Post-Marketing Safety Study of Ramucirumab Plus FOLFIRI: Analysis of Age and Initial Dose of Irinotecan in Patients with Metastatic Colorectal Cancer.

BACKGROUND: There is limited real-world evidence regarding the safety of ramucirumab plus FOLFIRI in patients with metastatic colorectal cancer (mCRC). OBJECTIVE: We evaluated the safety of ramucirumab plus FOLFIRI in patients with mCRC by age and initial dose of irinotecan. PATIENTS AND METHODS: This single-arm, prospective, multicenter, non-interventional, observational study was conducted between December 2016 and April 2020. Patients were observed for 12 months. RESULTS: Of 366 enrolled Japanese patients, 362 were eligible for study inclusion. The frequency of grade ≥ 3 adverse events (AEs) by age (≥ 75 years vs < 75 years) was 56.1% versus 50.2%, indicating no substantial differences between age groups. Grade ≥ 3 notable AEs, including neutropenia, proteinuria, and hypertension, were also similar in both age groups, but the frequency of any grade venous thromboembolic events was higher in those aged ≥ 75 years than in those aged < 75 years (7.0% vs 1.3%). The frequency of grade ≥ 3 AEs was slightly lower in patients receiving > 150 mg/m2 of irinotecan than in those receiving ≤ 150 mg/m2 of irinotecan (42.1% vs 53.6%); however, the frequency of grade ≥ 3 diarrhea, but not any grade diarrhea, and liver failure/injury was higher in patients receiving > 150 mg/m2 of irinotecan than in those receiving ≤ 150 mg/m2 of irinotecan (4.6% vs 1.9% and 9.1% vs 2.3%, respectively). CONCLUSIONS: The safety profile of ramucirumab plus FOLFIRI in mCRC patients was similar in subgroups by age and initial irinotecan dose in real-world settings.

Colorectal cancer (CRC), also known as bowel cancer, is a common cancer and a leading cause of death. Chemotherapy is a treatment option for CRC. It consists of one or more powerful medications to destroy cancer cells with the aim of prolonging life and reducing symptoms. These medications can cause side effects such as nausea, vomiting, infections, and high blood pressure. Sometimes these side effects can be so severe that patients stop or reduce their treatment. The safety and efficacy of these anti-cancer drugs are established from clinical trials, but, in daily clinical practice, patient outcomes are affected by various factors, such as general health, age, prior treatments, and lifestyle. Ramucirumab plus FOLFIRI is considered a standard treatment for CRC in patients who have disease progression after first-line treatment. In this study, we collected data from patients with CRC who were given ramucirumab plus FOLFIRI under routine clinical practice in Japan. Data were collected for 12 months from the start of treatment and based on various patient demographics such as age less than or greater than 75 years and treatment with a lower or higher dose of the anti-cancer drug irinotecan. We found that ramucirumab plus FOLFIRI is manageable in patients with CRC regardless of these patient demographics and initial irinotecan dose. This article aims to inform patients and primary care providers regarding real-world treatment outcomes to assist with CRC treatment decision making.

Safety and effectiveness of dulaglutide 0.75 mg in Japanese patients with type 2 diabetes in real-world clinical practice: 36 month post-marketing observational study.

AIMS/INTRODUCTION: This study evaluated the safety and effectiveness of dulaglutide in patients with type 2 diabetes in the real-world setting in Japan. MATERIALS AND METHODS: This prospective, observational post-marketing surveillance study was conducted for 36 months (July 2016 to July 2021) in Japan. Investigators reported data via an electronic data capture system. Data were analyzed by overall population and age group (<65, ≥65 to <75, and ≥75 years). RESULTS: The analysis population (N = 3,136) included 1,538 (49.04%), 869 (27.71%), and 729 (23.25%) patients aged <65 years, ≥65 to <75 years, and ≥75 years, respectively. Overall, 231 patients (7.37%) experienced ≥1 adverse drug reactions, with the highest frequency in the ≥75 years group. The most common adverse drug reactions were gastrointestinal disorders (n = 106; 3.38%). Severe hypoglycemia (n = 4; 0.13%), major adverse cardiovascular events (n = 4; 0.13%), and acute pancreatitis (n = 1; 0.03%) were uncommon. The mean glycated hemoglobin and bodyweight were reduced from baseline by -0.76% and -1.6 kg, respectively (last observation carried forward). The rate of dulaglutide continuation at 36 months was 58.03% overall and 59.43%, 63.13%, and 48.88% in the <65, ≥65 to <75, and ≥75 years groups, respectively. A factor analysis showed age ≥65 years was associated with a greater incidence of gastrointestinal adverse drug reactions as well as larger reductions in glycated hemoglobin and bodyweight. CONCLUSIONS: The current real-world data are in accordance with clinical trial findings and further confirm the safety and effectiveness of dulaglutide for elderly patients, whose numbers were limited in the clinical trials.

