Phase II study of FOLFIRI with low-dose irinotecan plus ramucirumab as second-line treatment in Japanese patients with metastatic colorectal cancer (Study rindo)

Phase II study of FOLFIRI with low-dose irinotecan plus ramucirumab as second-line treatment in Japanese patients with metastatic colorectal cancer (Study rindo) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Phase II study of FOLFIRI with low-dose irinotecan plus ramucirumab as second-line treatment in Japanese patients with metastatic colorectal cancer (Study rindo) Norifumi Hattori, Goro Nakayama, Shinichi Umeda, Takayoshi Kishida, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5041539/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective This multicenter, single-arm, phase II study aimed to evaluate the efficacy and safety of fluorouracil, levofolinate, and irinotecan (150 mg/m², standard dose in Japan) (FOLFIRI) plus ramucirumab (RAM) as second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Methods On day 1 of each 2-week cycle, patients with unresectable mCRC who were refractory to oxaliplatin and fluoropyrimidine in combination with bevacizumab or anti-epidermal growth factor receptor antibodies as first-line treatment received 8 mg/kg RAM, followed by the FOLFIRI regimen with low-dose irinotecan (150 mg/m²). The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), treatment compliance, and safety. Results A total of 62 patients were enrolled from 15 institutions between January 2018 and August 2021. The intent-to-treat and safety populations included 61 and 58 patients, respectively. Median PFS and OS were 5.9 months (95% CI, 4.8–6.9 months) and 17.0 months (95%CI, 12.0–21.0 months), respectively. The objective response rate and disease control rate were 8.2% and 74%, respectively. The median time to treatment failure was 4.8 months (95% CI, 3.2–5.9 months). Median relative dose intensities of irinotecan, 5-fluorouracil, and RAM were 73.8% (range, 40.3-102.4%), 58.5% (range, 22.8-102.4%), and 80.8% (range, 36.1-102.4%), respectively. Frequencies of Grade ≥ 3 hematologic, non-hematologic, and RAM-associated adverse events were 43%, 24%, and 17%, respectively. The observed Grade ≥ 3 adverse events included neutropenia (40%), diarrhea (8.6%), decreased appetite (10%), hypertension (6.9%), and proteinuria (3.4%). Conclusion FOLFIRI with low-dose irinotecan plus RAM is a feasible second-line treatment in Japanese patients with mCRC. Metastatic colorectal cancer Ramucirumab FOLFIRI Japanese patients Second-line chemotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Colorectal cancer (CRC) is the third most common cancer, with an incidence rate of 10%. CRC is associated with a mortality rate of 9.4% worldwide, which makes it the second most common cause of cancer deaths following lung cancer [ 1 ]. The standard treatment for unresectable metastatic colorectal cancer (mCRC) is systemic chemotherapy, and the efficacy of combination therapy with molecular-targeted agents as first-line treatment has been reported for bevacizumab (BEV), cetuximab, and panitumumab [ 2 ]. Several phase III trials of second-line combination therapy with molecular-targeted agents after first-line treatment with BEV demonstrated significant improvements in overall survival (OS) [ 3 – 5 ]. Based on these results, combination therapies with angiogenesis inhibitors such as BEV, aflibercept, and ramucirumab (RAM) have become standard second-line treatments [ 2 ]. RAM is a fully human immunoglobulin G1 monoclonal antibody that binds to VEGF receptor-2, preventing VEGF-A, VEGF-C, and VEGF-D ligand binding and inhibiting tumor angiogenesis by suppressing endothelial cell proliferation, migration, and survival [ 6 ]. The RAISE trial demonstrated a median OS of 13.3 months in patients treated with fluorouracil, levofolinate, and irinotecan (FOLFIRI) plus RAM versus 11.7 months in those treated with FOLFIRI plus placebo [hazard ratio (HR), 0.844; 95% confidence interval (CI), 0.73–0.98; log-rank p = 0.02] [ 5 ]. The irinotecan dose used in the FOLFIRI regimen was 180 mg/m 2 , which is higher than the recommended dose of 150 mg/m 2 in Japan [ 7 – 9 ]. In the RAISE trial, median relative dose intensities (RDI) of RAM and irinotecan were 88.2% and 77.0%, respectively, in all patients, and 82.9% and 63.8%, respectively, in the Japanese population [ 10 ], showing no difference for RAM but a lower RDI for irinotecan in the Japanese population. Moreover, incidence rates of adverse events leading to discontinuation of cytotoxic agents were 26.8% in all patients and 48.6% in the Japanese population [ 10 ]. Based on these results, we conducted a prospective trial to investigate the efficacy and safety of FOLFIRI with low-dose irinotecan (150 mg/m², standard dose in Japan) plus RAM as second-line treatment for mCRC in Japanese patients who are refractory to oxaliplatin (OX) and fluoropyrimidine plus molecular-targeted agents. PATIENTS AND METHODS Study design This multicenter, single-arm, phase II clinical trial was conducted by the Chubu Clinical Oncology Group (CCOG) at 15 hospitals in Japan. Inclusion criteria were as follows: age ≥ 20 years; histologically proven adenocarcinoma of the colon or rectum; unresectable metastasis; confirmed radiographic disease progression during first-line combination therapy of OX and fluoropyrimidine with BEV or anti-epidermal growth factor receptor (EGFR) antibodies; the presence of at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1); Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and adequate hematologic, hepatic, and renal function. Patients who had received first-line treatment with IRI and had uridine diphosphate glucuronosyltransferase (UGT)1A1 gene status of homo type (*28/*28, *6/*6) or double hetero-type genetic polymorphisms (*6/*28), brain metastasis, clinically significant cardiovascular disease, double cancer, bowel obstruction, uncontrolled diabetes mellitus, hypertension, or congestive heart failure were excluded. This study was conducted in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent prior to participation. The ethics committees of Nagoya University Hospital (approval number 2016 − 0527) and all other participating facilities approved the study. This trial was registered with the University Hospital Medical Information Network (UMIN000025659) and Japan Registry of Clinical Trials (jRCTs041180074). Treatment plan On day 1 of each two-week cycle, patients with unresectable mCRC after first-line combination therapy of OX and fluoropyrimidine with BEV or anti-EGFR antibodies received 8 mg/kg RAM as a 60-min intravenous infusion, followed by the FOLFIRI regimen with low-dose irinotecan (150 mg/m² intravenous irinotecan given over 90 min, 200 mg/m² intravenous leucovorin given over 120 min, 400 mg/m² fluorouracil given as an intravenous bolus over 2–4 min, and 2400 mg/m² fluorouracil given as a continuous infusion over 46 h). The treatment was continued until any one of the following occurred: radiographic confirmation of disease progression, unacceptable toxicity, deterioration of ECOG performance status to > 2, or withdrawal of patient consent. Dose modifications reflecting treatment-related toxicities were carried out in accordance with the study protocol. Assessments The primary endpoint was progression-free survival (PFS), defined as the time from the date of registration until disease progression or death from any cause. Secondary endpoints were OS, defined as the time from the date of registration until death from any cause; time to treatment failure (TTF), defined as the time from the date of registration until death from any cause or cessation of the protocol treatment; objective response rate (ORR), defined as the proportion of patients whose best response was complete response (CR) or partial response (PR); disease control rate (DCR), defined as the proportion of patients whose response was CR, PR, or stable disease (SD); treatment compliance; and adverse events. Tumor size was assessed using computed tomography at baseline and every eight weeks thereafter. Treatment response was assessed according to the RECIST criteria, version 1.1, by the investigators. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. All analyses of efficacy were based on the intent-to-treat (ITT) population, defined as eligible and assessable enrolled patients. The safety population was defined as all patients receiving ≥ 1 dose of the protocol treatment. Statistical analysis Statistical power was calculated based on the following assumptions: an PFS threshold of 4.3 months and expected PFS of 5.7 months based on data from a Japanese subgroup of the RAISE trial [ 5 ], with an enrollment period of two years and follow-up period of three years. To ensure an alpha level of 0.1 (one-side) and a detection power (1-β) of 80%, 59 patients were required. Therefore, the planned sample size was 60 patients to account for possible loss to follow-up. Time-to-event variables, PFS, OS, and TTF were analyzed by the Kaplan–Meier method. If the lower limit of the 95% confidence interval exceeded 4.3 months, which was set as the threshold PFS, the protocol treatment was considered to be effective. P values less than 0.05 were considered statistically significant. Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary NC). RESULTS Patient characteristics A total of 62 patients were prospectively enrolled from 15 institutions between January 2018 and August 2021. One patient was excluded after enrollment because of ineligibility. The ITT population comprised 61 patients. Three patients were excluded from the safety analysis, including two patients who could not receive chemotherapy because their general condition worsened due to acute disease progression after enrollment, and one patient who refused to receive protocol treatment. Thus, the safety population comprised 58 patients (Fig. 1 ). Baseline clinical characteristics are summarized in Table 1 . Median age of patients was 69 years (range, 43–80 years); 32 patients (52%) were male, and 59 patients (97%) had ECOG performance status 0. The primary tumor location was the right side in 15 patients (25%) and the left side in 46 (75%). The RAS status was wild type in 29 patients (48%) and mutant in 32 (52%). Combination molecular-targeted drugs used in first-line chemotherapy were BEV in 44 patients (72%) and anti-EGFR antibodies in 17 (28%). Thirty-five patients (57%) had two or more metastatic sites, with the most common metastatic site being the liver (61%) followed by the lungs (56%). Treatment exposure The median time to treatment failure was 4.8 months (95% CI, 3.2–5.9 months) (Fig. 2 ). The median number of treatment cycles was eight (range, 1–27). The median RDI was 50.5% (range, 0-102.4%) for bolus fluorouracil, 74.5% (range, 28.5-102.4%) for infusion fluorouracil, 73.8% (range, 40.3-102.4%) for irinotecan, and 80.8% (36.1-102.4%) for RAM (Table 2 ). Common reasons for treatment discontinuation were disease progression (67%), adverse events (16%), and patient decision (8%). Efficacy The cutoff date for the primary analysis was December 2023. Disease progression and death occurred in 53 patients (87%) and 52 patients (85%), respectively. The median length of follow-up for censored cases was 16.4 months (range, 1–57 months). At study cutoff, no patients were receiving FOLFIRI plus RAM. Median PFS (primary endpoint) was 5.9 months (95% CI, 4.8–6.9 months) (Fig. 3 A). The lower limit of 95% CI was higher than the threshold of 4.3 months, and hence, the primary endpoint was met. Median OS was 17.5 months (95% CI, 12.3–21.7 months) (Fig. 3 B). The tumor response was assessed in the ITT population (61 patients): five patients (8.2%) were not evaluated. The CR rate was 0%, the PR rate was 8.2%, the SD rate was 66%, the PD rate was 18%, the objective response (CR + RR) rate was 8.2% (95% CI, 3.6–17.7%), and the disease control rate (CR + PR + SD) was 74% (95% CI, 61.5–83.1%). Median PFS was 5.7 months (95% CI, 4.4–6.8 months) in patients treated with first-line chemotherapy with BEV and 7.4 months (95% CI, 4.6–11.0 months) in those treated with first-line chemotherapy with anti-EGFR antibodies (HR, 1.17; 95% CI, 0.64–2.12; p = 0.60) (Fig. 4 A); median OS was 19.8 months (95% CI, 10.4–22.4 months) and 17.5 months (95% CI, 11.5–26.1 months), respectively (HR, 0.96; 95% CI, 0.52–1.78; p = 0.91) (Fig. 4 B). Safety Safety was assessed in 58 patients. The incidence of treatment-related adverse events is shown in Table 3. Frequencies of Grade ≥ 3 hematologic, non-hematologic, and RAM-associated adverse events were 43%, 24%, and 12%, respectively. The most frequent Grade ≥ 3 hematologic adverse event was neutropenia (40%). In addition, four (6.9%) patients experienced Grade 3 febrile neutropenia. Frequent Grade ≥ 3 non-hematologic adverse events were anorexia (10%) and diarrhea (8.6%). Frequent Grade ≥ 3 RAM-associated adverse events were hypertension (6.8%) and proteinuria (3.4%). There were no unexpected serious adverse events or treatment-related deaths. DISCUSSION This phase II trial was conducted to evaluate the efficacy and safety of FOLFIRI with low-dose irinotecan (150 mg/m², standard dose in Japan) plus RAM as second-line treatment for mCRC in Japanese patients. The median PFS (primary endpoint) of 5.9 months (95% CI, 4.8–6.9 months) was considered acceptable according to our hypothesis that assumed the threshold and expected PFS of 4.3 months and 5.7 months, respectively. Moreover, the median OS (secondary endpoint) of 17.5 months (95% CI, 12.3–21.7 months) was comparable to those reported by previous RCTs, including the RAISE trial, for second-line angiogenic therapies. The RDIs of cytotoxic agents have been shown to have significant effects on tumor response and survival benefits in patients with various cancer types [ 11 – 15 ]. In Japanese clinical practice, irinotecan at 150 mg/m² is the standard dosage used in the FOLFIRI regimen. The RDI for irinotecan, which was notably lower than other drugs in Japanese population of RAISE trial, was maintained at 73.8%. Regarding tumor response, the ORR and DCR in the Japanese population of the RAISE trial were 8.1% and 82.4%, respectively [ 10 ], which were comparable to the ORR (8.2%) and DCR (74%) observed in the present study. This study prospectively confirmed that treatment efficacy on tumor response and survival was comparable to those of Japanese population