RESUMEN
PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label, phase 1/2 study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase 2 dose (RP2D), and characterize the pharmacokinetics (PK); exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were grade 1/2. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The RP2D was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7 to 46.9), and the objective response rate as assessed by independent radiological review using Response Evaluation Criteria in Solid Tumors version 1.1 was 72%. CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT whose disease is not amenable to surgery.
RESUMEN
BACKGROUND: Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis. METHODS: The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS). FINDINGS: Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI. INTERPRETATION: The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS. FUNDING: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds-2016, Italian Ministry of Health; AIRC Grant [ID#28546].
Asunto(s)
Linfocitos Infiltrantes de Tumor , Terapia Neoadyuvante , Sarcoma , Humanos , Sarcoma/tratamiento farmacológico , Sarcoma/mortalidad , Sarcoma/inmunología , Sarcoma/patología , Femenino , Masculino , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Pronóstico , Persona de Mediana Edad , Adulto , Anciano , Resultado del Tratamiento , Microambiente Tumoral/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , InmunohistoquímicaRESUMEN
INTRODUCTION: While available systemic treatments have modest long term efficacy in advanced angiosarcoma, immunotherapy represents an interesting new therapeutic opportunity. To establish its benefit, it is required to conduct a clinical trial assessing its efficacy and toxicity compared to standard treatments. MATERIAL AND METHODS: This is a literature review from PubMed search. RESULTS: Several systemic treatments (chemotherapy and TKI) are currently used in advanced angiosarcoma with ORR ranging from 12.5 to 68 % and PFS from 2 to 7 months. However, few randomized trials, mainly phase II, has been conducted to compare these treatments. While most centers propose doxorubicin containing regimens or paclitaxel in 1st or 2nd line, a high heterogeneity of regimens administered in this setting is observed even across sarcoma specialized centers with no consensual standard treatment. Encouraging signals of immunotherapy activity have been reported in angiosarcoma from several retrospective and phase II studies assessing anti-PD1 either alone or in combination with anti CTLA4 or TKI. Although cutaneous and head and neck location seems to benefit more from immunotherapy, response may be observed in any angiosarcoma subtype. In sarcoma in general and AS in particular, no biomarker has been clearly established to predict the efficacy of immunotherapy: high tumor mutational burden and presence of tertiary lymphoid structures are under assessment. DISCUSSION: Even essential, developing a randomized clinical trial in AS struggles with the heterogeneity of the disease, the lack of consensual standard regimen, the uncertainty on optimal immunotherapy administration and the absence of established predictive biomarkers. CONCLUSION: International collaboration is essential to run randomized trial in advanced AS and asses the efficacy of immune therapy in this rare and heterogeneous disease.
Asunto(s)
Hemangiosarcoma , Humanos , Hemangiosarcoma/terapia , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/patología , Inmunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos como Asunto , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
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.
Asunto(s)
Tumor de Células Gigantes de las Vainas Tendinosas , Humanos , Método Doble Ciego , Masculino , Femenino , Persona de Mediana Edad , Adulto , Tumor de Células Gigantes de las Vainas Tendinosas/tratamiento farmacológico , Anciano , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Resultado del Tratamiento , Anilidas , QuinolinasRESUMEN
Developing new drugs or generating evidence for existing drugs in new indications for ultra-rare cancers is complex and carries a high-risk of failure. This gets even harder in ultra-rare tumours, which have an annual incidence of 1 per 1,000,000 population or less. Here, we illustrate the problem of adequate evidence generation in ultra-rare tumours, using Alveolar Soft-Part Sarcomas (ASPS) - an ultra-rare sarcoma newly diagnosed in approximately 60 persons a year in the European Union - as an exemplar case showing challenges in development despite being potentially relevant for classes of agents. We discuss some possible approaches for addressing such challenges, especially focussing on constructive collaboration between academic groups, patients and advocates, drug manufacturers, and regulators to optimise drug development in ultra-rare cancers. This article, written by various European stakeholders, proposes a way forward to ultimately get better options for patients with ultra-rare cancers.
