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1.
Lancet ; 403(10445): 2709-2719, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38843860

RESUMO

BACKGROUND: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery. METHODS: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete. FINDINGS: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted. INTERPRETATION: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients. FUNDING: Deciphera Pharmaceuticals.


Assuntos
Tumor de Células Gigantes de Bainha Tendinosa , Humanos , Método Duplo-Cego , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Tumor de Células Gigantes de Bainha Tendinosa/tratamento farmacológico , Idoso , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Resultado do Tratamento , Anilidas , Quinolinas
2.
Cancer ; 125(8): 1341-1349, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30768786

RESUMO

BACKGROUND: A subset of patients treated with immune checkpoint inhibitors experience an accelerated tumor growth rate (TGR) in comparison with pretreatment kinetics; this is known as hyperprogression. This study assessed the relation between hyperprogressive disease (HPD) and treatment-related toxicity and clinical factors. METHODS: This study reviewed patients with solid tumors who were enrolled in early-phase immunotherapy trials at Princess Margaret Cancer Centre between August 2012 and September 2016 and had computed tomography scans in the pre-immunotherapy (reference) and on-immunotherapy (experimental) periods. HPD was defined as progression according to Response Evaluation Criteria in Solid Tumors 1.1 at the first on-treatment scan and a ≥2-fold increase in TGR between the reference and experimental periods. Treatment-related toxicities requiring systemic therapy, drug delays, or discontinuation were considered clinically significant adverse events (CSAEs). RESULTS: Of 352 patients, 182 were eligible for analysis. The median age was 60 years, and 54% were male. The Eastern Cooperative Oncology Group performance status was 0 (32%) or 1 (68%). The Royal Marsden Hospital (RMH) prognostic score was 0/1 in 59%. Single-agent immunotherapy was given to 80% of the patients. Most patients (89%) received anti-programmed death (ligand) 1 antibodies alone or in combination with other therapies. HPD occurred in 12 of 182 patients (7%). A higher proportion of females was seen among HPD patients (P = .01), but no association with age, performance status, tumor type, RMH prognostic score, combination immunotherapy, or CSAEs was found. The 1-year overall survival rate was 28% for HPD patients and 53% for non-HPD patients (hazard ratio, 1.7; 95% confidence interval, 0.9-3.3; P = .11). CONCLUSIONS: HPD was observed in 7% of patients with solid tumors treated with immunotherapy. HPD was not associated with CSAEs, age, tumor type, or the type of immunotherapy but was more common in females.


Assuntos
Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Progressão da Doença , Feminino , Humanos , Imunoterapia/classificação , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/imunologia , Prognóstico , Fatores Sexuais , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
3.
Ther Adv Med Oncol ; 16: 17588359241266179, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39386314

RESUMO

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.

4.
JCO Precis Oncol ; 8: e2400100, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39178369

RESUMO

PURPOSE: Immune gene expression signatures are emerging as potential biomarkers for immunotherapy (IO). VIGex is a 12-gene expression classifier developed in both nCounter (Nanostring) and RNA sequencing (RNA-seq) assays and analytically validated across laboratories. VIGex classifies tumor samples into hot, intermediate-cold (I-Cold), and cold subgroups. VIGex-Hot has been associated with better IO treatment outcomes. Here, we investigated the performance of VIGex and other IO biomarkers in an independent data set of patients treated with pembrolizumab in the INSPIRE phase II clinical trial (ClinicalTrials.gov identifier: NCT02644369). MATERIALS AND METHODS: Patients with advanced solid tumors were treated with pembrolizumab 200 mg IV once every 3 weeks. Tumor RNA-seq data from baseline tumor samples were classified by the VIGex algorithm. Circulating tumor DNA (ctDNA) was measured at baseline and start of cycle 3 using the bespoke Signatera assay. VIGex-Hot was compared with VIGex I-Cold + Cold and four groups were defined on the basis of the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA). RESULTS: Seventy-six patients were enrolled, including 16 ovarian, 12 breast, 12 head and neck cancers, 10 melanoma, and 26 other tumor types. Objective response rate was 24% in VIGex-Hot and 10% in I-Cold/Cold. VIGex-Hot subgroup was associated with higher overall survival (OS) and progression-free survival (PFS) when included in a multivariable model adjusted for tumor type, tumor mutation burden, and PD-L1 immunohistochemistry. The addition of ΔctDNA improved the predictive performance of the baseline VIGex classification for both OS and PFS. CONCLUSION: Our data indicate that the addition of ΔctDNA to baseline VIGex may refine prediction for IO.


Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos , Biomarcadores Tumorais , DNA Tumoral Circulante , Neoplasias , Transcriptoma , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/análise , Feminino , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Masculino , Pessoa de Meia-Idade , Antineoplásicos Imunológicos/uso terapêutico , Idoso , Resultado do Tratamento , Adulto
5.
Nat Med ; 30(2): 498-506, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38182785

RESUMO

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.


Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Naftiridinas , Ureia/análogos & derivados , Adulto , Humanos , Sunitinibe/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Biomarcadores , Mutação/genética , Antineoplásicos/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia
6.
Cancer Med ; 12(18): 18872-18881, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37724607

RESUMO

OBJECTIVES: We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra-skeletal mesenchymal CS (ESMC). METHODS: After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12-76); median starting dose was 60 mg for CABO (n = 37, range 40-60) and 120 mg for REGO (n = 29, range 40-160). Twenty-eight (42.4%) patients required dose reduction: hand-foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7-13.1); 13.4 months (n = 18, 95% CI 3.4-27.2), 8.1 (n = 4, 95% CI 4.1-9.3) and 18.2 (n = 5, 95% CI (10.4-na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8-5), 3.9 (n = 18, 95% CI 2.1-5.9), 5.53 (n = 4. 95% CI 2.13-NA) and 11.4 (n = 5, 95% CI 1.83-14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis. CONCLUSION: Our real-world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research.


Assuntos
Neoplasias Ósseas , Condrossarcoma , Osteossarcoma , Sarcoma de Ewing , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Adulto , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Recidiva Local de Neoplasia/tratamento farmacológico , Canadá , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Sarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/patologia , Osteossarcoma/patologia , Estudos Retrospectivos
7.
Oral Oncol ; 145: 106495, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37478572

RESUMO

OBJECTIVE: The aim of the study is to describe the factors that influence outcome in adults with head and neck osteosarcoma (HNO) with a specific focus on the margin status. METHODS: Patients with a diagnosis of HNO between the years 1996-2021 were reviewed from the Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) Database. Baseline characteristics, pathology, treatment, and outcomes were analyzed. Univariable (UVA) and multivariable (MVA) Cox regression models were performed. 5-year locoregional control rate and overall survival (OS) were estimated using Kaplan-Meier method and Log-Rank test. RESULTS: Of 50 patients with a median age of 40 years (range 16-80), 27 (54%) were male. HNO commonly involved the mandible (n = 21, 42%) followed by maxilla (n = 15, 30%). Thirteen (33.3%) had low-intermediate grade and 26 (66.6%) had high grade tumors. Three patients (6%) had negative resection margins (>5 mm), 24 (48%) had close margins (1-5 mm), 15 (30%) had positive margins (<1mm) and 7 (16%) had unknown margin status. In total, 39 (78%) received chemotherapy - 22 (44%) received neoadjuvant chemotherapy while 17 (34%) received adjuvant chemotherapy. A total of 12 (24%) patients received radiotherapy, of whom 8 (16%) had adjuvant and 3 (6%) had neo-adjuvant. Median follow-up time was 6.3 years (range 0.26-24.9). Disease recurred in 21 patients (42%), of whom 15 (30%) had local recurrence only, 4 (8%) had distant metastasis, and 2 (4%) had both local and distant recurrence. 5-year locoregional control rate and OS was 62% and 79.2% respectively. Resection margins <3 mm was associated with lower 5 years OS and locoregional control rate (Log-Rank p = 0.02, p = 0.01 respectively). CONCLUSION: Osteosarcomas of the head and neck are rare and local recurrence remains a concern. Surgical resection with negative resection margins may improve survival, and a 3 mm resection margin threshold may optimize survival. Radiotherapy and/or chemotherapy should be considered in a multidisciplinary setting based on risk-features.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Adulto , Masculino , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Margens de Excisão , Canadá/epidemiologia , Osteossarcoma/patologia , Sarcoma/patologia , Neoplasias Ósseas/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia
8.
Eur J Cancer ; 192: 113245, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37598656

RESUMO

PURPOSE: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up. RESULTS: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days). CONCLUSION: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.


