Clinical End Points and Trial Designs Undergo Evolution in RCC

Chung-Han Lee, MD, PhD, outlines common clinical trial end points in renal cell carcinoma and those that may provide a more complete picture of a drug’s activity, particularly as the standard of care evolves.

Trial end points provide an important framework for understanding the clinical activity of treatment in oncology, but they are only the starting point when it comes to discussing clinical benefit with patients.

“What we’re really trying to do with all of these end points is think about how to quantify the patient experience. When we talk about the kind of predefined framework that the regulatory environment provides us, what designates a positive clinical trial is really the beginning of the story, and a lot of what comes down the line in terms of how this affects our patients is still left to be written,” Chung-Han Lee, MD, PhD, assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, said in a presentation at the 2022 International Kidney Cancer Symposium.

During his presentation, Lee outlined common clinical trial end points and those that may provide a more complete picture of a drug’s activity, particularly as the standard of care evolves.

Overall survival (OS) has been and will continue to be the gold standard when it comes to clinical trial end points, Lee explained. Along with being a universally accepted measure of direct benefit, OS is easily and precisely measured. However, it is not the only accepted end point, according to Lee, who also pointed to progression-free survival (PFS), time to progression, time to next treatment, objective response rate (ORR), and duration of response as adequate assessments of efficacy.

Comprehensive evaluations of efficacy are especially important now that the frontline paradigm of advanced, clear cell renal cell carcinoma (RCC) has evolved from one of single-agent therapy to dual immune checkpoint blockade and combined VEGF/checkpoint inhibition.

Available combinations now include nivolumab (Opdivo) plus ipilimumab (Yervoy), pembrolizumab (Keytruda) plus axitinib (Inlyta), avelumab (Bavencio) plus axitinib, nivolumab plus cabozantinib (Cabometyx), and pembrolizumab plus lenvatinib (Lenvima).

“Treatment in the first-line setting [of RCC] remains a clinical decision [because we have] limited biomarkers for stratification and no prospective head-to-head comparisons available,” Lee said.

Without definitive head-to-head data, investigators look to cross-trial comparisons to gain semblance of a regimen’s relative activity. For example, Lee pointed to the ORR, PFS, and OS data from the pivotal phase 3 CheckMate-214 (NCT02231749; ORR, 39.1%; HR for PFS, 0.89; HR for OS, 0.69), KEYNOTE-426 (NCT02853331; ORR, 60%; HR for PFS, 0.71; HR for OS, 0.68), CheckMate 9ER (NCT03141177; ORR, 55.7%; HR for PFS, 0.51; HR for OS, 0.60), and CLEAR (NCT02811861; ORR, 71%; HR for PFS, 0.39; HR for OS, 0.66) trials to illustrate the relative measure of each combination’s activity.

Despite these tried-and-true end points, investigators have proposed additional measures of efficacy to augment existing ones, such as the time from initiation of frontline therapy to progression on first subsequent therapy (PFS2), which has been proposed as a potential surrogate for OS. Despite the advantages of OS, Lee noted that one limitation is that it may require a larger trial population and longer follow-up to show statistical difference between groups.

PFS2 may help negate the confounding effect of subsequent lines of treatment and has been endorsed by the European Medicines Agency as a prespecified outcome measure in oncologic clinical trials where OS evaluation is not possible.

Additionally, Lee explained that newer end points such as treatment-free interval, although valuable to an extent, fail to capture the patient’s experience as it relates to ongoing toxicity.

“If we think about it a little bit more beyond treatment-free survival, what we’re looking for [with] our patients is not necessarily for them to be treatment free, but toxicity free. That’s a metric that we may want to start thinking about in the future, [which asks:] What is the time that’s spent either without toxicity, or very low-grade toxicities?” Lee said.

Lee also noted that changes in the standard of care will affect how trials are designed and what end points are selected for primary and secondary evaluation.

“The other question that comes up now that we have divergent treatment approaches is: Do same metrics mean the same thing? That certainly is a question that with more data will be up for debate,” Lee said.

To date, both dual checkpoint blockade and combined VEGF/checkpoint inhibition have served as control arms in large, phase 3 studies. Most notably, the phase 3 COSMIC-313 (NCT03937219) and LITESPARK-012 (NCT04736706) trials, respectively.

“When we ultimately think about the way that we’ll be integrating this data into our treatment modality to see benefit, what we may be focusing on is going to be slightly different depending on which of those choices have been made with regard to that control arm,” Lee concluded.


Lee CH. Choosing endpoints and designs of future trials. Presented at: International Kidney Cancer Symposium; November 4-5, 2022. Austin, TX. Session 8.