Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma.

PURPOSE: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. METHODS: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. RESULTS: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. CONCLUSION: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

Cutaneous and Noncutaneous Adverse Effects in Patients with Advanced Melanoma Receiving Immunotherapy.

Relationships between cutaneous adverse effects (CAEs) and noncutaneous adverse effects (NCAEs) of melanoma immunotherapy may help identify patterns tied to distinct immunologic pathways. The objective of this study was to determine the associations between CAEs and NCAEs among patients with stages III-IV melanoma receiving immunotherapy and who were enrolled in a prospective cohort. Electronic medical record data were abstracted from the first immunotherapy infusion until 1 year later. CAEs were rash or itch. NCAEs were symptoms and/or laboratory abnormalities documented as immunotherapy related. NCAE onset and time to NCAE were compared between participants with and without CAEs using ORs and Wilcoxon rank sum tests. Of 34 participants, 11 (32.4%) developed no adverse effects, 7 (20.1%) developed CAEs only, 3 (8.8%) developed NCAEs only, and 13 (38.2%) developed both CAEs and NCAEs. After adjustment for age, sex, and immunotherapy regimen, CAE was associated with higher odds of NCAE development (OR = 9.72; 95% confidence interval = 1.2-76.8). Median NCAE onset was 63 days in those with CAEs and 168 days in those without CAEs (P = 0.41). Limitations included a small sample size, and larger prospective studies should be performed to confirm findings. CAE was associated with NCAE development. Early identification and treatment of NCAEs may reduce symptom burden and hospitalizations associated with NCAEs.

Case Report: Delayed Onset Multi-Organ Toxicities in a Melanoma Patient Achieving Complete Response to BRAF/MEK Inhibition.

Autoimmune toxicities, while common following treatment with cancer immunotherapies, are not well-characterized in patients treated with BRAF/MEK inhibitors. Emerging data suggest that autoimmune effects may be linked with superior responses to both treatment modalities; however, there is little evidence describing mechanisms of immune-related toxicity for patients on BRAF/MEK inhibitors. Here we describe the experience of a 59-year-old HLA-A2, A29, B27-positive male with recurrent/metastatic melanoma. After progression on checkpoint inhibitor therapy, he was treated with dabrafenib/trametinib followed by encorafenib/binimetinib, which were well-tolerated and resulted in a complete response. Eighteen months into BRAF/MEK inhibitor therapy, and three months after initially finding a complete response, he developed a series of sudden-onset, severe toxicities: namely, bilateral panuveitis, cytopenias, joint pain, skin rash, hypercalcemia, and interstitial nephritis, which led to BRAF/MEKi cessation. Immunological analyses revealed induction of a peripheral type-17 cytokine signature characterized by high IL-23, IL-6, IL-10, IL-17A/F, IL-1ß, and IL-21 among other cytokines in plasma corresponding with the height of symptoms. These findings highlight a novel instance of delayed autoimmune-like reaction to BRAF/MEK inhibition and identify a possible role for Th/Tc17 activation in their pathogenesis thus warranting future clinical and immunological characterization.

Clinical Correlation between Acute Exudative Polymorphous Paraneoplastic Vitelliform Maculopathy and Metastatic Melanoma Disease Activity: A 48-month Longitudinal Case Report.

PURPOSE: Longitudinal evaluation of acute exudative polymorphous paraneoplastic vitelliform maculopathy (AEPPVM) following diagnosis and treatment of metastatic melanoma. METHODS: Case report of a 47-year-old male with unknown primary metastatic melanoma and AEPPVM monitored before and during melanoma treatment using clinical exam, retinal imaging, and electroretinograms (ERG). Genetic testing and autoantibody panels were performed. RESULTS: He presented within a month of metastatic melanoma diagnosis with numerous bilateral vitelliform lesions in the posterior pole, consistent with AEPPVM. Metastatic disease was treated with immunotherapy, radiosurgery, and radiation over 48 months. Maculopathy and metastatic disease improved and worsened in parallel. Genetic testing was negative for bestrophin-1. An autoantibody panel was positive for anti-recoverin and transducin-α. CONCLUSION: AEPPVM is an uncommon paraneoplastic retinopathy found in patients with metastatic malignancy. To our knowledge, this is the first report demonstrating a temporal association between metastatic disease activity and quantifiable changes in retinal imaging over a 4-year period.