in the RAISE trial. Evidence is insufficient with regard to second-line treatment after first-line treatment with anti-EGFR antibodies, and no phase III clinical trials have evaluated combinations of molecular-targeted agents in second-line treatment. Suzuki et al. compared the efficacy and safety of FOLFIRI plus RAM as second-line treatment for unresectable mCRC in patients who received first-line treatment with or without BEV. The PFS and DCR were better in BEV-naive patients than in those who had received first-line treatment with BEV [ 16 ]. In the present study, molecular-targeted agents used in first-line treatment were BEV in 44 patients (72%) and anti-EGFR antibodies in 17 patients (28%) in the ITT population; median PFS was 5.7 months (95% CI, 4.4–6.8 months) in the former group and 7.4 months (95% CI, 4.6–11.0 months) in the latter group. These findings suggest a trend toward greater efficacy in patients who did not use BEV as first-line treatment. The JACCRO CC-16 study also investigated the efficacy and safety of FOLFIRI plus RAM as second-line treatment in patients with RAS wild-type mCRC who were refractory or intolerant to OX and fluorouracil (doublet) or OX, irinotecan, and fluorouracil (triplet) plus anti-EGFR antibodies [ 17 ]. Median PFS in the doublet plus anti-EGFR antibody regimen group was 7.4 months (95% CI 5.7-9.0 months), which was comparable to that observed in the present study for anti-EGFR antibody combination therapy. These results suggest that FOLFIRI plus RAM is effective as second-line treatment after first-line treatment with anti-EGFR antibodies. In terms of safety, the most frequent adverse events were neutropenia and RAM-associated events, such as hypertension and proteinuria. Among Grade ≥ 3 adverse events, neutropenia, hypertension, and proteinuria were observed at frequencies of 40%, 6.8%, and 3.4%, respectively. In the Japanese population of the RAISE trial, frequencies of Grade ≥ 3 neutropenia, hypertension, and proteinuria were 59.5%, 17.6%, and 8.1%, respectively [ 10 ]. In a phase 1b study conducted prior to the RAISE study, severe neutropenia of Grade 3 or higher was observed in five of six patients (83.3%) with 180 mg/m 2 irinotecan [ 18 ]. The low dose of irinotecan (150 mg/m 2 ) in this study resulted in lower frequency of Grade ≥ 3 neutropenia than that of Japanese population in the RAISE trial. In Japanese patients, low-dose irinotecan (150 mg/m²) is appropriate from safety perspectives, and FOLFIRI plus RAM therapy is performed with appropriate dose reduction and treatment delay. The incidence of hypertension was higher compared with Japanese population of the RAISE study for all grades. This may be because, in the present study, roughly 30% of patients were BEV-naive in first-line treatment, and some appeared to have developed hypertension after the use of RAM in second-line treatment. The incidence of Grade ≥ 3 hypertension and that of proteinuria were both lower than those in Japanese population of the RAISE study. All physicians performed quantitative urine tests and closely monitored blood pressure, and control of Grade ≥ 3 adverse events could be achieved through appropriate RAM dose modification and use of antihypertensive drugs when needed. This study has several limitations. First, the single-arm design and relatively small sample size necessitate confirmation of our results in a larger cohort. Second, tumor size and response according to the RECIST criteria were not centrally evaluated. Third, the background of the present study population differed from that of the RAISE study population. All patients in the RAISE study were previously treated with BEV, whereas the present study used a heterogeneous treatment population including not only patients who received BEV but also those who received anti-EGFR antibodies as first-line treatment. Therefore, data are not directly comparable between the present study and the RAISE study. In conclusion, we demonstrated that FOLFIRI plus RAM therapy performed in the setting of irinotecan 150 mg/m 2 can be safely administered without decreasing the therapeutic effect and can achieve survival comparable to that of Japanese population in the RAISE study. FOLFIRI with low-dose irinotecan (150 mg/m², standard dose in Japan) plus RAM is a feasible second-line treatment in Japanese patients with mCRC. Declarations Acknowledgments The following physicians and research coordinators provided care to patients in this study: S. Sueoka (H. Tokai); T. Asada (H. Tajimi); N. Yabusaki (H. Okazaki); M. Shoka (H. Nisio); S. Takeda (H. Tosei); R. Hashimoto (H. Nakatsugawa); N. Mashita (H. Konan); F. Sugiura (H. Nagoya University); and M. Aoki and H. Hattori (CCOG data center). The authors thank these individuals for their cooperation and support. The results of this study were presented in part at the 61st Annual Meeting of the Japan Society of Clinical Oncology on October 19-21, 2023, in Yokohama, Japan. Funding This work was supported by Eli Lilly Japan. The funders did not have any involvement in the design of this study; the data collection, analysis, and interpretation of the data; and writing of this manuscript. Conflict of Interest Statement The authors report no conflicts of interest. References Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians 71 (3):209–249. https://doi.10.3322/caac.21660 Hashiguchi Y, Muro K, Saito Y, Ito Y, Ajioka et al (2020) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. International journal of clinical oncology 25 (1):1–42. https://doi.10.1007/s10147-019-01485-z Bennouna J, Sastre J, Arnold D et al (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. The Lancet Oncology 14 (1):29–37. https://doi.10.1016/s1470-2045(12)70477-1 Van Cutsem E, Tabernero J, Lakomy R et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 30 (28):3499–3506. https://doi.10.1200/jco.2012.42.8201 Tabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. The Lancet Oncology 16 (5):499–508. https://doi.10.1016/s1470-2045(15)70127-0 Falcon BL, Chintharlapalli S, Uhlik MT et al (2016) Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents. Pharmacology & therapeutics164:204–225. https://doi.10.1016/j.pharmthera.2016.06.001 Sunakawa Y, Ichikawa W, Fujita K et al (2011) UGT1A1*1/*28 and *1/*6 genotypes have no effects on the efficacy and toxicity of FOLFIRI in Japanese patients with advanced colorectal cancer. Cancer chemotherapy and pharmacology 68 (2):279–284. https://doi.10.1007/s00280-010-1485-8 Yamashita K, Nagashima F, Fujita K et al (2011) Phase I/II study of FOLFIRI in Japanese patients with advanced colorectal cancer. Japanese journal of clinical oncology 41 (2):204–209. https://doi.10.1093/jjco/hyq197 Kochi M, Akiyama Y, Aoki T et al (2013) FOLFIRI plus bevacizumab as a first-line treatment for Japanese patients with metastatic colorectal cancer: a JACCRO CC-03 multicenter phase II study. Cancer chemotherapy and pharmacology 72 (5):1097–1102. https://doi.10.1007/s00280-013-2292-9 Ramucirumab (Cyramuza) review report. Pharmaceuticals and Medical Devices Agency. _https://www.pmda.go.jp/drugs/2016/P20160518002/530471000_22700AMX00664_K100_2.pdf Accessed 31 July 2024 Kwak LW, Halpern J, Olshen RA et al (1990) Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 8 (6):963–977. https://doi.10.1200/jco.1990.8.6.963 Repetto L, Pace M, Mammoliti S et al (1993) The impact of received dose intensity on the outcome of advanced ovarian cancer. European journal of cancer (Oxford, England: 1990) 29a (2):181–184. https://doi.10.1016/0959-8049(93)90169-g Luciani A, Bertuzzi C, Ascione G et al (2009) Dose intensity correlate with survival in elderly patients treated with chemotherapy for advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 66 (1):94–96. https://doi.10.1016/j.lungcan.2008.12.019 Loibl S, Skacel T, Nekljudova V et al (2011) Evaluating the impact of Relative Total Dose Intensity (RTDI) on patients' short and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer- a pooled analysis. BMC cancer 11:131. https://doi.10.1186/1471-2407-11-131 Nakayama G, Tanaka C, Uehara K et al (2014) The impact of dose/time modification in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer. Cancer chemotherapy and pharmacology 73 (4):847–855. https://doi.10.1007/s00280-014-2416-x Suzuki T, Shinozaki E, Osumi H et al (2019) Second-line FOLFIRI plus ramucirumab with or without prior bevacizumab for patients with metastatic colorectal cancer. Cancer chemotherapy and pharmacology 84 (2):307–313. https://doi.10.1007/s00280-019-03855-w Yasui H, Okita Y, Nakamura M et al (2023) Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16. ESMO open 8 (5):101636. https://doi.10.1016/j.esmoop.2023.101636 Yoshino T, Yamazaki K, Gotoh M et al (2015) Safety and Pharmacokinetics of Second-line Ramucirumab plus FOLFIRI in Japanese Patients with Metastatic Colorectal Carcinoma. Anticancer Res 35(7):4003–4007 Tables Tables 1 to 3 are available in the Supplementary Files section. Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5041539","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":449917434,"identity":"337946c9-2f64-4e38-bac4-471d3599a1aa","order_by":0,"name":"Norifumi 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School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Goro","middleName":"","lastName":"Nakayama","suffix":""},{"id":449917436,"identity":"e6e89897-da3c-467c-9d68-75ba663ea6c5","order_by":2,"name":"Shinichi Umeda","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Shinichi","middleName":"","lastName":"Umeda","suffix":""},{"id":449917437,"identity":"84497df9-d9c2-4004-a6cc-5b1d69d0373a","order_by":3,"name":"Takayoshi Kishida","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka 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Municipal","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Tsutsuyama","suffix":""},{"id":449917441,"identity":"9e1b78cd-fd5b-49ad-bca1-575d8624dd80","order_by":7,"name":"Mitsuru Sakai","email":"","orcid":"","institution":"City Hospital: Hospital Municipal","correspondingAuthor":false,"prefix":"","firstName":"Mitsuru","middleName":"","lastName":"Sakai","suffix":""},{"id":449917442,"identity":"7da77815-ac19-46b2-83aa-2a217f71a1bd","order_by":8,"name":"Masashi Hattori","email":"","orcid":"","institution":"National Hospital Organization Nagoya Medical Center: Kokuritsu Byoin Kiko Nagoya Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Masashi","middleName":"","lastName":"Hattori","suffix":""},{"id":449917443,"identity":"5e0320e7-7f1f-4b88-872b-a950600f1c28","order_by":9,"name":"Takeshi Ito","email":"","orcid":"","institution":"City Hospital: Hospital Municipal","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Ito","suffix":""},{"id":449917444,"identity":"b26fcffa-fe19-4753-bc65-55206c39a615","order_by":10,"name":"Mitsuro Kanda","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Mitsuro","middleName":"","lastName":"Kanda","suffix":""},{"id":449917445,"identity":"8403b6b9-3b5b-4860-b5a3-900217457c61","order_by":11,"name":"Chie Tanaka","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Chie","middleName":"","lastName":"Tanaka","suffix":""},{"id":449917446,"identity":"5136168c-78fe-463d-83ca-f62c2848a598","order_by":12,"name":"Kenta Murotani","email":"","orcid":"","institution":"Kurume University: Kurume Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Kenta","middleName":"","lastName":"Murotani","suffix":""},{"id":449917447,"identity":"88a1803e-36ab-4d8d-9ad4-cfb80e705734","order_by":13,"name":"Masahiko Ando","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Masahiko","middleName":"","lastName":"Ando","suffix":""},{"id":449917448,"identity":"02fedd87-c245-45d7-9c0c-65d9e9c0d556","order_by":14,"name":"Yasuhiro Kodera","email":"","orcid":"","institution":"National Hospital Organization Nagoya Medical Center: Kokuritsu Byoin Kiko Nagoya Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Yasuhiro","middleName":"","lastName":"Kodera","suffix":""}],"badges":[],"createdAt":"2024-09-06 04:47:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5041539/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5041539/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82064827,"identity":"09d49b61-dc44-4bad-8f0a-d75b36407c19","added_by":"auto","created_at":"2025-05-06 12:26:15","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26524,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eConsort diagram\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 62 patients were enrolled between January 2018 and August 2020. FOLFIRI plus RAM chemotherapy was administered to 58 patients.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eN\u003c/em\u003e total number of patients, \u003cem\u003en\u003c/em\u003e number of patients, \u003cem\u003eFOLFIRI\u003c/em\u003e fluorouracil, levofolinate, and irinotecan, \u003cem\u003ePD\u003c/em\u003e progression disease\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5041539/v1/6ecd229d107b6f06983d0a77.jpg"},{"id":82064829,"identity":"735b242a-c935-47f8-ae1a-6b460f06a88d","added_by":"auto","created_at":"2025-05-06 12:26:15","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":17507,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime to treatment failure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTTF\u003c/em\u003e time to treatment failure, \u003cem\u003eCI\u003c/em\u003e confidence interval\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5041539/v1/6b3f424de8244d1f6b91e579.jpg"},{"id":82065543,"identity":"231b0cc9-8f9e-4368-880d-88bdc1a97d8b","added_by":"auto","created_at":"2025-05-06 12:34:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":52871,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival outcomes in the ITT population (N = 61)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: Progression free survival. B: Overall survival.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePFS\u003c/em\u003e progression free survival, \u003cem\u003eOS\u003c/em\u003e overall survival, \u003cem\u003eCI\u003c/em\u003e confidence interval\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5041539/v1/ac4e2cab2595543be7bd7f02.png"},{"id":82065545,"identity":"2fd5d876-0828-4f94-a267-c09855e8a9bb","added_by":"auto","created_at":"2025-05-06 12:34:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":73669,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival outcomes by previous therapy (BEV or anti-EGFR antibodies)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: Progression free survival. B: Overall survival.