Combination Of Irinotecan Research Articles

Melanocortin-4 receptor antagonist TCMCB07 alleviates chemotherapy-induced anorexia and weight loss in rats.

Cancer patients undergoing chemotherapy often experience anorexia and weight loss that substantially deteriorates overall health, reduces treatment tolerance and quality of life, and worsens oncologic outcomes. There are currently few effective therapeutic options to mitigate these side effects. The central melanocortin system, which plays a pivotal role in regulating appetite and energy homeostasis, presents a logical target for treating anorexia and weight loss. In this preclinical study, we evaluated the efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor, in mitigating anorexia and weight loss in several rat models of chemotherapy: cisplatin, 5-fluorouracil, cyclophosphamide, vincristine, doxorubicin, and a combination of irinotecan and 5-fluorouracil. Our results indicate that peripheral administration of TCMCB07 improved appetite, stabilized body weight, preserved fat and heart mass, and slightly protected lean mass after multiple cycles of chemotherapy. Furthermore, combining TCMCB07 with a growth differentiation factor 15 antibody enhanced treatment effectiveness. Similar effects from TCMCB07 treatment were observed in a rat tumor model following combination chemotherapy. No notable adverse effects nor increased chemotherapy-related toxicities were observed with TCMCB07 treatment. These findings suggest that peripheral administration of TCMCB07 holds promise as a therapeutic approach for alleviating chemotherapy-induced anorexia and weight loss, potentially benefiting numerous patients undergoing chemotherapy.

Phase II Study of Irinotecan, Trifluridine/tipiracil (TAS-102) plus Bevacizumab as a Later-line Therapy for Patients with Metastatic Colorectal Cancer (mCRC): a prospective single-center explorative study.

To explore the efficacy and safety of the combination of irinotecan, trifluridine/tipiracil (TAS-102), and bevacizumab in a later-line setting for metastatic colorectal cancer (mCRC) patients. This was a single-center, phase II trial. The mCRC patients who are refractory to standard first-line and second-line treatment are eligible. Patients who previously received irinotecan while progressing during maintenance therapy are also eligible. The primary endpoint was the objective response rate (ORR). Between August 1, 2022, and September 30, 2023, 35 patients were enrolled, and 31 of them were evaluable for efficacy. The ORR was 25.8% (8/31), and the disease control rate (DCR) was 93.5% (29/31). As of April 30, 2024, the median progression-free survival (PFS) was 9.2 months (95% CI 6.285-12.115), whereas the median overall survival (OS) was not reached with the 1-year OS rate of 73.5%. The most common grade 3/4 treatment-related adverse events were neutropenia (34.3%), anemia (17.1%), and thrombocytopenia (8.6%). Irinotecan, TAS-102 plus bevacizumab regimen preliminarily demonstrated promising efficacy with tolerable toxicity for mCRC patients as later-line treatment. This regimen warrants further exploration in refractory mCRC patients.

Real-world outcomes of FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer: the JSCCR-TRIPON study.

FOLFOXIRI plus bevacizumab is a standard first-line chemotherapy for patients with metastatic colorectal cancer (mCRC). However, due to the severe toxicities, this regimen is not widely used. There is limited data on the real-world efficacy and safety. We conducted a retrospective analysis of clinical data from mCRC patients who received FOLFOXIRI plus bevacizumab as first-line chemotherapy at 31 institutions. The initial dose was standardized according to the TRIBE regimen. Induction therapy was defined as a combination of oxaliplatin, irinotecan, and fluorouracil. Out of 104 patients who met the criteria, the median age was 58years (range, 16-72). 81% of patients had an eastern cooperative oncology group performance status (PS) of 0. An initial dose reduction was observed in 63% of patients. The median number of preplanned induction therapy cycles was 12 (range, 4-12). The completion of scheduled induction therapy cycles was observed in 45% of patients, with treatment-related toxicities being the main reason for discontinuation (63%). The median progression-free survival and overall survival were 12.8months (95% CI, 10.6-15.0) and 27.9months (95% CI 21.6-34.2), respectively. The objective response rate and disease control rate were 63.7% and 98.9%, respectively. The R0 resection rate was 21.2%. The main grade 3 or higher toxicities were neutropenia (51%), febrile neutropenia (10%), and nausea/vomiting (5%). No treatment-related deaths were observed. In a real-world clinical setting, FOLFOXIRI plus bevacizumab demonstrated efficacy and safety comparable to previous clinical trials.

