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The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/terapia , Melanoma/diagnóstico , Melanoma/patología , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Estadificación de Neoplasias , Oncología Médica/normas , Oncología Médica/métodosRESUMEN
Personalized neoantigen vaccines have achieved major advancements in recent years, with studies in melanoma leading progress in the field. Early clinical trials have demonstrated their feasibility, safety, immunogenicity, and potential efficacy. Advances in sequencing technologies and neoantigen prediction algorithms have substantively improved the identification and prioritization of neoantigens. Innovative delivery platforms now support the rapid and flexible production of vaccines. Several ongoing efforts in the field are aimed at improving the integration of large datasets, refining the training of prediction models, and ensuring the functional validation of vaccine immunogenicity.
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Personalized vaccines directed to tumor mutations have recently gained significant momentum. On the basis of the concept of stimulating T-cell responses against neoantigens encoded by a tumor's host of personal mutations, these vaccines utilize genome or exome sequencing, mutation calling, and epitope prediction followed by manufacturing of a customized vaccine for each patient. In their 2012 Cancer Research publication, Castle and colleagues provided evidence that vaccinating with long peptide vaccines encompassing neoantigens can generate robust immune responses and induce antitumor activity in a mouse B16F10 melanoma. This approach, harnessing the exquisite specificity of mutations to the tumor and thus providing an effective target for cancer vaccines, was subsequently shown to be safe and immunogenic in a series of small first in man trials in patients with melanoma. The field has accelerated and expanded substantially over the last 5 years, propelled by increasing evidence for vaccine-mediated clinical efficacy, leading to ongoing registrational trials using personalized RNA neoantigen vaccines in patients with melanoma and several other malignancies. See related article by Castle and colleagues, Cancer Res 2012;72:1081-91.
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Vacunas contra el Cáncer , Melanoma , Neoplasias , Humanos , Animales , Ratones , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/uso terapéutico , Antígenos de Neoplasias/genética , Neoplasias/genética , Neoplasias/terapia , Linfocitos T , Mutación , InmunoterapiaRESUMEN
Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.
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Antibacterianos , Microbioma Gastrointestinal , Melanoma , Humanos , Melanoma/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Nivolumab/uso terapéutico , Nivolumab/administración & dosificación , Biomarcadores de Tumor , Vancomicina/uso terapéutico , Adulto , COVID-19/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunologíaRESUMEN
BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors. METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments. RESULTS: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab. CONCLUSIONS: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer. TRIAL REGISTRATION NUMBERS: NCT02110082; NCT02253992.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares , Melanoma , Humanos , Nivolumab/farmacología , Nivolumab/uso terapéutico , Cetuximab/farmacología , Cetuximab/uso terapéutico , Neoplasias Pulmonares/inducido químicamente , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors. Objectives of Part 1 were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of feladilimab in combination with tremelimumab. In Part 2, the antitumor activity of the combination (administered at the RP2D determined in Part 1) was to be assessed in patients with relapsed/refractory head and neck squamous cell carcinoma. Primary endpoints included the rates of dose-limiting toxicities (DLTs), adverse events (AEs), AEs of special interest, and serious AEs. Secondary endpoints included overall response rate, while biomarker assessment was exploratory. A total of 26 patients were enrolled, 18 (69%) of whom had completed the study at end date. One patient, in the highest dose group (24/225 mg feladilimab/tremelimumab), experienced a DLT 18 days after the first dose of study treatment. All patients experienced at least one AE; AEs led to treatment discontinuation in four (15%) patients. Partial response was observed in one patient. Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2.
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Anticuerpos Monoclonales Humanizados , Neoplasias de Cabeza y Cuello , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , InmunoterapiaRESUMEN
PURPOSE: Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS: Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS: Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION: In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.
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Ácidos Nucleicos Libres de Células , Neoplasias Renales , Trasplante de Riñón , Melanoma , Adulto , Humanos , Nivolumab/uso terapéutico , Ipilimumab/uso terapéutico , Tacrolimus/efectos adversos , Prednisona/uso terapéutico , Trasplante de Riñón/efectos adversos , Estudios Prospectivos , Creatinina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Melanoma/patología , Neoplasias Renales/patologíaRESUMEN
BACKGROUND: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy. METHODS: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively. RESULTS: In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients. CONCLUSIONS: Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma. TRIAL REGISTRATION NUMBER: NCT02298959.