A post-marketing safety study of ramucirumab with FOLFIRI in patients with metastatic colorectal cancer.

Background: Ramucirumab [human vascular endothelial growth factor (VEGF) receptor-2 monoclonal antibody] + levofolinate, fluorouracil, and irinotecan (FOLFIRI) was approved for the treatment of metastatic colorectal cancer (CRC) in Japan based on the results from the phase 3 RAISE trial (NCT01183780). However, safety information of ramucirumab + FOLFIRI in the real-world setting is limited. Therefore, the present study was conducted to evaluate the safety of ramucirumab + FOLFIRI under routine clinical practice in patients with metastatic CRC (mCRC) after first-line chemotherapy. Methods: A single-arm, prospective, multicenter, non-interventional, observational study was conducted between August 2016 and May 2020. Patients with mCRC treated with ramucirumab + FOLFIRI for the first time were included. Patients were observed for 12 months from the start of ramucirumab. Data were recorded using the electronic data capture system. Results: In total, 362 patients with a mean age of 64.1 years were evaluated for safety, of whom 355 patients were evaluated for effectiveness. A higher proportion of the patients were males (n=200; 55.2%), had metastases and recurrent sites (n=362, 100.0%), and had received prior anti-cancer treatment (n=355; 98.1%). Approximately 83.7% (n=303) and 25.4% (n=92) of patients had medication history of bevacizumab and anti-epidermal growth factor receptor (EGFR) antibodies, respectively. Overall, 84.3% (n=305) of patients experienced any grade adverse events (AEs). Neutrophil count decreased (n=138; 38.1%), hypertension (n=58; 16.0%), and diarrhea (n=57; 15.7%) were observed frequently. The clinically relevant grade ≥3 AEs of special interest (AESIs) with >2% incidence included neutropenia (n=101; 27.9%), hypertension (n=35; 9.7%), proteinuria (n=23; 6.4%), hepatic dysfunction (n=15; 4.1%), febrile neutropenia (n=10; 2.8%), and leukopenia (n=9; 2.5%). The presence of renal disease at baseline increased the risk of proteinuria [risk ratio: 2.1; 95% confidence interval (CI): 1.1-4.2]. Three deaths were reported due to AEs, of which 1 was study treatment related. The 12-month survival rate of the ramucirumab + FOLFIRI regimen was 59%, mortality mainly (90%) occurring due to progressive disease. Conclusions: Although the current observational study enrolled patients with various medication history, the regimen of ramucirumab + FOLFIRI was manageable under clinical practice. No new safety concerns beyond the findings observed in previous clinical trials were reported.

Safety and effectiveness of ramucirumab and docetaxel: a single-arm, prospective, multicenter, non-interventional, observational, post-marketing safety study of NSCLC in Japan.

