Fluoropyrimidine Research Articles

Oxaliplatin Added to Fluoropyrimidine/Bevacizumab as Initial Therapy for Unresectable Metastatic Colorectal Cancer in Older Patients: A Multicenter, Randomized, Open-Label Phase III Trial (JCOG1018).

Doublet chemotherapy with fluoropyrimidine (FP) and oxaliplatin (OX) plus bevacizumab (BEV) is a standard regimen for unresectable metastatic colorectal cancer (MCRC). However, the efficacy of adding OX to FP plus BEV (FP + BEV) remains unclear for older patients, a population for whom FP + BEV is standard. We aimed to confirm the superiority of adding OX to FP + BEV for this population. This open-label, randomized, phase III trial was conducted at 42 institutions in Japan. Patients with unresectable MCRC age 70-74 years with Eastern Cooperative Oncology Group performance status (ECOG-PS) 2 and those 75 years and older with ECOG-PS 0-2 were randomly assigned (1:1) to an FP + BEV arm or an OX addition (FP + BEV + OX) arm. Fluorouracil plus levofolinate calcium or capecitabine was declared before enrollment. The primary end point was progression-free survival (PFS). The study was registered in the Japan Registry of Clinical Trials (identifier: jRCTs031180145). Between September 2012 and March 2019, 251 patients were randomly assigned to the FP + BEV arm (n = 125) and the FP + BEV + OX arm (n = 126). The median age was 80 and 79 years in the respective arm. The median PFS was 9.4 months (95% CI, 8.3 to 10.3) in the FP + BEV arm and 10.0 months (9.0 to 11.2) in the FP + BEV + OX arm (hazard ratio [HR], 0.84 [90.5% CI, 0.67 to 1.04]; one-sided P = .086). The median overall survival was 21.3 months (18.7 to 24.3) in the FP + BEV arm and 19.7 months (15.5 to 25.5) in the FP + BEV + OX arm (HR, 1.05 [0.81 to 1.37]). The proportion of any grade ≥3 adverse events was higher in the FP + BEV + OX arm (52% v 69%). There was one treatment-related death in the FP + BEV arm and three in the FP + BEV + OX arm. No benefit of adding OX to FP + BEV as first-line treatment was demonstrated in older patients with MCRC. FP + BEV is recommended for this population.

Novel Genetic Variants Explaining Severe Adverse Drug Events after Clinical Implementation of DPYD Genotype-Guided Therapy with Fluoropyrimidines: An Observational Study.

Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35-23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41-28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice.

Routine, prospective DPYD genotyping guided dose-individualisation for patients receiving fluoropyrimidines: Implementation, prevalence and patient safety outcomes from a multi-institutional clinical trial.

12121 Background: Prospective data regarding the prevalence of DPYD variant alleles and the impact of genotype guided dosing on safety and efficacy of fluoropyrimidines (FP) remains limited. We assessed the feasibility and safety impact of routine, prospective, DPYD genotype guided FP dosing. Methods: Adult patients (>18 years), commencing FP for the first time were enrolled. Sanger PCR sequencing was designed to target DPYD variants NM_000110.4:c.1905+1G>A (DPYD*2A), NM_000110.4:c.1679T>G (DPYD*13), NM_000110.4:c.1236G>A and NM_000110.4:c.2846A>T. Dose reductions were implemented as per current international pharmacogenomic guidelines. Gr3/4 toxicity, dose reductions/delays and hospital admissions were reviewed for the first 60 days after commencement. For comparison purposes, a retrospective review of patients receiving FP without testing in a prior year was completed. Results: Between July 2021 – May 2023, 334 patients were enrolled for testing. 95% ECOG 0-1. 57% curative treatment intent. Mean time from phlebotomy to result 6.9 days (range 2-15). Clinician/patient acceptance was high (>95% of eligible patients starting FP were enrolled). 20 (6.0%) variant DPYD allele carriers were detected. 11 heterozygous for c.1236G>A, 5 heterozygous for C.1905+1G>A, 3 heterozygous for c.2846A>T and 1 homozygous for c.1236G>A. 295 of patients tested proceeded to receive FP. 62% received Infusional-FP, 38% Capecitabine. 39 patients commenced treatment prior to DPYD result being available (treating clinician decision). Dose modification recommendations were followed in all but two patients. 24% experienced FP related Grade 3/4 toxicity within 60 days. (23% DPYD wild type, 37% DPYD variant) versus 35% in the retrospective cohort. 16% had FP related dose delays (16% DPYD wild type, 12% DPYD variant) versus 25% retrospective cohort. 14% had FP related dose reductions (13% DPYD wild type, 25% DPYD variant) versus 12% retrospective cohort. 13% had FP related hospital admissions (13% DPYD wild type, 19% DPYD variant) versus 17% retrospective cohort. 1 death in the DPYD wild type cohort was deemed potentially related to FP. Conclusions: Prospective DPYD genotype guided dosing was feasible in clinical practice, with prevalence of variant alleles comparable to published literature. There was a modest reduction in risk of FP related severe toxicity, dose delays, and hospital admissions with DPYD guided dosing compared to a historical, untested cohort. Clinical trial information: ACTRN12621001117808.

