Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma.

BACKGROUND: Ripretinib, a broad-spectrum KIT and platelet-derived growth factor receptor A switch-control tyrosine kinase inhibitor, is approved for the treatment of adult patients with advanced gastrointestinal stromal tumor as ≥ fourth-line therapy. We present the efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma enrolled in the expansion phase of the ripretinib phase I study. PATIENTS AND METHODS: Patients with KIT-altered metastatic melanoma were enrolled and treated with ripretinib at the recommended phase II dose of 150 mg once daily in 28-day cycles. Investigator-assessed responses according to Response Evaluation Criteria In Solid Tumors version 1.1 were carried out on day 1 of cycles 3, 5, 7, every three cycles thereafter, and at a final study visit. RESULTS: A total of 26 patients with KIT-altered metastatic melanoma (25 with KIT mutations, 1 with KIT-amplification) were enrolled. Patients had received prior immunotherapy (n = 23, 88%) and KIT inhibitor therapy (n = 9, 35%). Confirmed objective response rate (ORR) was 23% [95% confidence interval (CI) 9%-44%; one complete and five partial responses] with a median duration of response of 9.1 months (range, 6.9-31.3 months). Median progression-free survival (mPFS) was 7.3 months (95% CI 1.9-13.6 months). Patients without prior KIT inhibitor therapy had a higher ORR and longer mPFS (n = 17, ORR 29%, mPFS 10.2 months) than those who had received prior KIT inhibitor treatment (n = 9, ORR 11%, mPFS 2.9 months). The most common treatment-related treatment-emergent adverse events (TEAEs) of any grade in ≥15% of patients were increased lipase, alopecia, actinic keratosis, myalgia, arthralgia, decreased appetite, fatigue, hyperkeratosis, nausea, and palmar-plantar erythrodysesthesia syndrome. There were no grade ≥4 treatment-related TEAEs. CONCLUSIONS: In this phase I study, ripretinib demonstrated encouraging efficacy and a well-tolerated safety profile in patients with KIT-altered metastatic melanoma, suggesting ripretinib may have a clinically meaningful role in treating these patients.

Dysregulation of interleukin-10 production in relatives of patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate interleukin-10 (IL-10) production in relatives of patients with systemic lupus erythematosus (SLE). METHODS: Production of IL-10 was evaluated in 13 families in which several members had SLE. The constitutive IL-10 production in SLE patients (n = 16) was compared with that in healthy members of these multiplex families (n = 70), in 30 SLE patients who had no relatives with SLE, and in 46 healthy unrelated controls. RESULTS: The level of IL-10 production did not differ between SLE patients who were members and those who were not members of multiplex families (mean +/- SEM 4,384 +/- 908 pg/ml and 4,709 +/- 560 pg/ml, respectively), but was higher in both groups than in healthy unrelated controls (515 +/- 88 pg/ml). The healthy members of the multiplex families constitutively produced large amounts of IL-10 (3,080 +/- 311 pg/ml; P < 0.001 compared with healthy unrelated controls). This high IL-10 production was independent of age and sex, and was similar in first- and second-degree relatives of SLE patients. The IL-10 was produced both by monocytes and by a subpopulation of B lymphocytes in SLE patients and in their relatives. CONCLUSION: The dysregulation of IL-10 production previously identified in SLE patients is also present in healthy members of families with several cases of SLE, and it may contribute to the immunologic abnormalities affecting relatives of SLE patients.

Cytokine gene expression in cirrhotic and non-cirrhotic human liver.

BACKGROUND/AIMS: In order to explore the role of cytokines in the pathogenesis of liver cirrhosis, we analyzed their gene expression in hepatic biopsies from patients with alcoholic liver cirrhosis, post-hepatitis C liver cirrhosis, and with idiopathic portal hypertension without cirrhosis. METHODS: We assessed the gene expression of interleukins 1 beta, 2, 6, 8, and 10, as well as of tumor necrosis factor-alpha, transforming growth factor-beta and interferon-gamma by a quantitative polymerase chain reaction. RESULTS: We found high levels of transforming growth factor-beta in post-hepatitis C liver cirrhosis, high to moderate in alcoholic liver cirrhosis and low in non-cirrhotic specimens. Expression of interleukin-10, tumor necrosis factor-alpha, and interferon-gamma genes was detected in most post-hepatitis C liver cirrhosis, but not in idiopathic portal hypertension or alcoholic liver cirrhosis biopsies. The interleukin1-beta, 6 and 8 gene expression was significantly lower in alcoholic liver cirrhosis compared to post-hepatitis C liver cirrhosis, but higher compared to idiopathic portal hypertension specimens. Thus, post-hepatitis C liver cirrhosis samples showed a high degree of cytokine gene expression, whereas in alcoholic liver cirrhosis it tended to be moderate, and restricted to some cytokines (transforming growth factor-beta, interleukin-1, 6 and 8, but not interleukin-10, tumor necrosis factor-alpha or interferon-gamma). In contrast, most non-cirrhotic specimens showed a restricted and low cytokine gene expression. CONCLUSIONS: These data suggest that transforming growth factor-beta may have an important role in liver fibrosis and inflammation. Interleukin-1 beta, 6, 8, tumor necrosis factor-alpha and interferon-gamma, appear to participate in the pathogenesis of the mild to severe inflammatory phenomena seen in alcoholic and post-hepatitis C liver cirrhosis, respectively. Our data suggest that tumor necrosis factor-alpha does not participate in the hepatocellular damage of alcoholic liver cirrhosis, and indicate that neither interferon-gamma nor interleukin-10, at least at the levels observed in post-hepatitis C liver cirrhosis, are able to counteract the fibrotic/inflammatory process seen in this condition.