A phase III study of adjuvant girentuximab in patients with high-risk clear cell RCC showed that the drug provided no clinical benefit compared with placebo.
A phase III study of adjuvant girentuximab, a chimeric monoclonal antibody that binds carbonic anhydrase IX, in patients with high-risk clear cell renal cell carcinoma (RCC) showed that the drug provided no clinical benefit compared with placebo. Disease-free and overall survival were similar between all patients in the ARISER trial.
“The fact that virtually all trials of adjuvant therapy in high-risk RCC have failed to show a treatment benefit, including the recently published ECOG-ACRIN (ASSURE) E2805 trial, illustrates the difficulty in successful adjuvant RCC therapeutic discovery,” wrote researcher Karim Chamie, MD, MSHS, of the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues in a study published in JAMA Oncology. “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.”
The multicenter, international trial was conducted from June 2004 to April 2013. It included 864 patients from 142 centers in 15 countries. Patients had undergone partial or radical nephrectomy for clear cell RCC and were considered to have high-risk disease. Patients were randomly assigned to girentuximab 50 mg in week 1 followed by weekly infusions at 20 mg for weeks 2 to 24, or placebo.
After 5 years of follow-up, participants assigned to girentuximab had no significant improvement in disease-free survival (hazard ratio [HR], 0.97 [95% CI, 0.79–1.18]) or overall survival (HR, 0.99 [95% CI, 0.74–1.32]) compared with patients assigned to the placebo arm. The median disease-free survival was 71.4 months for girentuximab and was not reached for the placebo arm. Median overall survival was not reached for either arm.
“After 5 years of follow-up, more than half of patients remained free of recurrence,” the researchers wrote. “These excellent survival rates observed in ARISER may be driven in part by improvements in computed tomographic sensitivity, which may contribute to earlier and more thorough detection of previously occult disease, thereby excluding patients with rapidly progressing disease from study inclusion. As such, historical relapse rates, such as those used in the power calculations in ARISER, may no longer be consistent with contemporary clinical experience.”
Overall the drug was well tolerated. Drug-related adverse events occurred in 21.6% of patients and was similar between the two study arms. Serious adverse events occurred in 8.4% of patients.
The researchers quantified a carbonic anhydrase IX (CAIX) score for 98% of the intent-to-treat population. Median CAIX score was 190. The researchers found nonsignificant benefit to girentuximab with increasing CAIX score. Those patients with a score of 200 or greater had a nonsignificant improvement in disease-free survival (HR, 0.75 [95% CI, 0.55–1.04]; P = .08). According to the researchers, this difference warrants “further study of CAIX score as a predictive biomarker.”
Commenting on what can be learned from the negative trial in an editorial, Martin H. Voss, MD, and Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York, wrote: “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.”