We previously reported initial results of the pivotal phase II trial of atezolizumab for patients with alveolar soft part sarcoma (ASPS; ClinicalTrials.gov identifier: NCT03141684). Here, we report on three additional years of observation. Fifty-three patients with ASPS received atezolizumab. Median duration of response increased to 37.0 months. Objective response rate (ORR) and median progression-free survival (mPFS) remained essentially as previously reported (35.8% [95% CI, 23.1 to 50.2] and 20.8 months [IQR, 7.6-not reached], respectively). ASPSCR1::TFE3 fusion type was determined for 47/53 patients; ORR and mPFS were higher among the 41 patients expressing type 1 (43.9% [95% CI, 28.5 to 60.2] and 28.3 months [IQR, 9.2-not reached], respectively) than the six patients expressing type 2 (0% [95% CI, 0 to 45.9] and 7.5 months [IQR, 3.9-not reached], respectively, PFS HR, 3.2 [95% CI, 1.01 to 10.2]). Eleven patients chose a per-protocol drug holiday (range, 3.5-26.4 months) after ≥2 years of treatment; two experienced disease progression during the holiday. Nine eligible patients elected to receive bevacizumab plus atezolizumab after progressing on monotherapy; ORR was 0% and mPFS was 18.5 months (IQR, 7.9-21.1) in this small cohort. Long-term results support using atezolizumab to treat ASPS, even for several years; a drug holiday with careful monitoring may be an option for some patients.

Abstract Immune checkpoint inhibitors (ICIs) are often stopped after 2 years (yrs) because studies have shown no overall survival benefit beyond 2 yrs and prolonged exposure has the potential to produce late-onset adverse events (AEs). However, questions remain about optimal treatment duration. Data in sarcoma are anecdotal and not confined to a specific histology; clinical trial data are lacking. The efficacy of atezolizumab (atezo) in advanced ASPS was demonstrated in a phase 2 trial, with an objective response rate of 37% reported.1 The trial has further matured and the duration of atezo monotherapy (monoTx) response now ranges from 10 to 69 months. We analyzed the safety data of patients (pts) who received more than 34 cycles (c) (i.e., >2 yrs) of atezo, either as monoTx or with the VEGF inhibitor bevacizumab (NCT03141684). Pts >2 yrs old with unresectable or metastatic ASPS were treated with 1200 mg/m2 atezo or a pediatric dose of 15 mg/kg q 3 weeks. Adult pts whose disease progressed on atezo were given the opportunity to cross over to receive atezo and bevacizumab (15 mg/kg q 3 weeks). Pts were seen q 3 weeks for assessment of AEs, which were reported using CTCAE v5. As of 6/16/25, 54 pts were enrolled. Seventeen pts aged 11-56 years (median: 29) received atezo with or without bevacizumab for >34 c: 12 pts with monoTx only (35-103 c) and 5 pts with monoTx followed by combination therapy (39-124 c across both arms). Three (18%) of the 17 pts reported new onset of grade 2 or 3 treatment-related AEs (TRAEs) after c 34: 1 pt (29 yrs old at entry) experienced grade 3 AST (probable attribution to atezo), 1 pt (31 yrs old at entry) experienced grade 2 hypertension and grade 2 proteinuria (both with a definite attribution to study agents, without distinction between the two), and 1 pt (36 yrs old at entry) experienced grade 2 pruritus (probable attribution to atezo). The pruritus began as grade 1 pruritus during c47; the pt began a drug holiday 2 c later and the pruritus advanced to grade 2 and then resolved with topical and oral medical management 5 months into the holiday. No grade 4 or 5 toxicities were reported. All TRAEs resolved. None of these pts came off study due to toxicity. This is the first report of the safety of prolonged ICI treatment and late AEs in sarcoma, specifically young ASPS pts, with careful monitoring. Late AEs were not seen in this treatment group. This is important in this AYA-dominant sarcoma. With the approval of atezo in multiple countries, real world data will continue to provide insight into the prolonged use of ICs in the young ASPS population. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, and by Genentech Inc. (member of the Roche Group), which provided drug and funding. Reference 1. Chen AP, Sharon E, O'Sullivan-Coyne G, et al. Atezolizumab for Advanced Alveolar Soft Part Sarcoma. New Engl J Med 2023;389:911-921. Citation Format: Alice P. Chen, Nancy Moore, Jared Foster, Christina Rosenberger, Geraldine O'Sullivan Coyne, John Glod, James Hu, Anthony Conley, William Read, Hari Despande, Gary Schwartz, James Chen, Scott Okuno, Richard Riedel, Elad Sharon, James Doroshow. Safety of prolonged checkpoint inhibitor exposure in alveolar soft part sarcoma (ASPS) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT004.