BACKGROUND: This study evaluated the safety and effectiveness of ramucirumab and docetaxel for non-small cell lung cancer (NSCLC) in real-world settings. RESEARCH DESIGN AND METHODS: This single-arm, prospective, multicenter, non-interventional, post-marketing study was conducted in Japan between August 2016 and January 2020. Patients diagnosed with unresectable advanced/recurrent NSCLC were eligible for study inclusion. Data on adverse events (AEs) and survival were collected electronically. RESULTS: Of 401 enrolled patients, 398 were eligible for study inclusion. Most patients were male (68.6%) with a median age of 67.0 years. Patients were predominantly diagnosed with adenocarcinoma (78.1%) or squamous cell carcinoma (16.6%); 46.2% received prior treatment with bevacizumab and 38.7% with immune-checkpoint inhibitors. AEs (any grade) were observed in 323 patients (81.2%; grade ≥ 3: n = 174, 43.7%). The most common AEs (any grade) were malaise (14.3%), decreased appetite (13.0%), and neutrophil count decrease (11.6%). At 12 months from treatment commencement, 93.2% of patients had discontinued, mostly due to progressive disease (53.4%) or AEs (28.3%). The 12-month survival rate was 56.7% (95% confidence interval: 51.5-61.8). CONCLUSIONS: Data from real-world settings demonstrate ramucirumab and docetaxel treatment appears to be tolerable and effective in Japanese patients regardless of patient baseline characteristics and prior treatment.

A post-marketing observational study of ramucirumab in patients with gastric cancer in Japan.

BACKGROUND: This study evaluated the safety and effectiveness of ramucirumab monotherapy and combination therapy for advanced gastric cancer in the real-world setting. METHODS: This single-arm, prospective, multicenter, non-interventional, observational, post-marketing study was conducted in Japan from August 2015 to March 2019. Patients with unresectable advanced or recurrent gastric cancer and newly prescribed ramucirumab were followed for up to 12 months after first treatment. Data on adverse events and survival were collected via Electronic Data Capture. RESULTS: Of 687 enrolled patients, 658 were eligible for analysis. Most patients received either ramucirumab monotherapy (123/658; 18.7%) or ramucirumab plus paclitaxel combination therapy (528/658; 80.2%). The majority of patients reported ≥ 1 adverse events in both the combination therapy (any grade, 479/528; 90.7%; ≥ Grade 3, 321/528; 60.8%) and monotherapy groups (any grade, 77/123; 62.6%; ≥ Grade 3, 42/123; 34.2%). The most common any grade adverse events were neutropenia (combination: 49.6%; monotherapy: 8.9%), fatigue (combination: 19.5%; monotherapy: 13.8%), and decreased appetite (combination: 18.2%; monotherapy: 10.6%). Grade 5 adverse events were reported in 4 patients, including metastases to meninges, pneumonia aspiration, death, and gastric perforation; of these, gastric perforation was deemed treatment-related. Median survival time was 5.7 months (95% confidence interval: 4.1-6.8 months) following monotherapy and 11.0 months (95% confidence interval: 9.8-12.2 months) following combination therapy. CONCLUSIONS: This analysis adds to the limited data available on ramucirumab use in a real-world setting, demonstrating similar safety and effectiveness for ramucirumab in treating advanced gastric cancer in routine clinical practice in Japan to that of global clinical trials.

Treatment satisfaction, safety, and effectiveness of biosimilar insulin glargine is comparable in patients with type 2 diabetes mellitus after switching from insulin glargine or insulin degludec: a post-marketing safety study.

OBJECTIVE: To evaluate insulin treatment satisfaction, safety, and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice for Japanese patients with type 2 diabetes mellitus (T2DM) who switched from originator insulin glargine (100 U/mL) or insulin degludec treatment to GLY treatment. METHODS: The Insulin Treatment Satisfaction Questionnaire (ITSQ) was used to assess treatment satisfaction in a subgroup analysis of a post-marketing safety study. Hypoglycemia incidence rates and blood glucose control are also reported during the 12-month observation period for GLY-switched patients. RESULTS: Of 1104 patients with T2DM enrolled to participate, 565 patients switched from either insulin glargine U100/mL (n = 470) or insulin degludec (n = 95) to GLY. The mean total change from baseline to 3 months for total ITSQ score was 1.35 (95% confidence interval [CI] - 0.13 to 2.83, p = .073) for patients who switched from insulin glargine and 2.63 (95% CI -1.43 to 6.70, p = .195) for patients who switched from insulin degludec to GLY treatment. The mean change from baseline to 12 months in hypoglycemia events reported per month was -0.04% (95% CI -0.12 to 0.03, p = .236) for patients who switched from insulin glargine and no change for patients who switched from insulin degludec (0.00, 95% CI -0.20 to 0.20, p = 1.000). Non-significant mean changes from baseline to 12 months were observed for hemoglobin A1c and fasting plasma glucose in GLY-switched patients. CONCLUSIONS: Treatment satisfaction does not change significantly in Japanese patients with T2DM who switch to GLY from the reference product or from insulin degludec. Safety and effectiveness over a 12-month period were similar in GLY-treated patients who switched from either insulin glargine or insulin degludec. CLINICALTRIALS.GOV: Not applicable.