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Anticuerpos Monoclonales Humanizados , Melanoma , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Humanos , Melanoma/tratamiento farmacológico , Leucocitos Mononucleares , Factor A de Crecimiento Endotelial VascularRESUMEN
Precision cancer medicine is a multidisciplinary team effort that requires involvement and commitment of many stakeholders including the society at large. Building on the success of significant advances in precision therapy for oncological patients over the last two decades, future developments will be significantly shaped by improvements in scalable molecular diagnostics in which increasingly complex multilayered datasets require transformation into clinically useful information guiding patient management at fast turnaround times. Adaptive profiling strategies involving tissue- and liquid-based testing that account for the immense plasticity of cancer during the patient's journey and also include early detection approaches are already finding their way into clinical routine and will become paramount. A second major driver is the development of smart clinical trials and trial concepts which, complemented by real-world evidence, rapidly broaden the spectrum of therapeutic options. Tight coordination with regulatory agencies and health technology assessment bodies is crucial in this context. Multicentric networks operating nationally and internationally are key in implementing precision oncology in clinical practice and support developing and improving the ecosystem and framework needed to turn invocation into benefits for patients. The review provides an overview of the diagnostic tools, innovative clinical studies, and collaborative efforts needed to realize precision cancer medicine.
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Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión , EcosistemaRESUMEN
BRAF/MEK targeted therapies and immune checkpoint inhibition have dramatically improved disease control and survival of patients with advanced melanoma. However, most patients do not have durable benefit from either of these therapies. BRAF targeted therapy often has a limited duration of efficacy due to the development of resistance. Pre-clinical data suggest that one possible way to overcome resistance to BRAF/MEK targeted therapy may be the addition of CSF1R inhibition. In this phase I/II study we evaluated the safety and efficacy of LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody in combination with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to discontinuation of the development program for LY3022855 by the sponsor. Between August 2017 and May 2018 five pts were enrolled. Three patients experienced grade 3 events that were deemed possibly related to LY3022855. There were no grade 4 or grade 5 events related to LY3022855. One of the 5 patients had a complete response (CR), whereas the other 4 had progressive disease (PD). Median progression free survival was 3.9 months (90% CI: 1.9-37.2 mos). CSF1R inhibition with LY3022855 in combination with BRAF/MEK inhibition with vemurafenib and cobimetinib was difficult to tolerate in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.
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Melanoma , Neoplasias Cutáneas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Quinasas de Proteína Quinasa Activadas por Mitógenos , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/patología , Vemurafenib/uso terapéuticoRESUMEN
In the past decade, immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cell therapy have brought immunotherapy to the forefront of cancer treatment; however, only subsets of patients benefit from current approaches. Neoantigen-driven therapeutics specifically redirect the immune system of the patient to enable or reinduce its ability to recognize and eliminate cancer cells. The tumor specificity of this strategy spares healthy and normal cells from being attacked. Consistent with this concept, initial clinical trials have demonstrated the feasibility, safety, and immunogenicity of neoantigen-directed personalized vaccines. We review neoantigen-driven therapy strategies as well as their promise and clinical successes to date.
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Antígenos de Neoplasias , Neoplasias , Humanos , Inmunoterapia , Inmunoterapia Adoptiva , Sistema InmunológicoRESUMEN
Despite the wide use of immune checkpoint inhibition for the treatment of melanoma, the mechanisms leading to long-term stable disease are incompletely understood. Patients with metastatic melanoma who had received ipilimumab alone or ipilimumab plus nivolumab 2+years prior and attained at least 6 months of stable disease were identified. Positron emission tomography/computed tomography (PET/CT) was performed. Pretreatment and posttreatment biopsies of areas of stable disease were assessed for tumor, fibrosis, and inflammation. Seven patients underwent PET/CT and tissue biopsy. Fluorodeoxyglucose avid lesions on PET/CT ranged from no activity to an SUV of 22. In 6 patients, the residual stable lesions were composed of necrosis and fibrosis with a prominent pigment containing macrophages and no residual melanoma. In 1 patient, a nodal lesion demonstrated melanoma with active inflammation. In most patients with durable stable disease after treatment with ipilimumab or ipilimumab/nivolumab, residual lesions demonstrated predominantly necrosis and fibrosis consistent with resolving lesions. The presence of melanophages in these samples may suggest ongoing immune surveillance. One patient did demonstrate residual melanoma, indicating the need for ongoing monitoring of this patient population.
