Irinotecan Monotherapy Research Articles

Ramucirumab Beyond Disease Progression After Paclitaxel Plus Ramucirumab in Gastric Cancer: A Phase II Trial.

Irinotecan monotherapy was the most widely used third-line chemotherapy for unresectable advanced or recurrent gastric cancer in Japan until the approval of nivolumab in September 2017 and trifluridine/tipiracil in August 2019. The benefit of continuing ramucirumab with irinotecan, an anti-VEGFR-2 monoclonal antibody, after the failure of paclitaxel plus ramucirumab (PTX+RAM) as second-line chemotherapy, has been under debate. A single-center phase II study was conducted in patients with unresectable advanced or recurrent gastric cancer previously treated with fluoropyrimidines and platinum, who received PTX+RAM as second-line therapy and irinotecan plus ramucirumab (IRI+RAM) as third-line therapy after treatment failure (UMIN000022956). Eleven patients were enrolled from July 2016 to July 2018. Enrolment was discontinued due to difficulties in case ascertainment because of expanded third-line treatment options (originally planned for 53 patients). The median progression-free survival (the primary endpoint) of the IRI+RAM was 3.98 months [95% confidence interval (CI)=1.78-NA]. Among secondary endpoints, the transition rate to IRI+RAM was 45%, the rate of 8-week treatment continuation for IRI+RAM was 100%, the response rate for IRI+RAM was 0%, the median overall survival (OS) for PTX+RAM was 13.53 months (95%CI=1.61-24.36), and the median OS for IRI+RAM was 9.99 months (95CI=4.5-NA). The transition rate from PTX+RAM to IRI+RAM was reasonable. Ramucirumab beyond progressive disease may be beneficial for patients who are able to transition to IRI+RAM.

A scoring system for selecting nivolumab or irinotecan in the later-line chemotherapy for advanced gastric cancer: A Japanese multicenter retrospective study.

266 Background: Although Nivolumab (NIVO) or Irinotecan (IRI) monotherapy is one of the later-line chemotherapies for the advanced gastric cancer (AGC) patients, there are no prospective data of their comparison, and no indicators for selection of them. Methods: Clinical data of AGC patients treated with NIVO or IRI as later-line were collected from 7 institutions between September 2015 and September 2018. Efficacy of the two treatment groups was compared in the entire cohort and in the propensity score matching cohort. Factors which affect the prognosis were explored by multivariate analyses and the scoring system was developed using Cox regression. Results: In the analysis of entire cohort (317 patients), the median OS was 4.8 months (95% CI: 3.6–5.8) in the NIVO group and 5.9 months (95% CI: 4.9–7.2) in the IRI group, and those were 4.8 months (95% CI: 3.6–5.7) and 6.0 months (95% CI: 4.5–7.2) in the analysis of the propensity score matching cohort (248 patients), respectively. There were no differences in OS. We developed a risk score involving 1-Neutrophil to Lymphocyte Ratio (NLR), 2-age, 3-ECOG performance status, 4-peritoneal metastasis, 5-gastrectomy, and 6-liver metastasis to assess potential effect modification. Based on the result, IRI was favored in the higher-risk group (≥4 points, with double weight to 2, 3, and 4) for both OS/PFS. In contrast, NIVO was better OS/PFS in the lower-risk group (<1 point). Conclusions: According to the real-world data from multicenter in Japan, NIVO and IRI generally showed equivalent outcomes. The scoring system we explored may be useful for selecting appropriate later-line chemotherapy, either NIVO or IRI.

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.

A prospective phase II single-arm study and predictive factor analysis of irinotecan as third-line treatment in patients with metastatic gastric cancer.