BackgroundThe efficacy of locoregional therapy with intraperitoneal (IP) drug delivery plus systemic chemotherapy for peritoneal carcinomatosis is understudied. We investigated progression-free survival (PFS) and overall survival (OS) in patients with peritoneal carcinomatosis from gastric, appendiceal, or small bowel adenocarcinoma who received intravenous (IV) and IP paclitaxel plus capecitabine or nilotinib.MethodsTwo separate single-institution phase II clinical trials evaluating IP and IV paclitaxel therapy plus capecitabine or nilotinib for peritoneal carcinomatosis were analyzed. Enrolled patients with peritoneal-only metastatic gastric cancer received IP and IV paclitaxel plus capecitabine. Participants with peritoneal carcinomatosis from appendiceal, gastric, or small bowel adenocarcinoma received IP and IV paclitaxel plus nilotinib.ResultsTwelve patients with a median age of 46 years (range 38-64) received bidirectional paclitaxel plus capecitabine. Median overall PFS and OS was 5.3 months (95% confidence interval [CI] 1.5-13.3) and 12.5 months (95% CI 4.7-14.7), respectively. Seven patients with peritoneal carcinomatosis from appendiceal, gastric, or small bowel adenocarcinoma with a median age 59 years (range 46-69) received bidirectional paclitaxel plus nilotinib. Median PFS and OS was 3.6 months (range 2.6-6.6) and 8.3 months (range 2.8-10.2), respectively, for those receiving bidirectional paclitaxel plus nilotinib. Adverse events (AEs) were common; grade 3-5 AEs occurred in 90.1% (10/11) of participants receiving IP/IV paclitaxel plus capecitabine and 100% (7/7) of patients receiving IP/IV paclitaxel plus nilotinib. There was no extra-peritoneal disease progression, suggesting tumor confinement among all participants.ConclusionsBidirectional paclitaxel-based chemotherapy plus capecitabine may delay progression of gastric adenocarcinoma with peritoneal-only metastasis. Bidirectional paclitaxel-based chemotherapy plus nilotinib was associated with mostly stable peritoneal disease in this small, heterogenous cohort. Bidirectional paclitaxel combinations are feasible and may have a role in therapy for disease stabilization in individuals with peritoneal carcinomatosis.

Indenoisoquinolines are a class of topoisomerase I (TOP1) inhibitors designed to overcome clinical limitations of camptothecins. Three indenoisoquinolines (LMP400, LMP776, and LMP744) demonstrated activity in murine models and a comparative canine lymphoma study. Clinical data for LMP400 were previously reported (NCT01051635). The maximum tolerated dose (MTD), safety, and clinical data from phase 1 studies of LMP776 (NCT01051635) and LMP744 (NCT03030417) are reported herein. Patients ≥ 18 years of age with advanced, refractory solid tumors or lymphomas received either LMP776 (n = 34) or LMP744 (n = 35) intravenously following a Simon accelerated titration design. Both LMP776 and LMP744 were administered daily for 5 days (QDx5) in 28-day cycles. Adverse events and clinical responses were evaluated according to CTCAE and RECIST v1.1 criteria, respectively. Pharmacokinetic and pharmacodynamic changes were evaluated. The MTD of LMP776 was 12 mg/m2/day and that of LMP744 was 190 mg/m2/day. Dose-limiting toxicities (DLTs) for LMP776 included hypercalcemia, anemia, and hyponatremia; DLTs for LMP744 included hypokalemia, anemia, and weight loss. There was 1 confirmed partial response (cPR) among 35 patients receiving LMP744 (overall response rate 3