[Incidence of Proteinuria among Japanese Colorectal Cancer Patients after Receiving Ramucirumab-Cohort Study Using Claim Database].

We evaluated the incidence of proteinuria after receiving ramucirumab for the patients with advanced colorectal cancer using claim database. Among 1,706 evaluable patients, incidence proportion of proteinuria was 21.8% and incidence rate (/100 person-years)was 75.3. In patients with history of proteinuria or previous bevacizumab use, incidence rate was high and many patients tend to occur proteinuria in the early stage after initiating ramucirumab prescription. Appropriate management by periodical monitoring from the early stage after initiating ramucirumab prescription is important.

Long-term safety and effectiveness of biosimilar insulin glargine in Japanese patients with diabetes mellitus in routine clinical practice: results of a post-marketing safety study.

Objective: To evaluate the long-term safety and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice.Methods: This prospective, non-interventional, multicenter, observational, post-marketing safety study (PMSS) enrolled Japanese patients with type 1 or 2 diabetes mellitus (T1DM or T2DM) starting GLY therapy, and was required by Japanese Pharmaceutical Affairs Law mandating post-marketing safety surveillance to acquire safety and effectiveness data of biosimilar products. Data collected from the 12-month observation included patient characteristics, adverse events, and blood glucose control.Results: The study enrolled 141 patients with T1DM and 1104 patients with T2DM. Pre-study insulin was used by 94.1% of patients with T1DM and 75.0% with T2DM. 65.4% of patients with T1DM and 64.3% with T2DM switched from the reference product (GLY-switched), while 25.0% with T2DM were insulin-naive. Adverse events were reported by 5.7% and 8.5% in T1DM and T2DM, respectively. Similar incidences were reported in GLY-switched. Adverse events were reported by 10.7% in insulin-naive T2DM. Baseline mean hypoglycemic events/month were 1.8 and 0.1 in T1DM and T2DM, respectively: the mean change from baseline (CFB) was -1.2 (p = .066) and 0.0 (p = .915), respectively. Baseline mean HbA1c was 8.4% and 8.7% in T1DM and T2DM, respectively; the mean CFB was -0.5% (p < .001) and -0.9% (p < .001), respectively, and -1.5% (p < .001) in insulin-naive T2DM.Conclusions: This first long-term Japanese PMSS of GLY demonstrated adverse events, hypoglycemia, and glycemic control consistent with the known GLY profile for T1DM and T2DM patients, in routine clinical practice.

Dose-escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma.

B-cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti-BAFF monoclonal antibody. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m(2) . All patients had treatment-emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose-limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438).

[Safety profiles of gemcitabine hydrochloride(GEMZAR®)in Japanese clinical studies].

To elucidate the detailed profiles of major adverse events associated with gemcitabine hydrochloride, such as myelosuppression and interstitial pneumonitis (IP), we reanalyzed the results from Japanese clinical studies conducted by Eli Lilly Japan K. K. in patients with various types of cancer. Myelosuppression was clearly apparent after starting therapy at 2-3 weeks in the 28- day course monotherapy group, and at 2 weeks in the 21-day course combination therapy group with paclitaxel, cisplatin, or docetaxel. Increases in the number of courses did not necessarily lead to worsening of myelosuppression. IP possibly related to gemcitabine was seen in 6 out of 5 23 monotherapy patients and 5 out of 233 combination therapy patients. Five of these 11 patients were diagnosed in the first course; however, another patient was diagnosed with IP in Course 6. Two of these patients died of IP, one of whom had a past history of interstitial lung disease. These results indicate that ample attention should be paid to myelosuppression 2-3 weeks after the start of therapy, and to IP during the entire course of therapy.