Therapy For Metastatic Melanoma Research Articles

Single-institution outcomes with less than two-year anti-PD-1 antibody therapy in metastatic melanoma.

e22001 Background: Optimal duration of anti-PD-1 antibody therapy remains undefined. Currently, treatment is given up to two years in metastatic melanoma based on clinical trials. However, recent observations suggest that anti-PD-1 antibodies may work as well if given for shorter time periods. To better understand duration of anti-PD-1 antibody treatment, we reviewed outcomes for patients who discontinued immunotherapy earlier than 2 years in our Cancer Center. Methods: This is a retrospective, single-institution review of metastatic melanoma patients who received anti-PD-1 antibodies from January 2010 to December 2019. We further identified the patients discontinuing treatment before completion of 2 years for reasons other than disease progression. Duration was categorized into three groups: < 6 months (A), 6-12 months (B) and > 12 months (C) and outcomes were analyzed. Progression free survival (PFS) was defined as the time from the initiation of anti-PD1-therapy to the date of progression as determined by treating physician based on radiological, biochemical and/or clinical criteria. Results: 25 patients with mean age 69 years (49-91; N = 19 > 60yo) were identified. Number of patients who received anti-PD-1 antibodies were N = 8, N = 9 and N = 8 in in groups A, B and C respectively. 44% of patients discontinued treatment after achieving either partial or near complete remission, whereas the remaining 66% of patients discontinued treatment due to adverse events. Majority of patients who stopped treatment due to adverse events were older than 60 (71.4%). In 29 months of median follow up (range 11-54), none of patients who received treatment in group B progressed, whereas in groups A and C, 25% percentage progressed in each group with 80% PFS at 12.8 months and 88% PFS at 26 months respectively. 12.5% of patients in group A had progression at 12 months follow up, where no progression was noticed in groups B and C during the same time period. Conclusions: Retrospective analysis of our experience supports other retrospective findings that treatment with anti-PD-1 antibodies more than 12 months might not add further benefit in responding or non-progressing older patients though further study with longer follow up is required.

Real-world experience of talimogene laherparepvec in patients receiving immunotherapy in metastatic melanoma.

e22003 Background: Talimogene laherparepvec (TVEC) is an oncolytic herpes virus approved by the FDA for intralesional therapy in unresectable metastatic melanoma. However, little is known regarding the effectiveness of TVEC+checkpoint inhibition (CPI) outside of clinical trials. We present outcomes of the largest single institution experience with TVEC in the context of different immune checkpoint inhibitors. Methods: All patients with stage III-IV unresectable melanoma having received TVEC were evaluated. Patient demographics, clinicopathological characteristics, TVEC treatment response and outcomes were assessed. Final analysis included those who received TVEC adjacent to CPI with a minimum 6-month follow-up, excluding patients on clinical trials. Response was estimated by sequential measurement of injectable on-target lesions. Results: A total of 62 patients received TVEC from 2016 to 2019, of which 43 remained excluding Merkel cell carcinoma, patients on trials, and TVEC monotherapy. Of 30 patients with available treatment response data and at least 6-months follow-up, median age was 68.5 years (30-99 years), 40% were female, 16 (53.3%) stage IV. Median follow-up was 17.5 months (6-43 months). At 6 months, 20 (67.7%) patients were alive; at 1 year, 17 (56.7%) patients were alive. Eighteen patients received pembrolizumab, 7 nivolumab and 5 ipilimumab/nivolumab. Median number of TVEC doses received was 8 (3-31 doses). Median time on TVEC therapy was 4 months (1-26 months). Overall response rate for on-target lesions was 24 (80%), with complete local response (CR) in 15 (50%), partial response (PR) in 9 (30%), and progressive disease (PD) in 6 (20%). Median time to response was 6 weeks (2-17 weeks); 5 in CR, 6.5 in PR and 5.5 in PD groups. Adverse events were mostly mild and limited to constitutional symptoms. Conclusions: To our knowledge this is the largest real-world experience assessing TVEC in patients receiving CPI. Local overall response rate appears higher in comparison to historic numbers for TVEC monotherapy. The findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma and has robust outcomes in real-life clinical settings.