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePFS\u003c/em\u003e progression free survival, \u003cem\u003eOS\u003c/em\u003e overall survival, \u003cem\u003eCI\u003c/em\u003e confidence interval, \u003cem\u003eBEV\u003c/em\u003e bevacizumab, \u003cem\u003eEGFR \u003c/em\u003eepidermal growth factor receptor\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5041539/v1/74f12493cdb4c0ffaf320c8c.png"},{"id":83522919,"identity":"99a194df-1c01-4d1b-9777-629efb4f6a00","added_by":"auto","created_at":"2025-05-28 00:42:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":750465,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5041539/v1/da72815d-9a0c-40e8-ac20-ae20e0ce0a09.pdf"},{"id":82067168,"identity":"c6dabfd9-a220-4505-a019-9a20a286d63f","added_by":"auto","created_at":"2025-05-06 12:42:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":281281,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5041539/v1/e09efdad7bc758f3df1aae89.docx"}],"financialInterests":"","formattedTitle":"Phase II study of FOLFIRI with low-dose irinotecan plus ramucirumab as second-line treatment in Japanese patients with metastatic colorectal cancer (Study rindo)","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eColorectal cancer (CRC) is the third most common cancer, with an incidence rate of 10%. CRC is associated with a mortality rate of 9.4% worldwide, which makes it the second most common cause of cancer deaths following lung cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The standard treatment for unresectable metastatic colorectal cancer (mCRC) is systemic chemotherapy, and the efficacy of combination therapy with molecular-targeted agents as first-line treatment has been reported for bevacizumab (BEV), cetuximab, and panitumumab [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Several phase III trials of second-line combination therapy with molecular-targeted agents after first-line treatment with BEV demonstrated significant improvements in overall survival (OS) [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Based on these results, combination therapies with angiogenesis inhibitors such as BEV, aflibercept, and ramucirumab (RAM) have become standard second-line treatments [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRAM is a fully human immunoglobulin G1 monoclonal antibody that binds to VEGF receptor-2, preventing VEGF-A, VEGF-C, and VEGF-D ligand binding and inhibiting tumor angiogenesis by suppressing endothelial cell proliferation, migration, and survival [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The RAISE trial demonstrated a median OS of 13.3 months in patients treated with fluorouracil, levofolinate, and irinotecan (FOLFIRI) plus RAM versus 11.7 months in those treated with FOLFIRI plus placebo [hazard ratio (HR), 0.844; 95% confidence interval (CI), 0.73\u0026ndash;0.98; log-rank p\u0026thinsp;=\u0026thinsp;0.02] [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The irinotecan dose used in the FOLFIRI regimen was 180 mg/m\u003csup\u003e2\u003c/sup\u003e, which is higher than the recommended dose of 150 mg/m\u003csup\u003e2\u003c/sup\u003e in Japan [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the RAISE trial, median relative dose intensities (RDI) of RAM and irinotecan were 88.2% and 77.0%, respectively, in all patients, and 82.9% and 63.8%, respectively, in the Japanese population [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], showing no difference for RAM but a lower RDI for irinotecan in the Japanese population. Moreover, incidence rates of adverse events leading to discontinuation of cytotoxic agents were 26.8% in all patients and 48.6% in the Japanese population [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Based on these results, we conducted a prospective trial to investigate the efficacy and safety of FOLFIRI with low-dose irinotecan (150 mg/m\u0026sup2;, standard dose in Japan) plus RAM as second-line treatment for mCRC in Japanese patients who are refractory to oxaliplatin (OX) and fluoropyrimidine plus molecular-targeted agents.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis multicenter, single-arm, phase II clinical trial was conducted by the Chubu Clinical Oncology Group (CCOG) at 15 hospitals in Japan. Inclusion criteria were as follows: age\u0026thinsp;\u0026ge;\u0026thinsp;20 years; histologically proven adenocarcinoma of the colon or rectum; unresectable metastasis; confirmed radiographic disease progression during first-line combination therapy of OX and fluoropyrimidine with BEV or anti-epidermal growth factor receptor (EGFR) antibodies; the presence of at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1); Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and adequate hematologic, hepatic, and renal function. Patients who had received first-line treatment with IRI and had uridine diphosphate glucuronosyltransferase \u003cem\u003e(UGT)1A1\u003c/em\u003e gene status of homo type (*28/*28, *6/*6) or double hetero-type genetic polymorphisms (*6/*28), brain metastasis, clinically significant cardiovascular disease, double cancer, bowel obstruction, uncontrolled diabetes mellitus, hypertension, or congestive heart failure were excluded.\u003c/p\u003e \u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent prior to participation. The ethics committees of Nagoya University Hospital (approval number 2016\u0026thinsp;\u0026minus;\u0026thinsp;0527) and all other participating facilities approved the study. This trial was registered with the University Hospital Medical Information Network (UMIN000025659) and Japan Registry of Clinical Trials (jRCTs041180074).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment plan\u003c/h3\u003e\n\u003cp\u003eOn day 1 of each two-week cycle, patients with unresectable mCRC after first-line combination therapy of OX and fluoropyrimidine with BEV or anti-EGFR antibodies received 8 mg/kg RAM as a 60-min intravenous infusion, followed by the FOLFIRI regimen with low-dose irinotecan (150 mg/m\u0026sup2; intravenous irinotecan given over 90 min, 200 mg/m\u0026sup2; intravenous leucovorin given over 120 min, 400 mg/m\u0026sup2; fluorouracil given as an intravenous bolus over 2\u0026ndash;4 min, and 2400 mg/m\u0026sup2; fluorouracil given as a continuous infusion over 46 h). The treatment was continued until any one of the following occurred: radiographic confirmation of disease progression, unacceptable toxicity, deterioration of ECOG performance status to \u0026gt;\u0026thinsp;2, or withdrawal of patient consent. Dose modifications reflecting treatment-related toxicities were carried out in accordance with the study protocol.\u003c/p\u003e\n\u003ch3\u003eAssessments\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was progression-free survival (PFS), defined as the time from the date of registration until disease progression or death from any cause. Secondary endpoints were OS, defined as the time from the date of registration until death from any cause; time to treatment failure (TTF), defined as the time from the date of registration until death from any cause or cessation of the protocol treatment; objective response rate (ORR), defined as the proportion of patients whose best response was complete\u003c/p\u003e \u003cp\u003eresponse (CR) or partial response (PR); disease control rate (DCR), defined as the proportion of patients whose response was CR, PR, or stable disease (SD); treatment compliance; and adverse events.