Risk factors for recurrence in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer in Japan: a systematic literature review and meta-analysis.

BACKGROUND: The clinicopathological factors indicating risk of recurrence are used to guide the choice of perioperative therapy in patients with breast cancer. Although several risk factors for recurrence have been reported in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer in Japan, there has been no systematic review quantifying potential risk factors. METHODS: We performed a systematic literature review and meta-analysis using the MEDLINE, Embase, Cochrane CENTRAL, and Japan Medical Abstract Society databases to identify risk factors for recurrence in HR+/HER2- early breast cancer in Japan. The primary outcome was relapse-free or disease-free survival (RFS/DFS), and the secondary outcomes were overall survival and breast cancer-specific survival (BCSS). RESULTS: Searches identified 42 eligible publications. Meta-analyses identified lymph node metastasis (hazard ratio: 2.76 [95% confidence interval: 1.97-3.88]), large tumor size (1.67 [1.24-2.23]), high histological grade (1.50 [1.04-2.16]), and high nuclear grade (2.02 [1.61-2.54]) as risk factors for RFS/DFS. Lymph node metastasis (2.43 [1.28-4.63]), large tumor size (1.80 [1.24-2.62]), and high histological grade (2.02 [1.44-2.84]) were also risk factors for overall survival, and high progesterone status was a possible favorable prognostic factor for BCSS (0.20 [0.10-0.42]). CONCLUSIONS: Identified risk factors were consistent with the previous reports, and this study provides quantitative summary of risk factors for HR+/HER2- early breast cancer recurrence in Japan. (PROSPERO Registration ID, CRD42022338391.).

Impact of Migraine on Daily Life: Results of the Observational survey of the Epidemiology, Treatment, and Care of Migraine (OVERCOME [Japan]) Study.

INTRODUCTION: The impacts of migraine on daily life, including daily activities and fundamental health indicators (sleep and mental health), have not been described in detail for people with migraine in Japan. METHODS: The cross-sectional ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) study was conducted between July and September 2020. Impacts of migraine on housework, family/social/leisure activities, driving, and sleep were assessed using questions from the Migraine Disability Assessment (MIDAS), Migraine-Specific Quality-of-Life Questionnaire, and Impact of Migraine on Partners and Adolescent Children scales and questions developed for OVERCOME (Japan). The Migraine Interictal Burden Scale (MIBS-4) evaluated burden on days without headaches. Depression and anxiety were assessed with the Patient Health Questionnaire (PHQ-8) and Generalized Anxiety Disorder (GAD-7) scales, respectively. Impacts on daily life were also described across MIDAS/MIBS-4 categories. RESULTS: Among 17,071 respondents with migraine, 24.8% required assistance with housework at least sometimes. Migraine interfered with relationships, leisure, and social activities at least sometimes for 31.8%, 41.6%, and 18.0% of respondents, respectively. Between headache days, 26.8% of respondents worried about planning social/leisure activities at least sometimes. Among respondents living with family (N = 13,548), migraine also had impacts on participation in and enjoyment of family activities. Among respondents who drove (N = 10,921), 43.9% reported that symptoms interfered with driving at least sometimes. Migraine interfered with sleep and mood at least sometimes for 52.7% and 70.7% of respondents, respectively. PHQ-8 and GAD-7 thresholds for clinical depression and anxiety were met by 28.6% and 22.0% of respondents, respectively. Impact of migraine on daily life increased with increasing severity of MIDAS/MIBS-4 categories. CONCLUSION: The burden of migraine on daily activities, sleep, and mental health is substantial for people with migraine in Japan. In clinical practice, it is important to evaluate the impact of migraine on daily life in addition to migraine symptoms.

Treatment patterns in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma post covalent Bruton tyrosine kinase inhibitor treatment: a Japanese claims database study.

