UGT1A1 genotype-guided irinotecan dosing during neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A prospective analysis of SN-38 concentration.

Irinotecan plays a crucial role in the neoadjuvant chemoradiotherapy (nCRT) of rectal cancer, but its optimal dosing is still unclear. In this study, we included 101 eligible patients with the UGT1A1*28 genotype of UGT1A1*1*1 (74.3%) and UGT1A1*1*28 (25.7%) and UGT1A1*6 genotypes of GG (63.4%), GA (32.7%), and AA (3.9%). All patients received preoperative radiotherapy (50 Gy/25 fractions) with concurrent irinotecan (UGT1A1*1*1: 80 mg/m2 ; UGT1A1*1*28: 65 mg/m2 ) and capecitabine (CapIri). SN-38 concentrations were measured at 1.5, 24, and 49 h post-administration. Patients were divided into four groups (Q1-Q4) based on the SN-38 concentration. The complete-response (CR) rate was the primary endpoint. The analysis demonstrated that the 49 h SN-38 concentration was relatively optimal for predicting efficacy and toxicity. The Q4 group had a significantly higher CR rate than the Q1 group (p = .019), but also higher rates of adverse events (p = .009). We screened the recommended 49 h SN-38, with a 0.5-1.0 ng/mL concentration range. We also validated the correlation between UGT1A1*6 polymorphism and SN-38 concentration, along with the clinical efficacy of irinotecan. In conclusion, our study identified the relatively optimal timepoint and concentration range for monitoring SN38 concentrations and revealed the clinical significance of UGT1A1*6 and UGT1A1*28 polymorphisms in guiding irinotecan administration, offering meaningful insights for personalised irinotecan dosing.

Clinical outcomes of liposomal irinotecan in patients with advanced pancreatic cancer previously treated with conventional irinotecan: A meta-analysis of real-world evidence.

BACKGROUND: Pivotal clinical trials supported survival benefits of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin in patients with pancreatic ductal adenocarcinoma (PDAC) who previously received gemcitabine-based therapy. There are concerns about the benefits of nal-IRI in patients who received FOLFIRINOX (combined fluorouracil, leucovorin, IRI, and oxaliplatin) because of potential cross-resistance to IRI. The objective of this meta-analysis was to characterize the impact of the previous receipt of IRI on the outcomes of nal-IRI regimens in patients with advanced PDAC. METHODS: Real-world studies evaluating the outcomes of nal-IRI in patients who had prior IRI exposure published up to April 2023 were searched using electronic databases. The meta-analysis was conducted using a random effects model to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Eight studies (n = 1368 patients) were included. The pooled median progression-free survival (PFS) was 2.02 months (95% CI, 1.43-2.57 months), and the median overall survival (OS) was 4.26 months (95% CI, 3.03-5.39 months). Patients with prior IRI exposure had PFS (HR, 1.17; 95% CI, 0.94-1.47; p = .17) and OS (HR, 1.16; 95% CI, 0.95-1.42; p = .16) comparable to patients without prior IRI exposure. Likewise, patients who had progressive disease on conventional IRI had PFS (HR, 1.50; 95% CI, 0.73-3.08; p = .24) and OS (HR, 1.70; 95% CI, 0.68-4.27; p = .26) with nal-IRI comparable to patients who had no progressive disease. CONCLUSIONS: Prior IRI exposure does not affect the survival outcomes of nal-IRI regimens in patients who have advanced PDAC. The selection of later lines of chemotherapy regimens should be based on the differential safety profile, patient status, the cost of treatment, and health-related quality of life.

A phase II trial of UGT1A1 genotype-guided FOLFIRI plus bevacizumab as first-line therapy for advanced, unresectable colorectal cancer.

BACKGROUND: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. METHODS: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). RESULTS: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. CONCLUSIONS: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.

SN-38, an active metabolite of irinotecan, inhibits transcription of nuclear factor erythroid 2-related factor 2 and enhances drug sensitivity of colorectal cancer cells.

Nuclear factor erythroid 2-related factor 2 (Nrf2) significantly contributes to drug resistance of cancer cells, and Nrf2 inhibitors have been vigorously pursued. Repurposing of existing drugs, especially anticancer drugs, is a straightforward and promising strategy to find clinically available Nrf2 inhibitors and effective drug combinations. Topoisomerase inhibitors SN-38 (an active metabolite of irinotecan), topotecan, mitoxantrone, and epirubicin were found to significantly suppress Nrf2 transcriptional activity in cancer cells. SN-38, the most potent one among them, significantly inhibited the transcription of Nrf2, as indicated by decreased mRNA level and binding of RNA polymerase II to NFE2L2 gene, while no impact on Nrf2 protein or mRNA degradation was observed. SN-38 synergized with Nrf2-sensitive anticancer drugs such as mitomycin C in killing colorectal cancer cells, and irinotecan and mitomycin C synergistically inhibited the growth of SW480 xenografts in nude mice. Our study identified SN-38 and three other topoisomerase inhibitors as Nrf2 inhibitors, revealed the Nrf2-inhibitory mechanism of SN-38, and indicate that clinically feasible drug combinations could be designed based on their interactions with Nrf2 signaling.