Tislelizumab plus cetuximab and irinotecan in refractory microsatellite stable and RAS wild-type metastatic colorectal cancer: a single-arm phase 2 study

Immunotherapy confers little to no benefit in the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Mechanistic insights suggested that epidermal growth factor receptor (EGFR) antibody plus irinotecan might augment the tumor immune response in mCRC. Therefore, we conducted a proof-of-concept, single-arm, phase 2 study (ChiCTR identifier: ChiCTR2000035642) of a combination treatment regimen including tislelizumab (anti-PD-1), cetuximab (anti-EGFR) and irinotecan in 33 patients with MSS and RAS wild-type (WT) mCRC who were previously treated with ≥2 lines of therapy. The primary endpoint was met, with a confirmed objective response rate of 33%. As secondary endpoints, the disease control rate was 79%, and the median progression-free survival and overall survival were 7.3 and 17.4 months respectively. Among the 33 patients, 32 (97.0%) had treatment-related adverse events (AEs). Three (9.1%) reported grade ≥ 3 AEs, including rash (n = 1), neutropenia (n = 2). The post-hoc evaluation of dynamic circulating tumor DNA using next generation sequencing and the analysis of peripheral immune proteomics landscape using Olink revealed that lower variant allele frequency (VAF) at baseline, greater reduction in VAF on treatment, and a hot peripheral macroenvironment were associated with the treatment response independently. Our study showed the antitumor activity of tislelizumab, cetuximab, and irinotecan combination with a tolerable safety profile in previously treated MSS and RAS WT mCRC.

Trametinib potentiates anti-PD-1 efficacy in tumors established from chemotherapy-primed pancreatic cancer cells.

Despite advances in immune checkpoint inhibitors (ICIs), chemotherapy remains the standard therapy for patients with pancreatic ductal adenocarcinoma (PDAC). As the combinations of chemotherapy, including the FOLFIRINOX (5-fluorouracil (5FU), irinotecan, and oxaliplatin) regimen, and ICIs have failed to demonstrate clinical benefit in patients with metastatic PDAC tumors, there is increasing interest in identifying therapeutic approaches to potentiate ICI efficacy in PDAC patients. In this study, we report that neoadjuvant FOLFRINOX-treated human PDAC tumors exhibit increased MEK/ERK activation. We also show elevated MEK/ERK signaling in ex vivo PDAC slice cultures and cell lines treated with a combination of 5FU (F), irinotecan (I), and oxaliplatin (O) (FIO). In addition, we find that the KPC-FIO cells, established from repeated treatment of mouse PDAC cell lines with 6-8 cycles of FIO, display enhanced ERK phosphorylation and demonstrate increased sensitivity to MEK inhibition in vitro and in vivo. Significantly, the KPC-FIO cells develop tumors with a pro-inflammatory immune profile similar to human PDAC tumors following neoadjuvant FOLFIRINOX treatment. Furthermore, we found that the MEK inhibitor Trametinib enables additional infiltration of highly functional CD8+ T cells into the KPC-FIO tumors and potentiates the efficacy of anti-PD-1 antibody in syngeneic mouse models. Our findings provide a rationale for combining Trametinib and anti-PD-1 antibodies in PDAC patients following neoadjuvant or short-term FOLFIRINOX treatment to achieve effective anti-tumor responses.

A phase-I study of second-line S-IROX for unresectable pancreatic cancer after gemcitabine plus nab-paclitaxel failure.

Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 120mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 150mg/m2).

Eribulin and irinotecan for refractory or recurrent Ewing sarcoma: A retrospective study.

e23502 Background: The effectiveness of eribulin and irinotecan in treatment of xenograft models of Ewing sarcoma is well-established but little clinical data has been reported. Encouraging results from preclinical models and a shortage of temozolomide in our hospital have prompted the administration of the eribulin as substitute for temozolomide and vincristine in combination of irinotecan at our institution from 2022 to 2023 in an off-label way. Methods: We retrospectively reviewed the medical records of patients treated for refractory or recurrent Ewing sarcoma with 1.4mg/m2 D1,8 eribulin and 20mg/m2/d D1-5,8-12 irinotecan at 21 day intervals (ERII) at Peking University People’s Hospital. Results: Finally, a total of 17 patients with median age 18.6 years were treated with a total of 77 courses of ERII between February 2022 and February 2023. The objective response rate was 35.3%, the disease control rate 58.9% and the median event-free survival (EFS) 2.07 months. 35.3% patients had 6 months EFS and overall survival was 66.9%. Grade 3 or 4 toxicities were observed in 37.6% courses and in 64.7% of the patients, with myelosuppression, especially neutropenia, being the most common and diarrhea / abdominal pain the second most common. In the dx5x2 VIT protocol the later portion was given two days after the end of early portion. However, in this substitute regimen of eribulin, the median time interval between the end of the early portion to the start of later portion was 5 days. The dose intensity of the regimen was reduced by 21% per cycle. The later portion was delayed mostly because of unrecovered myelosuppression. Conclusions: The efficacy and safety of eribulin and irinotecan as a second-line regimen was inferior to historical reports of temozolomide and irinotecan in the same institute. There was no need for further prospective trials on this combination unless mechanisms of synergy and biomarkers are identified. [Table: see text]

