Adjuvant Therapy For Melanoma Research Articles

The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma.

Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in patients with clinically occult disease. Since the advent of new systemic therapies, its role in melanoma has been extensively debated over the last years. In this article, three possible scenarios are discussed, considering the SLNB impact on the management of melanoma patients. First, pT1b and pT2a patients with negative SLNB (stages IA and IB) and those with positive SLNB (stage IIIA) would all not benefit from adjuvant treatment. Therefore, SLNB might be avoided in these categories of patients. Second, in IIB and IIC, melanoma patients are already candidates for adjuvant treatment; therefore, SLNB in patients with T3b, T4a, or T4b melanoma would not change treatment decisions. On the other end of the spectrum, patients with pT2b and pT3a melanomas (clinical stage IIA) represent the only two groups whose management would be significantly affected by the SLNB status, being adjuvant therapy only indicated for SLN-positive patients. Further studies are needed to investigate which melanoma patient deserves SLNB.

Deciphering the role of adjuvant therapy in melanoma and its actual benefits.

Numerous clinical trials have demonstrated a significant improvement in recurrence-free survival among melanoma patients receiving high-dose interferon-α, immune checkpoint inhibitors (pembrolizumab, nivolumab), and BRAF/MEK inhibitors (dabrafenib-trametinib). This study aimed to investigate whether these findings hold true in real-world conditions for patients with stage III and IV melanoma. In particular, the study explores the efficacy and side effects of adjuvant therapies, focusing on anti-PD-1 antibodies and BRAF/MEK inhibitors. While clinical trials have shown comparable efficacy, differences in side-effect profiles, especially the persistence of immune-related adverse events with anti-PD-1 antibodies, highlight the need for careful consideration in adjuvant settings. In the absence of established biomarkers for guiding adjuvant therapy decisions, it becomes imperative to transparently communicate the advantages and disadvantages of drug administration to patients. The study also delved into the impact of melanoma subtype and BRAF mutation status on the effectiveness of adjuvant therapy, emphasizing the need for further investigation.

Decoding the metastatic potential and optimal postoperative adjuvant therapy of melanoma based on metastasis score

Metastasis is a formidable challenge in the prognosis of melanoma. Accurately predicting the metastatic potential of non-metastatic melanoma (NMM) and determining effective postoperative adjuvant treatments for inhibiting metastasis remain uncertain. In this study, we conducted comprehensive analyses of melanoma metastases using bulk and single-cell RNA sequencing data, enabling the construction of a metastasis score (MET score) through diverse machine-learning algorithms. The reliability and robustness of the MET score were validated using various in vitro assays and in vivo models. Our findings revealed a distinct molecular landscape in metastatic melanoma characterized by the enrichment of metastasis-related pathways, intricate cell–cell communication, and heightened infiltration of pro-angiogenic tumor-associated macrophages compared to NMM. Importantly, patients in the high MET score group exhibited poorer prognoses and an immunosuppressive microenvironment, featuring increased infiltration of regulatory T cells and decreased infiltration of CD8+ T cells, compared to the low MET score patient group. Expression of PD-1 was markedly higher in patients with low MET scores. Anti-PD-1 (aPD-1) therapy profoundly affected antitumor immunity activation and metastasis inhibition in these patients. In summary, our study demonstrates the effectiveness of the MET score in predicting melanoma metastatic potential. For patients with low MET scores, aPD-1 therapy may be a potential treatment strategy to inhibit metastasis. Patients with high MET scores may benefit from combination therapies.

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

The landscape of melanoma management changed as randomized trials have launched adjuvant treatment. 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. 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. 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.

Fertility, teratogenicity, and contraception during therapy with BRAF/MEK inhibitors

Targeted mutation-based therapy with BRAF and MEK inhibitors has become an integral part of systemic therapy for metastatic melanoma in the advanced setting and for the adjuvant therapy of melanoma in stageIII after complete resection. Due to the increased chances of survival and early use in the adjuvant situation, fertility preservation as well as aspects of teratogenicity and pregnancy are increasingly relevant in patients who are often still young. To communicate the published and study-based information on fertility preservation, teratogenicity and pregnancy under therapy with BRAF and MEK inhibitors. Summaries of product characteristics as well as studies and case reports on BRAF and MEK inhibitors published in PubMed were used as sources of information. There are no specific preclinical studies or experience in humans on fertility, teratogenicity, and contraception with targeted therapy. Recommendations can only be derived from toxicity studies and individual case reports. Patients should be offered counseling on the options for fertility-protective measures before starting targeted therapy. Due to unclear teratogenicity, adjuvant melanoma therapy with dabrafenib and trametinib should not be initiated in pregnant patients. In the advanced metastatic situation, BRAF and MEK inhibitors should only be given after extensive interdisciplinary education and counselling of the pregnant patient and her partner. Patients should be informed about the need for adequate contraception during targeted therapy.

