RESUMO
Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.
Assuntos
Censos , Neoplasias/genética , Neoplasias/imunologia , Transcriptoma/genética , Microambiente Tumoral/imunologia , Biomarcadores Tumorais , Análise por Conglomerados , Estudos de Coortes , Biologia Computacional/métodos , Citometria de Fluxo/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/classificação , Neoplasias/patologia , RNA-Seq/métodos , São Francisco , UniversidadesRESUMO
Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Toxina Diftérica/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Quimiocinas/metabolismo , Linfócitos T Reguladores/imunologia , Microambiente TumoralRESUMO
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
Assuntos
Células Dendríticas/imunologia , Interferon gama/imunologia , Interleucina-12/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoterapia/métodos , Interferon gama/metabolismo , Interleucina-12/administração & dosagem , Interleucina-12/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , NF-kappa B/imunologia , NF-kappa B/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
The T cell receptor (TCR) endows T cells with antigen specificity and is central to nearly all aspects of T cell function. Each naïve T cell has a unique TCR sequence that is stably maintained during cell division. In this way, the TCR serves as a molecular barcode that tracks processes such as migration, differentiation, and proliferation of T cells. Recent technological advances have enabled sequencing of the TCR from single cells alongside deep molecular phenotypes on an unprecedented scale. In this review, we discuss strengths and limitations of TCR sequences as molecular barcodes and their application to study immune responses following Programmed Death-1 (PD-1) blockade in cancer. Additionally, we consider applications of TCR data beyond use as a barcode.
Assuntos
Autoimunidade , Neoplasias , Autoimunidade/genética , Humanos , Neoplasias/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos TRESUMO
BACKGROUND: Metastatic melanoma to the small bowel is an aggressive disease often accompanied by obstruction, abdominal pain, and gastrointestinal bleeding. With advancements in melanoma treatment, the role for metastasectomy continues to evolve. Inclusion of novel immunotherapeutic agents, such as checkpoint inhibitors, into standard treatment regimens presents potential survival benefits for patients receiving metastasectomy. CASE PRESENTATION: We report an institutional experience of 15 patients (12 male, 3 female) between 2014-2022 that underwent small bowel metastasectomy for metastatic melanoma and received perioperative systemic treatment. Median age of patients was 64 years (range: 35-83 years). No patients died within 30 days of their surgery, and the median hospital length of stay was 5 days. Median overall survival in these patients was 30.1 months (range: 2-115 months). Five patients died from disease (67 days, 252 days, 426 days, 572 days, 692 days postoperatively), one patient died of non-disease related causes (1312 days postoperatively), six patients are alive with disease, and three remain disease free. CONCLUSIONS: This case series presents an updated perspective of the utility of metastasectomy for small bowel metastasis in the age of novel immunotherapeutic agents as standard systemic treatment. Small bowel metastasectomy for advanced melanoma performed in conjunction with perioperative systemic therapy is safe and appears to promote long-term survival and enhanced quality of life.
Assuntos
Melanoma , Metastasectomia , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Melanoma/terapia , Melanoma/patologia , Qualidade de Vida , Imunoterapia , Intestino Delgado/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: The frequency of "exhausted" or checkpoint-positive (PD-1+CTLA-4+) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade. METHODS: Pretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan-Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. RESULTS: Of the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis. CONCLUSION: The results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.
Assuntos
Inibidores de Checkpoint Imunológico , Imunoterapia , Melanoma , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Estimativa de Kaplan-Meier , Melanoma/imunologia , Melanoma/terapia , Terapia Neoadjuvante , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Microambiente TumoralRESUMO
PURPOSE OF REVIEW: Recent developments in immunotherapy have transformed the landscape of melanoma therapy. Here, we review markers for response to immunotherapy. RECENT FINDINGS: Current immunotherapies disable immune checkpoints on T cells and other immune cells and allow immune rejection of tumor. This process depends crucially on a preexisting response to the development of the melanoma. Here we describe the complexity of the anti-tumor immune response and the links to the development of markers that are currently used or under investigation in the clinic. We describe immune response biomarkers along with new developments that could translate into advances.
Assuntos
Biomarcadores Tumorais/análise , Inibidores de Checkpoint Imunológico , Melanoma/imunologia , Melanoma/terapia , Antineoplásicos/efeitos adversos , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/sangue , Antígeno CTLA-4/antagonistas & inibidores , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Melanoma/genética , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologiaRESUMO
Immunotherapy for the treatment of advanced melanoma has become a primary treatment in the clinic. Current therapies include systemic cytokines, immune checkpoint inhibitors, and localized intratumoral therapies. Checkpoint inhibitors block natural pathways that dampen or inhibit an immune response to stimulus. These pathways include programmed cell death 1 receptor/programmed death-ligand 1 and cytotoxic T lymphocyte antigen-4. Systemic immunotherapies have proven to be effective in clinical trials both as monotherapy and in combination therapy. Oncolytic viruses are used to treat tumor locally and induce an effective immune response. Although some immune-mediated adverse events have been shown to occur with immunotherapy and may cause disease through systemic immune activation, most symptoms are mild to moderate. Overall immunotherapy in advanced melanoma has provided effective and durable responses to treat patients with advanced melanoma.
