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Background: In the phase II/III RELATIVITY-047 trial, a novel fixed-dose combination (FDC) of nivolumab plus relatlimab (NIVO + RELA; a programmed death-1 and a lymphocyte-activation gene 3 inhibitor, respectively) significantly improved progression-free survival (PFS) versus NIVO in patients with previously untreated unresectable or metastatic melanoma (median follow-up, 13.2 months) with stable health-related quality of life (HRQoL), although grade three or four treatment-related adverse events (TRAEs) were more frequent with the combination. Updated HRQoL results (median follow-up, 19.3 months) are presented. Methods: Patients were randomised to receive intravenous NIVO + RELA (480 mg and 160 mg, respectively) or NIVO (480 mg) every 4 weeks. HRQoL was assessed using the Functional Assessment of Cancer Treatment-Melanoma (FACT-M) and EQ-5D-3L questionnaires at baseline, before dosing at each treatment cycle, and at follow-up (posttreatment) visits. Results: Consistent with the initial analysis, HRQoL remained stable with NIVO + RELA on treatment and was similar to that with NIVO. Mean changes from baseline did not exceed clinically meaningful thresholds. HRQoL results were consistent across instruments and scales/subscales. Despite an increased rate of grade three or four TRAEs with NIVO + RELA versus NIVO, the proportion of patients reporting that they were bothered 'quite a bit' or 'very much' by TRAEs was low and comparable between treatments. Conclusion: Results from the RELATIVITY-047 trial show that the PFS benefit with NIVO + RELA FDC over NIVO was obtained with stable patient-reported HRQoL, supporting NIVO + RELA as a first-line treatment option for patients with advanced melanoma.

Immune-related adverse events (irAEs) are a major concern when treating cancer patients with immune checkpoint inhibitor (ICI) therapy. Selecting the most appropriate management of irAEs remains an ongoing challenge because prolonged use of glucocorticoids come with their own side effects and may counteract the antineoplastic effects from immunotherapy. In this case report, we present two patients with metastatic melanoma who developed symptoms of inflammatory arthritis attributed to ICI therapy. We found that treatment with secukinumab, an anti-IL-17A inhibitor, effectively managed their symptoms and did not lead to tumor progression. Our study suggests that secukinumab can be a safe and effective treatment option for ICI-induced inflammatory arthropathy.Immune-related adverse events (irAEs) are unwanted side effects commonly seen in cancer patients treated with immunotherapy. A frequently underreported irAE is inflammation of the joints (ankles, knees, shoulders, etc.), which is known as inflammatory arthropathy. Inflammatory arthropathy is frequently treated with steroids, but there is concern that it may counteract the anticancer effect from immunotherapy. Alternative treatments are needed to better treat this irAE without compromising the benefit of immunotherapy. In this case report, we present two patients with stage 4 melanoma who developed immunotherapy-induced inflammatory arthropathy and were successfully treated with secukinumab. We found that treating the inflammatory arthropathy was safe, effective, and did not lead to cancer progression in either patient.

Cardiac metastasis of melanoma is rare and typically diagnosed post-mortem. Here we perform a retrospective cohort study and systematic review of patients with metastatic melanoma to characterize prevalence, clinical characteristics, and outcomes of cardiac metastasis.We reviewed the electronic medical records of all outpatients with metastatic melanoma who underwent evaluation at the University of Michigan in Ann Arbor from January 2009 to January 2022, identifying patients with a clinical or histopathologic diagnosis of cardiac metastasis. We performed a systematic review of the literature to summarize the clinical characteristics and outcomes of patients with melanoma and cardiac metastasis.Overall, 23 of 1254 (1.8%) patients with metastatic melanoma were diagnosed with cardiac metastasis. Cardiac metastasis was reported in the right ventricle (65%), left ventricle (35%), and right atrium (35%). A total of 11 (48%) patients experienced at least one cardiovascular complication after the diagnosis of cardiac metastasis, the most common being arrhythmia (30%), heart failure (22%), and pericardial effusion (17%). Immunotherapy was more commonly used in patients with cardiac metastasis (80% vs 65%; p = 0.005). Mortality at 2-years post-diagnosis was higher for patients with cardiac metastasis compared to those without (59% vs 37%; p = 0.034). Progression of malignancy was the underlying cause of death of all patients.Cardiac metastasis occurs in2% of patients with metastatic melanoma, can affect all cardiac structures, and is associated with various cardiovascular complications and high mortality.

Background In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients. Methods Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months). Results Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed. Conclusions Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity. Liver metastases reduce clinical and preclinical immune-checkpoint inhibitor efficacy through hepatic siphoning of circulating activated CD8+ T cells, but therapeutic benefit can be improved by combining immunotherapy with liver-directed radiotherapy.

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 3 years 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 survival benefit 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.

Supplemental Digital Content is available in the text., CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3–4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79–84] and 70% (95% CI 66–74), respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.

Purpose To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. Methods and Materials Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume. Results Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01). Conclusions The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response.

ObjectiveTo evaluate the long-term outcomes of sentinel lymph node biopsy (SLNB) for head and neck cutaneous melanoma (HNCM).Study DesignRetrospective cohort study.SettingTertiary academic medical ...

