Treatment Of Advanced Melanoma Research Articles

Cutaneous Adverse Events of Systemic Melanoma Treatments: A Retrospective Single-Center Analysis.

Recent progress in the treatment of advanced melanoma has led to the improved survival of affected patients. However, novel treatments also lead to considerable and distinct skin toxicity. To further characterize cutaneous adverse events (AE) of systemic treatments, we conducted a single-center retrospective study of biopsy-proven cutaneous adverse events of melanoma treatment over a period of 10 years at the University Hospital of Zurich, Switzerland. In 102 identified patients, 135 individual skin AEs developed. Immune checkpoint blockade (ICB) was causal for 81 skin AEs, and 54 were related to targeted therapies (TT). Recorded types of skin AEs included lichenoid, maculopapular, acneiform, urticarial, panniculitis, folliculitis, psoriasiform, granulomatous, eczematous, and others. The incidence of skin AEs was higher with TT (18.54%) than with ICB (9.64%, p = 0.0029). Most AEs were low-grade, although 19.21% of AEs were common terminology criteria for adverse events (CTCAE) Grades 3 or 4. A large spectrum of skin AEs was documented during treatment of advanced melanoma, and distinct phenotypes were observed, depending on treatment classes. AEs occurred earlier during treatment with TT than with ICB, and distinct types of skin AEs were associated with respective treatment classes. This study comprehensively describes skin AEs occurring during systemic treatment for melanoma at a single center.

Nivolumab plus ipilimumab in metastatic melanoma: a critical appraisal focused on specific subpopulations.

The development of immune checkpoint inhibitors has revolutionized the landscape of treatment of advanced melanoma in recent years. Based on the efficacy results of the phase III CheckMate 067 trial, nivolumab in combination with ipilimumab is one of the first-line standard options for advanced melanoma along with pembrolizumab, nivolumab, and, recently, nivolumab plus relatlimab. Counterbalancing its efficacy, nivolumab plus ipilimumab is associated with severe immune-related toxicity. This article will review the efficacy and safety of the nivolumab plus ipilimumab combination in advanced melanoma across phase I, II, and III clinical trials that evaluated this approach. We also explore the benefit of the combination schedule across different subgroups of patients and possible predictive biomarkers for efficacy outcomes in order to elucidate which patients could be the best candidates for combination or single-agent therapy. Patients with BRAF-mutant tumours, asymptomatic brain metastases, or PD-L1-negative status appear to reach better survival outcomes with the combination relative to single-agent immunotherapy.

Current Patterns of Treatment and Outcomes in Advanced Melanoma at a Single Institution

IntroductionTreatment of advanced melanoma has been transformed by novel systemic therapies. The purpose of this study is to describe the current utilization patterns of immunotherapies with respect to survival outcomes in advanced melanoma. MethodsWe performed a retrospective cohort study of patients with Stage 3 and 4 melanoma at our institution (2009-2019). Primary outcomes included overall survival (OS) and progression free survival (PFS). Kaplan–Meier survival analysis and Cox proportional hazards regression analysis evaluated associations between covariates and survival outcomes. ResultsOf 244 patients, 5-y OS was 62.4%. Lymphovascular invasion (hazard ratio [HR] = 2.462, P = 0.030) was associated with shorter PFS whereas female gender (HR = 0.324, P = 0.010) was associated with longer PFS. Residual tumor (HR = 146, P = 0.006) and Stage 4 disease (HR = 3.349, P = 0.011) were associated with shorter OS. Use of immunotherapy increased from 2% to 23% over the study period, and use of neoadjuvant immunotherapy also increased up to 2016. Timing of immunotherapy administration was not significantly associated with survival. Of the 193 patients who received 2 or more treatment types, the most common treatment sequence was surgery followed by immunotherapy (n = 117, 60.6%). ConclusionsImmunotherapy is increasingly used for treatment of advanced melanoma. In this heterogeneous cohort, there was no significant association between timing of immunotherapy and survival outcomes.

Inmunoterapia vs. terapia diana en el paciente con melanoma avanzado y mutación BRAF V600, ¿por cuál comenzar?

Systemic treatment with immunotherapy or targeted therapy can significantly improve survival in patients with advanced (metastatic or high-risk) melanoma. Fifty percent of patients with melanoma have a BRAF mutation. Decisions on optimal sequencing of systemic treatments should take into account drug- and tumor-related factors and patient characteristics. Although the combination of ipilimumab and nivolumab is associated with the best survival outcomes, it is associated with significant toxicity. Targeted therapy may be a more favorable option in certain clinical situations. We review the literature on immunotherapy and targeted therapy in melanoma and present an algorithm for guiding decision-making on their use as first-line systemic treatments for advanced BRAF-mutated melanoma.

Camrelizumab combined with anlotinib and nab-paclitaxel in patients with untreated advanced mucosal melanoma: A single-arm, multicenter, exploratory study.