Currently, there is no recommended standard third-line chemotherapy for metastatic gastric cancer. In this study, we aimed to evaluate irinotecan's efficacy and safety in treating metastatic gastric cancer after the failure of first- and second-line chemotherapy. Prospective single-arm, two-center, phase II trial. Patients were aged 18-70 years, with histologically confirmed gastric adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0-1, progressed during or within 3 months following the last administration of second-line chemotherapy and had no other severe hematologic, cardiac, pulmonary, hepatic, or renal functional abnormalities or immunodeficiency diseases. Eligible patients received 28-day cycles of irinotecan (180 mg/m2 intravenously, days 1 and 15) and were assessed according to the RECIST 1.1 criteria every two cycles. Patients who discontinued treatment for any reason were followed up every 2 months until death. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity. A total of 98 eligible patients were enrolled in this study. In the intention-to-treat population, the median OS was 7.17 months, the median PFS was 3.47 months, and the ORR and DCR were 4.08% and 47.96%, respectively. In the per-protocol population, the median OS was 7.77 months, the median PFS was 3.47 months, and the ORR and DCR were 4.82% and 50.60%, respectively. The incidence of grade 3 or 4 hematological and non-hematological toxicities was 19.4%, and none of the patients died owing to adverse events. Cox regression analysis revealed neutropenia and baseline thrombocyte levels were independently correlated with PFS and OS. Irinotecan monotherapy is an efficient, well-tolerated, and economical third-line treatment for patients with metastatic gastric cancer as a third-line treatment. ClinicalTrials.gov identifier: NCT02662959.

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.

PP61 Cost-Effectiveness Analysis Of Trastuzumab Deruxtecan Versus Chemotherapy For Previously Treated HER2-Positive Gastric Cancer In Singapore

IntroductionThe phase two DESTINY-Gastric-01 trial demonstrated that trastuzumab deruxtecan (T-DXd) improved overall survival in Asian patients with human epidermal growth factor receptor 2 (HER2)-positive, advanced gastric or gastroesophageal adenocarcinoma that had progressed following two or more treatments, compared with chemotherapy (irinotecan or paclitaxel monotherapy). Considering the high cost of T-DXd, we assessed the cost-effectiveness of T-DXd versus chemotherapy from the Singapore healthcare system’s perspective.MethodsA partitioned survival model with three health states (progression-free, progressed disease and death) was developed, with a five-year time horizon. Survival curves from DESTINY-Gastric-01 were extrapolated beyond the trial duration using parametric functions. Health state utilities were obtained from published literature and direct costs were sourced from public healthcare institutions in Singapore. Utility decrements for adverse events such as interstitial lung disease was incorporated into the model for the differences in safety profiles. A discount rate of three percent was applied to costs and outcomes. One-way deterministic sensitivity analyses (OWSA) and scenario analyses were conducted to assess parameter and model uncertainties.ResultsTreatment with T-Dxd, compared to chemotherapy, had a high base case incremental cost-effectiveness ratio (ICER) of over SGD450,000 (USD334,900) per quality-adjusted life-year gained. The cost of T-DXd greatly influenced the results according to OWSA. Seventy-three percent of the total costs accrued in the T-DXd arm was due to the cost of the drug, compared to seven percent in the chemotherapy arm. The ICER was also sensitive to the assumptions around extrapolation of the survival curves, but when tested across all scenario analyses, the results remained unfavorable.ConclusionsAt the current cost, T-DXd does not represent good value compared to chemotherapy for previously treated HER2-positive gastric cancer in Singapore. The findings from our cost-effectiveness analysis, alongside other considerations, will be useful to inform policy makers on funding decisions.

A phase II clinical trial of prior regimen rechallenge in third- or later-line treatment for patients with metastatic colorectal cancer.