Mavorixafor, an Orally Bioavailable CXCR4 Antagonist, Increases Immune Cell Infiltration and Inflammatory Status of Tumor Microenvironment in Patients with Melanoma.

Purpose: Mavorixafor is an oral, selective inhibitor of the CXCR4 chemokine receptor that modulates immune cell trafficking. A biomarker-driven phase Ib study (NCT02823405) was conducted in 16 patients with melanoma to investigate the hypothesis that mavorixafor favorably modulates immune cell profiles in the tumor microenvironment (TME) and to evaluate the safety of mavorixafor alone and in combination with pembrolizumab. Experimental Design: Serial biopsies of melanoma lesions were assessed after 3 weeks of mavorixafor monotherapy and after 6 weeks of combination treatment for immune cell markers by NanoString analysis for gene expression and by multiplexed immunofluorescent staining for in situ protein expression. Serum samples taken at biopsy timepoints were evaluated for key chemokine and cytokine alterations using the Myriad Rules Based Medicine multiplex immunoassays. Results: Within the TME, mavorixafor alone increased CD8+ T-cell infiltration, granzyme B signal, antigen presentation machinery, and both tumor inflammatory signature (TIS) and IFNγ gene expression signature scores. Increases in the key serum cytokines CXCL9 and CXCL10 were further enhanced when mavorixafor was combined with pembrolizumab. Adverse events (AE), as assessed by the investigator according to NCI Common Terminology Criteria for Adverse Events (v4.03), related to either mavorixafor or pembrolizumab (≥15%) were diarrhea, fatigue, maculopapular rash, and dry eye. Reported AEs were all ≤ grade 3. Conclusion/Discussion: Treatment with single-agent mavorixafor resulted in enhanced immune cell infiltration and activation in the TME, leading to increases in TIS and IFNγ gene signatures. Mavorixafor as a single agent, and in combination with pembrolizumab, has an acceptable safety profile. These data support further investigation of the use of mavorixafor for patients unresponsive to checkpoint inhibitors. Significance: Despite survival improvements in patients with melanoma treated with checkpoint inhibitor therapy, a significant unmet medical need exists for therapies that enhance effectiveness. We propose that mavorixafor sensitizes the melanoma tumor microenvironment and enhances the activity of checkpoint inhibitors, and thereby may translate to a promising treatment for broader patient populations.

Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study.

BACKGROUND: The dependence of the adaptive immune system on circadian rhythm is an emerging field of study with potential therapeutic implications. We aimed to determine whether specific time-of-day patterns of immune checkpoint inhibitor infusions might alter melanoma treatment efficacy. METHODS: Melanoma Outcomes Following Immunotherapy (MEMOIR) is a longitudinal study of all patients with melanoma who received ipilimumab, nivolumab, or pembrolizumab, or a combination of these at a single tertiary cancer centre (Winship Cancer Institute of Emory University, Atlanta, GA, USA). For this analysis, we collected deidentified participant-level data from the MEMOIR database for adults (age ≥18 years) diagnosed with stage IV melanoma between 2012 and 2020. Those who received fewer than four infusions were excluded. Standard of care doses were used, with modifications at the treating physicians' discretion. The primary outcome was overall survival, defined as death from any cause and indexed from date of first infusion of immune checkpoint inhibitor. We calculated the association between overall survival and proportion of infusions of immune checkpoint inhibitors received after 1630 h (a composite time cutoff derived from seminal studies of the immune-circadian rhythm to represent onset of evening) using Cox regression and propensity score-matching on age, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy. Treatment-related adverse events that led to change or discontinuation of immune checkpoint inhibitors were also assessed. FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 481 patients with melanoma received treatment with immune checkpoint inhibitors at the study centre, of whom 299 had stage IV disease and were included in this study; median follow-up was 27 months (IQR 14 to 47). In the complete unmatched sample, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR 51 to 72). Every additional 20% of infusions of immune checkpoint inhibitors received after 1630 h (among all infusions received by a patient) conferred an overall survival hazard ratio (HR) of 1·31 (95% CI 1·00 to 1·71; p=0·046). A propensity score-matched analysis of patients who did (n=73) and did not (n=73) receive at least 20% of their infusions of immune checkpoint inhibitors after 1630 h (54 [37%] of 146 patients were women and 92 [63%] were men, with a median age of 58 years [IQR 48 to 68]) showed that having at least 20% of infusions in the evening was associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [1·04 to 4·00; p=0·038]). This result remained robust to multivariable proportional hazards adjustment with (HR 1·80 [1·08 to 2·98; p=0·023]) and without (2·16 [1·10 to 4·25; p=0·025]) inclusion of the complete unmatched study sample. The most common adverse events were colitis (54 [18%] of 299 patients), hepatitis (27 [9%]), and hypophysitis (15 [5%]), and there were no treatment-related deaths. INTERPRETATION: Our findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening than if stimulated in the daytime. Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma. FUNDING: National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute.