A phase II study of liposomal irinotecan-based chemotherapy with or without PD-1 inhibitor in patients with unresectable locally advanced or metastatic biliary tract cancer.

e15077 Background: Clinical outcomes for advanced biliary tract cancer (BTC) patients (pt) progressed on first-line therapy remain dismal. Liposomal irinotecan (LI) (HE072) is a formulation encapsulating I in a lipid bilayer vesicle and was approved in China in September 2022. It was used with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic pancreatic cancer progressing on gemcitabine treatment. We conducted an phase II study to investigate HE072 in combination with 5-FU and LV with or without a novel PD-1 inhibitor SG001 in patients with advanced BTC progressed on prior gemcitabine-based chemotherapy. Methods: This is a multi-center, non-randomized, open label phase II study in pts with unresectable locally advanced or metastatic BTC. Key inclusion factors were ECOG PS 0-1, prior gemcitabine-based chemotherapy, evidence of disease progression with at least one measurable lesion and adequate haematological/organ function. Key exclusion factor was brain metastases. Pts were treated with liposomal irinotecan (70 mg/m2) plus LV (400 mg/m2f) and 5-FU (2400 mg/m2) with or without SG001 (240mg) IV every 2 weeks for up to 2 years in absence of disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Primary endpoint was objective response rate (ORR). Secondary endpoints include progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: As of April 25, 2023, 17 BTC pts were enrolled into liposomal irinotecan-based chemotherapy arm (n = 7) and liposomal irinotecan-based chemotherapy plus SG001 arm (n = 10). ORR and DCR were 14.3% and 71.4% for chemotherapy arm, 20% and 40% for chemotherapy+ SG001 arm. Median OS and PFS for chemotherapy arm was 11.5(95% CI, 3.9-NE) and 4.2(95% CI, 1.4-NE) months, and for chemotherapy+PD-1 arm was 15.3 (95% CI, 3.6-17.0) and 3.8(95% CI, 1.4-6.9) months. All pts experienced treatment-related adverse events (TRAEs). The incidence of grade≥3 TRAEs was 58.8%(10/17), which occurred in 57% (4/7) of pts treated in chemotherapy arm vs 60% (6/10) in chemotherapy+SG001 arm. Among all patients, the most frequent grade ≥3 TRAEs were fatigue (29.4%), neutropenia (23.5%) and leukopenia (23.5%). One grade 4 TRAE leading to dose reduction in liposomal irinotecan was febrile neutropenia in chemotherapy arm. There were no treatment-related deaths. Conclusions: These preliminary results suggested that liposomal irinotecan plus 5-FU and LV was well-tolerated and showed promising and durable clinical activity in advanced BTC pts progressed on first-line treatment. Combined use of SG001 further improved clinical outcome in these pts without increased toxicity. Combination of liposomal irinotecan, 5-FU, LV and PD-1 inhibitor is a treatment strategy which is worthy of further exploration.

A phase ib-II study of dabrafenib, trametinib, cetuximab plus irinotecan in patients with BRAF mutant metastatic colorectal cancer: Subgroup analysis and biomarker identification.

