PFR Unaffected by Sequence of Cytoreductive Nephrectomy and Sunitinib in Patients With Synchronous mRCC

Axel Bex MD, PhD

Treating primary tumors by administering targeted therapy with sunitinib (Sutent) prior to cytoreductive nephrectomy (CN) did not improve the progression-free rate (PFR) at 28 weeks over a sequence of immediate CN followed by sunitinib in patients with synchronous metastatic renal cell carcinoma (mRCC), according to findings from a randomized trial presented at the 2017 ESMO Congress in Madrid, Spain.¹

“Overall survival and post-surgical complication rates were better with deferred versus immediate cytoreductive nephrectomy, while progression rates at 16 and 28 weeks were not significantly different between both sequences,” said Axel Bex MD, PhD, a urological surgeon in the Netherlands Cancer Institute in Amsterdam, The Netherlands.

To investigate whether reversing the sequence of CN followed by targeted therapy could improve outcome, Bex and colleagues randomized patients with mRCC to immediate CN followed by sunitinib versus 3 cycles of sunitinib followed by CN plus sunitinib. The EORTC 30073 SURTIME study (NCT01099423) included patients with histologically confirmed clear-cell subtype, and a resectable asymptomatic primary tumor plus 3 or fewer surgical risk factors, following preoperative variables determined by Stephen H. Culp, MD, PhD, and colleagues in 2010.²

Due to poor accrual, it was decided to report the PFR at week 28 as the primary endpoint, which required 98 patients, instead of median progression-free survival, which required 380 events to detect a 3-month increase (with a hazard ratio [HR] of 0.75) with deferred CN with a 2-sided 5% log rank test at 80% power. Overall survival (OS), adverse events (AEs), and post-operative progression in both arms were secondary endpoints.¹

“The trial accrued poorly, making these results mainly exploratory,” explained Bex. “In hindsight, PFS as a primary endpoint has shortcomings due to frequent treatment breaks.”

After 5.7 years, the study included 99 patients from 19 institutions. The immediate CN arm had 50 patients and the deferred CN arm had 49 patients. The majority of patients were male in both arms with a median age of 60 compared to 58 years, and Memorial Sloan Kettering Cancer Center intermediate risk was reported for 86% versus 87.7% of patients, respectively. In the respective arms, WHO performance status (PS) was 0 and 1 in 72% and 28% versus 63.3 % and 36.7% of patients; 86% versus 93.9% of patients had ≥2 measurable metastatic sites and the mean size of the primary tumour was 93.1 mm versus 96.8 mm.¹

At a median follow-up of 3.3 years, 46 out of 50 patients underwent CN in the immediate CN arm and 40 of these patients had received post-CN sunitinib. In the deferred CN arm, 48 out of 49 patients had been treated with sunitinib prior to CN; of these patients, 40 underwent CN and 26 also received post-CN sunitinib.

Although patients in each arm derived benefit from each sequence, no significant difference between the treatment sequence was observed in PFR, which was 42.0% (95% CI, 28.2-56.8) versus 42.9% (95% CI, 28.8-57.8) in the immediate and deferred arms, respectively (P >0.99).

“While the sequence of CN and sunitinib did not affect the PFR at 28 weeks, an OS signal was seen for deferred CN, but the sample size precludes definitive conclusions from other endpoints,” Bex commented, “The survival in the deferred arm is comparable to data reported from previous single arm phase II studies or presurgical sunitinib or pazopanib.”

However, OS stratified by WHO PS of the intention to treat (ITT) population showed a two-fold advantage favouring deferred versus immediate CN; median OS was 32.4 months (95% CI, 14.5-65.3) versus 15.1 months (95% CI 9.3-29.5), respectively, HR 0.57 (95% CI, 0.34-0.95; P = 0.032).¹

“The deferred CN approach initiates therapy quickly, does not lead to the inability to perform CN, and CN after sunitinib appears to be safe,” said Bex.

Fewer surgical complications were seen in the deferred arm, where complications occurred in 27.5% of patients compared to 43.5% of patients treated with immediate CN.

The PFR at 16 weeks was 46% in patients after immediate CN, compared to 32.7% in patients prior to planned CN in the deferred arm. The protocol recommended not to perform deferred CN in patients with progression. Session discussant Michael Staehler, MD, PhD, professor of urology at Klinikum Grosshadern, Ludwig Maximilians University of Munich in Munich, Germany, commented, “The low recruitment is likely explained by patient concerns about being randomized into the delayed surgery trial arm. The role of nephrectomy in metastatic renal cell carcinoma remains unclear and better criteria for selecting patients who will not benefit are urgently needed. Delaying cytoreductive nephrectomy is a viable option.”

This trial was funded by Pfizer.

References

1. Bex A, Mulders P, Jewett M, et al. Immediate versus deferred cytoreductive nephrectomy (CN) in patients with synchronous metastatic renal cell carcinoma (mRCC) receiving sunitinib (EORTC 30073 SURTIME). Abstract presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA35.
2. Culp SH, Tannir NM, Abel EJ, et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? Cancer. 2010;116(14):3378-3388. doi: 10.1002/cncr.25046.

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