PFS Recommended as Primary End Point for Phase 2 Immune Checkpoint Inhibitor Trials

For phase 2 checkpoint-inhibitor trials for advanced solid tumor cancers, 6-month progression-free survival (PFS) is recommended as a primary end point over objective response rate (ORR), according to a study published in JAMA Oncology.

Traditionally, ORR is used as the primary end point for trials evaluating new anticancer therapies. The therapies are assessed in single-arm trials, and their performance is measured against prespecified improvements in ORR, on the basis of historical control data, to identify which therapies undergo further testing in phase 3 randomized controlled trials (RCTs).

“However, the validity of ORR as a surrogate for PFS and overall survival [OS] is uncertain for checkpoint inhibitors because they have unique patterns of response that differ from those of chemotherapy or molecular targeted agents,” wrote the authors of the study.

Noting the importance of selecting an appropriate primary end point as crucial to inform the decision to proceed to phase 3 testing, the authors conducted a systematic search of electronic databases for trial results from January 2000 through January 2017. They identified trials using the keywords: ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, and tremelimumab.

Using data from randomized treatment comparisons, the authors examined the correlations between ORR odds ratio with PFS hazard ratio (HR) and OS HR. The correlation between 6-month PFS and 12-month OS rate ratios were also determined. An odds ratio or HR of less than 1 indicated a favorable result for checkpoint-inhibitor therapy versus non—checkpoint-inhibitor control therapy.

The authors identified 87 phase 2 trials, most of which (n = 59, 68%) were single-arm designs. ORR was the most common primary end point (n = 52, 60%), followed by PFS (n = 11, 13%), toxicity (n = 10, 11%), OS (n = 6, 7%), disease control rate (n = 2, 2%), and other molecular biomarker end points (n = 6, 7%). Twenty eligible RCTs were identified, including 4 with phase 2 designs, comprising of 25 treatment comparisons and 10,828 patients.

Checkpoint-inhibitor therapy was associated with a pooled ORR of 24%. For randomized comparisons, the correlation coefficient between ORR odds ratio and PFS HR was 0.63, between ORR odds ratio and OS HR was 0.57, and between PFS HR and OS HR was 0.42. For the association between 6-month PFS and 12-month OS rate ratios, the correlation coefficient was 0.55.

Within the checkpoint-inhibitor arms, the correlation coefficient between ORR and 6-month PFS was 0.37, between ORR and 12-month OS was 0.08, and between 6-month PFS and 12-month OS was 0.74.

“ORR correlated poorly with OS,” concluded the authors. “In future phase 2 checkpoint-inhibitor trials, 6-month PFS is recommended as an end point over ORR. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy.”

Reference

Ritchie G, Gasper H, Man J, et al. Defining the most appropriate primary end point in phase 2 trials of immune checkpoint inhibitors for advanced solid cancers [published online February 22, 2018]. JAMA Oncol. doi:10.1001/jamaoncol.2017.5236.