A novel strategy for axitinib dosing in the treatment of metastatic renal cell carcinoma.

Abstract

464 Background: The AXIS trial established axitinib as an effective second line treatment for patients with metastatic renal cell carcinoma (mRCC). The dosing schedule of axitinib in this trial begins at 5mg twice daily, with escalation of individual doses to 7mg and 10mg after consecutive 2 week intervals if tolerated. We observed significant drug-related toxicity using this dosing strategy, particularly after dose escalations, while clinical responses were often observed at the starting dose. We therefore switched to a pragmatic strategy where dose escalations were made only after disease progression or where a rapid response was deemed clinically pertinent. Methods: We performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for greater than 2 weeks at Addenbrooke’s Hospital, Cambridge, UK (a tertiary referral center), over a 40 month period to determine the clinical and radiological effects of dose escalations made according to the above strategy. Results: 42 patients fitting these criteria were identified; of these, 29 had at least one dose escalation event (DEE). A total of 58 DEEs were identified, with a median of 2 per patient, and the objective radiological consequences of 50 of these could be determined. The disease control rate (partial response or stable disease) after the first DEE instituted for disease progression was similar to that after the second DEE (68.8% versus 70%). 56% of all DEEs, and 62.5% of DEEs made as a result of disease progression, resulted in disease control. The median overall survival from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 6.7 months for non-dose-escalated patients. The median survival for dose-escalated patients with a higher than median time on a prior tyrosine kinase inhibitor has not been reached at the time of data cut-off. The mean dose (for all patients) at 90 days after starting axitinib was 5.92 mg. Conclusions: These data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and may reduce toxicity through lower drug exposure. Our survival data compares favourably to the AXIS trial in a real practice population.

Design, Synthesis and Antitumor Activity of 1H-indazole-3-amine Derivatives

“…At present, at least 43 kinds of indazole-based therapeutics have been used in clinical application or clinical trials [7,8]. For example, the representative compound shown in Figure 1, where Entrectinib is an anaplastic lymphoma kinase (ALK) inhibitor [9], Pazopanib is a multi-kinase inhibitor [10,11], Niraparib is a PARP1/PARP2 inhibitor [12], Linifanib is a multi-targeted ATP-competitive tyrosine kinase inhibitor [13], and Asitinib is an intravascular epidermal growth factor receptor (VEGFR) inhibitor [14]. Serotonin receptor antagonist Granisetron and non-steroidal anti-inflammatory drug Benzydamine are also used to treat vomiting caused by cancer chemotherapy [15,16].…”