Postmarketing surveillance of nivolumab plus ipilimumab combination therapy in Japanese patients with unresectable malignant melanoma.

Although malignant melanoma is relatively rare in Japan, it is often diagnosed at a later stage than in Western countries. Nivolumab and ipilimumab are immune checkpoint inhibitors targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein 4, respectively. Owing to their complementary anticancer effects, nivolumab and ipilimumab combination therapy (N + I) has been studied and approved for treating malignant melanoma in various countries including Japan. Real-world postmarketing surveillance was implemented to record treatment-related adverse events (TRAEs) in patients treated with N + I following its approval in Japan. Patients were eligible for registration if they had unresectable malignant melanoma and started N + I between September 2018 and August 2019. The observation period was 13 weeks from starting N + I. Only safety information was collected and evaluated. The final case report form lock was March 2021. Overall, 173 patients (median age, 66.0 years; performance status 0-1, 88.4%; skin: 53.2%; mucosal: 32.4%) were eligible for the analyses. Overall, 34.1% of patients completed 4 doses of N + I. N + I was discontinued by 63.0% (due to adverse events in 67.9% and disease progression/death in 22.9%). Any grade and grade ≥3 TRAEs were reported in 73.41% and 52.02%, respectively. TRAEs in ≥10 patients were hepatic function abnormal (any grade/grade ≥3: 23.12%/13.29%), pyrexia (10.40%/0.58%), diarrhea (9.25%/2.89%), rash (8.67%/0.58%), hypophysitis (5.78%/5.20%), interstitial lung disease (5.78%/2.89%), and liver disorder (5.78%/4.62%). TRAEs were classified as recovered (36.99% of patients), recovering (44.51%), unrecovered (13.29%), recovered with sequelae (2.31%), and death (1.73%). Overall, 24 of 34 patients (70.59%) with gastrointestinal-related and 53 of 65 (81.54%) liver-related TRAEs received treatment, such as a steroid with/without an immunosuppressant; most patients recovered within 1 to 2 months. In conclusion, this postmarketing surveillance of N + I in patients with unresectable malignant melanoma revealed no new safety concerns compared with results of prior studies. Immune-related TRAEs were generally manageable by appropriate treatment including a steroid.

The safety profile of nivolumab plus ipilimumab combination therapy in Japanese patients with renal cell carcinoma: results from post-marketing surveillance.

BACKGROUND: Nivolumab and ipilimumab combination therapy is approved in Japan for unresectable or metastatic renal cell carcinoma. Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. METHODS: Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. The observation period was 13 weeks. Safety data included treatment-related adverse events with a particular emphasis on the gastrointestinal-related (colitis, enteritis, diarrhoea and gastrointestinal perforation) and liver-related (hepatic failure, hepatic function abnormal, hepatitis and cholangitis sclerosing) treatment-related adverse events that are listed in the risk management plan for nivolumab and ipilimumab combination therapy. RESULTS: Of the 203 patients registered, safety data were available for 159 (119 males/40 females) with a median age of 67 years (range 22-88). Seventy-one patients received nivolumab and ipilimumab combination therapy four times per usual clinical therapy, and 33 continued nivolumab monotherapy thereafter. Any-grade treatment-related adverse events were reported in 102 (64.2%) patients and grade ≥ 3 in 63 (39.6%). Hepatic function abnormalities (13.2%), rash (8.8%) and interstitial lung disease (7.5%) were the most common treatment-related adverse events. Five patients died following treatment-related adverse events. Gastrointestinal-related and liver-related treatment-related adverse events occurred in 10 (6.3%; four with grade ≥ 3 treatment-related adverse events) and 27 (17.0%; 19 with grade ≥ 3 treatment-related adverse events) patients, respectively. CONCLUSIONS: This post-marketing surveillance in patients with unresectable or metastatic renal cell carcinoma revealed a safety profile for nivolumab and ipilimumab combination therapy consistent with CheckMate 214. Furthermore, no new safety concerns were identified including gastrointestinal-related and liver-related treatment-related adverse events.

Real-world safety and efficacy data of ipilimumab in Japanese radically unresectable malignant melanoma patients: A postmarketing surveillance.

