RESUMEN
BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Adyuvantes Inmunológicos/uso terapéutico , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/cirugía , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/cirugíaRESUMEN
PURPOSE OF REVIEW: Until recently, metastatic uveal melanoma was associated with essentially uniform fatality within months. However, recent developments in screening, improved understanding of the genetic underpinnings of metastatic disease, and pivotal medication approvals have improved the disease's rate of fatality. RECENT FINDINGS: Routine implementation of genetic testing at the time of primary tumor treatment via gene expression profiling or chromosomal analysis has identified patients who are at high risk for metastatic disease. Enhanced screening with imaging directed at the liver and lungs has allowed for identification of early disease and lower tumor burden. Significant work on improved liver directed therapy along with systemic chemotherapy and immunotherapy has improved life expectancy. The first systemic immunotherapy specifically for metastatic uveal melanoma was approved this year. This medication, tebentafusp, is likely to improve life expectancy for all patients with metastatic melanoma assuming they have appropriate human leukocyte antigen (HLA) markers. Multiple clinical trials with novel immunotherapeutic agents are promising as well. SUMMARY: The prognosis for patients with uveal melanoma is far better than ever before because of recent developments in the understanding and treatment of metastatic disease.
Asunto(s)
Melanoma , Neoplasias de la Úvea , Humanos , Melanoma/genética , Melanoma/terapia , Pronóstico , Proteínas Recombinantes de Fusión , Neoplasias de la Úvea/genéticaRESUMEN
Despite the significant progress in the treatment of unresectable or metastatic BRAF V600-mutant melanoma, there remains two primary treatment options: targeted therapy and immunotherapy. Targeted therapy or immunotherapy alone is associated with efficacy limitations including efficacy limited to select patient subsets. With separate mechanisms of action and different response patterns, the combination of targeted agents and immunotherapy to treat patients with BRAF V600-mutant melanoma may further improve patient outcomes. Current treatment guidelines recommend treatment with targeted agents alone, immunotherapy, or the combination of targeted agents and immunotherapy. The randomized, double-blind STARBOARD trial aims to evaluate efficacy and safety of encorafenib, binimetinib and pembrolizumab in treatment-naive patients with metastatic or unresectable locally advanced BRAF V600-mutant melanoma in comparison to pembrolizumab.
Targeted therapy, including BRAF- and MEK-inhibitors, and immunotherapies have greatly contributed to advances in the treatment of BRAF-mutant melanoma. Additionally, immunotherapy in combination with targeted therapy has been shown to improve patient outcomes. In this study, the authors assess the efficacy and safety of a combination of a BRAF-inhibitor (encorafenib), an MEK-inhibitor (binimetinib) and an anti-PD-1 (pembrolizumab) in patients with metastatic BRAF-mutant melanoma. Clinical Trial Registration: NCT04657991 (ClinicalTrials.gov).
Asunto(s)
Melanoma , Neoplasias Primarias Secundarias , Neoplasias Cutáneas , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles , Carbamatos , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Mutación , Neoplasias Primarias Secundarias/etiología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , SulfonamidasRESUMEN
BACKGROUND: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. METHODS: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study. FINDINGS: The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66-0·90] for progression-free survival and 0·74 [0·58-0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57-0·91] for progression-free survival and 0·60 [0·45-0·79] for overall survival) and immunotherapy (HR 0·75 [0·56-1·00] and 0·64 [0·47-0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65-1·17, pinteraction=0·61] for progression-free survival and 1·03 [0·80-1·34, pinteraction=0·01] for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40-0·70]), but no associations observed in women (HR 0·85 [0·61-1·18, pinteraction=0·03]). INTERPRETATION: Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Índice de Masa Corporal , Melanoma/tratamiento farmacológico , Terapia Molecular Dirigida , Obesidad/epidemiología , Neoplasias Cutáneas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Terapia Molecular Dirigida/efectos adversos , Terapia Molecular Dirigida/mortalidad , Obesidad/diagnóstico , Obesidad/mortalidad , Supervivencia sin Progresión , Factores Protectores , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC. MATERIALS AND METHODS: This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1-5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy. RESULTS: Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8-8.3). The clinical benefit rate was 57% (95% CI: 43-70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease. CONCLUSION: In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC.
Asunto(s)
Carcinoma Adenoide Quístico , Humanos , Carcinoma Adenoide Quístico/tratamiento farmacológico , Proteína-Arginina N-Metiltransferasas , Recurrencia Local de Neoplasia , Supervivencia sin ProgresiónRESUMEN
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).