e15583 Background: Current choices of systemic treatment for patients with metastatic colorectal cancer remained limited, with some patients facing drugless conditions after failure of standard treatment. For those who have responded to the front-line treatment, there is a lack of data from prospective studies, on whether reapplication of former regimens in the later line can still bring clinical benefits. We conducted an exploratory study to evaluate the efficacy and safety of prior regimen rechallenge in the third or later-line treatment in patients with metastatic colorectal cancer (mCRC). Methods: This is a single-arm prospective phase II study (ClinicalTrials.gov Identifier: NCT03485027). The key inclusion criteria were:(1) histologically confirmed mCRC; (2) treatment failure to at least two lines of systemic chemotherapy; progression free survival (PFS) of the rechallenged regimen should be at least four months in the prior setting without unrecoverable toxicity; (3) the time interval between the re-applied chemotherapy regimen and its previous administration was at least 6 months. Eligible patients received the reapplication regimens, including XELOX, FOLFOX, FOLFIRI, Irinotecan monotherapy with or without targeted drug, which was formerly used. Evaluation was repeated every 6 weeks and treatment continues until the disease progression or intolerable adverse effects. The primary end point is PFS. The secondary endpoint is overall survival (OS), objective response rate (ORR), disease control rate (DCR) and treatment safety. Results: From Jan 24, 2018 to Dec 24, 2022, a total of 53 patients were recruited, and 51 patients who had received at least one cycle of rechallenged medication were included in this analysis. The median age was 59 (range 36-82) years old. Among these patients, 38 were administrated with the combination of targeted and chemotherapy as the rechallenge regimen (24 with bevacizumab plus chemotherapy and 14 with cetuximab plus chemotherapy), and 13 with chemotherapy alone (7 with oxaliplatin-based chemotherapy and 6 with irinotecan-based chemotherapy). A total of 41 patients had received the efficacy evaluation after treatment. One patient achieved partial response (tumor change from baseline -38.4%), 23 patients with stable disease and 17 patients with progressive disease. The ORR and DCR were 2.4% and 58.5%, respectively. At the last follow-up date on Jan 31, 2023, the median PFS was 4.0 months (95% CI, 2.62–5.38). The data of OS was still immature. Grade 3 or 4 adverse events were reported in 6 patients (11.76%). The detailed grade 3 or 4 adverse events were neutropenia in 4 patients, oxaliplatin related acute anaphylaxis in 2 patients, diarrhea in 2 patients. Conclusions: For the patients with heavily treated mCRC, the re-application of chemotherapy with front-line treatment regimen has shown a decent effectiveness with acceptable safety. Clinical trial information: NCT03485027 .

High DCR and Better Survival in Patients with Advanced or Metastatic Gastric Cancer Receiving Anti-Angiogenic TKI plus Chemotherapy: A Real-World Study.

Objectives: This study was carried out to assess the efficacy and drug toxicity of anti-angiogenic tyrosine kinase inhibitor (TKI) plus chemotherapy as second-line or above therapeutic regime in advanced or metastatic gastric cancer patients. Methods: From November 2017 to April 2020, advanced or metastatic gastric cancer patients who have failed from prior treatment and received apatinib combined with irinotecan or irinotecan treatment were analyzed. The primary observed indicator was progression-free survival (PFS). Objective: response rate (ORR), disease control rate (DCR), overall survival (OS), and drug toxicity were also evaluated. Results: 26 patients received apatinib combined with irinotecan and 29 patients received irinotecan. The ORR in the combination therapy and monotherapy population was 26.9% and 17.2%, respectively. The DCR in the apatinib combined with irinotecan group was higher than in irinotecan monotherapy population (80.8% vs 55.2%, P = .043). Median PFS was 4.2 months in the combination group and 3.3 months in the monotherapy group (P = .020). Median OS was 8.0 months in the combination group and 5.9 months in the monotherapy group (P = .048). Except for ECOG PS 2, PFS and OS were generally consistent across subgroups by sex, age, number of metastatic sites and primary tumor site. The incidence of Grade 3-4 adverse events in combination and monotherapy group was 23.1% and 20.7%, respectively. In apatinib combined with irinotecan group, adverse events that were attributed to apatinib were secondary hypertension (in seven patients, 26.9%), hand-foot syndrome (5,19.2%), and proteinuria (5, 19.2%). Univariate analysis demonstrated that secondary hypertension was considered to be a favorable factor (P = .040) for longer OS in combination therapy group. Conclusions: Compared with chemotherapy alone, anti-angiogenic TKI plus chemotherapy showed better PFS, OS and DCR in advanced or metastatic gastric cancer as second-line or above therapy, with a tolerable and manageable safety profile.

Oxaliplatin plus irinotecan vs irinotecan as second-line treatment in pancreatic cancer patients: a randomized-controlled open-label Phase II study.