Implementing DPYD/UGT1A1testing to prevent treatment related adverse events (TRAE) in patients with gastrointestinal (GI) cancer: Results of a pragmatic implementation trial.

10599 Background: Fluoropyrimidines (FP), 5-FU and capecitabine, are standard treatments for many GI cancers. Irinotecan may be used with FPs in both the curative and palliative settings. 30-40% of patients experience severe TRAEs which can lead to treatment interruption and hospitalization. TRAE risk is higher in patients with pharmacogenetic variants in DPYD and/or UGT1A1. Methods: This is a non-randomized, open-label implementation study at 3 cancer care sites within an academic health system to determine feasibility of integrating DPYD/UGT1A1 testing into clinical care (IMPACT-GI; NCT#04736472). Test ordering and discrete variant resulting were available within the Electronic Health Record. The lab detected 5 DPYD variants with reduced or no function (c.1905+1G>A, c.2846A>T, c.1679T>G, c.1236G>A, c.557A>G) and 2 UGT1A1 (*6, *28) alleles. Patients with a GI cancer initiating treatment with 5-FU, capecitabine, or irinotecan underwent testing along with preemptive chemotherapy dose modifications. Carriers of 1 DPYD variant (i.e., intermediate metabolizers [IM]) and UGT1A1 homozygous carriers (i.e., poor metabolizers [PM]) were recommended a 50% and 30% dose reduction, respectively. The primary endpoints were feasibility (proportion of results available prior to cycle 1) and fidelity (genotype concordant dose modifications). Secondary endpoints included severe TRAE (requiring emergency room visit or hospitalization) comparing variant carriers vs. wildtype over the first 6 cycles. Results: From 3/2021- 12/2022, 224 patients received testing (54% male, 74% White, 18% Black, mean age 62 ±17 years. The most common diagnoses were 47% colorectal and 30% pancreatic cancers. The median lab turnaround time was 10 (IQR 9-13) calendar days with 57.2% of results available prior to cycle 1. Results available prior to cycle 1 varied by distance to lab (64.7% near sites vs. 32.7% far site, p<0.001). We identified 7 (3%) DPYD intermediate metabolizers (IM) and 33 (15%) UGT1A1 poor metabolizers (PM). Four (2%) patients carried a variant in both DPYD and UGT1A1. Chemotherapies were preemptively dose reduced for 6 of 7 DPYD carriers receiving FP and 5 of 8 UGT1A1 PMs receiving irinotecan. 2 (28%) DPYD carriers vs. 71 (33%) wildtype carriers had a severe TRAE. 4 (50%) UGT1A1 PMs vs. 11 (36%) UGT1A1 wildtype carriers experienced a severe TRAE. Conclusions: DPYD/UGT1A1 testing is feasible with oncology providers following the genotype guided dose reductions when results were available prior to cycle 1. Pretreatment DPYD/UGT1A1 testing in conjunction with preemptive dose reductions resulted a similar proportion of severe TRAE as compared with wild-type patients. Further workflow modifications are required to decrease test turnaround time to ensure results are available prior to chemotherapy initiation. Clinical trial information: NCT04736472 .

Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-NORTH AMERICA): NRG-GI008.

TPS3641 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines vserial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 02-02-2024) is 240/1,912. NCT05174169. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169 .

Phase IB/II first line panitumumab, irinotecan, trifluridine/tipiracil in RAS wild-type patients with metastatic colorectal cancer: PIT study.

e15532 Background: Trifluridine/tipiracil (TT) is an oral fluoropyrimidine (FP) currently used in later line therapy. Preclinical data have demonstrated synergistic activity when panitumumab (Pmab) or irinotecan (Ir) are combined with TT supporting use in combination schedules in early line protocols. PIT was a phase IB/II study determining the maximum tolerated dose (MTD), safety and tolerability of substituting FP with TT, combined with Pmab and Ir in RAS wild-type mCRC. Methods: Phase IB 3+3 design dose escalation study (Dose level 1: TT 20mg/m2 oral BD, Ir 150mg/m2 IV, Pmab 6mg/m2). Primary objective was MTD of the combination in RAS WT mCRC patients, either 1st or 2nd line. Treatment was administered in 14-day cycles. Pmab and Ir were administered intravenously on day 1 with TT dosed orally, bid, days 1-5. Once MTD was established the phase II expansion study was to enrol 50 previously untreated mCRC patients. Primary endpoint was modified to toxicity. Results: The study closed due to slow recruitment. 14 patients were enrolled from 6/18 to 10/21. Med follow up 23 months. Med age 59 yrs (range 37-74yrs). 60% were male. One patient each was BRAF MT and right sided. ECOG 0/1 50%/50%. Thirteen patients had PIT as first line, 57% had prior adjuvant therapy. There was one DLT in first 3 patients however based on additional toxicity data (Clin Cancer Res. 2020 Apr 1:1555) a decision was made to not dose escalate beyond level 1 and commence phase II. Overall Gd 3 toxicity: Acne/rash 46%, Diarrhoea 31%, Fatigue 8%, neutropenia 15%, hypomagnesaemia 23%. One patient had Gd 4 neutropenia and there was one treatment related death (neutropenic sepsis). 12 patients had evaluable disease, 58% PR, 42% SD. Survival: Med PFS 14.1 mths, Med OS 40.6mths and 12 mth OS 64%. Conclusions: The MTD was deemed TT 20mg/m2, irinotecan 150mg/m2 and panitumumab 6mg/kg. Toxicity was manageable however significant grade 3 diarrhoea and rash was seen. There was one toxic death contributed to therapy. Small numbers do make interpretation difficult however there is a signal of activity. The slow recruitment illustrates difficulty in exploring novel combinations in early lines and potentially the reluctance to consider first line anti-EGFR therapy. Clinical trial information: ACTRN12617001190392.

Review of Prodrug and Nanodelivery Strategies to Improve the Treatment of Colorectal Cancer with Fluoropyrimidine Drugs.

Fluoropyrimidine (FP) drugs are central components of combination chemotherapy regimens for the treatment of colorectal cancer (CRC). FP-based chemotherapy has improved survival outcomes over the last several decades with much of the therapeutic benefit derived from the optimization of dose and delivery. To provide further advances in therapeutic efficacy, next-generation prodrugs and nanodelivery systems for FPs are being developed. This review focuses on recent innovative nanodelivery approaches for FP drugs that display therapeutic promise. We summarize established, clinically useful FP prodrug strategies, including capecitabine, which exploit tumor-specific enzyme expression for optimal anticancer activity. We then describe the use of FP DNA-based polymers (e.g., CF10) for the delivery of activated FP nucleotides as a nanodelivery approach with proven activity in pre-clinical models and with clinical potential. Multiple nanodelivery systems for FP delivery show promise in CRC pre-clinical models and we review advances in albumin-mediated FP delivery, the development of mesoporous silica nanoparticles, emulsion-based nanoparticles, metal nanoparticles, hydrogel-based delivery, and liposomes and lipid nanoparticles that display particular promise for therapeutic development. Nanodelivery of FPs is anticipated to impact CRC treatment in the coming years and to improve survival for cancer patients.

Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study).