\u003c/p\u003e \u003cp\u003eTumor size was assessed using computed tomography at baseline and every eight weeks thereafter. Treatment response was assessed according to the RECIST criteria, version 1.1, by the investigators. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. All analyses of efficacy were based on the intent-to-treat (ITT) population, defined as eligible and assessable enrolled patients. The safety population was defined as all patients receiving\u0026thinsp;\u0026ge;\u0026thinsp;1 dose of the protocol treatment.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical power was calculated based on the following assumptions: an PFS threshold of 4.3 months and expected PFS of 5.7 months based on data from a Japanese subgroup of the RAISE trial [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], with an enrollment period of two years and follow-up period of three years. To ensure an alpha level of 0.1 (one-side) and a detection power (1-β) of 80%, 59 patients were required. Therefore, the planned sample size was 60 patients to account for possible loss to follow-up. Time-to-event variables, PFS, OS, and TTF were analyzed by the Kaplan\u0026ndash;Meier method. If the lower limit of the 95% confidence interval exceeded 4.3 months, which was set as the threshold PFS, the protocol treatment was considered to be effective. \u003cem\u003eP\u003c/em\u003e values less than 0.05 were considered statistically significant. Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary NC).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 62 patients were prospectively enrolled from 15 institutions between January 2018 and August 2021. One patient was excluded after enrollment because of ineligibility. The ITT population comprised 61 patients. Three patients were excluded from the safety analysis, including two patients who could not receive chemotherapy because their general condition worsened due to acute disease progression after enrollment, and one patient who refused to receive protocol treatment. Thus, the safety population comprised 58 patients (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Baseline clinical characteristics are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Median age of patients was 69 years (range, 43\u0026ndash;80 years); 32 patients (52%) were male, and 59 patients (97%) had ECOG performance status 0. The primary tumor location was the right side in 15 patients (25%) and the left side in 46 (75%). The RAS status was wild type in 29 patients (48%) and mutant in 32 (52%). Combination molecular-targeted drugs used in first-line chemotherapy were BEV in 44 patients (72%) and anti-EGFR antibodies in 17 (28%). Thirty-five patients (57%) had two or more metastatic sites, with the most common metastatic site being the liver (61%) followed by the lungs (56%).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eTreatment exposure\u003c/h3\u003e\n\u003cp\u003eThe median time to treatment failure was 4.8 months (95% CI, 3.2\u0026ndash;5.9 months) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The median number of treatment cycles was eight (range, 1\u0026ndash;27). The median RDI was 50.5% (range, 0-102.4%) for bolus fluorouracil, 74.5% (range, 28.5-102.4%) for infusion fluorouracil, 73.8% (range, 40.3-102.4%) for irinotecan, and 80.8% (36.1-102.4%) for RAM (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Common reasons for treatment discontinuation were disease progression (67%), adverse events (16%), and patient decision (8%).\u003c/p\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cp\u003eThe cutoff date for the primary analysis was December 2023. Disease progression and death occurred in 53 patients (87%) and 52 patients (85%), respectively. The median length of follow-up for censored cases was 16.4 months (range, 1\u0026ndash;57 months). At study cutoff, no patients were receiving FOLFIRI plus RAM. Median PFS (primary endpoint) was 5.9 months (95% CI, 4.8\u0026ndash;6.9 months) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). The lower limit of 95% CI was higher than the threshold of 4.3 months, and hence, the primary endpoint was met. Median OS was 17.5 months (95% CI, 12.3\u0026ndash;21.7 months) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB). The tumor response was assessed in the ITT population (61 patients): five patients (8.2%) were not evaluated. The CR rate was 0%, the PR rate was 8.2%, the SD rate was 66%, the PD rate was 18%, the objective response (CR\u0026thinsp;+\u0026thinsp;RR) rate was 8.2% (95% CI, 3.6\u0026ndash;17.7%), and the disease control rate (CR\u0026thinsp;+\u0026thinsp;PR\u0026thinsp;+\u0026thinsp;SD) was 74% (95% CI, 61.5\u0026ndash;83.1%).\u003c/p\u003e\n\u003cp\u003eMedian PFS was 5.7 months (95% CI, 4.4\u0026ndash;6.8 months) in patients treated with first-line chemotherapy with BEV and 7.4 months (95% CI, 4.6\u0026ndash;11.0 months) in those treated with first-line chemotherapy with anti-EGFR antibodies (HR, 1.17; 95% CI, 0.64\u0026ndash;2.12; p\u0026thinsp;=\u0026thinsp;0.60) (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA); median OS was 19.8 months (95% CI, 10.4\u0026ndash;22.4 months) and 17.5 months (95% CI, 11.5\u0026ndash;26.1 months), respectively (HR, 0.96; 95% CI, 0.52\u0026ndash;1.78; p\u0026thinsp;=\u0026thinsp;0.91) (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eB).\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eSafety\u003c/h2\u003e\n \u003cp\u003eSafety was assessed in 58 patients. The incidence of treatment-related adverse events is shown in Table\u0026nbsp;3. Frequencies of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 hematologic, non-hematologic, and RAM-associated adverse events were 43%, 24%, and 12%, respectively. The most frequent Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 hematologic adverse event was neutropenia (40%). In addition, four (6.9%) patients experienced Grade 3 febrile neutropenia. Frequent Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 non-hematologic adverse events were anorexia (10%) and diarrhea (8.6%). Frequent Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 RAM-associated adverse events were hypertension (6.8%) and proteinuria (3.4%). There were no unexpected serious adverse events or treatment-related deaths.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis phase II trial was conducted to evaluate the efficacy and safety of FOLFIRI with low-dose irinotecan (150 mg/m\u0026sup2;, standard dose in Japan) plus RAM as second-line treatment for mCRC in Japanese patients. The median PFS (primary endpoint) of 5.9 months (95% CI, 4.8\u0026ndash;6.9 months) was considered acceptable according to our hypothesis that assumed the threshold and expected PFS of 4.3 months and 5.7 months, respectively. Moreover, the median OS (secondary endpoint) of 17.5 months (95% CI, 12.3\u0026ndash;21.7 months) was comparable to those reported by previous RCTs, including the RAISE trial, for second-line angiogenic therapies.