ARISER study: No benefits but excellent safety with girentuximab in high-risk clear cell renal cell carcinoma

Adjuvant treatment with girentuximab did not improve disease-free survival (DFS) or overall survival (OS) compared with placebo in patients with fully resected, high-risk clear cell renal cell carcinoma (ccRCC), according to results from the ARISER study, which were published in JAMA Oncology.

“In this large prospective trial, adjuvant girentuximab therapy did not improve DFS or OS in patients with ccRCC at high risk for recurrence. Girentuximab was well tolerated, with an excellent safety profile and no reported drug-related serious AEs. In the subgroup of patients with carbonic anhydrase IX (CAIX) scores of 200 or greater, there was a nonsignificant DFS benefit,” wrote these authors.

In the ARISER trial (Adjuvant Rencarex Immunotherapy Phase 3 Trial to Study Efficacy in Nonmetastatic RCC), a randomized phase 3 clinical trial conducted at 142 sites in 15 countries, researchers sought to determine whether adjuvant weekly treatment with girentuximab after complete resection of clinically localized, high-risk ccRCC improves DFS and OS compared with placebo.

They included 864 patients (median age: 58 years; 66% male) who underwent partial or radical nephrectomy for histologically confirmed ccRCC at high-risk categorized as pT3/pT4Nx/N0M0, pTanyN+M0 or pT1b/pT2Nx/N0M0, with nuclear grade 3 or greater. Patients were randomized 1:1 to either a single loading doses of girentuximab (50 mg at week 1) followed by weekly IV infusions of girentuximab (20 mg from weeks 2-24) (n=433) or placebo (n=431).

Researchers assessed the study’s co-primary end points—DFS and OS—via imaging studies that were then assessed by an independent radiological review committee. The secondary endpoint of the study was safety.

In patients treated with girentuximab, researchers found no statistically significant advantages in DFS (HR: 0.97; 95% CI: 0.79, 1.18) or OS (HR: 0.99; 95% CI: 0.74, 1.32) compared with placebo. In the girentuximab group, median DFS was 71.4 months; in the placebo group, this was never reached. Regardless of which treatment was received, median OS was never reached.

Drug-related adverse events occurred in 21.6% of patients, and was similar in both arms of patients, as were serious adverse events, which occurred in 8.4%. In the placebo group, one drug-related serious adverse event occurred.

In an accompanying editorial, authors Martin H. Voss, MD, and Robert J. Motzer, MD, both from Memorial Sloan Kettering Cancer Center, New York, NY, wrote:

“With the successful development of 10 molecularly targeted agents during the course of the past decade, the management of metastatic renal cell cancer (RCC) has seen unparalleled progress owing to better understanding of the molecular biology of this disease.1 In contrast to these advances made for patients with disseminated disease, randomized clinical trials in the nonmetastatic setting have been largely unsuccessful, and the standard of care for resectable stages I to III disease remains nephrectomy followed by active surveillance.”

They added that despite the lack of improvements in DFS and OS researchers observed, their results, and those of other studies, are still important.

“ARISER is an impressive international effort to address a critical clinical need in this disease. The trial has helped to further our understanding of the prognostic significance of CAIX as a biomarker in early-stage RCC. Although the study cannot justify further adjuvant development of girentuximab, negative trial results can be instructive for future efforts in this space, and ARISER stresses the importance of choosing the correct study population in regard to the risk for recurrence and presence of the therapeutic target,” wrote Drs. Voss and Motzer.

“We should maximize our understanding of potential biomarkers from previously conducted metastatic trials first, and then optimize design of coming studies in the early-stage perioperative setting. Ultimately, these many ongoing and future efforts offer hope that we may still extend the success of targeted therapeutics in RCC to a broader patient population,” they concluded.

References

1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology—kidney cancer. NCCN Evidence Blocks, version 3.2016. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Published May 26, 2016. Accessed July 24, 2016.