The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.

Abstract CT276: Liberty-201: Maintenance fluoropyrimidine (FP) and bevacizumab with or without anti-lymphocyte activation gene-3 (LAG-3) antibody LBL-007 plus anti-programmed cell death protein-1 (PD-1) antibody tislelizumab (TIS) for patients (pts) with metastatic or unresectable microsatellite stable (MSS)/mismatch repair proficient (pMMR) colorectal cancer (CRC)

Abstract Background: LBL-007 is a monoclonal antibody targeting LAG-3, a receptor expressed on immune cells that negatively regulates T-cell proliferation and effector T-cell function. LAG-3 is frequently co-expressed with PD-1 on tumor-infiltrating T cells, and dual inhibition of LAG-3/PD-1 synergistically prevents tumor growth in mouse models. CRC is the second-highest cancer-related cause of death worldwide; pts diagnosed with metastatic CRC have a 5-year survival rate of 14%. Immunotherapy (IO) has only demonstrated clinical benefit in pts with microsatellite instability-high/MMR-deficient CRC, which accounts for 5% of CRC pts; however, improved therapy options for patients with MSS CRC remain limited. The combination of anti-LAG-3 + anti-PD-1 IO is currently being tested in clinical trials in pts with MSS CRC. Methods: This is a phase 1b/2, randomized, open-label study (NCT05609370). Pts with unresectable or metastatic CRC with locally or centrally confirmed pMMR or MSS status and no disease progression after induction treatment in first-line therapy are eligible. A maximum of 36 pts will be enrolled in phase 1b (safety run-in) to determine the recommended phase 2 dose. All pts will receive intravenous dual IO (LBL-007 + TIS) in combination with maintenance backbone (FP + bevacizumab). The dose of LBL-007 will be escalated from 150 mg every 3 weeks (Q3W) to 600 mg Q3W/400 mg Q2W using a Bayesian optimal interval design with informative prior. In phase 2, ~130 pts will be enrolled in the programmed death-ligand 1 (PD-L1)-positive group (tumor area positivity [TAP] ≥1%) and 60 patients in the PD-L1-negative group (TAP <1%). Pts with a PD-L1-positive status will be randomized 2:1:2 to receive dual IO + maintenance backbone (Arm A), LBL-007 + maintenance backbone (Arm B), or maintenance backbone only (Arm C). Pts with a PD-L1-negative status will be randomized 1:1 to receive dual IO + maintenance backbone (Arm D) or maintenance backbone only (Arm E). Treatment will continue until disease progression or unacceptable toxicity. The primary endpoint is safety in phase 1b and investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in phase 2. Secondary endpoints include overall survival, PFS2, overall response rate, duration of response, safety, pharmacokinetics, and immunogenicity. Exploratory endpoints include potential biomarkers (including but not limited to PD-L1 and LAG-3). Citation Format: Heinz-Josef Lenz, Ying Yuan, Vivian Li, Juan Zhang, Lubna Jamal, Xiao Lin, Fuxiang Zhu, John H. Strickler. Liberty-201: Maintenance fluoropyrimidine (FP) and bevacizumab with or without anti-lymphocyte activation gene-3 (LAG-3) antibody LBL-007 plus anti-programmed cell death protein-1 (PD-1) antibody tislelizumab (TIS) for patients (pts) with metastatic or unresectable microsatellite stable (MSS)/mismatch repair proficient (pMMR) colorectal cancer (CRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT276.

Enhanced Therapeutic Efficacy of the Nanoscale Fluoropyrimidine Polymer CF10 in a Rat Colorectal Cancer Liver Metastasis Model.

