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Purpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Experimental Design: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371). Results: DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI. Conclusions: These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies. See related commentary by Smalley, p. 5

Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133

New fecal microbiota for cancer patients The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy (see the Perspective by Woelk and Snyder). Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8 + T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients. Science , this issue p. 602 , p. 595 ; see also p. 573

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

BackgroundAnti-PD-1 immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of melanoma by producing durable long-term responses in a subset of patients. ICI-treated patients develop unique toxicities - immune related adverse events (irAEs) – that arise from unrestrained immune activation. The link between irAE development and clinical outcome in melanoma and other cancers is inconsistent; and little data exists on the occurrence of multiple irAEs. We sought to characterize development of single and multiple irAEs, and association of irAE(s) development with clinical variables and impact upon outcomes in advanced melanoma patients treated with anti-PD-1 ICIs.MethodsWe conducted a retrospective study of 190 patients with metastatic melanoma treated with single-agent anti-PD-1 ICI therapy between June 2014 and August 2020 at a large integrated network cancer center identified through retrospective review of pharmacy records. irAEs were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.Results190 patients were evaluated of whom 114 patients (60.0%) experienced ≥1 irAE, including 30 (15.8%) with grade 3/4 irAEs. The occurrence of any irAE was strongly associated with the development of investigator-assessed response to anti-PD-1 therapy (p < 0.0001); whether evaluated by current (p=0.0082) or best (p=0.0001) response. In patients with ≥2 irAEs, distinct patterns were observed. Median progression-free survival (PFS) and overall survival (OS) were greater in those with any irAE compared to those without (PFS, 28 monthsvs. 5 months, p < 0.0001; OS, not reachedvs. 9 months, p < 0.0001). Development of ≥2 irAEs had a trend towards improved PFS and OS compared to those who developed a single irAE, although this did not reach statistical significance (p=0.2555, PFS; p=0.0583, OS). Obesity but not age or gender was distinctly associated with irAE development.ConclusionsIn this study, we demonstrated that irAE occurrence was significantly associated with response to anti-PD-1 therapy and improved PFS/OS. Those who developed multiple irAEs had a trend towards improved PFS and OS compared to those who developed only a single irAE. Increased BMI but neither age nor gender were associated with irAE development. Distinct patterns of irAEs observed suggest shared etiopathogenetic mechanisms.

Most patients with advanced melanoma ultimately fail immune checkpoint inhibitor (ICI) therapy because of primary or acquired resistance. There remains a critical unmet need for new therapies that function via alternative immune activation mechanisms to safely trigger an antitumor immune response in patients with ICI-refractory disease. This commentary discusses the recent failures and hope for novel intratumoral therapies under development in the advanced refractory melanoma setting, outlining key mechanistic differences that may be critical to yielding success in this difficult-to-treat population.

Background The pivotal E1684, E1690, E1694, and E2696 trials of adjuvant high-dose interferon-α (HDI) enrolled nearly 2000 patients, and established HDI as the standard of care in adjuvant therapy for patients with resected high-risk melanoma. Herein, the authors present an updated analysis of these 4 trials. Methods Survival and disease status were updated in September 2016. These data represent a median follow-up of 17.9 years for the E1684 trial, 12.2 years for the E1690 trial, 16.0 years for the E1694 trial, and 16.5 years for the E2696 trial. Results The current analysis confirmed the benefit to recurrence-free survival (RFS) of HDI in the E1684 trial at a median follow-up of 17.9 years. The RFS benefit in the E1694 trial remained evident at a median follow-up of 16 years. Furthermore, the results of the current study confirmed the RFS benefit of adjuvant HDI compared with observation in a pooled analysis of the E1684 and E1690 trials. No overall survival benefit was apparent in this pooled analysis. Updated results for the E1690 and E2696 trials did not differ from those previously reported. In addition, to the authors' knowledge, the current study is the first to report a significant difference in melanoma-specific survival (MSS) between patients treated with HDI compared with the ganglioside GM2/keyhole limpet hemocyanin (GMK) vaccine in the E1694 trial. Conclusions In patients with resected high-risk melanoma, adjuvant HDI demonstrated improved RFS in the E1684 and E1694 trials, and improved MSS in a pooled analysis of HDI in the E1694 trial. To the authors' knowledge, these findings represent the most mature level of evidence for the benefit of HDI with respect to RFS and MSS. HDI is the only approved adjuvant treatment for which there are data available in patients with resected stage IIB/IIC melanoma, and remains a reasonable treatment option in this population.

Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4–5 December, 2019, Naples, Italy), and are summarised in this report.

Background Immunotherapy has changed the treatment landscape for melanoma, although many patients (pts) do not respond to treatment. While there are likely multiple mechanisms of resistance at play, one key mechanism is the generation of an immunosuppressive and metabolically harsh tumor microenvironment (TME).1 This is likely the result of an altered angiogenic pattern along with dysregulated metabolism of the tumor itself, which leads to hypoxia.2 CD8+ tumor infiltrating lymphocytes (TIL) isolated from tumors with high oxidative metabolism have an exhausted phenotype and decreased functionality (decreased IFN-У and TNF-α production).3 Thus, TIL may be blunted due to failure to meet their metabolic needs. Vascular endothelial growth factor (VEGF) is a critical mediator of angiogenesis and is overexpressed in many solid tumors, including melanoma. Axitinib has high inhibitory activity for VEGF receptors1, 2, and 3. In a preclinical B16 melanoma model, we found that anti-PD1 plus axitinib provided an improved and durable response compared to monotherapy with either agent. We hypothesize that by modulating angiogenesis, axitinib will reduce intra-tumoral hypoxia and resultant T cell dysfunction, which will re-sensitize melanoma to anti-PD1 therapy. Methods This is an investigator-initiated, phase II trial of nivolumab plus axitinib for pts with unresectable stage III or IV melanoma who have progressed on prior anti-PD1 therapy with or without concomitant anti-CTLA4. Prior treatment with BRAF/MEK inhibitors is permitted. Pts with brain metastases are permitted if they are asymptomatic and have stable disease 2 weeks after CNS-directed treatment. Pts will receive nivolumab 480 mg IV every 4 weeks and axitinib PO 5 mg twice daily for up to two years or until progression or unacceptable toxicity. Timing of biopsies is reported in figure 1, with an optional biopsy at progression. Pts will receive an oral dose of pimonidazole 0.5 mg/m2 before each biopsy to permit in vivo evaluation of intra-tumoral hypoxia. Primary endpoint: overall response rate (ORR). Secondary endpoints: safety, progression-free survival, overall survival, and correlative analyses (evaluation of hypoxia in the TME, TIL function, immune phenotype, and tumor cell metabolism). Statistical analysis includes Simon’s minimax two-stage design. The null hypothesis is that the true ORR is 10%, tested against a one-sided alternative of 25% or higher. N=31 patients with a type I error rate of 0.08 and power 0.81 when the true response rate is 0.25. Results N/A Conclusions N/A Trial Registration NCT04493203 Ethics Approval The study was approved by the University of Pittsburgh Institutional Review Board, approval number HCC 20-101. References Romero IL, Mukherjee A, Kenny HA, Litchfield LM, Lengyel E. Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clin Cancer Res 2015;21(4):680–6. doi: 10.1158/1078-0432.CCR-14-2198. PubMed PMID: 25691772. Justus CR, Sanderlin EJ, Yang LV. Molecular connections between cancer cell metabolism and the tumor microenvironment. Int J Mol Sci 2015;16(5):11055–86. doi: 10.3390/ijms160511055. PubMed PMID: 25988385. Najjar YG, Menk AV, Sander C, Rao U, Karunamurthy A, Bhatia R, et al. Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma. JCI insight. 2019;4(5). Epub 2019/02/06. doi: 10.1172/jci.insight.124989. PubMed PMID: 30721155; PubMed Central PMCID: PMCPMC6483505.

