PEPN1924, A Phase II Study of Trastuzumab Deruxtecan in Patients With Recurrent Human Epidermal Growth Factor Receptor 2+ Osteosarcoma: A Children’s Oncology Group Pediatric Early-Phase Clinical Trial Network Study

Abstract

PURPOSE

Human epidermal growth factor receptor 2 (HER2), a transmembrane receptor with kinase activity involved in cell signaling through the RAS pathway, is expressed in osteosarcoma (OST). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate with a HER2-targeting monoclonal antibody, trastuzumab, linked to a topoisomerase I inhibitor. We report results of a phase II study of T-DXd in adolescents and young adults with HER2-positive relapsed, unresectable OST (ClinicalTrials.gov identifier: NCT04616560).

METHODS

Patients age 12-39 years with relapsed, unresectable OST were eligible for centrally evaluated HER2 expression screening by immunohistochemistry. Patients with >10% of OST cells with cytoplasmic or membranous HER2 expression of any intensity were eligible to receive T-DXd at 5.4 mg/kg intravenously once every 3 weeks for up to 2 years. The study used a 9 + 15 Simon’s optimal two-stage design with a primary end point of event-free survival at 24 weeks.

RESULTS

Fifty patients were screened for HER2, and 41 met the inclusion criteria of 10% of OST cells having membranous or cytoplasmic HER2 expression. Nine eligible patients, two younger than 18 years, were enrolled and received T-DXd. With a single patient having more than 24 weeks of stable disease (SD) of the nine planned in the first stage, this study did not meet criteria to progress to stage II. The estimated SD rate at 24 weeks is 11.1%. The median (range) number of cycles of therapy was 2 (2-12). Grade 3 and 4 possibly related adverse events occurred in three of nine patients and included nausea, vomiting, tumor hemorrhage, cytopenias (n = 3), wound infection, and hypertension.

CONCLUSION

T-DXd did not demonstrate sufficient activity to expand enrollment to the planned second stage in patients with OST. No new safety signals were observed.

INTRODUCTION

Osteosarcoma (OST) is the most common bone cancer in children and young adults. Complete resection of the primary tumor is critical for cure, and adjuvant chemotherapy clearly improves survival.¹ However, overall survival (OS) for patients with recurrent OST remains poor, and new strategies beyond the standard 3-drug chemotherapy regimen of doxorubicin, cisplatin, and high-dose methotrexate are urgently needed, given the lack of improvement in outcome in over 3 decades.^2-5 The main predictors of survival after OST recurrence include the time to first recurrence, disease burden, and ability to achieve complete surgical remission after recurrence.^6-9 Relapsed and unresectable OST remains an unmet need with poor prognosis with established historical control event-free survival (EFS) rates of below 20% at 4 months being the standard benchmark to evaluate new agents for this patient population.^8,10-12

Human epidermal growth factor receptor 2 (HER2; gene ERBB2) is a transmembrane receptor with kinase activity when heterodimerized with other ERBB receptors. Along with HER1 (epidermal growth factor receptor [EGFR]), HER3, and HER4, it is involved in cell signaling through the RAS and PI3K pathways that are important for regulating cell growth, survival, and differentiation.¹³ ERBB2 is an oncogene with increased expression across a variety of cancers, most notably in breast cancer where, for example, the targeted monoclonal antibody therapy trastuzumab and the small molecule tyrosine kinase inhibitor lapatinib are US Food and Drug Administration (FDA) approved. HER2 expression evaluation in OST has been complicated by varying sensitivities of different antibodies, different thresholds of positivity across studies, varying publications in regard to HER2 being a prognostic marker, and by variably expressed HER2 both on the cell surface and within the cytoplasm.^14-21 A prospective Children’s Oncology Group (COG) study of trastuzumab in combination with cytotoxic chemotherapy (AOST0121) designed to evaluate safety and feasibility did not show improvement in survival for newly diagnosed patients with metastatic OST when compared with historical comparison data.²² In this study, 40% of patients (n = 100) had HER2-positive disease defined as 2+ staining, using the CB11 antibody, in >50% of cells. Compared with breast cancer, OST positivity for HER2 was not limited to the membrane, uses a different threshold for positivity, and a different antibody in the assay. More recently, multiple early-phase studies of HER2-targeted chimeric antigen receptor (CAR)–modified T cells were completed in HER2-positive recurrent or refractory sarcomas, with a total of 24 patients having OST.^23,24 Of the evaluable patients with OST receiving the CAR-T therapy across these two studies, five had stable disease (SD), some demonstrated >90% necrosis on tumor resection, and a single patient with microscopic positive margins at study entry remained without evidence of disease for over 3 years then progressed.^23,24

