RESUMEN
Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30-50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens-that is, both unmutated antigens and neoepitopes-may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-L-lysine carboxymethylcellulose) and granulocyte-macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.
Asunto(s)
Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Glioblastoma/diagnóstico , Glioblastoma/terapia , Medicina de Precisión/métodos , Adulto , Anciano , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/inmunología , Femenino , Glioblastoma/inmunología , Antígenos HLA-A/inmunología , Humanos , Memoria Inmunológica/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T Colaboradores-Inductores/inmunología , Resultado del TratamientoRESUMEN
The additional author support information was erroneously omitted from the Supplementary Information. This has been corrected online.
RESUMEN
BACKGROUND: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. PATIENTS AND METHODS: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. RESULTS: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.
Asunto(s)
Neoplasias , Medicina de Precisión , Humanos , Medicina de Precisión/métodos , Europa (Continente) , Neoplasias/terapia , Unión Europea , Reposicionamiento de Medicamentos , Ensayos Clínicos como Asunto/organización & administraciónRESUMEN
BACKGROUND: Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas. METHODS: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021. RESULTS: At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated larotrectinib therapy: two (6%) patients had bone sarcomas, four (11%) had gastrointestinal stromal tumors, and 30 (83%) had soft tissue sarcomas. All patients were evaluable for response and demonstrated an objective response rate of 58% (95% confidence interval, 41-74). Patients responded well to larotrectinib regardless of number of prior lines of therapy. Adverse events (AEs) were mostly grade 1/2. Grade 3 treatment-emergent AEs (TEAEs) occurred in 15 (42%) patients. There were no grade 4 TEAEs. Two grade 5 TEAEs were reported, neither of which were considered related to larotrectinib. Four (11%) patients permanently discontinued treatment due to TEAEs. CONCLUSIONS: Larotrectinib demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas with longer follow-up. These results continue to demonstrate that testing for NTRK gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas. PLAIN LANGUAGE SUMMARY: Tropomyosin receptor kinase (TRK) fusion proteins result from translocations involving the NTRK gene and cause cancer in a range of tumor types. Larotrectinib is an agent that specifically targets TRK fusion proteins and is approved for the treatment of patients with TRK fusion cancer. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. Over half of patients had a durable response to larotrectinib, with no unexpected side effects. These results show that larotrectinib is safe and effective in adult patients with TRK fusion sarcomas.
Asunto(s)
Neoplasias Óseas , Neoplasias , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Niño , Adulto , Adolescente , Tropomiosina/genética , Tropomiosina/uso terapéutico , Sarcoma/tratamiento farmacológico , Sarcoma/genética , Neoplasias/tratamiento farmacológico , Pirazoles/efectos adversos , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Fusión Génica , Proteínas de Fusión Oncogénica/genética , Neoplasias Óseas/tratamiento farmacológico , Receptor trkA/genéticaRESUMEN
BACKGROUND: Adoption of high-throughput, gene panel-based, next-generation sequencing (NGS) into routine cancer care is widely supported, but hampered by concerns about cost. To inform policies regarding genomic testing strategies, we propose a simple metric, cost per correctly identified patient (CCIP), that compares sequential single-gene testing (SGT) vs. multiplex NGS in different tumor types. MATERIALS AND METHODS: A genomic testing cost calculator was developed based on clinically actionable genomic alterations identified in the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets. Using sensitivity/specificity data for SGTs (immunohistochemistry, polymerase chain reaction, and fluorescence in situ hybridization) and NGS and marker prevalence, the number needed to predict metric was monetarized to estimate CCIP. RESULTS: At base case, CCIP was lower with NGS than sequential SGT for advanced/metastatic non-squamous non-small cell lung cancer (NSCLC), breast, colorectal, gastric cancers, and cholangiocarcinoma. CCIP with NGS was also favorable for squamous NSCLC, pancreatic, and hepatic cancers, but with overlapping confidence intervals. CCIP favored SGT for prostate cancer. Alternate scenarios using different price estimates for each test showed similar trends, but with incremental changes in the magnitude of difference between NGS and SGT, depending on price estimates for each test. CONCLUSIONS: The cost to correctly identify clinically actionable genomic alterations was lower for NGS than sequential SGT in most cancer types evaluated. Decreasing price estimates for NGS and the rapid expansion of targeted therapies and accompanying biomarkers are anticipated to further support NGS as a preferred diagnostic standard for precision oncology.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Masculino , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Hibridación Fluorescente in Situ , Medicina de Precisión , Biomarcadores , Oncología Médica , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , MutaciónRESUMEN
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.
