To evaluate the safety and efficacy of trabectedin in a phase II, open-label, multicenter, randomized study in adult patients with unresectable/metastatic liposarcoma or leiomyosarcoma after failure ...of prior conventional chemotherapy including anthracyclines and ifosfamide.
Patients were randomly assigned to one of two trabectedin regimens (via central venous access): 1.5 mg/m(2) 24-hour intravenous infusion once every 3 weeks (q3 weeks 24-hour) versus 0.58 mg/m(2) 3-hour IV infusion every week for 3 weeks of a 4-week cycle (qwk 3-hour). Time to progression (TTP) was the primary efficacy end point, based on confirmed independent review of images.
Two hundred seventy patients were randomly assigned; 136 (q3 weeks 24-hour) versus 134 (qwk 3-hour). Median TTP was 3.7 months versus 2.3 months (hazard ratio HR, 0.734; 95% CI, 0.554 to 0.974; P = .0302), favoring the q3 weeks 24-hour arm. Median progression-free survival was 3.3 months versus 2.3 months (HR, 0.755; 95% CI, 0.574 to 0.992; P = .0418). Median overall survival (n = 235 events) was 13.9 months versus 11.8 months (HR, 0.843; 95% CI, 0.653 to 1.090; P = .1920). Although somewhat more neutropenia, elevations in AST/ALT, emesis, and fatigue occurred in the q3 weeks 24-hour, this regimen was reasonably well tolerated. Febrile neutropenia was rare (0.8%). No cumulative toxicities were noted.
Prior studies showed clinical benefit with trabectedin in patients with sarcomas after failure of standard chemotherapy. This trial documents superior disease control with the q3 weeks 24-hour trabectedin regimen in liposarcomas and leiomyosarcomas, although the qwk 3-hour regimen also demonstrated activity relative to historical comparisons. Trabectedin may now be considered an important new option to control advanced sarcomas in patients after failure of available standard-of-care therapies.
PURPOSE Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic ...sarcoma. PATIENTS AND METHODS We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued. Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies. CONCLUSION As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.
Immune-based therapies for cancer are generating substantial interest because of the success of immune checkpoint inhibitors. This study aimed to enhance anticancer immunity by exploiting the ...capacity of dendritic cells (DCs) to initiate T cell immunity by efficient uptake and presentation of endocytosed material. Delivery of tumor-associated antigens to DCs using receptor-specific monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits robust antigen-specific immune responses in preclinical models. DEC-205 (CD205), a molecule expressed on DCs, has been extensively studied for its role in antigen processing and presentation. CDX-1401 is a vaccine composed of a human mAb specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase 1 trial assessed the safety, immunogenicity, and clinical activity of escalating doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8) and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies refractory to available therapies. Treatment induced humoral and cellular immunity to NY-ESO-1 in patients with confirmed NY-ESO-1-expressing tumors across various dose levels and adjuvant combinations. No dose-limiting or grade 3 toxicities were reported. Thirteen patients experienced stabilization of disease, with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients had tumor regression (~20% shrinkage in target lesions). Six of eight patients who received immune-checkpoint inhibitors within 3 months after CDX-1401 administration had objective tumor regression. This first-in-human study of a protein vaccine targeting DCs demonstrates its feasibility, safety, and biological activity and provides rationale for combination immunotherapy strategies including immune checkpoint blockade.
PURPOSE To evaluate the potential benefit of continuous daily dosing sunitinib in patients with advanced nongastrointestinal stromal tumor (GIST) sarcomas. PATIENTS AND METHODS A total of 53 patients ...with advanced non-GIST soft tissue sarcomas received sunitinib 37.5 mg daily. Primary end point was Response Evaluation Criteria in Solid Tumors defined response. Secondary end points were stable disease at 16 and 24 weeks. (18)F-fluorodeoxyglucose positron emission tomography was performed on a subset of 24 patients at baseline and after 10 to 14 days of therapy. Results Forty-eight patients were eligible for response. One patient (desmoplastic round cell tumor DSRCT) achieved a confirmed partial response (PR) and remained on study for 56 weeks. Ten patients (20%) achieved stable disease for at least 16 weeks. Metabolic PR was seen in 10 (47%) of 21 of patients. Metabolic stable disease was seen in 11 (52%) of 21. There were no unexpected toxicities observed. CONCLUSION Sunitinib demonstrated notable evidence of metabolic response in several patients with non-GIST sarcoma. The relevance of disease control observed in subtypes with an indolent natural history is unknown, however, the durable disease control observed in DSRCT, solitary fibrous tumor, and giant cell tumor of bone suggests that future evaluation of sunitinib in these subtypes may be warranted.