e15581 Background: About 5%-12% of patients with metastatic CRC (mCRC) have BRAF mutations in which BRAF V600E mutated was most common, accounts for approximately 90% of cases of BRAF mutation mCRC. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. The efficacy results of this study have been reported in 2023 ASCO GI (#156). The ORR was 30% (3/10), the DCR was 80% (8/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months. Here, we reported the results of subsequent analyses. Methods: In this phase Ib-II trial, 15 patients with BRAF-mutant mCRC received Dabrafenib, trametinib, cetuximab plus irinotecan combination therapy. Whole exome sequencing was conducted in 8 proficient mismatch repair (pMMR) mCRC patients with BRAF V600E-mutant. Patients were followed up clinically and radiographically. Response was defined as Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) were defined according to the response definitions of the RECIST criteria. Results: 3 mCRC patients (CR or PR) were divided into response group, 5 mCRC patients (SD or PD) were divided into non-response group. Age (59.6±4.22 vs 39.0±9.93), Gender (male 66.67% vs 80%), ECOG score (0.67 vs 0.60), ALT flare rate (66.67% vs 60%) were similar in the two group. Patients in response group have better 2-year survival rate (66.7% vs 0%, P < 0.05). Furthermore, response-related Differential Expression Genes (DEGs) (log2fc > 1, P < 0.05) were analyzed. Meanwhile, GO and KEGG pathway analysis was conducted based on DEGs. Results showed that MAPK signaling pathway related genes were down-regulated in response group such as EGF, FGF18, HGF, IGF1, MAPK10, NGF. While Apoptosis related genes were up-regulated in response group such as BCL2L1, AIFM1, DAXX. Moreover, Antigen processing and presentation related genes such as CALR, CANX, HSPA8 were enriched in response group, which indicated a more active immune microenvironment. On the contrary, Hedgehog signaling pathway related genes such as GLI1, HHIP, BOC were enriched in non-response group. Next, we verified the clinical significance of DEGS in TCGA CRC cohort database using Cox-regression analysis. Results showed that expression of IGF1, NGF, CAMK2B, CCNA1 were associated with poor prognosis and CANX, HSPA8 were associated with better prognosis, which is in accordance with our sequencing results. Conclusions: Inhibition of MAPK signaling and promoted Apoptosis was found in BRAF V600E-mutant mCRC patients who were response to Dabrafenib, trametinib, cetuximab plus irinotecan. It's worth noticing that immune activation occurred in responsive patients, indicated a potential benefit from immunotherapy combination therapy. Moreover, Hedgehog signaling pathway may be target in rescue therapy in mCRC patients. Clinical trial information: ChiCTR2200063316.

Therapy-related myeloid neoplasms after treatment for ovarian cancer: A retrospective single-center case series.

Therapy-related myeloid neoplasms (t-MNs) are often fatal and arise as late complications of previous anticancer drug treatment. No single-center case series has examined t-MNs in epithelial ovarian cancer (EOC). All patients with EOC treated at Chiba University Hospital between 2000 and 2021 were included. We retrospectively analyzed the characteristics, clinical course, and outcomes of patients who developed t-MNs. Among 895 cases with EOC, 814 cases were treated with anticancer drugs. The median follow-up period was 45 months (interquartile range, 27-81) months. Ten patients (1.2%) developed t-MNs (FIGO IIIA in one case, IIIC in three, IVA in one, and IVB in five). Nine patients were diagnosed with myelodysplastic syndrome and one with acute leukemia. One patient with myelodysplastic syndrome developed acute leukemia. The median time from the first chemotherapy administration to t-MN onset was 42 months (range, 21-94 months), with t-MN diagnoses resulting from pancytopenia in four cases, thrombocytopenia in three, and blast or abnormal cell morphology in four. The median number of previous treatment regimens was four (range, 1-7). Paclitaxel + carboplatin therapy was administered to all patients, gemcitabine and irinotecan combination therapy to nine, bevacizumab to eight, and olaparib to four. Six patients received chemotherapy for t-MN. All patients died (eight cancer-related deaths and two t-MN-related deaths). None of the patients was able to restart cancer treatment. The median survival time from t-MN onset was 4 months. Patients with EOC who developed t-MN were unable to restart cancer treatment and had a significantly worse prognosis.

Abstract 4547: A novel drug combination with improved therapeutic efficacy over sorafenib in multiple preclinical models of hepatocellular carcinoma