Fam-trastuzumab deruxtecan-nxki (trastuzumab deruxtecan, DS-8201a, T-DXd) is an antibody-drug conjugate (ADC) composed of the HER2-targeting antibody trastuzumab linked to a derivative of the topoisomerase I inhibitor exatecan (DXd [DX-8951 derivative]) through a maleimide glycine-glycine-phenylalanine-glycine peptide linker.^25-27 T-DXd exerts antitumor activity through binding HER2, being internalized where cleavage of the linker leads to delivery of the topoisomerase I inhibitor DXd within the cell which can also permeate neighboring cells through a by-stander effect.^28-30 At the time of study activation, T-DXd was FDA approved in HER2-positive and HER2-low breast cancer, HER2 mutant non–small cell lung cancer (NSCLC), and HER2-expressing gastric carcinoma, and it was being investigated in many additional histology specific and agnostic settings.^31-33 Perhaps of most interest to our OST study, the patients with low-expressing HER2 breast cancer had a response rate of 38.5% with a median progression-free survival of 10.1 months versus 5.4 months in the physician’s choice comparator arm and a 6.6-month OS advantage.³²

Preclinical in vivo studies in OST have been performed with T-DXd through the Pediatric Preclinical Testing Consortium demonstrating activity by prolongation of SD across a range of HER2 expression by immunohistochemistry (IHC). In addition, responses in HER2-expressing pediatric malignancies were seen in malignant rhabdoid tumor, Wilms tumor, and Ewing sarcoma.³⁴ The COG Bone Tumor Committee has recently conducted multiple phase II studies in the adolescent population using novel agents with targets relevant to OST but without available phase I pediatric data. Both AOST1321 (ClinicalTrials.gov identifier: NCT02470091, evaluating denosumab, a RANKL inhibitor) and AOST1521 (ClinicalTrials.gov identifier: NCT02487979 evaluating glembatumumab vedotin, the antibody-drug conjugate to GPNMB) successfully enrolled patients with adequate safety monitoring and demonstrated glembatumumab pharmacokinetics (PK) were similar to adults.¹⁰ In addition, FDA guidance supports the inclusion of adolescents age 12 years and older in oncology clinical trials assessing efficacy using safety and dosing from phase I trials in adults.³⁵ We thus developed a phase II, nonrandomized, single-agent T-DXd trial in patients with HER2-positive OST to evaluate if the agent could meaningfully prolong disease progression compared with a historical benchmark.

METHODS

Study Design

A 9 + 15 Simon’s optimal two-stage design was used to estimate the proportion of patients with recurrent measurable OST treated with T-DXd who are event-free (EF) at 24 weeks. T-DXd was administered at 5.4 mg/kg intravenously over 30-90 minutes once every 3 weeks. Investigational T-DXd supply was provided by National Cancer Institute/Cancer Therapy Evaluation Program (IND No.: 153036). This was a two-stage, phase II study with efficacy being defined as patients being EF at 24 weeks with a sample size powered (90%) to detect a difference between a 12% and 40% rate assuming α = .05. At least two patients were required to be EF at 24 weeks among nine evaluable patients to proceed to stage II enrollment. At least six of 24 were required to be EF at 24 weeks in stage II to warrant further research. The proportion of patients who are EF at 24 weeks is estimated by the uniform minimum variance unbiased estimator with a one-sided 95% CI.^36,37

The PEPN1924 trial was approved by the central institutional review board, and all patients, or their parent/legal guardian, signed informed consent; assent was obtained per institutional guidelines. Secondary aims included assessing the safety of T-DXd in patients with OST including evaluating T-DXd in the adolescent population for the first time, describing the PK, estimating the RECIST 1.1 objective response rate, EFS, OS, and duration of response of patients with recurrent, measurable OST, and describing circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) and other biomarkers in recurrent OST (ctDNA and CTC analyses pending).

