Treatment Of Advanced Melanoma Research Articles

Phase III study of adjuvant encorafenib plus binimetinib versus placebo in fully resected stage IIB/C BRAFV600-mutated melanoma: COLUMBUS-AD study design.

TPS9601 Background: Significant progress has been made in the treatment of advanced BRAFV600-mutant melanoma. Encorafenib in combination with binimetinib is a well-tolerated and effective treatment option, providing sustained progression-free and overall survival benefit in unresectable or metastatic setting. The focus has shifted to early-stage disease in order to prevent recurrence. 18% of stage IIB and 25% stage IIC patients die due to melanoma within 10 years from the diagnosis [Gershenwald and al 2017], indicating an unmet medical need. Currently only immunotherapy has been approved in first countries across the world in this setting. There is a need for more treatment options for BRAF-mutated stage II disease. We report here the rationale and design of COLUMBUS-AD (NCT05270044). Methods: COLUMBUS-AD study is an international randomized, placebo-controlled, triple-blind, multicenter Phase III trial evaluating adjuvant encorafenib + binimetinib against placebo in patients with fully resected stage IIB/C BRAF V600-mutant melanoma. Approximately 815 patients will be enrolled. More than 170 sites in up to 26 countries worldwide will participate in the study conducted in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC). Patients will receive encorafenib + binimetinib or placebo for 12 months, or until disease recurrence and will be followed monthly during treatment period, then every 3 months up to year 3, and then at regular intervals. The participants will be followed for a total of 10 years. Patients included in the study must have undergone resection of a stage IIB/C cutaneous melanoma with a BRAFV600E/K mutation, confirmed on resected tumor sample by a central laboratory, and a negative result on sentinel node biopsy. Patients must have recovered from surgery, have an ECOG 0/1, and adequate hematologic, hepatic, cardiac, coagulation and renal functions. Eligible patients will be randomized 1:1 to receive either encorafenib 450 mg once daily plus binimetinib 45 mg twice daily or matching placebos. The primary objective of the study is to evaluate the efficacy of the combination of encorafenib+ binimetinib for prolonging recurrence-free survival (RFS). The secondary objectives are to compare distant metastasis-free survival (DMFS), overall survival (OS), health-related quality of life (QoL), and safety and tolerability between the two arms and to provide additional pharmacokinetic data. Conclusion: COLUMBUS-AD is the first phase 3 randomised trial to evaluate adjuvant BRAFi/MEKi in stage IIB/C melanoma. This study will evaluate whether the combination of encorafenib and binimetinib can decrease the risk for recurrence and improve distant metastasis-free survival and overall survival versus placebo in completely resected IIB/C BRAFV600E/K-mutant cutaneous melanoma. Clinical trial information: NCT05270044 .

Key factors associated with response in the treatment of liver metastatic melanoma by cryoablation combined with PD-1 blockade therapy: The Cryo-Fire-001 study.

e21500 Background: Liver metastasis remains a challenge in the treatment of advanced stage melanoma through immunotherapy. Although our previous study showed cryoablation could enhance the efficacy of PD-1 blockade therapy in the treatment of melanoma patients with liver metastasis, the key factors correlated with survival and treatment response remains unknown. Methods: Between 2018 and 2022, 45 melanoma patients receiving combined PD-1 blockade therapy and cryoablation of liver metastasis were retrospectively analyzed. The technical parameters of cryoablation, the sequence of the combined treatment, tumor characteristics, important immune markers and their correlations with treatment response were evaluated. The associations between key factors and overall survival (OS) were determined by Cox regression. Results: Of the 45 patients, the 3-month overall response rate (RECIST 1.1 criteria) is 26.7%. Multivariate analysis showed the number of metastatic organs ( > 2 vs ≤2; HR 3.54; 95% CI 1.32-9.49; P = 0.012), pretreatment LDH level ( > 300 vs ≤300 U/L; HR 4.59; 95% CI 1.78-11.85; P = 0.002) and diameter of ablated lesion ( > 30 vs ≤30 mm; HR 3.27; 95% CI 1.17-9.15; P= 0.024) were independent unfavorable prognostic factors for OS. Further analysis showed patients with larger intrahepatic tumors ablated had larger tumor size (P < 0.001). A scatter plot by the two key variables showed patients with intrahepatic tumor size less than 45 mm and size of ablated lesion less than 30 mm had a marginally higher rate of 3-month response (10/28, 35.7%) compared to those not (2/17, 11.7%; P = 0.076). Large diameter of ablated lesion ( > 30 mm) require more ablation needles and cause greater elevation in the level of IL-6, CD8+T cell to Treg cell ratio and neutrophil to lymphocyte ratio after cryoablation while these changes disappeared when tested one month later. Conclusions: Fine selection based on baseline characteristics of patients and size of intrahepatic lesion for cryoablation are essential to achieve a high response rate during cryoablation-PD-1 combination treatment for liver metastatic melanoma.

Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma (AM) in patients with concomitant chronic lymphocytic leukemia (CLL).

e19511 Background: CLL is the most prevalent adult leukemia and is associated with an increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICI in patients with CLL. Immune checkpoint inhibitors (ICI) have revolutionized management of AM, but data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. We, therefore, sought to examine the efficacy of ICI for melanoma in patients with concomitant CLL and AM. Methods: In this international and multicentre retrospective study, review of clinical databases identified patients with concomitant CLL and AM treated with ICI from two US tertiary cancer centers (n = 39) and an Australian multi-institutional experience (AUS, n = 19). Objective response rates (ORR), defined as complete or partial response by RECIST v1.1, and survival outcomes (overall survival, OS, and progression-free survival, PFS) among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Results: Between 1997 and 2020, 58 patients with CLL were treated with ICI for concomitant AM. Among all patients with CLL and AM, ORR to ICI was 41% and median duration of response was 18 months. A majority were untreated for CLL (64%) at the time of ICI. Patients with prior history of treatment for CLL had significantly reduced ORRs (21% vs 51%, p = 0.04), PFS (3.6 vs. 14.6 months, p = 0.005), and OS (7.4 vs. 52.2 months, p = 0.002), compared to patients on observation for their CLL. Prior treatment with T-lymphocyte depleting chemoimmunotherapy (fludarabine, bendamustine, and alemtuzumab) was particularly associated with poor outcomes (median OS of 7.0 months, median PFS of 3.4 months). On univariate analysis, prior treatment for CLL, high risk CLL 17p deletion, and higher CLL Rai stage were associated with shorter PFS from ICI, though CLL treatment was the only factor independently associated with shorter PFS in the multivariate model (HR 6.5, [CI 2.1-20.3], p = 0.001]. Overall, 3 patients developed CLL progression while on ICI, though in two of these patients, the AM had an objective, durable clinical response to ICI. Overall, immune-related adverse events (irAE) occurred following 38% of ICI and rates of irAE were similar by CLL treatment status. Conclusions: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Relationship of adverse events after combined immunotherapy and treatment outcomes in patients with advanced melanoma: A multicenter experience in Poland.