Treatment with immune checkpoint inhibitors has improved prognosis among patients with cutaneous melanoma, but there are still unmet medical needs in Japan, especially for mucosal melanoma and acral lentiginous melanoma (ALM) subtypes. Ipilimumab, a fully human monoclonal antibody that specifically blocks cytotoxic T-lymphocyte-associated antigen 4 and potentiates antitumor T-cell response, was approved in Japan in 2015 for the treatment of radically unresectable malignant melanoma. This postmarketing surveillance (prospective, non-interventional, multicenter, observational study) evaluated the safety (occurrence of adverse drug reactions [ADR]) and efficacy (overall survival [OS]) of ipilimumab in a real-world setting in Japan. All patients with radically unresectable malignant melanoma undergoing treatment with ipilimumab in Japan during the registration period between August 2015 and February 2017 were enrolled. In total, 547 patients were analyzed; 67.5% were 60 years old or more, 85.7% had an Eastern Cooperative Oncology Group performance status of 0-1, 50.3% had melanoma of the skin (mainly of the ALM subtype) and 73.5% had negative BRAF mutation status. Most patients had experienced recurrence and received multiple treatments. The overall incidence of ADR and serious ADR was 69.5% and 40.8%, respectively. The most common ADR and serious ADR were liver disorder, colitis and diarrhea. The most common ADR of special interest were liver-related ADR (22.5%), skin-related ADR (22.1%), gastrointestinal-related ADR (20.3%) and endocrine system-related ADR (16.3%). Most of these events had recovered or were in remission by the last evaluation. The median OS was 7.52 months (95% confidence interval, 6.47-8.74). Median OS was 6.31 and 8.44 months in patients with mucosal melanoma and melanoma of the skin; 9.43 and 3.75 months in patients with and without ADR; and 10.32 and 6.11 months in patients with and without serious ADR, respectively. Ipilimumab was tolerable and showed efficacy in improving OS for these patients.

Safety and effectiveness of reduced-dose apixaban in Japanese patients with nonvalvular atrial fibrillation in clinical practice: A sub-analysis of the STANDARD study.

BACKGROUND: The safety and effectiveness of reduced-dose apixaban 2.5mg twice daily (BID) have not been elucidated thoroughly in Japanese patients with nonvalvular atrial fibrillation (NVAF). METHODS: A post-marketing survey study included NVAF patients who newly initiated apixaban for prevention of thromboembolism, and followed them for 104 weeks. Apixaban doses were selected at the discretion of treating physicians. Hemorrhagic and thromboembolic (ischemic stroke, systemic embolism, and transient ischemic attack) events were examined. The relationship between dose reduction criteria (DRC), selected doses, and outcome events was also examined. RESULTS: Of 6306 patients, 3600 (57.1%) received the standard dose (5mg BID) and 2694 (42.7%) received the reduced dose. Compared with the standard-dose group, the reduced-dose group had more female patients; the patients were older, of lower body weight, with reduced creatinine clearance, higher thromboembolic and hemorrhagic risk scores, and more frequent antiplatelet use. Incidence rates of major hemorrhage and thromboembolism were higher in the reduced-dose group compared with the standard-dose group (3.00%/year vs 1.93%/year, p=0.001 and 1.40%/year vs 0.72%/year, p=0.001, respectively). In the standard-dose group, 90.0% of patients did not meet the DRC (recommended standard-dose group). In the reduced-dose group, 62.4% of patients met the DRC (recommended reduced-dose group) and 34.9% did not (non-recommended reduced-dose group). Incidence rates of major hemorrhage and thromboembolism were numerically highest in the recommended reduced-dose group (3.30%/year, p=0.007 and 1.69%/year, p<0.001, respectively), followed by the non-recommended reduced-dose group. In multivariate analysis, apixaban dose was not associated with these outcome events. CONCLUSION: The reduced-dose group showed higher incidence rates of thromboembolic and major hemorrhagic events than the standard-dose group due to baseline clinical characteristics. The safety and effectiveness of reduced-dose apixaban need to be carefully monitored in clinical practice.