HER2 Expression Assay for Inclusion

Immunohistochemical study was performed on formalin-fixed paraffin-embedded unstained tissue sections using a mouse antihuman HER2 ready-to-use monoclonal antibody (clone CB11, Leica Biosystems, Buffalo Grove, IL). Other HER2 antibodies were explored but were far less likely to stain OST cells. The protocol specified that the most recent sample, preferably a metastatic lesion, not subjected to acid decalcification be submitted. Briefly, after deparaffinization and rehydration of the tissue sections, antigen retrieval was performed with a citrate-based buffer, pH 6.0 (Leica Biosystems) at 100°C for 30 minutes. Primary anti-HER2 antibody (clone CB11), previously pretitered by the manufacturer, was applied for 120 minutes. Primary antibody detection was carried out using the BOND Polymer Refine Detection kit (Leica Biosystems). Scoring was based on any degree of cytoplasmic staining and on the percent of OST positive cells rather than categorial (1+, 2+, etc) membranous staining. Patients with HER2-positive tumor were defined as >10% of OST cells having either membranous or cytoplasmic staining and were eligible. All others who did not meet this threshold were considered negative and not in the analysis cohort.

Patients

Patients age 12-39 years with HER2-positive, unresectable, measurable OST who had received at least standard initial therapy, defined as systemic therapy combined with either radiation or surgery for local control of the primary tumor at diagnosis, and with no limit on the number of previous therapies were eligible for screening. Previous therapy after relapse was not required. In addition, participants must have had a performance status corresponding to Eastern Cooperative Oncology Group scores of 0 or 1, recovered from the acute effects of previous therapies, and have not received previous HER2 therapies including ADCs (eg, TDM-1 or T-DXd), HER2-directed cellular therapies, HER2 receptor therapy (eg, trastuzumab or pertuzumab), or small molecule antagonists of HER2 (eg, lapatinib or neratinib). Standard laboratory parameters and organ function were used including having a pulse oximetry >93% on room air.

Toxicity Evaluation

Adverse event (AE) was graded according to the Common Terminology Criteria for Adverse Events version 5.0. The relative frequency of each AE considered possibly, probably, or likely related to T-DXd was monitored using the Bayesian Optimal Interval (BOIN) design. Following the BOIN design, three serial cohorts (each cohort included three patients) received T-DXd (5.4 mg/kg/dose) and completed cycle 1 dose-limiting toxicity (DLT) evaluations before opening the next cohort. Decisions to continue or stop the study due to excessive toxicity were based on observed DLT rates.^38,39 Additionally, all available safety data, including all toxicities (regardless of grade) for all patients who received at least one dose of study drug, were planned to be reviewed after stage I was completed.

Response Assessment

Tumor response assessment by anatomic imaging was performed after two cycles and then every two cycles thereafter and characterized as SD or progression by RECIST 1.1. Patients may have been treated up to 2 years (35 cycles).

Pharmacokinetics

Blood samples were collected for cycle 1 at time points preinfusion, postinfusion, 4 hours, 7 hours, and 24-30 hours, and 7 days and 14 days after the infusion start. Before the start of cycle 2, a preinfusion sample was collected followed by a 24- to 30-hour postinfusion sample. For the cycle 3 time point, blood sample collections include the preinfusion and postinfusion, 4 hours and 7 hours, and 7 days and 14 days. Cycle 4 collections were preinfusion and postinfusion. The PK parameters were calculated using the noncompartmental analysis (Phoenix 8.4, Certara USA, Radnor, PA).

Correlates

Ten milliliter of peripheral blood was collected in CellSave tubes for CTC collection and 10 mL of peripheral blood was collected in a Streck cfDNA tube for cfDNA analysis. Both were collected at cycle 1, day 1 within 30 minutes of the start of infusion and within 30 minutes after infusion completed. Both were also collected on days 2, 8, and 15 of cycle 1 and at any time of disease evaluation including with any progression of disease. Samples were shipped at ambient temperature overnight to a central laboratory.

RESULTS

Patients

The rate of HER2 expression at the 10% threshold for the screening (Step 0) assay required for inclusion for the trial was estimated to be 30%-40%. We instead found 41 of 50 screened patients had more than 10% of OST cells with cytoplasmic or membranous HER2 staining by IHC with the CB11 antibody (Fig 1). A single patient sample had a failed assay and the remaining eight patients had 10% or less OST cells with HER2 staining.

FIG 1.

Screening HER2 IHC results. (A) Percentages of OST cells with any HER2 expression by the centralized test performed with the CB11 antibody. (B, C) Representative images of HER2 staining of 85% and 0%, respectively. HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; OST, osteosarcoma.