Abstract Introduction: Due to the heterogeneity of hepatocellular carcinoma (HCC), the incidence of resistance and toxicity to first-line therapy sorafenib is high. Combinations of drugs can be used to exploit synergistic effects to reduce adverse events, while improving efficacy and survival. In-vitro studies performed by our team identified irinotecan and sonidegib to have potential for synergistic therapeutic effects in combination with sorafenib. Follow up in-vivo dose optimization studies in a murine NASH induced HCC found this 3-drug combination to be more effective than sorafenib-alone at arresting tumor development and progression. In this study, we tested the in-vivo efficacy of the combination in two separate preclinical cell-line derived xenograft (CDX) models. Experimental Procedure: HCC CDX models were generated by injecting two distinct HCC cell lines, Huh7 and HepG2, subcutaneously in the flank of male NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJ (NSG) mice. Mice were administered either vehicle, sorafenib, or a 3-drug combination, and mouse tumor volumes and weights were tracked for duration of study. Mice were all euthanized at study endpoint and tissues collected for analysis, including the assessment of tumor weights, differentiation, grade, necrosis, and proliferation status. Serum collected from endpoint blood was measured for human alpha fetoprotein (AFP) and alanine transaminase (ALT) levels. Changes in protein expression of tumors were assessed by western blot analysis. Results: Huh7 and HepG2 tumors were both sensitive to sorafenib-alone treatment. However, Huh7 tumors treated with the 3-drug combination had a significant decrease in tumor volume and weight at endpoint compared to the vehicle and sorafenib-alone. HepG2 tumors treated with the combination also had a significant decrease in tumor volume and weight at endpoint compared to the vehicle. Though the difference in tumor volume and weight was not statistically significant for the combination compared to sorafenib, a trend towards decrease was observed. This was further confirmed by significantly reduced AFP levels in the combination compared to the vehicle and sorafenib in HepG2 and Huh7. Drug toxicities, measured by mouse weights and ALT levels, were not significantly different. Histological and immunohistochemical assessment of tumors showed necrosis and Ki67 staining to be significantly elevated in vehicle and sorafenib-alone compared to the 3-drug group. The targets for all three drugs present in the combination were downregulated in the combination compared to the vehicle and sorafenib-alone. Conclusion: This study provides strong evidence that a novel 3-drug combination of irinotecan, sonidegib, and low dose sorafenib can significantly reduce tumor proliferation and burden in multiple independent pre-clinical in-vivo HCC models compared to high dose sorafenib monotherapy. Citation Format: Anastasia Chambers, Sunaina Shrestha, Alexandra Ladd, Sergio Duarte, Ali Zarrinpar. A novel drug combination with improved therapeutic efficacy over sorafenib in multiple preclinical models of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4547.

SOX2 and OCT4 mediate radiation and drug resistance in pancreatic tumor organoids

Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. In patients with unresectable disease, either FOLFIRINOX, a combination of 5-fluorouracil (5-FU), oxaliplatin and irinotecan, or gemcitabine plus nab-paclitaxel combined with radiation are frontline standard regimens. However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) using OCT4 and SOX2, CSC markers in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 μM of 5-FU (5-Fluorouracil), and 100 μM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as a single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and downregulation following 5-FU treatment. The expression of CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and downregulation to 5-FU chemotherapy drug. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT4 expression, indicating CSC self-renewal inhibition. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant OCT4 and SOX2 expression as compared to normal pancreas, indicating their potential role in pancreatic cancer growth and therapy resistance. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the β-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study emphasizes the crucial role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to explore the impact of CSCs in PC and identify new therapeutic targets.

The effective combination therapies with irinotecan for colorectal cancer.

Colorectal cancer is the third most common type of cancer worldwide and has become one of the major human disease burdens. In clinical practice, the treatment of colorectal cancer has been closely related to the use of irinotecan. Irinotecan combines with many other anticancer drugs and has a broader range of drug combinations. Combination therapy is one of the most important means of improving anti-tumor efficacy and overcoming drug resistance. Reasonable combination therapy can lead to better patient treatment options, and inappropriate combination therapy will increase patient risk. For the colorectal therapeutic field, the significance of combination therapy is to improve the efficacy, reduce the adverse effects, and improve the ease of treatment. Therefore, we explored the clinical advantages of its combination therapy based on mechanism or metabolism and reviewed the rationale basis and its limitations in conducting exploratory clinical trials on irinotecan combination therapy, including the results of clinical trials on the combination potentiation of cytotoxic drugs, targeted agents, and herbal medicine. We hope that these can evoke more efforts to conduct irinotecan in the laboratory for further studies and evaluations, as well as the possibility of more in-depth development in future clinical trials.

The efficacy and safety of vincristine, irinotecan and anlotinib in Epithelioid Sarcoma

BackgroundEpithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients.MethodsWe retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People’s Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021.ResultsA total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated.ConclusionsThe combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma.Trial registrationThis study was approved in the Medical Ethics Committee of Peking University People’s Hospital on October 28, 2022 (No.: 2022PHD015-002). The study was registered in Clinicaltrials.gov with identifier no. NCT05656222.