Asunto(s)
Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión , EcosistemaRESUMEN
BACKGROUND: An increasing number of trials indicate that treatment outcomes in cancer patients with metastatic disease are improved when targeted treatments are matched with druggable genomic alterations in individual patients (pts). An estimated 30-80% of advanced solid tumors harbor actionable genomic alterations. However, the efficacy of personalized cancer treatment is still scarcely investigated in larger, controlled trials due to the low frequency and heterogenous distribution of druggable alterations among different histologic tumor types. Therefore, the overall effect of targeted cancer treatment on clinical outcomes still needs investigation. STUDY DESIGN/METHODS: ProTarget is a national, non-randomized, multi-drug, open-label, pan-cancer phase 2 trial aiming to investigate the anti-tumor activity and toxicity of currently 13 commercially available, EMA-approved targeted therapies outside the labeled indication for treatment of advanced malignant diseases, harboring specific actionable genomic alterations. The trial involves the Danish National Molecular Tumor Board for confirmation of drug-variant matches. Key inclusion criteria include a) measurable disease (RECIST v.1.1), b) ECOG performance status 0-2, and c) an actionable genomic alteration matching one of the study drugs. Key exclusion criteria include a) cancer type within the EMA-approved label of the selected drug, and b) genomic alterations known to confer drug resistance. Initial drug dose, schedule and dose modifications are according to the EMA-approved label. The primary endpoint is objective response or stable disease at 16 weeks. Pts are assigned to cohorts defined by the selected drug, genomic alteration, and tumor histology type. Cohorts are monitored according to a Simon's two-stage-based design. Response is assessed every 8 weeks for the first 24 weeks, then every 12 weeks. The trial is designed similar to the Dutch DRUP and the ASCO TAPUR trials and is a partner in the Nordic Precision Cancer Medicine Trial Network. In ProTarget, serial fresh tumor and liquid biopsies are mandatory and collected for extensive translational research including whole genome sequencing, array analysis, and RNA sequencing. DISCUSSION: The ProTarget trial will identify new predictive biomarkers for targeted treatments and provide new data and essential insights in molecular pathways involved in e.g., resistance mechanisms and thereby potentially evolve and expand the personalized cancer treatment strategy. PROTOCOL VERSION: 16, 09-MAY-2022. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04341181. Secondary Identifying No: ML41742. EudraCT No: 2019-004771-40.
Asunto(s)
Neoplasias , Humanos , Dinamarca , Genómica , Neoplasias/patología , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Concurrent chronic diseases and treatment hereof in patients with cancer may increase mortality. In this population-based study we examined the individual and combined impact of multimorbidity and polypharmacy on mortality, across 20 cancers and with 13-years follow-up in Denmark. MATERIALS AND METHODS: This nationwide study included all Danish residents with a first primary cancer diagnosed between 1 January 2005 and 31 December 2015, and followed until the end of 2017. We defined multimorbidity as having one or more of 20 chronic conditions in addition to cancer, registered in the five years preceding diagnosis, and polypharmacy as five or more redeemed medications 2-12 months prior to cancer diagnosis. Cox regression analyses were used to estimate the effects of multimorbidity and polypharmacy, as well as the combined effect on mortality. RESULTS: A total of 261,745 cancer patients were included. We found that patients diagnosed with breast, prostate, colon, rectal, oropharynx, bladder, uterine and cervical cancer, malignant melanoma, Non-Hodgkin lymphoma, and leukemia had higher mortality when the cancer diagnosis was accompanied by multimorbidity and polypharmacy, while in patients with cancer of the lung, esophagus, stomach, liver, pancreas, kidney, ovarian and brain & central nervous system, these factors had less impact on mortality. CONCLUSION: We found that multimorbidity and polypharmacy was associated with higher mortality in patients diagnosed with cancer types that typically have a favorable prognosis compared with patients without multimorbidity and polypharmacy. Multimorbidity and polypharmacy had less impact on mortality in cancers that typically have a poor prognosis.