Limited second-line therapeutic options are available for metastasis pancreatic cancer (mPC). We aimed to explore the efficacy and safety of oxaliplatin plus irinotecan (IROX) in mPC patients. This is an open-label, Phase 2, randomized study of mPC patients (aged 18-75 years) who failed when using gemcitabine plus S-1 as first-line therapy. Block randomization with a block size of four was used to randomly assign patients (1:1) between October 2015 and December 2017 to receive either IROX (oxaliplatin 85 mg/m2 and irinotecan 160 mg/m2) or irinotecan monotherapy (irinotecan 180 mg/m2) until disease progression, unacceptable adverse events, or consent withdrawal. The primary end point was overall survival, and the secondary end points were progression-free survival, overall response rate, and adverse event rate. A total of 74 patients were enrolled in this study, including 44 males and 30 females, with an average age of 61 years. The median overall survival was 10.2 and 6.7 months (adjusted hazard ratio [HR], 0.7; 95% confidence interval [CI], 0.4-1.2; P = 0.20) and the median progression-free survival was 5.1 and 2.3 months (adjusted HR, 0.4; 95% CI, 0.2-0.6; P < 0.01) in the IROX group and irinotecan group, respectively. The overall response rates were 18.4% (7/38) in the IROX group and 5.5% (2/36) in the irinotecan group (P = 0.06). Grade 3-4 adverse events occurred in 34% (13/38) of patients in the IROX group and 19% (7/36) of patients in the irinotecan group (P = 0.15). IROX had no significant survival benefit over irinotecan monotherapy in our study. However, IROX reduced the risk of disease progression by 60%, with acceptable toxicity.

102P A real-world study comparing apatinib combined with irinotecan versus irinotecan as second-line or above therapy in patients with advanced or metastatic gastric cancer

Irinotecan monotherapy was the standard second-line treatment regimen for metastatic gastric cancer. Previous researches revealed that apatinib combined with chemotherapy is more effective compared with apatinib or chemotherapy alone.The present study was conducted to evaluate the efficacy and safety of apatinib combined with irinotecan versus irinotecan as second-line or above therapy for patients with advanced or metastatic gastric cancer.

Hyperprogressive disease during PD-1 blockade in patients with advanced gastric cancer

BackgroundInvestigations for programmed cell death-1 (PD-1) blockade-induced hyperprogressive disease (HPD) have not been stringently conducted in patients with advanced gastric cancer (AGC). We explored the occurrence of HPD and its clinical implications in patients with AGC and treated with PD-1 inhibitors. MethodsWe enrolled 169 patients with AGC and treated with either the PD-1 blockade (nivolumab or pembrolizumab; N = 112) or irinotecan monotherapy (N = 57) as a single agent. Tumour growth dynamics based on tumour growth kinetics and tumour growth rate (TGR) and time to treatment failure were analysed to define HPD. The incidence, clinical consequences and predictive markers of HPD were investigated. ResultsThe optimal criteria for HPD were 4-fold increases in both tumour growth kinetics and TGR ratios and a 40% increase in TGR based on the analysis for patients treated with irinotecan. In total, 10.7% (12/112) of patients experienced HPD after PD-1 inhibitor treatment. Patients with HPD had both shorter progression-free survival (hazard ratio: 2.318; 95% confidence interval: 1.205–4.460) and overall survival (hazard ratio: 2.542; 95% confidence interval: 1.314–4.918) than patients with progressive disease without HPD, losing opportunities for subsequent systemic treatments. Although other variables including PD-L1 expression were not associated with the occurrence of HPD, hypoalbuminemia (<3.25 mg/dL) at baseline was significantly associated with the occurrence of HPD (P < 0.001) and inferior survival outcomes. ConclusionsHPD occurs in a proportion of patients with AGC and treated with PD-1 inhibitors. PD-1 inhibitor-induced HPD is associated with worse outcome, loss of eligibility for subsequent treatment and hypoalbuminemia, warranting further investigation.

