CARMENA was a randomized phase 3 trial (Figure 1), testing the benefit of cytoreductive nephrectomy (CN) followed by sunitinib treatment vs. sunitinib alone, using the MSKCC risk groups in 450 metastatic renal cell carcinoma (mRCC) patients.1 The conclusion from this previously published study was that sunitinib alone was not inferior to CN, followed by sunitinib for overall survival (OS). The clinical benefit was significantly higher in the sunitinib alone arm. Therefore, the authors concluded in their publication that CN should no longer be considered the standard of care in mRCC patients, at least when medical treatment is required. However, questions have remained about which patients could still benefit from CN, especially in the intermediate risk group.
Figure 1 – CARMENA study design:
The objectives of this presentation are to update the long-term overall survival follow-up results, to focus on the IMDC intermediate risk group patients, demonstrate analyses on some subgroups of potential interest, and to ascertain the role of delayed nephrectomy.
The study took place between 2009 and 2017 enrolling 450 patients. The cutoff for the final analysis was October 2018, after 358 events had occurred. The median follow-up was 61.5 months. The intention to treat population is shown in figure 2, and the patient characteristics are demonstrated in Table 1. A total of 56% and 62% were intermediate IMDC risk category in the CN + sunitinib arm and in the sunitinib alone arm, respectively.
Figure 2- Intention to treat population:
Table 1 – Patient characteristics:
The updated overall survival details are shown in Table 2. The stratification of patients by the number of IMDC risk factors is shown in Table 3. A total of 56.2% and 62% of patients in the CN + sunitinib arm and sunitinib alone arm had 2 IMDC risk factors, respectively. The role of each IMDC risk factor specifically in the intermediate risk group is shown in Table 4.
Table 2 – Overall survival details:
Table 3 – Stratification of patients by IMDC risk factors:
Table 4 – Role of each IMDC risk factor in the intermediate risk group:
The overall survival rates of the intermediate risk patients are shown in Table 5, demonstrating a clear benefit in the sunitinib alone arm compared to the CN + sunitinib for patients with two IMDC risk factors (31.2 months vs. 17.6 months, p=0.033). Interestingly, in the CN + sunitinib arm, patients with two IMDC risk factors did not do as well as patients with one IMDC risk factor (17.6 months vs. 31.4 months, p=0.015). When stratifying the results by the number of metastasis sites, no difference was seen between the arms in patients with one site of metastases and those with more than one site. However, in the CN + sunitinib arm, patients with one site of metastasis had a longer median overall survival than those with more than one site (23.2 months vs. 14.4 months, p=0.032).
Table 5 – Median overall survival (intention to treat analysis) for intermediate risk patients only:
Next, Dr. Mejean addressed the patients that underwent secondary nephrectomy in the sunitinib alone arm. A total of 40 patients required secondary nephrectomy. This occurred after a median of 11.1 months from randomization to surgery (range 0.7-85.4 months). Overall, 31.4% of patients with secondary nephrectomy restarted sunitinib. The median overall survival of patients that underwent delayed nephrectomy was considerably higher than those in the sunitinib arm that did not (48.5 months vs. 15.7 months, with a hazard ratio of 0.34 [95% CI 0.22-0.54]), as seen in figure 3.
Dr. Mejean concluded his talk by reiterating some of his findings. With a longer follow-up of 61.5 months, the CARMENA trial confirms that CN is not superior to sunitinib alone in the intention to treat population, when either MSKCC or IMDCC risk groups are used. This update confirms that CN should still not be considered the standard of care. However, some important points need to be considered:
- CN might be beneficial for patients with only one IMDC risk factor, especially if they have only one metastatic site.
- The number of metastatic sites per se does not help define appropriate candidates for surgery
- Delayed nephrectomy after initial systemic treatment in good responders, is associated with longer overall survival, supporting this approach as a beneficial therapeutic strategy.
Figure 3 – Overall survival in the intention to treat population in the sunitinib alone arm comparing patients who underwent delayed nephrectomy to those that did not:
Presented by: Arnaud Mejean, MD, PhD, Department of Urology, Hôpital Européen Georges-Pompidou, Paris Descartes University, Paris, France
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA