlated with a longer OS (p = 0.041 and p = 0.024, respectively). CONCLUSIONS: Ipilimumab could be considered after anti-PD-1 treatment. Treatment with ipilimumab following anti-PD-1 therapy showed beneficial effects in patients with normal levels of LDH, 2 or less number of metastatic locations, and BRAF-mutated melanoma. However, further studies are required to confirm our results as the study included a low number of patients with BRAF mutation-positive melanoma. No significant increase in toxicity was detected with the use of ipilimumab after anti-PD-1 therapy.

BRAF and MEK inhibitors rechallenge as effective treatment for patients with metastatic melanoma.

Despite considerable progress made in the treatment of patients with advanced melanoma, the majority of the patients treated with BRAF and mitogen-activated protein inhibitors (BRAFi and MEKi) experience a disease progression due to acquired resistance. Currently, ongoing studies explore the possibility to overcome or reverse this process. Our multicenter retrospective analysis included 51 patients with metastatic BRAF-mutated melanoma who had previously progressed on BRAFi/MEKi than had progressed on immunotherapy (anti-progression disease-1 or anti-cytotoxic T-lymphocyte-associated protein 4) and next were rechallenged with BRAFi/MEKi. Median age at BRAFi/MEKi rechallenge was 56 (range: 31-82 y/o). Median overall survival from the start of the first BRAFi/MEKi therapy and from rechallenge BRAFi/MEKi treatment was 29.7 and 9.3 months, respectively, whereas median progression-free survival was 10.5 and 5.9 months, respectively. Six-month, annual, and 2-year overall survival rates on both treatments were: 98% and 55%, 92% and 29%, and 69% and 2%, respectively. A response rate to treatment was higher in the group receiving BRAFi/MEKi for the first time as compared with the group receiving BRAFi/MEKi rechallenge and was overall response rate 72% and 27%; disease control rate 92% and 63%. Time interval between the end of the first BRAFi/MEKi treatment and the beginning of BRAFi/MEKi rechallenge did not influence median overall survival or progression-free survival. A lower toxicity rate was noted with BRAFi/MEKi rechallenge. BRAFi/MEKi rechallenge treatment remains clinically important and is associated with the lower toxicity. BRAFi/MEKi rechallenge efficacy is higher in patients who are in good performance status, with normal lactate dehydrogenase, and without brain metastases.