From the Journals

Sunitinib alone not inferior to nephrectomy-sunitinib in metastatic RCC

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Patient selection plays critical role

The finding of the CARMENA trial that sunitinib was not inferior to nephrectomy should not lead to the abandonment of nephrectomy, according to Robert J. Motzer, MD, and Paul Russo, MD.

Instead, the results emphasize the importance of carefully selecting patients for nephrectomy based on published risk models, Dr. Motzer and Dr. Russo wrote in an editorial.

“We think that nephrectomy in properly chosen patients with metastatic renal cell carcinoma remains an essential component of care,” they said.

It is not surprising that the CARMENA study met its noninferiority endpoint, as it was “heavily weighted” toward poor-risk patients, they added.

Over an 8-year period, 79 European centers enrolled 450 patients out of 576 patients planned, or just 0.7 patients per site per year.

“This slow and incomplete enrollment raises the possibility that many centers saw few patients with stage IV disease, or that when surgeons saw patients with intermediate-risk disease who were likely to benefit from combination therapy, they were unwilling for them to undergo randomization and instead treated them outside the trial,” they wrote.

Over the same time frame at Dr. Motzer’s and Dr. Russo’s center, there were 189 patients with stage IV disease, or about 24 patients each year.

“We took care to avoid operating on poor-risk patients with extensive metastatic disease, instead focusing on intermediate-risk patients,” they explained in their editorial.

Dr. Motzer and Dr. Russo are with Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York. These comments come from their editorial in the New England Journal of Medicine. Dr. Russo had nothing to disclose. Dr. Motzer reported disclosures related to Genentech/Roche, Pfizer, Novartis, Exelixis, Eisai, Bristol-Myers Squibb, and Merck outside the submitted work.


 

FROM NEW ENGLAND JOURNAL OF MEDICINE

Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic, clear cell renal cell carcinoma (RCC), according to results of the randomized, phase 3 CARMENA trial.

Overall survival was not inferior in the sunitinib arm of the trial, which comprised 450 patients who were suitable candidates for nephrectomy and had MSKCC intermediate or poor risk disease.

These findings contrast with those of previous retrospective studies suggesting patients undergoing nephrectomy who were treated with targeted therapies had an overall survival benefit, according to Bernard Escudier, MD, of Gustave Roussy Institute, Villejuif, France, and his coauthors.

“Given the many approved options for systemic targeted therapy that are now available, the reassessment of the role of surgery in disease management is important,” Dr. Escudier and his colleagues noted. The report is in the New England Journal of Medicine.

The CARMENA trial enrolled 450 out of a planned 576 patients in 79 European centers between September 2009 and September 2017. A total of 226 were randomized to sunitinib alone and 224 to nephrectomy and sunitinib.

With a median follow-up of 50.9 months and 326 deaths, the hazard ratio for death was 0.89 (95% confidence interval, 0.71-1.10). The upper boundary of the 95% CI for noninferiority was 1.20, according to the report.

Median overall survival was 18.4 months for the sunitinib alone arm, and 13.9 months for the nephrectomy-plus-sunitinib arm. While the study was statistically underpowered because of incomplete enrollment, that “trend in longer overall survival” supports the findings favoring sunitinib alone in this noninferiority trial, the authors noted.

Safety results were as expected based on previous trial results, according to the investigators. Grade 3/4 adverse events occurred in 91 patients (42.7%) in the sunitinib group, and 61 (32.8%) in the nephrectomy-sunitinib group, they reported. Nine patients in the sunitinib group had grade 3/4 renal or urinary tract disorders, versus 1 in the nephrectomy-sunitinib group (P = .051).

These findings confirm current clinical practice guidelines on the use of systemic targeted therapy in patients with poor-risk metastatic RCC, according to the authors.

However, targeted therapy in this setting has evolved considerably since the CARMENA trial was designed.

Sunitinib remains one of the most commonly used treatments in patients with good or intermediate prognosis metastatic RCC; however, recent randomized trials show the superiority of the c-MET inhibitor cabozantinib and the immune checkpoint inhibitor combination of nivolumab plus ipilimumab over sunitinib.

Those newer agents will likely become initial treatment options for intermediate- and poor-risk groups, according to the authors.

Both cabozantinib and nivolumab plus ipilimumab are listed as first-line treatment options for intermediate- and poor-risk patients in the most recent clinical practice guidelines from the National Comprehensive Cancer Network.

Nephrectomy may have a role for symptom control in some patients with metastatic RCC, based on results of previous retrospective studies suggesting benefit.

“There is no ‘one size fits all’ approach,” Dr. Escudier and his coauthors wrote. “The multimodal approach of individualized treatment provides appropriate management of metastatic renal-cell carcinoma.”

Dr. Escudier reported personal fees from Bristol-Myers Squibb, EUSA Pharma, Ipsen, Novartis, Pfizer, and Roche outside the submitted work. Coauthors reported disclosures with Bayer, MSD, Janssen, Astellas, Bouchara, Ferring, and others.

SOURCE: Méjean A et al. N Engl J Med. 2018 Aug 2. doi: 10.1056/NEJMoa1803675.

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