Sunitinib Alone Shows Noninferiority Versus Standard of Care in mRCC

Arnaud Mejean, MD

Arnaud Mejean, MD

According to findings from the phase III CARMENA trial (NCT00930033) presented at the 2018 ASCO Annual Meeting, sunitinib (Sutent) monotherapy demonstrated noninferiority compared with cytoreductive nephrectomy in combination with sunitinib in patients with synchronous metastatic renal cell carcinoma (mRCC).¹

The median overall survival (OS) was 18.4 months for sunitinib compared with 13.9 months for cytoreductive nephrectomy plus sunitinib, the current standard of care (HR, 0.89; 95% CI, 0.71-1.10). The prespecified noninferiority margin was ≥1.20 for the upper bound of the confidence interval.

Sunitinib produced similar median OS results for patients with intermediate (23.4 vs 19.0 months; HR, 0.92; 95% CI, 0.68-1.24) and poor prognosis (13.3 vs 10.2 months; HR, 0.85; 95% CI, 0.62-1.17), according to MSKCC risk groups. Patients with good prognosis were excluded from the trial.

Median progression-free survival was 7.2 months (95% CI, 6.2-8.5) with sunitinib alone versus 8.3 months (95% CI, 6.2-9.9) with surgery/sunitinib.

“Sunitinib alone is not inferior to nephrectomy followed by sunitinib,” said lead study author Arnaud Méjean, MD, a urologist at Hôpital Européen Georges-Pompidou—Paris Descartes University. “When medical treatment is required, cytoreductive nephrectomy should no longer be considered the standard of care for these patients with synchronous metastatic disease.”

Méjean added that the receptor tyrosine kinase inhibitor appears to extend survival, but the trial was only powered to detect noninferiority, not superiority.

Patients at 79 centers in France, Norway, and the United Kingdom were assigned to cytoreductive nephrectomy followed by sunitinib 3 to 6 weeks later (n = 226) or 50 mg of once-daily sunitinib for 4 weeks on/2 weeks off (n = 224) from 2009 to 2017. In the surgery arm, 6.7% of patients did not undergo nephrectomy and 22.5% never received sunitinib. In the sunitinib arm, 4.9 % of patients never received sunitinib and 17% had secondary nephrectomy.

At a median follow-up of 50.9 months, investigators found that the overall response rate was 35.9% in both groups, and the rate of tumor shrinkage was similar between the treatment groups (27.4% vs 29.1%). The clinical benefit rate in the sunitinib group was 47.9% compared with 36.6% in the surgery group.

The FDA approved sunitinib for the adjuvant treatment of adults at high risk for recurrent RCC following nephrectomy in November 2017 based on results from the multicenter, international, double-blind, placebo-controlled, S-TRAC trial.^2,3

Investigators assigned patients to placebo or 50 mg of once-daily sunitinib for 4 weeks on/2 weeks off. After a median follow-up duration of 5.4 years, the median disease-free survival (DFS) was 6.8 years (95% CI, 5.8-not reached) in the sunitinib arm compared with 5.6 years (95% CI, 3.8-6.6) with placebo (HR, 0.76; 95% CI, 0.59-0.98;P= .03).

In higher-risk patients, the median DFS was 6.2 (95% CI, 4.9-not reached) versus 4.0 years (95% CI, 2.6-6.0) in favor of sunitinib (HR, 0.74; 95% CI, 0.55-0.99; P = .04).

ASCO expert Sumanta Kumar Pal, MD, associate clinical professor, Department of Medical Oncology and Therapeutics Research at City of Hope Comprehensive Cancer Center in Duarte, California, said that findings from retrospective studies appear to show a benefit associated with nephrectomy, but the prospective, randomized results from CARMENA show that this may not be the case.

“In the context of the targeted therapy sunitinib, there doesn’t necessarily seem to be a need to remove the kidney in patients with advanced and metastatic disease,” Pal said. “[Méjean has] really sort of flipped the existing paradigm that we have in the management of advanced kidney cancer in this regard.”

Pal noted that the recent approvals of cabozantinib (Cabometyx) for treatment-naïve patients and the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline treatment for patients with intermediate- and poor-risk disease may eventually make sunitinib obsolete.

In the phase II CABOSUN trial, first-line cabozantinib reduced the risk for progression or death by 52% compared with sunitinib. The median PFS was 8.6 months with cabozantinib versus 5.3 months for sunitinib (HR, 0.48; 95% CI, 0.31-0.74;P= .0008).⁴

In the phase III CheckMate-214 trial, the combination reduced the risk for death by 32% compared with sunitinib. The risk reduction was 37% in patients with intermediate- and poor-risk RCC, who constituted about 75% of the intent-to-treat population.⁵

“In the context of these newer therapies, we may potentially have to go back to the drawing board once again and assess the relevance of removing the primary tumor,” Pal concluded.

References

1. Méjen A, Escudier B, Thezenas S, et al. CARMENA: Cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—results of a phase III noninferiority trial.J Clin Oncol.2018;36(suppl; abstr LBA3).
2. Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy [published online October 10, 2016].N Engl J Med.doi: 10.1056/NEJMoa1611406.
3. Ravaud A, Motzer RJ, Pandha HS, et al. Phase III trial of sunitinib (SU) vs placebo (PBO) as adjuvant treatment for high-risk renal cell carcinoma (RCC) after nephrectomy (S-TRAC). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract for LBA11.
4. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). Presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.
5. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA5.