Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: An analysis of the National Cancer Database

Highlights

• Using the NCDB, patients undergoing CN with modern IO for mRCC exhibited better OS than those treated with IO alone.

• CN after prior IO is safe with pathologically favorable tumor characteristics.

• Defining the role for CN in the modern IO era warrants prospective validation.

Abstract

Objectives

Despite immune checkpoint inhibitor (ICI) approval for metastatic renal cell carcinoma (mRCC) in 2015, cytoreductive nephrectomy (CN) is guided by extrapolation from earlier classes of therapy. We evaluated survival outcomes, timing, and safety of combining CN with modern immunotherapy (IO) for mRCC.

Methods

From 96,329 renal cancer cases reported to the NCDB between 2015 and 2016, we analyzed 391 surgical candidates diagnosed with clear cell mRCC treated with IO ± CN and no other systemic therapies. Primary outcome was overall survival (OS) stratified by the performance of CN (CN + IO vs. IO alone). Secondary outcomes included OS stratified by the timing of CN, pathologic findings, and perioperative outcomes.

Results

Of 391 patients, 221 (56.5%) received CN + IO and 170 (43.5%) received IO only. Across a median follow-up of 14.7 months, patients who underwent CN + IO had superior OS (median NR vs. 11.6 months; hazard ratio 0.23, P < 0.001), which was upheld on multivariable analyses. IO before CN resulted in lower pT stage, grade, tumor size, and lymphovascular invasion rates compared to upfront CN. Two of 20 patients (10%) undergoing CN post-IO achieved complete pathologic response in the primary tumor (pT0). There were no positive surgical margins, 30-day readmissions, or prolonged length of stay in patients undergoing delayed CN.

Conclusion

Using a large, national, registry-based cohort, we provide the first report of survival outcomes in mRCC patients treated with CN combined with modern IO. Our findings support an oncologic role for CN in the ICI era and provide preliminary evidence regarding the timing and safety of CN relative to IO administration.

Introduction

Kidney cancer accounts for nearly 15,000 deaths annually in the United States (US) [1]. At diagnosis, approximately 30% to 40% of patients already harbor metastatic disease [2], and 5-year survival rates for these patients have traditionally been dismal, ranging from 0% to 20% [3], [4], [5]. Recently, immune checkpoint inhibitors (ICI) have revolutionized the contemporary management of immunogenic malignancies, including metastatic renal cell carcinoma (mRCC). The seminal CheckMate 025 trial heralded the modern immunotherapy (IO) era for mRCC resulting in the approval of the first ICI agent (nivolumab) to treat mRCC in 2015 [6]. Thereafter, several combination ICI regimens gained frontline approval based on results of the CheckMate 214 (nivolumab and ipilimumab) [7], KEYNOTE-426 (pembrolizumab and axitinib) [8], and JAVELIN Renal 101 (avelumab and axitinib) [9] trials.

With this new class of therapy, the role for surgically removing the primary tumor remains unknown. The first trials to investigate the benefit of offering cytoreductive nephrectomy (CN) in mRCC were conducted in the cytokine era [10,11]. A combined analysis of these trials, which compared interferon-alpha (IFN-α) alone vs. IFN-α plus CN, revealed a 31% decrease in the risk of death and a median survival advantage of 5.8 months in support of CN [12]. Survival benefits with CN in the targeted era have also been seen in multiple retrospective studies, including population-based analyses of the Surveillance, Epidemiology, and End Results registry and National Cancer Database (NCDB) [13], [14], [15], [16], [17], along with a meta-analysis [18].

The recent randomized, phase III CARMENA trial, however, challenged this notion by demonstrating noninferiority of sunitinib alone compared to sunitinib combined with CN [19]. While interpretation of the results from CARMENA is nuanced, the trial highlights the evolving question of when—and for whom—CN is indicated. Furthermore, as ICIs increasingly gain popularity among medical oncologists over sunitinib as the standard-of-care for treating mRCC, the relevance of the CARMENA trial in the ICI era is questionable. Without any published data regarding the role of combining CN with ICI, current clinical practice is guided by extrapolation from these earlier studies.

Thus, there is an urgent clinical need to elucidate the role, candidacy, and timing of offering CN to patients treated with ICI. Herein, using the NCDB, we provide the first report of survival outcomes in mRCC patients treated with CN combined with modern IO approaches vs. IO alone. Among patients who received CN, we also evaluate the timing of CN in relation to IO administration and the safety of CN after IO.