Advanced Leiomyosarcoma Research Articles

Phase 2 trial of avelumab in combination with gemcitabine in advanced leiomyosarcoma as a second-line treatment (EAGLES, Korean Cancer Study Group UN18-09).

In this single-arm, multicenter, phase 2 trial, the authors evaluated the efficacy and safety of avelumab plus gemcitabine in patients with leiomyosarcoma (LMS) who failed on first-line chemotherapy. Patients with advanced LMS received avelumab 10 mg/kg on days 1 and 15 (for up to 24 months) plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle until they developed disease progression or intolerable toxicity. The primary end point was the objective response rate (ORR). In total, 38 patients were enrolled. Of these, 35 patients were evaluable, and the ORR was 20% (95% confidence interval; [CI], 8%-37%). The disease control rate was 71%, and the median duration of response was 21.8 months (range, 7.6 to ≥43.3 months). The median progression free-survival was 5.6 months (95% CI, 4.5-6.8 months), and the median overall survival was 27.5 months (95% CI, 20.4-34.6 months). Grade 3-4 adverse events occurred in 70% of patients, of which neutropenia was the most common (54%). Immune-mediated adverse events occurred in five patients (14%; hypothyroidism, n=3; hepatitis, n=2). Patients who had a higher density of tumor-infiltrating lymphocytes (greater than the median) exhibited better ORR (35% vs. 8%; p=.104), progression-free survival (median, 7.3 vs. 3.3 months; p=.024), and overall survival (median, not reached vs. 21.5 months; p=.027). The combination of avelumab and gemcitabine demonstrated promising efficacy and manageable safety in patients with advanced LMS who progressed on first-line therapy. Tumor-infiltrating lymphocyte density may be an important factor in predicting the response to combining immunotherapy with chemotherapy.

An update on SOC-1882: A phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin for advanced leiomyosarcoma.

e23570 Background: Intratumoral injection of Talimogene Laherparepvec (TVEC) has a local oncolytic effect and evokes a cytotoxic immune response. The combination of Trabectedin (T) and Nivolumab (N) is a safe and effective therapy in soft tissue sarcoma (STS). Here, we report an update on an ongoing Phase 2 study that aims to determine the efficacy and safety of adding TVEC to the combination of T and N in advanced leiomyosarcoma (LMS). Objectives: Primary: To assess progression-free survival (PFS). Secondary: (1) To evaluate the best overall response, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 9, and 12 months, (4) Incidence of conversion from unresectable to the resectable tumor, and (5) Incidence of treatment-related adverse events (TRAEs). Patients and Methods: Eligible patients included patients ≥ 18 years of age with locally advanced unresectable or metastatic LMS, measurable disease by RECIST v1.1, and at least one accessible tumor for TVEC intratumoral injection. N (3 mg/kg q2 weeks), T (1.2 mg/m2 q3 weeks), and TVEC (1x108 PFU/ml q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x106 PFU/ml) was initially given, followed by a total dose of 1x108 PFU/ml q 2 weeks depending on tumor size) three weeks later. Results: Efficacy: Per protocol, there were 17 evaluable subjects (Modified Intention to Treat [mITT] patients who had completed at least one treatment cycle and had a follow-up CT scan). The median number of prior lines of therapy was 4 (range 1-9). The disease control rate (PR+SD) was 94% with 1 PR, and 15 SD. The median PFS was 8.0 months (95% CI:4.8-11.28) with a 6-month PFS rate of 71%; median OS 19.2 months (95% CI:12.7- 25.7); 6-month OS rate, 82%. Safety: 22 patients (Intention to treat [ITT] who had received at least one-time drug administration) were evaluated for safety analysis. The > Grade 3 TRAEs include anemia (n = 3), thrombocytopenia (n = 3), neutropenia (n = 1), increased ALT (n = 1), increased GGT (n = 1), decreased LVEF (n = 1), dehydration (n = 1), hyponatremia (n = 1). There were no new safety signals noted in this study. Conclusions: Taken together, the data confirms our previous report that (1) the combination regimen using Talimogene laherparepvec, Nivolumab & Trabectedin may be more effective and treatment for previously treated patients with advanced leiomyosarcoma with manageable toxicity, and (2) The best responders are patients with HR+ uterine LMS. Clinical trial information: NCT03886311 .