Asunto(s)
Melanoma , Multimorbilidad , Masculino , Humanos , Estudios de Cohortes , Polifarmacia , Enfermedad Crónica , Sistema de Registros , Dinamarca/epidemiologíaRESUMEN
BACKGROUND: Larotrectinib is a precision oncology treatment for solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Larotrectinib efficacy has been evaluated in single-arm basket trials with limited follow-up and sample sizes at the initial regulatory approval due to the rarity of solid tumors with NTRK gene fusion. OBJECTIVES: We aim to demonstrate that trends in progression-free survival (PFS) and overall survival (OS) in survival data with longer follow-up may be predicted from long-term survival estimates from survival data with shorter follow-up, including predictions for median survival when it is not observed in the trial. METHODS: Patient-level data were pooled from 3 clinical trials (NCT02122913, NCT02576431, and NCT02637687) using the 2018 and 2020 data cuts for the same subset of pediatric and adult patients. The Weibull distribution was selected for survival models. Survival predictions using 2018 data were compared to 2020 Kaplan-Meier (KM) curves. RESULTS: A total of 102 patients representing 15 tumor types were included in the analysis, with a mean age of 37 years. When comparing PFS from the 2018 survival prediction to observed 2020 KM data, the 12-month PFS rate was identical (66.6%). The 36-month PFS rate was lower for the 2018 prediction (35.3%) compared to 2020 KM data (44.4%). The median OS had not yet been reached in either data cut but was predicted to be 90 months using the 2018 data. When comparing OS from the 2018 survival prediction to the observed 2020 KM data, the 12-month OS rate was 89.0% and 86.6% and the 48-month OS rate was 67.2% and 63.0%, respectively. CONCLUSION: Long-term PFS predictions deviated from observed PFS rates due to response differences across tumor types and heavy censoring towards the end of the survival curve. However, for OS, the 48-month survival prediction was consistent with the observed 2020 KM estimate.
Asunto(s)
Neoplasias/tratamiento farmacológico , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Adolescente , Adulto , Niño , Ensayos Clínicos como Asunto , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Tropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods. METHODS: ON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients < 18 years old will be enrolled under a 'pediatric' cohort regardless of tumor type and will be followed for 5 years to evaluate the risk of potential long-term adverse effects of larotrectinib on their growth and development. The effectiveness of larotrectinib in the overall study population as well as in patient subgroups will also be evaluated. Procedures avoided in patients with infantile fibrosarcoma (e.g., amputation) and the number of patients who were able to undergo surgery with a curative intent (excluding amputation) because of the use of larotrectinib will be described. Larotrectinib treatment patterns in real-world practice, including dosing and duration of treatment, will be described. DISCUSSION: The FDA Accelerated Approval Program allows for earlier approval of and patient access to drugs that treat serious conditions and fill an unmet medical need. This study is designed to fulfill post-approval requirements set by the FDA as well as post-marketing requirements set forth by local regulatory bodies and is part of the risk management plan for the EMA. STUDY REGISTRATION: This study is registered at ClinicalTrials.gov ( NCT04142437 ). PROTOCOL VERSION: v2.5, 25 March 2021.
Asunto(s)
Fibrosarcoma , Neoplasias Primarias Secundarias , Neoplasias , Adulto , Niño , Fibrosarcoma/tratamiento farmacológico , Fusión Génica , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Neoplasias Primarias Secundarias/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles , Pirimidinas/farmacología , Receptor trkA/genéticaRESUMEN
BACKGROUND: Psychological distress may be present among patients who are considering enrollment in phase 1 cancer trials, as they have advanced cancer and no documented treatment options remain. However, the prevalence of psychological distress has not been previously investigated in larger cohorts. In complex phase 1 cancer trials, it is important to ensure adequate understanding of the study premises, such as the undocumented effects and the risk of adverse events. MATERIALS AND METHODS: In a prospective study, patients completed questionnaires at two time points. We investigated psychological distress, measured as stress, anxiety, and depression, among patients at their first visit to the phase 1 unit (N = 229). Further, we investigated the understanding of trial information among patients who were enrolled in a phase 1 cancer trial (N = 57). RESULTS: We enrolled 75% of 307 eligible patients. We found a lower mean score of stress in our population compared to population norms, while the mean scores of anxiety and depression were higher. A total of 9% showed moderate to severe symptoms of anxiety and 11% showed moderate to severe symptoms of depression, which indicates higher levels than cancer patients in general. A total of 46 (81% of enrolled patients) completed questionnaires on trial information and consent. The understanding of the information on phase 1 cancer trials in these patients was slightly lower than the level reported for cancer trials in general. Some aspects relating to purpose, benefit, and additional risks were understood by fewer than half of the patients. CONCLUSION: Our results suggest that distress is not as prevalent in the population of patients referred to phase 1 cancer trials as in the general cancer population. Although patients' understanding of trial information was reasonable, some aspects of complex phase 1 cancer trials were not easily understood by enrolled patients.