PURPOSE The purpose of this trial was to assess the efficacy of imatinib in patients with one of 10 different subtypes of advanced sarcoma. PATIENTS AND METHODS Eligible patients were treated daily ...with imatinib dosed at 300 mg twice a day (for body-surface area > or = 1.5 m(2)). The primary end point was response (clinical benefit response CBR), defined as complete (CR) or partial response (PR) at 2 months, or stable disease, CR, or PR at 4 months. Rules for early termination within each disease type were based on a Bayesian hierarchical probability model (BHM) accounting for correlation of the responses of the 10 subtypes. Available tissue samples were analyzed for molecules within the KIT/platelet-derived growth factor receptor (PDGFR) signal transduction pathway. Results One hundred eighty-five assessable patients with one of 10 subtypes of sarcoma were treated. One CR and three PRs were achieved. A CBR was achieved in 28 patients treated overall and by subtype: two angiosarcomas (n = 16), 0 Ewing (n = 13), one fibrosarcoma (n = 12), six leiomyosarcomas (n = 29), seven liposarcomas (n = 31), three malignant fibrous histiocytomas (n = 30), five osteosarcomas (n = 27), one malignant peripheral-nerve sheath tumor (n = 7), 0 rhabdomyosarcoma (n = 2), and three synovial sarcomas (n = 22). Variable expression and mutations within the KIT/PDGFR pathway were observed. CONCLUSION This is the first phase II study of a new agent in sarcoma to include sufficient patients with each of the common histologic subtypes to permit generalizable conclusions. The BHM is an effective method for studying rare diseases and their subtypes, when it is reasonable to assume that their response rates are exchangeable. Although rare dramatic responses were seen, imatinib is not an active agent in advanced sarcoma in these subtypes.
Purpose
The aim of this study was to determine outcomes and prognostic factors for patients with primary and locally recurrent extra-abdominal desmoid tumors who underwent percutaneous cryoablation, ...and to compare with patients treated with surgery.
Methods
Group characteristics were compared using Fisher’s exact test, and propensity score matching was performed using the nearest-neighbor approach. Kaplan–Meier and log-rank analyses were used to evaluate the variation in first local recurrence and disease control, while multivariate Cox regression was used to identify factors associated with first local recurrence. All statistical tests were two-sided and a
p
-value of 0.05 was considered statistically significant.
Results
Twenty-two cryoablation patients were matched with 33 surgical patients (
n
= 55). Median follow-up after cryoablation was 16.3 months versus 14.9 months after surgery. Two-year local recurrence-free survival (LRFS) was 59% after cryoablation and 71% after surgery, and median LRFS was 26.6 months after cryoablation but was not reached after surgery. Two-year disease control for all patients was 85%, however median disease control was not reached in either the cryoablation or surgery groups. There was no significant difference in LRFS or disease control between matched cryoablation and surgical patients. No local recurrences occurred after the first cryoablation in patients with zero or one of the following risk factors: tumor size > 5 cm, age ≤ 25 years, or locally recurrent disease. All patients with two or more of these risk factors recurred locally after the first cryoablation.
Conclusion
Percutaneous cryoablation of primary and locally recurrent extra-abdominal desmoid tumors provides freedom from first local recurrence and long-term disease control comparable with surgery.
