Keedy, Vicki L.

11502 Background: To report results from the open-label alveolar soft part sarcoma (ASPS) cohort of the phase III APROMISS trial (NCT03016819) evaluating Catequentinib hydrochloride (AL3818), an oral multitargeted receptor tyrosine kinase inhibitor, in adults with advanced or metastatic ASPS. Methods: Adult patients with pathologic and molecularly confirmed advanced ASPS, either treatment-naive or previously treated (excluding cediranib), were enrolled in the open-label, non-randomized ASPS cohort of the phase III APROMISS trial conducted across the United States, Asia, and Europe. Catequentinib hydrochloride was administered orally at 12 mg once daily in 21-day cycles (14 days on/7 days off) until disease progression, toxicity, or death. The primary endpoint was objective response rate (ORR) assessed per RECIST by Blinded Independent Central Review (BICR) (predefined threshold: 31%). Secondary endpoints included duration of response (DOR) with a predefined target of =/>6 months, progression free survival (PFS) and overall survival (OS). Results: From July 2017 to August 2022, a total of 56 patients entered the trial; 56 patients were evaluable for the primary endpoint. Median (m-) age was 29.5 years (range: 18 – 66), with 24 female and 32 male. Best overall response included 1/56 complete response (1.8%), 14/56 partial responses (25.0%), 36/56 stable disease (64.3%), and 3/56 (5.4%) progressive disease. RECIST ORR by BICR was 26.8% (95% CI, 15.8–40.3); m-DOR was 22.57 months (95%CI: 10.38-NE). The study data was collected close to 8 years for all patients. mPFS was 18.33 months (95% CI, 14.19–23.13), with 6- and 12-month progression-free rates of 88.77% (95% CI, 76.68–94.79) and 65.54% (95% CI, 50.42–77.06), respectively. mOS was 59.27 months (95% CI, 44.09–NE), with 6- and 12-month overall survival rates of 94.64% (95% CI, 84.30–98.24) and 90.81% (95% CI, 79.30–96.08), respectively. Overall, 27/56 (48.2%) patients experienced grade ≥3 treatment-related adverse events, most commonly diarrhea (50.0%), hypertension (44.6%), fatigue (37.5%), nausea (35.7%), and palmar-plantar erythrodysesthesia syndrome (30.4%); one patient (1.8%) had a grade 5 event (respiratory failure). Conclusions: Catequentinib hydrochloride demonstrated meaningful antitumor activity and durable responses in adults with advanced ASPS. Despite the ORR of 26.8% slightly below the predefined 31% threshold, disease control was prolonged, with a m-DOR exceeding 22 months. Favorable PFS and OS outcomes, together with a manageable safety profile, support its clinical benefit in this ultra-rare sarcoma. Clinical trial information: NCT03016819 .

TPS11580 Background: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. KIT and platelet-derived growth factor receptor α ( PDGFRA ) mutations remain the key oncogenic drivers in the majority of patients with advanced GIST, with acquired secondary drug-resistant mutations contributing to the heterogeneity and complexity of the disease. The diversity of these resistance mutations allows escape from standard-of-care tyrosine kinase inhibitor (TKI) therapy, creating an unmet need for novel therapies that inhibit all clinically relevant GIST-driving mutations. DCC-3009 is an investigational, highly potent, and selective switch-control KIT and PDGFRA inhibitor designed to act against known clinically relevant primary and secondary GIST-driving mutations while limiting off-target effects. Preclinical data showed that DCC-3009 has strong antitumor effects in xenograft models driven by resistant KIT mutations, optimized solubility and oral bioavailability, and low risk of cytochrome P450 inhibition. Here, we describe an ongoing phase 1/2 study evaluating DCC-3009 as a monotherapy in patients with advanced GIST. Methods: This study is a multicohort, open-label, phase 1/2 trial evaluating the safety, tolerability, and efficacy of DCC-3009 in patients with advanced GIST (NCT06630234). This trial uses a modular approach, with each module defined according to the therapy (DCC-3009 alone or in combination with other anticancer agents) and divided into 2 parts (dose escalation and dose expansion). For inclusion in the DCC-3009 monotherapy dose escalation, adult patients (≥18 years) must have histologically or cytologically confirmed advanced GIST with documented KIT or PDGFRA mutation and progression on or intolerance to at least 1 approved TKI regimen in the advanced setting (imatinib if KIT -mutant). Patients must have at least 1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1) and an Eastern Cooperative Oncology Group Performance Status of 0 or 1 at screening. Exclusion criteria include receiving systemic anticancer therapy (encompassing investigational agents) within 14 days or less than 5 half-lives, radiotherapy within 14 days prior to first dose of study drug, prior or concurrent malignancy requiring treatment or expected to need treatment for active cancer, known allergy or hypersensitivity to the study drug components or any of its excipients, and impaired oral absorption or malabsorption syndrome. Enrolled patients across monotherapy dose escalation will receive DCC-3009 orally in 28-day cycles. The primary outcome measures for monotherapy dose escalation include safety assessment. Secondary outcome measures include objective response rate, duration of response, and progression-free survival by mRECIST v1.1, as well as overall survival and pharmacokinetics. Clinical trial information: NCT06630234 .

Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.

PURPOSE CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1–specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti–programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma. PATIENTS AND METHODS Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed. RESULTS A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1–specific T cells ( P = .01) and NY-ESO-1–specific antibody responses ( P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02). CONCLUSION Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti–programmed death ligand-1 therapies merits further evaluation in other clinical contexts.

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

The NCCN Guidelines for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with soft tissue sarcomas. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including the development of a separate and distinct guideline for gastrointestinal stromal tumors (GISTs); reconception of the management of desmoid tumors; inclusion of further recommendations for the diagnosis and management of extremity/body wall, head/neck sarcomas, and retroperitoneal sarcomas; modification and addition of systemic therapy regimens for sarcoma subtypes; and revision of the principles of radiation therapy for soft tissue sarcomas.

Abstract Trial Information Click here to access other published clinical trials. Lessons Learned The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. Background Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. Methods Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. Results Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92–3.67) months for regorafenib versus 2.07 (95% CI, 1.64–3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16–23.48) months for regorafenib and 4.89 (95% CI, 3.02–9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31–1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. Conclusion Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.

11011 Background: CMB305 (C) is an immunotherapy designed to generate an anti-NY-ESO-1 immune response (IR). C consists of a dendritic cell-targeting lentiviral vector encoding NY-ESO-1 gene (LV305), and a TLR-4 agonist NY-ESO-1 recombinant protein plus GLA-SE (G305). A Phase 1 study demonstrated C is safe, generates IR and conveys a median overall survival (mOS) of 23.7 months (15.5, not reached [NR]) for soft tissue sarcomas & 29.2 months (12.2, NR) for synovial sarcoma (SS) (ESMO 2018). We evaluated efficacy and safety of C and atezolizumab (A) vs A alone in NY-ESO-1+ SS and myxoid round cell liposarcoma (MRCL). Methods: A prospective randomized open label phase 2 study of C (LV305 Intradermal Days 0, 14, 42, 70 + G305 Intramuscular Days 28, 56, 84 then q 6wk up to one year (yr)) + A (1200mg IV q3wk) vs A alone in advanced NY-ESO-1+ SS/MRCL. Primary endpoints of OS and progression-free survival (PFS); secondary endpoints of safety, IR, and response rate and post hoc analysis by line of therapy. Results: 88 patients (pts) were enrolled and dosed. Arm C+A: median age 48 yrs, 73% SS, 98% relapsed metastatic, 73% ≥2 prior lines chemotherapy; Arm A: 47 yrs, 67% SS, 84% relapsed metastatic, 53% ≥2 prior lines chemotherapy. Most treatment-related adverse events (TRAE) Grade 1/2, no treatment related deaths. Summary of clinical outcomes. Conclusions: Despite no major differences in PFS and OS between the treatment arms (Arm C+A had more advanced disease and more prior lines of chemotherapy), Arm A +C achieved PRs, a higher level of anti-NY-ESO-1 IR, and pts with IR had numerically superior outcomes. Moreover, the clinical benefit of C+A in earlier lines of therapy warrant further study. Clinical trial information: NCT02609984. [Table: see text]