Granulomatous and Sarcoid-like Immune-Related Adverse Events following CTLA4 and PD1 Blockade Adjuvant Therapy of Melanoma: A Combined Analysis of ECOG-ACRIN E1609 and SWOG S1404 Phase III Trials and a Literature Review.

Treatment with immune checkpoint inhibitors (ICIs) has been linked to granulomatous and sarcoid-like lesions (GSLs) affecting different organs. This study sought to evaluate GSL incidence in patients with high-risk melanoma treated with cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 (PD1) blockade adjuvant therapy in two clinical trials: ECOG-ACRIN E1609 and SWOG S1404. Descriptions and GSL severity ratings were recorded. Data were collected from ECOG-ACRIN E1609 and SWOG S1404. Descriptive statistics along with GSL severity grades were reported. Additionally, a literature review for such cases was summarized. A total of 11 GSL cases were reported among 2878 patients treated with either ICI or with High-Dose Interferon Alfa-2b (HDI) in ECOG-ACRIN E1609 and SWOG S1404 trials. Cases were numerically more commonly reported with ipi10, followed by pembrolizumab, ipi3, and HDI, respectively. Most of the cases were grade III. Further, organs involved included lung, mediastinal lymph nodes, skin and subcutaneous tissue, and eye. Furthermore, a summary of 62 reports in the literature was described. GSLs following anti-CTLA4 and anti-PD1 antibody therapy in patients with melanoma were reported unusually. Reported cases ranged in grade from I to III and appeared manageable. Careful attention to these events and their reporting will be essential to better guide practice and management guidelines.

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.

Cell Immunotherapy against Melanoma: Clinical Trials Review.

Melanoma is one of the most aggressive and therapy-resistant types of cancer, the incidence rate of which grows every year. However, conventional methods of chemo- and radiotherapy do not allow for completely removing neoplasm, resulting in local, regional, and distant relapses. In this case, adjuvant therapy can be used to reduce the risk of recurrence. One of the types of maintenance cancer therapy is cell-based immunotherapy, in which immune cells, such as T-cells, NKT-cells, B cells, NK cells, macrophages, and dendritic cells are used to recognize and mobilize the immune system to kill cancer cells. These cells can be isolated from the patient's peripheral blood or biopsy material and genetically modified, cultured ex vivo, following infusion back into the patient for powerful induction of an anti-tumor immune response. In this review, the advantages and problems of the most relevant methods of cell-based therapy and ongoing clinical trials of adjuvant therapy of melanoma are discussed.

LBA6 Neoadjvuant versus adjuvant pembrolizumab for resected stage III-IV melanoma (SWOG S1801)

Adjuvant therapy (AT) is currently considered for resected stage IIB-III melanoma and selected patients with resected stage IV melanoma. AT for melanoma is anti-PD-1 or targeted therapy in the presence of a BRAF mutation. Neoadjuvant therapy (NAT) with anti-PD-1 therapy is hypothesized to generate a stronger immune response from the activation of resident tumor-infiltrating lymphocytes against in vivo tumor antigens, but this has not been demonstrated in a prospective randomized trial.

Adjuvant Anti-PD-1 Antibody Therapy for Advanced Melanoma: A Multicentre Study of 78 Japanese Cases.