Standard treatment has not been established for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after discontinuation of covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. This retrospective, administrative database (Medical Data Vision) study described the patient characteristics, treatment patterns, and factors associated with receiving post-first-cBTKi treatment in Japanese patients with CLL/SLL. Patients aged ≥18 years with confirmed CLL/SLL diagnosis and treated with anti-neoplastic drugs indicated for CLL/SLL between March 2013 and February 2022 were included. Patient characteristics at baseline (first line), first cBTKi exposure (first-cBTKi), post-first-cBTKi treatment received, and the treatment sequence of CLL drugs received first line through third line, were described. Time-to-event analyses used the Kaplan-Meier method. Multivariable logistic regression analysis was used to explore factors associated with receiving post-first-cBTKi treatment among patients who discontinued first-cBTKi treatment. Among 2,424 eligible patients (median age: 72.0 years, 61.9% male), 450 (18.6%) received cBTKi in any treatment line. Among patients treated with cBTKi, 273 (60.7%) discontinued treatment; 56.0% of them (n = 153/273) received subsequent treatment. Median duration of post-first-cBTKi treatment was 2.2 months (95% confidence interval [CI]: 1.8, 3.5). The most common regimens post-first-cBTKi were cBTKi therapy (47.7%), bendamustine-based therapy (17.0%), and venetoclax-based therapy (13.1%). Patients aged <75 years (odds ratio [OR] [95% CI]: 2.0 [1.2, 3.4]) and those who did not receive blood transfusion during cBTKi treatment (OR [95% CI]: 2.3 [1.3, 4.1]) were more likely to receive post-first-cBTKi treatment. In conclusion, Japanese patients with CLL/SLL received various treatments for short duration after first-cBTKi discontinuation.

[Impact of migraine on family members: an investigation by Impact of Migraine on Partners and Adolescent Children (IMPAC)].

Using the Japanese version of the Impact of Migraine on Partners and Adolescent Children (IMPAC) and Family Question prepared based on IMPAC, we investigated the impact of migraine on family members from the perspectives of both patients and their family members. Our results showed that migraine had an impact on the family members living with the patients in Japan as well, and the perception of migraine differed partially between patients and their family members. We also found that the Japanese version of the IMPAC showed a correlation with existing instruments to evaluate impact of migraine, indicating its validity. The application of this study's findings in clinical practice could help alleviate the disease burden of migraine on patients and their family members.

[Ramucirumab Treatment for Unresectable Advanced Hepatocellular Carcinoma-A Review of Clinical Trial Data and Real-World Evidence in Japan].

Ramucirumab was approved in June 2019 in Japan for the treatment of patients with unresectable advanced hepatocellular carcinoma(HCC)with serum alpha-fetoprotein ≥400 ng/mL, whose disease had worsened following chemotherapy. According to the Japan Society of Hepatology clinical practice guidelines for HCC revised in 2021, treatment with ramucirumab is recommended as second-line or subsequent systemic therapy for patients with Child-Pugh class A liver function and serum alpha-fetoprotein ≥400 ng/mL who have discontinued treatment with sorafenib because of radiologic progression or adverse events. To assess the efficacy and safety of treatment with ramucirumab in Japanese clinical practice for patients with unresectable advanced HCC, we reviewed evidence from original articles published after 2019, when ramucirumab was approved as a treatment for HCC in Japan. In addition, we evaluated a pooled data analysis of 2 global phase 3 studies(REACH and REACH-2), in which ramucirumab was administered as second-line therapy after the treatment of sorafenib in patients with unresectable advanced HCC, and the results of the REACH-2 expansion cohort of patients who received ramucirumab after systemic therapy other than sorafenib.

Real-world clinical profile, treatment patterns and patient-reported outcomes for thyroid cancer in Japan.

Aim: To provide a real-world snapshot of the clinical profile, management, and patient-reported outcomes (PRO) for advanced medullary and papillary thyroid cancer prior to the availability of rearranged during transfection (RET) inhibitors in Japan. Materials & methods: Physicians completed patient-record forms for eligible patients seen during routine clinical practice. Physicians were also surveyed about their routine practice and patients were asked to provide PRO data. Results: RET testing patterns varied by hospital type; no therapeutic relevance was a commonly cited reason to not carry out testing. Multikinase inhibitors were the main systemic therapies prescribed, although timing to start multikinase inhibitors varied; adverse events were reported as challenges. PROs revealed high disease/treatment burden. Conclusion: More effective and less toxic systemic treatment targeting genomic alterations is needed to improve long-term outcomes of thyroid cancer.