Safety and effectiveness of apixaban in Japanese patients with nonvalvular atrial fibrillation in clinical practice: A regulatory postmarketing surveillance, the STANDARD study.

BACKGROUND: Apixaban, a non-vitamin K oral anticoagulant (NOAC), was approved in Japan in 2012 for the prevention of thromboembolic events in patients with nonvalvular atrial fibrillation (NVAF). However, the safety and effectiveness of apixaban in clinical practice have not yet been elucidated thoroughly among Japanese NVAF patients. METHODS: A postmarketing surveillance study was conducted to determine the safety and effectiveness of apixaban. Patients were followed-up for 104 weeks. Outcome events included adverse drug reactions (ADRs), hemorrhages, and thromboembolic events (ischemic stroke, systemic embolism [SE], and transient ischemic attack [TIA]). RESULTS: Among 6306 NVAF patients in the safety analysis set (age, 74.5 ± 10.1 years; women, 41.1%; and CHADS 2 score, 2.0 ± 1.4), 3600 patients (57.1%) received the standard dose (5 mg twice daily) and 2694 (42.7%) received a reduced dose (2.5 mg twice daily) of apixaban. ADRs occurred in 604 patients (9.58%), with the most common being epistaxis (0.86%), subcutaneous hemorrhage (0.67%), and hematuria (0.57%). Incidence rate of any hemorrhages and major hemorrhage was 5.52% per year and 2.36% per year, respectively. Incidence rate of ischemic stroke/SE/TIA was 1.00% per year among 6286 patients in the effectiveness analysis set. Among three subgroups (3106 apixaban initiators, 2038 patients switched from warfarin, and 1118 patients switched from other NOACs), incidence rates of major hemorrhage (P = 0.221 for trend) and ischemic stroke/SE/TIA (P = 0.686 for trend) were comparable. CONCLUSIONS: No new safety signals of apixaban were identified in Japanese NVAF patients. Safety and effectiveness of apixaban were consistent with those in the ARISTOTLE study.

Safety and effectiveness of daclatasvir and asunaprevir dual therapy in patients with genotype 1 chronic hepatitis C: results from postmarketing surveillance in Japan.

BACKGROUND: Safety and effectiveness of daclatasvir (DCV)/asunaprevir (ASV) dual therapy were demonstrated in Japanese patients with chronic hepatitis C (CHC) genotype (GT) 1b in phase III studies. This postmarketing surveillance (PMS) was conducted to assess the safety and effectiveness of DCV/ASV in Japanese patients with GT-1 CHC treated in routine clinical practice. METHODS: This PMS was conducted between September 2014 and February 2017 at 261 centers in Japan. Patients with GT-1 CHC with or without compensated cirrhosis starting DCV and ASV dual therapy were observed from treatment initiation until 24 weeks after completing treatment. Safety and effectiveness assessments included incidence of adverse drug reactions (ADRs) and sustained viral response (SVR) rates at 24 weeks (SVR24). RESULTS: Of 2820 patients (median age, 71.0 years; ≥ 65 years, 73.1%; female, 56.1%; with compensated cirrhosis, 39.1%) in the safety population, 726 (25.7%) experienced 1063 ADRs and 47 (1.7%) experienced 55 serious ADRs. Overall, 532 hepatic ADRs were reported; most hepatic ADRs occurred between > 4 and ≤ 12 weeks after treatment initiation. Subgroup analysis showed a higher incidence of ADRs in female, elderly, underweight, and renal function-impaired patients. SVR24 and SVR at 12 weeks (SVR12) were 87.3% (2216/2538) and 88.4% (2284/2584), respectively. Patients without (SVR12, 89.1%; SVR24, 87.9%) and with (SVR12, 87.3%; SVR24, 86.3%) compensated cirrhosis had similar SVR rates. CONCLUSION: Results from this large PMS indicate that DCV and ASV dual therapy is generally well tolerated and effective in routine clinical practice in Japanese patients with GT-1 CHC with or without compensated cirrhosis.

Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Clinical Microbiology in 2009: general view of the pathogens' antibacterial susceptibility.