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Melanoma , Nivolumab , Humanos , Ipilimumab/efectos adversos , Nivolumab/efectos adversos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Melanoma/patología , Inflamación/inducido químicamenteRESUMEN
BACKGROUND: Prognosis for patients with metastatic melanoma has been improved dramatically with the development of BRAF/MEK directed therapy and immune checkpoint inhibition. However, resistance to therapy remains a challenge, particularly with BRAF/MEK targeted therapy which often has a limited duration of efficacy. Pre-clinical data suggest that adding CSF1 inhibition to BRAF/MEK targeted therapy may reduce resistance and increase efficacy. METHODS: We performed a phase I/II study to determine the safety and efficacy of CSF1 inhibition with MCS110 in combination with BRAF/MEK inhibition with dabrafenib/trametinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to a decision by the study sponsor to cease further development of MCS110. RESULTS: Between September 2018 to July 2019 six patients were enrolled on the study. Patients were evenly split between female (50%) and male (50%) with a median age of 59.5 yrs. (26-71). Five patients experienced grade 3 toxicities that were possibly related to one of the therapies, there were no grade 4 or grade 5 events. One patient had a partial response (PR) by RECIST 1.1, one patient had stable disease (SD), 3 patients had disease progression (PD). Median progression free survival was 2.3 months (90% CI: 1.3 mos to not reached). CONCLUSION: MCS110 in combination with dabrafenib and trametinib was reasonably well tolerated in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.
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Melanoma , Proteínas Proto-Oncogénicas B-raf , Neoplasias Cutáneas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica , Melanoma/patología , Quinasas de Proteína Quinasa Activadas por Mitógenos , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/patologíaRESUMEN
Kidney transplant recipients are at particular risk for developing tumors, many of which are now routinely treated with immune checkpoint inhibitors (ICIs); however, ICI therapy can precipitate transplant rejection. Here, we use TCR sequencing to identify and track alloreactive T cells in a patient with melanoma who experienced kidney transplant rejection following PD-1 inhibition. The treatment was associated with a sharp increase in circulating alloreactive CD8+ T cell clones, which display a unique transcriptomic signature and were also detected in the rejected kidney but not at tumor sites. Longitudinal and cross-tissue TCR analyses indicate unintended expansion of alloreactive CD8+ T cells induced by ICI therapy for cancer, coinciding with ICI-associated organ rejection.
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Linfocitos T CD8-positivos , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Riñón , Rechazo de Injerto/prevención & control , Células Clonales , Receptores de Antígenos de Linfocitos T , AloinjertosRESUMEN
A fundamental prerequisite for the efficacy of cancer immunotherapy is the presence of functional, antigen-specific T cells within the tumor. Neoantigen-directed therapy is a promising strategy that aims at targeting the host's immune response against tumor-specific antigens, thereby eradicating cancer cells. Initial forays have been made in clinical environments utilizing vaccines and adoptive cell therapy; however, many challenges lie ahead. We provide an in-depth overview of the current state of the field with an emphasis on in silico neoantigen discovery and the clinical aspects that need to be addressed to unlock the full potential of this therapy.
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Vacunas contra el Cáncer , Neoplasias , Humanos , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/tratamiento farmacológico , Antígenos de Neoplasias , Inmunoterapia , Linfocitos TRESUMEN
BACKGROUND: Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors. METHODS: Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every 4 weeks (Q4W)) intravenously. Dose-expansion: patients with melanoma (n=10) and NSCLC (n=20) who progressed on prior anti-programmed death receptor 1/programmed death ligand-1 and/or anti-cytotoxic T-lymphocyte-associated antigen 4 (melanoma) received ivuxolimab 30 mg Q2W intravenously plus utomilumab 20 mg Q4W intravenously. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and immune-related RECIST (irRECIST). Paired tumor biopsies and whole blood were collected to assess pharmacodynamic effects and immunophenotyping. Whole blood samples were collected longitudinally for immunophenotyping. RESULTS: Dose-escalation: 57 patients were enrolled; 2 (3.5%) patients with melanoma (0.3 mg/kg+20 mg and 0.3 mg/kg+100 mg) achieved partial response (PR), 18 (31.6%) patients achieved stable disease (SD); the disease control rate (DCR) was 35.1% across all dose levels. Dose-expansion: 30 patients were enrolled; 1 patient with NSCLC achieved PR lasting >77 weeks. Seven of 10 patients with melanoma (70%) and 7 of 20 patients with NSCLC (35%) achieved SD: median (range) duration of SD was 18.9 (13.9-49.0) weeks for the melanoma cohort versus 24.1 (14.3-77.9+) weeks for the NSCLC cohort; DCR (NSCLC) was 40%. Grade 3-4 treatment-emergent AEs were reported in 28 (49.1%) patients versus 11 (36.7%) patients in dose-escalation and dose-expansion, respectively. There were no grade 5 AEs deemed attributable to treatment. Ivuxolimab area under the concentration-time curve increased in a dose-dependent manner at 0.3-3 mg/kg doses. CONCLUSIONS: Ivuxolimab+utomilumab was found to be well tolerated and demonstrated preliminary antitumor activity in selected groups of patients. TRIAL REGISTRATION NUMBER: NCT02315066.