Asunto(s)
Sarcoma de Parte Blanda Alveolar , Neoplasias de los Tejidos Blandos , Humanos , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Sarcoma de Parte Blanda Alveolar/patología , Neoplasias de los Tejidos Blandos/patología , Unión Europea , Incidencia , Desarrollo de MedicamentosRESUMEN
Background: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, vascular sarcoma with clinical presentation ranging from an indolent to an aggressive form. Over 50% of patients present with metastatic disease, requiring systemic therapy, although no systemic therapies are specifically approved for EHE. Retrospective evidence supports the activity of mTOR inhibitors (e.g. sirolimus), although available only off-label. EHE patients and advocates are therefore working to support approval of effective treatments by collecting data on patient perspectives and experiences. Materials and methods: In February 2023, the EHE Rare Cancer Charity (UK) and The EHE Foundation (US), with other advocates, conducted a survey of perspectives and experiences of EHE patients regarding the use and accessibility of sirolimus. The survey consisted of 20 questions designed for individuals undergoing treatment, those who had been treated, or had never been treated with the drug. Widely promoted within the patient community, the online survey categorized patients into three cohorts for the analysis: liver transplant patients, non-transplant patients who had ever taken sirolimus and sirolimus-naïve non-transplant patients. Results: The survey evaluated data from 129 patient responses from 21 countries, mostly from USA, UK, Australia, and Canada (70%). The liver transplant, sirolimus and non-sirolimus cohorts were 16%, 25% and 59%, respectively. In the sirolimus group 66% reported treatment durations exceeding one year, with 16% exceeding five years, indicating the drug's efficacy. In the non-sirolimus group, the drug was not available for 42% and for 11% sirolimus was available but not selected for treatment because of its off-label status. Overall, 87% of all patients across all cohorts expressed the importance of the drug's availability as hugely or very important. Conclusion: The survey responses highlight the activity of sirolimus for EHE and the importance of securing a label extension for the drug delivering equitable access to this treatment for patients.
RESUMEN
PURPOSE: A randomized trial was conducted to compare neoadjuvant standard (S) anthracycline + ifosfamide (AI) regimen with histology-tailored (HT) regimen in selected localized high-risk soft tissue sarcoma (STS). The results of the trial demonstrated the superiority of S in all STS histologies except for high-grade myxoid liposarcoma (HG-MLPS) where S and HT appeared to be equivalent. To further evaluate the noninferiority of HT compared with S, the HG-MLPS cohort was expanded. PATIENTS AND METHODS: Patients had localized high-grade (cellular component >5%; size ≥5 cm; deeply seated) MLPS of extremities or trunk wall. The primary end point was disease-free survival (DFS). The secondary end point was overall survival (OS). The trial used a noninferiority Bayesian design, wherein HT would be considered not inferior to S if the posterior probability of the true hazard ratio (HR) being >1.25 was <5%. RESULTS: From May 2011 to June 2020, 101 patients with HG-MLPS were randomly assigned, 45 to the HT arm and 56 to the S arm. The median follow-up was 66 months (IQR, 37-89). Median size was 107 mm (IQR, 84-143), 106 mm (IQR, 75-135) in the HT arm and 108 mm (IQR, 86-150) in the S arm. At 60 months, the DFS and OS probabilities were 0.86 and 0.73 (HR, 0.60 [95% CI, 0.24 to 1.46]; log-rank P = .26 for DFS) and 0.88 and 0.90 (HR, 1.20 [95% CI, 0.37 to 3.93]; log-rank P = .77 for OS) in the HT and S arms, respectively. The posterior probability of HR being >1.25 for DFS met the Bayesian monitoring cutoff of <5% (4.93%). This result confirmed the noninferiority of trabectedin to AI suggested in the original study cohort. CONCLUSION: Trabectedin may be an alternative to standard AI in HG-MLPS of the extremities or trunk when neoadjuvant treatment is a consideration.