Belinostat was approved in 2014 for the treatment of relapsed or refractory peripheral T-cell lymphoma, however, there was insufficient data to recommend a dose in patients with moderate to severe hepatic impairment. The purpose of this analysis was to characterize the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers and varying degrees of liver dysfunction. A population pharmacokinetic model was therefore developed to describe the parent-metabolite system. The final model was then implemented to assess the effect of liver impairment on each metabolic pathway of belinostat. It was determined that significant pharmacokinetic differences could only be demonstrated in patients with severe hepatic impairment. The final model estimated a 35

11557 Background: The U.S. Food and Drug Administration (FDA) recently approved the anti-PD-L1 antibody atezolizumab for alveolar soft part sarcoma (ASPS). Selinexor, a selective XPO1 inhibitor, demonstrated cytotoxic activity in ASPS-KY and ASPS-1 cell lines of ASPS and other sarcoma cell lines; it has been approved as a part of regimens to treat multiple myeloma and diffuse large B-cell lymphoma. Preliminary clinical data demonstrate acceptable safety profiles in patients with melanoma who received selinexor in combination with an anti-PD-1 antibody. Methods: We designed a randomized phase 2 study to evaluate atezolizumab with or without selinexor in adult patients with ASPS that included a safety run-in (SR) open to patients with soft tissue sarcoma (NCT05333458). Prior immune checkpoint inhibitor therapy was not allowed. During the SR, patients received selinexor (60 mg PO) on days 1, 8, and 15 of the 28-day cycle and atezolizumab (1200 mg flat dose IV) on day 8 at the Developmental Therapeutics Clinic. Protocol-defined treatment-related adverse events (TRAEs) occurring during cycle 1 would either expand accrual to the SR or close the study. Safety data were evaluated by the principal investigator and NCI CTEP (National Cancer Institute Cancer Therapy Evaluation Program). Results: Six patients were enrolled in the SR and were evaluated weekly during the first cycle of study treatment. All patients were female with a median age of 47 years (range: 22-71 years). Diagnoses included sclerosing epithelioid fibrosarcoma (n=2), dedifferentiated liposarcoma (n=1), metastatic leiomyosarcoma (n=1), metastatic angiosarcoma (n=1), and ASPS (n=1). No patients were removed from the SR due to AEs. Two patients experienced grade 3 TRAEs, including one instance each of neutropenia and lymphopenia (Table). Beyond cycle 1, there was 1 occurrence of grade 3 lymphopenia. No grade 4 or 5 AEs have occurred during the SR. Fatigue and nausea were the most prevalent TRAEs, but only one patient experienced grade 2 nausea; all other occurrences of nausea and fatigue were at grade 1. Conclusions: The safety run-in completed without any occurrences of protocol-defined treatment-related toxicity during cycle 1. The treatment was well tolerated. Based on these data, the randomized part of this study began accruing patients with ASPS across the ETCTN (Experimental Therapeutics Clinical Trials Network). Clinical trial information: NCT05333458 . [Table: see text]