e21511 Background: The combination of nivolumab and ipilimumab has become the standard of care for the first-line treatment of advanced melanoma. In this study, our objective was to evaluate the frequency of immune-related adverse events (irAEs) and to establish their relationship with treatment outcomes. Methods: We evaluated the medical records of 99 patients with advanced melanoma treated with combined immunotherapy in 7 oncology units in Poland in the period between October 2020 (the beginning of the reimbursement policy) and October 2022. We recorded therapy efficacy and irAEs at a follow-up period of 3, 12 and 18 months. Responders were defined as the patients with at least stable disease in a first follow-up, and non-responders as those with progressive disease (PD). The associations between the occurrence of irAEs and the treatment results (overall survival [OS] and progression-free survival [PFS]) were calculated using the Cox proportional hazards model. The log-rank test was applied to compare the survival distribution between the chosen factors. Results: The median duration of treatment was 2 months (interquartile ranges [IQR]: 2-6) and during the analysis, the patients were observed for a median follow-up of 6 months (IQR:3-13). After 3 months, the respondents constituted 54.5% (n = 54). At the last follow-up, 33.3% (n = 33) of the patients continued treatment and immunotherapy was stopped in the remaining patients due to PD (n = 33, 33.3%), toxicity (n = 24, 24.2%) or death (n = 8, 8.1%). In the entire group, the median OS was not reached (NR), (IQR: 8.7 months -NR) whereas PFS was 7 months (IQR:2-NR). Any grade (G) of irAEs was reported in 65 individuals (65.7%) with G3/G4 in 28 of them (43%). Thirty-one patients developed more than one episode of irAEs (2 episodes in 17.2%, n = 17; 3 episodes in 10.1%, n = 10; 4 episodes in 4%, n = 4; p = 0.006). The frequency of irAEs was 83.3% (n = 45) and 44.7% (n = 17) in responders and non-responders respectively, p = 0.0001. The OS and PFS values for patients who experienced irAEs did not reach medians and upper quartiles, but those without any irAEs had significantly worst outcome (10.5 months [IQR: 3-NR] for OS, p = 0.002; 2 months [IQR: 2-5.2] for PFS, p = 0.01). The patients with irAEs had a 30% lower risk of death (hazard ratio [HR] 0.7, 95% confidence interval [CI 0.56-0.86]) and a 40% lower risk of PD (HR 0.6, 95%CI [0.48- 0.74]). The most common irAEs were endocrine (n = 25), hepatic (n = 22) and cutaneous (n = 17). In a pairwise comparison the patients with endocrine irAEs (p = 0.01), receiving immunosuppressants for irAEs treatment (p = 0.01), and without brain metastases (p = 0.02) had a better survival rate. Conclusions: Patients with advanced melanoma treated with combined immunotherapy who experienced irAEs have a more favorable outcome, which is even better in those with more episodes of toxicity. The type of irAEs may also have predictive value.

A phase II randomized trial of talimogene laherparepvec (T-VEC) oncolytic immunotherapy with or without radiotherapy for patients with cutaneous metastases from solid tumors.

2639 Background: Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy made from a modified herpes virus expressing granulocyte-macrophage colony-stimulating factor and is FDA approved for the treatment of advanced melanoma. Laboratory studies suggest radiotherapy (RT) may interact with oncolytic immunotherapy to facilitate an immune-mediated anticancer response. We hypothesized that the combination of T-VEC+RT would produce tumor responses in distant (non-irradiated and non-injected) metastases. Methods: A prospective phase II, randomized, Simon two-stage clinical trial of T-VEC with or without RT was conducted with the primary objective of determining if the response rate of the largest non-injected and non-irradiated metastasis was ≥27%. Eligible patients had ≥1 cutaneous metastasis from a solid tumor amenable to T-VEC and RT and 1 measurable metastasis that would not be treated with T-VEC or RT. Using type I and II error probabilities of 10% and 20%, it was calculated that 9 patients would be enrolled in each arm, and if at least 1 of 9 patients subjects exhibited a response, then 6 additional patients would be enrolled in the second stage. Tumor and overall response was assessed using modified World Health Organization (mWHO) and immune related response criteria (irRC). Treatment-emergent and treatment-related adverse events (TEAEs and TRAEs) were characterized using CTCAE v4.0. Results: 19 patients were enrolled and randomized to receive T-VEC alone (n=9) or T-VEC+RT (n=10). One patient in each arm demonstrated a complete response in the largest non-irradiated and non-injected metastasis but progressed in new metastases. The composite response rate in target tumors not injected or irradiated was 13% and 0% in the T-VEC alone and T-VEC+RT arms, respectively. The composite response rate in target tumors treated with T-VEC alone or T-VEC+RT was 7% and 22%, respectively. Because no patient exhibited an overall mWHO or irRC defined response and due to slow accrual, the trial was closed after the first stage of enrollment despite meeting the prespecified response rate to continue enrollment in the second stage. Grade 3-4 TEAEs and TRAEs occurred in 9 and 2 patients, with similar frequencies between study arms. The most common AE was fever and occurred in 47% of patients. Peripheral blood-based immunologic analyses will be presented. Conclusions: The response rate in the largest non-injected or non-irradiated metastasis following T-VEC with or without RT given to a cutaneous metastasis from solid tumor could be ≥27% but was not determined in this trial due to premature closure, in part due to slow accrual rate and no observed mWHO defined overall responses. Cutaneous metastases responded more often after TVEC+RT than T-VEC alone, but the response in non-injected and non-irradiated tumors was more frequent after T-VEC alone. Clinical trial information: NCT02819843 .