Asunto(s)
Liposarcoma Mixoide , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Humanos , Terapia Neoadyuvante , Liposarcoma Mixoide/tratamiento farmacológico , Trabectedina/uso terapéutico , Polonia , Teorema de Bayes , Ifosfamida/uso terapéutico , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia , Antibióticos Antineoplásicos/uso terapéutico , Antraciclinas/uso terapéutico , ItaliaRESUMEN
Importance: Gastrointestinal stromal tumor (GIST) follow-up is recommended by international guidelines, but data on the role of follow-up in patients with low relapse risk are missing. For these patients, the potential benefit of anticipating recurrence detection should be weighed against psychological burden and radiologic examination loads in terms of costs and radiation exposure. Objective: To evaluate the outcomes of guideline-based follow-up in low-risk GIST. Design, Setting, and Participants: This multi-institutional retrospective cohort study involving Italian Sarcoma Group reference institutions evaluated patients with GIST who underwent surgery between January 2001 and June 2019. Median follow-up time was 69.2 months. Data analysis was performed from December 15, 2022, to March 20, 2023. Patients with GIST at low risk according to Armed Forces Institute of Pathology criteria were included provided adequate clinical information was available: primary site, size, mitotic index, surgical margins, and 2 or more years of follow-up. Exposures: All patients underwent follow-up according to European Society for Medical Oncology (ESMO) guidelines. Main Outcomes and Measures: The primary outcome was the number of tests needed to identify a relapse according to ESMO guidelines follow-up plan. Secondary outcomes included relapse rate, relapse timing, disease-free survival (DFS), overall survival (OS), GIST-specific survival (GIST-SS), postrelapse OS, secondary tumor rates, and theoretical ionizing radiation exposure. An exploratory end point, new follow-up schedule proposal for patients with low-risk GIST according to the observed results, was also assessed. Results: A total of 737 patients (377 men [51.2%]; median age at diagnosis, 63 [range, 18-86] years) with low-risk GIST were included. Estimated 5-year survival rates were 95.5% for DFS, 99.8% for GIST-SS, and 96.1% for OS. Estimated 10-year survival rates were 93.4% for DFS, 98.1% for GIST-SS, and 91.0% for OS. Forty-two patients (5.7%) experienced disease relapse during follow-up (9 local, 31 distant, 2 both), of which 9 were detected after 10 or more years. This translated into approximately 1 relapse detected for every 170 computed tomography scans performed, with a median radiation exposure of 80 (IQR, 32-112) mSv per patient. Nongastric primary tumor (hazard ratio [HR], 2.09; 95% CI, 1.14-3.83; P = .02), and KIT mutation (HR, 2.77; 95% CI, 1.05-7.27; P = .04) were associated with a higher risk of relapse. Second tumors affected 187 of 737 patients (25%), of which 56 were detected during follow-up and represented the primary cause of death in these patients. Conclusions and Relevance: In this cohort study on patients affected by low-risk GISTs, the risk of relapse was low despite a follow-up across 10 or more years. These data suggest the need to revise follow-up schedules to reduce the anxiety, costs, and radiation exposure of currently recommended follow-up strategy.
Asunto(s)
Tumores del Estroma Gastrointestinal , Sarcoma , Masculino , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Tumores del Estroma Gastrointestinal/cirugía , Estudios de Cohortes , Estudios de Seguimiento , Estudios Retrospectivos , Recurrencia Local de Neoplasia/epidemiología , Recurrencia , Italia/epidemiologíaRESUMEN
BACKGROUND: To investigate the activity of regorafenib in advanced solitary fibrous tumour (SFT). METHODS: An Italian monocentric investigator-initiated exploratory single-arm Phase II trial was conducted of regorafenib in adult patients with advanced and progressive SFT, until progression or limiting toxicity. Prior treatment with antiangiogenics was allowed. Primary and secondary end-points were: overall response rate (ORR) by Choi criteria, and ORR by RECIST, progression-free survival (PFS), overall survival (OS). RESULTS: From January 2016 to February 2021, 18 patients were enroled [malignant-SFT = 13; dedifferentiated-SFT (D-SFT) = 4; typical-SFT (T-SFT) = 1]. Fourteen patients were pre-treated, in 12 cases with antiangiogenics (median [m-] lines of treatment = 3). Sixteen patients were evaluable for response (one screening failure; one early discontinuation). Six/16 (35.2%) required a definitive dose reduction. ORR by Choi was 37.5% (95% CI: 15.2-64.6), with 6/16 (37.5%) partial responses (PR), 6/16 (37.5%) stable disease (SD) and 4/16 (25%) progressions; 5/6 responses occurred in patients pre-treated with antiangiogenics. No responses were detected in D-SFT. Best RECIST responses were: 1/16 (6.2%) PR, 12/16 (75%) SD, 3/16 (18.8%) progressions. At 48.4 month m-FU, m-PFS by Choi was 4.7 (inter-quartile range: 2.4-13.1) months, with 31.2% patients progression-free at 1 year. CONCLUSION: Regorafenib showed activity in SFT, with 30% patients free-from-progression at one year. Responses were observed also in patients pretreated and refractory to another antiangiogenic agents. However, ORR and m-PFS were lower than reported with other antiangiogenics, and this was possibly due to discrepancies in the patient population and the high-rate of dose reductions.