Abstract Introduction: Clear cell sarcoma (CCS) constitutes <1% of sarcomas and frequently presents in adolescents and young adults. Chondrosarcoma is one of the most common bone malignancies in adults, occurring as conventional chondrosarcoma (CS) or the more-aggressive dedifferentiated chondrosarcoma (dCS). There is no standard of care therapy approved for these malignancies. The activity of immune checkpoint inhibition (ICI) in alveolar soft part sarcoma, together with case reports of ICI activity in these other sarcoma subtypes, prompted us to conduct a phase 2 clinical trial of atezolizumab (atezo), in patients (pts) with advanced CCS, CS, or dCS (NCT04458922). Methods: We evaluated the effect of targeting PD-L1 with atezo upon the growth and immune landscape of CCS, CS, and dCS. Pts received intravenous atezo 1200 mg/m2 once every 21 days. Prior ICI therapy was not allowed. Tumor biopsy pairs for immuno-pharmacodynamic (IO-PD) studies were collected at baseline and on Cycle 3 Day 1(C3D1); paraffin sections were analyzed using immunofluorescence (IF) microscopy after staining with two multiplexed antibody panels (CD4/FOXP3 and PD-L1/CD8/CD3ζ pY142). Biomarker-positive cells within the tumor area and margins were quantified using image analysis algorithms. Activated cytotoxic T lymphocytes (CTLs) were defined as CD8+ CD3ζ pY142+ and reported as the percentage of the total CD8+ cell density. Results: Nine pts were enrolled per disease cohort. No RECIST objective responses were observed; accrual was closed due to futility. Median progression-free survival (PFS) was 2.66 months (range: 1.3 to 11.7) in CCS, 3.22 (range: 1.4 to 8.9) in CS, and 2.04 (range: 0.4 to 11.7) in dCS. IF microscopy of biopsy pairs from five CCS pts revealed varied immune landscapes: 4/5 C3D1 biopsies contained PD-L1+ cells, 4/5 contained CD8+ cells, and 3/5 contained activated CTLs. Immune phenotype did not generally correlate with response; however, the highest percentage of activated CTLs occurred in the CCS pt with the longest PFS and this pt showed an increase in PD-L1+ cells on treatment—consistent with target engagement of the PD-L1/PD-1 immune checkpoint. dCS biopsy pairs (N=3) also contained a range of biomarker densities that did not correlated with PFS. In dCS and CCS, on-treatment increases in the percentage of activated CTLs were accompanied by increased Treg cell density in some pts. In contrast, CS biopsies (N=5) were uniformly devoid of infiltrating immune cells. Conclusion: The tumor microenvironment of CS is an immune desert, while dCS and CCS tumors contain a range of immune cell compositions. Atezo treatment increased the percentage of activated CTLs and density of PD-L1+ cells in some tumors, but an increase in Treg cells may explain why that pharmacodynamic evidence of ICI activity (the increase in activated CTLs) was not associated with clinical response. Funded NCI Contract No. HHSN261201500003I. Citation Format: Katherine V. Ferry-Galow, Kristin K. Fino, Geraldine O'Sullivan Coyne, Nancy Moore, Elad Sharon, Melissa Burgess, James Chen, Anthony P. Conley, Elizabeth J. Davis, Priscilla Merriam, Albiruni R. Abdul Razak, Brian Van Tine, Jared C. Foster, Naoko Takebe, Christina L. Rosenberger, James H. Doroshow, Alice P. Chen, Ralph E. Parchment. Atezolizumab clinical trial biopsies reveal varied immune landscapes in clear cell sarcoma and chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT263.

Clear Cell Sarcoma (CCS) is an extremely aggressive, rare soft tissue cancer accounting for approximately 1% of all sarcomas. Often diagnosed in young adults with a median age of 25 years, CCS has a strong propensity for local recurrence and metastasis with an overall high mortality rate. Current treatment recommendations include radical surgical extirpation, followed by radiation or chemotherapy. Nonetheless, there is a need for extensive postoperative follow-up as the efficiency of adjuvant therapy in managing this disease remains poor. Consequently, it is imperative to identify clinically relevant models to advance our understanding of CCS tumor biology and facilitate the development of novel therapies. Compared to conventional preclinical tumor models, patient-derived organoids (PDOrgs) better recapitulate the patient tumor biology, genetic heterogeneity, and therapeutic responses. Here, we describe the development and validation of a human biopsy-derived CCS organoid model 1010561-T. 1010561-T was established from a male patient's metastatic paraspinal mass. This PDOrg demonstrates a moderate growth rate (doubling time of ~20 days) and pleomorphic traits, consisting mainly of solid, grape-like clusters, as well as elongated cells of mixed morphology. Furthermore, this model was successfully maintained over 7 months in culture and remained stable more than one year after cryopreservation. 1010561-T exhibits the cytogenetic hallmark of CCS which is the presence of a recurrent t(12;22)(q13;q12) chromosomal translocation, resulting in a fusion between the Ewing sarcoma gene and activating transcription factor 1 (EWS/ATF1 fusion). Reverse-transcription polymerase chain reaction (RT-PCR) confirmed that 1010561-T harbors a dual EWS/ATF1 fusion, namely EWS exon 8 to ATF1 codon 65 fusion (type 1) and EWS exon 7 to ATF1 codon 110 fusion (type 3). Quantitative RT-PCR and immunocytochemistry revealed strong expression of melanocytic differentiation markers typical of CCS including melanocyte inducing transcription factor (MITF), melan-A (MLANA), premelanosome protein (PMEL), and S100 calcium binding protein A11 (S100A11). Additionally, the gene expression profile of 1010561-T is in concordance with a well-established CCS cell line, SU-CCS-1. To our knowledge, 1010561-T is the first human CCS organoid model. It is, therefore, a valuable resource for advancing our understanding of the biology of this very rare disease, in addition to being a useful tool for validating new preclinical therapies that are undoubtedly needed to achieve better clinical outcomes for patients. To this end, 1010561-T will be transferred to the National Cancer Institute’s Patient-Derived Models Repository (https://pdmr.cancer.gov) where it will be made available to the scientific community. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201800001I. Citation Format: Petreena S. Campbell, Erik D. Harris, Nancy Moore, Ralph E. Parchment, Nathan P. Coussens, Beverly A. Teicher, Alice Chen, James H. Doroshow, Annamaria Rapisarda. Establishment and characterization of a novel clear cell sarcoma organoid model derived from a human biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 154.

