Centre Georges François Leclerc

The use of plasma uracil measurements to detect dihydropyrimidine dehydrogenase (DPD) deficiency is one of the methods for preventing toxicities associated with fluoropyrimidines, including 5-Fluorouracil (5-FU). Unfortunately, this measurement is subject to variations, that may lead to unnecessary dosage reductions and therefore to a reduced efficacy of treatment. Recently, new factors such as hepatic and renal impairment have been proposed as also influencing uracil concentration. The aim of our study was therefore to study the influence of renal or hepatic function on 5-FU clearance.

This was a retrospective study, using patients treated with 5-FU between September 1, 2018 to December 1, 2022 in a French Clinical Cancer Center. Patients were included after treatment with 5FU and therapeutic monitoring of 5FU concentrations after each course of chemotherapy. For each patient, DPD phenotyping by uracil concentration measurement was determined before the first course of 5FU. Blood samples were then taken the day after the start of the 5-FU infusion, between 8 and 10 am, for the first three cycles of 5-FU. With the exception of uracil concentration, which was determined only once, the various data were recorded for each course of 5FU chemotherapy performed. Patients with incomplete information (missing one of the above parameters) were excluded from the database.

We included 227 patients, corresponding to 227 uracil concentrations and 575 5-FU concentrations. In an original development, our results show for the first time that 5-FU clearance was proportionally correlated with eGFR (calculated according to CKD-EPI formula). Although we failed to demonstrate this hypothesis significantly, we observed that 5-FU clearance may be more dependent on eGFR than on uracil concentration for low uracil concentrations values.

Our study reinforces the still poorly accepted idea of the value of focusing on eGFR in 5-FU dose adjustment.

Treatment options for advanced head and neck squamous cell carcinoma (HNSCC) previously treated with platinum-based chemotherapy and a PD-1 inhibitor are limited. Trophoblast cell-surface antigen 2 (Trop-2) is highly expressed in HNSCC. Sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate approved for patients with certain previously treated solid tumors.

TROPiCS-03 (NCT03964727) is an open-label, multicohort, phase II study evaluating SG in advanced solid tumors, including HNSCC. Adults with locally advanced or metastatic HNSCC that progressed following platinum-based chemotherapy and anti–PD-(L)1 therapy [given sequentially (either order) or in combination] were administered SG 10 mg/kg on days 1 and 8 of a 21-day cycle. The primary endpoint was the investigator-assessed objective response rate. Secondary endpoints included duration of response, clinical benefit rate, progression-free survival, overall survival, and safety.

Patients (N = 43) received a median of 3 (range, 2–9) prior anticancer regimens. The objective response rate was 16% [95% confidence interval (CI), 7%–31%], with seven confirmed partial responses. The clinical benefit rate was 28% (95% CI, 15%–44%). The median (95% CI) duration of response, progression-free survival, and overall survival were 4.2 (2.6–not reached), 4.1 (2.6–5.8), and 9.0 (7.1–10.5) months, respectively. The most common treatment-emergent adverse events (TEAE) were diarrhea (47%), nausea (47%), and neutropenia (47%). Grade ≥3 TEAE occurred in 58% of patients. Three patients died from TEAE, with one event (septic shock) considered related to SG.

These data demonstrate the clinical potential of Trop-2–directed therapy in managing heavily pretreated patients with advanced HNSCC.

Evidence suggests that ctDNA may be a reliable biomarker to monitor metastatic colorectal cancer (CRC) evolution. Nevertheless, evidence on the potential of liquid biopsy in this setting is still low quality, mostly consisting of retrospective studies.

COPERNIC is an international, multicenter clinical trial. The pilot study aims to confirm the predictive potential of early on-treatment ctDNA dynamics, and inform the design of a larger ctDNA-driven trial. Advanced CRC patients who are candidates for ≥3rd lines of systemic therapy undergo longitudinal blood sample collection during treatment (day 1, 15 and 29 for 2- or 4-weekly treatment regimens; day 1, 22 and 43 for 3-weekly treatment regimens) and at each imaging assessment. ctDNA analyses are carried out with the FoundationOne Liquid CDx and FoundationOneMonitor assays, and ctDNA changes during treatment are correlated with radiologic response (as assessed every 8-12 weeks by RECIST v1.1). The primary objective is to select the optimal timepoint and cut-off value for early ctDNA changes (at day 15/22) to predict progressive disease as best radiological response with a high positive predictive value. The cut-off value for ctDNA will be defined based on nonparametric ROC-curves with bootstrapping. Based on the expected rate of progressive disease and statistical assumptions, 109 patients are needed to be screened to have 87 assessable patients. COPERNIC is sponsored by the Institut Jules Bordet, and supported by Roche and Foundation Medicine. Recruitment is open in 13 centres across Belgium and France. The study is registered with clinicaltrials.gov (NCT05487248).