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BACKGROUND: Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoints. The safety and efficacy of davoceticept monotherapy and davoceticept and pembrolizumab combination therapy in adult patients with advanced solid tumors were explored in NEON-1 and NEON-2, respectively. METHODS: In NEON-1 (n=58), davoceticept 0.001-10 mg/kg was administered intravenous either once weekly (Q1W) or once every 3 weeks (Q3W). In NEON-2 (n=29), davoceticept was administered intravenously at 2 dose levels (0.1 or 0.3 mg/kg) Q1W or Q3W with pembrolizumab (400 mg once every 6 weeks). In both studies, primary endpoints included incidence of dose-limiting toxicities (DLT); type, incidence, and severity of adverse events (AEs) and laboratory abnormalities; and seriousness of AEs. Secondary endpoints included antitumor efficacy assessed using RECIST v1.1, pharmacokinetics, anti-drug antibodies, and pharmacodynamic biomarkers. RESULTS: The incidence of treatment-related AEs (TRAEs) and immune-related adverse events (irAEs) was 67% (39/58) and 36% (21/58) with davoceticept monotherapy, and 62% (18/29) and 31% (9/29) with davoceticept and pembrolizumab combination, respectively. The incidence of ≥grade (Gr)3 TRAEs and ≥Gr3 irAEs was 12% (7/58) and 5% (3/58) with davoceticept monotherapy, and 24% (7/29) and 10% (3/29) with davoceticept and pembrolizumab combination, respectively. One DLT of Gr3 immune-related gastritis occurred during davoceticept monotherapy 3 mg/kg Q3W. During davoceticept combination with pembrolizumab, two Gr5 cardiac DLTs occurred; one instance each of cardiogenic shock (0.3 mg/kg Q3W, choroidal melanoma metastatic to the liver) and immune-mediated myocarditis (0.1 mg/kg Q3W, microsatellite stable metastatic colorectal adenocarcinoma), prompting early termination of both studies. Across both studies, five patients with renal cell carcinoma (RCC) exhibited evidence of clinical benefit (two partial response, three stable disease). CONCLUSIONS: Davoceticept was generally well tolerated as monotherapy at intravenous doses up to 10 mg/kg. Evidence of clinical activity was observed with davoceticept monotherapy and davoceticept in combination with pembrolizumab, notably in RCC. However, two fatal cardiac events occurred with the combination of low-dose davoceticept and pembrolizumab. Future clinical investigation with davoceticept should not consider combination with programmed death-1-inhibitor anticancer mechanisms, until its safety profile is more fully elucidated. TRIAL REGISTRATION NUMBER: NEON-1 (NCT04186637) and NEON-2 (NCT04920383).
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Anticuerpos Monoclonales Humanizados , Antígeno CTLA-4 , Neoplasias , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Masculino , Femenino , Neoplasias/tratamiento farmacológico , Persona de Mediana Edad , Anciano , Adulto , Antígeno CTLA-4/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Anciano de 80 o más Años , Antígenos CD28RESUMEN
Despite remarkable advances in immunotherapy, melanoma remains a significant cause of cancer mortality. Many factors concerning melanoma mortality are poorly understood, posing an obstacle to optimal care. We conducted a retrospective observational cohort study of 183 patients with metastatic melanoma who died following immunotherapy treatment to investigate sites of metastases at death, settings of death, and mechanisms of death. The median time from metastatic diagnosis to death was 16.1 months (range 0.3-135.1 months). Most patients experienced hospitalization within 3 months before death (80.3%), with 31.7% dying while hospitalized, 31.2% while in inpatient hospice, and 29.4% while in home hospice. The most common sites of metastases at death were distant lymph nodes (62.8%), lung (57.9%), liver (50.8%), brain (38.8%), and bone (37.7%). The most common causes of death were progressive failure to thrive (57.5%), respiratory failure (22.4%), and infection (21.8%); the vast majority (87.9%) of patients died from melanoma-specific causes. Overall, 10.9% of patients in our cohort had survival >5 years after metastatic diagnosis, and 76.2% of long-term survivors died due to melanoma. This study describes factors associated with melanoma mortality, highlighting an ongoing need for therapeutic advancements.
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The clinical research pipeline is critical to ensuring continued development of novel treatments that can offer patients with cancer safe and effective options. Unfortunately, progress has slowed since the COVID-19 pandemic due to uncovered, systemic inefficiencies across critical processes. Towards initiating discussion on how to reinvigorate clinical research, the Society for Immunotherapy of Cancer (SITC) hosted a virtual summit that characterized issues and formed potential solutions. This commentary serves to highlight the crisis facing clinical research as well as stimulate field-wide discussion on how to better serve patients into the future.
