PEPN1924, a phase 2 study of trastuzumab deruxtecan (DS-8201a, T-DXd) in adolescents and young adults with recurrent HER2+ osteosarcoma: A children’s oncology group pediatric early-phase clinical Trial Network study.
Authors: Reed Damon R. , Janeway Katherine A. , Minard Charles G. , Hall David , Crompton Brian D. , Lazar Alexander J. , Wang Wei-Lien , Voss Stephan D. , Militano Olga , Gorlick Richard Greg , Pickett-Gies Cheryl Ann , Fox Elizabeth , Weigel Brenda 
Published: June 2023

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Background: Overall survival for patients (pts) with recurrent, unresectable osteosarcoma (OS) remains poor, and event free survival (EFS) based on historical benchmarks has been used to determine efficacy of investigational agents. HER2, a transmembrane receptor with kinase activity involved in cell signaling through the RAS pathway, is expressed in OS. T-DXd is a HER2 targeting antibody linked to DXd with preclinical in vitro studies demonstrating activity in OS correlating with the presence of HER2 expression. We report results of a Phase 2 study of T-DXd in adolescents and young adults with HER2 positive relapsed, unresectable OS. Methods: Pts (12-39 yrs) with relapsed, unresectable OS were eligible for screening. The most recent available tissue sample was centrally evaluated for HER2 expression by immunohistochemistry. Pts with greater than 10% of OS cells with cytoplasmic or membranous HER2 expression of any intensity were eligible to receive T-DXd at 5.4mg/kg IV every 3 wks for up to 2 yrs. The proportion of pts with an EFS at 24 wks was the primary endpoint estimated using a 9+15 Simon’s optimal two-stage design assuming an unacceptable response rate of 12%, acceptable response rate of 40%, 5% type 1 error, and 90% power. Results: 50 pts were screened for HER2, and 41 samples met the membranous or cytoplasmic HER2 expression inclusion criteria. A single pt had an assay failure and 8 pts had tumor samples with less than 10% HER2+ cells. Nine eligible pts were enrolled (7 male) between April 15th and November 11th of 2021 and received T-DXd. 2 pts were < 18 yrs old and the median age was 19.3 years. Seven pts received 2 cycles and had progressive disease (PD) at the first evaluation. A single pt withdrew consent before the first evaluation. The final pt was event free at wk 24, meeting the protocol specified criteria for a response. With a single pt having more than 24 wks of stable disease (SD) of the 9 planned in the first stage, this study did not meet criteria to progress to stage 2. The estimated response rate is 11.1% (1-sided 95% CI LB: 0.6%). The single responder with SD for 12 cycles had 15% HER2 positive OS cells and the remaining pts had 30-100% HER2 staining. A single cycle 1 DLT of thrombocytopenia (GR4) was observed. No unexpected or at least possibly or greater related AE’s were observed. Grade 3-4 at least possibly related AE’s occurred in 3 of 9 patients and included nausea, vomiting, tumor hemorrhage, cytopenias (n = 3), wound infection, and hypertension. Conclusions: T-DXd did not demonstrate sufficient response to expand enrollment to the planned second stage in pts with OS. None of the pts had significant HER2 membranous staining which may account for the limited efficacy. No new toxicities were observed. Further correlative studies including PK, anti-T-DXd analyses and circulating tumor DNA are ongoing. Clinical trial information: NCT04616560 .