Assuntos
Tumores do Estroma Gastrointestinal , Humanos , Sunitinibe/efeitos adversos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/efeitos adversos , Qualidade de Vida , Medidas de Resultados Relatados pelo Paciente , Constipação Intestinal/induzido quimicamente
9.
Adv Radiat Oncol ; 7(6): 101055, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36420200

RESUMO

Purpose: Only 9% of adult rhabdomyosarcomas (RMS) present with primary disease in the head and neck (HNRMS). Management is often extrapolated from the pediatric experience in which prognosis is better but treatment imperatives differ. We report management and outcomes of adult HNRMS treated over 3 decades. Methods and Materials: Adult HNRMS treated from 1984 to 2017 were reviewed. HNRMS were categorized as embryonal/alveolar (E/A) or pleomorphic (P). Standard management was as follows: E/A-HNRMS were treated with neoadjuvant chemotherapy, definitive chemoradiotherapy (CRT), and then maintenance chemotherapy. P-HNRMS were generally treated with surgery +/- radiation. Intensity modulated radiation therapy (IMRT) was adopted from 2005 onward. Results: Fifty-eight patients were eligible; the median age was 32 years. Seventy-six percent of tumors (n = 45) were parameningeal and 45% (n = 26) were >5 cm. Of 45 patients with M0 HNRMS treated with curative intent, 33 (73%) were E/A-HNRMS and 12 (27%) P-HNRMS. Patients with E/A-HNRMS received definitive RT with 66 to 70 Gy in 2 Gy per fraction. Elective nodal RT was routinely delivered. In the pre-IMRT era (before 2005), 12 of 23 (52%) patients with M0 E/A-HNRMS experienced locoregional recurrences. In the IMRT era (2005 and onward), 1 of 10 patients (10%) with M0 disease recurred locally; this patient achieved a complete clinical response despite a 3-week interruption after 48 Gy because of local toxicity but experienced an in-field local recurrence 45 months later that resulted in death. Locoregional control was superior in the IMRT era vs pre-IMRT era (P = .049). Distant metastasis among patients with E/A-HNRMS was the predominant mode of treatment failure (n = 17 of 33, 52%). Conclusions: Our study shows a high rate of locoregional control for adult E/A-HNRMS following definitive CRT using IMRT, and CRT should be considered for the majority of patients in this population. In contrast, P-HNRMS is distinct and requires surgery +/- RT.

10.
J Clin Oncol ; 40(34): 3918-3928, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-35947817

RESUMO

PURPOSE: Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501). PATIENTS AND METHODS: Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS: Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib (KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION: Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/efeitos adversos , Sunitinibe/uso terapêutico , Pirróis/efeitos adversos , Indóis/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/efeitos adversos , Mutação , Antineoplásicos/efeitos adversos , Proteínas Proto-Oncogênicas c-kit/genética
11.
J Clin Oncol ; 40(22): 2479-2490, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35394800

RESUMO

PURPOSE: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461). RESULTS: Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION: Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.


Assuntos
Hidrazinas , Lipossarcoma , Triazóis , Criança , Método Duplo-Cego , Humanos , Hidrazinas/efeitos adversos , Lipossarcoma/tratamento farmacológico , Lipossarcoma/patologia , Triazóis/efeitos adversos
12.
JNCI Cancer Spectr ; 5(3)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34056539

RESUMO

Background: The correlation between blood-based tumor mutation burden (bTMB) and tissue-based tumor mutation burden(tTMB) has not been broadly tested in a multicancer cohort. Here, we assess the correlation between bTMB with tTMB in phase I trial patients treated with immunotherapy. As an exploratory analysis, we evaluated circulating tumor DNA (ctDNA) dynamics in responders. Methods: Patients treated with immunotherapy at the Princess Margaret phase I trials unit were enrolled. Pretreatment plasma ctDNA and matched normal blood controls were collected. Available archival tissue formalin-fixed paraffin-embedded (FFPE) samples were analyzed. A 425-gene panel was used to sequence both ctDNA and FFPE samples. Samples with TMB within the highest tertile were considered as high TMB. Results: Thirty-eight patients were accrued from 25 different trials, 86.8% of which involved an anti-PD-1/PD-L1 agent. Thirty patients (78.9%) had detectable mutations in ctDNA, of which the median (range) bTMB was 5 (1-53) mutations per megabase (mut/Mb). Of the 22 patients with available FFPE samples, mutations were detected in 21 (95.4%); the median (range) tTMB was 6 (2-124) mut/Mb. Among the 16 patients with detectable mutations in both FFPE and ctDNA, a statistically significant correlation between bTMB and tTMB was observed (ρ = 0.71; P = .002). High TMB was not associated with better survival. All 3 responders had a decrease in the variant allele frequency of mutations detected in ctDNA at a second timepoint relative to baseline, indicating a potential early marker of response. Conclusions: In this small series, bTMB correlated with tTMB. An on-treatment decrease in VAF of mutations detected in ctDNA at baseline was observed in responders. Larger studies to verify our findings are warranted.