Asunto(s)
Inhibidores de la Angiogénesis , Tumores Fibrosos Solitarios , Adulto , Humanos , Inhibidores de la Angiogénesis/farmacología , Compuestos de Fenilurea/farmacología , Piridinas/farmacología , Tumores Fibrosos Solitarios/tratamiento farmacológicoRESUMEN
BACKGROUND: To explore the correlation between pathological and radiological response to preoperative treatments and outcome in surgically treated patients with myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS). METHODS: All consecutive patients with primary localized MFS and UPS of the extremities and trunk wall surgically treated with curative intent at our center (2005-2021) were included. Clinical data including residual visible tumor (VT%) on surgical specimen and Response Evaluation Criteria in Solid Tumor (RECIST) were retrieved. Kaplan-Meier curves for overall survival and disease-free survival, and cumulative incidence of local relapse and distant metastasis were estimated in a competing risk framework according to RECIST and VT%, overall and by treatment group. Cox and Fine and Gray multivariable models were performed. RESULTS: Of 693 patients affected by primary MFS and UPS, 233 (66 MFS and 167 UPS) were treated by neoadjuvant chemotherapy (naChT), radiotherapy (naRT), or both (naChT-RT). VT% was ≤5% in 13/46 (28.2%), 24/99 (24.2%), and 40/88 (45.4%) patients, respectively. There were 11/46 (29.7%), 22/99 (22.7%), and 23/88 (26.1%) RECIST partial responses and 18/46 (48.6%), 59/99 (60.8%), and 60/88 (68.2%) RECIST stable disease, respectively. In naChT, a trend for a better survival was observed when VT% ≤5% (p = .09), whereas RECIST partial responses and stable disease had the same outcome. VT% was not associated with outcome in naRT or naChT-RT, whereas RECIST response was. CONCLUSION: In primary localized MFS and UPS treated with neoadjuvant therapies, VT% seems more relevant than size reduction after naChT, whereas the opposite is true when naRT is administered alone or concurrent to ChT.
RESUMEN
This study exploited a novel patient-derived xenograft (PDX) of desmoplastic small round cell tumor (DSRCT), which reproduces histomorphological and molecular characteristics of the clinical tumor, to assess the activity of cytotoxic and targeted anticancer agents. Antitumor effect was moderate for doxorubicin, pazopanib and larotrectenib [maximum tumor volume inhibition (max TVI), 55-66%], while trabectedin had higher activity (max TVI, 82%). Vinorelbine, irinotecan and eribulin achieved nearly complete tumor growth inhibition (max TVI, 96-98%), although tumors regrew after the end of treatment. The combination of irinotecan with either eribulin or trabectedin resulted in complete responses, which were maintained until the end of the experiment for irinotecan plus trabectedin. Irinotecan-based combinations nearly abrogated the expression of proteins of the G2/M checkpoint, preventing cell entrance in mitosis, and induced apoptotic and necroptotic cell death. Consistently, irinotecan plus trabectedin resulted in reprogramming of DSCRT transcriptome, with downregulation of E2F targets, G2/M checkpoint and mitotic spindle gene sets. This study emphasizes the importance of patient-derived preclinical models to explore new treatments for DSRCT and fosters clinical investigation into the activity of irinotecan plus trabectedin.