BackgroundAngiosarcoma is a histologically and molecularly heterogeneous vascular neoplasm with aggressive clinical behavior. Emerging data suggests that immune checkpoint blockade (ICB) is ...efficacious against some angiosarcomas, particularly cutaneous angiosarcoma of the head and neck (CHN).MethodsPatients with histologically confirmed angiosarcoma treated with ICB-based therapy at a comprehensive cancer center were retrospectively identified. Clinical characteristics and the results of targeted exome sequencing, transcriptome sequencing, and immunohistochemistry analyses were examined for correlation with clinical benefit. Durable clinical benefit was defined as a progression-free survival (PFS) of ≥16 weeks.ResultsFor the 35 patients included in the analyses, median PFS and median overall survival (OS) from the time of first ICB-based treatment were 11.9 (95% CI 7.4 to 31.9) and 42.5 (95% CI 19.6 to 114.2) weeks, respectively. Thirteen patients (37%) had PFS ≥16 weeks. Clinical factors associated with longer PFS and longer OS in multivariate analyses were ICB plus other therapy regimens, CHN disease, and white race. Three of 10 patients with CHN angiosarcoma evaluable for tumor mutational burden (TMB) had a TMB ≥10. Five of six patients with CHN angiosarcoma evaluable for mutational signature analysis had a dominant mutational signature associated with ultraviolet (UV) light. No individual gene or genomic pathway was significantly associated with PFS or OS; neither were TMB or UV signature status. Analyses of whole transcriptomes from nine patient tumor samples found upregulation of angiogenesis, inflammatory response, and KRAS signaling pathways, among others, in patients with PFS ≥16 weeks, as well as higher levels of cytotoxic T cells, dendritic cells, and natural killer cells. Patients with PFS <16 weeks had higher numbers of cancer-associated fibroblasts. Immunohistochemistry findings for 12 patients with baseline samples available suggest that neither PD-L1 expression nor presence of tumor-infiltrating lymphocytes at baseline appears necessary for a response to ICB-based therapy.ConclusionsICB-based therapy benefits only a subset of angiosarcoma patients. Patients with CHN angiosarcoma are more likely to have PFS ≥16 weeks, a dominant UV mutational signature, and higher TMB than angiosarcomas arising from other primary sites. However, clinical benefit was seen in other angiosarcomas also and was not restricted to tumors with a high TMB, a dominant UV signature, PD-L1 expression, or presence of tumor infiltrating lymphocytes at baseline.
Abstract Background Neoplasms of histiocytic and dendritic cell origin, including follicular dendritic cell sarcoma (FDCS), histiocytic sarcoma (HS) and interdigitating dendritic cell sarcoma (IDCS), ...are extremely rare, and data on their natural history and treatment outcomes are sparse. We evaluated the impact of surgery, radiation and systemic therapies on overall survival (OS). Methods We conducted a retrospective chart review of patients with FDCS, IDCS and HS treated at Memorial Sloan Kettering Cancer Center between 1995 and 2014. Results We identified 31, 15 and 7 patients with FDCS, HS and IDCS, respectively. Median age was 48.7, 42.3 and 58.8 years for FDCS, HS and IDCS, respectively. Only a slight disparity in gender distribution existed for FDCS and HS; however, IDCS predominantly affected males (6:1). The most common sites of presentation were abdomen and pelvis (42%), extremities (33%) and head and neck (57%) for FDCS, HS and IDCS, respectively. At diagnosis, 74%, 40% and 86% of patients presented with localised disease in FDCS, HS and IDCS, respectively. Patients with localised disease had significantly improved OS than those with metastatic disease in FDCS ( P = 0.04) and IDCS ( P = 0.014) but not in HS ( P = 0.95). In FDCS and HS, adjuvant or neo-adjuvant therapy was not associated with improved OS compared with observation. In IDCS, surgery alone provided a 5-year overall survival rate of 71%. Conclusions Adjuvant or neo-adjuvant treatment in FDCS and HS did not affect OS. Patients with IDCS had an excellent outcome with surgery. In the metastatic setting, chemotherapy and small molecule inhibitors may provide benefit.
Lessons Learned
The combination of pexidartinib and binimetinib was safe and tolerable and demonstrated encouraging signs of efficacy in two patients with advanced gastrointestinal stromal tumor ...(GIST) refractory to tyrosine kinase inhibitors (TKIs).
Molecular profiling of GISTs at diagnosis and upon progression may provide insight into the mechanisms of response or resistance to targeted therapies.
Additional trials are needed to further explore combined KIT and MEK inhibition in treatment‐naïve and TKI‐refractory patients with advanced GIST.
Background
Nearly all patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor activity in preclinical GIST models.
Methods
This was an investigator‐initiated, phase I, dose escalation study of the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who progressed on imatinib. The primary endpoint was phase II dose determination; secondary endpoints included safety, tolerability, and efficacy. An expansion cohort to further evaluate safety and efficacy was planned.
Results
Two patients were treated at dose level one (binimetinib 30 mg b.i.d. and pexidartinib 400 mg every morning and 200 mg every evening), after which the study was terminated by the manufacturer. No dose‐limiting toxicities (DLTs) were reported, and treatment was well tolerated. The only grade ≥3 treatment‐emergent adverse event (TEAE) was asymptomatic elevated creatine phosphokinase (CPK). Both patients had a best response of stable disease (SD) by RECIST. Progression‐free survival (PFS) and overall survival (OS) were 6.1 and 14.6 months, respectively, in one patient with five prior lines of therapy. The second patient with NF1‐mutant GIST had a 27% decrease in tumor burden by RECIST and remains on study after 19 months of treatment.