Hepatic passaging of NRAS-mutant melanoma influences adhesive properties and metastatic pattern

BackgroundLiver metastasis is a poor prognostic factor for treatment of advanced cutaneous melanoma with either immunotherapy or targeted therapies. In this study we focused on NRAS mutated melanoma, a cohort with high unmet clinical need.MethodsWT31 melanoma was repeatedly passaged over the liver after intravenous injections five times generating the subline WT31_P5IV. The colonization of target organs, morphology, vascularization and the gene expression profiles of metastases were analyzed.ResultsAfter intravenous injection lung metastasis was significantly decreased and a trend towards increased liver metastasis was detected for WT31_P5IV as compared to parental WT31. Besides, the ratio of lung to liver metastases was significantly smaller. Histology of lung metastases revealed reduced proliferation of WT31_P5IV in relation to WT31 while both size and necrotic areas were unaltered. Liver metastases of both sublines showed no differences in vascularization, proliferation or necrosis. To identify tumor-intrinsic factors that altered the metastatic pattern of WT31_P5IV RNA sequencing was performed and revealed a differential regulation of pathways involved in cell adhesion. Ex vivo fluorescence imaging confirmed that initial tumor cell retention in the lungs was significantly reduced in WT31_P5IV in comparison to WT31.ConclusionThis study demonstrates that tumor-intrinsic properties influencing the metastatic pattern of NRAS mutated melanoma are strongly affected by hepatic passaging and the hematogenous route tumor cells take. It has implications for the clinical setting as such effects might also occur during metastatic spread or disease progression in melanoma patients.

Cost-Effectiveness of Pembrolizumab as an Adjuvant Treatment in Colombia for Melanoma Patients with Lymph Node Involvement After Complete Resection.

The KEYNOTE-054 trial found that adjuvant treatment with pembrolizumab improved recurrence-free survival versus placebo in completely resected high-risk stage III melanoma patients. We assessed the cost-effectiveness of adjuvant pembrolizumab in Colombia compared with watchful waiting, a widely used strategy despite the high risk of recurrence with surgery alone. A four-health state [recurrence-free (RF), locoregional recurrence (LR), distant metastases (DM), and death) Markov model was developed to assess the lifetime medical costs and outcomes (3% annual discount), along with cost-effectiveness ratios (ICERs). The transitions from the RF and LR states were modeled using KEYNOTE-054 data, and those from the DM state were modeled using data from the KEYNOTE-006 trial and a network meta-analysis of advanced treatments received after adjuvant pembrolizumab and watchful waiting. The health state utilities were derived from KEYNOTE-054 Euro-QoL data and literature. Costs are expressed in 2021 Colombian pesos (COP). Over a 46-year time horizon, patients on adjuvant pembrolizumab and watchful waiting were estimated to gain 9.69 and 7.56 quality-adjusted life-years (QALYs), 10.83 and 8.65 life-years (LYs), and incur costs of COP 663,595,726 and COP 563,237,206, respectively. The proportion of LYs spent in RF state was 84.63% for pembrolizumab and 72.13% for watchful waiting, yielding lower subsequent treatment, disease management, and terminal care costs for pembrolizumab. Adjuvant pembrolizumab improved survival by 2.18 LYs and 2.13 QALYs versus watchful waiting. The ICER per QALY was COP 47,081,917, primarily driven by recurrence rates and advanced melanoma treatments. The deterministic sensitivity analysis results were robust and consistent across various reasonable inputs and alternative scenarios. At a willingness-to-pay threshold of COP 69,150,201 per QALY, the probability of pembrolizumab being cost-effective was 65.70%. Pembrolizumab is cost-effective as an adjuvant treatment compared to watchful waiting among patients with high-risk stage III melanoma after complete resection in Colombia.