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Investigación Biomédica , COVID-19 , Inmunoterapia , Neoplasias , SARS-CoV-2 , Humanos , COVID-19/epidemiología , SARS-CoV-2/inmunología , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , PandemiasRESUMEN
Background: Immunotherapy agents are approved for adjuvant treatment of stage III melanoma; however, evidence for survival benefit in early stage III disease is lacking. Current guidelines for adjuvant immunotherapy utilization in stage IIIA rely on clinician judgment, creating an opportunity for significant variation in prescribing patterns. This study aimed to characterize current immunotherapy practice variations and to compare patient outcomes for different prescribing practices in stage IIIA melanoma. Study design: Patients with melanoma diagnosed from 2015-2019 that met American Joint Committee on Cancer 8th edition criteria for stage IIIA and underwent resection were identified in the National Cancer Database. Multiple imputation by chained equations replaced missing values. Factors associated with receipt of adjuvant immunotherapy were identified. Multivariable Cox proportional hazards regression compared overall survival across groups. Results: Of 4,432 patients included in the study, 34% received adjuvant immunotherapy. Patients had lower risk-adjusted odds of receiving immunotherapy if they were treated at an academic center (OR=0.48, 95%CI=0.33-0.72, p<0.001 vs. community facility) or at a high-volume center (OR=0.69, 0.56-0.84, p<0.001 vs. low-volume). Immunotherapy receipt was not associated with risk-adjusted survival (p=0.095). Moreover, patients treated at high-volume centers experienced longer overall risk-adjusted survival than those treated at low-volume centers (HR=0.52, 0.29-0.93, p=0.030). Risk-adjusted survival trended toward being longer at academic centers than at community centers, but the difference was not statistically significant. Conclusion: Academic and high-volume centers utilize significantly less adjuvant immunotherapy in stage IIIA melanoma than community and low-volume centers without compromise in overall survival. These findings suggest that this population may benefit from more judicious immunotherapy utilization.
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Despite the remarkable success of anti-cancer immunotherapy, its effectiveness remains confined to a subset of patients-emphasizing the importance of predictive biomarkers in clinical decision-making and further mechanistic understanding of treatment response. Current biomarkers, however, lack the power required to accurately stratify patients. Here, we identify interferon-stimulated, Ly6Ehi neutrophils as a blood-borne biomarker of anti-PD1 response in mice at baseline. Ly6Ehi neutrophils are induced by tumor-intrinsic activation of the STING (stimulator of interferon genes) signaling pathway and possess the ability to directly sensitize otherwise non-responsive tumors to anti-PD1 therapy, in part through IL12b-dependent activation of cytotoxic T cells. By translating our pre-clinical findings to a cohort of patients with non-small cell lung cancer and melanoma (n = 109), and to public data (n = 1440), we demonstrate the ability of Ly6Ehi neutrophils to predict immunotherapy response in humans with high accuracy (average AUC ≈ 0.9). Overall, our study identifies a functionally active biomarker for use in both mice and humans.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Ratones , Animales , Interferones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neutrófilos/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Biomarcadores , InmunoterapiaRESUMEN
While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for molecular residual disease (MRD) detection, its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read level, achieving an error rate of 4.2×10 -7 , which is about two orders of magnitude lower than a read-centric de-noising method. When applied to MRD detection, AccuScan demonstrated analytical sensitivity down to 10 -6 circulating tumor allele fraction at 99% sample level specificity. In colorectal cancer, AccuScan showed 90% landmark sensitivity for predicting relapse. It also showed robust MRD performance with esophageal cancer using samples collected as early as 1 week after surgery, and predictive value for immunotherapy monitoring with melanoma patients. Overall, AccuScan provides a highly accurate WGS solution for MRD, empowering circulating tumor DNA detection at parts per million range without high sample input nor personalized reagents. One Sentence Summary: AccuScan showed remarkable ultra-low limit of detection with a short turnaround time, low sample requirement and a simple workflow for MRD detection.
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Importance: While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. Objective: To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Design, Setting, and Participants: Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Exposures: Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main Outcomes and Measures: Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Results: Overall, data for 242â¯371 patients were analyzed. The study included 20â¯415 patients with stage IV melanoma, 197â¯331 patients with stage IV NSCLC, and 24â¯625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Conclusions and Relevance: Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Melanoma , Humanos , Masculino , Anciano , Femenino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estudios de Cohortes , Estudios Retrospectivos , Neoplasias Pulmonares/tratamiento farmacológico , Disparidades en Atención de Salud , Inmunoterapia , MuerteRESUMEN
Prospective and between trial comparisons indicate that first-line treatment with immune checkpoint inhibitors improves survival outcomes compared to first-line therapy with combined BRAF and MEK inhibitors in metastatic melanoma containing BRAFV600E/K mutations. Long-term outcomes for BRAF/MEK inhibition after progression on immunotherapy have not been reported. Moreover, clinical variables associated with outcome from treatment with combined BRAF/MEK inhibition were previously identified in the first-line setting but have not been investigated when targeted therapies are administered after progression on immune therapy. We performed a retrospective single institution analysis of 40 metastatic melanoma patients receiving combined BRAF/MEK inhibitors after progression on an anti-PD-1 or ipilimumab plus nivolumab to assess response rate by RECIST 1.1, progression-free and overall survival (PFS and OS). Pretreatment clinical variables were analyzed for association with OS. Ipilimumab/nivolumab was the first-line immunotherapy regimen in 39 patients (97.5%), and BRAFV600E/K mutations were present in 33 (83%) and 7 (17%) patients, respectively. The median OS from start of BRAF/MEK inhibitors was 20.3 months (1.73-106.4+, 95% CI of median 13.3-30.7). Clinical characteristics associated with worse survival prior to starting BRAF/MEK inhibitors included ageâ >â 60 years (median OS 14 vs. 28 months; HR 2.5; 95% CI 0.91-6.87, Pâ =â .023), ECOG-PSâ >â 2 (median OS 7 vs. 33 months; HR 2.89; 95% CI 0.78-10.76, Pâ =â .018), and presence of bone metastases (median OS 9 vs. 52 months; HR 3.17; 95% CI 1.33-7.54, Pâ =â .002). These associations with shorter survival maintained their significance on multivariate analysis. If confirmed in larger cohorts, the identified prognostic variables can be used for stratification of patients in future randomized trials.
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Melanoma , Neoplasias Cutáneas , Humanos , Persona de Mediana Edad , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Nivolumab/uso terapéutico , Estudios Retrospectivos , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
PURPOSE: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a unique epitope specificity and Fc receptor binding profile optimized for activation of CD40-expressing antigen-presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase II trial to evaluate the combination of sotigalimab 0.3 mg/kg and nivolumab 360 mg every 3 weeks in patients with advanced melanoma following confirmed disease progression on a PD-1 inhibitor. The primary objective was to determine the objective response rate (ORR). RESULTS: Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months, whereas the other three responders relapsed at 41.1, 18.7, and 18.4 months. The median duration of response was at least 26 months. Two additional patients had stable disease for >6 months. Thirty-four patients (89%) experienced at least one adverse event (AE), and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs. CONCLUSIONS: Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting. See related commentary by Wu and Luke, p. 9.
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Melanoma , Nivolumab , Humanos , Nivolumab/efectos adversos , Melanoma/patología , Anticuerpos Monoclonales/efectos adversos , Progresión de la Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Stimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma. METHODS: We employed a Simon's two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects. RESULTS: Thirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses. CONCLUSIONS: Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03502330.
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Anticuerpos Monoclonales , Melanoma , Humanos , Animales , Ratones , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Nivolumab/uso terapéutico , Melanoma/patología , Proteínas Tirosina Quinasas ReceptorasRESUMEN
PURPOSE: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma. METHODS: Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and exploratory end points included additional efficacy measures, safety, and pharmacokinetics (PKs) and pharmacodynamics analyses. RESULTS: In 783 patients (n = 391, BEMPEG plus NIVO; n = 392, NIVO monotherapy), the median follow-up was 11.6 months in the intent-to-treat population. The ORR with BEMPEG plus NIVO was 27.7% versus 36.0% with NIVO (two-sided P = .0311). The median PFS with BEMPEG plus NIVO was 4.17 months (95% CI, 3.52 to 5.55) versus 4.99 months (95% CI, 4.14 to 7.82) with NIVO (hazard ratio [HR], 1.09; 97% CI, 0.88 to 1.35; P = .3988). The median OS was 29.67 months (95% CI, 22.14 to not reached [NR]) with BEMPEG plus NIVO versus 28.88 months (95% CI, 21.32 to NR) with NIVO (HR, 0.94; 99.929% CI, 0.59 to 1.48; P = .6361). Grade 3-4 treatment-related adverse events (AEs) and serious AE rates were higher with the combination (21.7% and 10.1%, respectively) versus NIVO (11.5% and 5.5%, respectively). BEMPEG PK exposure and absolute lymphocyte count changes after BEMPEG plus NIVO were comparable between PIVOT IO 001 and PIVOT-02. CONCLUSION: The PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.
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Melanoma , Nivolumab , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ipilimumab , Melanoma/patología , Nivolumab/uso terapéuticoRESUMEN
Immune-related toxicities, otherwise known as immune-related adverse events (irAEs), occur in a substantial fraction of cancer patients treated with immune checkpoint inhibitors (ICIs). Ranging from asymptomatic to life-threatening, ICI-induced irAEs can result in hospital admission, high-dose corticosteroid treatment, ICI discontinuation, and in some cases, death. A deeper understanding of the factors underpinning severe irAE development will be essential for improved irAE prediction and prevention, toward maximizing the benefits and safety profiles of ICIs. In recent work, we applied mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing, and bulk T-cell receptor (TCR) sequencing to identify pretreatment determinants of severe irAE development in patients with advanced melanoma. Across 71 patients separated into three cohorts, we found that two baseline features in circulation-elevated activated CD4 effector memory T-cell abundance and TCR diversity-are associated with severe irAE development, independent of the affected organ system within 3 months of ICI treatment initiation. Here, we provide an extended perspective on this work, synthesize and discuss related literature, and summarize practical considerations for clinical translation. Collectively, these findings lay a foundation for data-driven and mechanistic insights into irAE development, with the potential to reduce ICI morbidity and mortality in the future.
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Antineoplásicos Inmunológicos , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Linfocitos T CD4-Positivos , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: Despite improvements in the treatment of primary uveal melanoma (UM), patients with metastatic disease continue to exhibit poor survival. METHODS: A retrospective review of metastatic UM patients at Yale (initial cohort) and Memorial Sloan Kettering (validation cohort) was conducted. Cox proportional hazards regression was used to determine baseline factors that are associated with overall survival, including sex, Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, laboratory measurements, metastasis location, and use of anti-CTLA-4 and anti-PD-1 therapies. Differences in overall survival were analyzed using Kaplan-Meier analysis. RESULTS: A total of 89 patients with metastatic UM were identified; 71 and 18, in the initial and validation cohorts, respectively. In the initial cohort, median follow-up was 19.8 months (range, 2-127 months) and median overall survival was 21.8 months (95% CI, 16.6-31.3). Female sex, anti-CTLA-4, and anti-PD-1 therapy were associated with better survival outcomes with adjusted death hazard ratios (HRs) of 0.40 (95% CI, 0.20-0.78), 0.44 (0.20-0.97), and 0.42 (0.22-0.84), respectively, whereas development of hepatic metastases and ECOG score ≥1 (per 1 U/L) were associated with worse survival outcomes with HRs of 2.86 (1.28-7.13) and 2.84 (1.29-6.09), respectively. In both the initial and validation cohorts, use of immune checkpoint inhibitors was associated with improved overall survival after adjusting for sex and ECOG score, with death HRs of 0.22 (0.08-0.56) and 0.04 (0.002-0.26), respectively. CONCLUSIONS: Development of extrahepatic-only metastases, ECOG of 0, immune checkpoint therapy, and female sex were each associated with more than 2-fold reductions in risk of death. PLAIN LANGUAGE SUMMARY: Metastatic uveal melanoma patients face limited treatment options and poor survival rates. Results from this retrospective analysis indicate that immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 therapies, were associated with improved survival outcomes. Factors such as extrahepatic-only metastases, better baseline performance status, and female sex contributed to a more than 2-fold reduction in death risk. These findings highlight the potential of immunotherapy in treating metastatic uveal melanoma.