Predictive role of homologous recombination deficiency (HRD) for irinotecan in combination with venadaparib, a novel PARP1/2 inhibitor, as third- or fourth-line treatment in patients with advanced gastric cancer.

380 Background: Tumors with homologous recombination deficiency (HRD), including BRCA and ATM mutations, have shown to predict response to poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors. The associations between treatment efficacy of PARP inhibitor-based regimen and mutations in BRCA (BRCAm) or ATM gene (ATMm) are not well known in previously treated advanced gastric cancer (GC). Combining PARP inhibitor and irinotecan is known to synergize cytotoxicity. The aim of this analysis was to evaluate the association of HRD and efficacy of irinotecan and venadaparib combined, in patients with metastatic GC who had failed at least 2 lines of therapy. Methods: MTT assays were performed in vitro to verify and characterize synergism between venadaparib and SN-38. Data were analyzed using the GraphPad Prism (version 9.5.1) and CompuSyn (version 1.0) software. Patients with at least two prior palliative treatments were enrolled in a multi-national phase Ib trial (NCT04725994). Tumor response was evaluated according to RECIST 1.1. Exploratory genomic analysis was included to assess the correlation between efficacy and HRD. Genomic analysis was conducted using ctDNA (GuardantOMNI Gene Panel version 1.0, Redwood City, CA) on Day 1 pre-dose. Results: In MTT assays, the combination of SN-38 and venadaparib exerted synergistic effect with combination indices (CI) ranging from 0.013 to 0.991 in SNU-638 (BRCA2m), SNU-668 (BRCA1m), AGS (low ATM) and SNU-484 (HR proficient) cells. We observe the synergistic effect between SN-38 and venadaparib remained consistent even at low concentrations of venadaparib (SN-38 IC50; without venadaparib → with 10 nM of venadaparib; SNU-638(1.72→0.28), SNU-668(10.7→1.5), AGS (0.62→0.049), SNU-484(2.25->0.38)). In the dose-finding part of the clinical study, 26 patients were enrolled, 13 had received two prior treatments and 13 had received three prior treatments. At data cut-off, median duration of follow-up (range) was 4.4 (1.3 – 23.7) months. Of the 26 patients enrolled, 5 (1 BRCA2m and 4 ATMm) had HRD (19.2%) and were treated with varying doses of irinotecan and venadaparib. In the five patients with HRD, an objective response rate (ORR) was 60% and median progression-free survival (mPFS) (95% CI) was not reached (1.2–21.5). Of the 26 patients enrolled, 11 received varying doses of venadaparib plus 100 mg/m2 of irinotecan, with an ORR of 36.4% and mPFS (95% CI) of 5.6 (3.5–not reached) months. Conclusions: Venadaparib in combination with irinotecan showed synergistic effect in vitro assays and promising clinical efficacy in the systemic treatment of refractory GC, particularly in patients with HRD. The dose expansion phase of the study is ongoing to investigate the optimal biological dose and patient selection strategies, in a randomized design. Clinical trial information: NCT04725994 .

Results of a phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI study).

655 Background: Neoadjuvant treatment for resectable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. The modified FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen often requires dose modifications, delays and growth factor support due to toxicity. Liposomal irinotecan injection (Nal-IRI) is FDA-approved with a well-tolerated safety profile in relapsed, refractory mPDAC. This current study substitutes Nal-IRI for traditional irinotecan in the mFOLFIRINOX regimen (NALIRIFOX) and aims to demonstrate safe neoadjuvant delivery. NALIRIFOX is currently under review by the FDA for frontline mPDAC. Methods: This phase 2, open-label, multicenter single-arm study enrolled adult patients (pts) with operable PDAC, resectability (borderline vs. resectable) confirmed by multiD conference, adequate organ function, and ECOG performance status (0-1). Pts received NALIRIFOX (per NAPOLI-3) every 2 wks x 4 mo followed by repeat imaging and surgical resection 4-8 wks later. Primary endpoint is the composite 30 day post-op major complication rate (hospital re-admission, death, second surgery, procedure or major complication extending hospital stay). A sample size of 25 pts will detect a 20% reduction in 1° endpoint (from 30% to 10%; 1-sided exact test; α=0.05; β=.8). Toxicity, treatment completion, R0 resection, clinical, biochemical and radiographic response rates and QOL during treatment (FACT-G) are 2° endpoints. Serial microbiota specimens have been collected for exploratory analysis. Results: From May 2019 to Feb 2023, 45 pts were enrolled from 4 centers. Median age was 63 (41-76), majority women (53%), white (89%) with borderline (n=30) or resectable (n=15) disease. All 45 pts initiated treatment with 34 proceeding to surgery and 29 completing definitive resection. Most common grade >3 AEs included non-febrile neutropenia (41%), diarrhea (30%), and anorexia (22%). Those not obtaining definitive resection had progressive disease (radiographic n=6; intra-op n=5), physician change of tx (n=2), toxicity (n=2; CMV colitis and TPN requirement/sepsis) or consent withdraw (n=1). Three (10%) pts had a post-op major complication (p=0.012). One pt died from post-op bleeding complications. Resections included both borderline (n=15) and resectable (n=14) initial disease with overall R0 resection rate of 89%. Conclusions: Neoadjuvant NALIRIFOX was safe, having met the primary study objective, with reasonable rates of treatment completion and surgical outcomes for this relatively high-risk group of pts. Additional analyses are ongoing and will be reported at the meeting. Clinical trial information: NCT03483038 .