BACKGROUND:Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. METHODS:We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. RESULTS:A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. CONCLUSIONS:Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).

This study aimed at characterizing indotecan population pharmacokinetics and explore the indotecan–neutropenia relationship in patients with solid tumors. Population pharmacokinetics were assessed using nonlinear mixed-effects modeling of concentration data from two first-in-human phase 1 trials evaluating different dosing schedules of indotecan. Covariates were assessed in a stepwise manner. Final model qualification included bootstrap simulation, visual and quantitative predictive checks, and goodness-of-fit. A sigmoidal Emax model was developed to describe the relationship between average concentration and maximum percent neutrophil reduction. Simulations at fixed doses were conducted to determine the mean predicted decrease in neutrophil count for each schedule. 518 concentrations from 41 patients supported a three-compartment pharmacokinetic model. Body weight and body surface area accounted for inter-individual variability of central/peripheral distribution volume and intercompartmental clearance, respectively. Estimated typical population values were CL 2.75 L/h, Q3 46.0 L/h, and V3 37.9 L. The estimated value of Q2 for a typical patient (BSA = 1.96 m2) was 17.3 L/h, while V1 and V2 for a typical patient (WT = 80 kg) was 33.9 L and 132 L. The final sigmoidal Emax model estimated that half-maximal ANC reduction occurs at an average concentration of 1416 µg/L and 1041 µg/L for the daily and weekly regimens, respectively. Simulations of the weekly regimen demonstrated lower percent reduction in ANC compared to the daily regimen at equivalent cumulative fixed doses. The final PK model adequately describes indotecan population pharmacokinetics. Fixed dosing may be justified based on covariate analysis and the weekly dosing regimen may have a reduced neutropenic effect.