This survey, conducted in Japan in 2020, included doctors who treat thyroid cancer and their patients. It is called a real-world survey because it provides information such as the types of tests and treatments used for thyroid cancer management in everyday clinical practice. The survey focused on two types of thyroid cancer: papillary thyroid cancer (PTC), a common type, and medullary thyroid cancer (MTC), an uncommon type. About 10­20% of people with PTC and most people with MTC have alterations in a gene called RET, which caused the cancer. Laboratory tests can identify these gene alterations, fusions (joining the parts of two different genes) or mutations (changes to a gene's DNA sequence) and results can help guide treatment decisions. The survey showed that testing for RET gene alterations was less than optimal and varied by the type of hospital/center. Common reasons provided by doctors for not testing for RET alterations were, "no therapeutic relevance for patient management" and "specific targeted therapies not available". However, the survey was conducted before the availability in Japan of the treatment selpercatinib, which selectively targets/inhibits tumors with RET alterations. Most patients in the survey, including those with RET alterations, received treatment with a type of inhibitor called multikinase inhibitors, as per available guidelines. Doctors considered side effects due to inhibition of multiple targets by multikinase inhibitors to be among areas for improvement needed. People with PTC and MTC also reported substantial burdens (i.e., negative impact on their lives) from the disease/treatment. The researchers concluded that barriers to RET testing need to be overcome, and more effective and less toxic treatments targeting gene alterations are needed to improve long-term outcomes.

Patient characteristics, treatment patterns, and outcomes of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer patients prescribed cyclin-dependent kinase 4 and 6 inhibitors: large-scale data analysis using a Japanese claims database.

PURPOSE: The aim was to understand real-world cyclin-dependent kinase (CDK) 4 and 6 inhibitor use in Japan. METHODS: This retrospective observational study used a Japanese administrative claims database and included patients with presumptive hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) prescribed CDK4 and 6 inhibitor therapy between December 2017 and March 2021. Patient characteristics, treatment patterns, and selected clinical and safety outcomes were descriptively summarized. Time to discontinuation (TTD) and chemotherapy-free survival (CFS) were examined using Kaplan-Meier estimates. RESULTS: The study cohort (N = 6442) was predominantly female (99.4%; median [range] age 64 [26-99] years) with records of metastases (79.6%) within 1 year prior to initiating CDK4 and 6 inhibitor therapy. In total, 4463 (69.3%) and 1979 (30.7%) were prescribed palbociclib and abemaciclib, respectively, as their first CDK4 and 6 inhibitor, most commonly in combination with fulvestrant (n = 3801; 59.0%). Overall, 3756 patients initiated a subsequent anticancer treatment, of whom 748 (19.9%) initiated a different CDK4 and 6 inhibitor in combination with the same or different endocrine therapy. Median TTD (95% confidence interval) was 9.7 (9.3, 10.1) months for the first CDK4 and 6 inhibitor therapy. Median CFS was 26.1 (24.6, 27.8) months. Incidence of clinically relevant diarrhea was higher after abemaciclib initiation (9.8%) than after palbociclib initiation (1.5%). More patients experienced dose reduction with palbociclib (69.3%) than with abemaciclib (53.0%). CONCLUSION: The data provide insights into current clinical practices for CDK4 and 6 inhibitor use in Japan that could help establish future treatment strategies for ABC.

Multikinase Inhibitor Treatment Patterns for Advanced Thyroid Cancer in Japan: An Administrative Claims Database Study.