Assuntos
Imunidade Celular , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Melanoma/terapia , Terapia de Alvo Molecular/métodos , Neoplasias Cutâneas/terapia , Humanos , Melanoma/imunologia , Neoplasias Cutâneas/imunologiaRESUMO
BACKGROUND: Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized. METHODS: Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined. RESULTS: Of 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6% (95% confidence interval [CI], 1.8%-22.5%). Stable disease (≥6 months) was observed in 5 patients (9%). The median PFS was 2.6 months (95% CI, 2.4-2.8 months), and the median OS was 7.6 months (95% CI, 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity. CONCLUSIONS: PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population. Cancer 2016;122:3344-3353. © 2016 American Cancer Society.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Melanoma/patologia , Mucosa/patologia , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Uveais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Pessoa de Meia-Idade , Mucosa/efeitos dos fármacos , Estadiamento de Neoplasias , Nivolumabe , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas , Taxa de Sobrevida , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/imunologia , Melanoma Maligno CutâneoRESUMO
Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.
Assuntos
GTP Fosfo-Hidrolases/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas de Membrana/genética , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Nus , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Imunoterapia , Melanoma , Humanos , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Terapia NeoadjuvanteRESUMO
ABSTRACT: Intratumoral therapies represent a unique avenue for drug development in melanoma as patients often have accessible lesions that are particularly amenable to these approaches. In addition, a majority of intratumoral therapies have focused on stimulating antitumor immune responses, making them a particularly attractive option for use in melanoma. In this review, we describe applications for talimogene laherparepvec, a US Food and Drug Administration-approved intratumoral therapy in melanoma, as well as several classes of intratumoral therapies in development including novel oncolytic viruses, mRNA-based intratumoral injections, and cytokines and other signaling molecules.
Assuntos
Melanoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Melanoma/tratamento farmacológico , Injeções Intralesionais , Imunoterapia , Vírus Oncolíticos/genéticaRESUMO
There have been many recent advances in melanoma therapy. While 50% of melanomas have a BRAF mutation and are a target for BRAF inhibitors, the remaining 50% are BRAF wild-type. Immune checkpoint inhibitors targeting PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and lymphocyte activated gene-3 (Lag-3) are all approved for the treatment of patients with advanced BRAF wild-type melanoma; however, treatment of this patient population following initial immune checkpoint blockade is a current therapeutic challenge given the lack of other efficacious options. Here, we briefly review available US FDA-approved therapies for BRAF wild-type melanoma and focus on developing treatment avenues for this heterogeneous group of patients. We review the basics of genomic features of both BRAF mutant and BRAF wild-type melanoma as well as efforts underway to develop new targeted therapies involving the mitogen-activated protein kinase (MAPK) pathway for patients with BRAF wild-type tumors. We then focus on novel immunotherapies, including developing checkpoint inhibitors and agonists, cytokine therapies, oncolytic viruses and tumor-infiltrating lymphocytes, all of which represent potential therapeutic avenues for patients with BRAF wild-type melanoma who progress on currently approved immune checkpoint inhibitors.
Assuntos
Inibidores de Checkpoint Imunológico , Melanoma , Mutação , Proteínas Proto-Oncogênicas B-raf , Neoplasias Cutâneas , Humanos , Melanoma/terapia , Melanoma/genética , Melanoma/tratamento farmacológico , Melanoma/imunologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Terapia de Alvo Molecular/métodos , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Terapia Viral Oncolítica/métodosAssuntos
Procedimentos Cirúrgicos Dermatológicos/métodos , Melanoma , Neoplasias Cutâneas , Biópsia , Saúde Global , Humanos , Incidência , Melanoma/diagnóstico , Melanoma/epidemiologia , Melanoma/cirurgia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/cirurgiaRESUMO
KEY POINTS: Patients treated with pembrolizumab experience an increase in paranasal sinus inflammation Use of topical triamcinolone in carboxymethylcellulose is a treatment option for such patients.
Assuntos
Seios Paranasais , Rinite , Sinusite , Humanos , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Doença CrônicaRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Immune checkpoint inhibitors have led to unprecedented prolongation of overall survival (OS) for patients with advanced melanoma. Five-year follow-up of KEYNOTE-006 showed pembrolizumab prolonged survival versus ipilimumab. Efficacy results with 7-year follow-up are presented. At data cutoff (April 19, 2021), median follow-up was 85.3 months (range, 0.03-90.8 months). Median OS was 32.7 months for pembrolizumab versus 15.9 months for ipilimumab (hazard ratio [HR], 0.70; 95% CI, 0.58 to 0.83); 7-year OS was 37.8% and 25.3%, respectively. OS HRs favored pembrolizumab regardless of BRAF status or prior BRAF/MEK-inhibitor treatment and prognostic characteristics (elevated lactate dehydrogenase, large tumor size, and brain metastasis). Median modified progression-free survival (mPFS) was 9.4 months for pembrolizumab versus 3.8 months for ipilimumab; 7-year mPFS was 23.8% and 13.3%, respectively. In patients who completed ≥94 weeks of pembrolizumab, the 5-year OS was 92.9% and the 5-year mPFS was 70.1%. The objective response rate with second-course pembrolizumab (n = 16) was 56% (95% CI, 30 to 80) and the 2-year mPFS was 62.5%. These findings confirm that pembrolizumab provides long-term survival benefit in advanced melanoma.
Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos , Ipilimumab , Melanoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Seguimentos , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêuticoRESUMO
PURPOSE: Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II panRAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib. METHODS: This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics. RESULTS: Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg. CONCLUSIONS: The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings. GOV IDENTIFIER: NCT01425008.