TPS9593 Background: Anti-programed cell death-1 (PD-1) monotherapy is a part of the standard treatment for cutaneous melanoma, but its efficacy in mucosal melanoma is not ideal. In vivo studies have demonstrated that co-inhibition of the VEGF receptor (VEGFR) and PD-1 pathways increased T cell infiltration and suppressed tumor growth synergistically. Early phase trial data confirmed that PD-1 inhibitors combined with anti-angiogenic drugs showed efficacy in the treatment of advanced mucosal melanoma, but still did not meet clinical needs. Previous studies have shown that chemotherapy combined with anti-angiogenic drugs has significantly improved median PFS and median OS compared with chemotherapy alone, and has a certain effect as a salvage treatment for progression after PD-1 inhibitor treatment. In addition, previous retrospective analysis showed that PD-1 inhibitors combined with chemotherapy drugs such as nab-paclitaxel were superior to anti-PD-1 monotherapy in the treatment of advanced mucosal melanoma. In summary, the combination of anti-PD-1, anti-angiogenic drugs and chemotherapy may bring new hope for the treatment of advanced mucosal melanoma. Methods: This is a single-arm, multicenter, exploratory study to evaluate the efficacy and safety of camrelizumab combined with anlotinib and nab-paclitaxel as first-line therapy in patients with advanced mucosal melanoma. The trial is expected to enrol 66 patients. Key Inclusion Criteria are pts with confirmed recurrence, unresectable or metastatic mucosal melanoma after surgery (stage III/IV) and ECOG performance status of ≤1.Pts with previous adjuvant therapy or neoadjuvant therapy (except PD-1/PDL1 monoclonal antibody and VEGFR TKI) at least 4 weeks before the first administration of the study drug are allowed. Patients received intravenous camrelizumab (200 mg) on day 1, intravenous nab-paclitaxel (260mg/m2) on day 1, and oral anlotinib (8mg) on days 1-14 every 3 weeks. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR),progression-free survival (PFS), and 2-year overall survival (OS). Clinical trial information: NCT04979585 .

A phase 1 study of fianlimab (anti-LAG-3) in combination with cemiplimab (anti-PD-1) in patients with advanced melanoma: Poor-prognosis subgroup analysis.

9548 Background: Co-blockade of LAG-3 improves the effectiveness of anti-PD-1 treatment (Tx) in advanced melanoma (Mel) patients (pts). We previously reported high clinical activity of the combination immunotherapy of anti-LAG-3 (fianlimab) and anti-PD-1 (cemiplimab) in pts (N = 80) with anti–PD-1/PD-ligand (L)1-naïve advanced Mel enrolled in two expansion phase 1 cohorts. The objective response rate (ORR) (N = 80) and disease control rate (DCR) was 63.8% and 80.0%, respectively with median duration of response (mDOR) not reached (NR). Factors associated with poor prognosis include elevated lactate dehydrogenase (LDH) levels and sites of metastases, including liver or other visceral organs (M1c). Here we present updated efficacy data in poor prognosis pts from three phase 1 advanced Mel expansion cohorts: cohort 6 and 15 of anti-PD-(L)1/systemic Tx-naïve pts and cohort 16 of pts previously exposed to adjuvant (adj) or neo-adj systemic Tx including anti-PD-1. Methods: Pts with advanced Mel (excluding uveal Mel) were treated with fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for 12 months (+ additional 12 months if clinically indicated). Tumor measurements were assessed by RECIST 1.1 every 6 weeks for 24 weeks, then every 9 weeks. Results: 40 pts each in cohort 6 and 15, and 18 pts in cohort 16 (total N = 98) were enrolled and treated with fianlimab + cemiplimab as of 01 Nov 2022 data cutoff. In the adj/neo-adj setting, 23.5% of pts had received prior systemic Tx for Mel including 15.3% with prior exposure to immune checkpoint inhibitors (iCPIs). Median follow up was 12.6 months and median Tx duration was 32.9 weeks. ORR among all 98 pts and in 15 pts with prior iCPIs was 61.2% and 60.0%, respectively. In pts with LDH > upper limit of normal (ULN) (N = 32, 32.7%), ORR, DCR, and mDOR were 53.1%, 71.9%, and NR (95% CI, 7.4– not estimated [NE]), respectively, and median progression-free survival (mPFS) was 11.8 months (95% CI, 3.7–NE). In pts with liver mets at baseline (BL) (N = 21, 21.4%), ORR, DCR, and mDOR were 42.9%, 57.1%, and 9.0 months (95% CI, 2.8–NE), respectively, and mPFS was 4.2 months (95% CI, 1.2–NE). In pts with any M1c disease and LDH > ULN at BL (N = 17, 17.3%), ORR, DCR, mDOR were 35.3%, 58.8%, and NR (95% CI, 5.7–NE), respectively, and mPFS was 7.1 months (95% CI, 1.2–NE). Overall, 43.9% and 32.7% of pts reported grade ≥3 Tx-emergent adverse events (TEAEs) and serious TEAEs. Correlative biomarkers analyses are in progress and will be included in the presentation. Conclusions: The combination of fianlimab and cemiplimab showed high activity in pts with advanced Mel and poor prognosis features at BL. The ORR and DCR observed in these subgroups compare positively with the available data for approved combinations of iCPIs in the same clinical setting. A phase 3 trial (NCT05352672) of fianlimab + cemiplimab in Tx-naïve advanced Mel pts is ongoing. Clinical trial information: NCT03005782 .

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.

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.

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.

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.