Abstract
Background/Aim: The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC. Patients and Methods: Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/m2 intravenously on day 1, whereas S-1 80 mg/m2 was administered orally twice daily until day 15, followed by a 7-day drug holiday period. The primary end point was 6-month progression-free survival (PFS) rate. Results: In total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed. Conclusion: The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.
The combination of folinic acid and fluorouracil with either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) has been established as a standard regimen for patients with metastatic colorectal cancer (mCRC). Tournigand et al. (1) investigated two sequences – FOLFIRI followed by FOLFOX and FOLFOX followed by FOLFIRI – and found no difference in overall survival (OS) between the two regimens.
Therefore, in cases where oxaliplatin-based regimens were used in the first-line setting, irinotecan-based regimens were recommended as second-line treatments, and vice versa. To improve the therapeutic effects of these cytotoxic drug regimens only, it has become possible to use molecular target drugs such as vascular endothelial growth factor (VEGF) inhibitors or anti-epidermal growth factor receptor (EGFR) antibody drugs together with cytotoxic regimens (2-4). Bevacizumab was reported to prolong survival in two observational studies and one phase III trial when used continuously in patients with mCRC after standard first-line bevacizumab-based treatment (5-7). Regarding anti-EGFR antibody as first-line treatment, the combination of anti-EGFR antibody and cytotoxic drugs has been shown to improve prognosis in patients with RAS wild-type mCRC, and this combination regimen is recommended in the latest guidelines in several countries (2-4). According to these guidelines, the optimal second-line regimen after standard first-line anti-EGFR-based treatment is VEGF inhibitor-based treatment. However, the usefulness of second-line VEGF inhibitors after the progression of first-line anti-EGFR-based treatment has not been fully investigated. According to a post-hoc analysis of subsequent therapies in the FIRE-3 trial comparing first-line cetuximab and bevacizumab with FOLFIRI in KRAS wild-type mCRC, about half of the patients in the first-line cetuximab group received bevacizumab in subsequent treatment lines. As a result, OS and progression-free survival (PFS) were improved from the start of the second-line treatment compared with patients in the first-line bevacizumab group (8). These findings suggested that the subsequent use of anti-VEGF agents after first-line anti-EGFR treatment failure may contribute to favorable clinical outcomes.
In recent years, treatments that replace intravenous fluorouracil with oral fluoropyrimidines have been developed. Regimens containing oral fluoropyrimidine play a significant role in improving quality of life because continuous infusion is not required. Furthermore, in addition to capecitabine plus oxaliplatin (CapeOX), which has already become the standard of care, combinations of tegafur– gimeracil–oteracil potassium capsules (S-1), which were developed in Japan, plus oxaliplatin (SOX) (9), S-1 plus irinotecan (IRIS: 4-week regimen or SIR: 3-week regimen) (10, 11), and the combinations of oral fluoropyrimidines plus oxaliplatin or irinotecan with bevacizumab (12-14) have also been reported. However, the efficacy and safety of SIR plus bevacizumab (SIRB regimen) has not been fully investigated in the second-line setting for patients with oxaliplatin and anti-EGFR antibody-refractory RAS wild-type mCRC. Therefore, we conducted a phase II study to verify the efficacy and safety of the SIRB regimen for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC.
Patients and Methods
Study design. This phase II, multi-institutional clinical trial was conducted to evaluate the efficacy and safety of a triweekly SIRB regimen for KRAS exon 2 wild-type mCRC treated with cetuximab and oxaliplatin as first-line therapy. The study was performed in compliance with the Declaration of Helsinki and ethical guidelines for clinical studies. The protocol of this study was approved by the institutional review board or ethics committee of each institution (JACCRO R2-8). Written informed consent was obtained from all patients before the study began. This study has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000010319).
