Safety in Japanese Advanced Breast Cancer Patients Who Received Abemaciclib in MONARCH 2 and MONARCH 3: Assessment of Treatment-Emergent Neutropenia, Diarrhea, and Increased Alanine Aminotransferase and Aspartate Aminotransferase Levels.

Purpose: Our objective was to gain a better understanding of the safety of abemaciclib in Japanese patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Patients and Methods: Treatment-emergent adverse events (TEAEs) were assessed in pooled Japanese subpopulation data from two phase 3 studies assessing abemaciclib/placebo in combination with fulvestrant (MONARCH 2; M2) or non-steroidal aromatase inhibitors (MONARCH 3; M3). For common, clinically relevant TEAEs, event characteristics and management were summarized by study. Results: In the Japanese safety subpopulation (abemaciclib: N=101; placebo: N=46), all patients experienced ≥1 TEAE (Grade ≥ 3: abemaciclib, 71.3%; placebo, 23.9%; no Grade 5). Clinically relevant TEAEs that were more frequent in abemaciclib-treated Japanese patients compared to the overall safety populations included diarrhea (any grade, 95.0%; Grade ≥ 3, 12.9%), neutropenia (any grade, 75.2%; Grade 3-4, 35.6%), increased alanine aminotransferase (ALT; any grade, 39.6%; Grade 3-4, 14.9%), and increased aspartate aminotransferase (AST; any grade, 37.6%; Grade 3-4, 8.9%). Diarrhea was Grade ≤3 and successfully managed with medications (≥87%) and dose reductions (≤25%) and/or omissions (≤23.3%). Most Grade ≥2 diarrhea occurred in the first treatment cycle, declining thereafter. Neutropenia, the most common Grade ≥3 TEAE in abemaciclib-treated Japanese patients, was generally manageable with dose omissions (M2: 42.0%; M3: 23.1%) and/or reductions (M2: 16%; M3: 15.4%). Neutrophil counts plateaued after Cycle 2, recovering to pretreatment levels after discontinuation of abemaciclib. Hepatic events were managed with medication (≤21%) and dose adjustments (≤33.3%), with most Grade ≥2 events occurring in early treatment cycles. Discontinuation of any study treatment in Japanese patients occurred more frequently due to increased ALT/AST (M2: 9.1%/10.5%; M3: 16.7%/10.5%) compared with diarrhea (M2: 0%; M3: 2.8%) or neutropenia (M2: 0%; M3: 3.8%). Conclusion: Abemaciclib was well tolerated in Japanese patients in MONARCH 2 and MONARCH 3, with common, clinically relevant TEAEs manageable with appropriate interventions.

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.

[Development of CDK4 & 6 Inhibitor Abemaciclib in Breast Cancer].

Abemaciclib is a selective cyclin-dependent kinase(CDK)4 & 6 inhibitor, which induces G1 cell cycle arrest and tumour growth inhibition. Abemaciclib has been developed for use in hormone receptor positive(HR+)breast cancer, dosed daily in combination with endocrine therapy. In a phase Ⅲ clinical trial, MONARCH 2, for women with HR+ and human epidermal growth factor receptor 2 negative(HER2-)advanced breast cancer who progressed after endocrine therapy, abemaciclib in combination with fulvestrant significantly improved not only progression-free survival and objective response rate but also overall survival, and demonstrated a tolerable safety profile. Another phase Ⅲ clinical trial, MONARCH 3, for women with HR+ and HER2- advanced breast cancer, abemaciclib in combination with nonsteroidal aromatase inhibitor as an initial therapy also significantly improved progression-free survival and objective response rate. This review presents the rationale for the use of CDK4 & 6 inhibitors in the treatment of breast cancer, background on the development of abemaciclib, clinical data focusing on phase Ⅲ studies of abemaciclib, and information on ongoing clinical studies of abemaciclib.

Clinical Impact of a Shortened Infusion Duration of Ramucirumab in Japanese Patients -A Model-Based Approach.

AIM: We evaluated the safety and potential clinical impact of shortened ramucirumab infusion in Japanese patients from clinical studies. METHODS: Multivariate logistic regression analysis was used to assess any association between infusion rate and increased risk of an immediate infusion-related reaction(IRR). Population pharmacokinetic modeling was used to simulate concentration-time profiles and exposure parameters following a 30- or 60-minute infusion with ramucirumab. RESULTS: From 8 pooled ramucirumab clinical studies, 55 of 559(9.8%)Japanese patients experienced at least one immediate IRR(any grade). When grouped according to infusion rate quartile, the incidence of immediate any-grade IRR was similar across quartiles. Infusion rate was not significantly associated with an increased risk of an immediate IRR; odds ratio per 1 mg/min increase was 0.912, 95% confidence interval 0.724 to 1.149, p=0.436. Patients aged ≥65 years may have a reduced risk of an immediate IRR compared with those aged <65 years, and premedication use was also associated with a reduced risk. Ramucirumab pharmacokinetic profiles were comparable following a 30- or 60-minute infusion. CONCLUSIONS: A shortened infusion duration of ramucirumab is unlikely to affect the efficacy or safety profile in Japanese patients and may be clinically beneficial for patients and health care providers. CLINICAL TRIAL REGISTRATION: RAINBOW-NCT01170663, RAISE- NCT01183780, REACH-NCT01140347, REACH-2-NCT02435433, RAINFALL-NCT02314117, RANGE-NCT02426125, RELAY-NCT02411448, I4T-MC-JVCG-NCT01703091.

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.

Characteristics of interstitial lung disease in patients from post-marketing data on metastatic breast cancer patients who received abemaciclib in Japan.

BACKGROUND: This study evaluated characteristics of patients treated with abemaciclib and diagnosed with interstitial lung disease (ILD), using 12-month post-marketing data from the real-world setting in Japan. METHODS: Spontaneous reports of adverse events in patients receiving abemaciclib were collected regularly from healthcare providers (HCPs) from November 30, 2018, to November 29, 2019. Detailed follow-up was requested on suspected ILD cases via questionnaires and/or interviews. Radiological images (when available) were reviewed by an ILD adjudication committee of specialists. The age distribution of patients prescribed abemaciclib in Japan was estimated based on insurance claims data. RESULTS: Of 4700 patients estimated to be exposed to abemaciclib, 82 cases of ILD were reported (46 serious, 13 fatal). Most (91%) had ≥ 1 symptom at diagnosis, commonly dyspnea/shortness of breath (59%), cough (44%), and/or fever (37%). The majority (68%) received steroid therapy (24 [56%] recovered/recovering; 5 [12%] not recovered; 13 [30%] deaths, 1 [2.3%] unknown). No specific imaging patterns or sites of predilection were identified, but a diffuse alveolar damage (DAD) pattern was observed at outcome in 3 of 4 evaluated fatal cases (16 in total evaluated). Features of fatal cases included advanced age, pre-existing interstitial change, and advanced Eastern Cooperative Oncology Group Performance Status. CONCLUSION: Advanced age and a DAD pattern were identified as potential risk factors for cases with poorer outcomes, as previously reported for drug-induced ILD. HCPs should consider the benefit-risk profile when prescribing abemaciclib, informing patients of risks and regularly monitoring treated patients to ensure early detection and treatment of ILD.

[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.