Asunto(s)
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
Introduction: Although checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy. Methods: TYRP1-TCB (RO7293583; RG6232) is a T-cell engaging bispecific (TCB) antibody that targets tyrosinase-related protein 1 (TYRP1), which is expressed in many melanomas, thereby directing T cells to kill TYRP1-expressing tumor cells. Preclinical studies show TYRP1-TCB to have potent anti-tumor activity. This first-in-human (FIH) phase 1 dose-escalation study characterized the safety, tolerability, maximum tolerated dose/optimal biological dose, and pharmacokinetics (PK) of TYRP1-TCB in patients with metastatic melanoma (NCT04551352). Results: Twenty participants with cutaneous, uveal, or mucosal TYRP1-positive melanoma received TYRP1-TCB in escalating doses (0.045 to 0.4 mg). All participants experienced ≥1 treatment-related adverse event (TRAE); two participants experienced grade 3 TRAEs. The most common toxicities were grade 1-2 cytokine release syndrome (CRS) and rash. Fractionated dosing mitigated CRS and was associated with lower levels of interleukin-6 and tumor necrosis factor-alpha. Measurement of active drug (dual TYPR1- and CD3-binding) PK rapidly identified loss of active drug exposure in all participants treated with 0.4 mg in a flat dosing schedule for ≥3 cycles. Loss of exposure was associated with development of ADAs towards both the TYRP1 and CD3 domains. A total drug PK assay, measuring free and ADA-bound forms, demonstrated that TYRP1-TCB-ADA immune complexes were present in participant samples, but showed no drug activity in vitro. Discussion: This study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed.
RESUMEN
PURPOSE: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents. EXPERIMENTAL DESIGN: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). RESULTS: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA. CONCLUSIONS: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers. SIGNIFICANCE: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Hepáticas , PPAR alfa , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Ácidos Grasos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Nivolumab/uso terapéutico , PPAR alfa/antagonistas & inhibidoresRESUMEN
RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAF V600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in BRAF-mutant cancer patients refractory to approved RAF inhibitors.
RESUMEN
PURPOSE: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. METHODS: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. RESULTS: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. CONCLUSION: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína del Gen 3 de Activación de Linfocitos , Melanoma , Humanos , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Melanoma/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano de 80 o más Años , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Supervivencia sin ProgresiónRESUMEN
PURPOSE: No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available. PATIENTS AND METHODS: In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms). RESULTS: Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. CONCLUSION: Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Exantema , Neoplasias Pulmonares , Melanoma , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Melanoma/genética , Piridonas , Pirimidinonas , Exantema/inducido químicamente , Exantema/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Mutación , Proteínas de la Membrana/genética , GTP Fosfohidrolasas/genéticaRESUMEN
BACKGROUND: The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors. METHODS: GSK3174998 (0.003-10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity. RESULTS: 138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56-CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response. CONCLUSIONS: GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers. TRIAL REGISTRATION NUMBER: NCT02528357.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Neoplasias/patología , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Microambiente TumoralRESUMEN
Uveal melanoma is a rare malignancy affecting 5.1 patients/million per year with definitive treatment options of enucleation or radiation therapy to the primary tumor. Unfortunately, no FDA-approved systemic therapies exist for patients in the adjuvant or metastatic setting. Molecular profiling over the past decade has helped define uveal melanomas by characteristic mutations: GNAQ, GNA11, BAP1, SF3B1, and EIF1AX mutations. GNAQ/11 mutations are present in over 90% of patients with uveal melanoma and lead to signal transduction through G-protein coupled receptors to downstream growth factors. PKC inhibition has been an active area of investigation targeting this pathway specific to uveal melanoma. Several molecules have been developed and evaluated in clinical trials. Responses have been noted but clinical development has also yielded multiple toxicities and pathways of resistance limiting both breadth and durability of responses leading to combination therapy approaches. PKC inhibition remains an active and encouraging area of research to determine effective therapies for patients with uveal melanoma.
Asunto(s)
Melanoma , Neoplasias de la Úvea , Humanos , Subunidades alfa de la Proteína de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/uso terapéutico , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/genética , Melanoma/tratamiento farmacológico , Melanoma/genética , MutaciónRESUMEN
INTRODUCTION: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown. METHODS: Patients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined. RESULTS: In total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0-108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2-15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0-43.1 months). No unexpected toxicities were observed. CONCLUSION: Chemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma.