Asunto(s)
Antineoplásicos , Tumor Desmoplásico de Células Pequeñas Redondas , Humanos , Trabectedina/uso terapéutico , Trabectedina/farmacología , Irinotecán/farmacología , Irinotecán/uso terapéutico , Tumor Desmoplásico de Células Pequeñas Redondas/tratamiento farmacológico , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Xenoinjertos , Antineoplásicos/uso terapéuticoRESUMEN
OPINION STATEMENT: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated vascular sarcoma. EHE can have different clinical presentations from indolent to rapidly evolving cases, behaving as a high-grade sarcoma. Serosal effusion and systemic symptoms such as fever and severe pain are known as adverse prognostic factors; however, outcome prediction at disease onset remains a major challenge. In spite of its rarity, an international collaborative effort is in place with the support of patient advocates to increase the knowledge of EHE biology, develop new treatment options, and improve patient access to new active medications. Currently, systemic therapies are indicated only for patients suffering from progressive and/or symptomatic disease and in patients with a high risk of organ dysfunction. Standard systemic agents available so far for treatment of sarcomas, and in particular anthracycline-based chemotherapy, have marginal activity in EHE. On this background, EHE patients should be always considered for clinical study when available. The MEK inhibitor trametinib has been recently investigated prospectively in advanced EHE showing some activity, but the publication of the full dataset is still awaited to better interpret the results. Besides, there are data on response to antiangiogenics such as sorafenib and bevacizumab and, from retrospective studies, interferon, thalidomide, and sirolimus. Unfortunately, none of these agents is formally approved for EHE patients and access to treatments varies greatly between countries causing a huge disparity in patient care from one country to another.
Asunto(s)
Hemangioendotelioma Epitelioide , Sarcoma , Humanos , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/tratamiento farmacológico , Hemangioendotelioma Epitelioide/etiología , Estudios Retrospectivos , Sorafenib/uso terapéutico , PronósticoRESUMEN
BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).
Asunto(s)
Antineoplásicos , Fibromatosis Agresiva , Inhibidores y Moduladores de Gamma Secretasa , Tetrahidronaftalenos , Adulto , Femenino , Humanos , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Antineoplásicos/uso terapéutico , Método Doble Ciego , Fibromatosis Agresiva/tratamiento farmacológico , Inhibidores y Moduladores de Gamma Secretasa/uso terapéutico , Supervivencia sin Progresión , Calidad de Vida , Tetrahidronaftalenos/uso terapéutico , Valina/análogos & derivadosRESUMEN
OBJECTIVE: To report on a retrospective study of primary DSRCT aiming at characterizing long-term survivors (LTS). METHODS: All consecutive patients treated at our institution for a primary DSRCT between 2000 and 2021 were retrospectively identified. Patients received multiagent chemotherapy ± surgery ± hyperthermic intraperitoneal chemotherapy (HIPEC) ± whole abdomino-pelvic radiotherapy (WAP-RT) ± high-dose chemotherapy ± maintenance chemotherapy (MC). Event-free survival (EFS) and overall survival (OS) were estimated by Kaplan-Meier method. Patients alive, without evidence of disease at ≥36 months from diagnosis, were defined as LTS. RESULTS: Thirty-eight patients were identified. All received multiagent chemotherapy; 27/38 (71%) surgery (7/27 [26%] plus HIPEC), 9/38 (24%) WAP-RT, 12/38 (32%) MC. At a median-follow-up of 37 months (IQR 18-63), overall median-EFS and median-OS were 15 and 37 months, respectively. All events occurred within 35 months. In patients who underwent surgery, median-EFS and median-OS were 19 and 37 months (23 and 43 months after R0/R1, and 10 and 19 months after R2 resection), respectively. LTS were 5/38 (13%), alive at 37, 39, 53, 64, 209 months. None had liver or extra-abdominal metastasis at diagnosis, they all received R0/R1 resection, 3/5 had WAP-RT, 2/5 MC, 1/5 received high-dose chemotherapy, none HIPEC. CONCLUSIONS: In our series cure was likely achieved in 13% of DSRCT. LTS had no liver/extra-abdominal disease, were treated with complete surgery, and possibly WAP-RT/MC.
