Metastatic Soft Tissue Sarcoma Research Articles

Abstract IA09: Immunotherapeutic approaches for pediatric solid tumors

Abstract For patients with primary metastatic or recurrent soft tissue sarcomas, cytotoxic chemotherapy is currently the primary treatment modality. Despite intensive chemotherapy, the outcome is poor and additional new therapeutic strategies in combination with chemotherapy have to be investigated. Immunotherapy, which involves the patient’s own or a new allogeneic immune system, might have great potential to improve the outcome of affected patients. We have focused on the use of haploidentical transplantation as a form of intensive immunotherapy in order to utilize a graft-versus-solid tumor effect, which might be exerted by donor-derived alloreactive Natural Killer (NK) cells, but also by donor-derived T cells. In a first pilot trial, we have transplanted 26 patients with relapsed neuroblastoma from a haploidentical donor. The transplant-related mortality (TRM) was 0% and the overall survival (OS) was 20%. We then started a protocol using haploidentical transplantation in 68 patients followed post-transplant by 6-9 cycles of the monoclonal anti-GD2 antibody ch14.18CHO. The TRM was 5% and the 3-year OS is 58%. In addition to neuroblastoma, we also hope to apply similar strategies to other pediatric advanced solid tumors including Ewing’s sarcoma, rhabdomyosarcoma, and others. We conclude that haploidentical transplantation of patients with relapsed/refractory solid tumors is a platform on which further immunotherapeutic strategies can be developed, such as antibodies directed against other targets than GD2, such as CD276, or bispecific T-cell engagers (BiTEs), chimeric antigen receptor (CAR) T-cells or CAR NK cells, or antibody/cytokine fusion proteins, and these approaches will be discussed. The main goal of immunotherapy, however, must be to establish a long-term memory immune response against the tumor, and haploidentical transplantation might facilitate such a response. Citation Format: Rupert Handgretinger. Immunotherapeutic approaches for pediatric solid tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA09.

A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas.

Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients—72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS.

The Evolving Role of Radiation Therapy in Patients with Metastatic Soft Tissue Sarcoma.

The management of metastatic disease is evolving. As systemic therapies continue to improve, there is increasing recognition that local therapy to distant sites of disease impacts outcomes among many histologies, including sarcoma. Various local therapy strategies exist, but radiation therapy (RT) is particularly critical as it provides a non-invasive, yet locally ablative strategy for metastatic management. Various delivery techniques including stereotactic body radiation therapy (SBRT) or hypofractionated RT can escalate the biologic dose while avoiding normal tissues in order to reduce tumor burden, provide durable local control, palliate symptoms, potentially prevent further seeding of metastatic lesions, and potentially prolong survival. This review summarizes the current state of the literature on the important role of RT for the treatment of metastatic sarcoma organized by the site of metastatic disease. Particularly for patients presenting with oligometastatic or oligoprogressive disease, consolidative RT is an important local therapy strategy to be considered in a multidisciplinary setting.

A pilot study evaluating the safety, tolerability, and efficacy of doxorubicin and pembrolizumab in patients with metastatic or unresectable soft tissue sarcoma.

