Considerations for the Next Clinical Trial Evaluating the Role of Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma

Abstract

Trials SWOG 8949 and EORTC 30947 had the same eligibility criteria and established the role of cytoreductive nephrectomy for metastatic renal cell carcinoma. The more recently published CARMENA trial calls into question the need for cytoreductive nephrectomy. A systematic comparison of CARMENA and SWOG 8949 suggests that cytoreductive nephrectomy may be beneficial for patients receiving immunotherapy but not targeted therapy. The approval of immune checkpoint inhibitors for previously untreated metastatic renal cell carcinoma underlines the need for another randomized phase 3 trial of cytoreductive nephrectomy for patients receiving powerful modern immunotherapies.

1. Background

The role of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) remains an open question. In 2001, two landmark trials established the role of CN for kidney cancer. The Southwest Oncology Group (SWOG) and European Organization for Research and Treatment of Cancer (EORTC) published two separate phase 3 trials demonstrating a statistically significant improvement in overall survival for patients who underwent CN before systemic interferon therapy [1,2].

Publication of the CARMENA trial in 2018 provided the first level 1 evidence for the role of CN in the targeted therapy era [3]. The conclusion from CARMENA was that for patients treated with sunitinib, overall survival in the no-nephrectomy group was not inferior to that in the group that was first treated with CN. Therefore, the role of CN has been called into question. It is instructive to compare CARMENA and SWOG 8949 to try to understand why the studies led to differing conclusions.

2. Potential explanations

2.1. Patients in CARMENA probably had higher risk than those in SWOG 8949

In CARMENA, 43% of patients were classified as having intermediate risk and 57% as high risk according to the Memorial Sloan Kettering Cancer Center scheme. SWOG 8949 did not report risk groups, but all patients would have had intermediate or high risk. It is reasonable to speculate that SWOG 8949 would have tended to enroll patients with intermediate risk. However, a subgroup analysis of CARMENA suggests that a trial comprising only patients in the intermediate risk group would have reached the same conclusion.

2.2. Patients in CARMENA may have had a greater metastatic burden

There is no way to directly compare metastatic burden between the two studies. However, data reported for SWOG 8949 suggest that patients had a low metastatic tumor burden: 34% had non–lung metastasis and 22% had no measurable metastatic disease after nephrectomy. By contrast, 72% of the patients in CARMENA had non–lung metastasis and the metastatic tumor burden was high: the median tumor burden defined according to Response Evaluation Criteria in Solid Tumors 1.1, which only represents a maximum of five target metastases, was 14.2 cm. In comparison, the median diameter of the primary tumor was only 8.6 cm.

2.3. Patients in CARMENA received a more effective therapy than interferon

Sunitinib is a more effective therapy than interferon. The argument is that sunitinib was so effective that it left “no room” for CN to improve survival. However, this seems unlikely given that sunitinib improved overall survival by 4.6 months for untreated patients while CN improved survival by 3–10 mo [1,2], suggesting that the survival benefits are similar. Therefore, it is hard to argue that sunitinib “overpowered” a small benefit provided by surgery.

2.4. CN improves survival for patients receiving immunotherapy but not targeted therapy

This is a possibility that has become more urgent following approval of the immune checkpoint inhibitor combination of ipilimumab and nivolumab as front-line therapy for mRCC. The registration trial for this combination showed that the benefits of tyrosine kinase inhibitors and checkpoint inhibitors are context-dependent: among patients with favorable risk, sunitinib led to better survival, while among patients with higher risk, checkpoint inhibitors led to better survival [4], Therefore, it is conceivable that benefit of CN is similarly context-dependent. Although modern checkpoint inhibitors and interferon have very different mechanisms of action, both therapies modulate the immune system and may benefit from CN.

3. Proposed clinical trial

The publication of CARMENA has not resolved the debate on the role of CN. Therefore, SWOG has proposed another randomized CN trial (Fig. 1) that focuses on potential explanation 4. This trial incorporates findings from the recently reported SURTIME trial [5], which compared deferred nephrectomy and immediate nephrectomy for patients receiving sunitinib for mRCC. The SURTIME trial was considered a negative study because the predetermined primary endpoint was progression-free survival. However, for the exploratory endpoint of overall survival, deferred nephrectomy was associated with significantly better survival when compared to immediate nephrectomy. Therefore, patients in the experimental arm of our proposed study will undergo deferred nephrectomy following immune induction therapy with ipilimumab and nivolumab. Having the primary tumor in place also provides the theoretical benefit of maximizing the antigen load during immune induction. As secondary objectives, this clinical trial will assess tumor burden and risk category as potential predictors of benefit from CN in mRCC.

Fig. 1 –

Proposed trial scheme. RCC = renal cell carcinoma; IMDC = International Metastatic RCC Database Consortium; inter = intermediate; OS = overall survival; nivo = nivolumab; ipi = ipilimumab; q3w = every 3 wk; q4w = every 4 wk.

4. Conclusions

After a systematic comparison of CARMENA and SWOG 8949, we consider the possibility that CN improves survival among patients receiving an immunotherapy-based regimen. SWOG is proposing a randomized phase 3 trial to assess the impact of CN on overall survival among RCC patients receiving ipilimumab and nivolumab, which are powerful modern immunotherapies.