The Role Ipilimumab Plays in the Treatment of Melanoma

While melanoma is not as common as other types of skin cancer among the whole dermatologic cancer category, it appears to be extremely aggressive for its high death rates. Conventional treatments like radiation therapy (RT), chemotherapy, and surgery have showed either significant side effects or limited improvement to the disease. Ipilimumab, anti-CTLA-4 antibodies, is immune checkpoint Inhibitor (ICI) approved by the FDA for being one source of treatment in the advanced melanoma in 2011 as an immunotherapeutic approach. Anti-CTLA-4 is authorized for usage as monotherapy treatment for advanced metastatic melanoma. it licensed as combination treatment for melanoma. The new study shown that the ipilimumab combined with pembrolizumab may be feasible in treating more cancerous diseases. For individuals that suffer from advanced malignant melanoma, ipilimumab decrease the overall death rates in randomized trials. The combined approach of anti-PD-1 and anti-CTLA-4 antibodies has shown feasibility.

MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2.

Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.

Current application of immunotherapy in melanoma.

Current application of immunotherapy in melanoma.

Adjuvant treatment in advanced melanoma: How far have we come?

Adjuvant treatment in advanced melanoma: How far have we come?

Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

Long-term clinical evidence of comparable efficacy and toxicity of nivolumab and pembrolizumab in advanced melanoma treatment.

Pembrolizumab and nivolumab (anty-PD-1 antibody) are commonly used for the treatment of melanoma patients. However, their efficacy and safety have never been directly compared, leaving little guidance for clinicians to select the best therapy. The study included patients with inoperable or metastatic melanoma treated in first line with anti-PD-1 immunotherapy (nivolumab or pembrolizumab). In total 1037 patients were enrolled in the study, 455 (44%) patients were treated with pembrolizumab and 582 (56%) with nivolumab. The estimated median overall survival (OS) in the pembrolizumab and nivolumab groups was 17.4 and 20.0 months [ P = 0.2323; hazard ratio (HR), 1.1; 95% confidence interval (CI), 0.94-1.28], respectively, whereas the median progression-free survival (PFS) was 5.6 and 7.5 months ( P = 0.0941; HR, 1.13; 95% CI, 0.98-1.29), respectively. The estimated 2- and 3-year OS in the pembrolizumab and nivolumab groups were 42/34% and 47/37%, respectively, and the PFS was 25/21% and 29/23%, respectively. There were 391 (49%) immune-related adverse events (irAEs) of any grade during treatment, including 133 (42%) related to pembrolizumab treatment and 258 (53%) to nivolumab treatment. A total of 72 (9.6%) irAEs were in G3 or G4, including during pembrolizumab 29 (9%) and nivolumab 48 (11%). There were no differences in OS, PFS and overall response rates between nivolumab and pembrolizumab therapy in previously untreated patients with advanced/metastatic melanoma. There were no differences in the frequency of G1/G2 or G3/G4 irAEs. The choice of treatment should be based on the preferences of the patient and the clinician.

PD-L1 Tumor Expression as a Predictive Biomarker of Immune Checkpoint Inhibitors' Response and Survival in Advanced Melanoma Patients in Brazil.