Background XmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report preliminary data from an ongoing, multicenter, Phase 1 study investigating the safety/tolerability, pharmacokinetics/pharmacodynamics, and clinical activity (RECIST 1.1) of XmAb20717 in patients with selected advanced solid tumors. Methods A 3+3 dose-escalation design was used to establish a maximum tolerated (MTD)/recommended dose for evaluation in parallel expansion cohorts, including melanoma, renal cell carcinoma, non-small cell lung cancer (NSCLC), prostate cancer, and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI; n≤20 each). XmAb20717 was administered as an infusion on Days 1 and 15 of each 28-day cycle. Results As of 08Jul2020, 109 patients had been treated (table 1), and 30 were continuing treatment. In escalation, 6 dose levels (0.15–10.0 mg/kg) were evaluated (n=34); an MTD was not established. Expansion cohorts were initiated at 10 mg/kg (n=72), and a 15 mg/kg escalation cohort was added (n=3). T-cell proliferation was noted in peripheral blood at doses as low as 3 mg/kg and was highest at 10 mg/kg. At this dose, consistent proliferation of CD8+ and CD4+ T cells was observed, indicative of dual PD-1 and CTLA-4 checkpoint blockade (figure 1). Paired pre- and post-dosing biopsies showed increased intratumoral T-cell infiltration and IFN-response signatures following treatment. Grade 3/4 treatment-related adverse events (TRAEs) reported for ≥3 patients included rash (13%), transaminase elevations (7%), lipase increased (4% [2% with amylase increased]), and acute kidney injury (3%), all considered immune-related. There were 2 Grade 5 TRAEs: immune-mediated pancreatitis (in the presence of pancreatic metastases) and immune-mediated myocarditis (Grade 4) that contributed to respiratory failure. A complete response was reported as the best overall response for 1 patient (melanoma); partial responses were reported for 5 patients (2 melanoma, 2 NSCLC, 1 ovarian). The objective response rate was 13% overall and 21% at 10 mg/kg (6/46 and 6/29 evaluable patients, respectively). All responders had prior CI exposure. Responses were observed only at 10 mg/kg and, within the 10 mg/kg group, appeared to correlate with higher peak serum concentration and area under the curve. Conclusions XmAb20717 induced T-cell proliferation in peripheral blood consistent with dual-checkpoint blockade. Preliminary data indicate XmAb20717 was generally well-tolerated and associated with evidence of antitumor activity in CI-pretreated patients with various types of advanced solid tumors. Trial Registration NCT03517488 Ethics Approval The study was approved by each institution’s IRB.

BackgroundUveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.MethodsWe conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.Results89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).ConclusionsDual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.

Background: Monoclonal antibodies (mAb) targeting the programmed cell death protein 1 (PD-1) receptor provide durable long-term benefit in a subset of patients (pts) with advanced melanoma with response rates of 35-42% and 4-year progression-free survival (PFS) rate of 27%. Separately, the composition of the gut microbiota has been shown to correlate with anti-PD-1 efficacy in human cancer pts with melanoma, renal cell cancer and non-small cell lung cancer (NSCLC) although the precise organisms differ considerably across various studies. In preclinical models, responder-derived fecal microbiome and microbiome consortia produce anti-tumor responses. The effect of microbiome modulation in pts with anti-PD-1 refractory melanoma has not been evaluated. Methods: To evaluate whether primary resistance to anti-PD-1 immunotherapy could be overcome by intestinal microbiome modulation, we designed and conducted a phase II study (NCT03341143). We enrolled pts with primary refractory metastatic melanoma with best response of short-term stable disease (≤6 months) or progressive disease (PD) to prior anti-PD-1 based immunotherapy. Pts received single-administration of responder-derived fecal microbiota transplantation (R-FMT) together with pembrolizumab. Candidate donors were pts with advanced melanoma treated with anti-PD-1 immunotherapy with durable partial or complete response (PR, CR). Pembrolizumab was continued till intolerable toxicity or disease progression. Safety and clinical activity (based on RECIST v1.1) were main objectives; while progression-free survival (PFS) was a key secondary endpoint. Results: As of December 1, 2020, 16 pts with primary refractory melanoma were enrolled, of whom 15 were evaluable. LDH was elevated in 14/15 pts; and the median number of prior therapies was 2. Recipient pts were seromatched to receive a single R-FMT from one of eight candidate donors (5 CR; 3 PR; median PFS 58 months, range 43-70). R-FMT was administered via colonoscopy after bowel preparation with no use of antibiotics. Pembrolizumab was administered IV per label. R-FMT/pembrolizumab was well-tolerated, with no unusual toxicity signals. R-FMT induced rapid and durable microbiota perturbation in most pts; while 6 of 15 evaluable pts had evidence of clinical benefit. Response to R-FMT/pembrolizumab was associated with an increased abundance of taxa previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of IL-8 expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Conclusions: In pts with anti-PD-1 primary refractory melanoma, R-FMT/pembrolizumab changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 immunotherapy. Response was associated with CD8 T cell induction and reduction of IL-8 expressing myeloid cells. Citation Format: Diwakar Davar, Amiran Dzutsev, John A. McCulloch, Richard R. Rodrigues, Joe-Marc Chauvin, Robert M. Morrison, Richelle N. Deblasio, Carmine Menna, Quanquan Ding, Ornella Pagliano, Bochra Zidi, Shuowen Zhang, Jonathan H. Badger, Marie Vetizou, Alicia M. Cole, Miriam R. Fernandes, Stephanie Prescott, Raquel G. Costa, Ascharya K. Balaji, Andrey Morgun, Ivan Vujkovic-Cvijin, Hong Wang, Amir A. Borhani, Marc B. Schwartz, Howard M. Dubner, Scarlett J. Ernst, Amy Rose, Yana G. Najjar, Yasmine Belkaid, John M. Kirkwood, Giorgio Trinchieri, Hassane M. Zarour. Efficacy of Responder-derived Fecal Microbiota Transplant (R-FMT) and Pembrolizumab in Anti-PD-1 Refractory Patients with Advanced Melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB062.

