Real-world outcomes of avelumab plus axitinib as first-line therapy in patients with advanced renal cell carcinoma in Japan: A multicenter, retrospective, observational study (J-DART).

OBJECTIVES: In the phase 3 JAVELIN Renal 101 trial in patients with advanced renal cell carcinoma (aRCC), objective response rate (ORR) and progression-free survival (PFS) were significantly improved in patients treated with first-line avelumab plus axitinib vs sunitinib. Here we evaluate real-world outcomes with first-line avelumab plus axitinib in Japanese patients with aRCC. METHODS: In this multicenter, noninterventional, retrospective study, clinical data from patients with aRCC treated with first-line avelumab plus axitinib between December 2019 and December 2020 in Japan were reviewed. Endpoints included ORR and PFS per investigator assessment, and time to treatment discontinuation (TTD). RESULTS: Data from 48 patients (median age, 69 years) from 12 sites were analyzed. Median follow-up was 10.4 months (range, 2.6-16.5), and median duration of treatment was 7.4 months (range, 0.5-16.5). International Metastatic RCC Database Consortium risk category was favorable, intermediate, or poor in 16.7%, 54.2%, and 29.2% of patients, respectively. The ORR was 48.8% (95% CI, 33.3%-64.5%), including complete response in 3/43 patients (7.0%). Thirteen patients (27.1%) had disease progression or died, and median PFS was 15.3 months (95% CI, 9.7 months - not estimable). At data cutoff, 24 patients (50.0%) were still receiving avelumab plus axitinib, and median TTD was 15.2 months (95% CI, 7.4 months - not estimable). Three patients (6.3%) received high-dose corticosteroid treatment for immune-related adverse events, and 8 (16.7%) received treatment for infusion-related reactions. CONCLUSIONS: We report the first real-world evidence of the effectiveness and tolerability of first-line avelumab plus axitinib in Japanese patients with aRCC. Results were comparable with the JAVELIN Renal 101 trial.

Effect of troglitazone on the excess testosterone and LH secretion in thyroidectomized, insulin-resistant, type 2 diabetic Goto-Kakizaki rats.

Our previous study suggested that hypothyroidism in Goto-Kakizaki (GK) rats with insulin resistance and type 2 diabetes elevates their serum testosterone and luteinizing hormone (LH) levels and ovarian LH receptor messenger RNA (mRNA) expression. The present study assessed the effects of troglitazone (Tro), an insulin-sensitizing agent, on these hypothyroidism-induced hormonal changes in GK rats. GK and normal (Wistar strain) female rats were thyroidectomized (Tx) and then injected with 5 IU of equine chorionic gonadotropin (eCG) for 5 d starting 1 wk after thyroidectomy (the control groups). In the test groups, Tx GK and Wistar rats were injected with both eCG and Tro (100 mg kg-1) po for 5 d. Tro treatment had no effect on the elevated LH serum levels in eCG-treated Tx GK rats but suppressed their enhanced serum testosterone levels as well as significantly decreasing their LH receptor mRNA expression. Tro lowered testosterone and LH receptor mRNA levels in cultured theca cells. These results indicate that Tro lowers the elevated testosterone secretion and ovarian LH receptor mRNA expression that is induced in GK rats by Tx and gonadotropin treatment, which suggests that insulin resistance may be involved in enhancing testosterone production and LH receptor expression in the ovary.

Changes in ovarian steroidogenesis in insulin-resistant, type 2 diabetic Goto-Kakizaki rats after thyroidectomy and gonadotropin treatment.

The present study used thyroidectomized insulin-resistant, type 2 diabetic Goto-Kakizaki (GK) rats to assess whether insulin resistance and hypothyroidism modulate ovarian physiology. Animals were treated with daily injections of 5 IU equine chorionic gonadotropin for 5 days starting 1 week after thyroidectomy. Control groups included rats of GK and control (Wistar) strains treated only with equine chorionic gonadotropin or thyroidectomy, or with no treatment (intact). In Wistar rats, equine chorionic gonadotropin injections tended to increase the serum concentrations of luteinizing hormone (LH) and testosterone more in the thyroidectomy group than in intact rats. Similar changes in LH and testosterone were observed in the thyroidectomy + equine chorionic gonadotropin and equine chorionic gonadotropin groups of GK rats, but the LH and testosterone levels in the thyroidectomy + equine chorionic gonadotropin group were significantly higher in GK rats. Expression of ovarian LH receptor messenger RNA (mRNA) was enhanced by thyroidectomy. The LH receptor mRNA levels were significantly higher in the thyroidectomy+equine chorionic gonadotropin group of GK rats than in the corresponding group of control rats. These results indicate that hypothyroidism in animals with insulin resistance and type 2 diabetes promotes LH and testosterone secretions, and suggests that the enhanced-testosterone levels is partially mediated by the enhancement of LH receptor expression and an increase in the serum level of LH.