Randomized controlled, open-label, phase IIb/III study of lurbinectedin in combination with doxorubicin versus doxorubicin alone as first-line treatment in patients with metastatic leiomyosarcoma.

TPS11590 Background: Lurbinectedin (LUR) is a synthetic chemical entity structurally related to trabectedin that inhibits oncogenic transcription and is active in tumors addicted to transcription. Synergistic activity of the combination of LUR with Doxorubicin (DOX) was found in solid tumors. Preliminary results from two trials showed efficacy for LUR/DOX in anthracycline-naïve advanced Leiomyosarcoma (LMS) (1st or 2nd line) at different doses. In a phase 2 trial in soft tissue sarcoma (STS) patients (pts) (mostly with LMS: 12/20 pts), a combination of DOX 50 mg/m2 + LUR 2 mg/m2 Day (D)1 q3wk resulted in a response rate (RR) of 35% (4/7 LMS pts responding) and a disease control rate (DCR) at 24 wks of 40% (1). A phase 1b/2 trial in 10 advanced STS pts found a RR of 60% (5 were LMS, with 3 partial responses) treated at DOX 25 mg/m2 D1 or D1,D8 + LUR 3.2 mg/m2 D1 q3wk, (2). The promising results of these trials provide a rationale for further exploring this combination in a phase 2b/3 trial as first-line therapy for metastatic LMS (SaLuDo - NCT06088290). Methods: SaLuDo is a randomized, open-label study evaluating LUR in combination with DOX compared to DOX alone as first-line treatment of pts with metastatic LMS. The primary endpoint is progression-free survival (PFS) according to Independent Radiological committee (IRC). Secondary endpoints include overall survival, PFS according to Investigator assessment (IA), overall response rate, duration of response, and clinical benefit rate (according to IRC and IA), safety profile, patient-reported outcomes, pharmacokinetics, and exploratory pharmacogenomic analysis. Main inclusion criteria include age ≥ 18 years, confirmed diagnosis of metastatic LMS, and no prior systemic treatment for metastatic disease. Exclusion criteria include prior treatment with anthracyclines, lurbinectedin or trabectedin. The phase 2b part of the study will randomize approximately 120 pts into 3 arms (1:1:1): Control arm (DOX 75 mg/m2 D1 q3wk; experimental ARM A (DOX 50 mg/m2 D1 + LUR 2.2 mg/m2 D1 + 1ry GCSF prophylaxis q3wk), and experimental ARM B (DOX 25 mg/m2 D1 + LUR 3.2mg/m2 D1 + 1ry GCSF prophylaxis q3wk). Stratification will be done according to site of primary tumor (uterine vs. soft tissue), sites of metastatic disease (lung as unique site vs. other) and time from diagnosis to study entry (≤ 12 months vs. >12 months). One of the two experimental arms will be dropped out at the end of phase 2b. The study will then enter the phase 3 part and approximately 120 pts will be randomized 1:1 between the control arm and the selected experimental arm. An Independent Data Monitoring Committee will oversee the conduct of the study. The first patient was randomized in 09/2023. The phase 2b part of the study is ongoing and recruiting patients in Europe and the USA. 1. Cote EJC 2020; 126:21-32. 2. Cote. JCO 2023; 41: Abst 11507. Clinical trial information: NCT06088290 .

Efficacy and safety of anthracycline combined with alkylating agent for treatment of advanced leiomyosarcoma.

