The monoclonal antibody girentuximab does not appear to have a clinical benefit in patients with high-risk clear cell renal cell carcinoma (ccRCC).

Adjuvant therapy with girentuximab failed to improve either disease-free or overall survival, compared with placebo, in a cohort of patients who had undergone full surgical resection, according to phase 3 results of the ARISER trial.

In a subset of patients with CAIX scores of 200 or greater, however, there was disease-free survival benefit although it did not reach significance, reported lead author Karim Chamie, MD, of the David Geffen School of Medicine at UCLA, and his colleagues (JAMA Oncol. 2017;3[7]:913-20).

The drug was well tolerated, with an excellent safety profile, and there were no reported drug-related serious adverse events.

“Our finding that girentuximab was more effective in the subgroup of patients younger than 65 years is consistent with these observations and, while requiring prospective confirmation, suggests that an insufficient activation of [antibody-dependent cellular cytotoxicity] could explain the failure of its efficacy,” wrote Dr. Chamie and his colleagues.

The authors also point out that “virtually all trials of adjuvant therapy in high-risk RCC have failed to show a treatment benefit,” and thus illustrates the difficulty in identifying successful adjuvant therapies.

“The success of future adjuvant trials will require use of inclusion criteria sufficiently broad to meet accrual goals while limiting inclusion to patients who are most likely to benefit from therapy,” they write.

Girentuximab is a chimeric monoclonal antibody that binds carbonic anhydrase IX, a cell surface glycoprotein that is ubiquitously expressed in ccRCC. Phase 2 studies showed the agent to be safe and active in this setting, and served as the basis for conducting the current phase 3 ARISER trial (Adjuvant Rencarex Immunotherapy Phase 3 Trial to Study Efficacy in Nonmetastatic RCC).

The randomized, double-blind, placebo-controlled trial was conducted at 142 academic medical centers in 15 countries in North and South America and Europe and included a cohort of 864 patients who had undergone partial or radical nephrectomy for ccRCC and fell into one of the following high-risk groups: pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater.

The cohort was randomly assigned to either a single loading dose of girentuximab, 50 mg (week 1), followed by weekly intravenous infusions of girentuximab, 20 mg (weeks 2-24), or placebo, stratified by risk group and region.

The overall disease-free survival was comparable for the two groups: at 5 years it was 53.9% and 51.6% for the girentuximab and placebo groups, respectively, while the median disease-free survival was 71.4 months (interquartile range, 3 months to not reached) for patients who received girentuximab and was not reached for those receiving placebo (P = .74).

Median overall survival was not reached for either of the two groups, and there was no difference in overall survival between arms (hazard ratio, 0.99; 95% confidence interval, 0.74-1.32).

Adverse events were reported in 185 patients (21.6%), and were comparable between groups, and serious events occurred in 72 patients (8.4%), and were also comparable between the two arms.

The study was funded by Wilex, AG. Dr. Chamie receives research support from and serves as a consultant for UroGen Pharma, receives grant support from Phase One Foundation and Stop Cancer, and is a consultant for Cold Genesys and a scientific advisory board member of Altor. Several coauthors reported relationships with industry.