BACKGROUND: The multikinase inhibitors (MKIs) sorafenib, lenvatinib, and vandetanib are approved for advanced thyroid cancer (TC) in Japan. How sequential treatment with MKIs is conducted in Japanese clinical practice is unknown. METHODS: This retrospective observational cohort study used a Japanese administrative claims database (April 2008-September 2021). Patients with a confirmed TC subtype diagnosis of papillary (PTC), follicular (FTC), medullary (MTC), or anaplastic (ATC), who received MKI treatment after TC diagnosis within the index period (June 2014-August 2021), were included. Overall MKI treatment duration was estimated by Kaplan-Meier analysis. RESULTS: The analysis population included 795 patients (PTC, N = 447; FTC, N = 86; MTC, N = 32; ATC, N = 230). Median age was ≥ 64 years; most patients (> 60%) were female except for the MTC subgroup (43.8%). First-line (1L) MKI treatment was mainly lenvatinib for PTC (81.7%), FTC (83.7%), and ATC (97.8%), and vandetanib for MTC (62.5%). Among patients discontinuing 1L MKI treatment and evaluable for subsequent therapy [PTC: 57.9% (259/447); FTC: 48.8% (42/86); MTC: 62.5% (20/32); ATC: 70.4% (162/230)], 26.3% (68/259), 21.4% (9/42), 50.0% (10/20), and 4.9% (8/162) of PTC, FTC, MTC, and ATC patients, respectively, received second-line (2L) treatment. Median (95% CI) overall MKI treatment duration was 21.2 (17.9-27.5), 43.9 (30.9-not assessable), 39.0 (17.7-not assessable), and 4.0 (3.0-4.8) months for PTC, FTC, MTC, and ATC, respectively. CONCLUSION: Advanced TC treatment options are limited. In this study, most patients received only 1L MKI treatment; of those who discontinued 1L, ≤ 50% progressed to 2L.

Real-World Patient Characteristics, Treatment Patterns, and Outcomes of HR+, HER2- Early Breast Cancer Patients in Japan: An Analysis with National Database(NDB).

Real-world evidence for clinical outcomes and treatment patterns in patients with hormone receptor-positive(HR+)and human epidermal growth factor receptor 2-negative(HER2-)early breast cancer(EBC)in Japan is limited. We aimed to provide recent evidence in this population using the National Database of Health Insurance Claims and Specific Health Check-ups of Japan(NDB). Adults ≥20 years old who were diagnosed with HR+/HER2- breast cancer and underwent breast resection surgery were followed up. Patient characteristics and treatment patterns were evaluated. Durations of overall post-operative endocrine therapy(ET)and luteinizing hormone-releasing hormone(LH-RH)agonist therapy, and time to metastasis/recurrence after surgery were analyzed using Kaplan-Meier method. Overall, 294,904 patients were included. Cyclophosphamide and tamoxifen were the most common peri-operative chemotherapeutic and ET drugs. Median(95% confidence interval[CI])duration of post-operative ET and LH-RH agonist therapy was 5.01(5.01-5.01)years and 2.13 (2.12-2.14)years, respectively. Five-year cumulative rate(95% CI)of any recurrence was 8.6%(8.5-8.7), visceral metastasis being the most common. Nation-wide treatment patterns were described, which were consistent with guideline recommendations for patients with HR+, HER2- EBC. Further discussion is required to delay metastasis/recurrence and improve clinical outcomes(Fig. 1: Plain language summary of the study).

Patients' Preferences for Attributes of Molecular Targeting Therapies for Advanced Non-Small Cell Lung Cancer with EGFR Mutations in Japan-A Discrete-Choice Experiment.

AIM: This study aims to evaluate Japanese patients' preferences in first-line therapy choice for advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutations. METHODS: A cross-sectional discrete-choice experiment was conducted on advanced NSCLC patients in Japan. Participants completed the online questionnaire that included different levels of 5 treatment attributes: time to disease progression, chance of rash, next therapy option, frequency of health care visits and administration route. The primary analysis estimated the relative attribute importance. The preferences of EGFR mutation-positive patients were compared with those of EGFR mutation-negative/unknown patients to observe whether preference differs by mutation status. RESULTS: A total of 158 participants completed the survey. The analysis on the overall study population revealed next therapy option(mean relative attribute importance[SD]: 39.30 [17.07])as the most important attribute, followed by time to disease progression(25.52[10.51]), chance of rash(21.58 [11.74]), with administration route(7.63[6.99])and frequency of health care visits(5.96[3.40])the least preferred. The results in the subgroups by EGFR mutation status were similar. CONCLUSION: Next therapy option is the major influencing factor for treatment choice of molecular targeting therapy among advanced NSCLC patients in Japan, emphasizing the importance of communicating the next treatment options to patients at the time of their first treatment.