BACKGROUND: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation. METHODS: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group. CONCLUSIONS: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).

Summary Background Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. Methods This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5–3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0–2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov , NCT02320058 . Findings Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7–36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2–35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2–67·2]) of 101 patients in cohort A and three (16·7% [3·6–41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3–63·5]) patients in cohort A and three (16·7% [3·6–41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7–64·1) and overall survival was 71·9% (61·8–79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6–40·5) and overall survival was 36·6% (14·0–59·8). The most common grade 3–4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). Interpretation The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. Funding Bristol Myers Squibb.

BACKGROUND Pembrolizumab immunotherapy has been associated with hepatotoxicity in 1%-10% of oncology patients treated in clinical trials. AIM To describe the incidence, phenotypes and outcomes of liver injury in a large cohort of solid organ tumour patients receiving pembrolizumab METHODS: Liver injury was defined by serum alanine aminotransferase, alkaline phosphatase, and/or total bilirubin levels exceeding threshold values. The likelihood of drug-induced liver injury was adjudicated by expert opinion. RESULTS Seventy (14.3%) of the 491 pembrolizumab-treated patients developed liver injury at a median of 62 days (6-478) and 71.4% had a cholestatic injury profile at onset. The median age, gender and tumour types of liver injury patients were similar to those without, but hepatic metastases (53% vs 21%, P

9503 Background: Immune checkpoint inhibitor therapy has revolutionized the treatment of patients with advanced melanoma. However, novel combinations are needed to optimize the benefit-risk profile. Lymphocyte-activation gene 3 (LAG-3) regulates an immune checkpoint pathway, which inhibits T-cell activity, and is upregulated in many tumor types including melanoma. Relatlimab (RELA), a human IgG4 LAG-3-blocking antibody, restores effector function of exhausted T cells. RELA in combination with nivolumab (NIVO; anti-programmed death [PD]-1) modulates potentially synergistic immune checkpoint pathways and can enhance antitumor immune responses. RELATIVITY-047 is a global, randomized, double-blind, phase II/III study evaluating a novel immune checkpoint inhibitor combination of RELA+NIVO as a fixed-dose combination (FDC) treatment in first-line advanced melanoma. Methods: Patients with previously untreated advanced melanoma were randomized 1:1 to receive RELA 160 mg + NIVO 480 mg FDC intravenously (IV) every 4 weeks (Q4W) or NIVO monotherapy 480 mg IV Q4W, stratified by LAG-3 expression, programmed death ligand 1 expression, BRAF mutation status, and AJCC (v8) M stage. The primary endpoint was progression-free survival (PFS) per RECIST v1.1 as assessed by blinded independent central review. Secondary endpoints were overall survival and objective response rate. PFS in prespecified subgroups and safety were additional objectives. Results: 714 patients were randomized to RELA+NIVO FDC (n = 355) or NIVO (n = 359). Patient characteristics were well balanced between treatment groups. Median follow-up was 13.2 months. Median PFS in the RELA+NIVO FDC group (10.1 months [95% CI, 6.4–15.7]) was significantly longer than in the NIVO group (4.6 months [95% CI, 3.4–5.6]; hazard ratio, 0.75 [95% CI, 0.6–0.9]; P = 0.0055). PFS rates at 12 months were 47.7% (95% CI, 41.8–53.2) and 36.0% (95% CI, 30.5–41.6) for RELA+NIVO FDC and NIVO, respectively. PFS favored RELA+NIVO FDC across key prespecified subgroups. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was higher in the RELA+NIVO FDC group (18.9%) versus NIVO (9.7%). There were 3 treatment-related deaths with RELA+NIVO FDC and 2 with NIVO. TRAEs (any grade) led to treatment discontinuation in 14.6% and 6.7% of patients in the RELA+NIVO FDC and NIVO groups, respectively. Conclusions: First-line treatment with RELA+NIVO FDC demonstrated a statistically significant PFS benefit compared to NIVO monotherapy in patients with advanced melanoma. RELA+NIVO FDC was well tolerated with a manageable safety profile and without unexpected safety signals. This is the first phase III study of a novel FDC to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways. Clinical trial information: NCT03470922.

9530 Background: Treatment with PD-1 inhibitor-based therapy has significantly improved survival in patients with metastatic melanoma over the past decade. Many of these patients achieve complete metabolic response (CMR) by FDG-PET/CT and electively stop treatment. However, the outcomes of patients who relapse after CMR remain uncertain. In this study, we attempt to further characterize metastatic melanoma patients who relapsed following elective discontinuation of anti-PD-1 based therapy due to CMR. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2021 who were treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) or combination ipilimumab/nivolumab (I/N), with or without local therapies (surgery or radiation therapy). Patients who achieved a CMR from treatment were identified. CMR was defined as no evidence of metabolically active disease on full-body 18F-FDG-PET/CT and no evidence of new intracranial metastasis on MRI brain. Multiple clinical variables and survival outcomes were assessed. Results: Among 386 advanced stage melanoma patients analyzed, 87 achieved a CMR followed by elective treatment cessation with a median anti-PD-1 therapy duration of 10.4 months. 19/87 patients had brain metastasis at baseline. 17/87 patients had disease relapse with a median time to relapse from CMR of 12.1 months. Of those 17 patients, 8 received I/N, 9 received anti-PD-1 monotherapy, and 2 required local therapies to obtain CMR. 7/17 patients were able to achieve CMR again following resumption of anti-PD-1 monotherapy (n = 6) and BRAF/MEK targeted therapy (n = 1). 10/17 patients relapsed in the brain with 7 of those patients having no history of brain metastasis at baseline. Median overall survival after relapse from CMR was 34.1 months. The most common cause of death following relapse from CMR was brain metastasis progression (n = 5). Conclusions: A small proportion of metastatic melanoma patients who achieve complete metabolic (CMR) following treatment with anti-PD-1 therapy develop disease relapse. We found that relapse in the brain is common, regardless of baseline involvement at time of therapy, and is a common cause of mortality suggesting the importance of intracranial surveillance following treatment cessation. Ongoing studies are warranted to identify clinicopathologic factors that predict relapse to better inform patients and providers who elect to stop anti-PD-1 therapy.