Inclusion criteria. Patients meeting the following criteria were included in the study: age ≥20 years at the time of providing informed consent; likely to survive for ≥3 months; capable of oral ingestion; histologically confirmed mCRC; advanced unresectable/recurrent mCRC resistant to first-line fluoropyrimidine and oxaliplatin plus cetuximab therapy; evaluable lesions (regardless of whether they were measurable); able to provide written informed consent after receiving a thorough explanation of the contents of this study; and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. In addition, patients who met the following criteria for major organ function within 14 days of enrollment were also included: white blood cell count in the range of 3,000-12,000 per mm3; neutrophil count ≥1,500 per mm3; platelets ≥10.0×104 per mm3; hemoglobin ≥9.0 g/dl; blood bilirubin ≤1.5 mg/dl; aspartate transaminase ≤100 IU/l (200 IU/l if liver metastasis was present); alanine transaminase ≤ 100 IU/l (200 IU/l if liver metastasis was present); serum creatinine ≤1.2 mg/dl; creatinine clearance ≥50 ml/min; proteinuria ≤1+; and prothrombin time/international normalized ratio <1.5.
Exclusion criteria. Patients with the following conditions were excluded from the study: brain metastases; interstitial pneumonia or pulmonary fibrosis; present or previous history of serious heart disease; history of thromboembolism; history of hemoptysis; severe paresthesia or dysesthesia with functional impairment; large amounts of cancerous fluids (e.g., pleural effusion, ascites, pericardial effusion); radiotherapy for primary or metastatic disease; treatment with drugs that inhibit platelet function (aspirin preparation at 325 mg/day); hemorrhagic tendencies, coagulopathy, or clotting factor abnormalities; active peptic ulcer disease; watery stool or uncontrollable diarrhea; or intestinal paralysis and/or intestinal obstruction.
Treatment protocol. Bevacizumab 7.5 mg/kg was administered as a 30-90-min infusion on day 1 and irinotecan 150 mg/m2 as a 90-min infusion on day 1 every 3 weeks. The dose of S-1 was determined according to the patient’s body surface area (BSA) as follows: BSA <1.25 m2: 80 mg/day; BSA 1.25-1.5 m2: 100 mg/day; and BSA >1.5 m2: 120 mg/day (for creatinine clearance 50-60 ml/min, the initial dose of S-1 was reduced by one level) administered orally twice daily after breakfast and dinner (from after dinner on day 1 to after breakfast on day 15 followed by 7 days of drug holiday). A single cycle lasted 3 weeks. Premedication with a 5-hydroxytryptamine-3-receptor antagonist combined with dexamethasone 6.6 mg was recommended before the administration of irinotecan.
End points. The primary end point of this phase II study was 6-month PFS rate. The secondary end points were PFS, OS, response rate (RR), and safety (incidence rate and severity of adverse events).
Safety and response evaluation. Response Evaluation Criteria in Solid Tumors (RECIST ver. 1.1) was used to determine the tumor response, and the Common Terminology Criteria for Adverse Events v4.0 Japanese Translated Japan Clinical Oncology Group Version (CTCAE v4.0-JCOG) was used to evaluate adverse events. The ECOG PS scale was used to assess the general condition of the patients.
Statistical analysis. The rationale for determining the target sample size was as follows. In the FIRIS study, which tested the non-inferiority of IRIS versus FOLFIRI as second-line treatment for unresectable advanced or recurrent mCRC, patients with resistance to prior fluoropyrimidine plus oxaliplatin treatments had a 6-month PFS rate of approximately 40% in the IRIS group and 30% in the FOLFIRI group (11). In the ML18147 study, wherein the importance of continuing bevacizumab as second-line therapy in patients with mCRC resistant to the bevacizumab-containing regimen in first-line therapy was studied, the 6-month PFS rate was approximately 45% in patients who received the regimen and approximately 30% in those who did not (7). Based on these results, we assumed a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45% for this study. The calculation of the required sample size at a=0.05 and b=0.20 indicated that 61 cases needed to be enrolled. Therefore, the sample size for our study was set at 70, considering possible dropouts.
Survival time analysis for PFS and OS was performed on the analysis population. Survival functions were estimated using the Kaplan–Meier method along with median and annual PFS. The Greenwood formula was used to obtain 95% confidence intervals (CIs). In terms of tumor shrinkage, point estimates were calculated for the RR, and two-sided 95%CIs were calculated for the analysis population. An accurate CI based on the binomial distribution was used for interval estimation.