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma.

BACKGROUND: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. METHODS: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. CONCLUSIONS: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

Changing Therapeutic Landscape for Melanoma With Multiple Brain Metastases.

Over 90 000 people are expected to be diagnosed with melanoma in the United States this year. The development of brain metastases is particularly difficult to manage. Over the past few years, melanoma patients with multiple unresectable brain metastases for which stereotactic surgery might also not be a viable option have fortunately experienced a dramatic expansion in available management options given improvements made to targeted agents, immunotherapy, and radiotherapy. Whole-brain radiation therapy (WBRT) is a long-standing radiation technique that has become increasingly sophisticated. In this review, we summarize retrospective and prospective studies on individual advances in targeted agents, immunotherapy, and WBRT, highlighting important variables such as overall survival, intracranial progression-free survival, control and response rates, and toxicities. We also discuss the recent integration of these therapies into a multimodality approach, which has shown promise in the clinical setting although toxicities have not been insignificant. Finally, we describe ongoing prospective trials relevant to melanoma with brain metastases, and we conclude with our own thoughts on the optimal approach for these patients.

Chemokine receptor 4 targeted protein MRI contrast agent for early detection of liver metastases.

Liver metastases often progress from primary cancers including uveal melanoma (UM), breast, and colon cancer. Molecular biomarker imaging is a new non-invasive approach for detecting early stage tumors. Here, we report the elevated expression of chemokine receptor 4 (CXCR4) in liver metastases in UM patients and metastatic UM mouse models, and development of a CXCR4-targeted MRI contrast agent, ProCA32.CXCR4, for sensitive MRI detection of UM liver metastases. ProCA32.CXCR4 exhibits high relaxivities (r 1 = 30.9 mM-1 s-1, r 2 = 43.2 mM-1 s-1, 1.5 T; r 1 = 23.5 mM-1 s-1, r 2 = 98.6 mM-1 s-1, 7.0 T), strong CXCR4 binding (K d = 1.10 ± 0.18 µM), CXCR4 molecular imaging capability in metastatic and intrahepatic xenotransplantation UM mouse models. ProCA32.CXCR4 enables detecting UM liver metastases as small as 0.1 mm3. Further development of the CXCR4-targeted imaging agent should have strong translation potential for early detection, surveillance, and treatment stratification of liver metastases patients.

Predictors of Overall and Progression-Free Survival in Patients with Ocular Melanoma Metastatic to the Liver Undergoing Y90 Radioembolization.

PURPOSE: To investigate predictors of overall survival (OS) and progression-free survival (PFS) in patients with ocular melanoma metastatic to the liver undergoing yttrium-90 (Y90) radioembolization, including the effect of concurrent immunotherapy. METHODS: An IRB-approved retrospective review of 24 patients with ocular melanoma metastatic to the liver who underwent Y-90 treatment between June 2003 and January 2018 was performed. Data regarding patients' performance status at the time of Y90, intra-/extrahepatic tumor burden, and treatment response were evaluated. RECIST was used to determine objective tumor response. Kaplan-Meier analysis was used to calculate OS and PFS from the first Y90 therapy. Log-rank analysis was used to determine predictors of prolonged OS and PFS. RESULTS: Median OS from primary diagnosis and diagnosis of liver metastases was 66 months (mo) and 26.3 mo, respectively. Median OS for those who received immunotherapy within 3 months of undergoing Y90 was prolonged at 26.0 mo versus 9.5 mo for others (p = 0.014). Median OS for patients with an ECOG performance status of 0 was prolonged at 26 mo versus 5.5 mo for others (p = 0.003). Median hepatic PFS was prolonged in patients treated with Y-90 on concurrent immunotherapy at 10.3 mo versus 2.7 mo for TARE only (p = 0.002). Patients with an ECOG performance status of 0 had prolonged PFS (p = 0.002). CONCLUSIONS: Concurrent immunotherapy and an ECOG performance status of 0 at the time of Y90 therapy appear to be predictors of prolonged OS and PFS in patients with ocular melanoma metastatic to the liver.