2664 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced stage skin malignancies. Immunotherapy related adverse events (irAE) are toxicities associated with ICI therapy. Myocarditis is a rare life-threatening irAE. We attempt to characterize cases of myocarditis related to ICI therapy that have occurred since the start of the COVID-19 pandemic. Methods: We performed a single-center, retrospective cohort analysis of patients with advanced stage skin cancers who were treated with ICIs and identified cases of ICI-mediated myocarditis. ICI-mediated myocarditis was defined as evidence of myocardial injury in the setting of irAEs and exclusion of cardiovascular causes. Clinicopathologic variables and clinical outcomes were assessed in these patients. Results:A review of 361 patients that received ICI from 9/2014 – 10/2019 found 0 cases of ICI-mediated myocarditis. From 11/2019 – 12/2021, an additional 425 patients were identified of whom 11 (2.6%) developed ICI-mediated myocarditis. 10 patients had melanoma and 1 patient had Merkel cell carcinoma. 10/11 patients were male. 9/11 were treated with anti-PD-1 monotherapy and 2/11 were treated with ipilimumab with nivolumab. All patients had elevated high sensitivity troponin (median 361 pg/mL on presentation, reference range 0-19 pg/mL). 11/11 patients presented with elevated CPK (median 1734 IU/L, reference range 38-240 IU/L) and 8/11 presented with elevated AST:ALT ratio (median 1.58:1) on routine screening which prompted further investigation. 1 patient tested positive for COVID-19 13 days after initial biochemical concern for myocarditis, and 5 patients had received COVID-19 vaccines between 2.5-11 months prior to myocarditis onset. All patients were treated with high dose steroids, and 4 were treated with abatacept. 2 patients died within 30 days after diagnosis of myocarditis and 2 patients later died from malignancy progression. 2 patients developed progressive disease and 1 was successfully rechallenged with ICI with no myocarditis recurrence. 2 patients remain on active surveillance, 2 continue on a steroid taper, and 1 was lost to follow up. All patients with at least 5 months of follow up from myocarditis onset (n = 5) had persistently elevated HS-troponin despite normalization of CPK levels. Conclusions: In this single center study, we noted an increase in the frequency of ICI-mediated myocarditis in patients with advanced skin cancers during the pandemic era (2.6% vs 0% pre-pandemic) which is higher than reported in the literature (0.04-1.14%). The impact of COVID-19 during this time is suspicious and warrants further investigation. Therefore, we suggest heightened awareness in the COVID-19 era that elevated CPK levels and AST:ALT ratios merits further diagnostic investigation of ICI-mediated myocarditis.

9522 Background: Durable clinical benefit has been achieved with nivolumab (NIVO) + ipilimumab (IPI), including an overall survival (OS) of 49% and a melanoma-specific survival (MSS) of 56%, with median MSS not reached (NR) at 6.5-y minimum follow-up. Here we report sustained efficacy outcomes at 7.5 y. Methods: Patients (pts) with previously untreated, unresectable stage III/IV melanoma were randomly assigned 1:1:1 and stratified by PD-L1 status, BRAF mutation status, and metastasis stage to receive NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314); NIVO 3 mg/kg Q2W + placebo (n = 316); or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) and OS with NIVO + IPI or NIVO alone versus IPI. Results: With a minimum follow-up of 7.5 y, median OS remained stable at 72.1 mo (NIVO + IPI), 36.9 mo (NIVO), and 19.9 mo (IPI); median MSS was NR, 49.4 mo, and 21.9 mo, respectively (Table). While the objective response rate remained stable at 58% (NIVO + IPI), 45% (NIVO), and 19% (IPI), median duration of response had now been reached for NIVO at 90.8 mo and remains NR and 19.2 mo for NIVO + IPI and IPI, respectively. Subsequent systemic therapy was received by 36%, 49%, and 66% of NIVO + IPI-, NIVO-, and IPI-treated patients, respectively, and median time to that therapy was NR (95% CI, 45.9–NR), 24.7 mo (16.0–38.7), and 8.0 mo (6.5–8.7). Of patients alive at 7.5 y, 106/138 (77%, NIVO + IPI), 80/115 (70%, NIVO), and 27/60 (45%, IPI) were off treatment and had never received subsequent systemic therapy. No change to the safety summary was observed with additional follow-up; updated health-related quality of life data will be reported. Of the 10 new deaths since the 6.5-y follow-up (ie, 5 NIVO + IPI; 3 NIVO; 2 IPI), none were treatment-related; 4 were due to melanoma progression; 1 was due to an unknown cause; and 5 were due to other causes, but not associated with a COVID diagnosis. Conclusions: The 7.5-y follow-up continues to demonstrate the durability of responses with NIVO + IPI and an ongoing survival plateau. A substantial difference in median OS and MSS between patients treated with NIVO + IPI or NIVO was observed in descriptive analyses. Clinical trial information: NCT04540705. [Table: see text]