11519 Background: Doxorubicin has been the traditional standard therapy for treatment of advanced soft tissue sarcoma (STS). The addition of cytotoxic agents leads to increased toxicity with minimal improvement in efficacy. Pembrolizumab monotherapy has demonstrated activity and tolerability in previous study of advanced STS. This study combined pembrolizumab with doxorubicin to determine safety and efficacy in the frontline setting. Methods: This single-center, single-arm, phase 2 trial enrolled subjects with unresectable or metastatic STS and no prior anthracycline therapy. Subjects were treated with pembrolizumab 200 mg IV and doxorubicin 60 mg/m2 (75 mg/m2 dose escalation per investigator discretion) IV every 3 weeks. The primary endpoint of safety, based on Bayesian stopping rules, evaluated if the severe or life-threatening treatment emergent adverse event (TEAE) rate exceeded 0.55. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression free survival (PFS). Efficacy and safety were based on RECIST 1.1 and CTCAE v 4.0, respectively. Kaplan-Meier methods evaluated time to event outcomes. Results: From 4/2017 to 12/2019, 30 subjects (53% female, median age 61.5 years, 10 patients > 70 years (33%)) were enrolled in the study with 6 (20%) patients still on treatment and 27 evaluable for response. The most common histologic subtypes were leiomyosarcoma (33%) and liposarcoma (23%), and a majority of patients demonstrated high grade disease (60%). Current analysis shows a median follow-up of 9.9 months. One subject experienced a stopping rule event (grade 3 autoimmune disorder). ORR was 33% (95% CI 17-54%), with documented disease control in 78% (95% CI 57.7-91.4%) of patients. Eight (30%) patients achieved a partial response, one (4%) patient achieved a complete response and 12 (44%) patients had stable disease. Preliminary results demonstrate median PFS of 6.9 months (PFS-6 mo: 52%) and median OS of 15 months (OS-6 mo: 81%) compared to historical PFS-6mo of 4.6 months and OS of 12.8 months with doxorubicin alone.1 Most common grade 3+ TEAEs included neutropenia (11 [37%]), febrile neutropenia (6 [20%]), anemia (5 [17%]), and nausea (4 [13%]). Molecular and biomarker analysis is currently in progress. Conclusions: The combination of pembrolizumab with doxorubicin has manageable toxicity and preliminary promising activity in the treatment of anthracycline-naive advanced soft tissue sarcomas. Ref: 1. Lancet Oncol. 2014 Apr; 15(4):415-23. Clinical trial information: NCT03056001 .

Prognostic influence of the treatment approach for pulmonary metastasis in patients with soft tissue sarcoma.

Soft tissue sarcomas (STSs) are rare heterogeneous malignancies of mesenchymal origin. Pulmonary metastases develop in approximately 50% of the patients with high-grade STS, being the major cause of mortality in patients with metastatic STS. Pulmonary metastasectomy has been reported to contribute to long-term survival; however, an appropriate treatment has not been established. We aimed to identify factors associated with post-metastasis survival in STS patients with pulmonary metastasis and determine the appropriate treatment for each patient. We retrospectively reviewed the records of metastatic STS patients treated between 2000 and 2017 and analyzed the clinico-pathologic variables to identify factors associated with the survival. The median survival after pulmonary metastasis was 20.6months, and the 1-, 3-, and 5-year survival rates were 68.6%, 36.0%, and 25.1%, respectively. The survival was significantly greater in patients who underwent pulmonary metastasectomy than in those without surgery (38.9months vs. 10.5months; p < 0.0001). Among those who did not undergo surgery, the survival was significantly greater in patients who received chemotherapy than in those without chemotherapy (19.1months vs. 6.3months, p = 0.037). Multivariate analysis identified pulmonary metastasectomy as the most important prognostic factor for post-metastasis survival (Hazard ratio 5.623; 95% Confidence Interval 2.733-11.572; p < 0.0001). In conclusion, pulmonary metastasectomy was the most important prognostic factor for post-metastasis survival in patients with metastatic STS. In addition, chemotherapy could prolong survival in patients who were not eligible for pulmonary resection. Although we should carefully weigh the risks and benefits, appropriate treatment for pulmonary metastases could contribute to long-time survival.

Phase II study of eribulin and pembrolizumab in patients (pts) with metastatic soft tissue sarcomas (STS): Report of LMS cohort.