Toripalimab for the treatment of melanoma

ABSTRACT Introduction Immune therapies have dramatically changed the treatment landscape for melanoma in the past decade. Ipilimumab, nivolumab, and pembrolizumab have been approved by U.S. Food and Drug Administration for the treatment of metastatic melanoma sequentially. Toripalimab, a humanized IgG4 monoclonal antibody against programmed cell death protein-1 (PD-1), was approved by National Medical Product Administration in China in 2018 as second-line therapy for metastatic melanoma. Areas covered This is a comprehensive review of the literature and studies of toripalimab in melanoma, including clinical trials and translational research. Expert opinion Toripalimab is not inferior to pembrolizumab as a second-line therapy for metastatic melanoma. Prospective validated predictive markers are lacking. Programmed cell death ligand 1 expression and tumor mutational burden are two common recognized biomarkers, but the predictability of these markers requires additional improvement. A number of studies have confirmed that PD-1 inhibitors, including toripalimab, are not as effective in mucosal and acral melanomas as in non-acral cutaneous subtype. Toripalimab in combination with tyrosine kinase inhibitor axitinib has shown a promising result for metastatic mucosal melanoma. It is crucial to explore the mechanisms underlying the varying biological behavior of melanoma subtypes, which may also provide clues of innate and acquired resistance to PD-1 blockade.

ANT2 (SLC25A5) balances the pro-apoptotic vs. effector signals of Bim in CD8 T cells

Abstract The immune response to anti-PD-1 therapy in cancer patients is not completely defined due to lack of reliable biomarkers that can determine T cell function. Bim, a member of the Bcl-2 family, was recently identified as a downstream signaling molecule in the PD-1 pathway. Within CD8 T cells, Bim appears to have a dual function, and can be pro-apoptotic or promote effector activity. Our clinical data has shown that high levels of Bim in CD8 T cells are predictive of response to anti-PD-1 therapy in metastatic melanoma whereas in colorectal cancer, a low level of Bim is associated with treatment response. Thus, we sought to determine what molecular partners might influence the role of Bim. Using co-immunoprecipitation, high resolution microscopy and FRET we identified ANT2 (Adenine Nucleotide Translocase 2), an inner membrane protein of mitochondria, as a protein that interacts with Bim. Accordingly, we found CD8 T cells with low and high mitochondrial potential demonstrated different ANT2/Bim ratios, and a low ANT2/Bim ratio was present in effector T cells with low mitochondrial potential but high cytotoxic activity. Given the pro-survival function of ANT2, our results indicate that ANT2 may balance the pro-apoptotic and effector roles of Bim in mitochondria in order to preserve effector T cells before contraction. Understanding the molecular mechanism of Bim and ANT2 interactions in CD8 T cells may provide a novel marker to predict clinical response to anti-PD-1 therapy.

PCN94 HEALTHCARE UTILIZATION AND COSTS ASSOCIATED WITH SYSTEMIC METASTATIC MELANOMA THERAPIES BETWEEN 2012 AND 2017

Metastatic melanoma (MM) treatment has been revolutionized in the past decade with the FDA approvals of immune checkpoint inhibitors and targeted therapies. This study aimed to compare healthcare utilization and costs during first-line MM therapy.

Regulation of eIF2α by RNF4 Promotes Melanoma Tumorigenesis and Therapy Resistance

Among the hallmarks of melanoma are impaired proteostasis and rapid development of resistance to targeted therapy that represent a major clinical challenge. However, the molecular machinery that links these processes is unknown. Here we describe that by stabilizing key melanoma oncoproteins, the ubiquitin ligase RNF4 promotes tumorigenesis and confers resistance to targeted therapy in melanoma cells, xenograft mouse models, and patient samples. In patients, RNF4 protein and mRNA levels correlate with poor prognosis and with resistance to MAPK inhibitors. Remarkably, RNF4 tumorigenic properties, including therapy resistance, require the translation initiation factor initiation elongation factor alpha (eIF2α). RNF4 binds, ubiquitinates, and stabilizes the phosphorylated eIF2α (p-eIF2α) but not activating transcription factor 4 or C/EBP homologous protein that mediates the eIF2α-dependent integrated stress response. In accordance, p-eIF2α levels were significantly elevated in high-RNF4 patient-derived melanomas. Thus, RNF4 and p-eIF2α establish a positive feed-forward loop connecting oncogenic translation and ubiquitin-dependent protein stabilization in melanoma.