\u003c/p\u003e \u003cp\u003eThe RDIs of cytotoxic agents have been shown to have significant effects on tumor response and survival benefits in patients with various cancer types [\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In Japanese clinical practice, irinotecan at 150 mg/m\u0026sup2; is the standard dosage used in the FOLFIRI regimen. The RDI for irinotecan, which was notably lower than other drugs in Japanese population of RAISE trial, was maintained at 73.8%. Regarding tumor response, the ORR and DCR in the Japanese population of the RAISE trial were 8.1% and 82.4%, respectively [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], which were comparable to the ORR (8.2%) and DCR (74%) observed in the present study. This study prospectively confirmed that treatment efficacy on tumor response and survival was comparable to those of Japanese population in the RAISE trial.\u003c/p\u003e \u003cp\u003eEvidence is insufficient with regard to second-line treatment after first-line treatment with anti-EGFR antibodies, and no phase III clinical trials have evaluated combinations of molecular-targeted agents in second-line treatment. Suzuki et al. compared the efficacy and safety of FOLFIRI plus RAM as second-line treatment for unresectable mCRC in patients who received first-line treatment with or without BEV. The PFS and DCR were better in BEV-naive patients than in those who had received first-line treatment with BEV [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In the present study, molecular-targeted agents used in first-line treatment were BEV in 44 patients (72%) and anti-EGFR antibodies in 17 patients (28%) in the ITT population; median PFS was 5.7 months (95% CI, 4.4\u0026ndash;6.8 months) in the former group and 7.4 months (95% CI, 4.6\u0026ndash;11.0 months) in the latter group. These findings suggest a trend toward greater efficacy in patients who did not use BEV as first-line treatment. The JACCRO CC-16 study also investigated the efficacy and safety of FOLFIRI plus RAM as second-line treatment in patients with RAS wild-type mCRC who were refractory or intolerant to OX and fluorouracil (doublet) or OX, irinotecan, and fluorouracil (triplet) plus anti-EGFR antibodies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Median PFS in the doublet plus anti-EGFR antibody regimen group was 7.4 months (95% CI 5.7-9.0 months), which was comparable to that observed in the present study for anti-EGFR antibody combination therapy. These results suggest that FOLFIRI plus RAM is effective as second-line treatment after first-line treatment with anti-EGFR antibodies.\u003c/p\u003e \u003cp\u003eIn terms of safety, the most frequent adverse events were neutropenia and RAM-associated events, such as hypertension and proteinuria. Among Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events, neutropenia, hypertension, and proteinuria were observed at frequencies of 40%, 6.8%, and 3.4%, respectively. In the Japanese population of the RAISE trial, frequencies of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia, hypertension, and proteinuria were 59.5%, 17.6%, and 8.1%, respectively [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In a phase 1b study conducted prior to the RAISE study, severe neutropenia of Grade 3 or higher was observed in five of six patients (83.3%) with 180 mg/m\u003csup\u003e2\u003c/sup\u003e irinotecan [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The low dose of irinotecan (150 mg/m\u003csup\u003e2\u003c/sup\u003e) in this study resulted in lower frequency of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia than that of Japanese population in the RAISE trial. In Japanese patients, low-dose irinotecan (150 mg/m\u0026sup2;) is appropriate from safety perspectives, and FOLFIRI plus RAM therapy is performed with appropriate dose reduction and treatment delay. The incidence of hypertension was higher compared with Japanese population of the RAISE study for all grades. This may be because, in the present study, roughly 30% of patients were BEV-naive in first-line treatment, and some appeared to have developed hypertension after the use of RAM in second-line treatment. The incidence of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 hypertension and that of proteinuria were both lower than those in Japanese population of the RAISE study. All physicians performed quantitative urine tests and closely monitored blood pressure, and control of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events could be achieved through appropriate RAM dose modification and use of antihypertensive drugs when needed.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the single-arm design and relatively small sample size necessitate confirmation of our results in a larger cohort. Second, tumor size and response according to the RECIST criteria were not centrally evaluated. Third, the background of the present study population differed from that of the RAISE study population. All patients in the RAISE study were previously treated with BEV, whereas the present study used a heterogeneous treatment population including not only patients who received BEV but also those who received anti-EGFR antibodies as first-line treatment. Therefore, data are not directly comparable between the present study and the RAISE study.\u003c/p\u003e \u003cp\u003eIn conclusion, we demonstrated that FOLFIRI plus RAM therapy performed in the setting of irinotecan 150 mg/m\u003csup\u003e2\u003c/sup\u003e can be safely administered without decreasing the therapeutic effect and can achieve survival comparable to that of Japanese population in the RAISE study. FOLFIRI with low-dose irinotecan (150 mg/m\u0026sup2;, standard dose in Japan) plus RAM is a feasible second-line treatment in Japanese patients with mCRC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe following physicians and research coordinators provided care to patients in this study: S. Sueoka (H. Tokai); T. Asada (H. Tajimi); N. Yabusaki (H. Okazaki); M. Shoka (H. Nisio); S. Takeda (H. Tosei); R. Hashimoto (H. Nakatsugawa); N. Mashita (H. Konan); F. Sugiura (H. Nagoya University); and M. Aoki and H. Hattori (CCOG data center). The authors thank these individuals for their cooperation and support. The results of this study were presented in part at the 61st Annual Meeting of the Japan Society of Clinical Oncology on October 19-21, 2023, in Yokohama, Japan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Eli Lilly Japan. The funders did not have any involvement in the design of this study; the data collection, analysis, and interpretation of the data; and writing of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians 71 (3):209\u0026ndash;249. https://doi.10.3322/caac.21660\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHashiguchi Y, Muro K, Saito Y, Ito Y, Ajioka et al (2020) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. International journal of clinical oncology 25 (1):1\u0026ndash;42. https://doi.10.1007/s10147-019-01485-z\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBennouna J, Sastre