9505 Background: In the phase 2/3 RELATIVITY-047 trial, NIVO + RELA as a fixed-dose combination (FDC) significantly improved the primary endpoint of progression-free survival (PFS) versus NIVO in patients (pts) with previously untreated metastatic or unresectable melanoma. Secondary endpoints showed a clinically meaningful improvement in overall survival (OS), although not statistically significant, and a higher objective response rate (ORR). As previously reported, PFS and OS favored NIVO + RELA over NIVO across prespecified stratification factors (LAG-3 expression, PD-L1 expression, BRAF V600 mutation status, and metastasis stage). Here we report the first disclosure of ORR analyzed by prespecified stratification factors and OS and ORR in additional subgroups. Methods: Pts were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg FDC or NIVO 480 mg intravenously Q4W. The primary endpoint was PFS per RECIST v1.1 assessed by blinded independent central review (BICR). Secondary endpoints were OS and ORR by BICR, tested in hierarchy. Exploratory analyses were performed for PFS, OS, and ORR by prespecified subgroups. Results: PFS continued to favor NIVO + RELA over NIVO across key subgroups. OS and ORR also favored NIVO + RELA over NIVO across key subgroups including those associated with poor prognosis (Table). ORR favored NIVO + RELA over NIVO for pts with LAG-3 expression ≥ 1% (47% vs 35%) and < 1% (31% vs 24%), PD-L1 expression ≥ 1% (53% vs 45%) and < 1% (36% vs 24%), and BRAF wild-type (43% vs 34%) and mutant (43% vs 31%) melanoma, respectively. Additional key prespecified subgroups will be presented. In all treated pts, NIVO + RELA maintained a manageable safety profile with no new or unexpected safety signals. Conclusions: NIVO + RELA was favored over NIVO across key subgroups for PFS, OS, and ORR, and findings appeared consistent with outcomes in the overall population. NIVO + RELA had a favorable benefit-risk profile. Clinical trial information: NCT03470922. [Table: see text]

360385 Background: RELATIVITY-047, a global, randomized, double-blind, phase II/III study, met its primary endpoint of progression-free survival (PFS). Relatlimab and nivolumab (RELA + NIVO) as a fixed-dose combination (FDC) demonstrated a significant PFS benefit (median PFS was 10.1 months [mo]; 95% CI, 6.4–15.7) with RELA + NIVO vs. 4.6 mo (95% CI, 3.4–5.6) with NIVO; hazard ratio (HR) 0.75 (95% CI, 0.6–0.9; p = .0055), with a manageable safety profile, compared to NIVO alone in patients with previously untreated metastatic or unresectable melanoma (Lipson EJ et al. J Clin Oncol 2021;39[15_suppl]:9503P). Here we report updated PFS and the first disclosure of secondary endpoints, overall survival (OS), and overall response rate (ORR). Methods: Patients were randomized 1:1 to receive RELA 160 mg + NIVO 480 mg FDC or NIVO 480 mg alone, given intravenously every 4 weeks, as previously described (Lipson EJ et al. J Clin Oncol 2021;39[15_suppl]:9503P). The primary endpoint of PFS per RECIST v1.1 was assessed by blinded independent central review (BICR). Secondary endpoints were OS and ORR by BICR, to be tested hierarchically. The OS boundary for statistical significance was p < .04302 (2-sided) based on 69% power for a target HR of 0.75. Results: Patients (714 patients) were randomly selected to receive RELA + NIVO (355 patients) or NIVO (359 patients). Median follow-up was 19.3 mo. Updated median PFS was 10.2 mo (95% CI, 6.5–14.8) with RELA + NIVO vs. 4.6 mo (95% CI, 3.5–6.4) with NIVO (HR 0.78; 95% CI, 0.6–0.9). Median OS was not reached (NR; 95% CI, 34.2–NR) with RELA + NIVO vs. 34.1 mo (95% CI. 25.2–NR) with NIVO (HR 0.80; 95% CI, 0.6–1.0; p = .0593). OS rates at 12 mo were 77.0% (95% CI, 72.2–81.1) vs. 71.6% (95% CI, 66.6–76.0) and at 24 mo were 63.7% (95% CI, 58.1–68.7) vs. 58.3% (95% CI, 52.7–63.4) with RELA + NIVO vs. NIVO, respectively. Subsequent systemic therapy rates and types were generally similar between treatment groups. Confirmed ORR per BICR was 43.1% (95% CI, 37.9–48.4) with RELA + NIVO vs. 32.6% (95% CI, 27.8–37.7) with NIVO. Complete responses were observed in 16.3% of patients on RELA + NIVO vs. 14.2% on NIVO. Grade 3/4 treatment-related adverse events (TRAEs) were observed in 75 (21.1%) patients on RELA + NIVO and 40 (11.1%) on NIVO. There were four treatment-related deaths in the RELA + NIVO group and two in the NIVO group. TRAEs (any grade) leading to treatment discontinuation were observed in 54 (15.2%) patients on RELA + NIVO and 26 (7.2%) on NIVO. Conclusions: RELA + NIVO continued to demonstrate a PFS benefit vs. NIVO alone in patients with previously untreated metastatic or unresectable melanoma, consistent with the primary analysis. RELA + NIVO demonstrated a 20% reduction in risk of death and numerically improved OS rates vs. NIVO, although statistical significance was not reached for this secondary endpoint. ORR was higher with RELA + NIVO vs. NIVO. The safety profile of RELA + NIVO remained manageable with no new or unexpected safety signals. Clinical trial information: NCT03470922.

Background Recent studies report of liver metastases (LM) as a poor prognostic factor in patients treated with immune checkpoint inhibitors (ICIs),1 but clinical outcomes associated with different ICI regimens remains uncertain. In this study, we investigate melanoma patients with and without LM and assess differential treatment outcomes associated with anti-PD-1 monotherapy and combination ipilimumab/nivolumab (I/N). Methods We conducted a single-center, retrospective review of advanced stage melanoma patients with and without LM treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) or I/N between 2012 and 2018. Overall survival (OS) and progression free survival (PFS) were measured from the first dose of treatment to date of death and clinical or radiographic progression, respectively. Univariate and multivariate analysis were performed using Cox proportional hazard (CPH) models and logistic regression models. Inverse probability of treatment weighting using propensity scores in CPH models was used to account for the following baseline covariates: age, ECOG performance status, BRAF status, pre-treatment LDH level, prior therapy status, and number and sites of metastases. Results 327 patients were identified, 87 with LM and 240 without LM. Patients with LM was associated with worse PFS [HR: 2.1, 95% CI, 1.5 – 3.1] (figure 1) and OS [HR: 3.4, 95% CI, 2.2 – 5.2] (figure 2). Respective 3-year PFS and OS estimates associated with anti-PD-1 monotherapy were 21.8% and 28.7% in patients with LM (figure 3, figure 4); and 36.5% and 57.6% without LM (figure 5, figure 6). Respective 3-year PFS and OS estimates associated with I/N were 46.7% and 56.7% in patients with LM; and 58.0% and 74.4% without LM. Conclusions In melanoma patients treated with PD-1 inhibitor-based regimens, the presence of LM leads to poorer survival outcomes. Our study suggests the poor prognosis associated with LM can be substantially mitigated by treatment with combination I/N over anti-PD-1 monotherapy. Further studies are warranted to investigate the anti-immunotherapy effect associated with LM. Ethics Approval The study was approved by the University of Michigan institutional ethical guidelines and patients‘ consents were waived following Institutional Review Board protocol review (HUM00156014). Reference Bilen MA, Shabto JM, Martini DJ, et al. Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy. BMC Cancer 2019; 19(1):857.

Nearly half of all metastatic melanoma patients possess the BRAF V600 mutation. Several therapies are approved for advanced stage melanoma, but it is unclear if there is a differential outcome to various immunotherapy regimens based on BRAF mutation status. We retrospectively analyzed a cohort of metastatic or unresectable melanoma patients who were treated with combination ipilimumab/nivolumab (ipi/nivo) or anti-PD-1 monotherapy, nivolumab, or pembrolizumab, as first-line treatment. 235 previously untreated patients were identified in our study. Our univariate analysis showed no statistical difference in progression-free survival (PFS) or overall survival (OS) with ipi/nivo versus anti-PD-1 monotherapy in the BRAF V600 mutant cohort, but there was improved PFS [HR: 0.48, 95% CI, 0.28-0.80] and OS [HR: 0.50, 95% CI, 0.26-0.96] with ipi/nivo compared to anti-PD-1 monotherapy in the BRAF WT group. After adjusting for known prognostic variables in our multivariable analysis, the BRAF WT cohort continued to show PFS and OS benefit with ipi/nivo compared to anti-PD-1 monotherapy. Our single-institution analysis suggests ipi/nivo should be considered over anti-PD-1 monotherapy as the initial immunotherapy regimen for metastatic melanoma patients regardless of BRAF mutation status, but possibly with greater benefit in BRAF WT.

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups. The randomized phase 2 trial S1320 comparing different dosing schedules of BRAF/MEK inhibitor combination in BRAF-mutated advanced melanoma shows intermittent therapy does not result in superior progression-free survival in patients.

Immune checkpoint inhibitors (ICIs) have been a transformational advance in cancer therapy in the past decade. However, ICIs can produce immune-related adverse effects (irAEs), which can lead to both morbidity and premature termination of therapy. Recent studies suggest that the gut microbiota and its metabolites affect ICI efficacy and toxicity. Herein, we review such evidence in the context of ICI-induced colitis. In particular, the short-chain fatty acid butyrate, a microbial metabolite, has known protective effects on the intestine. We discuss how the use of dietary prebiotics, which can be metabolized by bacteria to produce butyrate, can be an intriguing new investigational approach to prevent ICI-associated colitis and lead to improved patient outcomes.