Combination chemotherapy regimens that include fluoropyrimidine (FP) drugs, e.g., 5-fluorouracil (5-FU), are central to the treatment of colorectal cancer liver metastases (CRLMs), a major cause of cancer mortality. We tested a second-generation FP polymer, CF10, in a CC531/WAGRij syngeneic orthotopic rat model of liver metastasis to determine if CF10 improved response relative to 5-FU. CF10 displayed increased potency relative to 5-FU in CC531 rat colorectal cancer cells based on clonogenic assay results and caused increased apoptosis, as shown using a live/dead assay. The increased potency of CF10 to CC531 cells was associated with increased replication stress, as assessed by Western blot for biomarkers of ATR/Chk1 and ATM/Chk2 pathway activation. CF10 dosed to deliver equivalent FP content as an established dose of 5-FU in rats (50 mg/kg) did not cause weight loss in WAGRij rats even when combined with ethynyl uracil (EU), an inhibitor of dihydropyrimidine dehydrogenase, the enzyme primarily responsible for 5-FU degradation in the liver. In contrast, 5-FU caused significant weight loss that was exacerbated in combination with EU. Importantly, CF10 was significantly more effective than 5-FU at inhibiting tumor progression (~90% reduction) in the CC531/WAG/Rij CRLM model. Our results reveal strong potential for CF10 to be used for CRLM treatment.

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment.

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology.

Relationship between fluoropyrimidine (FPD) exposure and outcomes in patients with metastatic colorectal cancer (mCRC) receiving trifluridine/tipiracil (FTD/TPI) with or without bevacizumab (BEV) in the phase 3 SUNLIGHT trial.

114 Background: Standard first- and second-line chemotherapy regimens for mCRC are FPD-based. In the phase 3 SUNLIGHT trial, the addition of BEV to FTD/TPI significantly improved overall survival (OS) compared with FTD/TPI alone in patients with mCRC who had received no more than two prior chemotherapy regimens. Here, we assessed the effect of timing of prior exposure to FPD on efficacy outcomes among patients treated in SUNLIGHT. Methods: In this post-hoc analysis, OS, progression-free survival (PFS), and disease control rate (DCR) were assessed in patients treated with FPD within 2 months of enrollment (<2 months FPD-free exposure) and patients who had not received FPD for ≥2 months prior to enrollment (≥2 months FPD-free exposure). Differences in OS between FTD/TPI + BEV and FTD/TPI alone were assessed in each subgroup. The Kaplan-Meier method and log-rank test were used to compare differences in OS/PFS; DCR was compared using Fisher's exact tests. The hazard ratio (HR) for OS was estimated using a Cox proportional hazards model. Results: Of 246 patients randomized to FTD/TPI + BEV, 79 had ≥2 months FPD-free exposure and 167 had <2 months FPD-free exposure. Median OS (95% CI) was 11.8 months (9.4–not estimable) for patients with ≥2 months FPD-free exposure and 10.5 months (8.6–11.3) for patients with <2 months FPD-free exposure ( P=0.095); median PFS was 6.7 months (4.6–7.5) and 5.2 months (4.2–5.7), respectively ( P=0.043). The DCR among patients treated with FTD/TPI + BEV was 79.8% for patients with ≥2 months FPD-free exposure and 64.7% for patients with <2 months FPD-free exposure, with a between-group difference of 15.1% (95% CI: 3.6%–26.5%; P=0.018). Of 246 patients randomized to FTD/TPI alone, 91 had ≥2 months FPD-free exposure and 155 had <2 months FPD-free exposure. Median OS was 9.3 months (6.7–10.9) and 6.8 months (6.0–7.8) for patients with ≥2 and <2 months FPD-free exposure, respectively ( P=0.106) and median PFS was 3.6 months (2.1–3.9) and 2.1 months (2.0–2.7) ( P=0.002). The between-group difference in the DCR was 13.8% (50.6% vs. 36.7% for ≥2 and <2 months FPD-free exposure; 95% CI: 1.0%–26.6%; P=0.044). Compared with FTD/TPI alone, FTD/TPI + BEV resulted in longer OS in both the ≥2-month (HR 0.61, 95% CI: 0.41–0.93) and <2-month (HR 0.59, 95% CI: 0.45–0.78) groups, respectively. Conclusions: Owing to imbalances between the ≥2- and <2-month FPD-free exposure groups, the data need to be interpreted with caution. However, with both FTD/TPI + BEV and FTD/TPI alone, OS, PFS, and DCR were numerically higher in patients with ≥2 months FPD-free exposure than in those with <2 months FU-free exposure, potentially reflecting the better prognosis of the former group. The survival benefits of adding BEV to FTD/TPI were maintained regardless of the timing of exposure to FPD prior to enrollment. Clinical trial information: NCT04737187 .