Bifidobacterium longum SX-1326 ameliorates gastrointestinal toxicity after irinotecan chemotherapy via modulating the P53 signaling pathway and brain-gut axis.

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignant malignancy affecting the gastrointestinal tract that is usually treated clinically with chemotherapeutic agents, whereas chemotherapeutic agents can cause severe gastrointestinal toxicity, which brings great pain to patients. Therefore, finding effective adjuvant agents for chemotherapy is crucial. METHODS: In this study, a CRC mouse model was successfully constructed using AOM/DSS, and the treatment was carried out by probiotic Bifidobacterium longum SX-1326 (B. longum SX-1326) in combination with irinotecan. Combining with various techniques of modern biomedical research, such as Hematoxylin and Eosin (H&E), Immunohistochemistry (IHC), Western blotting and 16S rDNA sequencing, we intend to elucidate the effect and mechanism of B. longum SX-1326 in improving the anticancer efficacy and reducing the side effects on the different levels of molecules, animals, and bacteria. RESULTS: Our results showed that B. longum SX-1326 enhanced the expression of Cleaved Caspase-3 (M vs. U = p < 0.01) and down-regulated the expression level of B-cell lymphoma-2 (Bcl-2) through up-regulation of the p53 signaling pathway in CRC mice, which resulted in an adjuvant effect on the treatment of CRC with irinotecan. Moreover, B. longum SX-1326 was also able to regulate the gut-brain-axis (GBA) by restoring damaged enterochromaffin cells, reducing the release of 5-hydroxytryptamine (5-HT) in brain tissue (I vs. U = 89.26 vs. 75.03, p < 0.05), and further alleviating the adverse effects of nausea and vomiting. In addition, B. longum SX-1326 reversed dysbiosis in CRC model mice by increasing the levels of Dehalobacterium, Ruminnococcus, and Mucispirillum. And further alleviated colorectal inflammation by downregulating the TLR4/MyD88/NF-κB signaling pathway. CONCLUSIONS: In conclusion, our work reveals that B. longum SX-1326 has a favorable effect in adjuvant irinotecan for CRC and amelioration of post-chemotherapy side effects, and also provides the theoretical basis and data for finding a safe and efficient chemotherapeutic adjuvant.

Liposomal irinotecan (HR070803) in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors: a phase 1b dose-escalation and expansion study.

This phase 1b study aimed to evaluate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of HR070803, a novel nanoliposomal formulation of irinotecan, in combination with 5-fluorouracil and leucovorin in patients with pretreated advanced solid tumors. This study consisted of dose-escalation and expansion stages. Dose escalation was performed with a traditional 3 + 3 design; patients received intravenous infusion of HR070803 from 60 to 80 mg/m2, followed by leucovorin (200 mg/m2) and 5-fluorouracil (2000 mg/m2) every 2 weeks. In the expansion stage, patients received treatments at selected tolerable dose. Fifteen patients received treatments at 60 mg/m2 (n = 12) and 80 mg/m2 (n = 3). DLTs occurred in 2 patients at 80 mg/m2 (grade 2 neutropenia that resulted in a dose delay of ≥ 7 days, n = 1; grade 3 febrile neutropenia, n = 1). The MTD was determined to be 60 mg/m2. The most frequent HR070803related adverse events included anorexia, leukopenia, neutropenia, nausea, fatigue, and diarrhea. SN-38, the active metabolite of irinotecan, exhibited lower maximum plasma concentrations and a prolonged terminal half-life when irinotecan was administered via nanoliposome compared to conventional injection. Overall, 4 patients achieved a partial response (confirmed, n = 2), and 9 had stable disease. The MTD of HR070803 was 60 mg/m2 when infused with 5-fluorouracil and leucovorin. Nanoliposomal encapsulation modified the pharmacokinetics of irinotecan and SN-38. HR070803 with 5-fluorouracil and leucovorin demonstrated a manageable safety profile and promising antitumor efficacy in advanced solid tumors. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05086848. Retrospectively registered on Oct. 12, 2021.

Phase I study of trifluridine/tipiracil (TAS-102) plus irinotecan in combination with bevacizumab as a second-line therapy for patients with metastatic colorectal cancer.

PURPOSE: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment. METHODS: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose. RESULTS: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease. CONCLUSION: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.

