Dr Haas on Evolutions in Clinical Trial Design in the RCC Treatment Paradigm

"KEYNOTE-564 looked specifically at an ICI—pembrolizumab. Patients received that for 1 year vs placebo."

Naomi B. Haas, MD, a professor of medicine at the Hospital of the University of Pennsylvania and the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center, discussed the rationale for the phase 3 KEYNOTE-564 trial (NCT03142334) of adjuvant pembrolizumab (Keytruda) in patients with clear cell renal cell carcinoma (RCC).

Several adjuvant clinical trials in RCC have been initiated in recent years, largely driven by the promising efficacy observed with immune checkpoint inhibitors (ICIs) in this disease, Haas began. Most of these studies enrolled patients with clear cell histology, reflecting both the prevalence of this subtype and its inclusion in prior advanced disease trials, she said. The design of these adjuvant and perioperative trials was informed by earlier studies conducted between approximately 2007 and 2011 that evaluated VEGF TKIs in the adjuvant setting, she noted. However, in contrast to earlier studies, the more recent ICI-based trials typically focused on populations at higher risk of recurrence, often including patients with at least pT2 high-grade tumors, although inclusion criteria varied slightly across studies, she explained.

One example of a study with broader inclusion criteria is the phase 3 PROSPER EA8143 trial (NCT03055013) of nivolumab (Opdivo) in patients with localized kidney cancer undergoing nephrectomy, which stratified patients based on clinical staging rather than pathologic staging, according to Haas. This stratification factor made this trial unique among the trials that generally required pathologic confirmation post-nephrectomy, she reported. This reliance on pathologic staging in most studies reflects the enrollment of patients following surgical resection of the primary tumor, she stated.

Differences in trial design were also noted among studies like the KEYNOTE-564 study and others, particularly regarding treatment duration and therapeutic combinations, Haas continued. Some trials explored 6-month treatment durations or included combinations of ICIs and CTLA-4 inhibitors, she added. KEYNOTE-564 specifically evaluated adjuvant pembrolizumab monotherapy—administered for a duration of 1 year—vs placebo. This trial enrolled 994 patients, with investigator-assessed disease-free survival as the primary end point. Overall survival and safety outcomes were included as key secondary end points.