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Melanoma , Neoplasias de la Úvea , Humanos , Femenino , Ipilimumab/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , Melanoma/tratamiento farmacológicoRESUMEN
PURPOSE: IFN signaling in the tumor microenvironment is a critical determinant of both response and resistance of cancer to immune checkpoint inhibitors (ICI). We hypothesized that distinct patterns of IFN signaling in melanoma are associated with clinical response or resistance to ICIs. EXPERIMENTAL DESIGN: Two tissue microarrays containing samples from 97 patients with metastatic melanoma who received nivolumab, pembrolizumab, or a combination of ipilimumab and nivolumab at Yale New Haven Hospital between 2011 and 2017 were randomized into discovery and validation cohorts. Samples were stained and visualized using multiplexed immunofluorescence microscopy for STAT1, STAT1 phosphorylated at Y701 (pSTAT1Y701), and PD-L1, and signals were quantified using the automated quantitative analysis method of quantitative immunofluorescence. Treatment response was assessed using RECIST, and overall survival was analyzed. For in vitro studies, human melanoma cell lines were stimulated with IFNγ and IFNß, and Western blotting was performed. RESULTS: Pretreatment STAT1 levels were higher in responders to ICIs [complete response/partial response/stable disease (SD) for > 6 months] than in nonresponders (SD < 6 months/progressive disease). Higher pretreatment STAT1 levels were associated with improved survival after ICIs in both the discovery and validation cohorts. Western blot analysis of human melanoma cell lines stimulated with IFN demonstrated distinct patterns of upregulation of STAT1 compared with pSTAT1Y701 and PD-L1. When combining STAT1 and PD-L1 markers, patients with STAT1highPD-L1low tumors had improved survival compared with those with STAT1lowPD-L1high tumors. CONCLUSIONS: STAT1 may better predict melanoma response to ICIs than current strategies, and combined STAT1 and PD-L1 biomarkers may provide insight into IFN-responsive versus IFN-resistant states.
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Melanoma , Nivolumab , Humanos , Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/uso terapéutico , Melanoma/patología , Nivolumab/uso terapéutico , Microambiente TumoralRESUMEN
BACKGROUND: In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab. METHODS: In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1-4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated. RESULTS: At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug-drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges. CONCLUSIONS: M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Medicina Estatal , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Interleucina-12RESUMEN
PURPOSE: To validate the prognostic usefulness of gene expression profile (GEP) testing in patients with uveal melanoma. To determine whether combining tumor size with the GEP classification provides additional prognostic value. DESIGN: Retrospective analysis. PARTICIPANTS: Patients with a diagnosis of choroidal melanoma examined at Yale New Haven Hospital; University of California, San Diego; and Memorial Sloan Kettering Cancer Center. METHODS: Patients' demographic and clinical data and tumor characteristics were collected. Univariate and multivariate Cox hazard regression analysis were used to assess the association between tumor characteristics and GEP classification with metastasis as an outcome. MAIN OUTCOME MEASURES: Metastasis-free survival (MFS). RESULTS: Of the 337 individuals included in the study, 87 demonstrated metastases. The mean follow-up time was 37.2 (standard deviation [SD], 40.2) months for patients with metastases and 55.0 (SD, 49.3) months for those without metastases. Tumors of larger thickness and GEP class 2 (vs. class 1) were associated significantly with increased risk of metastasis. Tumor thickness showed better prognostic usefulness than GEP classification (Wald statistic, 40.7 and 24.2, respectively). Class 2 tumors with a thickness of 7.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 7.0 mm (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.61-6.51), whereas class 1 tumors with a thickness of 9.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 9.0 mm (HR, 2.07; 95% CI, 0.86-4.99). No difference in MFS was found between patients with class 1A tumors compared with those with class 1B tumors (P = 0.8). Patients with class 2 tumors showed an observed 5-year MFS of 47.5% (95% CI, 36.0%-62.8%). CONCLUSIONS: Tumor size was the most significant predictor of metastasis and provided additional prognostic value independent of GEP classification. In addition, rates of metastasis for class 2 tumors were lower than estimates reported by Castle Bioscience, and no difference in rates of metastasis were found between class 1A and 1B tumors. This indicates that tumor size should be accounted for when relying on GEP for prognostication and that patients with GEP class 1A or 1B tumors may benefit from the same metastatic surveillance protocols. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Asunto(s)
Melanoma , Neoplasias de la Úvea , Humanos , Pronóstico , Estudios Retrospectivos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/metabolismo , Neoplasias de la Úvea/diagnóstico , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/patología , Perfilación de la Expresión Génica/métodosRESUMEN
PURPOSE: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. PATIENTS AND METHODS: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. RESULTS: Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. CONCLUSION: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.
RESUMEN
Various approaches are being explored to address the unmet medical need among patients with advanced cancer who do not respond to immune checkpoint inhibitors. Interleukin-2 has become a prominent focus of preclinical and clinical investigation, because of its known clinical activity, the important role of this cytokine in immune biology, and the ability to engineer variant proteins with potentially improved antitumor immunomodulatory activity and reduced toxicity. Bempegaldesleukin, the first of the modified IL-2 agents to reach phase 3 evaluation in combination with an anti-PD-1, did not improve outcome for patients with metastatic melanoma and renal carcinoma. The disappointing data raise important questions about the potential efficacy of other interleukin-2 variants, however, several of the other variants appear to be sufficiently differentiated in anticipated pharmacokinetic properties and immune modulatory effects to warrant continued clinical development.