Asunto(s)
Tumor Desmoplásico de Células Pequeñas Redondas , Neoplasias Peritoneales , Humanos , Estudios Retrospectivos , Neoplasias Peritoneales/secundario , Terapia Combinada , Tumor Desmoplásico de Células Pequeñas Redondas/terapia , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Estudios de Seguimiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Complex surgical resection and reconstruction for rare thoracic cancers (RTCs) represent a major challenge, given their very low frequency, extreme variability of presentation, multi-modality treatment options and inadequate outcome prediction. We analysed the experience of a tertiary referral centre on a consecutive series of patients with thoracic germ cell tumours, thymomas and sarcomas, with the aim of reporting the long-term outcome by cancer type and complexity of surgical procedures. METHODS: From Jan 2003 to Dec 2018, 768 surgical procedures were performed with curative intent on 644 RTC patients. Study endpoints were: post-operative hospital stay (Pod), 30-day and 90-day mortality, 5-year and 10-year overall survival (OS). Median follow-up of alive patients was 7.2 years. RESULTS: Median Pod was 7 days, with a 1.2% 30-day and 2.9% 90-day mortality. OS was 90.8% at one year, 74.2% at five years and 62.8% at 10 years. Ten-year OS was 73.0% in low, 65.3% in intermediate, and 55.6% in high complexity score (Log-rank tests p<0.0001); 66.6% in patients with one or two reconstructions and 46.4% in patients with three or more reconstructions (p<0.0001); 46.0% with vascular and 50.0% with chest wall reconstruction; 71.8% in germ cell tumours, 64.6% in thymoma and 51.3% in sarcoma (p<0.0001). CONCLUSION: Complex surgical resection and reconstruction was associated with acceptable 90-day mortality and good 10-year survival in all RTC types. A predictive score based on surgical complexity and cancer type can help the clinical decision making.
Asunto(s)
Procedimientos de Cirugía Plástica , Sarcoma , Neoplasias de los Tejidos Blandos , Neoplasias Torácicas , Pared Torácica , Humanos , Pared Torácica/patología , Sarcoma/patología , Neoplasias Torácicas/cirugía , Neoplasias Torácicas/patología , Pronóstico , Neoplasias de los Tejidos Blandos/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Undifferentiated small round cell sarcomas (URCSs) represent a diagnostic challenge, and their optimal treatment is unknown. We aimed to define the clinical characteristics, treatment, and outcome of URCS patients. METHODS: URCS patients treated from 1983 to 2019 at 21 worldwide sarcoma reference centres were retrospectively identified. Based on molecular assessment, cases were classified as follows: (1) CIC-rearranged round cell sarcomas, (2) BCOR::CCNB3-rearranged round cell sarcomas, (3) unclassified URCSs. Treatment, prognostic factors and outcome were reviewed. RESULTS: In total, 148 patients were identified [88/148 (60%) CIC-rearranged sarcoma (median age 32 years, range 7-78), 33/148 (22%) BCOR::CCNB3-rearranged (median age 17 years, range 5-91), and 27/148 (18%) unclassified URCSs (median age 37 years, range 4-70)]. One hundred-one (68.2%) cases presented with localised disease; 47 (31.8%) had metastases at diagnosis. Male prevalence, younger age, bone primary site, and a low rate of synchronous metastases were observed in BCOR::CCNB3-rearranged cases. Local treatment was surgery in 67/148 (45%) patients, and surgery + radiotherapy in 52/148 (35%). Chemotherapy was given to 122/148 (82%) patients. At a 42.7-month median follow-up, the 3-year overall survival (OS) was 92.2% (95% CI 71.5-98.0) in BCOR::CCNB3 patients, 39.6% (95% CI 27.7-51.3) in CIC-rearranged sarcomas, and 78.7% in unclassified URCSs (95% CI 56.1-90.6; p < 0.0001). CONCLUSIONS: This study is the largest conducted in URCS and confirms major differences in outcomes between URCS subtypes. A full molecular assessment should be undertaken when a diagnosis of URCS is suspected. Prospective studies are needed to better define the optimal treatment strategy in each URCS subtype.