PURPOSE Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti–PD-1 in the neoadjuvant setting for resectable MCC. METHODS In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies. RESULTS Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation. CONCLUSION Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.

Given the rarity of vaginal melanoma (VM), sparse retrospective data guide current clinical management. Standard treatment for localized disease involves wide local excision with negative margins, but due to multifocality of disease, local invasion, and anatomic constraints, it is often difficult to achieve negative margins without more extensive surgery including potentially pelvic exenteration. Additionally, despite aggressive loco-regional multi-modality therapy with surgery and with or without adjuvant radiation therapy (RT), outcomes remain poor for VM with high rates of distant recurrence. Radiation therapy has also evolved for melanoma, suggesting higher dose per fraction may overcome relative radioresistance and promote immunogenicity. More recently immunotherapy (IO) has shown promise in treating mucosal melanoma. As a result, treatment selection for these patients can be challenging given the needs to balance the morbidity of local therapies with propensity for distant metastatic disease and overall poor outcomes. Herein, we present two cases of vaginal melanoma treated at comprehensive cancer centers managed with a multi-modality approach of stereotactic body radiation therapy (SBRT) with concurrent IO with or without surgical debulking. Local treatment was safe and effective option for these patients with vaginal melanoma and can be considered in addition to enrollment on clinical trials during multi-disciplinary discussions of care.

Introduction L’essai de phase 3 CheckMate 067 a montre un benefice clinique durable et prolonge avec l’association nivolumab (NIVO) + ipilimumab (IPI) et avec NIVO seul vs IPI sur une periode de suivi de 5 ans (taux de survie globale [SG] et de survie sans progression [SSP] : 52 %, 44 %, 26 % et 36 %, 29 %, 8 %, respectivement). Sont presentees ici les donnees d’efficacite et de tolerance a 6,5 ans. Materiel et methodes Les patients (pts) eligibles presentant un melanome de stade III/IV non resecable, naifs de traitement, ont ete randomises selon un ratio 1 :1 :1, et stratifies selon le statut PD-L1, le statut mutationnel BRAF et le stade metastatique. Les pts ont recu 4 doses de NIVO 1 mg/kg + IPI 3 mg/kg Q3 W, puis NIVO 3 mg/kg Q2 W (n = 314), NIVO 3 mg/kg Q2W + placebo (n = 316), ou 4 doses d’IPI 3 mg/kg toutes Q3W + placebo (n = 315), jusqu’a progression ou toxicite non acceptable. Les co-criteres primaires d’evaluation etaient la SSP et la SG avec NIVO + IPI ou NIVO vs IPI. Les criteres d’evaluation secondaires incluaient le taux de reponses objectives (ORR), une analyse descriptive de l’efficacite de NIVO + IPI vs NIVO seul, et la tolerance. Resultats Apres un suivi minimum de 6,5 ans, la SG mediane etait de 72,1 mois avec NIVO + IPI, 36,9 mois avec NIVO, et 19,9 mois avec IPI (tableau). La mediane de l’intervalle entre randomisation et le traitement systemique ulterieur n’est pas atteinte avec NIVO + IPI (NA ; IC 95 %, 59,6–NA), mais elle est de 25,2 mois (IC 95 %, 16,0–43,2) avec NIVO, et de 8,0 mois (IC 95 %, 6,5–8,7) avec IPI ; respectivement 36 %, 49 %, et 66 % des pts de ces 3 groupes ont recu un traitement systemique ulterieur. La mediane de l’intervalle sans traitement (en excluant les pts ayant interrompu le suivi avant l’initiation du traitement ulterieur) etait de 27,6 mois (0–83,0), 2,3 mois (0,2–81,6), et 1,9 mois (0,1–81,9) avec NIVO + IPI, NIVO, et IPI, respectivement. Parmi les pts toujours suivis, 112/138 (81 % ; NIVO + IPI), 84/114 (74 % ; NIVO), et 27/63 (43 % ; IPI) n’ont plus de traitement et n’ont jamais recu de traitement ulterieur tandis que 7, 8, et 0 pts, respectivement, sont toujours sous traitement. La proportion de pts presentant des evenements indesirables de grade 3/4 lies au traitement est de 59 % avec NIVO + IPI, 24 % avec NIVO, et 28 % avec IPI. Depuis l’analyse a 5 ans, aucun nouveau signal de tolerance et aucun deces additionnel lie au traitement n’ont ete observes. Discussion A l’ere des combinaisons d’inhibiteurs de checkpoints et des therapies ciblees, cette analyse a 6,5 ans represente le suivi le plus long rapporte a partir d’un essai de phase 3 dans le melanome avance. Les resultats confirment la superiorite durable sur le long terme de l’utilisation en 1re ligne de NIVO + IPI ou NIVO sur celle d’IPI, et un benefice persistant de NIVO + IPI vs la monotherapie avec NIVO en termes de SG, SSP et ORR. © 2021 ASCO, Inc. Reused with permission. This abstract was presented at the 2021 ASCO. All rights reserved.