J, Arnold D et al (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. The Lancet Oncology 14 (1):29\u0026ndash;37. https://doi.10.1016/s1470-2045(12)70477-1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Cutsem E, Tabernero J, Lakomy R et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 30 (28):3499\u0026ndash;3506. https://doi.10.1200/jco.2012.42.8201\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. The Lancet Oncology 16 (5):499\u0026ndash;508. https://doi.10.1016/s1470-2045(15)70127-0\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFalcon BL, Chintharlapalli S, Uhlik MT et al (2016) Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents. Pharmacology \u0026amp; therapeutics164:204\u0026ndash;225. https://doi.10.1016/j.pharmthera.2016.06.001\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSunakawa Y, Ichikawa W, Fujita K et al (2011) UGT1A1*1/*28 and *1/*6 genotypes have no effects on the efficacy and toxicity of FOLFIRI in Japanese patients with advanced colorectal cancer. Cancer chemotherapy and pharmacology 68 (2):279\u0026ndash;284. https://doi.10.1007/s00280-010-1485-8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamashita K, Nagashima F, Fujita K et al (2011) Phase I/II study of FOLFIRI in Japanese patients with advanced colorectal cancer. Japanese journal of clinical oncology 41 (2):204\u0026ndash;209. https://doi.10.1093/jjco/hyq197\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKochi M, Akiyama Y, Aoki T et al (2013) FOLFIRI plus bevacizumab as a first-line treatment for Japanese patients with metastatic colorectal cancer: a JACCRO CC-03 multicenter phase II study. Cancer chemotherapy and pharmacology 72 (5):1097\u0026ndash;1102. https://doi.10.1007/s00280-013-2292-9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamucirumab (Cyramuza) review report. Pharmaceuticals and Medical Devices Agency.\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e_https://www.pmda.go.jp/drugs/2016/P20160518002/530471000_22700AMX00664_K100_2.pdf\u003c/span\u003e\u003cspan address=\"http://_https://www.pmda.go.jp/drugs/2016/P20160518002/530471000_22700AMX00664_K100_2.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Accessed 31 July 2024\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwak LW, Halpern J, Olshen RA et al (1990) Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 8 (6):963\u0026ndash;977. https://doi.10.1200/jco.1990.8.6.963\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRepetto L, Pace M, Mammoliti S et al (1993) The impact of received dose intensity on the outcome of advanced ovarian cancer. European journal of cancer (Oxford, England: 1990) 29a (2):181\u0026ndash;184. https://doi.10.1016/0959-8049(93)90169-g\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuciani A, Bertuzzi C, Ascione G et al (2009) Dose intensity correlate with survival in elderly patients treated with chemotherapy for advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 66 (1):94\u0026ndash;96. https://doi.10.1016/j.lungcan.2008.12.019\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoibl S, Skacel T, Nekljudova V et al (2011) Evaluating the impact of Relative Total Dose Intensity (RTDI) on patients' short and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer- a pooled analysis. BMC cancer 11:131. https://doi.10.1186/1471-2407-11-131\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakayama G, Tanaka C, Uehara K et al (2014) The impact of dose/time modification in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer. Cancer chemotherapy and pharmacology 73 (4):847\u0026ndash;855. https://doi.10.1007/s00280-014-2416-x\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuzuki T, Shinozaki E, Osumi H et al (2019) Second-line FOLFIRI plus ramucirumab with or without prior bevacizumab for patients with metastatic colorectal cancer. Cancer chemotherapy and pharmacology 84 (2):307\u0026ndash;313. https://doi.10.1007/s00280-019-03855-w\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYasui H, Okita Y, Nakamura M et al (2023) Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16. ESMO open 8 (5):101636. https://doi.10.1016/j.esmoop.2023.101636\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshino T, Yamazaki K, Gotoh M et al (2015) Safety and Pharmacokinetics of Second-line Ramucirumab plus FOLFIRI in Japanese Patients with Metastatic Colorectal Carcinoma. Anticancer Res 35(7):4003\u0026ndash;4007\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Metastatic colorectal cancer, Ramucirumab, FOLFIRI, Japanese patients, Second-line chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-5041539/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5041539/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter, single-arm, phase II study aimed to evaluate the efficacy and safety of fluorouracil, levofolinate, and irinotecan (150 mg/m², standard dose in Japan) (FOLFIRI) plus ramucirumab (RAM) as second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn day 1 of each 2-week cycle, patients with unresectable mCRC who were refractory to oxaliplatin and fluoropyrimidine in combination with bevacizumab or anti-epidermal growth factor receptor antibodies as first-line treatment received 8 mg/kg RAM, followed by the FOLFIRI regimen with low-dose irinotecan (150 mg/m²). The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), treatment compliance, and safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 62 patients were enrolled from 15 institutions between January 2018 and August 2021. The intent-to-treat and safety populations included 61 and 58 patients, respectively. Median PFS and OS were 5.9 months (95% CI, 4.8–6.9 months) and 17.0 months (95%CI, 12.0–21.0 months), respectively. The objective response rate and disease control rate were 8.2% and 74%, respectively. The median time to treatment failure was 4.8 months (95% CI, 3.2–5.9 months). Median relative dose intensities of irinotecan, 5-fluorouracil, and RAM were 73.8% (range, 40.3-102.4%), 58.5% (range, 22.8-102.4%), and 80.8% (range, 36.1-102.4%), respectively. Frequencies of Grade ≥ 3 hematologic, non-hematologic, and RAM-associated adverse events were 43%, 24%, and 17%, respectively. The observed Grade ≥ 3 adverse events included neutropenia (40%), diarrhea (8.6%), decreased appetite (10%), hypertension (6.9%), and proteinuria (3.4%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFOLFIRI with low-dose irinotecan plus RAM is a feasible second-line treatment in Japanese patients with mCRC.\u003c/p\u003e","manuscriptTitle":"Phase II study of FOLFIRI with low-dose irinotecan plus ramucirumab as second-line treatment in Japanese patients with metastatic colorectal cancer (Study rindo)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 12:26:10","doi":"10.21203/rs.3.rs-5041539/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d1d62b98-aba9-4d30-ae9a-97d8d66c5f6f","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-28T00:33:55+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-06 12:26:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5041539","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5041539","identity":"rs-5041539","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}