e23558 Background: Leiomyosarcoma(LMS) accounts for 12-14% of all soft tissue sarcomas(STSs) and this STS subtype has high metastatic potential. We evaluated the efficacy and safety of epirubicin combined with temozolomide(EPI-TMZ) for treatment of advanced LMS. Methods: Oral TMZ(200 or 300 mg) was administered each day on days 1-5, and intravenous EPI(60 mg/m2) was administered on days 1-4, with even distribution over these 96h within a 21‐day cycle. After 8 cycles of intensive chemotherapy, monodrug maintenance therapy consisted of TMZ alone(dosing as in the primary therapy, most choices, stop taking medication after 1 year control), and two-drug maintenance therapy consisted of TMZ with thalidomide(only 3 patients). All patients-initiated EPI-TMZ treatment between January 2018 and January 2024. Results: We examined 31 patients who received EPI-TMZ. There were 25 females and 6 males, with average age 50.5 years old. All were unresectable patients derived from abdominal retroperitoneum, uterus, inferior vena cava, mesentery, small intestine, stomach, thighs, elbows, wrists, pancreas, nasal cavity, meantime with distant metastasis. Average Ki67 is above 40%. This was a first-line treatment in 16 patients, a second- or third-line in 13, and a fourth-line in 2. At the time of data cutoff (January 31, 2024), the median PFS was 12.6 months, 1 patient had cCR, 9 PR and 20 SD. The ORR was 32.3%(10/31) and DCR was 96.8%(30/31). The only patient who progressed after two cycles of medication had PMS2 deficiency, and studies have reported that it may have a primary resistance mechanism. Even the shortest disease control period is also 5 months, indicating this regime has significant clinical benefit. Some patients have undergone tumor reduction surgery to improve quality of life after achieving significant tumor relief. The current longest PFS is 42 months up to now and under continuous tumor control. Previous retrospective studies indicated the best mPFS was 9.2 months and the best ORR was 30.9%. 2023 ESMO declared prospective doxorubicin with trabectedin obtained mPFS of 12.19 months. The most common treatment-related adverse effects were leukopenia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, and oral mucositis. Two patients had severe febrile neutropenia, but there were no treatment-related deaths, survival data follow-up. Conclusions: EPI-TMZ is potentially effective for treatment of advanced LMS, and the adverse effects appear tolerable. EPI-TMZ may provide better outcomes than reported in previous studies of other treatments for advanced LMS, worth further prospective research.

Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma.

This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS). Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m2 intravenously (IV) once every 21 days. The time-to-event continual reassessment method was used to determine the RP2D on the basis of dose-limiting toxicities (DLTs) assessed during the first two 21-day treatment cycles. All explored doses of unesbulin (200 mg up to 400 mg) were in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the RP2D. Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m2 IV once every 21 days was identified as the RP2D. On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%. Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m2 once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS.

Pharmacokinetics of Dacarbazine and Unesbulin and CYP1A2-Mediated Drug Interactions in Patients With Leiomyosarcoma.

Unesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5-aminoimidazole-4-carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m2 ) was administered to patients with LMS via 1-hour intravenous (IV) infusion on Day 1 of every 21-day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (BIW), starting on Day 2 of every cycle, except for Cycle 2 (C2), where unesbulin was dosed either on Day 1 together with DTIC or on Day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in Cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached Cmax immediately or shortly after end of infusion at 1.0 and 1.4 hours (Tmax ), respectively. Coadministration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2-mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC Cmax by 69.4% and AUCinf by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m2 IV DTIC q21d and 300 mg unesbulin BIW in a staggered regimen is well tolerated in patients with LMS.

Trabectedin and low-dose radiation therapy in patients with advanced leiomyosarcoma.

Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients. As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected. A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] versus 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, p = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) versus 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, p = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients. Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.

1930P phase II trial of avelumab in combination with gemcitabine in advanced leiomyosarcoma as a second-line treatment (KCSG UN18-06)

1930P phase II trial of avelumab in combination with gemcitabine in advanced leiomyosarcoma as a second-line treatment (KCSG UN18-06)

1934P Pharmacokinetics of unesbulin in a phase Ib study of patients with advanced leiomyosarcoma

1934P Pharmacokinetics of unesbulin in a phase Ib study of patients with advanced leiomyosarcoma

1925P Results of SOC-2082 phase II study using metronomic gemcitabine, doxorubicin, and docetaxel plus nivolumab as second/third-line therapy for advanced leiomyosarcoma

1925P Results of SOC-2082 phase II study using metronomic gemcitabine, doxorubicin, and docetaxel plus nivolumab as second/third-line therapy for advanced leiomyosarcoma

Safety, immunologic and clinical activity of Durvalumab in combination with Olaparib or Cediranib in advanced leiomyosarcoma: Results of the DAPPER clinical trial.

Non-inflamed (cold) tumors such as leiomyosarcoma (LMS) do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis-, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pre-treated LMS patients. Patients were randomized to receive durvalumab 1500mg IV q4w with either Olaparib 300mg bid PO (Arm A) or Cediranib 20mg qd PO on 5 days/week (Arm B) until unacceptable toxicity or disease progression. Paired tumor biopsies, serial radiological assessments and stool collections were performed. Primary endpoints were safety, and immune cell changes in the TME. Objective responses and survival were correlated with transcriptomic, radiomic and microbiome parameters. Among 30 heavily pre-treated patients (15 on each arm), grade ≥ 3 toxicity occurred in 3 (20%) and 2 (13%) on Arms A and B, respectively. On arm A, 1 patient achieved partial response (PR) with increase in CD8 T-cells and macrophages in the TME during treatment, while 4 had stable disease ≥ 6 months (SD-6m). No patients on Arm B achieved PR or SD-6m. Transcriptome analysis showed that baseline M1-macrophage and B-cell activity were associated with overall survival. Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some LMS patients. Baseline M1-macrophage and B-cell activity may identify LMS patients with favorable outcomes on immunotherapy and should be further evaluated.