The tumor microenvironment presents physical, immunologic, and metabolic barriers to durable immunotherapy responses. We have recently described roles for both T cell metabolic insufficiency as well as tumor hypoxia as inhibitory mechanisms that prevent T cell activity in murine tumors, but whether intratumoral T cell activity or response to immunotherapy varies between patients as a function of distinct metabolic profiles in tumor cells remains unclear. Here, we show that metabolic derangement can vary widely in both degree and type in patient-derived cell lines and in ex vivo analysis of patient samples, such that some cells demonstrate solely deregulated oxidative or glycolytic metabolism. Further, deregulated oxidative, but not glycolytic, metabolism was associated with increased generation of hypoxia upon implantation into immunodeficient animals. Generation of murine single-cell melanoma cell lines that lacked either oxidative or glycolytic metabolism showed that elevated tumor oxygen consumption was associated with increased T cell exhaustion and decreased immune activity. Moreover, melanoma lines lacking oxidative metabolism were solely responsive to anti-PD-1 therapy among those tested. Prospective analysis of patient sample immunotherapy revealed that oxidative, but not glycolytic, metabolism was associated with progression on PD-1 blockade. Our data highlight a role for oxygen as a crucial metabolite required for the tumor-infiltrating T cells to differentiate appropriately upon PD-1 blockade, and suggest that tumor oxidative metabolism may be a target to improve immunotherapeutic response.

Aim: To describe treatment patterns among patients with stage III melanoma who underwent surgical excision in years 2011–2016, and assess outcomes among patients who subsequently received systemic adjuvant therapy versus watch-and-wait. Methods: Chart review of 380 patients from 17 melanoma centers in North America, South America and Europe. Results: Of 129 (34%) patients treated with adjuvant therapy, 85% received interferon α-2b and 56% discontinued treatment (mostly due to adverse events). Relapse-free survival was significantly longer for patients treated with adjuvant therapy versus watch-and-wait (hazard ratio = 0.63; p < 0.05). There was considerable heterogeneity in adjuvant treatment schedules and doses. Similar results were found in patients who received interferon-based adjuvant therapy. Conclusion: Adjuvant therapies with better safety/efficacy profiles will improve clinical outcomes in patients with stage III melanoma.

Background In a previously reported study, patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab (ipi) (Tarhini in PLoS ONE 9(2): e87705, 3). Significant changes in circulating myeloid derived suppressor cells (MDSC), regulatory T cells (Treg) and peptide specific type I CD4+ and CD8+ T cells were noted at week 6 that correlated with clinical outcome. Characterization of antigen-specific effector T cell secreted cytokines may shed insights into ipi associated T cell activation and function. Methods Patients were treated with neoadjuvant ipi (10 mg/kg every 3 weeks ×2) administered intravenously before and after surgery. Peripheral blood mononuclear cells (PBMC) that were collected at baseline and week 6 (after ipi) were tested here. Each sample was divided into 5 groups and stimulated with controls or shared melanoma antigen overlapping peptide pools (NY-ESO 1, gp-100, MART-1). Secreted cytokines, chemokines and growth factors were assessed using Luminex. Cytokine expression levels between the 3 antigen groups were compared using the Wilcox rank-sum test. Results Seventeen cytokines were differentially expressed with stimulation by each antigen at baseline (p value

There will be an estimated 76,100 new cases of melanoma diagnosed in 2015 and 9710 deaths. Patients with stage I/II disease have excellent outcomes, and the treatment landscape for patients with metastatic disease has been transformed by the approval of several immune checkpoint inhibitors and molecular targeted therapies. Patients with stage III disease, however, continue to have very limited options, as the only agent shown to improve survival in the adjuvant setting is high-dose IFN-α. Neoadjuvant trials of chemotherapy and chemobiotherapy have not been successful, and while neoadjuvant ipilimumab and high-dose interferon have shown promise in small trials, neither agent has been approved. Current trials are testing immune therapy and targeted therapy combinations in the neoadjuvant setting.