11533 Background: Chondrosarcoma (CS) is one of the most common bone malignancies in adults. Contrary to the indolent nature of low-grade CS, the dedifferentiated subtype (dCS), representing 5-10% of all CS, is known for aggressive behavior, high risk of relapse following resection, and poor prognosis. Expression of PD-L1 has been demonstrated in dCS samples and correlated with high numbers of tumor-infiltrating lymphocytes (Kostine, et al., Mod Pathol, 2016). Response to anti-PD1 therapy has not been evaluated prospectively. We report here the outcomes of a dCS cohort treated with the anti-PD-L1 agent, atezolizumab (atezo). Methods: Patients (pts) 2 years of age or older received intravenous atezolizumab 1200 mg (15 mg/kg with a 1200 mg cap in pediatric pts) once every 21 days. Prior immune checkpoint inhibitor therapy was not allowed. Primary objective was response rate (ORR). Imaging was carried out at the end of cycle 3 and then every two cycles; responses were evaluated per RECIST 1.1. The study employed a Simon two-stage design. If no responses were observed within 9 months of the ninth patient being enrolled, the cohort was to be terminated early. Research biopsies for immuno-pharmacodynamic (IO-PD) studies were collected at baseline, prior to C3D1, and optionally at progression. Results: Nine pts were enrolled to the dCS cohort. Three pts were female, 8 pts were White (1 unknown), all had an ECOG performance score ≤1, and their median age was 63 years (range, 53-85). Primary disease sites were pelvis (2); sternum (2); femur, hip, chest, scapula, and lung (1 each). Median duration of treatment for all pts was 9 weeks. Seven pts were evaluated for response, of whom 3 (42.9%) were documented to have stable disease (SD) as best response, lasting a median of 25.9 weeks (range, 15-38.3 weeks). Four pts had a best response of disease progression. Two pts died prior to first response assessment. No RECIST objective responses were observed; the cohort was closed due to futility. Reasons for treatment discontinuation included progression (n = 6), death (1, respiratory failure unrelated to treatment), withdrawal of consent (1), and SARS-CoV-2 infection (1). Treatment-related adverse events (TrAE), grades 1-3, occurred in 7 pts (78%). Grade 3 TrAEs occurred in 2 pts (22%), included infusion reaction, myonecrosis, and anemia. IO-PD studies are ongoing to elucidate changes within the tumor microenvironment. Conclusions: Though objective response was not seen, atezo showed stabilization of disease in 1/3 of the patients with this aggressive tumor. IO-PD results will be critical to identify determinants of atezolizumab resistance within this dCS cohort and to identify possible partners for combination therapy. Funded by NCI Contract No. HHSN261201500003I. This project was also supported in with funding and drug supply from Genentech Inc (a member of the Roche group). Clinical trial information: NCT04458922 .

11528 Background: Chondrosarcoma is one of the most common bone malignancies in adults, and the third most common in pediatric patients (pts). The most prevalent subtype, conventional chondrosarcoma, is a slow growing tumor that is historically known to be refractory to chemotherapy. Anecdotal reports indicated a role for anti-PD-(L)1 in the treatment of this disease. This is the first prospective report on the efficacy of the PD-L1-targeting agent, atezolizumab, in this rare disease. Methods: Patients (pts) ages 2 and older with unresectable grade 2 or 3 conventional chondrosarcoma were eligible. No prior anti-PD-(L)1 treatment was allowed, otherwise pts were eligible irrespective of prior therapies as long as protocol-specified washout period requirements were met. Pts received atezolizumab 1200 mg (15 mg/kg with 1200 mg cap in pediatric pts) once every 21 days. Imaging was carried out at end of cycle 3, and then every two cycles. Research biopsies were collected from adult pts prior to C1D1, prior to C3D1, and at progression. Immuno-pharmacodynamic (IO-PD) studies were performed on paired tumor samples and circulating immune cells to help elucidate signaling pathways mediating the immune response, with focus on subsets of effector cells in the tumor microenvironment. Results: A total of 9 pts (7 males, 2 females) were enrolled in 6 centers across the US and Canada. Six pts were Caucasian/White, 1 Asian, 1 Hispanic, and 1 unknown. Median age was 49 years (42-72). No objective responses were seen. Three pts (33%) experienced disease stability (SD) per RECIST 1.1, for a median duration of 21 weeks as of data cutoff (January 2022). A patient with SD remains on active treatment (tx) for 35 weeks. Three patients had no tx-related adverse events (AEs). Six pts (67%) experienced at least one tx-related AE. Two patients experienced > G2 AEs, but only one was considered tx-related (lymphopenia). Immune-related AEs were all G1/2 and included hepatitis (2), hypothyroidism (1), hyperthyroidism (1), and maculopapular rash (1). IO-PD studies are ongoing and will be reported at the conference if available. Conclusions: Atezolizumab was well-tolerated but demonstrated limited activity in this cohort of pts with few treatment options. Ongoing IO-PD studies will provide insight into atezolizumab’s effect upon immune cell content and activation in the tumor microenvironment that will help design future immunotherapy trials in this disease and other sarcoma types. The study was funded by NCI Contract HHSN261201500003I. Clinical trial information: NCT04458922.