Assuntos
DNA Tumoral Circulante/genética , Análise Mutacional de DNA/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Acúmulo de Mutações , Neoplasias/genética , Adulto , Idoso , DNA Tumoral Circulante/sangue , Ensaios Clínicos Fase I como Assunto , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Neoplasias/terapia , Inclusão em Parafina , Projetos Piloto , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto Jovem
13.
F1000Res ; 9: 337, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299547

RESUMO

Background: Validated biomarkers are needed to identify patients at increased risk of immune-related adverse events (irAEs) to immune checkpoint blockade (ICB). Antibodies directed against endogenous antigens can change after exposure to ICB. Methods: Patients with different solid tumors stratified into cohorts received pembrolizumab every 3 weeks in a Phase II trial (INSPIRE study). Blood samples were collected prior to first pembrolizumab exposure (baseline) and approximately 7 weeks (pre-cycle 3) into treatment. In a discovery analysis, autoantibody target immuno-mass spectrometry was performed in baseline and pre-cycle 3 pooled sera of 24 INSPIRE patients based on clinical benefit (CBR) and irAEs. Results: Thyroglobulin (Tg) and thyroid peroxidase (TPO) were identified as the candidate autoantibody targets. In the overall cohort of 78 patients, the frequency of CBR and irAEs from pembrolizumab was 31% and 24%, respectively. Patients with an anti-Tg titer increase ≥1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without this increase in unadjusted, cohort adjusted, and multivariable models (OR=17.4, 95% CI 1.8-173.8, p=0.015). Similarly, patients with an anti-TPO titer ≥ 1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without the increase in unadjusted and cohort adjusted (OR=6.1, 95% CI 1.1-32.7, p=0.035) models. Further, the cohort adjusted analysis showed patients with anti-Tg titer greater than median (10.0 IU/mL) at pre-cycle 3 were more likely to have irAEs (OR=4.7, 95% CI 1.2-17.8, p=0.024). Patients with pre-cycle 3 anti-TPO titers greater than median (10.0 IU/mL) had a significant difference in overall survival (23.8 vs 11.5 months; HR=1.8, 95% CI 1.0-3.2, p=0.05). Conclusions: Patient increase ≥1.5x of anti-Tg and anti-TPO titers from baseline to pre-cycle 3 were associated with irAEs from pembrolizumab, and patients with elevated pre-cycle 3 anti-TPO titers had an improvement in overall survival.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Autoanticorpos/sangue , Iodeto Peroxidase/imunologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tireoglobulina/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores/sangue , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Adulto Jovem
14.
Nat Cancer ; 1(9): 873-881, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-35121950

RESUMO

Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB.


Assuntos
DNA Tumoral Circulante , Neoplasias , Anticorpos Monoclonais Humanizados , Biomarcadores , DNA Tumoral Circulante/genética , Humanos , Neoplasias/tratamento farmacológico , Estudos Prospectivos
15.
Clin Transl Radiat Oncol ; 15: 13-19, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30582016

RESUMO

The tumor, node, metastases (TNM) anatomic staging system plays a pivotal role in cancer care, research, and cancer control activities. Since the first edition of the American Joint Committee on Cancer TNM staging classification published in 1977, soft tissue sarcomas have been staged in an anatomic site agnostic fashion whereby the primary tumor size (T) was categorized as T1 if <=5 cm and T2 if >5 cm; this remained unchanged through the 7th edition of the TNM. However, soft tissue sarcomas of the head and neck (STSHN) usually present smaller than sarcomas of other sites, but carry a disproportionate risk of local recurrence. Up to 70% of tumors are less than 5 cm at presentation, and therefore classified together as T1. Given the rarity of STSHN, there is a paucity of data to guide progress in their classification. Moreover, the majority of publications only report tumor size as less than or greater than 5 cm, presumably based on conventions of the TNM system that remained unchanged for 40 years, thereby affecting progress of STSHN classification. This formed the impetus for change in the 8th edition in 2 key ways: 1) several soft tissue sarcoma site based changes occurred including STSHN now having its own system, and 2) primary tumor size cut-offs of 2 cm and 4 cm used in STSHN now reflect sizes that head and neck specialists commonly encounter in their practice. This update was pragmatic in modifying the TNM from a system with a T category not serving STSHN and which was originally based on sarcoma data from non-head and neck anatomic sites. The background to this change is outlined which provides a framework in which data can be reported to generate evidence for future staging modifications.

16.
J Clin Oncol ; 34(32): 3950, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27551121
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