Abstract Purpose: Leptomeningeal disease (LMD) from breast cancer remains associated with poor outcomes and there are limited tools for quantitative response assessment. We evaluated cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) as a biomarker of treatment response in patients with LMD treated with trastuzumab deruxtecan (T‑DXd) in a prospective clinical trial cohort. Experimental Design: Serial CSF and plasma samples were collected from seven patients with cytology-confirmed LMD enrolled in cohort 5 of the phase II DEBBRAH trial. ctDNA tumour fraction (TF) was quantified using ultra-low-pass whole-genome sequencing, and targeted unique molecular identifiers (UMI)-based sequencing was performed for mutational profiling. Results: ctDNA was detected by ulpWGS in all baseline CSF samples but in only two of six baseline plasma samples. Early reductions in CSF ctDNA TF were observed within 1–2 cycles of T‑DXd and were associated with prolonged radiological control of LMD. In contrast, plasma ctDNA primarily reflected extracranial disease status. Genomic profiling revealed marked compartmentalization between CSF and plasma, including copy number alterations and subclonal variants which may correlate with treatment response and resistance. Conclusions: CSF ctDNA represents a potential sensitive and dynamic biomarker of LMD burden and treatment response, supporting its integration into clinical trials for precision monitoring of LMD disease.
Abstract Purpose: To evaluate long-term outcomes and determine whether longitudinal plasma profiling provides biological insight into disease progression after proton hypofractionated ablative radiation therapy (HART) for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Patients and Methods: In this single-arm, multi-institutional phase II trial, 92 patients with localized unresectable HCC or ICC with Child-Pugh class A/B liver function received HART (up to 67.5 GyE in 15 fractions). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Plasma samples were collected at baseline, days 1, 8, 15, and 1-month after treatment for exploratory correlative analyses. Results: Among evaluable patients (44 HCC, 39 ICC), median OS was 29.2 months (HCC) and 20.8 months (ICC), with 5-year OS rates of 25.9% and 12.3%, respectively. Median PFS was 13.8 months (HCC) and 8.4 months (ICC). In-field local failure occurred in 2 HCC (4.5%) and 7 ICC (17.9%) patients, whereas out-of-field intrahepatic/distant progression remained the predominant pattern of failure. No grade >3 treatment-related toxicities were observed. Exploratory plasma profiling identified distinct biological signatures associated with progression: HCC was characterized by markers of hypoxia, inflammation, vascular remodeling, stromal activation, and hepatic regeneration, whereas associations in ICC predominantly involved signatures of hypoxia and vascular remodeling. Conclusions: HART provides durable long-term in-field local control with minimal toxicity, but disease progression remains predominantly out-of-field intrahepatic/distant. Exploratory correlative analyses suggest that biological signatures reflecting vascular remodeling, hypoxia, inflammation, stromal activation, and hepatic reserve are associated with progression despite successful local therapy, informing future translational studies and combination strategies.
Abstract Purpose: COPE evaluated serial circulating tumor DNA (ctDNA) profiling with molecular tumor board (MTB) review during first-line therapy for advanced non–small cell lung cancer (NSCLC). Experimental Design: COPE was a multicenter, randomized (2:1), noncomparative phase II trial. Arm A underwent serial plasma profiling with every report reviewed at a weekly virtual MTB; Arm B received standard management. The primary endpoint was 18-month overall survival (OS) in Arm A versus a prespecified 40% historical benchmark; no between-arm comparison was planned. Results: Among 176 patients, 117 were assigned to Arm A and 59 to Arm B. Eighteen-month OS was 53.8% (95% CI, 44.3–62.5) and 65.7% (95% CI, 52.0–76.3), respectively. Baseline plasma profiling provided contributory information in 32 of 35 patients with noncontributory or unavailable tissue, increasing genotyping success from 69% to 97%. Paired baseline and early on-treatment samples were available in 90 patients (median, 21 days; range, 19–64). ctDNA clearance was associated with higher objective response rate (83% vs. 52%), longer progression-free survival (22.9 vs. 5.4 months; P<0.001), and longer OS (not reached vs. 17.1 months; P=0.004) than persistent detection. Conclusions: Serial ctDNA profiling with weekly MTB review was operationally feasible and complemented tissue genotyping. Clinical benefit was not demonstrated; early ctDNA kinetics require validation in interventional trials.