Anti-PD-1 antibodies (Abs) are among the optimal adjuvant therapies for melanoma at high risk of recurrence, especially BRAF wild-type melanoma, but the anti-tumour effects of anti-PD-1 Abs in the adjuvant setting for acral melanoma have not been evaluated previously. The aim of this study was to analyse the efficacy and safety profiles of anti-PD-1 Ab monotherapy in the adjuvant setting in an Asian population including a high ratio of acral melanoma. The efficacy and safety profiles of anti-PD-1 Ab monotherapy in the adjuvant setting were retrospectively analysed in 78 Japanese patients with advanced melanoma, including 31 cases (40%) of acral melanoma. Overall relapse-free survival was 60.3% (47 of 78 cases, 95% confidence interval (CI) 49.2-70.4%), and 39.7% of patients (31 of 78 patients, 95% CI 29.6-50.8%) relapsed during the adjuvant PD-1 Ab treatment. Six cases (7.9%) discontinued the protocol due to serious adverse events. One case (1.3%) discontinued the protocol due to trauma. The relapse-free survival of acral melanoma was 25.8%, whereas that of high cumulative sun damage was 60.0%, and that of low cumulative sun damage was 57.1%. The acral type had a significantly lower 12-month relapse-free survival than other cutaneous types (p = 0.029). The acral type appeared to be an independent prognostic factor on multivariate analysis (p = 0.015). Adverse events due to anti-PD-1 antibody were observed in 37.1% overall. The results of this study suggest that anti-PD-1 Ab therapy in the adjuvant setting is less effective for acral melanoma than for other cutaneous types.

Adjuvant nivolumab versus ipilimumab (CheckMate 238 trial): Reassessment of 4-year efficacy outcomes in patients with stage III melanoma per AJCC-8 staging criteria

PurposeNivolumab was approved as adjuvant therapy for melanoma based on data from CheckMate 238, which enrolled patients per American Joint Committee on Cancer version 7 (AJCC-7) criteria. Here, we analyse long-term outcomes per AJCC-8 staging criteria compared with AJCC-7 results to inform clinical decisions for patients diagnosed per AJCC-8. Patients and methodsIn a double-blind, phase 3 trial (NCT02388906), patients aged ≥15 years with resected, histologically confirmed AJCC-7 stage IIIB, IIIC, or IV melanoma were randomised to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks, both intravenously ≤1 year. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were assessed in patients with stage III disease, per AJCC-7 and AJCC-8. ResultsPer AJCC-7 staging, 42.4% and 57.3% of patients were in substage IIIB and IIIC, respectively; per AJCC-8, 1.1%, 30.4%, 62.8%, and 5.0% were in IIIA, IIIB, IIIC, and IIID. After 4 years' minimum follow-up, the AJCC-7 superior efficacy of nivolumab over ipilimumab in patients with resected stage III melanoma was preserved per AJCC-8 analysis. No statistically significant difference in RFS between stage III substage hazard ratios was observed per AJCC-7 or -8 staging criteria (interaction test: AJCC-7, P = 0.8115; AJCC-8, P = 0.1051; P = 0.8392 ((AJCC-7) and P = 0.8678 (AJCC-8) for DMFS). ConclusionsCheckMate 238 4-year RFS and DMFS outcomes are consistent per AJCC-7 and AJCC-8 staging criteria. Outcome benefits can therefore be translated for patients diagnosed per AJCC-8.

Real-World nivolumab dosing patterns and safety outcomes in patients receiving adjuvant therapy for melanoma.

Nivolumab at a dose of 480 mg every 4 weeks (Q4W) is approved for the adjuvant treatment of melanoma. However, real-world data on this regimen are limited in this setting. This retrospective observational study utilized data from the US Oncology Network iKnowMed electronic health record database and patient medical charts. Eligible patients were diagnosed with melanoma and received adjuvant nivolumab monotherapy from March to August 2018. Patients were grouped by dosing regimen: cohort 1 (C1), de novo nivolumab 480 mg Q4W; cohort 2 (C2), switched to nivolumab 480 mg Q4W after nivolumab 240 mg or 3mg/kg every 2 weeks (Q2W); cohort 3 (C3), de novo nivolumab 3mg/kg Q2W; or cohort 4 (C4), de novo nivolumab 240 mg Q2W. Patients were followed for up to 12 months. Duration of therapy and safety/tolerability were assessed. One hundred ninety-one patients were included (C1, n=40; C2, n=74; C3, n=22; C4, n=55). Duration of therapy was relatively consistent across cohorts (median, 10.3months; range, 8.3-10.7). Likewise, proportions of patients experiencing treatment-related adverse events (TRAEs) were similar (range, 54.5%-60.1%), as were the most common events (fatigue, rash, diarrhea, hypothyroidism, nausea, and pruritus). However, proportions experiencing 'significant' TRAEs varied between cohorts. Proportions discontinuing treatment were relatively consistent across cohorts. Propensity score matching and sensitivity analyses generally supported the unadjusted findings. Real-world safety profiles of nivolumab 240 mg Q2W and 480 mg Q4W were similar, and both were comparable to the well-documented safety of weight-based dosing (3mg/kg Q2W), further supporting their approval and use in the adjuvant setting for melanoma.