Conclusion
Pexidartinib combined with binimetinib was tolerable, and meaningful clinical activity was observed in two imatinib‐refractory patients.
经验总结
• 在两名对酪氨酸激酶抑制剂 (TKI) 不敏感的晚期胃肠道间质瘤 (GIST) 患者中，pexidartinib联合binimetinib用药具有安全性和可耐受性，并显现出具有一定疗效的迹象，令人振奋。
• 在诊断时及病情进展后对GIST的分子分析可能会就对靶向治疗的反应或抵抗机理提供宝贵意见。
• 还需开展其他试验以进一步研究抑制 KIT 和 MEK 的联合疗法对于从未接受治疗且酪氨酸激酶抑制剂难以控制的晚期GIST患者是否有效。
摘要
背景。几乎所有晚期胃肠道间质瘤 (GIST) 患者均对伊马替尼产生耐药性，而且随后的治疗效果有限。在临床前GIST模型中，对 KIT 和 MAPK 通路的双重抑制表现出协同抗肿瘤活性。
方法。这是一项由研究者发起的 I 期剂量递增研究，旨在评估 MEK 抑制剂binimetinib联合pexidartinib(一种针对 CSF1R、KIT 及 FLT3 蛋白的强效抑制剂)对经伊马替尼治疗后病情进展的晚期或转移性GIST患者是否有效。主要终点是第 II 阶段剂量测定；次要终点包括安全性、耐受性和疗效。计划扩增队列，以进一步评估疗效和安全性。
结果。两名患者接受了一级剂量治疗(binimetinib 30 mg，每日两次，pexidartinib每天早上 400 mg，每天晚上 200 mg)，之后，制造商终止了研究。无剂量限制性毒性 (DLT) 报告，治疗耐受性良好。唯一≥ 3 级的需紧急治疗的不良事件 (TEAE) 是无症状性肌酸磷酸激酶 (CPK) 升高。根据实体瘤疗效评定标准 (RECIST)，两名患者均出现了疾病稳定 (SD) 的最佳缓解。无进展生存期 (PFS) 和总生存期 (OS) 分别为 6.1 个月和 14.6 个月，其中一名患者既往接受了五线治疗。根据RECIST，另一名具有 NF1 突变的GIST患者肿瘤负荷降低了 27%，在接受治疗 19 个月后仍在参与研究。
结论。在采用伊马替尼难以控制的两名患者中，pexidartinib联合binimetinib呈现良好的耐受性，并观察到具有意义的临床活性。
To determine if a targeted exome panel utilizing matched normal DNA can accurately detect germline and somatic HLA genes in patients with synovial sarcoma (SS) and whether select HLA-A*02 genotypes ...are prognostic or predictive of outcome in metastatic SS.
Patients with metastatic SS consented to HLA typing by a Clinical Laboratory Improvement Amendments (CLIA)-certified test to determine eligibility for a clinical trial of NY-ESO-1-specific engineered T cells restricted to carriers of HLA-A*02:01, -A*02:05, or -A*02:06 (HLA-A*02 eligible). HLA genotype was determined from Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT), where feasible, and somatic loss of heterozygosity (LOH) in HLA alleles was identified. Overall survival (OS) was estimated and stratified by HLA-A*02 eligibility.
A total of 23 patients had HLA genotyping by a CLIA-certified lab and MSK-IMPACT. Ninety percent (108/110) of the sequenced alleles were concordant between IMPACT and the outside lab. LOH of HLA genes was detected in three tumors, one had loss of HLA-A*02:01. In total, 66 patients were screened for T-cell therapy and 20 (30%) were HLA-A*02 eligible on outside testing. Univariate analysis of OS from the time of metastasis found HLA-A*02 eligibility was marginally associated with shorter OS HR = 1.95; 95% confidence interval (CI), 0.995-3.813;
= 0.052. On multivariate analysis, older age and larger tumor size, but not HLA-A*02 eligibility, were significantly associated with decreased OS. HLA-A*02 eligibility did not impact OS after chemotherapy or pazopanib in the metastatic setting.
Targeted gene panels like MSK-IMPACT may accurately report HLA type and identify loss of somatic HLA alleles. In a multivariable model, HLA-A*02 eligibility was not significantly associated with OS in patients with metastatic SS.
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