Outcomes for Recurrent Mantle Cell Lymphoma Post-Ibrutinib Therapy: A Retrospective Cohort Study from a Japanese Administrative Database.

INTRODUCTION: Treatment options in patients with mantle cell lymphoma (MCL) failing ibrutinib are limited, with no standard therapies defined. This study aimed to investigate real-world treatment patterns and outcomes for patients with MCL following ibrutinib. METHODS: This study utilized a de-identified hospital-based claims database (Medical Data Vision) in Japan. Eligible patients were adults who were diagnosed with MCL and had received antitumor drugs between December 2010 and July 2020. Patients were followed from the first antitumor drug treatment until the end of available data up to July 2021. Time-to-event analyses utilized the Kaplan-Meier method. Factors for receiving post-ibrutinib therapy were explored with logistic regression analysis. RESULTS: Of the 1386 patients who started antitumor drug therapy, 247 patients received and discontinued ibrutinib at any line of therapy. Among them, 137 patients (55.5%) received subsequent therapy. The median age at the end of ibrutinib therapy was 77 (range 42-95), and 44 patients had a dependent activity of daily living (ADL). Factors negatively associated with receiving post-ibrutinib therapy after discontinuation of ibrutinib were age ≥ 75 years (odds ratio [95% CI] 0.46 [0.26-0.80]) and emergency hospital admissions (0.37 [0.17-0.84]). Immediate post-ibrutinib therapy regimens were highly diverse, with BR (bendamustine, rituximab) only prescribed in more than 10% of patients. The median duration of post-ibrutinib therapy was 1.5 months (95% CI 1.07-2.07). The median overall survival from the end of ibrutinib therapy in patients regardless of the receipt of post-ibrutinib therapy (n = 247), in those who did not receive post-ibrutinib therapy (n = 110), and in those who received post-ibrutinib therapy (n = 137) was 5.6 months (95% CI 3.8-8.7), 2.3 months (95% CI 1.2-3.9), and 8.7 months (95% CI 5.6-13.8), respectively. The most common adverse event during post-ibrutinib therapy was infection, with the use of anti-infectives (17%). CONCLUSIONS: Patients with MCL previously treated with ibrutinib have poor ability to carry out ADL and experience very poor outcomes. New safe, effective therapies are needed.

Real-World Data Analysis of Second-Line Antiangiogenic Targeted Treatments Following Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies and First-Line FOLFOX for Patients with Metastatic Colorectal Cancer.

INTRODUCTION: Evidence is lacking on second-line and later treatments for patients with RAS wild-type colorectal cancer (CRC) who receive first-line anti-epidermal growth factor receptor (EGFR) antibody therapy. In this study, we explored the real-world treatment sequences, treatment duration, and factors associated with treatment sequences and durations in Japanese patients with CRC. METHODS: This retrospective observational cohort study used a Japanese administrative claims database (April 2008 to July 2021). Patients with confirmed CRC (presumed RAS wild-type) who received first-line FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) plus anti-EGFR therapy in or after May 2016, followed by second-line irinotecan-based chemotherapy plus an antiangiogenic drug, were included. Treatment durations were estimated by the Kaplan-Meier method. Cox regression analysis was used to identify factors associated with treatment duration. RESULTS: Analysis populations consisted of 1163 (first-line and second-line) and 645 (third-line) patients. At the start of first-line therapy, 67.8% of patients were male, the mean age was 64 years, 83.4% had left-sided CRC, and 84.3% were prescribed FOLFOX plus panitumumab. For second-line therapy, patients were prescribed bevacizumab (63%), ramucirumab (27%), or aflibercept beta (10%). Median (95% CI) treatment durations from the start of second-line therapy to the end of antitumor drug therapies were similar for bevacizumab (12.5 months [11.2, 14.0]), ramucirumab (12.5 months [11.2, 14.8]), and aflibercept beta (14.0 months [10.4, 17.0]). Treatment duration from second-line was positively associated with first-line treatment duration of 6 months or more, CRC surgery before starting first-line therapy, and liver surgery during first-line therapy, and was negatively associated with use of nonsteroidal anti-inflammatory drugs before second-line therapy. CONCLUSION: Real-world data revealed that all three antiangiogenic drugs were used as second-line therapy after first-line anti-EGFR antibodies and showed similar treatment durations.