BACKGROUND KIT-directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT-mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun-damaged (CSD) melanoma. Dasatinib has superior preclinical activity in comparison with other tyrosine kinase inhibitors against cells with the most common KIT mutation, exon 11L576P. The ECOG-ACRIN E2607 trial assessed dasatinib in patients with these melanoma subtypes. METHODS Patients received 70 mg of oral dasatinib twice daily. The primary objective for this 2-stage phase 2 trial was response rate. Stage I was open to KIT+ and wild-type KIT (KIT–) mucosal, acral, and CSD melanoma (n = 57). Stage II accrued only KIT+ tumors (n = 30). To enrich the trial for KIT+ tumors, vulvovaginal melanoma was added, and CSD melanoma was removed from eligibility. Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. RESULTS From May 2009 to December 2010, the first stage enrolled 57 patients. Among the evaluable patients, 3 of 51 (5.9%) achieved a partial response: all were KIT–. Stage II closed early because of slow accrual (November 2011 to December 2015). In stage II, 4 of 22 evaluable patients (18.2%) had a partial response; the median duration was 4.2 months. The median PFS was 2.1 months (n = 73; 95% confidence interval [CI], 1.5-2.9 months). The median OS was 7.5 months (95% CI, 6.0-11.9 months). In exploratory analyses, no differences were seen in PFS or OS with the KIT status or subtype. Dasatinib was discontinued because of adverse events in 9 of 75 patients (12%). CONCLUSIONS The dasatinib response rate among KIT+ melanoma patients was low. In view of its clinical activity, it is recommended that imatinib remain the KIT tyrosine kinase inhibitor of choice for unresectable KIT+ melanoma. Cancer 2017;123:2688-97. © 2017 American Cancer Society.

BACKGROUND Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

9506 Background: In the phase 3 CheckMate 067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) + ipilimumab (IPI) and NIVO alone vs IPI at 5-y of follow-up (overall survival [OS] and progression-free survival [PFS] rates: 52%, 44%, 26% and 36%, 29%, 8%, respectively). Here we report 6.5-y efficacy and safety outcomes. Methods: Eligible pts with previously untreated unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio and stratified by PD-L1 status, BRAF mutation status, and metastasis stage. Pts received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W (n = 314), NIVO 3 mg/kg Q2W + placebo (n = 316), or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were PFS and OS with NIVO + IPI or NIVO vs IPI. Secondary endpoints included objective response rate (ORR), descriptive efficacy assessments of NIVO + IPI vs NIVO alone, and safety. Results: With a minimum follow-up of 6.5 y, median OS was 72.1 mo with NIVO + IPI, 36.9 mo with NIVO, and 19.9 mo with IPI (table). Median time from randomization to subsequent systemic therapy was not reached (NR; 95% CI, 59.6–NR) with NIVO + IPI, 25.2 mo (95% CI, 16.0–43.2) with NIVO, and 8.0 mo (95% CI, 6.5–8.7) with IPI; 36%, 49%, and 66% of pts, respectively, received any subsequent systemic therapy. Median treatment-free interval (which excluded pts who discontinued follow-up prior to initiation of subsequent systemic therapy) was 27.6 mo (range, 0–83.0), 2.3 mo (range, 0.2–81.6), and 1.9 mo (range, 0.1–81.9) with NIVO + IPI, NIVO, and IPI, respectively. Of the pts alive and in follow-up, 112/138 (81%; NIVO + IPI), 84/114 (74%; NIVO), and 27/63 (43%; IPI) were off treatment and never received subsequent systemic therapy; 7, 8, and 0 pts, respectively, were still on treatment. Grade 3/4 treatment-related adverse events were reported in 59% of NIVO + IPI-treated pts, 24% of NIVO-treated pts, and 28% of IPI-treated pts. Since the 5-y analysis, no new safety signals were observed and no additional treatment-related deaths occurred. Conclusions: This 6.5-y analysis represents the longest follow-up from a phase 3 melanoma trial in the modern checkpoint inhibitor combination therapy and targeted therapy era. The results show durable improved outcomes with NIVO + IPI and NIVO vs IPI in pts with advanced melanoma. We observed improvement in OS, PFS, and ORR with NIVO + IPI over NIVO alone. Clinical trial information: NCT01844505. [Table: see text]

9549 Background: Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis. Results: 199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.23, 95% CI 0.14-0.39; p

