Phase 2 Trial of Neoadjuvant Axitinib in Patients with Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma

Abstract

Background Previous studies have shown modest impact of tyrosine kinase inhibitors on primary renal tumors. These studies were mostly retrospective and heterogeneous in their eligibility criteria with regards to histology, disease stage, duration of therapy, and time off therapy prior to surgery. Objective To prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with non-metastatic biopsy-proven clear cell renal cell carcinoma (ccRCC). Design, Setting, and Participants This is a single-institutional, single-arm phase 2 clinical trial. Patients with locally-advanced non-metastatic biopsy-proven ccRCC were eligible. This trial was registered with clinicaltrials.gov(NCT01263769). Intervention Patients received axitinib 5mg for up to 12 weeks. Axitinib was continued until 36 hours prior to surgery. Patient underwent partial or radical nephrectomy after axitinib therapy. Outcome Measurements and Statistical Analysis The primary outcome was objective response rate prior to surgery. Secondary outcomes included safety, tolerability, and quality of life. A dedicated radiologist independently reviewed all CT scans to evaluate for response using RECIST. Results and Limitations Twenty-four patients were treated. 22 patients continued axitinib for 12 weeks, while 1 patient continued axitinib for 11 weeks, and underwent surgery as planned. One patient stopped treatment at 7 weeks due to adverse events. Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response by RECIST; 13 had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted. No grade 4 or 5 complications occurred. FKSI (Functional Assessment of Cancer Therapy-Kidney Specific Index-15) changed over time, with quality of life worsening while on therapy, but by week 19, it was not statistically different from screening. Limitations include single-arm design and small patient numbers. Conclusions Axitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally-advanced non-metastatic ccRCC.

The role of neoadjuvant therapy in the management of locally advanced renal cell carcinoma

“…In the study by Karam and colleagues, five (21.8%) of 24 patients underwent partial nephrectomy after neoadjuvant axitinib therapy without any intraoperative or postoperative complications [Karam et al 2014]. It is important to note that undergoing a partial nephrectomy was also not a prespecified endpoint in the study.…”

“…Lastly, a recent phase II clinical trial published by Karam and colleagues reported on the experience with neoadjuvant axitinib in 24 patients with biopsy-proven clear cell locally advanced nonmetastatic RCC [Karam et al 2014]. Patients received daily axitinib for 12 weeks, which was discontinued only 36 h prior to nephrectomy.…”

“…[Powles et al 2011b]. In the neoadjuvant axitinib study (in which axitinib was stopped 36 h prior to surgery) [Karam et al 2014], only one patient (4.2%) experienced a superficial wound healing complication, which resolved with conservative management. In the neoadjuvant pazopanib study [Rini et al 2015], none of the patients experienced a fascial dehiscence or wound healing impairment.…”

Clinical and Translational Assessment of VEGFR1 as a Mediator of the Premetastatic Niche in High-Risk Localized Prostate Cancer

“…Given limited accrual to the randomized, phase II clinical trial reported herein, we are limited in our conclusions and can only suggest that axitinib is safe and well-tolerated in the neoadjuvant setting, consistent with findings from a neoadjuvant trial of axitinib in localized renal cell carcinoma (16). An ongoing study at the MD Anderson Cancer Center is comparing axitinib with ADT to axitinib alone before radical prostatectomy in a similar patient population (17).…”

Contrast media enhancement reduction predicts tumor response to presurgical molecular-targeting therapy in patients with advanced renal cell carcinoma

“…A presurgical setting is ideal to make comparisons between radiologic and pathologic responses. Although the role of presurgical molecular-targeting therapy for advanced RCCs has not been clearly established, several studies have suggested a survival benefit [4][5][6][7][8][9][10][11] that corresponds to accumulating evidences of efficacy and safety. Here, we investigated the clinical implication of CMER in patients with advanced RCC who underwent presurgical molecular-targeting therapy followed by radical nephrectomy, and compared radiologic tumor responses by RECIST, Choi, and CMER with pathological outcomes in those patients.…”