Abstract C088: Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer

Abstract Pancreatic cancer is a devastating disease with an overall five-year survival rate of ~12% according to the American Cancer Society. Novel chemotherapeutics and targeted therapies in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received accelerated FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin is a chemotherapeutic synthetic tetrahydroisoquinoline alkaloid that inhibits active transcription by binding to guanine rich sequences in the minor groove of DNA. Lurbinectedin has been shown to reduce oncogenic transcription by stalling and degrading RNA Polymerase II and inducing breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin’s highly efficient killing of pancreatic tumor cells as a single agent in PANC-1, BxPC-3, and HPAF-II cell lines, with 72-hour IC-50s ranging from 0.266 – 0.964 nM. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells in vitro. Synergism was calculated using SynergyFinder, with HSA scores exceeding 15 in every cell line (synergy scores greater than 10 are considered synergistic according to the website manufacturer). Western Blot analysis of combination therapy indicates an upregulation of γH2AX and ATR, indicating DNA damage likely plays a role in the synergistic effects of the drugs. Bcl-2 downregulation in combination therapy indicates that the Bcl-2 family proteins likely play a role in the apoptosis of the cancer cells. Cytokine profiling analysis indicates an upregulation of the Fas apoptosis-inducing ligand under lurbinectedin and irinotecan monotherapy and combination therapy. VEGF and prolactin were downregulated in combination therapy. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-Fluorouracil (5-FU) enhances % inhibition as each drug concentration increases, and the presence of lurbinectedin enhances the synergism between irinotecan and 5-FU. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer. Citation Format: Tej Tummala, Arielle De La Cruz, Ash Uruchurtu, Nicholas R. Liguori, Abbas E. Abbas, Leiqing Zhang, Chistopher G. Azzoli, Lanlan Zhou, Wafik S. El-Deiry. Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C088.

Bevacizumab Alone Versus Bevacizumab Plus Irinotecan in Patients With Recurrent Glioblastoma: A Nationwide Population-Based Study.

For treating recurrent glioblastoma, for which there is no established treatment, the antiangiogenic antibody, bevacizumab, is used alone or with irinotecan. This study was aimed at comparing the survival of patients with recurrent glioblastoma receiving bevacizumab monotherapy and those receiving bevacizumab plus irinotecan combination therapy (B+I) by using a nationwide population-based dataset. Patients matching the International Classification of Diseases code C71.x were screened from the Health Insurance Review and Assessment Service database. From January 2008 to November 2021, patients who underwent surgery or biopsy and subsequent standard concurrent chemoradiation with temozolomide were included. Among them, those who received bevacizumab monotherapy or B+I were selected. Demographic characteristics, inpatient stay, prescription frequency, survival outcomes, and steroid prescription duration were compared between these two groups. Eight hundred and forty-six patients who underwent surgery or biopsy and received concurrent chemoradiotherapy with temozolomide were included. Of these, 450 and 396 received bevacizumab monotherapy and B+I, respectively. The corresponding median overall survival from the initial surgery was 22.60 months (95% confidence interval [CI], 20.50-24.21) and 20.44 months (95% CI, 18.55-22.60; P = 0.508, log-rank test). The B+I group had significantly more bevacizumab prescriptions (median 5 times; BEV group: median 3 times). Cox analysis, based on the postsurgery period, revealed that male sex (hazard ratio [HR], 1.28; P = 0.002), older age (HR, 1.01; P = 0.042), and undergoing biopsy instead of surgery (HR, 1.79; P < 0.0001) were significantly associated with decreased survival. Fewer radiotherapy cycles correlated with improved survival outcomes (HR, 0.63; P = 0.001). Cox analysis, conducted from the start of chemotherapy including bevacizumab, showed that male sex was the only variable significantly associated with decreased survival (HR, 1.18; P = 0.044). We found no significant difference in overall survival between the bevacizumab monotherapy and B+I groups. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy could be a suitable treatment option for treating recurrent glioblastoma.