Cutaneous adverse events: a predictor of tumour response under anti-PD-1 therapy for metastatic melanoma, a cohort analysis of 189 patients.

Cutaneous adverse events (AEs) are the most prevalent toxicity under checkpoint inhibitors in clinical trials. In 'real-life' conditions of use, skin toxicities under anti-PD-1 have not been described to date in a large cohort. The objective of this study was to determine the clinical features of skin toxicities in patients with advanced melanoma receiving anti-PD-1 therapy under 'real-life' conditions of use. Secondary objectives were to evaluate the characteristics of patients with skin toxicities and to analyse associated extra-cutaneous toxicities, progression-free survival (PFS) and overall survival (OS). Advanced melanoma patients treated with nivolumab or pembrolizumab between August 2014 and October 2017 were included. Patients lost to follow-up or receiving anti-PD-1 as part of a clinical trial were excluded. One hundred and eighty-nine patients with metastatic melanoma (with 109 men (57.7%) were included. Cutaneous AE occurred in 39 patients (20.6%). The three most prevalent cutaneous AEs were skin eruption (macular-papular or eczematous) (n=18, 9.5%), vitiligo (n=16; 8.5%) and isolated pruritus (n=5, 2.6%). Grade 3-4 skin toxicity was diagnosed in five patients (2.6%). Atopy (28.2% vs. 12.0%; P=0.024), hypereosinophilia (20.5% vs. 8.7%; P=0.046), thyroiditis (17.9% vs. 4.7%; P=0.011) and renal toxicity (15.4% vs. 4%; P=0.019) were significantly associated with cutaneous AE. Patients with skin eruption (log-rank=0.001), vitiligo (log-rank=0.001) and any type of cutaneous AE (log-rank<0.001) had a better overall survival. Cutaneous AEs are frequent and often manageable toxicity and were a predictor of tumour response in melanoma patients under anti-PD-1 therapy in this cohort.

Protein Expression in Metastatic Melanoma and the Link to Disease Presentation in a Range of Tumor Phenotypes.

Malignant melanoma is among the most aggressive skin cancers and it has among the highest metastatic potentials. Although surgery to remove the primary tumor is the gold standard treatment, once melanoma progresses and metastasizes to the lymph nodes and distal organs, i.e., metastatic melanoma (MM), the usual outcome is decreased survival. To improve survival rates and life span, advanced treatments have focused on the success of targeted therapies in the MAPK pathway that are based on BRAF (BRAF V600E) and MEK. The majority of patients with tumors that have higher expression of BRAF V600E show poorer prognosis than patients with a lower level of the mutated protein. Based on the molecular basis of melanoma, these findings are supported by distinct tumor phenotypes determined from differences in tumor heterogeneity and protein expression profiles. With these aspects in mind, continued challenges are to: (1) deconvolute the complexity and heterogeneity of MM; (2) identify the signaling pathways involved; and (3) determine protein expression to develop targeted therapies. Here, we provide an overview of the results from protein expression in MM and the link to disease presentation in a variety of tumor phenotypes and how these will overcome the challenges of clinical problems and suggest new promising approaches in metastatic melanoma and cancer therapy.

New Systematic Therapies and Trends in Cutaneous Melanoma Deaths Among US Whites, 1986-2016.

Objectives. To determine the effect of new therapies and trends toward reduced mortality rates of melanoma.Methods. We reviewed melanoma incidence and mortality among Whites (the group most affected by melanoma) in 9 US Surveillance, Epidemiology, and End Results registry areas that recorded data between 1986 and 2016.Results. From 1986 to 2013, overall mortality rates increased by 7.5%. Beginning in 2011, the US Food and Drug Administration approved 10 new treatments for metastatic melanoma. From 2013 to 2016, overall mortality decreased by 17.9% (annual percent change [APC] = -6.2%; 95% confidence interval [CI] = -8.7%, -3.7%) with sharp declines among men aged 50 years or older (APC = -8.3%; 95% CI = -12.2%, -4.1%) starting in 2014. This recent, multiyear decline is the largest and most sustained improvement in melanoma mortality ever observed and is unprecedented in cancer medicine.Conclusions. The introduction of new therapies for metastatic melanoma was associated with a significant reduction in population-level mortality. Future research should focus on developing even more effective treatments, identifying biomarkers to select patients most likely to benefit, and renewing emphasis on public health approaches to reduce the number of patients with advanced disease.