Real-world analysis of irinotecan (iri) with or without fluorouracil (5FU) in the second line treatment (2L) of metastatic colorectal cancer (mCRC).

102 Background: The most used 1st line (1L) chemotherapy backbone for mCRC is fluoropyrimidine (FP) + oxaliplatin. In the 2L, iri alone or with 5FU (FOLFIRI), ± a biologic agent (biologic), are options. It is unclear whether adding 5FU to iri is beneficial following disease progression on prior FP. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database to identify patients diagnosed with mCRC from 01-01-2013 to 02-13-2023, who received 1L with FP + oxaliplatin ± biologic, and 2L with irinotecan ± 5FU ± biologic. Baseline patient/tumor characteristics were obtained. The number of major comorbidities was computed using ICD-9-CM/10 codes within 1 year prior to 2L (Quan, 2005). Time to next treatment (TTNT) was defined from the start of 2L to the start of next line treatment (excluding maintenance). For survival outcomes, the median survival time and 95% confidence interval (CI) were estimated using the Kaplan-Meier method. Uni- and multi-variable analyses (UVA and MVA) were performed with the cox proportional hazard model. All covariates were evaluated in UVA, and those significant were included in MVA with adjusted hazard ratio (HR) and 95% CI. Results: 3,215 patients met criteria; most previously received a biologic with 1L (70.5% prior anti-angiogenesis and 5.9% prior anti-EGFR) and had 0 structured major comorbidity diagnoses (82.1%). In the 2L, FOLFIRI was the most used chemotherapy backbone (90.6%, vs iri 9.4%), 79% of patients also received a biologic, and patients who received FOLFIRI were younger (median age 61 vs 65 years) and had better ECOG performance status (87.8% vs 81.8% ECOG 0-1). Overall survival (OS) was longer with FOLFIRI than iri (median 14.4 vs 9.8 months, p<0.001), as was TTNT (median 7.6 vs 5.3 months, p<0.001). In MVA, when controlling for age, comorbidities, CEA, ECOG performance status, and 1L, iri was associated with shorter OS than FOLFIRI (HR 1.38, 95% CI 1.21-1.57, p<0.001). In MVA, the addition of a biologic to FOLFIRI and iri prolonged OS and TTNT in some subgroups (Table). Conclusions: In this retrospective real-world analysis of 3,215 patients with mCRC who received 1L with FP + oxaliplatin ± biologic, 2L FOLFIRI was associated with longer OS compared to iri alone (both ± biologic). [Table: see text]

NRG-GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-NORTH AMERICA).

TPS243 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (SignateraÔ, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines vs. serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs. more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate vs. delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169 .

Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

Clinical Implementation of Rare and Novel DPYD Variants for Personalizing Fluoropyrimidine Treatment: Challenges and Opportunities.

Fluoropyrimidines (FLs) [5-Fluorouracil, Capecitabine] are used in the treatment of several solid tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for FL detoxification, and its deficiency could lead to severe, life-threatening or fatal toxicity after FL administration. Testing with a pharmacogenetic panel of four deleterious variants in the dihydropyrimidine dehydrogenase gene (DPYD) (DPYD*2A, DPYD*13, c.2846A > T, c.1129-5923C > G) prior to FL treatment, is recommended by scientific consortia (e.g., CPIC, DPWG) and drug regulatory agencies (e.g., EMA). However, this panel identifies < 20% of patients at risk of severe FL-related toxicity. Cumulative recent evidence highlights the potential clinical value of rare (minor allele frequency < 1%) and novel DPYD genetic variants for identifying an additional fraction of DPD-deficient patients at increased risk of severe FL-related toxicity. In this review, we aimed to comprehensively describe the available evidence regarding the potential clinical predictive role of novel and rare DPYD variants as toxicity markers in FL-treated patients, and to discuss the challenges and opportunities in tailoring FL treatment based upon clinical application of such markers. Although we must overcome existing barriers to the clinical implementation, the available data support that comprehensive assessment of the DPYD sequence, including rare and novel genetic variants, may significantly enhance the pre-emptive identification of at-risk patients, compared to the current targeted approach.