Results
Patient characteristics. A total of 17 patients were enrolled from eight centers between July 2013 and May 2015. Enrollment was stopped in October 2015 due to poor patient accrual. Data were extracted in December 2017, after which, the analysis was performed. Of the 17 patients enrolled, there were no ineligible patients or patients who withdrew before treatment, thus all 17 were included in the full analysis set. No protocol deviations occurred after treatment initiation, and thus all 17 patients were likewise included in the per protocol set and safety analysis. The mean observation period was 21.8 months (95%CI=2.89-44.32). The clinical characteristics of the patients are shown in Table I. The median age was 67 years (range=49-78 years). There were 11 (64.7%) males and 6 (35.3%) females. The ECOG PS was 0 in 14 patients (82.4%) and 1 in 3 (17.6%). The primary tumor sites were the colon and rectum, in 11 (64.7%) and 6 (35.3%) patients, respectively. All cases had undergone surgical resection before the initiation of first-line treatment. The metastatic sites were the liver, lungs, abdominal lymph nodes, and other, in 11 (64.7%), 9 (52.9%), 9 (52.9%), and 5 (29.4%) patients, respectively. The UGT1A1 gene was wild-type (*1/*1) in 8 (47.1%) patients, heterozygous (*1/*6, *1/*28) in 6 (35.3%), homozygous or double heterozygous (*6/*6, *28/*28, *6/*28) in none, and unmeasured in 3 (17.6%). First-line therapy included treatment with FOLFOX plus cetuximab and SOX plus cetuximab in 8 (47.1%) and 9 (52.9%) patients, respectively. The best response of the first-line therapy was complete response (CR) in 1 patient (5.9%), partial response (PR) in 14 (82.4%), stable disease (SD) in 1 (5.9%), and progressive disease (PD) in 1 (5.9%). The median treatment duration of the first-line therapy was 11.0 months (range=1.0-30.0 months).
Patient characteristics.
Efficacy and safety. The 6-month PFS rate was 64.7% (95%CI=41.99-87.43%), median PFS was 10.1 months (95%CI=4.11-17.28) and patients were followed for a median of 10.1 months (range=1.84-17.38 months) (Figure 1). The median OS was 21.8 months (95%CI=9.79-37.91) and patients were followed for a median of 21.8 months (range=2.89-44.32 months) (Figure 2). The RR was 23.5% (95%CI=6.81-49.90), with 0 CR, 4 (23.5%) PR, 11 (64.7%) SD, and 2 (11.8%) PD cases. The disease control rate was 88.2% (95%CI=63.56-98.54) (Table II). The median number of treatment cycles was 7 (range=1-25). The median relative dose intensities of each agent were 85.2% for irinotecan, 78.1% for S1, and 95.8% for bevacizumab. The safety results of the 17 patients are shown in Table III. Grade ≥3 adverse events were noted in 10% of the patients and included leukopenia in 3 patients (17.6%), neutropenia in 5 (29.4%), anorexia in 2 (11.8%), diarrhea in 2 (11.8%), and hypertension in 3 (17.6%). No febrile neutropenia or treatment-related deaths occurred.
Progression-free survival (PFS) of S-1 and irinotecan plus bevacizumab as a second-line regimen (n=17). The 6-month PFS was 64.7% [95% confidence interval (CI)=41.99-87.43]. The median PFS was 10.1 months (95%CI=4.11-17.28). CI: Confidence interval; PFS: progression-free survival.
Overall survival (OS) of S-1 and irinotecan plus bevacizumab as a second-line regimen (n=17). The median OS was 21.8 months (95% confidence interval=9.79-37.91).
Response of patients to treatment.
Adverse events according to the Common Terminology Criteria for Adverse Events.
Discussion
This phase II study demonstrated that a triweekly SIRB regimen might be an effective and well-tolerated second-line treatment for patients with KRAS wild-type mCRC who have become refractory to cetuximab and oxaliplatin as first-line treatment. Our results indicated a promising 6-month PFS rate of 64.7%, median PFS of 10.1 months, and median OS of 21.8 months. The number of cases was 17, which was less than the 70 cases for which the sample size was initially set, but was considered suitable for the primary end point. To the best of our knowledge, this is the first multicenter phase II clinical trial conducted to evaluate the clinical efficacy and safety of second-line bevacizumab-containing regimens in patients with anti-EGFR antibody-refractory KRAS wild-type mCRC.