In Vitro Biophysical and Biological Characterization of Lipid Nanoparticles Co-Encapsulating Oncosuppressors miR-199b-5p and miR-204-5p as Potentiators of Target Therapy in Metastatic Melanoma.

Uncontrolled MAPK signaling is the main oncogenic driver in metastatic melanomas bearing mutations in BRAF kinase. These tumors are currently treated with the combination of BRAF/MEK inhibitors (MAPKi), but this therapy is plagued by drug resistance. In this context we recently discovered that several microRNAs are involved in the development of drug resistance. In particular miR-204-5p and miR-199b-5p were found to function as antagonists of resistance because their enforced overexpression is able to inhibit melanoma cell growth in vitro either alone or in combination with MAPKi. However, the use of miRNAs in therapy is hampered by their rapid degradation in serum and biological fluids, as well as by the poor intracellular uptake. Here, we developed lipid nanoparticles (LNPs) encapsulating miR-204-5p, miR-199b-5p individually or in combination. We obtained LNPs with mean diameters < 200 nm and high miRNA encapsulation efficiency. These formulations were tested in vitro on several melanoma cell lines sensitive to MAPKi or rendered drug resistant. Our results show that LNPs encapsulating combinations of the two oncosuppressor miRNAs are highly efficient in impairing melanoma cell proliferation and viability, affect key signaling pathways involved in melanoma cell survival, and potentiate the efficacy of drugs inhibiting BRAF and MEK. These results warrant further assessment of the anti-tumor efficacy of oncosuppressor miRNAs encapsulating LNPs in in vivo tumor models.

Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma and to Provide New Insights into Intrinsic and Acquired Mechanism of Resistance.

Mitogen-activated protein kinase (MAPK) inhibition with the combination of BRAF (Rapidly Accelerated Fibrosarcoma) and MEK (Mitogen-activated protein kinase kinase) inhibitors has become the standard of first-line therapy of metastatic melanoma harbouring BRAF V600 mutations. However, about half of the patients present with primary resistance while the remaining develop secondary resistance under prolonged treatment. Thus, there is a need for predictive biomarkers for sensitivity and/or resistance to further refine the patient population likely to benefit from MAPK inhibitors. In this study, we explored a top-down approach using a multiplex kinase assay, first, to discover a kinome signature predicting sensitivity, intrinsic and acquired resistance to MAPK inhibitors in melanoma, and second, to understand the mechanism of resistance using cell lines. Pre-dose tissues from patients (four responders and three non-responders to BRAFi monotherapy) were profiled for phosphotyrosine kinase (PTK) and serine-threonine kinase (STK) activities on a PamChip® peptide microarray in the presence and absence of ex vivo BRAFi. In addition, molecular studies were conducted on four sensitive parental lines, their offspring with acquired resistance to BRAFi and two lines with intrinsic resistance. PTK and STK activities in cell lysates were measured in the presence and absence of ex vivo BRAFi and/or MEKi. In tissue lysates, concentration-dependent ex vivo inhibition of STK and PTK activities with dabrafenib was stronger in responders than in non-responders. This difference was confirmed in cell lines comparing sensitive and resistant ones. Interestingly, common features of resistance were increased activity of receptor tyrosine kinases, Proto-oncogene tyrosine-protein kinase Src (Src) family kinases and protein kinase B (PKB, AKT) signalling. These latter results were confirmed by Western blots. While dabrafenib alone showed an inhibition of STK and PTK activities in both tissues and cell lines, the combination of dabrafenib and trametinib showed an antagonism on the STK activities and a synergism on PTK activities, resulting in stronger inhibitions of overall tyrosine kinase activities. Altogether; these data reveal that resistance of tumours and cell lines to MAPK inhibitors can be predicted using a multiplex kinase assay and is associated with an increase in specific tyrosine kinase activities and globally to AKT signalling in the patient’s tissue. Thus, such a predictive kinome signature would help to identify patients with innate resistance to MAPK double inhibition in order to propose other therapies.

