Phase III RCC trial challenges current standard of care

"Journal Article of the Month” is a new Urology Times section in which Badar M. Mian, MD (left), offers perspective on noteworthy research in the peer-reviewed literature.  Dr. Mian is associate professor of surgery in the division of urology at Albany Medical College, Albany,

NY. In patients presenting with metastatic kidney cancer, cytoreductive nephrectomy along with immunotherapy (interferon, interleukin) has long been the standard of care due the improved patient survival associated with this approach. However, a recent phase III trial demonstrated that anti-VEGF targeted therapy alone provided similar overall survival, without the need for cytoreductive nephrectomy 

(N Engl J Med 2018; 379:417-27).

The CARMENA trial aimed to study the benefit of initial nephrectomy followed by targeted therapy in patients with metastatic kidney cancer compared to targeted therapy (sunitinib [Sutent]) alone. The trial was designed to show that sunitinib alone was not inferior to the usual combination of nephrectomy plus sunitinib. Between September 2009 and September 2017, 450 patients with clear cell renal cell carcinoma, confirmed on mandatory biopsy, and metastatic disease were randomized 1:1 to receive nephrectomy-sunitinib or sunitinib alone. The median follow-up was 50.9 months.

The median overall survival in the sunitinib-alone group was longer (18.4 months) than in the nephrectomy-sunitinib group (13.9 months). In the overall survival analysis, the hazard ratio of death was 0.89 (95% CI: 0.71-1.10) in favor of the sunitinib-alone group, suggesting that this approach was “noninferior” to the combination of nephrectomy followed by sunitinib. In subgroup analysis, both the intermediate-risk and high-risk patients were noted to have longer median overall survival and lower hazard ratio of death in the sunitinib-alone group.

The median progression-free survival was similar amongst the sunitinib-alone group and the nephrectomy-sunitinib group (8.3 months vs. 7.2 months). Similarly, the objective response rate was comparable between the sunitinib-alone group (29.1%) and the nephrectomy-sunitinib group (27.4%).

Sunitinib-related grade 3 or 4 adverse events were reported by 32.8% in the nephrectomy-sunitinib group and 42.7% in the sunitinib-alone group (p=.04). Postoperative complications in the nephrectomy-sunitinib group, including Clavien-Dindo grade ≥III, were reported in 13 patients (6%).

It’s worth noting that randomized controlled trials are difficult to perform and often have to overcome significant challenges. Over a period of 8 years, the trial was open at 79 European centers that recruited, on average, less than one patient per year per site! Of the planned 576 patients, only 450 patients were recruited and the trial was closed early, after an interim analysis, due to slow recruitment.

Next:Results contrary to those of previous studies

Results contrary to those of previous studies

This trial challenges the current standard of care. These results are unexpected and are contrary to what had been learned through previous retrospective studies. The patient inclusion criteria appear to be different from some previous studies in that a large proportion of patients in the CARMENA trial were in the high-risk category (ie, multiple adverse features). This may explain the lower-than-expected survival rate in these patients compared to other trials. It is difficult to explain the longer survival in the group without nephrectomy. It’s unlikely that removal of the primary tumor is resulting in poor survival, either due to some biologic effect or procedure related mortality. It’s likely an epiphenomenon related to trial design, patient accrual, and inclusion criteria.

In routine clinical practice, high-risk patients are not considered good candidates for cytoreductive nephrectomy because much of the benefit of cytoreductive nephrectomy has been noted in the intermediate-risk patients. In this trial, both the intermediate- and high-risk patients appear to have better outcomes without initial nephrectomy. However, slow accrual, early termination of the trial, and the lower-than-planned number of subjects can introduce confounders and reduce the statistical power of the study, especially when separately analyzing the outcomes of intermediate-risk and high-risk subgroups.

Cytoreductive nephrectomy as the standard of care was based on the two non-specific immunotherapy trials using cytokines (IL-2, interferon) reported in 2001. Since then, we have moved through several targeted agents (anti-VEGF, anti-mTOR) and have re-introduced immunotherapy in the form of immune checkpoint inhibitors (nivolumab [Opdivo], ipilimumab [Yervoy]). Can the results of CARMENA be extrapolated to the use of checkpoint inhibitors? Is it feasible to perform another randomized trial of checkpoint inhibitors, with or without nephrectomy?

As the authors correctly point out, a “one-size-fits-all” approach cannot be applied to patients with metastatic kidney cancer. Proper patient selection, including those with low-/intermediate-risk disease, is paramount. Reserving cytoreductive nephrectomy for those patients who have symptoms related to the primary tumor or those with favorable/intermediate risk criteria will help avoid unnecessary surgery and/or any delay in the initiation of systemic therapy.