Asunto(s)
Neoplasias , Distrés Psicológico , Ansiedad/epidemiología , Ansiedad/etiología , Ansiedad/psicología , Depresión/epidemiología , Depresión/etiología , Depresión/psicología , Humanos , Neoplasias/psicología , Neoplasias/terapia , Estudios Prospectivos , Estrés Psicológico/epidemiología , Estrés Psicológico/etiología , Estrés Psicológico/psicologíaRESUMEN
BACKGROUND: This study aimed to investigate the distribution and frequency of concurrent alterations in different cancers across KRAS subtypes and in different KRAS subtypes across cancers, and to identify potentially actionable targets and patients who received targeted treatment matched to their genomic profile (GP). MATERIALS AND METHODS: In this descriptive and single-center study, we included 188 patients with solid tumors harboring KRAS mutations in codon 12, 13, 61, 117, or 146, referred to the Phase 1 Unit, Rigshospitalet, Copenhagen, Denmark from mid-2016 to 2020. Genomic co-alterations were detected with whole-exome sequencing, RNA sequencing, SNP array, and mRNA expression array on fresh biopsies. The study is part of the Copenhagen Prospective Personalized Oncology study (NCT02290522). RESULTS: The majority of patients had colorectal cancer (60.1%), non-small cell lung cancer (11.2%), or pancreatic cancer (10.6%). Most tumors were KRAS-mutated in codon 12 or 13 (93.7%) including G12D (27.1%), G12V (26.6%), G12C (11.7%), and G13D (11.2%). A total of 175 different co-alterations were found, most frequently pathogenic APC and TP53 mutations (55.9% and 46.4%, respectively) and high expression of CEACAM5 (73.4%). Different cancers and KRAS subtypes showed different patterns of co-alterations, and 157 tumors (83.5%) had potentially actionable targets with varying evidence of targetability (assessed using ESMO Scale for Clinical Actionability of molecular Targets). Of the 188 patients included in the study, 15 (7.4%) received treatment matched to their GP (e.g., immunotherapy and synthetic lethality drugs), of whom one had objective partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CONCLUSION: Performing extensive genomic analysis in patients with known KRAS-mutated solid tumors may contribute with information to the genomic landscape of cancers and identify targets for immunotherapy or synthetic lethality drugs, but currently appears to have overall limited clinical impact, as few patients received targeted therapy matched to their GP.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Estudios Prospectivos , Neoplasias Pulmonares/genética , Mutación , Genómica , CodónRESUMEN
BACKGROUND: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. RESULTS: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias/química , Proteínas de Fusión Oncogénica/análisis , Proteínas Quinasas/análisis , Proteínas Quinasas/genética , Adulto JovenRESUMEN
Molecular characterization of tumors has shifted cancer treatment strategies away from nonspecific cytotoxic treatment of histology-specific tumors toward targeting of actionable mutations that can be found across multiple cancer types. The development of high-throughput technologies such as next-generation sequencing, combined with decision support applications and availability of patient databases, has provided tools that optimize disease management. Precision oncology has proven success in improving outcomes and quality of life, as well as identifying and overcoming mechanisms of drug resistance and relapse. Addressing challenges that impede its use will improve matching of therapies to patients. Here we review the current status of precision oncology medicine, emphasizing its impact on patients - what they understand about precision oncology medicine and their hopes for the future.
Lay abstract Precision oncology offers individualized treatment of cancer on a per-patient basis, based on the unique DNA fingerprint of a patient's cancer. New, advanced technologies for DNA sequencing have led to rapid advancement in developing novel therapies. Decision-making tools have followed pace, leading to improved matching of therapy to patient, ultimately improving outcomes (including quality of life), building trust between patient and physician, and increasing hope for the future.