Abstract B026: Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer

Abstract Pancreatic cancer is a devastating disease with an overall five-year survival rate of ~12% according to the American Cancer Society. Novel chemotherapeutics and targeted therapies in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received accelerated FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin is a chemotherapeutic synthetic tetrahydroisoquinoline alkaloid that inhibits active transcription by binding to guanine rich sequences in the minor groove of DNA. Lurbinectedin has been shown to reduce oncogenic transcription by stalling and degrading RNA Polymerase II and inducing breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin’s highly efficient killing of pancreatic tumor cells as a single agent in PANC-1, BxPC-3, and HPAF-II cell lines, with 72-hour IC-50s ranging from 0.266 – 0.964 nM. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells in vitro. Synergism was calculated using SynergyFinder, with HSA scores exceeding 15 in every cell line (synergy scores greater than 10 are considered synergistic according to the website manufacturer). Western Blot analysis of combination therapy indicates an upregulation of γH2AX and ATR, indicating DNA damage likely plays a role in the synergistic effects of the drugs. Bcl-2 downregulation in combination therapy indicates that the Bcl-2 family proteins likely play a role in the apoptosis of the cancer cells. Cytokine profiling analysis indicates an upregulation of the Fas apoptosis-inducing ligand under lurbinectedin and irinotecan monotherapy and combination therapy. VEGF and prolactin were downregulated in combination therapy. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-Fluorouracil (5-FU) enhances % inhibition as each drug concentration increases, and the presence of lurbinectedin enhances the synergism between irinotecan and 5-FU. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer. Citation Format: Tej Tummala, Arielle De La Cruz, Ash Uruchurtu, Nicholas R Liguori, Abbas E Abbas, Leiqing Zhang, Christopher Azzoli, Lanlan Zhou, Wafik S El-Deiry. Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B026.

DDEL-02. CLINICAL BENEFIT OF BEVACIZUMAB AND IRINOTECAN (BEV+IRI) IN PATIENTS WITH RELAPSED/REFRACTORY GLIOBLASTOMA (R/RGBM) AND ITS POTENTIAL PREDICTORS

Abstract BACKGROUND/AIM: Bevacizumab-containing chemotherapy constitutes an important salvage treatment for recurrent/refractory glioblastoma(r/rGBM). Patients and methods: We retrospectively collected the data of r/rGBM patients treated with the combination of bevacizumab and irinotecan (BEV+IRI) as their salvage treatment from July 2013 and December 2021 in Konkuk Medical Center of Korea. Patients with available results from molecular diagnostic tests were eligible, and markers of interest were examined including the presence of MGMT methylation, IDH1/2 mutation, or 1p/19q co-deletion. Efficacy of BEV+IRI and its potential biomarker was explored. RESULTS: Among 21 patients, 38.1% demonstrated European Cooperative Oncology Group-Performance scale (ECOG-PS) ≥3. The majority (71.4%) received BEV+IRI as their second-line chemotherapies, and the median dose was 5 (range=1-25). Objective response rate (ORR) was 33.3% and disease-control rate (DCR) was 85.7%. Irrespective of objective response, early clinical response was achieved in 14(66.7%) patients. During the median follow-up of 16.4 months for survivors, median progression-free survival (PFS) and overall survival (OS) were 3.6 and 6.8 months, respectively. ECOG PS≥3 and TP53 loss were independent predictors of an unfavorable OS, while prompt clinical improvement could predict favorable OS. Any molecular aberration was associated with OS or PFS in the study. CONCLUSION: Salvage BEV+IRI treatment in r/rGBM conferred comparable clinical benefit. ECOG PS ≥3, TP53 loss, and lack of prompt clinical improvement after the treatment were significantly associated with an unfavorable OS.