Bi-weekly irinotecan is an effective and convenient regimen in the treatment of relapsed or refractory small cell lung cancer.

BACKGROUND: Despite initial dramatic responses, metastatic small cell lung cancer (SCLC) invariably recurs. Irinotecan is one of the active agents for patients with recurrent SCLC. In the second line, weekly or three-weekly irinotecan regimens have been adopted, however, the optimal dose and schedule is not defined. In our institution, we use a bi-weekly regimen of irinotecan. In this study, we aimed to investigate the safety and efficacy of the bi-weekly irinotecan in the second- or third-line treatment of SCLC patients. METHODS: The study population consisted of advanced stage SCLC patients who were followed at Hacettepe University Cancer Institute between January 2007 and March 2021 and received salvage irinotecan 180 mg/m2 every two weeks, following progression after platinum-etoposide treatment. RESULTS: One hundred patients were included. At diagnosis, nineteen patients (19%) had limited stage and 81 patients (81%) had extensive stage SCLC. Objective response rates (ORR) were 44.6% and 46.2% for patients who received irinotecan treatment in second line, and in third line, respectively. Seventeen percent of all the patients had grade 3 and above adverse events during irinotecan treatment. In our study, 45.8% of patients were able to complete at least 6 cycles of irinotecan treatment and 69.8% were able to receive at least 3 cycles of irinotecan treatment without any dose interruption or reduction. CONCLUSIONS: Irinotecan 180 mg/m2 every two weeks appears to be safe and effective in the 2nd- and 3rd-line treatment of advanced stage SCLC. Bi-weekly administration allows G-CSF prophylaxis in between doses, leading to an uninterrupted administration.

Real-world outcomes of third-line immune checkpoint inhibitors versus irinotecan-based chemotherapy in patients with advanced gastric cancer: a Korean, multicenter study (KCSG ST22-06).

BACKGROUND: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy is frequently used after failure of second-line paclitaxel plus ramucirumab treatment for patients with locally advanced unresectable or metastatic advanced gastric cancer (AGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with AGC. METHODS: We retrospectively reviewed patients with AGC, whose third-line treatment started between July 2019 and June 2021 at 17 institutions in Korea. The ICI group included patients who received nivolumab or pembrolizumab, and the irinotecan-based chemotherapy group included patients who received irinotecan or FOLFIRI (5-fluorouracil, leucovorin and irinotecan). RESULTS: A total of 363 patients [n = 129 (ICI) and n = 234 (irinotecan-based chemotherapy)] were analyzed. The median progression-free survival was 2.3 and 2.9 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.802). The median overall survival (OS) was 5.5 and 6.0 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.786). For all patients included in this study, multivariable analysis showed that weight loss, peritoneal metastasis, low serum sodium or albumin, and short duration of second-line treatment were associated with inferior OS (p < 0.05). ICI showed significantly longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis. Whereas ICI showed significantly shorter OS in patients without PD-L1 expression than irinotecan-based chemotherapy. CONCLUSIONS: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for AGC patients. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression. TRIAL REGISTRATION: This study was registered in the Clinical Trial Registry of Korea ( https://cris.nih.go.kr : KCT 0007732).

Survival outcome of different treatment sequences in patients with locally advanced and metastatic pancreatic cancer.

BACKGROUND: Despite some therapeutic advances, improvement in survival rates of unresectable and/or metastatic pancreatic ductal adenocarcinoma (PDAC) has been minimal over recent decade. We aimed to evaluate the impact of different treatment sequences on clinical outcomes of advanced PDAC at our academic institution. METHODS: In this single institution retrospective analysis, we assessed characteristics and survival rates of unresectable and/or metastatic pancreatic PDAC patients who started a systemic treatment between 01/2015 and 12/2021. Survival analyses were performed by Kaplan-Meier and Cox proportional hazards model. RESULTS: The number of 285 patients received at least two lines of treatment, but only 137 patients were suitable for third-line treatment. Subgroup analysis showed that thirty-seven patients received A line (gemcitabine/nab-paclitaxel or nab-paclitaxel combined therapy to FOLFIRINOX) therapy, 37 patients received B line (nab-paclitaxel combined therapy to gemcitabine combined therapy to FOLFIRINOX) therapy, 21 patients received C line (nab-paclitaxel combined therapy to gemcitabine combined therapy to oxaliplatin or irinotecan combined therapy) therapy. Survival rates for different treatment lines were significantly different and median overall survival (OS) was 14.00, 18.00, and 14.00 months, respectively (p<0.05). CONCLUSION: Our study provides real-world evidence for the effectiveness of different treatment sequences and underscores the treatment sequences on survival outcome when considering the entire management in advanced PDAC.