Clinical Outcomes of Immune Checkpoint Blocker Therapy for Malignant Melanoma in Korean Patients: Potential Clinical Implications for a Combination Strategy Involving Radiotherapy.

PurposeWe investigated the clinical efficacy of immune checkpoint blocker (ICB) therapy for metastatic or advanced melanoma in Korean patients. As well, we assessed whether the effects of ICBs can be enhanced by combination therapy with palliative radiotherapy (RT).Materials and MethodsWe retrospectively reviewed the records of 127 patients with metastatic melanoma who received ICB with or without palliative RT between 2014 and 2018. The melanoma subtypes were classified as follows: chronic sun-damaged (CSD), acral, mucosal, and uveal. The primary endpoint was the objective response rate (ORR).ResultsThe overall ORR was 15%, with 11 complete and eight partial responses. ORRs for CSD, acral/mucosal, and uveal melanomas were 50%, 16.5%, and 0%, respectively (p=0.009). In addition to the subtype, stage at treatment, total tumor burden at treatment, and ICB type were significantly associated with ORR (all p < 0.05). Palliative RT was administered in 44% of patients during the treatment, and it did not affect ORR. Clinical responders to ICB therapy exhibited significantly higher 1-year progression-free and overall survival rates than nonresponders.ConclusionORR for ICB monotherapy in Korean patients with melanoma is relatively modest compared with that in Western patients because the non-CSD subtypes are predominant in the Korean population. Our findings regarding combination therapy with ICB provided a rationale for the initiation of our phase II study (NCT04017897).

Correlation between immune-related adverse events and outcomes in nivolumab/ipilimumab combination therapy for metastatic melanoma.

58 Background: Systemic immune checkpoint blockade therapy anti-PD1 nivolumab combined with anti-CTLA-4 ipilimumab is an effective therapy for metastatic melanoma. The treatment, however, has a high frequency of immune related adverse events. Interestingly, immune-related adverse events in anti-PD1 and anti-CTLA4 monotherapy have been associated with an improved overall survival in melanoma. Whether immune-related events correlate with enhanced outcomes in ipilimumab/nivolumab combination therapy is unknown. Methods: Clinical data from patients diagnosed with untreated cutaneous stage IV melanoma receiving ipilimumab/nivolumab combination therapy between 2015-2018 at the Massachusetts General Hospital (MGH) and have been analyzed retrospectively. Tumor response was measured using RECIST criteria. Primary endpoints were frequencies and characteristics of immune-related adverse events, overall survival, and response to therapy. Results: A total of 57 patients received ipilimumab/nivolumab combination therapy. During a mean follow-up period of 26 months, 28 (49%) patients completed the therapy. Immune-related adverse events were observed in 45 (79%) patients, with rash (28%), colitis (23), hepatitis (21%) and fever (21%) being the most frequent. Overall survival was 29 months in patients with immune-adverse related events and 14 months in the group without any adverse events (p-value &lt; 0.01). The onset of hypophysitis correlated with tumor response (p = 0.02) and hepatitis showed a trend in a correlation to response of therapy (p = 0.06). Conclusions: Our study demonstrates the association between improved overall survival and the onset of immune-related adverse events in ipilimumab/nivolumab combination therapy. A trend correlated with improved outcomes and onset of immune-related adverse events was seen in hepatitis and was significantly associated with hypophysitis, however these results must be interpretated carefully as larger studies must confirm our findings. Despite small study size, we are the first to describe an association between immune-related adverse events in ipilimumab/nivolumab combination therapy.

Cell-free DNA BRAF V600E measurements during BRAF inhibitor therapy of metastatic melanoma: long-term analysis.