Surgical Considerations and Systemic Therapy of Melanoma.

Recent advances in effective medical therapies have markedly improved the prognosis for patients with advanced melanoma. This article aims to highlight the current era of integrated multidisciplinary care of patients with advanced melanoma by outlining current approved therapies, including immunotherapy, targeted therapy, radiation therapy, and other strategies used in both the adjuvant and the neoadjuvant setting as well as the evolving role of surgical intervention in the changing landscape of advanced melanoma.

Approaches to High-Risk Resected Stage II and III Melanoma.

Over the last decade, several therapies, including both targeted and immune checkpoint inhibitors, have dramatically changed the treatment landscape for patients with metastatic melanoma. These same therapies are now being used in the adjuvant setting with the hope of delaying or preventing the development of metastatic disease. Although phase III trials have shown a clear benefit for patients with resected bulky nodal disease, treatment decisions for patients with earlier-stage (high-risk stage II and stage IIIA) melanoma in the adjuvant setting are less straightforward given the small number of patients studied so far. Among patients with stage IIIB and worse disease, both targeted and immune checkpoint inhibitors have shown benefit in recurrence-free survival. Although a head-to-head comparison has not been completed, patient and tumor characteristics can guide the optimal treatment of an individual.

Multiple keratin granulomata: A potential histologic clue to cutaneous squamous cell carcinoma responding to programmed cell death protein 1 inhibitor therapy.

We present histologic features of a locally advanced cutaneous squamous cell carcinoma (cSCC) treated with the programmed cell death protein-1 (PD-1) antagonist, pembrolizumab, with a partial response. This contributes to a growing body of literature supporting the efficacy of pembrolizumab in treatment of surgically unresectable cSCC. We also provide a detailed description of the histologic features, particularly keratin granulomata with adjacent lymphocytic aggregates and fibrosis, observed in cSCC under treatment with a PD-1 antagonist.

The importance of surgery in scalp angiosarcomas.

BACKGROUND: Scalp angiosarcomas (SA) are rare, representing <1% of soft tissue sarcomas. The optimal management of these tumors is unknown, with management based on small case series. We sought to assess the impact of different therapies on overall survival (OS), the practice patterns nationally, and identify factors associated with OS for non-metastatic scalp angiosarcomas. METHODS: A prospectively maintained database was used to identify non-metastatic scalp angiosarcomas who received some form of definitive therapy. Logistics regression, Kaplan-Meier, and Cox proportional-hazard models were utilized. RESULTS: A total of 589 patients met study entry criteria with a median follow-up of 4.2 years. The majority (482 patients, 81.8%) had upfront definitive resection and an additional 317 patients (65.8%) received postoperative radiation. Of the 107 patients who didn't have surgery, the majority (65 patients, 60.7%) received definitive radiation and 42 patients (39.3%) received radiation and chemotherapy. One-year and five-year survival estimates for patients not receiving definitive surgery were 68.0% (95%CI: 57.5-76.4) and 18.0% (95%CI: 10.2-27.5) respectively compared to 78.2% (95%CI: 74.0-81.9) and 34.1% (95%CI: 28.9-39.3) for patients receiving definitive surgery (p < 0.01). On multivariable analysis, age ≥65 years, tumor size ≥5 cm, and not receiving definitive surgery was associated with worse OS. CONCLUSIONS: The majority of patients with non-metastatic scalp angiosarcomas had upfront definitive surgery, with a subsequent improvement in OS, including when accounting for other patient and tumor factors. Postoperative radiation was frequently given. Our large series confirmed age and tumor size as prognostic factors for this rare disease.

Systemic Therapy Options for Patients With Unresectable Melanoma.