Second-line VEGF inhibitors plus standard chemotherapy are known as a safe and effective option for patients with mCRC who received bevacizumab plus chemotherapy as a first-line treatment, regardless of their RAS status. In the phase III ML18147 trial, which investigated the continuous use of bevacizumab plus standard second-line chemotherapy in patients with progression of mCRC after standard first-line bevacizumab-based chemotherapy, the primary end point of OS in the second-line therapy was 11.2 months in the bevacizumab group and 9.8 months in the chemotherapy-only group [hazard ratio (HR)=0. 81, p=0.0062] (6). The survival benefit of both ramucirumab and aflibercept plus FOLFIRI as second-line treatment for patients with cancer progression who had received bevacizumab as first-line treatment were also shown in the RAISE and VELOUR trials, respectively (15, 16). Therefore, VEGF inhibitors used in combination with fluoropyrimidine and irinotecan as a second-line treatment have been shown to prolong OS, even after patients became refractory to bevacizumab as a first-line treatment. Median OS and PFS in the present study were 21.8 and 10.1 months; in contrast, median OS and PFS of continuous use of VEGF inhibitors after refractory to bevacizumab in these three phase III trials (ML18147, RAISE, VELOUR) were 11.2-13.5 and 5.7-6.9 months, respectively (7, 15, 16). As one of the reasons for the good clinical outcome in our study, the subsequent use of bevacizumab after failure of first-line anti-EGFR treatment may contribute to prolong OS and PFS.
In a preliminary study, VEGF receptor-1 was found to be expressed in human cancer cells that were resistant to anti-EGFR drugs (17). After patients become refractory to first-line anti-EGFR antibody drugs, the use of VEGF inhibitors in second-line treatments can be beneficial. However, a phase III trial using many VEGF inhibitors as second-line treatment demonstrated the usefulness of continued bevacizumab and other VEGF inhibitors after the development of treatment resistance to first-line bevacizumab. To our knowledge, no studies have prospectively investigated the optimal use of VEGF inhibitors as second-line therapy for patients with RAS wild-type mCRC using first-line anti-EGFR drugs. The results of the FIRE-3 study suggested that the first-line introduction of anti-EGFR therapy may induce good tolerability and efficacy for second-line anti-VEGF therapy (8). In that phase III trial, OS favored the first-line cetuximab group, which had a median OS of 7.5 months longer than that observed in the first-line bevacizumab group. On the other hand, PFS was similar in both groups. According to an analysis of subsequent therapies with regard to this trial, about half of the patients in the cetuximab group received bevacizumab in subsequent treatment lines, and PFS from the start of second-line therapy in the cetuximab group was 6.5 months, compared with 4.7 months in the bevacizumab group (p<0.001), and OS from the start of second-line therapy was 16.3 and 13.2 months (p=0.021), respectively. Similarly, Hsu et al. (18) retrospectively evaluated the clinical outcomes of patients with KRAS wild-type mCRC treated with cetuximab or bevacizumab as first- or third-line treatment. Compared with the reverse sequence group, the first-line cetuximab followed by third-line bevacizumab group had better clinical outcomes. Considering these preclinical and clinical results, the subsequent use of anti-VEGF agents after failure of first-line anti-EGFR treatment may contribute to favorable clinical outcomes after second-line treatment. Conversely, three randomized phase II studies examining the subsequent use of second-line anti-EGFR therapy after first-line bevacizumab did not show better clinical outcomes compared with the continuous use of bevacizumab from first- to second-line therapy. In patients with RAS wild-type mCRC, first-line introduction of anti-EGFR therapy followed by second-line anti-VEGF may represent an optimal sequence with a better survival advantage (19-21). In fact, in the present study, median PFS and OS were 10.1 and 21.8 months, respectively, which was non-inferior to the PFS (6.5 months) and OS (13.2 months) from the start of second-line therapy in the cetuximab group in the FIRE-3 trial.