11559 Background: Responses to single agent PD-1/PD-L1 inhibitors in STS remain limited with occasional responses in undifferentiated pleomorphic sarcomas (UPS), liposarcomas (LPS), and other sarcomas, and rare responses in leiomyosarcoma (LMS). Since cytotoxics and/or targeted therapies such as CDK4/6 inhibitors may alter the tumor microenvironment (TME) and potentiate the effect of immunotherapy, combination approaches may be needed to potentiate STS immunotherapy. The mechanism by which eribulin controls LPS may involve TME modification, and therefore it is attractive to test in combination with pembrolizumab in STS subtypes. This report summarizes the results from the LMS cohort from this ongoing trial. Methods: Pts treated with at least one prior therapy received eribulin 1.4mg/m2 (day 1, 8) and pembrolizumab 200mg (day 1), every 21 days. Pts continued therapy until progressive disease, death, or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) at 12 weeks, with 60% PFS at 12 weeks required to deem the combination promising. Tumor assessments (RECIST 1.1) were performed at screening and every 6 weeks thereafter. Secondary endpoints included overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Results: Nineteen pts with LMS were enrolled from May 2019 to Sept 2019. The median age was 62 (range 48-80). Eleven (58%) patients had uterine LMS. The median # of prior therapies was 4 (range 1-7). The median follow-up was 19.7 weeks. The PFS at 12 weeks was 42.1% (90% CI: 27.0%-65.5%), with median PFS of 11.1 weeks. Median OS was not reached during the follow-up period. There was 1 partial response, and 5 confirmed stable disease for ORR of 5.3% and CBR of 26.3%, after 12 weeks. The rate of grade 3 or higher toxicity was 68% overall, most commonly neutropenia, anemia, weight loss, diarrhea, elevations of lipase, and alkaline phosphatase. These side effects were reversible. The most common adverse events were fatigue, neutropenia, anorexia, AST increase, and nausea. Conclusions: Eribulin and pembrolizumab in LMS did not meet the predefined endpoint for efficacy. The LPS and “other STS subtype” cohorts of this trial are actively enrolling. Clinical trial information: NCT03899805 .

SAINT: Results of an expanded phase II study using safe amounts of ipilimumab (I), nivolumab (N), and trabectedin (T) as first-line treatment of advanced soft tissue sarcoma [NCT03138161

11520 Background: Sarcoma cells are most immunogenic earlier in the disease. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first-line therapy. Methods: Eligible patients include previously untreated male or female patients, ≥ 18 years of age with locally advanced unresectable or metastatic soft tissue sarcoma (STS), with measurable disease by RECIST v1.1. Immune checkpoint inhibitors I (1 mg/kg i.v. q 12 weeks) and N (3 mg/kg i.v. q 2 weeks) were given with T (1.2 mg/m2 i.v. q 3 weeks), a tumoricidal agent that depletes growth-promoting macrophages in the tumor microenvironment. Primary endpoint: Objective response rate by RECIST v1.1; Secondary endpoints: (1) Progression-free survival (PFS) at 6 months, (2) Overall survival (OS) at 6, 9, 12, 24, and 48 months, and (3) Incidence of adverse events. Results: Efficacy analysis: There were forty-one evaluable subjects. Best overall response rate was 19.5%; disease control rate 87.8%. The median OS was &gt;12.5 months; median PFS was &gt;6.0 months (6-month OS rate: 75%; 6-month PFS rate: 50%). Safety analysis: Grade 3 TRAEs include fatigue (n = 5), increased TSH (n = 3), decreased TSH (n = 1), adrenal insufficiency (n = 1), hyperglycemia (n = 1), dehydration (n = 1), hyponatremia (n = 2), bipedal edema (n = 2), increased AST (n = 8), increased ALT (n = 19), increased ALP (n = 2), increased CPK (n = 3), port site infection (n = 2), psoriasis exacerbation (n = 1), anemia (n = 6), thrombocytopenia (n = 2), and neutropenia (n = 2). Grade 4 TRAES include neutropenia (n = 1), thrombocytopenia (n = 2), and increased CPK (n = 2). Conclusions: These data suggest that combinatorial therapy with Ipilimumab, Nivolumab and Trabectedin (1) may have synergistic activity in achieving disease control, and (2) is safe with manageable toxicity for patients with previously untreated STS. Clinical trial information: NCT03138161 . [Table: see text]

Current treatment efficacy for metastatic soft tissue sarcoma: A targeted literature review.