Abstract 5250: Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric cancer

Abstract Objective: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is a key enzyme in irinotecan metabolism. However, the relationship between UGT1A1 genotype and the safety and efficacy of irinotecan monotherapy in the treatment of Chinese advanced gastric cancer remains unclear. Methods: A total of 110 patients were enrolled. Intravenous irinotecan was administered every 3 weeks. Irinotecan dose was selected according to the polymorphism of UGT1A1 gene, which was divided into 3 groups: UGT1A1*6 wild-type (GG type): 125mg/m2, d1, d8; UGT1A1*6 mutant heterozygosity (GA type) 100mg/m2, d1, d8; UGT1A1*6 homozygosity mutation (AA type) 75mg/m2, d1, d8 or paclitaxel 125mg/m2, d1, d8. UGT1A1 genotypes were determined by direct sequencing or next-generation sequencing of genomic DNA extracted from peripheral blood. Results: Among 110 patients of the subjects, the genotypes of UGT1A1*28 were wild-type in 78 patients (70.91%), mutant heterozygosity in 28 (25.45%) and mutant homozygosity in 4 (3.64%). UGT1A1*6 were GG in 67 cases (60.91%), GA in 35 cases (31.82%), and AA in 8 cases (7.27%). There were two heterozygous mutations in 3 patients, and no homozygous mutation was detected. A total of 10 cycles of irinotecan were administered, with a median of five cycles per patient. There was no significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*28 genotypes (P&amp;gt;0.05), while there was significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*6 genotypes (P&amp;lt;0.05). The dose intensity of irinotecan was different in patients with different subtypes of UGT1A1*6 gene, and the dose intensity of heterozygous mutant patients was lower than that of wild-type patients. However, there were no significant differences in PFS and OS among patients with different subtypes after dose adjustment and program adjustment (P&amp;gt;0.05). Conclusion: UGT1A1*6 gene polymorphism was significantly associated with diarrhea and neutropenia induced by irinotecan. The safety and effectiveness of antitumor therapy might be significantly improved by individualized drug administration according to the results of UGT1A1*6 gene polymorphism. Citation Format: Huifang Lv, Yunduan He, Caiyun Nie, Beibei Chen, Jianzheng Wang, Weifeng Xu, Jing Zhao, Xiaobing Chen, Junling Zhang. Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5250.

Irinotecan combined with Panitumumab or cetuximab as third-line treatment for metastatic colorectal cancer.

e15551 Background: Literature suggests that the addition of cetuximab can overcome the resistance to irinotecan treatment for metastatic colorectal cancer (mCRC). It is unknown if the combination of panitumumab with irinotecan could also revert treatment resistance and offer a better response rate after progression on irinotecan monotherapy. In this study, we aim to compare the impact of panitumumab plus irinotecan (P+I) or cetuximab plus irinotecan (C+I) on overall survival as a third line mCRC treatment. Methods: This is a single institution, retrospective cohort analysis, evaluating the overall survival of mCRC patients exposed to an anti-EGFR antibody plus irinotecan, upon progression on irinotecan monotherapy. Overall survival function was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: We identified 460 patients with mCRC that fulfilled inclusion criteria, treated between July 2008 and April 2018. One hundred eighty-three (183) patients received (I+C), and 277 received (I+P). Upon diagnosis, the median age was 55.9 years (range, 19 - 83 years), with a male to female ratio of 1.3:1. All patients received the combination of irinotecan and anti-EGFR targeting antibodies for at least one cycle (D1 and D15). Partial response occurred in 22.6% of patients [23.5% for (I+C) and 22.0% for (I+P)], and 25,2% had stable disease [27.8% for (I+C) and 23.6% for (I+P)]. Interestingly, response rate in patients with right-sided tumors was 3.3% in the (I+C) regimen and 14.3% in the (I+P) regimen. The disease control rate was 50.3% in the (I+C) combination and 45.7% in the (I+P) combination (p = 0.358). The median overall survival (mOS) for all patients was 9.63 months, 8.97 to the group C+I and 10.74 to P+I (p = 0.73). Regarding primary tumor location, the mOS was 6.34 mo for right-sided tumors and 10.74 mo for left-sided tumors (p = 0.022). The 3-year survival rate was 5.6% for the (C+I) treated patients and 3.2% for (P+I). Conclusions: (P+I) and (C+I) combinations showed similar response rate and mOS as a third-line treatment for mCRC, suggesting that both anti-EGFR agents can be used in this setting. A perceived tendency for a superior response with the (I+P) regimen in right-sided tumors might warrant further investigation in prospective studies.