2097P Incidence, risk factors (RFs) and management of oral mucositis (OM) in patients (pts) treated with a fluoropyrimidines (FP)-based therapy (tp): A retrospective, monocentric experience

2097P Incidence, risk factors (RFs) and management of oral mucositis (OM) in patients (pts) treated with a fluoropyrimidines (FP)-based therapy (tp): A retrospective, monocentric experience

Efficacy and Safety of High-Dose Vitamin C Combined with Total Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer (HCCSC R02 Study).

Forpatients with locally advanced rectal cancer (LARC), the standard treatment is fluoropyrimidine (FU) -based neoadjuvant chemoradiotherapy (NCRT) combined with curative surgery. The CAO/ARO/AIO-04 trial and FORWARC trial reported that the addition of oxaliplatin to FU -based NCRT contributed to improve pathologic complete response (pCR), nevertheless, increased the acute therapeutic toxicity. Some studies showed that vitamin C (VitC) had potential benefits on anti-tumor therapy and anti-inflammatory response. Therefore, we conducted this HCCSC R02 study to explore the efficacy and safety of adding a high-dose intravenous VitC to mFOLFOX6/XELOX -based NCRT in LARC. HCCSCR02 study was designed as a prospective, single-center phase II trial, which including pts aged 18-75 years with stage II/III rectal adenocarcinoma, distance from anus ≤12cm. The enrollment criteria included: staged with MRI as cT3/cT4 or cN1/2, or mesorectal fascia involvement (MRF+), or difficult to preserve the anus. Patients with glucose-6-phosphate dehydrogenase enzyme(G6PD) deficiency were excluded. Pelvic intensity modulated radiation therapy (IMRT) was given in 45-50.4Gy/25-28 fractions. Concurrently, two cycles of chemotherapy (mFOLFOX6 or XELOX) were administered during IMRT, as well as intravenous VitC (24g) delivered daily after the end of each radiation therapy. Additional 2-3 cycles of mFOLFOX6 / XELOX were adopted between the completion of radiotherapy and surgery. The primary endpoint was pCR rate. The secondary endpoints included radiation-related toxicities, overall survival (OS) and disease-free survival (DFS). This study is still recruiting. From May 15, 2021 to Feb 8, 2023, 19 pts were recruited and finished all the scheduled NCRT, of which the proportion of cT4, cT3, cN2, cN1 were 31.6%, 63.2%, 52.6%, 36.8%, respectively. In addition, 10 pts (52.6%) were diagnosed as MRF+ initially, and 8 pts (42.1%) had a lower primary tumor(≤5cm) who were considered difficult for anal preservation before NCRT. All subjects enrolled were confirmed to be proficient mismatch repair (pMMR). As a result, 18 pts underwent a total mesorectal excision (TME) all with R0-resection, and 8 pts were evaluated as pCR (44.4%, 8/18, confidence interval: 0.246-0.663), 11 as major pathological response rate (MPR) (61.6%, 11/18), respectively. The anus preservation rate in patients with lower diseases was 87.5% (7/8). One case accepted a watch-and-wait strategy because of clinical complete response (cCR). Overall, grade 3 toxicities were observed in 4 pts, including 3 leucopenia (15.8%, 3/19), 2 neutropenia (10.5%, 2/19) and 1 diarrhea (5.3%, 1/19). No grade 4 adverse event was observed. The addition of high-dose VitC to the mFOLFOX6/XELOX-based NCRT in LARC showed a promising pCR, well tolerance, particularly low rate of diarrhea, thus warrants further investigation. NCT04801511.

Response to the FDA Decision Regarding DPYD Testing Prior to Fluoropyrimidine Chemotherapy.