Asunto(s)
Melanoma , Neoplasias Primarias Secundarias , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Melanoma/patología , Neoplasias Primarias Secundarias/etiología , Estudios Retrospectivos , Taxoides/uso terapéutico , Microambiente TumoralRESUMEN
Locally advanced and metastatic melanoma have historically had poor survival outcomes. Long-term follow-up of both targeted therapies and immune checkpoint inhibitors has confirmed the survival benefit of these agents in stage IV melanoma, and recent studies have now demonstrated relapse-free survival benefits from these targeted and immunotherapeutic agents in the adjuvant setting. Neoadjuvant treatment of locally advanced melanoma, including in-transit disease, is now under investigation. Clinical trials have shown early promising results using either combination targeted therapy or immune checkpoint inhibitors. Neoadjuvant treatment may improve surgical morbidity, but balancing treatment efficacy and toxicity has already been challenging in the use of combination immune checkpoint inhibitors preoperatively. While improvement in relapse-free survival has been noted, additional follow-up of patients receiving neoadjuvant treatment will be necessary to report on long-term outcomes. Neoadjuvant treatment also provides additional translational research opportunities to determine predictive biomarkers for targeted therapy and immune checkpoint inhibitors. Evidence of early resistance to treatment may also lead to novel combination therapies to explore in future clinical trials. While neoadjuvant treatment in locally advanced melanoma has exciting potential, more investigation is necessary to determine efficacious regimens with manageable toxicities.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/terapia , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Cutáneas/terapia , Antineoplásicos Inmunológicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Quimioradioterapia Adyuvante/métodos , Ensayos Clínicos como Asunto , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Procedimientos Quirúrgicos Dermatologicos/métodos , Resistencia a Antineoplásicos , Humanos , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Terapia Molecular Dirigida/métodos , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/mortalidad , Piel/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Stage III melanoma encompasses a range of disease burdens, including microscopic foci of metastatic melanoma in a sentinel lymph node; bulky, clinically detected lymphadenopathy; and in-transit dermal metastases. After initial surgical management, patients with stage III melanoma at highest risk for recurrence are most likely to benefit from adjuvant therapy. Novel therapies that have improved the disease response rates and long-term survival of patients with advanced or metastatic melanoma have now been evaluated in the adjuvant setting, with the goal of eliminating residual microscopic disease to improve relapse-free and overall survival. Alternatively, implementing systemic therapies in the neoadjuvant setting for bulky, clinically detected disease can potentially limit surgical morbidity and improve understanding of an individual's response to applied therapy. With multiple therapeutic approaches currently under evaluation for adjuvant and neoadjuvant treatment of high-risk melanoma, establishing optimal treatment regimens, appropriate clinical endpoints, and treatment risk-benefit profiles has become increasingly challenging. There is also a critical need to identify and validate biomarkers predictive of melanoma patient outcomes or treatment efficacy. This article provides an overview of current clinical evidence and ongoing trials of targeted therapy and immunotherapy in this rapidly evolving area of oncology.
Asunto(s)
Inmunoterapia , Melanoma/terapia , Terapia Neoadyuvante , Quimioterapia Adyuvante , Terapia Combinada , Humanos , Pronóstico , Radioterapia Adyuvante , Factores de RiesgoRESUMEN
BACKGROUND: Immune checkpoint inhibitors, including antibodies against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are being used with increasing frequency for the treatment of cancer. Immune-related adverse events (irAEs) including colitis, dermatitis, and pneumonitis are well described, but less frequent events are now emerging with larger numbers of patients treated. Herein we describe the incidence and spectrum of thrombocytopenia following immune checkpoint inhibitor therapy and two severe cases of idiopathic thrombocytopenic purpura (ITP). CASE PRESENTATIONS: A 47-year-old female with recurrent BRAF mutant positive melanoma received combination anti-PD-1 and anti-CTLA-4. Two weeks later, she presented with mucosal bleeding, petechiae, and thrombocytopenia and was treated with standard therapy for ITP with steroids and intravenous immunoglobulin (IVIG). Her diagnosis was confirmed with bone marrow biopsy, and given the lack of treatment response, she was treated with rituximab. She began to have recovery and stabilization of her platelet count that ultimately allowed her to be retreated with PD-1 inhibition with no further thrombocytopenia. A second patient, a 45-year-old female with a BRAF wild-type melanoma, received anti-PD-1 monotherapy and became thrombocytopenic 43 days later. Three weeks of steroid treatment improved her platelet count, but thrombocytopenia recurred and required additional steroids. She later received anti-CTLA-4 monotherapy and developed severe ITP with intracranial hemorrhage. Her ITP resolved after treatment of prednisone, IVIG, and rituximab and discontinuation of checkpoint inhibition. In a retrospective chart review of 2360 patients with melanoma treated with checkpoint inhibitor therapy, <1% experienced thrombocytopenia following immune checkpoint inhibition, and of these, most had spontaneous resolution and did not require treatment. CONCLUSIONS: Thrombocytopenia, especially ITP, induced by immune checkpoint inhibitors appears to be an uncommon irAE that is manageable with observation in mild cases and/or standard ITP treatment algorithms. In our series, the majority of patients had mild thrombocytopenia that resolved spontaneously or responded to standard corticosteroid regimens. However, in two severe cases, IVIG and rituximab, in addition to steroids, were required. Checkpoint inhibition was resumed successfully in the first patient but rechallenge was not tolerated by the second patient.