e23577 Background: Soft tissue sarcoma (STS) is a rare malignancy with an annual incidence rate of &lt; 5 cases per 100,000 persons; outcomes for metastatic STS (mSTS) are poor. A targeted literature review was conducted to quantify the efficacy/effectiveness of current mSTS therapies. Methods: A structured search based on the population, intervention, comparator, outcome, study type (PICOS) framework was performed on articles (2009–2019) in MEDLINE, Embase, and Cochrane Central. Limited congress searches (ESMO, AACR, ASCO 2016–2018/2019) were also conducted. Clinical trials (CT) and observational studies (Obs) involving patients (pts, any age) with advanced mSTS receiving any pharmacological intervention were included. After screening, selected efficacy (CT) or effectiveness (Obs) endpoints (including progression-free survival [PFS], overall survival [OS], overall response rate, and duration of response) stratified by line of treatment (LOT, if available) were extracted. Results: Overall, 85 studies (56 CT, 29 Obs) met inclusion criteria; study size was 20–4,274 pts. PFS and OS (from 70 studies) were reported for pts with mSTS treated with a wide range of interventions including doxorubicin, trabectedin, pazopanib, and gemcitabine. Across any LOT, median PFS ranged 1.5–9.3 months in CT and 2.1–11.0 months in Obs; ranges were 5.7─28.8 months and 7.0─38.6 months, respectively, for OS. Median PFS and OS were generally lower with later (vs initial) LOT; few studies assessed ≥4 LOT (Table). Outcome data (any LOT) for trabectedin and pazopanib (the only approved targeted mSTS treatments) are shown in Table. Conclusions: This review of the efficacy/effectiveness of current treatments highlights the unmet clinical need for therapies that improve survival outcomes in pts with mSTS. Results may be influenced by small sample size, pt population, and care improvements over the period studied. [Table: see text]

A randomized phase II study of gemcitabine (G) alone or with pazopanib (P) in refractory soft tissue sarcoma (STS).

11515 Background: Both G and P are active single-agents in the treatment of STS. We hypothesized that the anti-VEGF-R activity of P could augment the efficacy of G and conducted this study of G+P vs G+placebo (0). Methods: In this multi-center, double-blind study, eligibility included metastatic STS with receipt of 1–3 prior systemic regimens inclusive of an anthracycline. Patients (pts) were stratified by sarcoma subtype (liposarcoma (LPS) vs. other) and study site, then randomly assigned 1:1 to receive G 1000 mg/m2 IV over 30 minutes on days 1 and 8 every 21 days plus either P 800 mg PO or matching 0 daily. The primary endpoint was progression-free survival (PFS). Results: 54 pts were accrued from 2012–2019, Accrual was halted prior to the planned N of 80 due to withdrawal of funding. There were no differences in pt characteristics between the two arms including age (median = 60), sex (M/F 52/48%), histology (LPS 30%, leiomyosarcoma 26%, UPS 15%, synovial 11%, other 17%) and number of prior systemic therapies (median = 1). With a median follow-up of 19.1 months, PFS favored G+P and was significant using the Gehan-Wilcoxon test which favorably weighs earlier events (table). The response rate was 6.9% on the G+P arm and 8.0% on the G+0 arm; response rate was 22% for LPS treated with G+P. The most common grade ≥3 AEs (G+P v G+0) were: neutropenia (41% vs 40), hypertension (17% v 4), anemia (7% v 12). One patient died of hepatic failure on the G+P arm. Conclusions: This study demonstrated improved PFS with G+P as compared with G alone. Early termination limited statistical power. G+P is active in LPS, although P regulatory labeling currently limits use for LPS. Clinical trial information: NCT01532687 . [Table: see text]

Prognostic Value of a Three-DNA Methylation Biomarker in Patients with Soft Tissue Sarcoma.

Soft tissue sarcomas (STS) are a highly aggressive and heterogeneous group of malignant mesenchymal tumors. The prognosis of patients with advanced or metastatic STS remains poor, and the main therapy of STS patients combines primary surgery, radiotherapy, and chemotherapy. Aberrant DNA methylation shows close association with the pathogenesis and tumor progression. Therefore, DNA methylation biomarkers might have the potential in accurately predicting the survival of STS patients. In order to identify a prognostic biomarker based on DNA methylation sites, a comprehensive analysis of the DNA methylation profile of STS patients in the Cancer Genome Atlas (TCGA) database was performed. All samples were randomly divided into training and testing datasets. Cox proportional hazards regression analysis was performed to identify a prognostic biomarker that contains three DNA methylation sites. The Kaplan–Meier analysis demonstrated that the 3-DNA methylation biomarker discriminated patients into high-risk and low-risk groups, both in the training and in the testing datasets, and the area under the receiver operating characteristic curve values (AUCs) were 0.844 (P < 0.001, 95% CI: 0.740–0.948) and 0.710 (P = 0.002, 95% CI: 0.595–0.823), respectively. Besides, this biomarker presented superior prognostic performance in STS patients with different age, sex, tissue of origin, therapy, and histologic subtypes. Compared with other prognostic biomarkers, this biomarker tended to be a more precise prognostic factor in STS patients. Moreover, methylation sites in this biomarker might provide a new way for clinicians to make decisions regarding the intervention and assess the effectiveness of an individual therapeutic strategy.

Real-world experience with doxorubicin and olaratumab in soft tissue sarcomas in England and Northern Ireland

BackgroundA randomised phase II trial demonstrated that the addition of olaratumab to doxorubicin significantly increased overall survival (OS) in patients with advanced soft tissue sarcomas (STS) compared to doxorubicin alone. The recently presented phase III study of doxorubicin and olaratumab in advanced soft tissue sarcoma was discordant with this finding.MethodsWe performed a retrospective analysis of adult patients with advanced-/metastatic STS treated with at least two cycles of doxorubicin and olaratumab at eight sarcoma units across England and Northern Ireland between May 2017 and March 2019.Results172 patients were evaluable and 40 patients (23.3%) had died at the time of analysis. Median ECOG performance status (PS) was 1. Median progression free survival (PFS) was 6.8 months (95% CI 5.9–7.7 months). Leiomyosarcoma was the most common histological subtype (75 patients, 43.6%), followed by liposarcomas (19, 11.0%). The mean number of cycles was 5 (doxorubicin range 2–6; olaratumab range 2–23). Two patients (1.2%) had a complete response and 34 (19.8%) had a partial response. 79 (45.9%) had stable and 58 (33.7%) progressive disease. 57 patients (33.1%) experienced grade ≥ 3 neutropenia and 7 patients (4.1%) grade ≥ 3 febrile neutropenia. Grade ≥ 3 anaemia was seen in 21 patients (12.2%). Grade ≥ 3 non-haematological toxicities were seen in 35 patients (20.3%). A clinically significant drop in left ventricular ejection fraction was seen in 6 patients (3.5%). 48 patients (27.9%) required a dose reduction. Overall survival (OS) is pending.ConclusionsOur results are in keeping with the phase III study findings: response rate, PFS and OS were similar to those reported in the phase III ANNOUNCE trial.

Systemic Therapy Options for Locally Advanced and Metastatic Myxoid, Dedifferentiated and Pleomorphic Liposarcoma

Just a few years ago, all patients with metastatic soft tissue sarcoma received the same chemotherapy drugs. However, it is now recognised that the various sarcoma subtypes are different tumours with distinct genetic alterations and different biological behaviour, so that histology-specific treatment protocols have been increasingly implemented in recent years. This is also the case for the different subtypes of liposarcoma - the myxoid/round cell variant, as well as dedifferentiated and pleomorphic liposarcoma. This article will present published data and the authors' experience with the various systemic treatment options. both in first line and in subsequent lines of treatment, as well as a brief overview of experimental treatment approaches.

Current Approaches for Personalized Therapy of Soft Tissue Sarcomas.

Soft tissue sarcomas (STS) are a highly heterogeneous group of cancers of mesenchymal origin with diverse morphologies and clinical behaviors. While surgical resection is the standard treatment for primary STS, advanced and metastatic STS patients are not eligible for surgery. Systemic treatments, including standard chemotherapy and newer chemical agents, still play the most relevant role in the management of the disease. Discovery of specific genetic alterations in distinct STS subtypes allowed better understanding of mechanisms driving their pathogenesis and treatment optimization. This review focuses on the available targeted drugs or drug combinations based on genetic aberration involved in STS development including chromosomal translocations, oncogenic mutations, gene amplifications, and their perspectives in STS treatment. Furthermore, in this review, we discuss the possible use of chemotherapy sensitivity and resistance assays (CSRA) for the adjustment of treatment for individual patients. In summary, current trends in personalized management of advanced and metastatic STS are based on combination of both genetic testing and CSRA.

