Roberts, Ryan D.

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and osteosarcoma continue to have overall poor outcomes despite dose-intensive cytotoxic chemotherapy. The biology of treatment resistance is not currently well understood, partly due to limited availability of relevant tissue to study. There is a need for access to quality tumor specimens for molecular and other analyses to identify high-risk tumor subsets and drive discovery to improve patient outcomes. Given broad variability in bone tumor tissue procurement and processing across member institutions, the Children’s Oncology Group Bone Tumor Committee convened a multidisciplinary group of experts to outline the current and near-future tissue needs for optimal clinical care and access to research platforms. The goal of this working group was to provide high-level guidance on biopsy practices that safely meet these evolving needs. Harmonizing tissue collection practices is paramount to improving the care of children, adolescents, and young adults diagnosed with Ewing sarcoma and osteosarcoma.

PURPOSE Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration–approved for adults. METHODS ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m 2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. RESULTS Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was –41% (−90 to 13) in adults and –42% (−91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. CONCLUSION In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

11508 Background: Trabectedin(T) is a marine-derived minor groove DNA binding compound that alters transcription factor activity. Preclinical data suggests that T suppresses the oncogenic driver of ES, EWS::FLI1. This suppression requires a threshold concentration of T and is potentiated by low doses of Irinotecan(I). Preliminary clinical activity and reversal of the EWS::FLI1 transcriptome was seen in patients (pts) in the phase I portion of SARC037. Here we report the phase II results of T with I at the recommended dose in pts with relapsed/refractory ES. Methods: In this open-label multicenter study, T was given at 1 mg/m2 as a 1-h infusion on day(D)1 with I at 25 mg/m2 intravenously on D2 and D4 of a 21D cycle. Key eligibility criteria were EWS::FLI1 fusion transcript, age ≥6 years, ECOG ≤2, adequate organ function, and willing to have a research biopsy if safely accessible. The primary objective was to determine the objective response rate (ORR) assessed by RECIST v1.1. Secondary objectives were progression-free survival (PFS), duration of response (DOR), and safety. This study used a Simon two-stage design that required 4 or more responses (CR or PR) at the final analysis to establish treatment activity. Results: 18 pts enrolled from 12/2022-12/2023 across 6 sites, 8F/10M, median age 21y (9-43). Pts had a median of 3 (1-7) prior therapy lines, including I in 67% of pts. Of 16 pts evaluable for response at the cutoff date, 5 pts had a PR, and 2 pts had SD. Two pts have evaluations pending and two pts were removed for toxicity before the first evaluation. Median time to response was 2.6 months(m), 6-month PFS was 37.7% (95% CI 18.3%, 77.7%), and all responses were sustained at the time of data cutoff at 10.4+, 7.5+, 5.5+, 5.0+ and 4.6+ m. There were no G5 AEs. Most pts had molecular profiling, translocation testing, as well as ctDNA collection, quantitation, and analysis. A subset of pts had pre- and post-treatment biopsies for RNA sequencing and evaluation of the impact of drug exposure on the EWS::FLI1 transcriptome. Conclusions: T+I exhibited anti-tumor activity in heavily pretreated pts with ES and met its prespecified ORR with 5 PRs in 16 evaluable patients, all of which are ongoing at data cutoff. There were no unexpected safety signals. The combination of T given as a 1h infusion and low-dose I demonstrated meaningful clinical benefit and is worthy of further study in ES pts. Analysis of biological correlates is ongoing. Clinical trial information: NCT04067115 .