Fluoropyrimidine (FP) chemotherapy is associated with severe, life-threatening toxicities, particularly among patients who carry deleterious germline variants in the DPYD gene. Pretreatment DPYD testing is standard of care throughout most of Europe; however, it has not been recommended in clinical practice guidelines in the United States. Due to increased risk of severe toxicity, a Citizen's Petition asked the US Food and Drug Administration (FDA) to update language in FP drug labels to recommend DPYD testing as part of a boxed warning and recommend FP dose reduction in patients carrying deleterious germline variants. In response, the FDA updated the capecitabine package insert to inform patients about the toxicity risk and test availability and consider DPYD testing. However, the FDA did not include a testing recommendation or requirement, or a boxed warning. Additionally, the FDA did not recommend FP dose adjustment in DPYD variant carriers. This review provides a critical assessment of the DPYD-FP pharmacogenetic association using the FDA's previously published Pharmacogenetic Pyramid, demonstrating that the evidence is compelling for recommending DPYD testing prior to FP treatment. Additionally, the FDA's stated concerns about recommending DPYD testing and DPYD-guided FP dose adjustment are addressed and discussed in the context of the FDA's other genetic testing and dose adjustment recommendations. We call on the FDA to follow our European counterparts in recommending DPYD testing and genotype-based dose adjustment to ensure patients with cancer receive safe and effective FP chemotherapy.

Real-world experience of an in-house dihydropyrimidine dehydrogenase (DPYD) genotype test to guide fluoropyrimidine (FP) dosing at a multisite cancer hospital.

1534 Background: FPs, including 5-fluorouracil and capecitabine, are widely used to treat solid tumor malignancies like gastrointestinal (GI) cancers. One-third of patients (pts) develop severe toxicities which may lead to treatment delays or hospitalization. Toxicities can be partly due to genetic variations in DPYD. Herein, we describe the implementation of an in-house DPYD test and its impact on FP dosing at a multisite cancer hospital. Methods: This is an observational study of pts starting or continuing FP-based chemotherapy who received DPYD testing as part of routine care. Buccal swabs were collected in clinic and sent to an in-house lab for genotyping using a polymerase chain reaction-based Drug Metabolizing Enzyme assay that interrogates all 5 variants with moderate-to-strong evidence according to the Clinical Pharmacogenetics Implementation Consortium (CPIC) (c.1905+1G&gt;A, c.2846A&gt;T, c.1679T&gt;G, c.1236G&gt;A and c.557A&gt;G). Phenotype translations and dosing were based on CPIC guidelines. Test results and dose recommendations were uploaded to the electronic medical record (EMR) and emailed to the care team. In April 2022, pre- and post-test EMR alerts were built to prompt test ordering and dose modifications. The primary objective was to evaluate the proportion of DPYD variant carriers in tested pts receiving FP. Secondarily, we evaluated turnaround time and impact on FP dosing. Results: From March 2020-December 2022, 491 pts across 14 clinics received DPYD genotyping (54% male, 74% White, 20% Black, median age 53 years). GI cancers (~50% colorectal) represented 90% of the diagnoses. The median lab turnaround time was 3 (IQR 2-6) days. Pretreatment testing was ordered in 389 (79%) pts, of which 360 (93%) had results before cycle 1. Overall, 30 pts (6.1%) were heterozygous carriers (4.9% in pretreatment and 10.8% in reactive testing groups). Variants observed were c.1236G&gt;A (n=13), c.2846A&gt;T (n=8), c.1905+1G&gt;A (*2A) (n=4), c.557A&gt;G (n=4), and c.1679T&gt;G (*13) (n=1). FP dose was modified in 27 (90%) pts (reduced in 25, avoided in 1, discontinued in 1). Of 19 carriers with pretreatment testing, 17 (90%) received an upfront dose reduction (mean reduction 42%; 3 had subsequent dose escalations); 1 avoided FP and 1 declined chemotherapy. Of 11 carriers with reactive testing, 9 had dose reductions (mean reduction 39%) and 2 discontinued FP due to toxicity. The mean FP dose intensity at cycle 1 was 56% in pretreatment carriers, 97% in reactive carriers, and 94% in wild type pts. Conclusions: DPYD genotype-guided FP dosing is feasible at a multisite cancer hospital. In-house rapid turnaround DPYD testing identified variant carriers and resulted in treatment/dose modifications for most carriers, potentially avoiding or mitigating severe toxicities and/or hospitalization, particularly with pretreatment testing. Toxicity evaluation is ongoing.