Outcomes of metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) treated within the BERNIE study: a randomised, phase II study evaluating the addition of bevacizumab to chemotherapy

PurposeWe analysed the cohort of paediatric patients with metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) treated in the BERNIE protocol, i.e. open-label, multicentre, randomised phase II study evaluating the role of bevacizumab (BO20924/ITCC-006; ClinicalTrials.gov: NCT00643565). MethodsEligible patients were randomised 1:1 to add or not add bevacizumab to nine courses of intensive multi-drug chemotherapy, followed by 12-month maintenance chemotherapy (plus surgery and radiotherapy). The primary end-point was event-free survival (EFS); secondary objectives were objective response rate (ORR) and overall survival (OS). ResultsFrom 2008 and 2013, 49 NRSTS patients (out of 154 cases) were treated, 26 in the standard arm and 23 in the bevacizumab arm. ORR was seen in 10 out of 36 evaluable cases (27.7%), i.e. 4/18 standard arm cases and 6/18 bevacizumab arm cases. Two-year EFS was 27.3% (95% confidence interval [CI] 13.9–42.5) for all NRSTS patients, i.e. 34.9% (95% CI 14.6–56.2) for bevacizumab arm and 22.9% (95% CI 7.1–43.9) for standard arm (p-value = 0.19). Three-year OS (median follow-up 48.6 months) was 35.2%, with no differences in the two arms. Time to event and time to death were 16.3 and 17.2 months for bevacizumab arm and 2.1 and 7.6 months for standard arm, respectively. Patients not receiving any local treatment on primary disease had a worse outcome as compared to others. Treatment results were better for patients receiving surgical resection and worse for those who did not receive any specific treatment. ConclusionThe addition of the anti-angiogenic agent to the standard chemotherapy did not show statistically significant improvement in survival in metastatic NRSTS.

Treatment Patterns and Healthcare Resource Utilization among Patients with Advanced or Metastatic Soft Tissue Sarcoma in US Community Practices.

IntroductionThis study was designed to describe demographic and clinical characteristics of patients diagnosed with advanced or metastatic soft tissue sarcoma (STS) and to examine treatment and healthcare resource utilization patterns of this patient population in a United States (US) community-based oncology practice setting over time.Methods and MaterialsA retrospective observational study was conducted within the US Oncology Network (USON). Patients were eligible if they were diagnosed with advanced or metastatic STS and were treated at a USON site between 01 July 2015 and 31 August 2018. Demographic, clinical, and treatment characteristics were described for the overall study population. Comparisons between patients by time period (prior to and after October 2016) were evaluated using the T test for continuous variables and chi-squared test for categorical variables. Data were available for analysis through 31 August 2018.ResultsDemographic and clinical characteristics of the eligible study cohort (N = 376) were similar between patients who initiated treatment before and after October 2016 (all p > 0.05). Forty-three unique regimens were observed in the first-line setting, with the predominant regimen (gemcitabine + docetaxel) received by 33.2% (n = 125) patients. Prior to October 2016, 45.4% of patients received first-line gemcitabine + docetaxel, while 29.0% received this regimen after October 2016.ConclusionsWhile demographic and clinical characteristics were similar, treatment patterns changed in 2016. Future research should evaluate the impact of changing drug approvals and clinical trial results on future treatment patterns.

Ifosfamide, Carboplatin, and Etoposide (ICE) in Combination with Regional Hyperthermia as Salvage Therapy in Patients with Locally Advanced Nonmetastatic and Metastatic Soft-Tissue Sarcoma

Patients with localized relapse of soft-tissue sarcoma (STS) after anthracycline-based chemotherapy have a dismal prognosis, particularly when surgery is not possible. To facilitate resection and improve long-term tumor control, we applied an intensified perioperative treatment consisting of ICE (ifosfamide 6 g/m2, carboplatin 400 mg/m2, and etoposide 600 mg/m2) in combination with regional hyperthermia (RHT) to maximize local control. Here, we retrospectively evaluate the safety and efficacy of this strategy. Patients aged ≥18 years with locally advanced high-risk STS, either with or without metastasis, treated with ICE + RHT after the failure of first-line anthracycline-based chemotherapy were included in this analysis. Radiographic response, toxicity, progression-free survival (PFS), and overall survival (OS) were assessed. Between 1996 and 2018, 213 sarcoma patients received ICE at our centre. Of these, 110 patients met the selection criteria (progressive disease, suitable high-grade STS histology, anthracycline pretreatment, RHT treatment) for this analysis. Fifty-four patients had locally advanced disease without metastases (LA-STS), and 56 patients had additional metastatic disease (M-STS). Disease control was achieved in 59% of LA-STS patients and in 47% of M-STS patients. For LA-STS, 21% of the patients achieved radiographic response, facilitating resection in 4 patients (7%), compared with 11% of the M-STS patients, facilitating resection in 5 patients (9%). PFS was significantly longer in LA-STS than in M-STS (10 vs. 4 months, p < 0.0001). Median OS was 26 months in LA-STS and 12 months in M-STS. Disease control was the only independent prognostic factor for improved OS in multivariate analysis. Toxicity was high with neutropenic fever occurring in 25% of the patients and three therapy-related deaths (3%). ICE + RHT demonstrated activity in high-risk STS and facilitated resection in selected patients after anthracycline failure. Disease control was associated with improved OS. Based on the observed toxicities, the dose should be reduced to 75%.