There has been a therapeutic revolution in the treatment of metastatic melanoma over the past decade. Patients presenting with inoperable disease have several therapeutic options, which can include both targeted and immune therapy. Immune checkpoint inhibitors have demonstrated an improvement in overall survival and led to some durable responses. However, toxicity, especially in combination regimens, can be severe. Adverse events should be anticipated, diagnosed as early as possible, monitored, and managed. Combination BRAF and MEK inhibition has also been shown to improve overall survival in patients with V600E-mutated melanoma. Responses to therapy are often rapid, and treatment is not associated with immune-related adverse events. Current trials are under way to determine which option is optimal as frontline therapy for patients with V600E melanoma. In patients with progressive disease despite standard therapies, clinical trials are recommended. There are several promising agents in development.

Patient preferences regarding incidental genomic findings discovered during tumor profiling.

BACKGROUND: During the process of tumor profiling, there is the potential to detect germline variants. To the authors' knowledge, there currently is no accepted standard of care for how to deal with these incidental findings. The goal of the current study was to assess disclosure preferences among patients with cancer regarding incidental genomic variants that may be discovered during tumor profiling. METHODS: A 45-item questionnaire was administered to 413 patients in ambulatory oncology clinics. The survey captured demographic and disease variables and personal and family history, and presented case scenarios for different types of incidental germline variants that could theoretically be detected during genomic analysis of a patient's tumor. RESULTS: The possibility of discovering non-cancer-related, germline variants did not deter patients from tumor profiling: 77% wanted to be informed concerning variants that could increase their risk of a serious but preventable illness, 56% wanted to know about variants that cause a serious but unpreventable illness, and 49% wanted to know about variants of uncertain significance. The majority of patients (75%) indicated they would share hereditary information regarding predisposition to preventable diseases with family and 62% would share information concerning unpreventable diseases. The most frequent concerns about incidental findings were ability to obtain health (48%) or life (41%) insurance. Only 21% of patients were concerned about privacy of information. CONCLUSIONS: Patients with cancer appear to prefer to receive information regarding incidental germline variants, but there is substantial variability with regard to what information patients wish to learn. The authors recommend that personal preferences for the disclosure of different types of incidental findings be clarified before a tumor profiling test is ordered. Cancer 2016;122:1588-97. © 2016 American Cancer Society.

Tumor profiling and the incidentalome: patient decisions and risks.

In recent years, the field of oncology has witnessed rapid advancements in genetic sequencing simultaneously with steeply declining costs of sequencing technology. As a result, genomics-driven cancer medicine and the use of tumor profiling are quickly becoming mainstays of cancer therapy. Oncology patients can benefit from tumor profiling by allowing the selection of targeted therapies tailored to their disease. However, it is increasingly recognized that the process of determining a tumor DNA sequence may lead to incidental discovery of underlying germline mutations which can impact other aspects of a patient's health, and that of their family. How to handle the 'incidentalome' has been the subject of recent public debate, yet patient education about the potential risks of tumor profiling remains sparse. Patient perspectives and clinical implications of the tumor incidentalome must be specifically addressed by the oncology community as tumor profiling expands to become a new standard of care.

Advances in the systemic treatment of metastatic melanoma.

Prior to 2011, the only commercially available agents commonly used to treat metastatic melanoma-including dacarbazine, temozolomide (Temodar), fotemustine, carboplatin, paclitaxel, and interleukin-2-demonstrated limited efficacy, and no study involving these agents had shown an improvement in overall survival. The standard of care for the treatment of metastatic melanoma was radically changed by the subsequent approval of two agents, ipilimumab (Yervoy) and vemurafenib (Zelboraf), both of which improved survival in randomized phase III trials. Within the relatively short time that ipilimumab and vemurafenib have been commercially available, phase II data for the investigational agents nivolumab and MK-3475, for the combination of dabrafenib and trametinib, and for adoptive cell therapy strongly suggest even further improvements in treatment outcomes. Within this rich context of effective agents, the challenge for clinicians and investigators will be to develop predictive biomarkers of response, the optimal sequence of therapy for individual patients, and effective combinations. An additional challenge will be to find the appropriate venue and populations to test promising new agents arising from substantial advances in our understanding of molecular alterations in melanoma cells, of mechanisms of resistance to current agents, and of tumor-host immune interactions.