Treatment with sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with advanced renal cell carcinoma and intermediate to high risk in effect on overall survival.
Renal cell carcinoma (RCC) accounts for 5% of all cancers in men and 3% in women. In about 20% of patients, the disease has already metastasized at diagnosis. In the last 20 years, nephrectomy followed by systemic therapy has been standard in these cases. In the last 10 years, targeted therapies have been shown to be effective in patients with metastatic RCC. So far, however, there has been no direct comparison of targeted therapy with nephrectomy.
There are three situations with mRCC, depending on the progression of a tumor, explained the French oncologist. For patients with good performance status (PS 0) and low metastatic tumor load, nephrectomy is useful. It does not make sense for patients with PS 2 and high tumor load. The situation in patients with PS 0-1 and limited metastatic tumor load is still unclear.
Therefore, the Phase III CARMENA (Cancer Renal Metastatique Nephrectomie Antiangiogéniques) study compared the efficacy of sunitinib alone and nephrectomy followed by sunitinib in 450 patients in 79 centers in France, Norway, and the UK. The untreated patients were nephrectomized in arm A, 3 to 6 weeks later a treatment with sunitinib (50 mg/day over 4 weeks, then 2 weeks break) was started. Patients in arm B only received sunitinib. Primary endpoints were overall survival, secondary endpoints included progression-free survival (PFS), response rate, clinical benefit, and tolerability. The study was designed to prove non-inferiority.
The data presented were based on the results of the predefined second interim analysis with a median follow-up of 50.9 months. Based on the results, the Steering Committee recommended that the study be discontinued and the interim analysis is therefore considered the final analysis of the study.
The results of the randomized phase III study CARMENA were presented by Arnaud Méjean, Department of Urology, Hôpital Européen Georges-Pompidou, Paris, at the plenary session of the 2018 ASCO Annual Meeting in Chicago on June 3, 2018, and published in parallel in the New England Journal of Medicine.
The median age of the patients was 62 to 63 years, 75% were men. Arm A with nephrectomy and sunitinib included 226 patients, of whom 40 were not treated with sunitinib and 16 patients were not operated on. 11 patients in arm B of sunitinib (n = 224) did not receive sunitinib. In arm A 56% showed an intermediate risk and 44% a high risk, in arm B 59% and 41%.
At the time of the data analysis, 326 deaths had occurred, 91% of which were due to cancer. Patients of the sunitinib group survived in the median 18.4 months, those of the nephrectomy group 13.9 months (hazard ratio 0.89). Sunitinib did not prove inferior to the comparison strategy, the primary endpoint was thus reached. In both the intermediary and high-risk groups, median survival was better with sunitinib alone than with surgery plus sunitinib, with the intermediary risk it was 19.0 vs. 23.4 months (HR 0.92), with high risk 10.2 vs. 13.3 months (HR 0.86). Also in the per-protocol analysis, sunitinib was not inferior in effect on overall survival of nephrectomy plus sunitinib. The same applied to the effect on the PFS in both ITT and per-protocol analysis. In the ITT analysis, PFS with sunitinib was 8.3 months in the median and 7.2 months with combined therapy (HR 0.82).
Patients responded to sunitinib treatment with 29.1% and 27.4% to combined therapy, clinical benefit (disease control for longer than 12 weeks) was achieved in 47.9% and 36.6%, respectively.
The sunitinib treatment lasted 8.5 months in arm B and 6.7 months in the nephrectomy arm. Approximately 30.5% of patients in both groups needed a dose reduction, mostly due to side effects. Grade 3/4 side effects occurred in 32.8% of patients undergoing surgery and 42.7% of patients treated with sunitinib alone. Asthenia, hand-foot syndrome, anemia, and neutropenia were reported most frequently.
Méjean concluded: "Cytoreductive nephrectomy should no longer be regarded as the standard of care in the treatment of metastatic RCC, especially when drug treatment is required. However, nephrectomy remains the gold standard in patients who do not require systemic therapy and have very few metastases.
Robert Motzer and Paul Russo from the Memorial Sloan Kettering Cancer Center, New York, however, are somewhat less euphoric about the results in the accompanying editorial in the New England Journal of Medicine. It is not surprising that the primary endpoint has been reached, as the CARMENA study included a relatively large number of high-risk patients - 43%. They are unlikely to benefit from surgery and are more likely to suffer disadvantages as a result of the invasive procedure and potential complications. In addition, the higher percentage of locally advanced T3 or T4 tumors in the sunitinib group (70.1% vs. 51%) may have affected the outcome of the surgical group.
Motzer and Russo also believe that, despite ITT analysis, the interpretation of the results is complicated because, for example, 40 patients (17%) in the surgical group did not receive sunitinib and 16 patients (7%) did not undergo surgery at all. In the sunitinib group, 11 patients (4.9%) received no sunitinib and 38 (17%) were subsequently nephrectomized.
The editorialists recommend that these data should not lead to a renunciation of nephrectomy. It is important to carefully select patients for nephrectomy on the basis of published risk models. Risks of pre-treatment, resectability of the primary tumor, state of health and the presence of other diseases determined who could probably benefit from a nephrectomy.
Méjean A, et al. CARMENA: Cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma-Results of a phase III noninferiority trial. 2018 ASCO Annual Meeting, Chicago, June 1-5, 2018, Abstract LBA3. https://meetinglibrary.asco.org/record/161512/abstract
Méjean A, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N Engl J Med. published online on June 3, 2018. https://www.nejm.org/doi/full/10.1056/NEJMoa1803675
Motzer RJ, Russo P. Cytoreductive Nephrectomy - Patient Selection Is Key. N Engl J Med. published online on June 3, 2018. https://www.nejm.org/doi/full/10.1056/NEJMe1806331