Key Points Question Is the American Joint Committee on Cancer (AJCC) eighth edition staging of metastatic cutaneous melanoma prognostic in the era of immune checkpoint inhibition? Findings In this cohort study of 357 patients with metastatic cutaneous melanoma treated with immune checkpoint inhibitors, the AJCC eighth edition M staging showed limited prognostic stratification; however, the overall survival rates among patients with liver metastases and those with elevated serum lactate dehydrogenase (LDH) levels were much worse than among patients with metastatic involvement of other organs and those with serum LDH levels in the reference range. The importance of these factors was confirmed in a multi-institutional external validation cohort. Meaning These findings suggest that other biomarkers that are associated with overall survival, such as liver metastases and LDH level, should be considered for emphasis in future staging systems., This cohort study evaluates the outcomes of patients with metastatic cutaneous melanoma based on the M stage category from the American Joint Committee on Cancer (AJCC) eighth edition and determines whether these designations continue to inform the prognosis of patients who have received immune checkpoint inhibitors (ICIs)., Importance Immune checkpoint inhibitors (ICIs) have transformed the survival of patients with metastatic melanoma. Patient prognosis is reflected by the American Joint Committee on Cancer (AJCC) staging system; however, it is unknown whether the metastatic (M) stage categories for cutaneous melanoma remain informative of prognosis in patients who have received ICIs. Objectives To evaluate the outcomes of patients with metastatic cutaneous melanoma based on the M stage category from the AJCC eighth edition and to determine whether these designations continue to inform the prognosis of patients who have received ICIs. Design, Setting, and Participants This cohort study included patients with metastatic cutaneous melanoma who were treated between August 2006 and August 2019 at the University of Michigan. The estimated median follow-up time was 35.5 months. Patient data were collected via the electronic medical record system. Critical findings were externally validated in a multicenter nationwide cohort of patients treated within the Veterans Affairs health care system. Data analysis was conducted from February 2020 to January 2021. Exposures All patients were treated with dual-agent concurrent ipilimumab and nivolumab followed by maintenance nivolumab or single-agent ipilimumab, nivolumab, or pembrolizumab therapy. Patients were staged using the AJCC eighth edition. Main Outcomes and Measures Univariable and multivariable analyses were used to assess the prognostic value of predefined clinicopathologic baseline factors on survival. Results In a discovery cohort of 357 patients (mean [SD] age, 62.6 [14.2] years; 254 [71.1%] men) with metastatic cutaneous melanoma treated with ICIs, the M category in the AJCC eighth edition showed limited prognostic stratification by both univariable and multivariable analyses. The presence of liver metastases and elevated levels of serum lactate dehydrogenase (LDH) offered superior prognostic separation compared with the M category (liver metastases: hazard ratio, 2.22; 95% CI, 1.48-3.33; P

Immune checkpoint inhibitors have emerged as a mainstay of melanoma therapy and are playing an increasingly important role in the treatment of other tumor types. The clinical benefit afforded by these treatments can be accompanied by a unique spectrum of adverse events, called immune-related adverse events (irAEs), which reflect the drug's immune-based mechanism of action. IrAEs typically originate in the skin, gastrointestinal tract, liver, and endocrine system, although other organ systems may also be affected. This article provides an overview of irAEs associated with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab and pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab), followed by a discussion of irAEs of special clinical interest based on the potential for morbidity, frequent steroid use, and inpatient admission. We review clinical trial data and provide recommendations on how to manage irAEs associated with anti-PD-1 agents based on clinical experience and established management guidelines. We further illustrate the practical considerations of managing irAEs by presenting three cases of immune-related toxicity in melanoma patients treated with nivolumab or pembrolizumab. A better understanding of the identification and management of irAEs will help inform health care providers about the risks associated with anti-PD-1 treatment, to ensure the safe and appropriate use of these important new treatments. Implications for practice Immune checkpoint inhibitors have demonstrated significant clinical benefit in advanced melanoma and other tumor types. These treatments are associated with immune-related adverse events (irAEs), which most commonly affect the skin and gastrointestinal tract, and, to a lesser extent, the liver, endocrine system, and other organs. This review focuses on the management of irAEs after treatment with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab or pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab) in patients with advanced melanoma. A better understanding of the management of irAEs will help ensure the safe and appropriate use of anti-PD-1 agents in melanoma and other tumor types.

BACKGROUND: Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with RRx-001 and whole brain radiotherapy (WBRT) without neurologic or systemic toxicity in the context of a phase I/II clinical trial. RRx-001 is an reactive oxygen and reactive nitrogen species (ROS/RNS)-dependent systemically nontoxic hypoxic cell radiosensitizer with vascular normalizing properties under investigation in patients with various solid tumors including those with brain metastases. SIGNIFICANCE: Metastatic melanoma to the brain is historically associated with poor outcomes and a median survival of 4 to 5 months. WBRT is a mainstay of treatment for patients with multiple brain metastases, but no significant therapeutic advances for these patients have been described in the literature. To date, candidate radiosensitizing agents have failed to demonstrate a survival benefit in patients with brain metastases, and in particular, no agent has demonstrated improved outcome in patients with metastatic melanoma. Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with novel radiosensitizing agent RRx-001 and WBRT without neurologic or systemic toxicity in the context of a phase I/II clinical trial.

Overall cancer incidence is decreasing, whereas melanoma cases are increasing. Conditional survival estimates offer a more accurate prognosis for patients the farther they are from time of diagnosis. The effect of age and stage on a melanoma patient's conditional survival estimate is unknown. Surveillance, Epidemiology, and End Results data were utilized to identify newly diagnosed cutaneous melanoma patients (N=95 041), from 1998 to 2005, with up to 12 years of follow-up. Estimates of disease-specific survival by stage and age were determined by Cox regression analysis and transformed to estimated conditional 5-year survival. Localized melanoma patients have an excellent 5-year survival at diagnosis and over subsequent years. For patients with localized and regional disease, an age effect is present for disease-specific mortality when comparing older patients (70-79 years) with younger patients (