Interim results of a phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin for advanced leiomyosarcoma.

11556 Background: Intratumoral injection of Talimogene Laherparepvec (TVEC) has a local oncolytic effect and evokes a cytotoxic immune response. The combination of Trabectedin (T) and Nivolumab (N) is a safe and effective therapy in soft tissue sarcoma (STS). This study aims to determine the safety and efficacy of adding TVEC to the combination of T and N in advanced leiomyosarcoma (LMS). Methods: Objectives: Primary: To assess progression-free survival (PFS). Secondary: (1) To evaluate the best overall response, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 9, and 12 months, (4) Incidence of conversion from unresectable to the resectable tumor, and (5) Incidence of treatment-related adverse events (TRAEs). Patients and Methods: Eligible patients included patients ≥ 18 years of age with locally advanced unresectable or metastatic LMS, measurable disease by RECIST v1.1, and at least one accessible tumor for TVEC intratumoral injection. N (3 mg/kg q2 weeks), T (1.2 mg/m2 q3 weeks), and TVEC (1x10e8 PFU/ml q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x10e6 PFU/ml) was initially given, followed by a total dose of 1x10e8 PFU/ml q 2 weeks depending on tumor size) three weeks later. Results: Efficacy: Per protocol, there were 11 evaluable subjects (Modified Intention to Treat [mITT] patients who had completed at least one treatment cycle and had a follow-up CT scan). The median number of prior lines of therapy was 4 (range 1-8). Confirmed Best Overall Response (BOR)by RECIST v1.1 = 2 PR, 9 SD (BOR Rate 18.2%). The disease control rate (PR+SD) at week 6 was 100%. The median PFS was 7 months (range: 3- 18); 6-month PFS rate, 55%; median OS 18.2 months (range: 4- 32); 6-month OS rate, 91%. There was no conversion from unresectable to resectable tumor. Response was not related to PD-L1 positivity but both patients with PR were ER+/PR+ and had uterine LMS. There were 15 evaluable subjects for OS analysis under the Intention-to-Treat (ITT) population who received at least one dose of study drug. The median OS was 12 (range 0-32) months; 6-month OS rate, 60%. Safety: Eight of 15 (53.3%) patients experienced at least one > Grade 3 treatment-related adverse event (TRAE). Grade 3 TRAEs include anemia (n=3), thrombocytopenia (n=2), neutropenia (n=1), increased ALT (n=1), increased GGT (n=1), decreased LVEF (n=1), myalgia (n=1) . Grade 4 TRAE include thrombocytopenia (n=1). The TRAEs were related to Trabectedin use. No new safety signals noted in this study. Conclusions: These results suggest that (1) By indirect comparison, the combination regimen using Talimogene laherparepvec, Nivolumab & Trabectedin may be more effective as second/third-line/fourth therapy for advanced leiomyosarcoma with manageable toxicity (Trabectedin alone for LMS= 4.3 mos; Dacarbazine alone = 1.6 mos; Demetri 2015), and (2) The best responders are patients with HR+ uterine LMS. Clinical trial information: NCT03886311 .

Safety and clinical activity of TTI-621 in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma: Results from the low-dose expansion cohort.