We assessed the status of the BRAF V600E mutation in cell-free circulating tumor DNA (cfDNA) isolated from the plasma of patients with metastatic melanoma treated with the BRAF inhibitor vemurafenib, collected at different time points during therapy to evaluate the sensitivity and specificity of quantitative polymerase chain reaction and droplet digital polymerase chain reaction (ddPCR) and the correlation between the level of plasma cfDNA p.V600E and the long-term clinical outcome. cfDNA in patients with BRAF-mutated melanoma (n = 62) was analyzed at baseline and at 4-8 weeks from the start of vemurafenib therapy. BRAF mutations were assessed using tumor tissue-derived DNA and circulating cfDNA from plasma samples. Quantification of BRAF V600E was performed in cfDNA using ddPCR. cfDNA V600E was detected in the plasma of 48/62 (77%) patients at baseline and in 18/62 (29%) patients after 4-8 weeks of treatment. Patients positive for BRAF mutations in cfDNA at baseline had shorter progression-free survival (PFS) and overall survival (OS) compared with patients with undetectable cfDNA BRAF mutations. Undetectable cfDNA p.V600E at baseline and after 4-8 weeks of therapy was associated with the best prognosis. When treated as a continuous variable, the log-transformed concentration of baseline cfDNA p.V600E was significantly associated with both PFS and OS. This effect was retained in the multivariate OS Cox model adjusted for Eastern Cooperative Oncology Group performance status, the presence of brain metastases, patient age, and previous systemic treatment. Monitoring of plasma BRAF p.V600E cfDNA concentrations in patients with metastatic melanoma on targeted therapy may have prognostic value. Undetectable cfDNA p.V600E before and during treatment was associated with a favorable prognosis.

When is it OK to Stop Anti-Programmed Death 1 Receptor (PD-1) Therapy in Metastatic Melanoma?

Systemic therapy for metastatic melanoma has been revolutionized over the past decade with the development of highly effective immune checkpoint inhibition, specifically anti-Programmed Death1 receptor (PD-1) therapy. However, even though one-third of patients will have durable response to single-agent or combination therapy, the optimal duration of therapy is unknown. Identifying the optimal duration of therapy is important, as exposure to anti-PD-1 therapy increases the risk of developing immune-mediated toxicities that can have significant morbidity and are, at times, fatal. It has long been understood that patients with complete responses to high-dose interleukin-2 and ipilimumab typically maintain their responses after a brief treatment course; thus, it is important to better understand the data to help understand the optimal management of melanoma patients treated with anti-PD-1 therapy. The clinical data with anti-PD-1-based therapy and published data on the duration of therapy suggest that patients may not require a full 2years of anti-PD-1 therapy and that the risk of toxicity may be mitigated by further understanding the mechanisms and kinetics of response to therapy. Although novel markers to help guide therapeutic decision making are under investigation, there is an ongoing need to improve our tools to monitor response to therapy and disease activity.

Recent Advances in Systemic Therapy for Malignant Melanoma

Malignant melanoma is a major contributor of skin cancer related mortality with increasing incidence and resistance to therapy. Advanced melanoma has a poor prognosis with a median overall survival of 8-10 months and a 5-year survival rate of 10%. A better understanding of melanogenesis and the tumor microenvironment has led to the development of several new therapies for metastatic melanoma. This review will provide a comprehensive overview of FDA approved novel systemic therapies for advanced melanoma and of other classes of molecules under clinical investigation. This paper will then look at the key signaling pathways these therapies target and briefly discuss the utility of biomarkers in guiding targeted therapy.

Elevated baseline serum PD-1 or PD-L1 predicts poor outcome of PD-1 inhibition therapy in metastatic melanoma