Current State of Adjuvant Therapy for Melanoma: Less Is More, or More Is Better?

Advances in melanoma treatments over the past decade have changed the course of survival for patients. Several adjuvant therapies have been approved and are now considered standard of care for high-risk patients. These therapies have shown improvements for recurrence-free survival and distant metastases-free survival, but not overall survival, as the data are maturing. The 5-year recurrence-free survival in the COMBI-AD study, which compared dabrafenib and trametinib with placebo, was 65% and 58%, respectively. In the KEYNOTE-054 study, the recurrence-free survival at 3years was 63.7% versus 41%. Despite these advances, approximately 50% of patients will succumb to their disease. Adjuvant therapy is considered potentially curative and avoids the morbidity of relapsed disease and the poor outcomes seen in metastatic disease. However, the lack of overall survivalbenefit in clinical trials of patients with high-risk stage II and stage III disease raises the question of whether it is more efficacious to treat when there is residual microscopic disease, or to wait until the disease recurs to avoid treating those who may have been cured by surgery alone. Immunotherapy also has the potential for substantial toxicity that may be lifelong; hence, discussion of risks and benefits of therapy is warranted because there should be less tolerance for substantial toxicity in the adjuvant setting. Adjuvant trials are needed that will integrate biomarkers to allow for better selection of patients who will truly benefit from adjuvant therapy.

Adherence to Adjuvant Therapy in Patients with Resected Melanoma: An Application of the Theory of Planned Behavior.

IntroductionAdherence to adjuvant therapy is crucial for effective disease management in patients with resected melanoma. This study assessed patient-reported adherence to adjuvant therapy and identified behavioral/belief constructs associated with adherence in patients with resected melanoma.MethodsPatients with resected stage III/IV melanoma were recruited through the Melanoma Research Foundation and a patient panel to complete an online survey. Patient characteristics, medical history, and adherence to therapy were captured. In accordance with the theory of planned behavior (TPB), the survey measured behavioral, normative, and control beliefs, and intention to adhere to therapy. Structural equation modeling (SEM) examined their relationships with adherence.ResultsAmong all patients who received adjuvant therapy and completed the survey (n = 184), 69% received intravenous and 31% received oral therapy; the majority (85.3%) were somewhat involved in deciding to start therapy. Mean age was 45 years, 44% of patients were female, and 83% had stage III/IV disease at diagnosis. Patients had a mean disease duration of 1.5 years, a time since complete resection of 10 months, and an adjuvant therapy duration of 8 months. Adherence to adjuvant therapy was high overall and higher with intravenous than with oral therapy (98.4% versus 91.2%, P = 0.002). All underlying TPB constructs were significant in the SEM model, which explained 60.3% of the variance in intention to adhere. Control beliefs had the strongest association with intention to adhere (standardized estimate = 0.47, P < 0.001) and intravenous therapy was associated with greater adherence than oral therapy (standardized estimate = 0.26, P < 0.001).ConclusionsThis study found that patients with resected melanoma are highly engaged in the decision to initiate systemic adjuvant therapy, with an overall high adherence rate to prescribed adjuvant treatment. Enhancing patients’ view of their capability to adhere to treatments may further improve the adherence rate to melanoma adjuvant therapy.

Calcitriol Inhibits Proliferation and Potentially Induces Apoptosis in B16-F10 Cells.