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Humanos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inmunoglobulina G , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Importance: In 2015, first-line programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) were Food and Drug Administration (FDA)-approved and National Comprehensive Cancer Network (NCCN)-recommended for patients with stage IV melanoma. Few studies have assessed the overall survival (OS) and usage rate associated with first-line ICI following 2015. Objective: To determine the rates of ICI use for metastatic melanoma following FDA approval in 2015 and characterize OS associated with first-line ICI use in this patient population. Design, Setting, and Participants: In this retrospective, nationwide cohort study, adult patients (≥20 years of age) with newly diagnosed stage IV cutaneous melanoma from 2010 to 2019 were identified using the US National Cancer Database (NCDB). Data were released by NCDB in March 2022 and analyzed in June 2022. Interventions: Patients were compared based on first-line ICI receipt vs not. Main Outcomes and Measures: The OS and use of first-line ICI in 2016 to 2019 were assessed using multivariable Cox and logistic regression, respectively. To account for immortal time bias in receiving ICI, landmark time points were used (the 50th and 75th percentile times from diagnosis to ICI initiation). Results: Among 16â¯831 patients with stage IV melanoma, 11â¯435 (67.9%) of patients were male; 116 (0.69%) were Asian or Pacific Islander, 475 (2.82%) were Hispanic, 270 (1.60%) were non-Hispanic Black, 15â¯711 (93.55%) were non-Hispanic White, and 145 (0.86%) were other race and ethnicity; the median (IQR) age at diagnosis was 64 (54-73) years. First-line immunotherapy use increased from 8.9% (127 of 1429) in 2010 to 38.8% (685 of 1766) in 2015, and 62.5% (1223 of 1958) in 2019. Median OS improved from 7.7 months (95% CI, 7.1-8.6 months) in 2010 to 17.5 months (95% CI, 14.9-19.8 months) in 2018. For patients diagnosed in 2016 or later, OS improved with first-line ICI (median OS using the 78-day landmark: 43.7 months [95% CI, 38.1-49.1 months] vs 16.1 months [95% CI, 13.5-19.3 months] for targeted therapy or chemotherapy; adjusted P < .001)-even after adjusting for patient, disease, and treatment factors. Results were similar for the 48-day landmark. This included patients presenting with brain metastases (first-line ICI median OS using the 78-day landmark: 19.9 months [95% CI, 17.2-25.0 months] vs 10.7 months for targeted therapy [95% CI, 9.5-12.3 months], adjusted P = .001). First-line ICI use varied by patients' age, insurance status, zip code-level household income, and treating hospital type. Conclusions and Relevance: Following anti-PD-1 approval in 2015, first-line ICI was associated with substantial OS improvements for patients with stage IV melanoma, including those with brain metastases. As of 2019, 38% of patients still were not receiving first-line ICI in the US, with use varying by patients' socioeconomic factors.
Asunto(s)
Neoplasias Encefálicas , Melanoma , Neoplasias Primarias Secundarias , Neoplasias Cutáneas , Adulto , Neoplasias Encefálicas/secundario , Estudios de Cohortes , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Melanoma/patología , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
PURPOSE: In metastatic triple-negative breast cancer (mTNBC), consistent biomarkers of immune checkpoint inhibitor (ICI) therapy benefit remain elusive. We evaluated the immune, genomic, and transcriptomic landscape of mTNBC in patients treated with ICIs. METHODS: We identified 29 patients with mTNBC treated with pembrolizumab or atezolizumab, either alone (n = 9) or in combination with chemotherapy (n = 14) or targeted therapy (n = 6), who had tumor tissue and/or blood available before ICI therapy for whole-exome sequencing. RNA sequencing and CIBERSORTx-inferred immune population analyses were performed (n = 20). Immune cell populations and programmed death-ligand 1 expression were assessed using multiplexed immunofluorescence (n = 18). Clonal trajectories were evaluated via serial tumor/circulating tumor DNA whole-exome sequencing (n = 4). Association of biomarkers with progression-free survival and overall survival (OS) was assessed. RESULTS: Progression-free survival and OS were longer in patients with high programmed death-ligand 1 expression and tumor mutational burden. Patients with longer survival also had a higher relative inferred fraction of CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells and enrichment of inflammatory gene expression pathways. A mutational signature of defective repair of DNA damage by homologous recombination was enriched in patients with both shorter OS and primary resistance. Exploratory analysis of clonal evolution among four patients treated with programmed cell death protein 1 blockade and a tyrosine kinase inhibitor suggested that clonal stability post-treatment was associated with short time to progression. CONCLUSION: This study identified potential biomarkers of response to ICIs among patients with mTNBC: high tumor mutational burden; presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. Pretreatment deficiencies in the homologous recombination DNA damage repair pathway and the absence of or minimal clonal evolution post-treatment may be associated with worse outcomes.