Asunto(s)
Oncología Médica , Neoplasias/terapia , Medicina de Precisión , Técnicas de Apoyo para la Decisión , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Calidad de VidaRESUMEN
Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis to most patients. Immunotherapy of GBM is a potentially beneficial treatment option, whose optimal implementation may depend on familiarity with tumor specific antigens, presented as HLA peptides by the GBM cells. Further, early detection of GBM, such as by a routine blood test, may improve survival, even with the current treatment modalities. This study includes large-scale analyses of the HLA peptidome (immunopeptidome) of the plasma-soluble HLA molecules (sHLA) of 142 plasma samples, and the membranal HLA of GBM tumors of 10 of these patients' tumor samples. Tumor samples were fresh-frozen immediately after surgery and the plasma samples were collected before, and at multiple visits after surgery. In total, this HLA peptidome analysis involved 52 different HLA allotypes and resulted in the identification of more than 35,000 different HLA peptides. Strong correlations were observed in the signal intensities and in the repertoires of identified peptides between the tumors and plasma-soluble HLA peptidomes of the individual patients, whereas low correlations were observed between these HLA peptidomes and the tumors' proteomes. HLA peptides derived from Cancer/Testis Antigens (CTAs) were selected based on their presence among the HLA peptidomes of the patients and absence of expression of their source genes from any healthy and essential human tissues, except from immune-privileged sites. Additionally, peptides were selected as potential biomarkers if their levels in the plasma-sHLA peptidome were significantly reduced after the removal of tumor mass. The CTAs identified among the analyzed HLA peptidomes provide new opportunities for personalized immunotherapy and for early diagnosis of GBM.
Asunto(s)
Antígenos de Neoplasias/sangre , Neoplasias Encefálicas/sangre , Glioblastoma/sangre , Antígenos de Histocompatibilidad Clase I/sangre , Péptidos/sangre , Proteoma/metabolismo , Alelos , Biomarcadores de Tumor/sangre , Neoplasias Encefálicas/cirugía , Glioblastoma/cirugía , HumanosRESUMEN
NTRK fusions involving three neurotrophic tyrosine receptor kinase genes NTRK1, NTRK2, and NTRK3 and a variety of fusion partners were identified as oncogenic drivers across many cancer types. Drugs that target the chimeric protein product require the identification of the underlying gene fusion. This advocates the diagnostic use of molecular assays ranging from fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR)/Sanger approaches to targeted next-generation sequencing (NGS). Immunohistochemistry may be used as a screening tool and adjunct diagnostic assay in this context. Although FISH and RT-PCR/Sanger approaches are widely adopted in routine diagnostics, current experience with targeted RNA-based NGS is limited. Here, we report on the analysis of major assays (TruSight TST170 and TruSight RNA Fusion [Illumina]; Archer FusionPlex Solid Tumor, Archer FusionPlex Lung, and Archer FusionPlex Oncology [Archer]; Oncomine Comprehensive Assay v3 RNA and Oncomine Focus RNA [Thermo Fisher Scientific]) that are commercially available. The data set includes performance results of a multicentric comparative wet-lab study as well as an in silico analysis on the ability to detect the broad range of NTRK fusions reported until now. A test algorithm that reflects assay methodology is provided. This data will support implementation of targeted RNA sequencing in routine diagnostics and inform screening and testing strategies that have been brought forward.
Asunto(s)
Biomarcadores de Tumor , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Receptores de Factor de Crecimiento Nervioso/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Femenino , Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lactante , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Reproducibilidad de los Resultados , Flujo de Trabajo , Adulto JovenRESUMEN
BACKGROUND: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. METHODS: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting. FINDINGS: Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. INTERPRETATION: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. FUNDING: GlaxoSmithKline and Novartis.