11508 Background: TTI-621 is a recombinant fusion protein combining the Fc region of human IgG1 with a fragment of human SIRPα, designed as a decoy receptor for CD47 on tumor cells to interrupt CD47-SIRPα signaling and promote macrophage-mediated phagocytosis of tumor cells as well as activation of NK cells. Preclinical studies suggest TTI-621 may enhance the response to doxorubicin in macrophage-rich tumors that express CD47, such as leiomyosarcoma (LMS). A phase 1/2 dose escalation study with high- and low-dose expansion cohorts evaluating TTI-621 + doxorubicin in patients (pts) with advanced LMS is ongoing (NCT04996004); results from the low-dose expansion cohort are presented. Methods: This open-label study enrolled anthracycline-naïve pts aged ≥18 y with evaluable unresectable or metastatic high-grade LMS and ≤1 prior line of therapy for advanced disease. Pts in the low-dose expansion cohort received TTI-621 0.2 mg/kg on Days 1 and 8 in combination with doxorubicin 75 mg/m2 on Day 1 of 21-day cycles for a maximum 6 cycles, followed by TTI-621 monotherapy on Days 1 and 15 of 28-day cycles until objective disease progression. Primary objectives for the expansion phase were evaluation of safety and investigation of clinical activity via assessment of overall response and clinical benefit rates as defined by RECIST v1.1 criteria. Results: At data cut-off (Oct 3, 2022), 23 pts were evaluable for safety and 20 for clinical response. In the safety population, 39% had received prior treatment for advanced disease. Two pts (9%) experienced Grade ≥3 AE assessed as related to TTI-621 treatment: pancreatitis (n = 1, 4%) and platelet count decreased (n = 1, 4%). Seven pts (30%) experienced Grade ≥3 AE related to the combination of TTI-621 and doxorubicin, including two pts (9%) each with platelet count decreased and white blood cell count decreased and three pts (13%) with neutrophil count decreased. Grade ≥3 doxorubicin-related AEs were more common (n = 17, 74%); most frequent were neutrophil count decreased (n = 8; 35%), white blood cell count decreased (n = 7; 30%), and neutropenia (n = 6; 26%). One pt experienced an infusion-related reaction (Grade 1 chills) assessed as related to TTI-621. No pts attained complete response, but one pt had a complete resolution of all target lesions. Five pts (25%) attained partial response for an overall response rate of 25%; 11 pts (55%) attained stable disease for a disease control rate of 80%. Conclusions: Addition of TTI-621 to doxorubicin showed promising clinical activity and a favorable safety profile among pts with advanced LMS, including those with prolonged exposure to TTI-621 ( > 360 d). Clinical trial information: NCT04996004 .

Immune correlates of outcome in patients with leiomyosarcoma (LMS) treated with durvalumab plus olaparib or cediranib: Transcriptome analysis from the DAPPER study.

11567 Background: Immune checkpoint blockade (ICB) as monotherapy has not shown clinical benefit in non-inflamed (cold) tumors such as LMS. Combining ICB with angiogenesis, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). In the DAPPER trial [NCT03851614], advanced LMS pts were randomized to receive ICB (Durvalumab 1500mg IV q4w) with either angiogenesis- (Cediranib 20mg qd PO on 5 days/week) or PARP inhibition (Olaparib 300mg bid PO) until unacceptable toxicity or disease progression (Ayodele et al, J Clin Oncol, 2021). Here, we present the results of transcriptomic and immune biomarker analyses of patients (pts) in the whole cohort. Methods: Radiologic responses were assessed using RECISTv1.1 and survival analysis performed by Kaplan-Meier method. Transcriptome analysis by RNAseq was performed on fresh tumor biopsies obtained from all pts at screening. Relative fractions of 22 immune cell subsets in the TME were inferred from gene-expression profiles using CIBERSORT v1.06. Gene set variation analysis (GVSA) to identify transcriptomic signatures associated with progression-free (PFS) or overall survival (OS) benefit was performed using GSVA R package v1.42. For comparison with an independent cohort, GVSA was also performed using transcriptome data from LMS pts (n = 104) in the cancer genome atlas (TCGA) dataset. Results: Among 28 response-evaluable pts, 1 (3.6%) had partial response; 10 (35.7%) had stable disease (SD); and 17 (60.7%) had progressive disease. Median PFS and OS were 2.8 months (95% CI, 2.8 – 5.4) and 14.6 months (95% CI 10.7 – NR), respectively. RNAseq data of adequate quality was available for 17 pts. Using the median CIBERSORT score as cut-off, pts with high M1 macrophage levels at baseline had significantly longer OS (p = 0.0019). High M1/M2 macrophage ratio score was also associated with longer OS (p = 0.05). GVSA identified 7 immune- and angiogenesis-related signatures that were associated with significantly longer OS. After false discovery rate correction, 1 signature comprising genes reflective of high overall B-cell activity remained significant. No transcriptomic signatures were associated with OS in the TCGA LMS cohort where pts did not receive ICB. Conclusions: Transcriptomic analysis shows that macrophage presence in the TME is associated with longer OS. Association of the B-cell activity signature with longer OS in LMS pts on the DAPPER trial, but not in the ICB treatment-naïve TCGA cohort suggests that high B-cell activity may identify pts who are more likely to have favorable outcomes with ICB and supports previous reports in sarcoma (Petitprez et al, Nature, 2020). Our results support ongoing further evaluation and integration of these biomarkers in LMS. Clinical trial information: NCT03851614 .