BACKGROUND:Differential responses to tamoxifen may be due to inter-patient variability in tamoxifen metabolism into pharmacologically active Z-endoxifen. Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefitting patients responding sub-optimally to tamoxifen. MATERIALS AND METHODS:Patients with treatment-refractory gynecologic malignancies, desmoid tumors, or hormone receptor-positive solid tumors took oral Z-endoxifen daily with a 3+3 phase 1 dose escalation format over 8 dose levels (DLs). Safety, pharmacokinetics/pharmacodynamics, and clinical outcomes were evaluated. RESULTS:Thirty-four of 40 patients were evaluable. No maximum tolerated dose was established. DL8, 360 mg/day, was used for the expansion phase and is higher than doses administered in any previous study; it also yielded higher plasma Z-endoxifen concentrations. Three patients had partial responses and 8 had prolonged stable disease (≥ 6 cycles); 44.4% (8/18) of patients at dose levels 6-8 achieved one of these outcomes. Six patients who progressed after tamoxifen therapy experienced partial response or stable disease for ≥ 6 cycles with Z-endoxifen; one with desmoid tumor remains on study after 62 cycles (nearly 5 years). CONCLUSIONS:Evidence of antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy, supporting further study of Z-endoxifen, particularly in patients with desmoid tumors.

PURPOSEThis trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm).MATERIALS AND METHODSAdult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway.RESULTSAmong 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P = .038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm.CONCLUSIONFurther investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.

11519 Background: ASPS constitutes < 1% of soft tissue sarcomas and frequently presents in adolescents and young adults. There are no approved therapies for ASPS. We are currently evaluating the clinical activity of atezolizumab (atezo), an anti-PD-L1 antibody, in patients (pts) with advanced ASPS. Methods: This is a multicenter, open-label, single-arm phase II study where atezo is administered at a fixed dose of 1200 mg in adults or 15 mg/kg (1200 mg max) in pediatric pts age ≥2 once Q21 days. The primary objective is to determine the objective response rate (ORR) of atezo using RECIST 1.1. Secondary objectives include duration of response and correlating response with the immune effects of atezo in blood and paired tumor biopsies (pre- and post-treatment). Tumor specimens were analyzed with multiplex immunofluorescence immuno-oncology panels to quantify CD8+, PD-1+, and PD-L1+ cells/mm 2 in the tumor microenvironment. CD8+ density was calculated as the total number of CD8+ cells divided by the entire area (mm 2 ) of the tumor and invasive margins of the biopsy. Results: As of February 4, 2021, 44 pts have been enrolled. The median age in the study was 31 years (range, 12–70) with equal male: female distribution. 54.5% of pts were Caucasian. Baseline ECOG ≤1 was present in 97.7%. The median time on study was 11.5 months (range, 0.8–40.3 months). At data cutoff, response evaluation was available for 43 pts with an ORR of 37.2% (16/43). One pt experienced a complete response and 15 pts experienced a partial response (PR), of which 14 were confirmed. The median time to confirmed response was 3.5 months (range, 2.1–14.9 months). The median duration of confirmed response was 16.5 months (range, 4.9–38.1 months). Stable disease (SD) was present in 58.1% (25/43). One or more grade 3 adverse events potentially related to atezo were identified in 16.3% (7/43) pts. These include diarrhea, hypothyroidism, transaminitis, anemia, vertigo, extremity pain, myalgia, pneumonitis, rash, and stroke (n = 1 each). No grade 4 or 5 events have been reported. Among 8 cases with evaluable biopsy pairs, both baseline and C3D1 specimens in all cases demonstrated CD8+ T cell infiltration and PD-L1 expression. PD-1 expression was detected at baseline in 5 cases and at C3D1 in 7 cases. In 6 cases (3 SDs and 3 PRs), treatment did not change CD8+ cell density. In the other 2 cases (both PRs), CD8+ density increased > 3x above baseline by C3D1. Analysis of T cell activation using pharmacodynamic response biomarkers, along with whole exome and RNA-seq to evaluate the genomic and transcriptomic landscape of ASPS, are ongoing. Conclusions: Atezo is well tolerated and demonstrates promising single agent activity with durable responses in advanced ASPS. Preliminary tumor biomarker analysis confirms the presence of multiple PD-1/PD-L1 immune checkpoint (IC) components, indicating that advanced ASPS is an ideal candidate for therapeutic IC inhibition. Funded by NCI Contract No HHSN261200800001E. Clinical trial information: NCT03141684.