Immune checkpoint blockade (ICB) agents are prominent immunotherapies for the treatment of advanced melanoma. However, they fail to promote any durable clinical benefit in a large cohort of patients. This study assessed clinical and molecular predictors of ICB response and survival in advanced melanoma. A retrospective analysis was performed on 210 patients treated with PD-1 or CTLA-4 inhibitors at Barretos Cancer Hospital, Brazil. PD-L1 expression was assessed by immunohistochemistry using formalin-fixed paraffin-embedded tumor tissues collected prior to ICB therapy. Patients were divided into responders (complete and partial response and stable disease for more than 6 months) and non-responders (stable disease for less than 6 months and progressive disease). Among them, about 82% underwent anti-PD-1 immunotherapy, and 60.5% progressed after the ICB treatment. Patients that received ICB as first-line therapy showed higher response rates than previously treated patients. Higher response rates were further associated with superficial spreading melanomas and positive PD-L1 expression (>1%). Likewise, PD-L1 positive expression and BRAF V600 mutations were associated with a higher overall survival after ICB therapy. Since ICBs are expensive therapies, evaluation of PD-L1 tumor expression in melanoma patients should be routinely assessed to select patients that are most likely to respond.

Time interval from primary melanoma to first distant recurrence in relation to patient outcomes in advanced melanoma.

Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune-surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first-line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression-free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti-PD-1-based treatment (n=1844) or BRAF(/MEK) inhibition (n=1618). For ICI-treated patients with a TFDR <2 years, median OS was 25.0months, compared to 37.3months for a TFDR >5 years (P= .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6months for TFDR <2 years compared to 11.1months for >5 years, P= .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first-line ICI or targeted therapy.

121P Temozolomide plus cisplatin as first-line treatment for advanced or metastatic mucosal melanoma

121P Temozolomide plus cisplatin as first-line treatment for advanced or metastatic mucosal melanoma

Targeting Immune Checkpoint Pathways in Melanoma: Triumphs and Challenges

The immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma by significantly increasing survival rates, with the promise of durable disease remission in some patients. Herein we review the role of immune checkpoints in melanoma; the history of melanoma immunotherapy; pivotal clinical trial data for ipilimumab, pembrolizumab, nivolumab and relatlimab; and the current clinical role of each ICI. We discuss the challenges that accompany these triumphs in the treatment of melanoma, including: how to distinguish between responders and nonresponders; how to optimize ICI dosing and combinatorial approaches; and the best practices for monitoring response and managing immune-related toxicities. We offer our perspective on the financial toxicity of ICIs and new developments that could deliver answers to current challenges.

FDG PET/CT Prognostic Markers in Patients with Advanced Melanoma Treated with Ipilimumab and Nivolumab.

Background Despite improved response to combined ipilimumab and nivolumab (hereafter, IpiNivo) treatment for advanced melanoma, many patients exhibit primary or acquired resistance. This, combined with high risk of immune-related adverse events, makes identifying markers predictive of outcomes desirable. Purpose To investigate the prognostic value of fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT parameters at baseline and as part of response monitoring in patients with advanced melanoma undergoing IpiNivo treatment. Materials and Methods This was a single-center retrospective study of adult patients with melanoma who received IpiNivo. Baseline FDG PET/CT parameters that included metabolic tumor volume (MTV), tumor stage, mutation status, Eastern Cooperative Oncology Group performance score, lactate dehydrogenase level, and treatment line were correlated with overall survival in univariable and multivariable Cox regression analyses. Treatment response as determined with FDG PET/CT was correlated with overall survival. Results In total, 122 patients (median age, 61 years [IQR, 51-69 years]; 89 men) were included; 78% (95 of 122) had an Eastern Cooperative Oncology Group score of 0, 52% (45 of 86) had an elevated lactate dehydrogenase level, 39% (48 of 122) had a metastatic stage of M1c and 45% (55 of 122) M1d, 45% (55 of 122) had BRAF V600E/K mutation, and the median MTV was 42 mL. Patients with a higher than median MTV at baseline FDG PET/CT had a lower 12-month survival rate compared with those with a lower than median MTV (43% [95% CI: 32, 58] vs 66% [95% CI: 55, 79], P < .001). In multivariable analysis, higher versus lower than median MTV, Eastern Cooperative Oncology Group performance scores of 1-2 versus 0, and subsequent versus first-line IpiNivo treatment were independently associated with overall survival (hazard ratio [HR]: 1.68 [95% CI: 1.02, 2.78], P = .04; 3.1 [95% CI: 1.8, 5.4], P < .001; and 11.2 [95% CI: 3.4, 37.1], P = .002, respectively). The 12-month overall survival rate was lower in patients with progressive disease than in those without progression (35% [95% CI: 24, 51] vs 90% [95% CI: 83, 99]; HR, 7.3 [95% CI: 3.9, 13.3]; P < .001). Conclusion Baseline fluorine 18 fluorodeoxyglucose PET/CT metabolic tumor volume was an independent prognostic marker in patients with advanced melanoma who received ipilimumab and nivolumab treatment. © RSNA, 2023 Supplemental material is available for this article.