151 A RANDOMIZED,OPEN CLINICAL TRIAL TO COMPARE THE EFFICACY AND SAFETY OF ANLOTINIB PLUS IRINOTECAN VERSUS IRINOTECAN IN PATIENTS WITH ESCC

Abstract The benefit of systemic treatment in esophageal squamous cell carcinoma (ESCC) which has progressed after chemotherapy is still uncertain. Anlotinib (AL3818) is a novel multi-target TKI, inhibiting tumor angiogenesis and proliferation. A phase II trial (NCT02649361) has demonstrated that anlotinib has a durable antitumor activity with a manageable adverse event profile in refractory metastatic ESCC. This study (NCT03387904) aimed at comparing the effects and safety of Anlotinib Plus Irinotecan versus Irinotecan in patients with ESCC. Methods We conducted a prospective randomized, multicenter, phase II trial to compare the efficacy of Anlotinib Plus Irinotecan with Irinotecan in recurrent ESCC patients who had resistance to platinum or taxane-based chemotherapy. Eligible patients were adults with pathologically confirmed recurrent ESCC, and 82 patients were randomized 1:1 to Irinotecan (65 mg/m2/day 1 and day 8) with or without anlotinib (12 mg qd day 1 to 14) of a 21-day cycle till progression or intolerable. The primary endpoint is the disease control rate (DCR) and progression-free survival (PFS) and the secondary end points are objective response rate (ORR) and overall survival (OS). Results Between 13/1 2019 and 20/1 2020, a total of 43 patients were enrolled and randomly assigned to either the anlotinib plus irinotecan (n = 22) or the irinotecan group (n = 21).The mPFS was longer in trial group than in control group (89 days vs 66 days, HR = 0.447, P = 0.055). The Disease control rate (DCR) was 54.5% in trial group and 38.1% in the control group. The treatment-related adverse events (&amp;gt;10%) were fatigue (59.1%), nausea (50.0%), decreased appetite (36.4%), hoarseness (27.3%), thyroid-stimulating hormone elevation (22.7%), diarrhea (9.1%), and decreased lymphocytes count(9.1%) in trial group. Grade 3 AEs included fatigue (4.5% vs 4.8%), nausea (4.5% vs 0%) and diarrhea (4.5% vs 0%) in two groups. Conclusion Anlotinib plus irinotecan was similarly tolerable but prolonged PFS compared to irinotecan monotherapy as a second-line treatment in patients with recurrent ESCC.

1439TiP A randomized, double-blinded, placebo-controlled phase III trial of HX008 plus irinotecan as second-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma

Standard second-line therapy for patients with recurrent or metastatic gastric or gastroesophageal junction (G/GEJ) cancer includes taxane or irinotecan monotherapy, ramucirumab alone or in combination with paclitaxel. HX008 is a novel highly selective, fully humanized anti-PD-1 monoclonal antibody with an engineered Fc domain. Previous report of HX008 plus irinotecan has demonstrated promising efficacy and manageable safety profile in patients with advanced G/GEJ adenocarcinoma. A phase III trial has been conducted to evaluate the efficacy and safety of HX008 plus irinotecan versus placebo plus irinotecan as second-line treatment in patients advanced G/GEJ adenocarcinoma.

