Final analysis of a post-marketing surveillance study of dabrafenib and trametinib combination therapy in Japanese patients with unresectable malignant melanoma with BRAF V600 mutation.

Targeted therapy with a combination of dabrafenib and trametinib has been developed and widely used for treatment of melanoma. However, data regarding its safety and efficacy in Japanese patients with malignant melanoma are limited. A post-marketing surveillance (PMS) study was conducted to investigate the safety and efficacy of combination therapy in a Japanese clinical setting with a surveillance period of June 2016 to March 2022; 326 patients with unresectable malignant melanoma with BRAF mutation were enrolled. The interim results were published in July 2020. Herein, we report the results of the final analysis based on the data collected until the completion of the PMS study. The safety analysis population included 326 patients, the majority of whom had stage IV disease (79.14%) and Eastern Cooperative Oncology Group performance status 0 or 1 (85.28%). All patients were treated with the approved dose of dabrafenib, while 99.08% were treated with the approved dose of trametinib. Adverse events (AEs) occurred in 282 patients (86.50%) and the major AEs (incidence ≥5%) were pyrexia (47.85%), malignant melanoma (33.44%), hepatic function abnormal (9.82%), rash and blood creatine phosphokinase increased (8.59% each), malaise (6.44%), nausea (5.52%), and diarrhea and rhabdomyolysis (5.21% each). The incidences rates of adverse drug reactions of safety specifications were 45.71% for pyrexia, 15.95% for hepatic impairment, 12.58% for rhabdomyolysis, 4.60% for cardiac disorders, and 3.07% for eye disorders. In the efficacy analysis population of 318 patients, the objective response rate was 58.18% (95% confidence interval [CI] 52.54%-63.66%). The progression-free survival rates at 90, 180, and 360 days were 88.14% (95% CI 84.00%-91.26%), 69.53% (63.85%-74.50%), and 52.07% (45.71%-58.03%), respectively. Consistent with previous interim results, no new safety or efficacy concerns were observed in this final analysis of a PMS study conducted in a Japanese real-world clinical setting.

Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation.

PURPOSE: To investigate the safety and efficacy of dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive unresectable and metastatic melanoma in over 100 Japanese patients of a real-world clinical setting. PATIENTS: The surveillance period of interim post-marketing surveillance (PMS) analysis was from June 2016 to November 2018, and 112 patients with unresectable and metastatic BRAF V600 melanoma who received dabrafenib and trametinib were enrolled. RESULTS: The safety analysis set included 112 patients whom almost all patients had stage IV disease (n = 97, 86.61%) with an Eastern Cooperative Oncology Group performance status 0 or 1 (n = 102, 91.07%), and mean (standard deviation) lactate dehydrogenase level was 354.3 (456.4) U/L (n = 105) at baseline. Median daily dose of dabrafenib was 300.0 mg/day (118-300), and median daily dose of trametinib was 2.00 mg/day (1.0-4.0). Adverse drug reactions (ADRs) were reported in 84 patients (75%), and common ADRs (incidence ≥ 5%) were pyrexia (n = 49, 43.75%), hepatic function abnormal (n = 11, 9.82%), rash and blood creatine phosphokinase increased (n = 9 each, 8.04%), and erythema nodosum (n = 6, 5.36%). Majority of ADRs reported in this study were consistent with that reported in previous trials. In the efficacy analysis set of 110 patients, the objective response rate was 55.45% (95% confidence interval 45.67-64.93%), and median progression-free survival was 384.0 days (251.0 days-not reached). CONCLUSIONS: No new safety or efficacy concerns were observed in this interim PMS analysis in Japanese patients with unresectable and metastatic melanoma with BRAF gene mutation who received dabrafenib and trametinib combination therapy.

Post-marketing observational study of everolimus in patients with unresectable or metastatic renal cell carcinoma in Japan.

OBJECTIVE: To confirm the safety and efficacy of everolimus in patients with unresectable or metastatic RCC. METHODS: Patients with unresectable or metastatic RCC were included and were followed for up to 1 year from the start of everolimus. The study was conducted at 618 investigational sites in Japan from March 2010 through January 2018. Safety endpoints include adverse events (AEs), and efficacy endpoints were presence/absence of tumor response, progression-free survival (PFS), and overall survival (OS) rate. RESULTS: Of 1694 patients, majority were male (76.33%). Overall, 97.64% of patients experienced AEs and 49% reported serious AEs. The most common serious AEs (incidence of ≥ 5%) include malignant neoplasm progression (21.13%) and interstitial lung disease (10.86%). The incidences of adverse reactions of priority investigation items are as follows: interstitial lung disease (27.74%), infections (11.57%), stomatitis (45.45%), increased in serum creatinine (5.61%), hyperglycemia (14.23%), exacerbation of renal impairment (26.14%), and exacerbation of hepatic impairment (1.15%). The overall tumor response rate was 6.81% with 0.08% CR, and 6.73% PR. The SD was reported in 68.74% of patients. The median PFS was 196 days (95% CI: 181-216 days). The 365-day cumulative OS rate was 82.42%. CONCLUSIONS: The acceptable safety and efficacy findings in patients with unresectable or metastatic RCC were confirmed in this study, and are similar to those of pivotal study, which led to the approval, and no new issues were detected. There were no safety or efficacy issues in special populations including elderly and patients with renal/hepatic impairment.