Nicholas Wrigley

Detecting circulating tumor DNA (ctDNA) and identifying molecular residual disease (MRD) in patients with colorectal cancer (CRC) after surgery was assessed with greater sensitivity using the novel patient-specific prognostic and potential therapeutic marker tracking (brPROPHET) approach when compared with alternatives, according to findings presented at the 2023 Gastrointestinal Cancers Symposium

The brPROPHET approach detected ctDNA in 97.3% of the 74 patients enrolled for all 3 MRD assays, a higher value than investigators achieved with the fixed panel with informed calling (FI) assay (75.7%) and the fixed panel with agnostic calling (FA) assay (68.9%). This novel technology was also the only assay to capture baseline ctDNA in 15 of these patients (20.3%), who had lower median ctDNA levels (0.3 mean tumor molecules [MTM] / mL) than those captured by FI and FA fixed panels (3.0 MTM/mL; 

Across 135 postoperative blood samples tested by all 3 assays, brPROPHET achieved a positive rate of 14.8%, as compared with 8.1% and 6.7% achieved by the FI and FA fixed panel assays, respectively.

“This method [brPROPHET] was developed to detect MRD with a limit of detection of 0.004% and a sample level specificity of over 99% in the analytical validation,” presenting author Di Cao, MD, a physician at Sun Yat-sen University Cancer Center in Guangzhou, China, said during the presentation. “[Our] study reported that the clinical validation of the brPROPHET assay in colorectal cancer demonstrated superior sensitivity in detecting preoperative and post-operative ctDNA [vs] fixed-panel assays.”

The brPROPHET assay is designed to trace patient-specific somatic variants based on whole-exome sequencing of the tumor tissue and matched white blood cells. It targets up to 55 variants per patient.

The study investigators evaluated assay sensitivities in a population of 117 patients, including 53 (45.0%) with stage II CRC and 41 (35.0%) with stage III. They performed FI and FA fixed panel assays in a subset of patients with a 168-gene panel spanning 273 kilobases of the human genome for comparison with brPROPHET. Sixty (51.0%) patients received adjuvant therapy after surgery.

“Of the designed variants for ctDNA detection, only 6%...were included in the fixed panel. Seventy-five percent of genes selected for panel design were private to a specific patient, suggesting the broadness of MRD detection,” Cao said.

The median patient age of the population was 57 years. Most enrolled patients were male (55.5%), and a plurality had left-sided disease (42.7%) rather than right-sided (26.5%), rectal (23.9%), or transverse (6.8%) disease.

Preoperative ctDNA was detected in 97% of patients (n = 113) overall; much higher detection rates occurred in patients with later stage vs stage I disease. Additionally, median ctDNA levels were higher in patients with later stage disease and correlated with tumor volume.

The overall positivity rate declined to 18% on day 7 following surgery and 15% on day 30.

Two patients relapsed during the short follow-up period; ctDNA was detected prior to radiological relapse in both, with a lead time of 1 and 2 months, respectively.

“Identifying MRD with tailored, tumor-informed, ctDNA-based next-generation sequencing (NGS) assays after curative surgery could facilitate the individualized management of [patients with] resected CRC,” the investigators concluded. “Longitudinal monitoring is ongoing for further analysis of clinical outcomes and serial tests.”

Cao D, Wang F, Zhang R, et al. Patient-specific tumor-informed circulating tumor DNA (ctDNA) analysis for molecular residual disease (MRD) detection in surgical patients with stage I-IV colorectal cancer (CRC). 

2023;41(suppl 4):213. doi:10.1200/JCO.2023.41.3_suppl.213

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According to initial data presented at the 2023 Gastrointestinal Cancers Symposium, the novel, personalized, tumor-informed brPROPHET technology was more sensitive in detecting molecular residual disease vs other assays.

brPROPHET May Better Detect ctDNA and Identify MRD in Colorectal Cancer

Results from a first-in-human phase 1 study (NCT03960840) showed that next-generation CD19-directed chimeric antigen receptor (CAR) T-cell therapy rapcabtagene autoleucel, also known as YTB323, demonstrated encouraging efficacy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to 

2022 American Society of Hematology (ASH) Annual Meeting

Rates of complete response (CR) varied from 67% to 75% across the 4 dosage levels tested. Most patients received dose level 2 (n = 30) of 12.5 × 106 CAR-positive cells, and, among these, the CR rate was 73% (n = 22), with a further 10% (n = 3) achieving a partial response for an overall response rate (ORR) of 83% (95% CI, 65.3%-94.4%).

“Despite novel treatment options, a substantial portion of patients with [this disease] do not achieve sustained remission or do not have timely access to these therapies,” said lead study author Pere Barba, MD, PhD, a member of the Hematology Department at Hospital Universitario Vall d’Hebron and the Vall d’Hebron Institute of Oncology in Barcelona, Spain. “There remains an unmet need to further improve response rates, durability of response, safety, and accessibility to patients.”

The CR rates at 6 months and 1 year among patients who received dose level 2 were 62% and 50%, respectively, after a median follow-up of 16 months (range, 4.4-27.5 months). The median duration of response was 16 months (95% CI, 10.4-not estimable [NE]).

Barba also reported on findings regarding cell kinetics during the presentation. “At a 25-fold lower dose, rapcabtagene autoleucel expansion at dose level 2, measured by qPCR [quantitative polymerase chain reaction], was at the higher end of tisagenlecleucel expansion in lymphoma,” said Barba. “We did not observe an increase in expansion or persistence at dose level 3 or dose level 4 compared with dose level 2.”

In total, 47 patients with DLBCL received rapcabtagene autoleucel. The median age of the examined population was 65 years (range, 35-79) and a slim majority of patients had an International Prognostic Index (IPI) score smaller than 3 (n = 25; 53.2%) rather than 3 or larger (42.6%). Most patients (72.3%) had 2 prior lines of therapy, and most were either refractory to their last line of therapy (34.0%) or primary refractory (21.3%). More than 68% of patients required bridging therapy.

All patients experienced at least 1 adverse effect (AE), and the vast majority experienced an AE of grade 3 or higher (93% of those receiving dose level 2, 100% of those receiving any other dose levels). Two patients experienced dose-limiting toxicities, comprising grade 4 cytokine release syndrome (CRS) in one and grade 4 pancytopenia lasting more than 28 days post-infusion in the other. Most other instances of CRS were grade 1/2, and this toxicity affected 25% to 37% of patients across the 4 dosage groups. There was a single case each of grade 3 and grade 4 CRS. “Notably, the time to onset of CRS was 8 days, which is somewhat later than what has been described with other similar therapies in lymphoma,” said Barba. There were 14 deaths in the cohort but none were related to the agent.

There were also 5 total instances of immune effector cell–associated neurotoxicity syndrome (ICANS), 2 of which were grade 3/4 among patients receiving dose level 2. “Again, the median time of onset (of ICANS events) was on day 16 after infusion, longer than has been described with other CAR T-cell therapies,” said Barba.

When asked, Barba indicated that toxicities from bridging therapy and other factors affected vein-to-vein time in this study. “A dose-escalation trial [such as ours] is probably not the best design to assess vein-to-vein time,” he said. “This will be [examined] in the expansion cohort…and will certainly be an end point for the next studies of YTB323.”

Based on the safety and efficacy data obtained, the investigators recommended the level 2 dose for further investigation in later-phase studies.

Barba P, Kwon M, Briones J, et al. YTB323 (rapcabtagene autoleucel) demonstrates durable efficacy and a manageable safety profile in patients with relapsed/refractory diffuse large B-cell lymphoma: phase I study update. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 439.

Nicholas Wrigley | Authors

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