In the phase III FIRIS trial, the combination of S-1, an oral fluoropyrimidine, and irinotecan (IRIS: irinotecan 100 mg/m2 on days 1 and 15, S-1 80 mg/m2 twice daily for 2 weeks, followed by a 2-week rest period) was shown to be non-inferior to FOLFIRI as second-line treatment (11). It was also reported that the frequency of Grade 3 or higher neutropenia, diarrhea, anorexia, and fatigue was higher in the IRIS than in the FOLFIRI group. In the present study, Grade 3 neutropenia, diarrhea, and anorexia were observed in 29.4%, 11.8%, and 11.8% of the patients, respectively, compared with 3.62%, 20.5%, and 11.0% in the IRIS group in the FIRIS study, but all adverse events were manageable. Although our study regimen differed from the IRIS regimen in the FIRIS trial in terms of dosage and administration for S1 and irinotecan, and involved the combination of bevacizumab, the incidence of adverse events did not differ between the present study regimen and the IRIS regimen. Therefore, the combination of S1 and irinotecan plus bevacizumab may be a promising treatment modality alongside other VEGF inhibitor regimens and has the potential to become a favorable option in second-line settings.
The present study had several limitations. First, this was a single-arm trial with a limited sample size. Moreover, patient recruitment was terminated before the number of patients reached 70, which led to an underpowered analysis. Second, S-1 for colorectal cancer has only been available in European and Asian countries, and the pharmacokinetics and toxicities of S-1 are known to be different between European and East Asian patients (22). Third, only patients with KRAS exon 2 wild-type CRC were eligible; anti-EGFR antibody is considered ineffective in patients with KRAS exon 3, 4, NRAS, and BRAF V600E-mutated CRC. Since expanded RAS and BRAF testing was not approved in Japan at the start of this study, these patients could not be excluded.
SIRB, which was prospectively examined in the present study, was shown to be effective and tolerable in terms of safety. This regimen is mainly administered using oral preparations, and the infusion interval is every 3 weeks, which is a convenient treatment method for outpatients. Therefore, we believe that this regimen is one of useful second-line treatments for patients with oxaliplatin and cetuximab-refractory KRAS wild-type advanced unresectable or recurrent mCRC.
Acknowledgements
The Authors would like to thank the recruited patients and their families, the collaborators who contributed to this study, and the members of the Japan Clinical Cancer Research Organization (JACCRO) Data Center and Support Office. The Authors would also like to thank Yasuhiro Shimada, Kenji Omura, and Toru Takebayashi for the independent data and assistance with the safety monitoring committee.
Footnotes
Authors’ Contributions
Shimada, K., Tsuji, A., Kochi, M., Denda, T., Kotaka, M., Nakamura, M., Sunakawa, Y., Ichikawa, W. and Fujii, M. conceived and designed the study. Tanioka, H., Tsuji, A., Kochi, M., Kim, H. M., Takahashi, T., Denda, T., Takagane, A. and Watanabe, T. gathered the data. Takeuchi, M. analysed the data. All the Authors were involved in interpretation of the data, development review, and approval of the manuscript. Tanioka, H., Shimada, K., Ichikawa, W. and Fujii, M. were responsible for the final decision to submit for publication.
Conflicts of Interest
Tsuji, A. has received honoraria from Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd.; and scholarship donations from Taiho Pharmaceutical Co., Ltd. Takahashi, T. belongs endowed chair from Yakult Honsha Co., Ltd. Denda, T. has received honoraria from Sysmex Corporation and Ono Pharmaceutical Co., Ltd.; and fees for promotional materials from Sawai Pharmaceutical Co., Ltd.; and research funding from MSD K.K. and Ono Pharmaceutical Co., Ltd. Kotaka, M. has received honoraria from Chugai Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd. and Eli Lilly Japan K.K. Nakamura, M. has received honoraria from Bayer Yakuhin, Ltd., Bristol-Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan Co., Ltd., Merck Biopharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sanofi Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. Sunakawa, Y. has received honoraria and research funding from Taiho Pharmaceutical Co., Ltd. Ichikawa, W. has received honoraria from Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd. and Daiichi Sankyo Co., Ltd.; and research funding from Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd. and Daiichi Sankyo Co., Ltd. The other Authors declare that they have no conflicts of interest in relation to this study.
Funding
This study was funded by the Japan Clinical Cancer Research Organization (JACCRO).
- Received March 4, 2022.
- Revision received March 22, 2022.
- Accepted March 23, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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