Japanese subgroup analysis of the phase 3 MONARCH 3 study of abemaciclib as initial therapy for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.

BACKGROUND: This was a Japanese subpopulation analysis of MONARCH 3, a randomized, double-blind, placebo-controlled phase 3 study of abemaciclib plus nonsteroidal aromatase inhibitors (NSAIs) for initial therapy for advanced breast cancer (ABC). METHODS: Eligibility included postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative ABC who had no prior systemic therapy in the advanced disease setting. Patients (N = 493) were randomized 2:1 to receive abemaciclib or placebo (150 mg) plus either 1 mg anastrozole or 2.5 mg letrozole (physician's choice). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), pharmacokinetics (PK), safety, and health-related quality of life (HRQoL). RESULTS: In Japan, 53 patients were randomized (abemaciclib, n = 38; placebo, n = 15). At final PFS analysis (November 3, 2017), median PFS was 29.1 and 14.9 months in the abemaciclib and placebo groups, respectively (hazard ratio 0.537; 95% confidence interval 0.224-1.289). ORR in measurable disease was 62.1 and 50.0% in the abemaciclib and placebo groups, respectively. The Japanese PK profile was comparable to that of the overall population. Consistent with prior studies, the most frequent adverse events reported were diarrhea (abemaciclib: any grade, 94.7%; grade ≥ 3, 10.5%; placebo: any grade, 46.7%; grade ≥ 3, 0%) and neutropenia (abemaciclib: any grade, 68.4%; grade ≥ 3, 21.1%; placebo: any grade, 0%). HRQoL outcomes were generally similar between treatments except for the diarrhea score, which favored placebo. CONCLUSIONS: Consistent with findings in the overall population, abemaciclib plus NSAI was an effective initial treatment in the Japanese subpopulation, with a manageable safety profile. CLINICAL TRIAL REGISTRATION: NCT02246621; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02246621 .

Treatment Pattern for Advanced Gastric Cancer in Japan and Factors Associated with Sequential Treatment: A Retrospective Administrative Claims Database Study.

INTRODUCTION: Clinical trials have proven the efficacy and safety of new therapies for advanced gastric cancer (AGC), but how those therapies are used in the real world is poorly described. Real-world treatment patterns of antitumor therapies and factors associated with overall therapy duration in patients with AGC in Japan were investigated. METHODS: This retrospective cohort study used a Japanese administrative claims database (June 2014 to September 2019). Patients with AGC who started the guideline-recommended first-line combination regimens with platinum and fluoropyrimidine agents between June 2015 and July 2019 were included. Cox regression analysis was performed to identify factors associated with overall therapy duration (first line to last administration of guideline-listed agent). RESULTS: Of the 10,581 patients included, the most common first-line combination regimen without trastuzumab was S-1 plus oxaliplatin (4327/9069 patients; 47.7%) and with trastuzumab was capecitabine plus cisplatin (608/1512 patients; 40.2%). Most common second- and third-line regimens were ramucirumab plus taxane (3650/5358 patients; 68.1%) and nivolumab (1229/2390 patients; 51.4%), respectively. Factors positively associated with longer overall therapy duration were: oral fluoropyrimidine in first line (hazard ratio [95% confidence interval]: 0.63 [0.57-0.69]); trastuzumab in any line (0.73 [0.68-0.78]); treatment at a designated cancer hospital (0.89 [0.84-0.94]); dietary consultation within 1 month before/after start of first line (0.92 [0.86-0.98]); and treatment at a surgical department (0.94 [0.89-0.99]). Negatively associated factors were: edema (1.21 [1.07-1.37]); physical therapy (1.21 [1.12-1.31]); nutritional intervention (1.21 [1.14-1.28]) within 1 month before/after start of first line; thrombosis (1.13 [1.04-1.23]); renal disease (1.11 [1.02-1.21]); age (1.07 [1.02-1.13]); and peritoneal metastasis/ascites (1.06 [1.01-1.13]). CONCLUSIONS: In real-world treatment practice for AGC in Japan, therapy choice after the recommended first-line chemotherapy was consistent with guidelines. Factors associated with overall therapy duration were identified, which may assist in optimizing treatment sequence.

