In the modern era of targeted therapy, some patients with metastatic renal cell carcinoma may be able to forgo nephrectomy and be treated with sunitinib (Sutent) alone, according to results of the phase III CARMENA trial reported during the Plenary Session at the 2018 ASCO Annual Meeting.1 The median overall survival was 18.4 months for patients treated with targeted therapy using sunitinib vs 13.9 months for those treated with nephrectomy followed by sunitinib—the current standard of care. These findings were simultaneously published in The New England Journal of Medicine.2
Arnaud Méjean, MD, PhD
“Patients with kidney cancer who have metastasis when the cancer is first diagnosed account for about 20% of all kidney cancers worldwide. Our study is the first to question the need for surgery in the era of targeted therapies and clearly shows that surgery for certain people with kidney cancer should no longer be the standard of care,” said lead author Arnaud Méjean, MD, PhD, a urologist at the Hôpital Européen Georges-Pompidou-Paris Descartes University.
The key to this take-home message is the word “some.” Experts interviewed for this article agreed that nephrectomy should not be completely abandoned and that patient selection is key.
Words of Caution
ASCO expert Sumanta K. Pal, MD, was more cautious about widely applying these results. “The prognosis of advanced kidney cancer has improved markedly thanks to the advent of targeted therapy. The median survival has improved from 1 to 3 years with targeted therapy. We have been removing the kidney based largely on surveys and retrospective studies. The highest bar is a randomized trial, such as CARMENA. The study, a noninferiority study, suggests that in the context of sunitinib, there doesn’t seem to be an advantage
We may have to go back to the drawing board once again and assess the relevance of removing the kidney.— Sumanta K. Pal, MD
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for nephrectomy. We have to take these results with a grain of salt. New treatments may obviate sunitinib, such as cabozantinib (Cabometyx) and nivolumab (Opdivo)/ipilimumab (Yervoy). We may have to go back to the drawing board once again and assess the relevance of removing the kidney,” he said.
ASCO Chief Medical Officer Richard Schilsky, MD, commented: “Small noninferiority trials can’t answer questions like this. These questions require large prospective randomized trials.”
Nephrectomy has been the standard of care for metastatic renal cell carcinoma for 20 years, but now that targeted therapies have improved outcomes substantially, the question is whether all patients should have nephrectomy as well as targeted therapy. Nephrectomy poses risks for complications such as blood loss, infection, pulmonary embolism, and heart problems and may delay necessary systemic treatment for weeks. In some cases, a patient’s condition may worsen during treatment delay, and the patient may be unable to tolerate systemic treatment.
CARMENA enrolled 450 patients from September 2009 to September 2017 to determine whether upfront nephrectomy is necessary before sunitinib treatment. The study enrolled patients with metastatic clear cell renal cell carcinoma at the time of diagnosis. All patients were suitable candidates for nephrectomy. Symptomatic brain metastasis was an exclusion criterion. All patients had a good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1).
Patients were randomized 1:1 to receive nephrectomy followed by sunitinib or sunitinib alone. Sunitinib was given at 50 mg/d in cycles of 28 days on and 14 days off every 6 weeks. In the surgery arm, sunitinib was initiated 3 to 6 weeks after nephrectomy. Dose reductions or interruptions were allowed for the management of adverse events.
Patients were stratified as intermediate or poor risk according to Memorial Sloan Kettering Cancer Center (MSK) criteria. Both arms had a similar proportion of risk groups. The median age was 62; 75% were men. In the nephrectomy arm, 55.6% were considered intermediate risk and 44.4% were poor risk. In the sunitinib-alone group, 58.5% and 41.5% were intermediate and poor risk, respectively.
In the surgery arm, 7.1% did not have nephrectomy and 17.7% did not receive subsequent sunitinib. In the sunitinib arm, 4.9% did not receive sunitinib. The protocol allowed delayed nephrectomy for palliation or in cases of near-complete response of metastatic disease in the sunitinib-alone arm; 17% of patients underwent a secondary nephrectomy, a median of 11 months after randomization. Median follow-up for the entire population was 50.9 months.
Although the difference in survival favors sunitinib alone, this cannot be concluded from this trial. “The trial is a noninferiority trial and was not designed to prove that one treatment is superior to the other,” Dr. Méjean noted. He added that nephrectomy remains the gold standard for patients who do not require systemic therapy, such as those with one metastasis alone.
The median overall survival was noninferior in the sunitinib arm, and this was true for both intermediate- and poor-risk groups. In the intent-to-treat analysis, the median overall survival was 13.9 months in the surgery arm vs 18.4 months in the sunitinib-alone arm. For intermediate-risk patients, the median overall survival was 19 months vs 23.4 months, respectively. For poor-risk patients, the median overall survival was 10.2 months vs 13.3 months, respectively. Objective response rates and progression-free survival rates were no different between the two arms.
Overall, 38.1% of patients experienced a grade 3 or 4 adverse event (32.8% in the nephrectomy-sunitinib arm and 42.7% in the sunitinib-alone arm [P = .04]). The most common grade 3 and 4 events in the sunitinib arm were asthenia, hand-foot syndrome, anemia, and neutropenia. Grade 3 or 4 urinary tract disorders occurred in one patient in the nephrectomy-sunitinib group and in nine patients in the sunitinib-alone group. No other significant differences were observed between treatment arms.
DISCLOSURE: Dr. Méjean is a consultant or advisor with Sanofi, Bristol-Myers Squibb, and Janssen; has received travel expenses from Roche, Ipsen, Novartis, and Bristol-Myers Squibb; has received honoraria from Novartis, Pfizer, and Ipsen; and has received institutional research funding from Pfizer. Dr. Pal is a consultant for Genentech, Aveo, Eisai, Roche, Pfizer, Novartis, Exelixis, Ipsen, Bristol-Myers Squibb, and Astellas. Dr. Schilsky reported no conflicts of interest. ■
1. Méjean A, Escudier B, Thezenas S, et al: CARMENA: Cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma. 2018 ASCO Annual Meeting. Abstract LBA3. Presented June 3, 2018.
Daniel George, MD
Formal discussant of the CARMENA trial, Daniel George, MD, of Duke University Medical Center, Durham, North Carolina, had reservations about the broad application of these results. “CARMENA was designed to reassess the value and role of nephrectomy in patients who present ...!-->!-->