BackgroundMelanoma is one of the most aggressive types of cancer and it has shown a remarkable surge in incidence during the last 50 years. Melanoma has been projected to be continuously rising in the future. Therapy for advanced-type melanoma is still a challenge due to the low response rate and poor 10-year survival. Interestingly, several epidemiological and preclinical studies had reported that vitamin D deficiency was associated with disease progression in several cancer types. In vivo and in vitro studies revealed anti-proliferative, anti-angiogenic, apoptosis, and differentiation induction effects of calcitriol in various cancers. However, information on the effects of calcitriol (1,25(OH)2D3) on melanoma is still limited, and its mechanism remains unclear.Material/MethodsIn the present study, by utilizing B16–F10 cells, which is a melanoma cell line, we explored the anti-proliferative effect of calcitriol using cell viability assay, near-infrared imaging, expression of apoptosis-related genes using real-time polymerase chain reactions (PCR), and the expression of apoptosis proteins levels using western blot. In addition, we also assessed calcitriol uptake by B16–F10 cells using high-performance liquid chromatography (HPLC).ResultsWe found that calcitriol inhibits melanoma cell proliferation with an IC50 of 93.88 ppm (0.24 μM), as shown by cell viability assay. Additionally, we showed that B16–F10 cells are capable of calcitriol uptake, with a peak uptake time at 60 min after administration. Calcitriol was also able to induce apoptosis-related proteins such as caspase-3, caspase 8, and caspase-9. These effects of calcitriol reflect its potential utility as a potent adjuvant therapy for melanoma.ConclusionsCalcitriol inhibits cell proliferation and induces apoptosis in B16–F10 cells.

25 Years of Adjuvant Therapy in Melanoma: A Perspective on Current Approvals and Insights into Future Directions.

25 Years of Adjuvant Therapy in Melanoma: A Perspective on Current Approvals and Insights into Future Directions.

Epigenetic Silencing of BMP6 by the SIN3A-HDAC1/2 Repressor Complex Drives Melanoma Metastasis via FAM83G/PAWS1.

Aberrant epigenetic transcriptional regulation is linked to metastasis, a primary cause of cancer-related death. Dissecting the epigenetic mechanisms controlling metastatic progression may uncover important insights to tumor biology and potential therapeutic targets. Here, we investigated the role of the SIN3A histone deacetylase 1 and 2 (SIN3A-HDAC1/2) complex in cancer metastasis. Using a mouse model of melanoma metastasis, we found that the SIN3A-HDAC1/2 transcription repressor complex silences BMP6 expression, causing increased metastatic dissemination and tumor growth via suppression of BMP6-activated SMAD5 signaling. We further discovered that FAM83G/PAWS1, a downstream effector of BMP6-SMAD5 signaling, contributes critically to metastatic progression by promoting actin-dependent cytoskeletal dynamics and cell migration. Pharmacologic inhibition of the SIN3A-HDAC1/2 complex reduced the numbers of melanoma cells in the circulation and inhibited metastatic tumor growth by inducing disseminated cell dormancy, highlighting the SIN3A-HDAC1/2 repressor complex as a potential therapeutic target for blocking cancer metastasis. IMPLICATIONS: This study identifies the novel molecular links in the metastatic progression to target cytoskeletal dynamics in melanoma and identifies the SIN3A-HDAC1/2 complex and FAM83G/PAWS1 as potential targets for melanoma adjuvant therapy.

Pembrolizumab as adjuvant therapy in melanoma

Pembrolizumab as adjuvant therapy in melanoma

Délais administratifs des RTU, effet sur l’accès à l’innovation dans le mélanome

Melanoma has benefited in recent years from therapeutic innovations, which have improved overall survival of patients. France has developed a regulatory arsenal allowing faster access to innovative drugs before marketing authorization: temporary authorization for use (ATU) and temporary recommendation for use (RTU). We describe here the decision-making processes that led to the non-publication of the decree on the funding of three RTU in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib, and we analyse the fate of these drugs in order to quantify the potential loss of chance. On 03AUG2018, the French National Agency for Medicines and Health Product Safety (ANSM) published 3 RTU in order to give rapid access to major innovations in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib. These drugs have respectively demonstrated reductions in the risk of recurrence by 35%, 43% and 55% for target populations of 2200, 1900 and 650 patients per year. Despite a favourable opinion on reimbursement from the French National Authority for Health (HAS), the decrees on reimbursement will never be published, prohibiting the use of these products before the marketing authorisation, and depriving many patients of a potential cure. Despite a favourable opinion from scientists and health agencies for the rapid availability of a drug, the French public health code does not systematically imply access to a therapeutic innovation. The reform of access to innovation implemented on 01JUL2021 may help tackle this issue.