A systematic literature review of prognostic factors in patients with HR+/HER2- advanced breast cancer in Japan.

BACKGROUND: Breast cancer is the most prevalent cancer in women in Japan and the fifth in mortality. This systematic review summarized the evidence for prognostic factors for patients with HR+/HER2- advanced and metastatic breast cancer in Japan. METHODS: MEDLINE and EMBASE were searched with keywords 'breast neoplasms' AND 'Japan' AND 'advanced' or equivalent, and Japan Medical Abstract Society database with 'breast cancer' AND 'advanced/metastatic' for publications from January 2010 to October 2019. ASCO, ESMO, ABC4 abstracts and WHO website were hand searched. The endpoints of interest were overall survival, progression-free survival, tumour response and post-progression survival. Factors were evaluated based on the consistency in direction and the strength (hazard ratios) of association. RESULTS: Searches identified 4530 publications, of which 27 were eligible. All were observational studies. Among the endpoints, overall survival was the most commonly assessed (n = 22) and evaluated further. Ki-67 expression, progesterone receptor expression status, tumour grade and lymph node metastases were consistently associated with poor overall survival in univariate analysis but not in multivariate analysis. Short disease-free interval, the number of metastatic organs and liver metastasis were consistently associated with poor overall survival in both of univariate and multivariate analysis. The association was strong for liver metastasis (hazard ratio ≥2.8 in the majority of studies) and moderate for disease-free interval and the number of metastatic organs (hazard ratio 1.3-2.8 in the majority of studies). CONCLUSIONS: Disease-free interval, the number of metastatic organs and liver metastasis were identified as independent prognostic factors for overall survival. These findings may help clinical decision-making to improve outcomes in patients with HR+/HER2- advanced and metastatic breast cancer.

[FOLFIRI plus Ramucirumab Treatment for Metastatic Colorectal Cancer-Narrative Review of Real-World Evidence in Japan].

To assess the efficacy and safety of ramucirumab in combination with FOLFIRI in patients with unresectable metastatic colorectal cancer under clinical practice in Japan, we reviewed manuscripts reporting clinical research, including case reports, of Japanese patients with FOLFIRI plus ramucirumab therapy published starting from 2016, when ramucirumab was approved as a treatment for metastatic colorectal cancer in Japan, to June 2020. We also reviewed an interim report of post-marketing surveillance study. The efficacy of ramucirumab in combination with FOLFIRI including irinotecan 150 mg/m2, which is the recommended dose in Japan and is used as initial dose in Japanese clinical practice, was similar to that of the global, phase 3 RAISE study with irinotecan 180 mg/m2. The desirable effect of FOLFIRI plus ramucirumab was observed in patients with wild-type RAS, primary tumors on the left sides(descending, sigmoid, or rectum colons), or who received anti-epidermal growth factor receptor agents, including panitumumab or cetuximab, as previous treatment. Also, the effectiveness of FOLFIRI plus ramucirumab as a late-line treatment was suggested. Several patients were reported to have nephrosis syndrome after starting ramucirumab, but they recovered with discontinuation of ramucirumab and appropriate treatment. No new safety concerns were observed from the literature or the interim report of post-marketing surveillance study.

[Exon 19 Deletion and Exon 21 L858R Point Mutation in EGFR Mutation‒Positive Non‒Small Cell Lung Cancer].

Epidermal growth factor receptor(EGFR)is a transmembrane receptor tyrosine kinase the signaling of which is important for growth and progression of cancer. An exon 19 deletion mutation and an exon 21 L858R point mutation are frequently detected as EGFR mutations in patients with non‒small cell lung cancer. This review summarizes the differences in epidemiological, nonclinical, and clinical characteristics between the exon 19 deletion mutation and the exon 21 L858R point mutation.

Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy.

BACKGROUND: This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). METHODS: Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety. RESULTS: In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380-1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390-1.463). CONCLUSIONS: Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population. CLINICAL TRIAL REGISTRATION: NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703 .