Abstract No. 503 Effects of cryoablation with immunotherapy on patients with metastatic soft tissue sarcoma

Metastatic soft tissue sarcomas are associated with poor outcomes. Many patients undergo multiple treatment modalities for disease control. Of particular interest is the combination of cryoablation and immunotherapy on the progression of metastatic disease. This study aims to assess the effect of cryoablation on non-target pulmonary lesions in immunotherapy patients with metastatic leiomyosarcoma or liposarcoma. Single-center retrospective analysis was performed on 16 patients with leiomyosarcoma or liposarcoma who underwent cryoablation of lung metastases between 2014-2018. Twelve patients were identified who were receiving immunotherapy at time of ablation; these patients had shown disease progression on chemotherapy. Greatest single dimension measurements were performed on cryoablated metastases and up to three non-target lesions both before and after ablation. Linear regression analysis was performed to evaluate growth rates of each lesion before and after ablation. Twelve patients with leiomyosarcoma (N = 9) or liposarcoma (N = 3) underwent cryoablation of lung metastases while undergoing immunotherapy. Average age was 64 years, and 75% of patients were female. Average time between CT or PET-CT scans was 2.7 months. All patients remained on immunotherapy after cryoablation. Growth rate of targeted metastases prior to ablation was 1.39 mm/30 days. No growth of targeted metastases was seen after ablation. Growth rate for non-target lesions prior to ablation was 0.54 mm/30 days, while growth rate after ablation was 0.47 mm/30 days (P = 0.66). All non-target lesions continued to progress after ablation. Three patients developed pneumothorax requiring chest tube but no major complications were observed. Cryoablation of pulmonary metastases in immunotherapy patients with liposarcoma or leiomyosarcoma is technically feasible with high success rate of treated metastases without major complications. Though a mild difference in growth rate was observed in growth rates of non-target lesions before and after cryoablation, no statistical significance was reached. Additional data will be needed to determine if cryoablation slows growth significantly for non-target lesions.

Assessment of Safety and Efficacy of Combined Trabectedin and Low-Dose Radiotherapy for Patients With Metastatic Soft-Tissue Sarcomas

Active therapeutic combinations, such as trabectedin and radiotherapy, offer potentially higher dimensional response in second-line treatment of advanced soft-tissue sarcomas. Dimensional response can be relevant both for symptom relief and for survival. To assess the combined use of trabectedin and radiotherapy in treating patients with progressing metastatic soft-tissue sarcomas. Phase 1 of this nonrandomized clinical trial followed the classic 3 + 3 design, with planned radiotherapy at a fixed dose of 30 Gy (3 Gy/d for 10 days) and infusion of trabectedin at 1.3 mg/m2 as the starting dose, 1.5 mg/m2 as dose level +1, and 1.1 mg/m2 as dose level -1. Phase 2 followed the Simon optimal 2-stage design. Allowing for type I and II errors of 10%, treatment success was defined as an overall response rate of 35%. This study was conducted in 9 sarcoma referral centers in Spain, France, and Italy from April 13, 2015, to November 20, 2018. Adult patients with progressing metastatic soft-tissue sarcoma and having undergone at least 1 previous line of systemic therapy were enrolled. In phase 2, patients fitting inclusion criteria and receiving at least 1 cycle of trabectedin and the radiotherapy regimen constituted the per-protocol population; those receiving at least 1 cycle of trabectedin, the safety population. Trabectedin was administered every 3 weeks in a 24-hour infusion. Radiotherapy was required to start within 1 hour after completion of the first trabectedin infusion (cycle 1, day 2). The dose-limiting toxic effects of trabectedin (phase 1) and the overall response rate (phase 2) with use of trabectedin plus irradiation in metastatic soft-tissue sarcomas. Eighteen patients (11 of whom were male) were enrolled in phase 1, and 27 other patients (14 of whom were female) were enrolled in phase 2. The median ages of those enrolled in phases 1 and 2 were 42 (range, 23-74) years and 51 (range, 27-73) years, respectively. In phase 1, dose-limiting toxic effects included grade 4 neutropenia lasting more than 5 days in 1 patient at the starting dose level and a grade 4 alanine aminotransferase level increase in 1 of 6 patients at the +1 dose level. In phase 2, among 25 patients with evaluable data, the overall response rate was 72% (95% CI, 53%-91%) for local assessment and 60% (95% CI, 39%-81%) for central assessment. The findings of this study suggest that the recommended dose of trabectedin for use in combination with this irradiation regimen is 1.5 mg/m2. The trial met its primary end point, with a high overall response rate that indicates the potential of this combination therapy for achieving substantial tumor shrinkage beyond first-line systemic therapy in patients with metastatic, progressing soft-tissue sarcomas. ClinicalTrials.gov Identifier: NCT02275286.