Programmed cell death protein 1 (PD-1) checkpoint inhibition has recently advanced to one of the most effective treatment strategies in melanoma. Nevertheless, a considerable proportion of patients show upfront therapy resistance and baseline predictive biomarkers of treatment outcome are scarce. In this study we quantified PD-1 and programmed death-ligand 1 (PD-L1) in baseline sera from melanoma patients in relation to therapy response and survival. Sera taken at therapy baseline from a total of 222 metastatic melanoma patients (two retrospectively selected monocentric discovery cohorts, n= 130; one prospectively collected multicentric validation cohort, n= 92) and from 38 healthy controls were analyzed for PD-1 and PD-L1 concentration by sandwich enzyme-linked immunosorbent assay. Melanoma patients showed higher serum concentrations of PD-1 (P= 0.0054) and PD-L1 (P < 0.0001) than healthy controls. Elevated serum PD-1 and PD-L1 levels at treatment baseline were associated with an impaired best overall response (BOR) to anti-PD-1 (P= 0.014, P= 0.041), but not to BRAF inhibition therapy. Baseline PD-1 and PD-L1 serum levels correlated with progression-free (PFS; P= 0.0081, P= 0.053) and overall survival (OS; P= 0.055, P=0.0062) in patients who received anti-PD-1 therapy, but not in patients treated with BRAF inhibitors. By combining both markers, we obtained a strong discrimination between favorable and poor outcome of anti-PD-1 therapy, with elevated baseline serum levels of PD-1 and/or PD-L1 associated with an impaired BOR (P= 0.037), PFS (P= 0.048), and OS (P= 0.0098). This PD-1/PD-L1 combination serum biomarker was confirmed in an independent multicenter validation set of serum samples prospectively collected at baseline of PD-1 inhibition (BOR, P= 0.019; PFS, P= 0.038; OS, P= 0.022). Multivariable Cox regression demonstrated serum PD-1/PD-L1 as an independent predictor of PFS (P= 0.010) and OS (P= 0.003) in patients treated with PD-1 inhibitors. Our findings indicate PD-1 and PD-L1 as useful serum biomarkers to predict the outcome of PD-1 inhibition therapy in melanoma patients and to select patients for PD-1-based versus BRAF-based therapy strategies.

Complete and long-lasting clinical responses in immune checkpoint inhibitor-resistant, metastasized melanoma treated with adoptive T cell transfer combined with DC vaccination

ABSTRACT Development of T cell-directed immune checkpoint inhibitors (ICI) has revolutionized metastatic melanoma (MM) therapy, but <50% of treated patients experience durable responses. This phase I trial (NCT01946373) investigates the safety/feasibility of tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) combined with dendritic cell (DC) vaccination in MM patients progressing on ICI. An initial cohort (5 patients) received TIL therapy alone to evaluate safety and allow for optimization of TIL expansion protocols. A second cohort (first-in-man, 5 patients) received TIL combined with autologous tumor lysate-loaded DC vaccination. All patients received cyclophosphamide/fludarabine preconditioning prior to, and intravenous (i.v.) IL-2 after, TIL transfer. The DC vaccine was given as five intradermal injections after TIL and IL-2 administration. [18F]-FDG PET/CT radiology was performed to evaluate clinical response, according to RECIST 1.1 (on the CT part). Immunological monitoring was performed by flow cytometry and T-cell receptor (TCR) sequencing. In the safety/optimization cohort, all patients had a mixed response or stable disease, but none durable. In the combination cohort, two patients experienced complete responses (CR) that are still ongoing (>36 and >18 months, respectively). In addition, two patients had partial responses (PR), one still ongoing (>42 months) with only a small bone-lesion remaining, and one of short duration (<4 months). One patient died early during treatment and did not receive DC. Long-lasting persistency of the injected TILs was demonstrated in blood. In summary, we report clinical responses by TIL therapy combined with DC vaccination in 4 out of 4 treated MM patients who previously failed ICI.

WITHDRAWN

The document associated with this DOI has been withdrawn.

Clinical and Pathological Relevance of Drug-induced Vitiligo in Patients Treated for Metastatic Melanoma with Anti-PD1 or BRAF/MEK Inhibitors.

Current therapies for metastatic melanoma (anti-PD1 and BRAF/MEK inhibitors) can cause drug-induced vitiligo. The aim of this study is to dermatologically define and histologically characterize this new type of vitiligo, and assess the clinical course of the disease. Fourteen patients with metastatic melanoma treated with immune or targeted therapy were included in a dataset evaluating clinical data, vitiligo description and histopathological features. Vitiligo-like lesions occurred after a mean of 7.5 months from the start of the therapies (range 1–42 months), with a prevalence of the non-segmental variant (71.4%). Fifty percent of patients showed a clinical response (4 complete response and 3 partial response), 35.7% had stable disease, and one patient died after disease progression. Median survival from the start of the therapies was 32.5 months. Drug-induced vitiligo can be related to both immune and targeted therapies, is associated with a favourable prognosis, and has clinical characteristics different from the classical form.