Asunto(s)
Sarcoma de Células Pequeñas , Sarcoma , Neoplasias de los Tejidos Blandos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Biomarcadores de Tumor/genética , Ciclina B , Proteínas de Fusión Oncogénica , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Estudios Retrospectivos , Sarcoma/genética , Sarcoma/terapia , Sarcoma/patología , Sarcoma de Células Pequeñas/genética , Sarcoma de Células Pequeñas/terapia , Sarcoma de Células Pequeñas/diagnóstico , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive, mesenchymal tumor arising from the joints, bursa and tendon sheaths. TGCT comprises a nodular- and a diffuse-type, with the former exhibiting mostly indolent course and the latter a locally aggressive behavior. Although usually not life-threatening, TGCT may cause chronic pain and adversely impact function and quality of life (QoL). CSFR1 inhibitors are effective with benefit on symptoms and QoL but are not available in most countries. The degree of uncertainty in selecting the most appropriate therapy and the lack of guidelines on the clinical management of TGCT make the adoption of new treatments inconsistent across the world, with suboptimal outcomes for patients. A global consensus meeting was organized in June 2022, involving experts from several disciplines and patient representatives from SPAGN to define the best evidence-based practice for the optimal approach to TGCT and generate the recommendations presented herein.
Asunto(s)
Tumor de Células Gigantes de las Vainas Tendinosas , Calidad de Vida , Humanos , Consenso , Tumor de Células Gigantes de las Vainas Tendinosas/tratamiento farmacológico , Tumor de Células Gigantes de las Vainas Tendinosas/patologíaRESUMEN
BACKGROUND: The Complexity INdex in SARComas (CINSARC) is a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity. This study aims to assess CINSARC value of in an independent series of high-risk patients with localized soft tissue sarcoma (STS) treated with preoperative chemotherapy within a prospective, randomized, phase III study (ISG-STS 1001). PATIENTS AND METHODS: Patients with available pre-treatment samples, treated with 3 cycles of either standard (ST) preoperative or histotype-tailored (HT) chemotherapy, were scored according to CINSARC (low-risk, C1; high-risk, C2). The 10-year overall survival probability (pr-OS) according to SARCULATOR was calculated, and patients were classified accordingly (low-risk, Sarc-LR, 10-year pr-OS>60%; high-risk, Sarc-HR, 10-year pr-OS<60%). Survival functions were estimated using the Kaplan-Meier method and compared using log-rank test. RESULTS: Eighty-six patients were included, 30 C1 and 56 C2, 49 Sarc-LR and 37 Sarc-HR. A low level of agreement between CINSARC and SARCULATOR was observed (Cohen's Kappa = 0.174). The 5-year relapse-free survival in C1 and C2 were 0.57 and 0.55 (p = 0.481); 5-year metastases-free survival 0.63 and 0.64 (p = 0.740); 5-year OS 0.80 and 0.72 (p = 0.460). The 5-year OS in C1 treated with ST and HT chemotherapy was 0.84 and 0.76 (p = 0.251) respectively; in C2 treated it was 0.72 and 0.70 (p = 0.349). The 5-year OS in Sarc-LR treated with S and HT chemotherapy was 0.80 and 0.82 (p = 0.502) respectively; in Sarc-HR it was 0.70 and 0.61 (p = 0.233). CONCLUSIONS: Our results, although constrained by the small size of the series, suggest that CINSARC has weak prognostic power in high-risk, localized STS treated with neoadjuvant chemotherapy.