ImmunoSarc2: A Spanish Sarcoma Group (GEIS) phase Ib trial of doxorubicin and dacarbazine plus nivolumab in first line treatment of advanced leiomyosarcoma.

11502 Background: The immunogenic death caused by certain chemotherapy agents consists of molecular changes in tumor dying cells that stimulate immunogenicity and enhance antitumor effects. Doxorubicin is one validated drug related to immunogenic death, mainly through calreticulin membrane translocation that elicits immunogenic signals as phagocytosis by dendritic cells. Doxorubicin+pembrolizumab was explored in a phase I/II trial treating patients with metastatic/unresectable sarcomas, achieving 22% PR, 59% SD, and 19% PD, with mPFS of 8.1 months superior to historical controls. We hypothesized that the addition of an anti-PD1 (nivolumab) would increase the antitumor activity of commonly used upfront polychemotherapy in leiomyosarcoma (LMS) of doxorubicin plus dacarbazine. We present here the phase Ib, cohort 7b of ImmunoSarc2 trial. Methods: Adult patients (pts), with ECOG 0-1, naïve of previous anthracycline-containing treatments and with centrally confirmed diagnosis of advanced/metastatic leiomyosarcoma (LMS) were eligible. Initial dose level 0 (L0) was defined as doxorubicin (DOX) 75 mg/m2/d 20 min on D1 followed by dacarbazine (DAC) 400 mg/m2/d 60 min on D1 and 2, plus nivolumab (NIV) 360 mg on D2 after DAC Q3W with GCSF support. This combo would be given up to 6 courses of 21-day cycles, followed by 1-year NIV maintenance. A -1 dose level (L-1) was defined with the same regimen but with NIV 240 mg. A classic 3+3 phase 1 design was used to determine the MTD based on DLTs (main endpoint) observed during the first 21-day cycle. The cohort was foreseen to be extended with the RP2D up to 20 evaluable patients. Secondary endpoints included ORR and safety profile among others. Results: Between January 2022 and February 2023, 20 pts (M/F 6/14), ECOG 0/1 (15/5), with median age 54 years (31-72) were enrolled. All patients were treated with the initial L0 scheme and no DLTs were observed being L0 the RP2D. Grade 3-4 toxicities were neutropenia (20%), anemia (10%), febrile neutropenia, asthenia, and GGT increased (5% each). Four pts are not evaluable for efficacy (1 due to uncompliant dosing and 3 for not reaching the first tumor assessment yet). Of 16 efficacy-evaluable pts, RECIST ORR according to local clinical site assessment was 9 PR (56.2 %), 6 SD (37.5%), and 1 PD (6.3%) (2 SD cases had tumor size reductions > 20%). Five pts ended treatment due to progression (4 radiological, 1 clinical) and 15 pts remain under the trial therapy. mPFS for evaluable patients was 8.67 months (95% CI: 7.96-9.37) with a median follow-up of 8 months (2-12). Conclusions: DOX 75 mg/m2/d on D1 followed by DAC 400 mg/m2/d on D1 and 2, plus NIV 360 mg on D2 after DAC Q3W, followed by 1-year NIV maintenance is a feasible and well-tolerated scheme. Clinical activity is encouraging improving historical efficacy outcomes in first line of advanced LMS, which deserves further testing in phase II trials. Clinical trial information: NCT03277924 .

Therapeutic advances in leiomyosarcoma.