Of the 41 patients meeting the tumor HER2 tumor expression criterion, nine eligible patients were enrolled (seven male) between April 15th and November 11th of 2021 (Table 1). The reason many of the patients eligible by HER2 staining were not enrolled was slot availability. The median age was 19.3 years and two patients were younger than 18 years (17.9 and 16.8 years). All patients received previous myelosuppressive chemotherapy and surgery while no patients received previous cell therapy or radiation. Of the nine treated patients, the range of cells with HER2 staining was from 15% to 100% (Table 2). Accrual was brisk with cohorts 2 and 3 filled on the day they were opened to accrual.

TABLE 1.

Patient Characteristics

Characteristic	No. of Patients
Age, years
Mean (range)	21.4 (16.8-31.7)
>18	7
12-18	2
Sex
Male	7
Female	2
ECOG PS
0	5
1	4
RECIST measurable sites of disease
1	5 (four lung, one bone)
2	1 (lung only)
3	3 (two patients with lung and pleura; one patient with lung and bone)

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status.

TABLE 2.

Patient HER2 Status and Course

HER2% + Cells	Cycles Received	Best Response
100	2	PD
95	2	PD
95	2	PD
80	2	PD
80	2	PD
65	1	Withdrew consent
60	2	PD
30	2	PD
15	12	SD

Abbreviations: HER2, human epidermal growth factor receptor 2; PD, progressive disease; SD, stable disease.

Safety

There was a single DLT among the first nine patients on cycle 1. One patient experienced a cycle 1 DLT with grade 4 platelet count decrease attributable to T-DXd. This AE recurred in cycle 2 despite the protocol-specified dose reduction to 4.4 mg/kg. No other patients required dose de-escalations. No interstitial lung disease was observed. Non–dose-limiting grade 3 and 4 at least possibly related AEs occurred in three of nine patients with all three patients having cytopenias. Single-patient AEs, two of which rose to serious adverse events (SAEs), also included nausea, vomiting, tumor hemorrhage, wound infection, and hypertension (Table 3). One patient with SAE had a wound infection. A second patient had cycle 1 vomiting with probable attribution and cycle 2 grade 4 tumor hemorrhage with possible attribution. This tumor hemorrhage SAE was in the context of normal platelets and carefully locally adjudicated. Ultimately, the tumor hemorrhage was attributed to disease progression and the patient discontinued protocol therapy. Although the hemorrhage was controlled, the patient developed both respiratory failure and tracheal obstruction, both unrelated to T-DXd and definitely related to disease progression, that led to death within 30 days of enrolling on study.

TABLE 3.

AEs, Grade 3 or Higher With at Least Possible Attribution

AEs for Nine Patients, 27 Total Cycles Received	Treatment Cycle		AE Grade		Total
	1	2+	3	4
Hypertension	1		1		1
Lymphocyte count decreased	3	1	3	1	4
Nausea	1		1		1
Neutrophil count decreased	2		2		2
Platelet count decreased	1	1		2a,b	2
Tumor hemorrhage		1		1a,c	1
Vomiting	1		1c		1
WBC decreased	2		2		2
Wound infection	1		1c		1
Total	12	3	11	4	15

Abbreviations: AE, adverse event; DLT, dose-limiting toxicity.

^aDLT.

^bThe low platelet counts occurred in the same patient.

^cAEs that together constituted the single serious AE and admission.

Pharmacokinetics

The concentrations of T-DXd, the antibody component (trastuzumab), and the drug component (DXd) were characterized in serum for nine patients on cycle 1, eight patients on cycle 2, and 1 patient who completed 3+ cycles. The average concentration-time profiles for each analyte are illustrated in Figure 2, and PK parameters are summarized in Table 4 with median values and range. In cycle 1, where T-DXd was infused over 90 minutes, the C_max was reached at a median time of 1.77, 1.77, and 4.0 hours for T-DXd, trastuzumab, and DXd, respectively. The T-DXd and total anti-HER2 antibody had similar PK parameters; the median Cmax of T-DXd and total anti-HER2 antibody were 148 and 126 μg/mL, respectively, while the median AUCs were 676 and 678 d × μg/mL, respectively. The Cmax and AUC_tau parameters for DXd are approximately four orders of magnitude lower at 11.3 ng/mL and 36.2 d × ng/mL, respectively. The median half-life for DXd (5.63 days) is slightly longer than that of the T-DXd and total anti-HER2 antibody (4.71 and 4.9 days, respectively). The median apparent clearance of T-DXd and total anti-HER2 antibody were similar at 26.1 and 25.7 mL/h, respectively, while the median apparent clearance for DXd was 11.7 L/h. The C_max and AUCtau values for the two patients younger than 18 years were similar to those for the patients age 18 years and older for T-DXd and DXd (T-DXd C_max: 103 and 122 μg/mL, AUC_tau: 447 and 614 d × μg/mL; total antibody Cmax: 82.0 and 105 μg/mL, AUC_tau: 381 and 586 d × μg/mL; DXd C_max: 11.3 and 10.3 ng/mL, AUC_tau: 42 and 24 d × ng/mL, respectively).