Irinotecan Induces Disease Remission in Xenograft Mouse Models of Pediatric MLL-Rearranged Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) in infants (<1 year of age) remains one of the most aggressive types of childhood hematologic malignancy. The majority (~80%) of infant ALL cases are characterized by chromosomal translocations involving the MLL (or KMT2A) gene, which confer highly dismal prognoses on current combination chemotherapeutic regimens. Hence, more adequate therapeutic strategies are urgently needed. To expedite clinical transition of potentially effective therapeutics, we here applied a drug repurposing approach by performing in vitro drug screens of (mostly) clinically approved drugs on a variety of human ALL cell line models. Out of 3685 compounds tested, the alkaloid drug Camptothecin (CPT) and its derivatives 10-Hydroxycamtothecin (10-HCPT) and 7-Ethyl-10-hydroxycamtothecin (SN-38: the active metabolite of the drug Irinotecan) appeared most effective at very low nanomolar concentrations in all ALL cell lines, including models of MLL-rearranged ALL (n = 3). Although the observed in vitro anti-leukemic effects of Camptothecin and its derivatives certainly were not specific to MLL-rearranged ALL, we decided to further focus on this highly aggressive type of leukemia. Given that Irinotecan (the pro-drug of SN-38) has been increasingly used for the treatment of various pediatric solid tumors, we specifically chose this agent for further pre-clinical evaluation in pediatric MLL-rearranged ALL. Interestingly, shortly after engraftment, Irinotecan completely blocked leukemia expansion in mouse xenografts of a pediatric MLL-rearranged ALL cell line, as well as in two patient-derived xenograft (PDX) models of MLL-rearranged infant ALL. Also, from a more clinically relevant perspective, Irinotecan monotherapy was able to induce sustainable disease remissions in MLL-rearranged ALL xenotransplanted mice burdened with advanced leukemia. Taken together, our data demonstrate that Irinotecan exerts highly potent anti-leukemia effects against pediatric MLL-rearranged ALL, and likely against other, more favorable subtypes of childhood ALL as well.

Psychometric properties of patient reported outcome (PRO) instruments in patients with small cell lung cancer (SCLC) in RESILIENT part 1.

e24027 Background: The ongoing two-part phase 2/3 RESILIENT study (NCT03088813) is investigating the efficacy and safety of liposomal irinotecan monotherapy in patients with SCLC who have progressed on or after first line platinum-based chemotherapy. This exploratory analysis from RESILIENT part 1 was conducted to confirm the psychometric properties of established PRO instruments that had not previously been validated in patients with SCLC. Methods: Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) Core 30 (C30) and the EORTC QLQ Lung Cancer 13 (LC13) before treatment assignment (baseline), every 6 weeks thereafter, at treatment discontinuation and at the 30-day follow-up visit. Psychometric methods included descriptive statistics (items and scales), correlations (item-to-item and item-to-total), internal consistency (Cronbach’s α), test-retest reliability (intraclass correlation coefficient [ICC], two-way random effects model), construct validity and sensitivity to change. The analysis included patients who received at least one dose of study drug and completed at least one PRO assessment. Results: Thirty patients were enrolled in RESILIENT part 1 and included in the analysis. At baseline, 68% of patients reported ‘not severe’ or ‘mild’ symptoms. Floor effects (i.e. more than 25% of responses of ‘not at all’) were observed for several of the functioning/impact and symptom scales of the EORTC QLQ C30 and LC13. Moderate to strong correlations were found among most questionnaire items within their respective scales. Acceptable evidence for internal consistency and good test-retest reliability were observed. Selected results for the EORTC QLQ LC13, including dyspnea scales, are shown in the Table. The magnitude of correlations among PRO instruments supported evidence for convergent validity in this sample. Conclusions: In RESILIENT part 1, patients experienced low and tolerable symptoms at enrollment, limiting the potential for further improvement. Overall, these PRO instruments had acceptable psychometric properties (e.g. construct validity, reliability and ability to detect change) in this sample. However, these analyses should be repeated in a larger sample using data from RESILIENT part 2. Clinical trial information: NCT03088813. [Table: see text]

Bevacizumab or standard chemotherapy in previously treated patients with metastatic colorectal cancer — a systematic review