Asunto(s)
Neoplasias del Sistema Biliar/tratamiento farmacológico , Imidazoles/administración & dosificación , Oximas/administración & dosificación , Proteínas Proto-Oncogénicas B-raf/genética , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Mutación/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Oximas/efectos adversos , Piridonas/efectos adversos , Pirimidinonas/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: LMB-100 is an antibody-toxin conjugate with an antimesothelin Fab linked to a 24-kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of the current first-in-human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin. METHODS: Cohorts of 1 to 7 patients received intravenous LMB-100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21-day cycle. RESULTS: Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose-limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB-100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB-100 plasma concentrations were dose-dependent during cycle 1. The development of antidrug antibodies decreased LMB-100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3. CONCLUSIONS: The MTD for single-agent LMB-100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first-generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB-100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB-100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer. LAY SUMMARY: Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB-100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A. In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB-100, as well as the generation of antidrug antibodies. Ongoing phase 2 clinical trials are evaluating the combination of LMB-100 plus pembrolizumab in patients with treatment-refractory mesothelioma and non-small cell lung cancer.
Asunto(s)
Proteínas Ligadas a GPI/metabolismo , Inmunoconjugados/uso terapéutico , Inmunotoxinas/uso terapéutico , Mesotelioma/tratamiento farmacológico , Humanos , Inmunoconjugados/farmacología , Inmunotoxinas/farmacología , Mesotelina , Persona de Mediana EdadRESUMEN
BACKGROUND: Multimorbidity is a growing challenge worldwide. In this nationwide study, we investigated the prevalence of multimorbidity and polypharmacy at the time of diagnosis across 20 cancers. METHODS: We conducted a nationwide register-based cohort study of all Danish residents with a first primary cancer diagnosed between 1 January 2005 and 31 December 2015. Multimorbidity was defined as one or more of 20 conditions (131 specific diagnoses) registered in the Danish National Patient Registry < 5 years before the cancer diagnosis. Polypharmacy was defined as five or more medications registered in the Danish National Prescription Registry and redeemed twice 2-12 months before the cancer diagnosis. RESULTS: We included 261,745 patients with a first primary cancer, of whom 55% had at least one comorbid condition at diagnosis and 27% had two or more. The most prevalent conditions at the time of cancer diagnosis were cardiovascular disease, chronic obstructive pulmonary disease, diabetes, stroke and depression/anxiety disorder. Polypharmacy was present in one-third of the cancer patients with antihypertensives, anti-thrombotic agents, anti-hyperlipidaemic agents, analgesics and diuretics as the most prevalent redeemed medications. CONCLUSION: Among patients with a newly established cancer diagnosis, 55% had at least one comorbid condition and 32% were exposed to polypharmacy.
Asunto(s)
Costo de Enfermedad , Multimorbilidad , Neoplasias/economía , Polifarmacia , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Dinamarca , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Sistema de RegistrosRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapeutic landscape and our perception of interactions between the immune system and tumor cells. Despite remarkable progress, disease relapse and primary resistance are not uncommon. Understanding the biological processes that tumor-infiltrating lymphocytes (TILs) undergo during ICI, how this affects the tumor microenvironment (TME) and, ultimately, clinical outcome is, therefore, necessary to further improve treatment efficacy. AIM: In the current study, we sought to characterize TILs from patients with metastatic solid tumors undergoing ICI correlating flowcytometric findings with clinical outcome. METHODS: In total, 20 patients with 10 different metastatic solid tumors treated with ICIs targeting programmed-cell death-1 (PD-1)/PD-L1 axis were included in this study. The phenotype of T cells deriving from biopsies obtained prior to treatment initiation and on-treatment was investigaded. Analyses were focused on T cells' degree of differentiation and activity and how they correlate with transcriptomic changes in the TME. RESULTS: Data indicate that patients benefitting from ICIs accumulate CD8+central memory T cells. TILs developed an effector-like phenotype over time, which was also associated with a cytolytic gene signature. In terms of modulation of T-cell responses, we observed that high expression of checkpoint molecules pre-treatment (i.e., PD-1, lymphocyte activation gene-3 [LAG-3], B and T-lymphocyte attenuator [BTLA] and T-cell immunoglobulin and mucin domain containing-3 [TIM-3]) was associated with similar gene signature and correlated to treatment benefit. Increasing expression of LAG-3 and BTLA in the CD8 compartment and their co-expression with PD-1 during treatment were, however, a common feature for patients who failed to respond to ICIs. CONCLUSIONS: Besides identifying immune profiles suggestive of response to ICI, our results provide a more nuanced picture regarding expression of checkpoint molecules that goes beyond T-cell anergy.