Leiomyosarcoma is an aggressive mesenchymal malignancy and represents one of the most common subtypes of soft tissue sarcomas. It is characterized by significant disease heterogeneity with variable sites of origin and diverse genomic profiles. As a result, the treatment of advanced leiomyosarcoma is challenging. First-line therapy for metastatic and/or unresectable leiomyosarcoma includes anthracycline or gemcitabine based regimens, which provide a median progression-free survival time of about 5 months and overall survival time between 14-16 months. Effective later-line therapies are limited. Molecular profiling has enhanced our knowledge of the pathophysiology driving leiomyosarcoma, providing potential targets for treatment. In this review, we explore recent advances in our understanding of leiomyosarcoma tumor biology and implications for novel therapeutics. We describe the development of clinical trials based on such findings and discuss available published results. To date, the most promising approaches for advanced leiomyosarcoma include targeting DNA damage repair pathways and aberrant metabolism associated with oncogenesis, as well as novel chemotherapy combinations. This review highlights the recent progress made in the treatment of advanced leiomyosarcoma. Ongoing progress is contingent upon further development of clinical trials based on molecular findings, with careful consideration for clinical trial design, strong academic collaborations, and prospective correlative analyses.

1528TiP A phase II/III study evaluating the efficacy and safety of unesbulin in advanced leiomyosarcoma (SUNRISELMS)

Leiomyosarcoma (LMS) is one of the most common and aggressive subtypes of soft tissue sarcoma in adults, with the highest risk of recurrence and decreased disease-specific survival (George S, et al. J Clin Oncol. 2018; 36:144–150). A high unmet need remains for treatment of patients with unresectable or metastatic, relapsed or refractory LMS. In a Phase 1b study (NCT03761095), unesbulin, a microtubule polymerization inhibitor, plus dacarbazine (DTIC), was evaluated in patients with unresectable or metastatic, relapsed or refractory LMS, with acceptable benefit/risk ratio to support the start of a Phase 2/3 study.

1483O Results of a phase I/II combination regimen with ipilimumab (I), nivolumab (N) and trabectedin (T) as first line therapy for advanced leiomyosarcoma

A 5-year phase I/II with an expanded phase II study of 101 patients has been recently reported. A subgroup of patients with advanced leiomyosarcoma (LMS) participated in the study. Hypothesis: Sarcoma tumors are more immunogenic at the onset of disease. Immune checkpoint inhibitors that promote sustained T cell activation would be most effective when given as first line therapy, together with a tumoricidal agent such as Trabectedin that depletes growth promoting macrophages in the tumor microenvironment.

1492MO Immune and vascular biomarkers associated with efficacy and mechanism of actions of the combination of lenvatinib (L) and eribulin (E) in leiomyosarcoma (LMS) and liposarcoma (LPS)

The interactions with immune system and influence on the tumor microenvironment (TME) of L + E remain elusive. The LEADER study (NCT03526679) investigated the efficacy of L + E in advanced LMS and LPS and immune-related biomarkers were examined.

Efficacy of PD-1 inhibitors combined with pegylated liposomal doxorubicin and dacarbazine compared with liposomal doxorubicin and dacarbazine in advanced leiomyosarcoma patients: a retrospective, single-institutional cohort study.

BackgroundPD-1 inhibitor monotherapy is ineffective for metastatic leiomyosarcoma (LMS), but it remains unclear whether PD-1 inhibitors demonstrate any efficacy when combined with chemotherapy. This study retrospectively evaluated pegylated liposomal doxorubicin (PLD) and dacarbazine (DTIC) with/without PD-1 inhibitors for advanced/metastatic LMS patients treated in our single institution.MethodsThe inclusion criteria were a confirmed histological diagnosis of LMS, treatment between January 2020 and March 2022, measurable disease (evaluated by CT or MRI), an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and age ≥18 years. The endpoints were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR).ResultsA total of 41 patients were included in this study, among whom 21 received PLD and DTIC alone while 20 received PLD and DTIC with PD-1 inhibitors. There were no differences of clinical characteristics between the two groups. Although the chemo plus PD-1 group had a better ORR (30% vs. 4.8%, P=0.04), there were no benefits in terms of disease control rate (DCR) (80% vs. 66.7%, P=0.29), PFS (8.8 months, 95% CI: 4.57–13.0 vs. 6.1 months, 95% CI: 3.03–9.14, P=0.54), and OS (not reached in both groups, P=0.84) when compared to chemo alone. Multiple treatment lines and previous use of tyrosine kinase inhibitors (TKIs) seemed to be negative factors for PFS in the univariate analysis, but failed to be significant in the multivariate analysis.ConclusionsThis retrospective, single-institutional study showed that PD-1 inhibitors combined with standard PLD and DTIC chemotherapy failed to exert benefits on survival for LMS patients. Considering the small sample size and retrospective clinical research design, further explorations are needed to verify the conclusion.