Dabrafenib plus trametinib versus nivolumab for advanced melanoma

Introduction The incidence of cutaneous melanoma has increased worldwide over the years, and an incidence of 3 cases per 100,000 men and women is estimated in Chile. Though most of the patients are diagnosed at an early stage of the disease and have a good prognosis, advanced melanoma has poor survival results. For the treatment of melanoma, the combination of dabrafenib plus trametinib has been demonstrated to improve the outcome versus dabrafenib alone, but only indirect evidence is available for its efficacy and safety compared with immunotherapy, like nivolumab. The aim of this study is to review the available evidence to report results of efficacy and safety of dabrafenib plus trametinib in comparison with nivolumab in metastatic melanoma. Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews selected, reanalyzed data of primary studies, and generated a summary of the findings table using the GRADE approach. Results and conclusions We identified five systematic reviews, including seven studies overall that included one intervention of our interest, of which all were randomized trials. We only found indirect evidence comparing dabrafenib plus trametinib versus nivolumab that came from Network Meta-Analyses. We concluded that it is not possible to decide if dabrafenib plus trametinib is a better strategy for advanced melanoma treatment than nivolumab because the certainty of the evidence is very low for efficacy and safety outcomes.

CT radiomics compared to a clinical model for predicting checkpoint inhibitor treatment outcomes in patients with advanced melanoma

IntroductionPredicting checkpoint inhibitors treatment outcomes in melanoma is a relevant task, due to the unpredictable and potentially fatal toxicity and high costs for society. However, accurate biomarkers for treatment outcomes are lacking. Radiomics are a technique to quantitatively capture tumour characteristics on readily available computed tomography (CT) imaging. The purpose of this study was to investigate the added value of radiomics for predicting clinical benefit from checkpoint inhibitors in melanoma in a large, multicenter cohort. MethodsPatients who received first-line anti-PD1±anti-CTLA4 treatment for advanced cutaneous melanoma were retrospectively identified from nine participating hospitals. For every patient, up to five representative lesions were segmented on baseline CT, and radiomics features were extracted. A machine learning pipeline was trained on the radiomics features to predict clinical benefit, defined as stable disease for more than 6 months or response per RECIST 1.1 criteria. This approach was evaluated using a leave-one-centre-out cross validation and compared to a model based on previously discovered clinical predictors. Lastly, a combination model was built on the radiomics and clinical model. ResultsA total of 620 patients were included, of which 59.2% experienced clinical benefit. The radiomics model achieved an area under the receiver operator characteristic curve (AUROC) of 0.607 [95% CI, 0.562–0.652], lower than that of the clinical model (AUROC=0.646 [95% CI, 0.600–0.692]). The combination model yielded no improvement over the clinical model in terms of discrimination (AUROC=0.636 [95% CI, 0.592–0.680]) or calibration. The output of the radiomics model was significantly correlated with three out of five input variables of the clinical model (p < 0.001). DiscussionThe radiomics model achieved a moderate predictive value of clinical benefit, which was statistically significant. However, a radiomics approach was unable to add value to a simpler clinical model, most likely due to the overlap in predictive information learned by both models. Future research should focus on the application of deep learning, spectral CT-derived radiomics, and a multimodal approach for accurately predicting benefit to checkpoint inhibitor treatment in advanced melanoma.