Safety and Efficacy of PD-1 Inhibitors Plus Chemotherapy in Advanced Soft Tissue Sarcomas: A Retrospective Study.

PurposeProgrammed cell death 1 (PD-1) inhibitors are ineffective as monotherapy for the treatment of soft tissue sarcomas (STS). However, increasing evidence shows that the combination of PD-1 inhibitors and chemotherapy is efficacious and safe for many types of malignancies, including STS. This study aimed to assess the safety and efficacy of doxorubicin chemotherapy plus PD-1 inhibitor in the treatment of metastatic STS.Patients and MethodsWe retrospectively reviewed 21 patients with metastatic STS who received doxorubicin chemotherapy plus a PD-1 inhibitor between November 2017 and October 2018.ResultsThe objective response rate was 47.6%, the disease control rate was 71.40%, and the median progression-free survival was 6 months (95% CI, 2–8 months). The average change in target lesion diameter from baseline was −25.15 ± 41.61. Majority of the patients experienced grade 1/2 adverse events (AEs), the grade 3/4 AEs were few. The most common grade 3/4 AEs were as follows: leukopenia (23.8%) and anemia (19.0%). Immune-related AEs were common and included hypothyroidism (14.3%) and pneumonitiss (9.5%). No drug related deaths occurred.ConclusionThis study provides preliminary evidence that the combination of doxorubicin chemotherapy and PD-1 inhibitor for advanced STS is safe and effective. We plan to conduct randomized clinical trials to confirm and characterize the activity of the chemotherapy-immunotherapy combinations in the treatment of sarcomas.

Combination therapy with Olaratumab/doxorubicin in advanced or metastatic soft tissue sarcoma -a single-Centre experience

BackgroundThe antibody targeting platelet-derived growth factor receptor alpha (PDGFRA), olaratumab, was approved in 2016 for metastatic soft tissue sarcoma (STS) in combination with doxorubicin based on promising results of a phase Ib/II trial by the Food and Drug Administration (FDA). However, recently the phase III ANNOUNCE trial could not confirm the additional value of olaratumab in this context.MethodsHere, in a retrospective analysis we share our single-centre experience with olaratumab/doxorubicin in STS by including n = 32 patients treated with olaratumab/doxorubicin between 2016 and 2019.ResultsMedian progression-free survival (PFS) in the overall cohort was 3.1 months (range 0.6–16.2). A response [complete remission (CR), partial remission (PR) or stable disease (SD)] was seen in n = 11 (34%) cases, whereas n = 21 (66%) patients showed progressive disease (PD). In n = 9 patients surgery was performed subsequently in an individual therapeutic approach. Out of n = 5 patients receiving additional regional hyperthermia, n = 3 achieved PR or SD.ConclusionsThis single-centre experience does also not support the promising phase Ib/II results for olaratumab/doxorubicin in STS. However, our findings do not preclude that olaratumab combination therapy could be valuable in a neoadjuvant setting. This warrants further exploration also taking into account the heterogeneous nature of STS.