FIG 2.

Serum concentration time curves for T-DXd and the components total anti-HER2 antibody and exatecan derivative (DXd). HER2, human epidermal growth factor receptor 2; T-DXd, trastuzumab deruxtecan.

TABLE 4.

T-DXd Pharmacokinetics

Characteristic	T-DXd (ADC)	Total Anti-HER2 Antibody	DXd (released drug)
No.	9	9	9
Tmax, hours	1.77 (1.67-4.00)	1.77 (1.63-4.00)	4.00 (2.25-7.10)
Cmax	148 (91.8-197) μg/mL	126 (82.0-169) μg/mL	11.3 (8.55-20.0) ng/mL
Half-life, days	4.71 (3.87-5.57)	4.9 (4.07-9.35)	5.63 (3.27-7.46)
AUCtau	676 (388-767) day × μg/mL	678 (381-858) day × μg/mL	36.2 (18.6-61.1) day × ng/mL
Apparent clearance	26.1 (16.7-35.2) mL/h	25.7 (15.0-31.7) mL/h	11.7 (6.7-19.4) L/h

Abbreviations: ADC, antibody-drug conjugate; HER2, human epidermal growth factor receptor 2; T-DXd, trastuzumab deruxtecan.

Clinical Activity

Seven patients received two cycles of protocol therapy and had progressive disease at the first evaluation. A single patient withdrew consent before the first evaluation. The final patient was EF at week 24, meeting the protocol-specified criteria for efficacy having been EF at 24 weeks then progressed after nine cycles (Table 2). No partial responses were observed. With a single patient having more than 24 weeks of SD of the nine planned participants in the first stage, this study did not meet criteria to progress to stage II. The estimated SD rate at 24 weeks is 11.1% (onesided 95% CI lower bound, 0.6%). The single responder who met the protocol-specified duration of SD for efficacy signal and received 12 cycles had 15% HER2-positive OST cells. The remaining patients who received protocol therapy had 30%-100% of OST cells stain for HER2.

DISCUSSION

Although this trial failed to demonstrate a signal of activity for T-DXd in OST, several important observations resulted from PEPN1924 including brisk enrollment demonstrating an unmet need.¹² This robust accrual was also possible with biomarker selection using a screening step. In addition, this trial identified a higher-than-expected rate of HER2 positivity in OST, although the inclusion of cytoplasmic staining in the biomarker for inclusion was likely suboptimal, and the inability to clearly determine the presence or absence of surface expression may have contributed to the lack of activity. The historically controlled, 24-week EFS rate end point for this trial was ambitious in terms of the duration of disease control; however, the first stage threshold was similar to previous OST studies and a 16-week EFS end point as used in previous studies would not have altered the result.^8,10,11 This 24-week duration of disease control has been observed in several registration or label-expanding clinical trials in HER2-low breast, HER2-positive gastric, HER2-positive solid tumors, and HER2-mutant NSCLC.^31-33,40,41 Although response rates ranging from 37.1% to 70.6% were observed in these pivotal trials, OST is diagnosed by the presence of an osteoid matrix that often underestimates tumor cell death by traditional response criteria such as RECIST 1.1.⁴² Thus, EFS continues to be the primary end point for OST efficacy in similar phase II studies with objective responses often not factored into trial design beyond description of these rare responses.