For the purpose of nationwide surveillance of antimicrobial susceptibility of bacterial respiratory pathogens from patients in Japan, the Japanese Society of Chemotherapy (JSC) started a survey in 2006. From 2009, JSC continued the survey in collaboration with the Japanese Association for Infectious Diseases and the Japanese Society for Clinical Microbiology. The fourth-year survey was conducted during the period from January and April 2009 by the three societies. A total of 684 strains were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections. Susceptibility testing was evaluable with 635 strains (130 Staphylococcus aureus, 127 Streptococcus pneumoniae, 4 Streptococcus pyogenes, 123 Haemophilus influenzae, 70 Moraxella catarrhalis, 78 Klebsiella pneumoniae, and 103 Pseudomonas aeruginosa). A maximum of 45 antibacterial agents including 26 ß-lactams (four penicillins, three penicillins in combination with ß-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), four aminoglycosides, four macrolides (including ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standard Institute (CLSI). Incidence of methicillin-resistant S. aureus (MRSA) was as high as 58.5 %, and that of penicillin-intermediate and penicillin-resistant S. pneumoniae (PISP and PRSP) was 6.3 % and 0.0 %, respectively. Among H. influenzae, 21.1 % of them were found to be ß-lactamase-non-producing ampicillin (ABPC)-intermediately resistant (BLNAI), 18.7 % to be ß-lactamase-non-producing ABPC-resistant (BLNAR), and 5.7 % to be ß-lactamase-producing ABPC-resistant (BLPAR) strains. A high frequency (76.5 %) of ß-lactamase-producing strains has been suspected in Moraxella catarrhalis isolates. Four (3.2 %) extended-spectrum ß-lactamase-producing K. pneumoniae were found among 126 strains. Four isolates (2.5 %) of P. aeruginosa were found to be metallo-ß-lactamase-producing strains, including three (1.9 %) suspected multi-drug resistant strains showing resistance against imipenem, amikacin, and ciprofloxacin. Continuous national surveillance of the antimicrobial susceptibility of respiratory pathogens is crucial to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis.

walK and clpP mutations confer reduced vancomycin susceptibility in Staphylococcus aureus.

Vancomycin-intermediate Staphylococcus aureus (VISA) is generated from vancomycin-susceptible Staphylococcus aureus by multiple spontaneous mutations. We previously reported that sequential acquisition of mutations in the two-component regulatory systems vraSR and graRS was responsible for the VISA phenotype of strain Mu50. Here we report on the identification of a novel set of regulator mutations, a deletion mutation in two-component regulatory system walRK (synonyms, vicRK and yycFG), and a truncating mutation in a proteolytic regulatory gene, clpP, responsible for the raised vancomycin resistance in a laboratory-derived VISA strain, LR5P1-V3. The contributory effect of the two mutations to vancomycin resistance was confirmed by introducing the walK and clpP mutations into the vancomycin-susceptible parent strain N315LR5P1 by a gene replacement procedure. The vancomycin MIC of N315LR5P1 was raised from 1 to 2 mg/liter by the introduction of the walK or clpP mutation, but it was raised to 4 mg/liter by the introduction of both the walK and clpP mutations. The vancomycin MIC value of the double mutant was equivalent to that of strain LR5P1-V3. Like VISA clinical strains, LR5P1-V3 and the double mutant strain LR5P1walK*clpP* exhibited a thickened cell wall, slow growth, and decreased autolytic activity. Transcriptional profiles of the mutants with gene replacements demonstrated that introduction of both the walK and clpP mutations could alter expression of dozens or hundreds of genes, including those involved in cell envelope and cellular processes, intermediary metabolism, and information pathway. A mutation prevalence study performed on 39 worldwide clinical VISA strains showed that 61.5, 7.7, 10.3, and 20.5% of VISA strains harbored mutations in walRK, clpP, graRS, and vraSR, respectively. The mutation of walRK was most frequently carried by VISA strains. Together, these results suggested that the mutations of walK and clpP identified in LR5P1-V3 constitute a new combination of genetic events causing vancomycin resistance in Staphylococcus aureus.