Asunto(s)
Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Terapia Neoadyuvante , Estudios Prospectivos , Recurrencia Local de Neoplasia , Sarcoma/tratamiento farmacológico , Sarcoma/genética , PronósticoRESUMEN
BACKGROUND: The double-blind, randomized, placebo-controlled phase 3 study of orally administered PLX3397 in patients with pigmented villonodular synovitis or giant cell tumor of the tendon sheath (ENLIVEN) showed that pexidartinib provides a robust objective tumor response in adults with tenosynovial giant cell tumors (TGCT) not amenable to improvement with surgery. Based on these results, in 2019, pexidartinib received accelerated approval in the United States in this population as a breakthrough therapy under an orphan drug designation. However, the ability of pexidartinib to relieve pain in ENLIVEN was not fully detailed, and the relationship between pain relief and objective tumor response was not described. QUESTIONS/PURPOSES: (1) What level of pain relief was achieved by pexidartinib treatment in ENLIVEN? (2) How was pain relief related to objective tumor responses? (3) How durable was pain relief? METHODS: The current study included planned primary and exploratory assessments of patient-assessed worst pain at the site of the tumor in the ENLIVEN trial. ENLIVEN was a phase 3 randomized, placebo-controlled clinical trial in which adults with TGCT not amenable to improvement with surgery received pexidartinib or placebo for 24 weeks, after which eligible patients could receive open-label pexidartinib. Of 174 patients assessed for eligibility, 121 were randomized (50% [60] to placebo, 50% [61] to pexidartinib), and 120 were given either placebo or pexidartinib (59 received placebo and 61 received pexidartinib) and were included in an intent-to-treat analysis. Fifty-nine percent (71 of 120) of the overall treated population was female, and 88% (106 of 120) were White. Mean age was 45 ± 13 years. Tumors were mostly in the lower extremities (92% [110 of 120]), most commonly in the knee (61% [73 of 120]) and ankle (18% [21 of 120]). As a secondary outcome, patients scored worst pain at the site of the tumor in the past 24 hours on an 11-point numeric rating scale (NRS). The primary definition of a pain response was a decrease of at least 30% in the weekly mean worst-pain NRS score and increase of less than 30% in narcotic analgesic use between baseline and week 25. Planned exploratory assessments of pain included the frequency of a pain response using alternative thresholds, including a decrease in worst-pain NRS score of 50% or more and a decrease of at least 2 points (minimum clinically important difference [MCID]), the magnitude of pain reduction between baseline and week 25, correlation between worst-pain NRS score and tumor shrinkage by RECIST 1.1 criteria, and the durability of the pain response during the open-label extension. Pain responses during the randomized portion of the trial were compared according to intention-to-treat analysis, with a one-sided threshold of p < 0.025 to reduce the risk of false-positive results. Pain assessment was complete for 59% (35 of 59) of patients in the placebo group and 54% (33 of 61) of patients in the pexidartinib group. Demographic and disease characteristics did not differ between the two treatment groups. RESULTS: A difference in the primary assessment of a pain response was not detected between pexidartinib and placebo (response percentage 31% [19 of 61] [95% CI 21% to 44%] versus 15% [9 of 59] [95% CI 8% to 27%]; one-sided p = 0.03). In the exploratory analyses, pexidartinib provided a modest improvement in pain (response percentage 26% [16 of 61] [95% CI 17% to 38%] versus 10% [6 of 59] [95% CI 5% to 20%]; one-sided p = 0.02 using the 50% threshold and 31% [19 of 61] [95% CI 21% to 44%] versus 14% [8 of 59] [95% CI 7% to 25%]; one-sided p = 0.02 using the MCID threshold). The least-squares mean change in the weekly mean worst-pain NRS score between baseline and week 25 was larger in patients treated with pexidartinib than placebo (-2.5 [95% CI -3.0 to -1.9] versus -0.3 [95% CI -0.9 to 0.3]; p < 0.001), although the mean difference between the two groups (-2.2 [95% CI -3.0 to -1.4]) was just over the MCID. Improvement in the weekly mean worst-pain NRS score correlated with the reduction in tumor size (r = 0.44; p < 0.001) and tumor volume score (r = 0.61; p < 0.001). For patients in the open-label extension, the change in the worst-pain NRS score from baseline was similar to the change at the end of the randomized portion and just above the MCID (mean -2.7 ± 2.2 after 25 weeks and -3.3 ± 1.7 after 50 weeks of receiving pexidartinib). CONCLUSION: Based on the current study, a modest reduction in pain, just larger than the MCID, may be an added benefit of pexidartinib in these patients, although the findings are insufficient to justify the routine use of pexidartinib for pain relief. LEVEL OF EVIDENCE: Level II, therapeutic study.