Abstract Purpose: Engagement of the co-stimulatory receptor OX40on activated T cells enhances T-cell activation, survival, and proliferation. First-generation agonistic OX40 antibodies have shown limited clinical efficacy so far. The investigational HexaBody®-OX40 (GEN1055/BNT315) was designed to promote FcγR-independent higher-order OX40 clustering on the cell surface, thereby leveraging receptor biology to achieve optimal stimulation. We assessed the in vitro and in vivo functional activity of HexaBody-OX40, and evaluated the potential of concomitantly blocking PD-1/PD-L1 inhibitory signals to amplify T-cell activity. Experimental Design: Reporter assays and primary human T-cell assays using healthy donor and cancer patient cells were used to study the effects of HexaBody-OX40, alone and in combination with PD-(L)1 blocking antibodies, on T-cell activation and proliferation in vitro. Antitumor activity and pharmacodynamic effects were evaluated in human OX40 knock-in mice and human OX40/PD-1 double knock-in mice bearing MC38 tumors. Results: HexaBody-OX40 exhibited FcγR-independent OX40 agonistic activity in vitro, enhancing T-cell activation, proliferation, and cytokine secretion, and promoted tumor-infiltrating lymphocyte expansion in primary tumor samples ex vivo. In vivo, HexaBody-OX40 demonstrated antitumor activity accompanied by peripheral and intratumoral T-cell immunomodulation. PD-(L)1 blockade further potentiated HexaBody-OX40-induced T-cell proliferation, activation, and cytokine secretion in assays using PBMCs from either healthy donors or cancer patients previously treated with PD-(L)1 blocking antibody. Combined with pembrolizumab, HexaBody-OX40 enhanced antitumor activity and T-cell immunomodulation beyond either monotherapy in vivo. Conclusions: HexaBody-OX40 agonistically enhanced T-cell mediated antitumor immunity through FcγR-independent OX40 agonism. The combination of HexaBody-OX40 with PD-(L)1 blocking antibodies enhanced the effect of both single agent treatments.
Abstract Purpose: Evaluate efficacy and safety of carboplatin plus mirvetuximab soravtansine (MIRV) in folate receptor alpha (FRa)-expressing recurrent PSOC. Patients and Methods: This phase 2, single arm trial enrolled patients with recurrent FRa-expressing (≥25% of tumor cells with ≥2+ membrane intensity) PSOC and 1 prior platinum-based therapy. Patients received up to 6-8 cycles of carboplatin (AUC 5) plus MIRV (6mg/kg AIBW) Q3W, followed by single-agent MIRV. Primary and key secondary endpoints were investigator-assessed objective response rate (ORR) per RECIST v1.1 in the FRa ≥50% group and FRa ≥25% group (ie, overall population), respectively. Results: Among 125 enrolled patients (102 FRα ≥50%; 61 prior PARPi), ORR by end of 6 combination cycles was 62.7% (95% CI, 52.6–72.1) in the FRα ≥50% group and 62.4% (95% CI, 53.3–70.9) in the overall population. Most patients (n=101; 81%) transitioned to single-agent MIRV continuation with durable responses. Patients with FRa ≥25% had median duration of response of 11.2 months (95% CI, 8.5–13.6) and median progression-free survival of 11.0 months (95% CI, 9.8–13.1). Most common adverse events (AEs) were blurred vision (81%) and corneal events (74%); 96.7% of corneal cases resolved or had final grade 1. Treatment-emergent AEs led to MIRV and carboplatin discontinuation in 15% and 9%, respectively. Adjudicated treatment-related pneumonitis occurred in 19 (15.2%) patients: 14 grade 1–2; 3 grade 3–4, and 2 fatal cases. Conclusions: Carboplatin plus MIRV was manageable with dose modifications for AEs and showed meaningful activity, including in PARPi-exposed patients, supporting further evaluation in PSOC.