Association of Albumin-Bilirubin Grade and Sequential Treatment with Standard Systemic Therapies for Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study Using a Japanese Administrative Database.

BACKGROUND: Evidence about the relationship between albumin-bilirubin (ALBI) grade and sequential systemic therapy for advanced hepatocellular carcinoma in real-world Japanese clinical practice is limited. OBJECTIVE: The objective of this study was to investigate ALBI grades and sequential treatment for advanced hepatocellular carcinoma in Japanese clinical practice. METHODS: We conducted a retrospective cohort study using a Japanese hospital-based administration database to assess treatment sequence in patients with confirmed advanced hepatocellular carcinoma and first prescription (index line) of lenvatinib (July 2014-June 2019; N = 1558) or sorafenib (July 2014-June 2016 [sorafenib-A; N = 1511] or June 2017-June 2019 [sorafenib-B; N = 1276]). Transition to subsequent line was assessed in patients who completed the index line without transarterial chemoembolization. The ALBI grade and sequential treatment relationships were analyzed in patients with baseline and/or end of index line ALBI scores. RESULTS: Transition to a subsequent line was low (sorafenib-A [n = 1320]: 12.6%; sorafenib-B [n = 1049]: 40.7%; lenvatinib [n = 786]: 27.2%). In patients with baseline ALBI data (combined cohorts; n = 385), overall treatment duration was shorter in those with baseline ALBI grade 2b or 3 vs grade 1 or 2a (median: 7.1, 6.7, 4.5, and 3.0 months for grades 1, 2a, 2b, and 3, respectively). In patients with baseline and end of index line ALBI data (combined cohorts; n = 222), ALBI grade worsened during index line regardless of baseline grade. Of these patients in the sorafenib-B or lenvatinib cohorts who completed the index line without transarterial chemoembolization (n = 120), transition to a subsequent line was higher with the end of index line grade 1/2a (66.7/68.4%) than with grade 2b/3 (34.0/11.1%). CONCLUSIONS: Adequate liver function, indicated by ALBI grade, at the start and end of first-line treatment is associated with successful sequential therapy in Japanese clinical practice.

Treatment sequences of patients with advanced colorectal cancer and use of second-line FOLFIRI with antiangiogenic drugs in Japan: A retrospective observational study using an administrative database.

The objectives were to describe treatment sequences for advanced colorectal cancer (CRC), use of second-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) plus antiangiogenic drug (bevacizumab, ramucirumab, aflibercept beta) therapy, and the factors associated with the duration of antitumor drug treatment from second-line antiangiogenic therapy in Japan. This retrospective observational study was conducted using a Japanese hospital-based administrative database. Patients were enrolled if they started adjuvant therapy (and presumably experienced early recurrence) or first-line treatment for advanced CRC between May 2016 and July 2019, and were analysed until September 2019. Factors associated with overall treatment duration from second-line treatment with FOLFIRI plus antiangiogenic drugs were explored with multivariate Cox regression analysis. The most common first-line treatments were FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) with bevacizumab (presumed RAS-mutant CRC) and FOLFOX with panitumumab (presumed RAS-wild type CRC). The most common second-line treatments were FOLFIRI-based. Many patients did not transition to subsequent lines of therapy. For second-line treatment, antiangiogenic drugs were prescribed more often for patients with presumed RAS-mutant CRC, right-sided CRC, and independent activities of daily living (ADL). The median duration of second-line FOLFIRI plus antiangiogenic drug treatment was 4.5 months; 66.2% of patients transitioned to third-line therapy. Low body mass index and not fully independent ADL were significantly associated with shorter overall duration of antitumor drug treatment from second-line therapy. Left-sided CRC, presumed RAS-wild type CRC, previous use of oral fluoropyrimidines and use of proteinuria qualitative tests, antihypertensives, or anticholinergics during second-line therapy were significantly associated with longer treatment. Treatment of advanced CRC in Japan is consistent with both international and Japanese guidelines, but transition rates to subsequent therapies need improvement. In addition to antitumor drug treatment, better ADL, higher body mass index, management of hypertension, and proteinuria tests were associated with continuation of sequential therapy that included antiangiogenic drugs.