CME Author: Vicki Brower
Study Authors: Axel Bex, Peter Mulders, et al.; Primo Lara and Christopher Evans
Target Audience and Goal Statement:
Medical oncologists, nephrologists, surgical oncologists, urologic oncologists, and urologic surgeons
The goal was to determine whether treatment with sunitinib (Sutent) before cytoreductive nephrectomy (CN) improves outcomes for patients with metastatic renal cell carcinoma (mRCC) compared with the reverse — immediate CN followed by sunitinib.
Does treatment of mRCC with sunitinib, a targeted therapy, before CN, result in benefits compared with performing CN immediately and following with systemic treatment with sunitinib?
Study Synopsis and Perspective
In clinical practice, patients with primary mRCC are typically offered the option of having cytoreductive nephrectomy (CN) followed by targeted therapy with sunitinib, but the optimal sequence of surgery and systemic therapy has not been known — i.e., it has not been known if the reverse would be better.
The CARMENA (Clinical Trial to Assess the Importance of Nephrectomy) study reported at the 2018 American Society of Clinical Oncology annual meeting found that treatment with sunitinib alone was not inferior to CN followed by sunitinib.
The new study by Axel Bex, MD, PhD, of the Netherlands Cancer Institute, and colleagues, attempted to assess if the sequencing of surgical and systemic treatments could make a difference in outcomes. The results showed that progression-free survival (PFS) at 28 weeks did not increase when patients began sunitinib therapy before planned cytoreductive nephrectomy. With that approach, however, more patients received systemic therapy, and cytoreductive nephrectomy was able to be avoided in patients whose disease progressed.
“The results of SURTIME [Surgery after Sunitinib Maleate in Treating Patients with Metastatic Kidney Cancer] support data from CARMENA that showed that immediate CN does not result in additional benefit and may even be detrimental in patients with primary clear cell mRCC who require sunitinib,” Bex and co-authors wrote online in JAMA Oncology.
Specifically, SURTIME found that the progression-free rate at 28 weeks was 43% in patients who received sunitinib before CN vs 42% in patients who received immediate CN followed by the targeted agent (P=0.61). PFS was the primary end point, but because of the difficulty in accrual, the study did not have enough patients for the needed sample size of 458 patients — the study closed after 5.7 years with only 99 patients enrolled.
At 32.4 months vs 15.0 months, overall survival (OS) was longer in the intention-to-treat population for patients in the deferred-surgery arm of the study compared with those in the immediate-surgery arm (HR 0.57, 95% CI 0.34-0.95, P=0.03). However, in the per-protocol population this benefit lost significance (HR 0.71, 95% CI 0.40-1.24, P=0.23), the researchers reported.
The results indicate, the team concluded, that initiating treatment with sunitinib first and offering nephrectomy only to patients whose disease does not progress (i.e., who did not show resistance to the drug) might be a better option than upfront nephrectomy followed by sunitinib. “Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN,” the team wrote. “These data suggest that performing deferred CN in patients with non-progressing disease may confer a survival benefit instead of limiting CN to only the few patients who need surgery after treatment with sunitinib alone.”
All but one patient in the deferred-CN arm of the study received presurgical sunitinib, and 83% of the group received the requisite three cycles prior to surgery. Of those who received treatment, 23% achieved a partial response, while 29% had progressive disease prior to their scheduled nephrectomy.
In the immediate-CN arm, 92% of patients underwent nephrectomy and 80% received sunitinib; 4 weeks post-CN, 20% had progressed.
Most of the patients in either arm of the study discontinued treatment due to progressive disease at the time of the analysis, at which point 35 of 50 patients in the immediate-CN arm had died, as had 28 of 49 patients in the deferred-CN arm, almost all due to progressive disease.
JAMA Oncology, December 13, 2018; doi: 10.1001/jamaoncol.2018.5543
Study Highlights: Explanation of Findings
Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor with anti-angiogenic properties, which received approval by the U.S. Food and Drug Administration in 2006 for treatment of patients with clear-cell RCC whose disease has not spread. That drug, however, is now increasingly being replaced by checkpoint inhibitor immunotherapies, both as initial treatment and after anti-angiogenic drugs for patients treated first with targeted therapy.
The main goal of the SURTIME study was to test whether pretreatment with a multikinase receptor inhibitor could improve outcomes for mRCC by selecting out patients who are resistant to the drug, and are therefore also unlikely to benefit from CN.
Patients were randomized to have either immediate CN followed by sunitinib (n=50), or three cycles of sunitinib followed by deferred CN if disease had not progressed (n=49) and then have more sunitinib, which was administered at a dose of 50 mg per day for 4 weeks, followed by 2 weeks off.
In an accompanying commentary, Primo Lara Jr., MD, and Christopher Evans, MD, both of the University of California, Davis, said that SURTIME and CARMENA provide evidence that may be viewed as “practice confirming” rather than practice changing: “Both affirm the current requirement for careful patient selection and the abandonment of indiscriminate use of CN in certain high-risk patient subsets for whom immediate systemic therapy alone is likely to be best unless local tumor morbidity mandates surgical intervention,” they wrote in their commentary, which was titled “Cytoreductive Nephrectomy in Metastatic Renal Cell Cancer Not All That It’s Cut Out to Be.”
Regarding the difficulty in enrolling enough patients in the study — which had also been the case with CARMENA — the editorialists as well as Bex and co-authors noted that the slow accrual might have rendered the primary objective of the trial obsolete, since in the almost 6 years it took to close the study, newer, more active treatment options for mRCC patients emerged, including the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy).
“So what else have we learned?” Lara and Evans asked in their conclusion: First, CN is not for every patient, and nephrologists must assess each individual carefully before offering surgical treatment. Also, without prognostic biomarkers, only “rudimentary endpoints” such as disease progression and treatment response are available to determine the patients likely or unlikely to benefit from CN.
Careful patient selection with multidisciplinary input is essential, Lara and Evans emphasized, adding: “Ultimately, it may be that the disease rather than the physician decides who should undergo surgery.”
Pam Harrison wrote the original story for MedPage Today.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner