Elsevier

European Urology

Volume 66, Issue 5, November 2014, Pages 874-880
European Urology

Platinum Priority – Kidney Cancer
Editorial by Amanda Leiter and Matthew D. Galsky on pp. 881–883 of this issue
Phase 2 Trial of Neoadjuvant Axitinib in Patients with Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma

https://doi.org/10.1016/j.eururo.2014.01.035Get rights and content

Abstract

Background

Previous studies have shown a modest impact of tyrosine kinase inhibitors on primary renal tumors. Those studies were mostly retrospective or heterogeneous in their eligibility criteria with regard 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 nonmetastatic biopsy-proven clear cell renal cell carcinoma (ccRCC).

Design, setting, and participants

This was a single-institution, single-arm phase 2 clinical trial. Patients with locally advanced nonmetastatic biopsy-proven ccRCC were eligible.

Intervention

Patients received axitinib 5 mg for up to 12 wk. Axitinib was continued until 36 h prior to surgery. Patients 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 computed tomography scans to evaluate for response using Response Evaluation Criteria in Solid Tumors (RECIST).

Results and limitations

A total of 24 patients were treated. Twenty-two patients continued axitinib for 12 wk; 1 patient continued axitinib for 11 wk and underwent surgery as planned. One patient stopped treatment at 7 wk due to adverse events (AEs). Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response per 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. 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 nonmetastatic ccRCC.

Patient summary

In this prospective clinical trial, we found that axitinib, when given prior to surgery, results in significant shrinking of kidney cancers. Larger studies are needed prior to further clinical use.

Trial registration

This clinical trial was registered with clinicaltrials.gov (NCT01263769).

Introduction

Targeted therapy has broadened the horizon of treatment in patients with metastatic clear cell renal cell carcinoma (ccRCC), with its widespread use since 2006. Several agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin pathways important in the biology of ccRCC have been developed and utilized since then, with sequential refinements in the specificity of molecular targeting as well as improvements in tolerability and side effect profiles. The relative ease of administration of recently developed oral targeted therapies has led to their use in patients with their primary renal tumor in place, most commonly in poor surgical candidates and patients with unresectable primary renal tumors.

Around the time this current study was designed, one such molecule, axitinib—an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3—was studied in 52 patients with metastatic ccRCC who failed prior systemic therapy with interferon-α or interleukin-2 [1]. Responses were seen in 23 patients (44.2%), with two patients achieving complete response and one patient without prior nephrectomy having partial shrinkage of the primary renal tumor. Axitinib was also studied in 62 patients with metastatic ccRCC refractory to sorafenib [2], and a partial response was observed in 22.6% of patients, with 80% experiencing some degree of tumor shrinkage. As such, axitinib appeared to be a promising agent in the treatment of metastatic ccRCC. In 2010, given the promising data available then with axitinib, we decided to conduct a prospective trial in patients with nonmetastatic RCC with the primary renal tumor in situ using this particular agent. Since then, based on results from a phase 3 clinical trial, axitinib has been approved for use in a second-line setting in patients with metastatic ccRCC [3]. Potential advantages of neoadjuvant therapy include downsizing and/or downstaging of tumors to change surgical approach from radical to partial nephrectomy or from open to minimally invasive surgery, and to allow for resection of unresectable tumors. Few registered prospective clinical trials have been conducted and reported to date in this disease setting.

Section snippets

Eligibility criteria

This study was designed as a prospective, single-center, open-label, nonrandomized phase 2 study of axitinib for 12 wk prior to curative surgery in patients with locally advanced nonmetastatic ccRCC.

Patients were eligible for this study if they had clinical stage T2–T3b (using American Joint Committee on Cancer 2010 guidelines [4]) without any radiographic evidence of nodal or distant metastases, clear cell histology on pretreatment biopsy of the primary renal tumor, tumor amenable for curative

Patient characteristics

Twenty-four patients were treated with axitinib from May 2011 to April 2013 (Fig. 1). All patients had biopsy-proven ccRCC prior to starting treatment. Table 1 displays the baseline patient characteristics.

Drug treatment

Twenty-two patients completed 12 wk of axitinib, and one patient completed only 11 wk of treatment. These 23 patients underwent surgery as planned without delay. Another patient stopped treatment at 7 wk and was taken to surgery earlier than originally scheduled. Axitinib dose was titrated

Discussion

Since 2008, several agents such as bevacizumab, sorafenib, and sunitinib have been used in the neoadjuvant and presurgical setting in patients with their primary renal mass in situ (Supplemental Table 2). However, most of these studies were heterogeneous in several ways. Only a few studies were prospective in nature; biopsy-proven ccRCC was not always a prerequisite for inclusion in study; most of the studies included either exclusively patients with metastases (stage IV) or a wide range of

Conclusions

We report the first prospective clinical trial with the tyrosine kinase inhibitor axitinib, conducted exclusively in patients with locally advanced, nonmetastatic, biopsy-proven ccRCC, with predefined treatment duration, showing an excellent primary tumor response. We also showed that this approach is feasible and safe at least in the perioperative period, with manageable AEs while on drug therapy and postoperatively. For the time being, this approach should only be used in clinical trials or

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