Introduction. The BRAF V600E mutation ( BRAF mt) occurring in the metastatic colorectal cancer (mCRC) patients is associated with poorer prognosis, in comparison to the wild-type variant of the BRAF gene ( BRAF wt). Aim of this work was to assess the clinical efficacy of bevacizumab (BEVA) or standard chemotherapy (ChT) in the 2nd or further lines of treatment in mCRC BRAF mt population. Material and methods. MEDLINE/PubMed, Embase and Cochrane CENTRAL databases were systematically searched. The reference lists of relevant studies were also checked. Results. 6 eligible trials were identified: MOMA (BEVA ± ChT), allowing for limited overall survival (OS) assessment, WJOG 6210G (BEVA + FOLFIRI), RAISE and 20050181 (FOLFIRI), PICCOLO and Spindler 2013 (irinotecan monotherapy). None of those trials were designed for the treatment evaluation in BRAF mt population. Available evidence was restricted to limited analyses in small subgroups (from a few to several dozens of patients), occasionally comprising RAS gene mutation ( RAS mt) as well. Based on the identified studies, the comparison of BEVA ± ChT vs. ChT or among different ChTs in BRAF mt population was not feasible. In case of BEVA (MOMA), OS hazard ratio (HR) for BRAF mt vs. BRAF wt was 1.52 (95% CI: 0.79–2.89) with difference in medians equal to 12.1 months (19.2 vs. 31.3 months, respectivelly), and BRAF mt or RAS mt patients had median OS lower by 7.9 months and median progression free survival (PFS) by 3.0 months in WJOG 6210G trial. In case of ChT, median PFS was lower in BRAF mt by 12–67% (HRs range: 1.01–5.3), and median OS by 34–73% (HRs range: 1.05–5.00). Conclusions. Due to limited clinical evidence, assessment of further lines of treatment in BRAF mt mCRC patients is uncertain, however existing data consistently suggest lower effectiveness of BEVA ± ChT or ChT in BRAF mt, than in BRAF wt subgroup. Hopefully, combining anti-EGFR therapies with BRAF/MEK inhibitor is expected to improve prognosis of those patients.

MO01.39 Liposomal Irinotecan in Adults with Small Cell Lung Cancer who Progressed on Platinum-Based Therapy: Subgroup Analyses by Platinum Sensitivity

Most patients with extensive small cell lung cancer (SCLC) develop drug resistance to platinum-based first-line therapy or discontinue for other reasons, and second-line therapies are limited. RESILIENT (ClinicalTrials.gov identifier NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability and efficacy of second-line liposomal irinotecan monotherapy in adults with SCLC who progressed with platinum-based first-line therapy. Preliminary data from RESILIENT part 1 (cut off May 8 2019; ≥ 12 weeks follow-up) showed that liposomal irinotecan 70 mg/m2 free base every 2 weeks was generally well tolerated and had encouraging antitumor activity (Paz-Ares et al.

Irinotecan monotherapy as third- or further-line treatment for patients with small cell lung cancer

Background: Small cell lung cancer (SCLC) is a very aggressive cancer and recurrence is inevitable. Treatment of recurrent disease is important for improving the prognosis of patients with SCLC. Methods: We conducted a retrospective observational study to investigate the efficacy and safety of irinotecan monotherapy as third- or further-line treatment in patients with SCLC. Results: Data of 15 patients who had received irinotecan monotherapy as third- or further-line treatment between 2004 and 2019 were analyzed. The median progression-free survival duration (95% confidence interval) from the initiation of treatment with irinotecan was 2.7 (1.4–3.8) months, and the median overall survival duration (95% confidence interval) from the initiation of irinotecan treatment was 10.0 (3.9–12.9) months. Partial response, stable disease or non–complete response/non–progressive disease, and progressive disease were observed in 1, 6, and 8 patients, respectively. Adverse events ⩾ grade 3 in severity were observed in 2/2 (100%) patients who were homozygous for UGT1A1 mutation, 2/3 (66.7%) patients who were heterozygous for UGT1A1 mutation, 4/6 (66.7%) patients who had wild-type UGT1A1, and 2/4 (50.0%) patients in whom the UGT1A1 mutation status was unknown. Conclusion: Our results suggest that irinotecan monotherapy can be a useful alternative treatment option in the third-line setting for patients with SCLC.