As the first experience with T-DXd in younger patients, we did not identify any safety signals and no patients had pulmonary AEs or interstitial lung disease. The C_max, AUC, and clearance of T-DXd for all patients including the two patients younger than 18 years were similar to the C_max, AUC, and clearance of T-DXd observed in patients with breast and gastric cancers.⁴³ This supports the initial FDA guidance allowing patients age 12 years and older to be enrolled on initial ADC clinical trials.³⁵

The mechanism of action of ADCs include antibody binding to a cell surface target, internalization, cleavage of the linker and release of the cytotoxic payload. Thus, resistance can be through lack of surface expression of the target antigen, failure to internalize and release the payload, or intrinsic resistance to the payload. OST is sensitive to topoisomerase inhibition with doxorubicin being first-line therapy. HER2 expression in OST has been evaluated with a multitude of antibodies, thresholds for determining HER2-positive or HER2-negative, and often included cytoplasmic expression toward positivity. On this trial, we required HER2 positivity using the percentage of OST cells with either membranous or cytoplasmic staining as our integral marker for inclusion. We intentionally lowered the threshold of inclusion staging from the IHC score of 2+ or greater on the previous trastuzumab study in patients newly diagnosed with OST due to the activity in other HER2-low malignancies.^22,32 In retrospect, we interpret the lack of efficacy as being primarily related to lack of surface expression of HER2 in OST cells, although we were unable to quantitatively or qualitatively evaluate surface HER2 expression retrospectively in the enrolled patients. We do not have an explanation from IHC staining regarding how future patients with OST could be identified who may derive similar EF duration. With only eight evaluable patients, additional considerations for further evaluation could include using a different qualitative or quantitative threshold for inclusion along with on therapy biopsies to improve understanding or response and resistance. That the patient with the lowest percentage of cells stained positive was the only one to receive more than two cycles of therapy was unexpected as there was a modest correlation between HER2 expression and activity in preclinical evaluations with T-DXd in OST.³⁴ Further evaluations of the HER2 thresholds for activity are ongoing in many cancers and there is clear activity in breast cancer at low HER2 expression, previously considered negative, and novel assays to better identify patients with low expression levels likely to benefit from T-DXd.^44,45 Notably, HER2 is expressed in other pediatric and young adult malignancies including Wilms tumor,^46,47 desmoplastic small round cell tumor, atypical teratoid/rhabdoid tumor, and ependymoma.⁴⁸ The possibility of administration of T-DXd in pediatric patients on the basis of histology rather than limiting trial inclusion to a specific HER2 threshold determination is under consideration.

With a lack of clear targetable DNA point mutations in OST, surface proteins are increasingly promising targets for therapy. Characterization of the OST surfaceome has revealed multiple promising targets with abundant expression far greater than HER2 including MT1-MMP, LRRC15. EphA2, and B7H3 (CD276).^49-51 Early reports are confirming prolongation of SD and responses in relapsed OST with this surfaceome strategy with topoisomerase payloads appearing to have more efficacy than microtubule inhibitor payloads for OST.^10,52,53 The dynamics of surface protein expression during chemotherapy and in metastatic lesions also remains an area of exciting investigation. Pre-clinical modeling may assist with these investigations. Finally, detection of CTCs or novel ctDNA algorithms have demonstrated promise in serially assessing OST tumor dynamics and are in process for this trial.^54-57

CONTEXT.

Key Objective

We asked if human epidermal growth factor receptor 2 (HER2) immunohistochemical staining in relapsed osteosarcoma (OST) could enrich for responders treated with trastuzumab deruxtecan (T-DXd).

Knowledge Generated

With this novel assay for inclusion for HER2 expressing OST, we did not observe sufficient activity to expand to a second stage of this phase II study. Additional evaluations of surface targets and antibody-drug conjugates remain a high priority as relapsed OST remains an unmet clinical need.

Relevance (A.R. Abdul Razak)

This trial interrogated the activity and safety profile of T-DXd in adolescents and young adults with relapsed/metastatic OST. Patients were centrally tested for HER2 via immunohistochemistry. Although the trial did not meet efficacy criteria, it provided clinical, pharmacokinetic, and safety data that inform future efforts to optimize biomarker selection and targeted therapies in OST.*

Plain Language Summary (A.R. Abdul Razak)

This study tested a targeted cancer therapy called T-DXd in young people with relapsed OST whose tumors showed a specific marker called HER2. Although the treatment was well tolerated, it did not show enough benefit to continue the trial, highlighting the need for better biomarkers and new treatment strategies for this hard-to-treat cancer.^†

*Relevance section written by JCO Oncology Advances Associate Editor Albiruni Ryan Abdul Razak, MB BCh, MRCPI, CCT.

^†Plain Language Summary written by JCO Oncology Advances Associate Editor Albiruni Ryan Abdul Razak, MB BCh, MRCPI, CCT.