Six-Month PFS Predicts OS For Immune Checkpoint Inhibitor Trials

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Progression-free survival (PFS) at 6 months is a good predictor of overall survival (OS) in randomised clinical trials (RCTs) assessing immune checkpoint inhibitor (ICI) agents in patients with solid tumours, indicate the results of a systematic review and meta-analysis. 

As reported in JAMA Network Open, the investigators identified 60 RCTs assessing pembrolizumab, nivolumab, ipilimumab, durvalumab, tremelimumab, atezolizumab or avelumab that were published between January 2000 and June 2019. 

The studies included a total of 17,891 patients, of whom 36% had non-small-cell lung cancer, 16% melanoma and 47% other tumour types, such as triple-negative breast cancer, head and neck squamous cell carcinoma, and gastro-oesophageal cancer.

Peey-Sei Kok, from the University of Sydney in New South Wales, Australia, and co-workers divided the 74 treatment arms identified in the trials into a development data set of 25 trial arms and a validation data set of 49 trial arms.

They used linear regression to develop a 6-month PFS model designed to estimate 12-month OS after adjusting for tumour type. When applied to the validation data set, the model achieved “good calibration” for estimating 12-month OS, with an r value of 0.89. 

This was particularly true for studies assessing ICIs only (r=0.94) but was also effective for trials where ICIs were combined with chemotherapy, as well as for both first-line and later use of ICIs, and for studies where participants were selected or not selected according to PD-L1 expression. 

By contrast, there was a “poor calibration” between the objective response rate (ORR) and the estimated 12-month OS, with an r score of 0.47. This was true across all subgroups, including for studies assessing ICIs alone or in combination with other treatments. 

Further analysis of 63 ICI arms revealed a “strong” correlation between 6-month PFS and 12-month OS (r=0.83), while analysis of 64 ICI arms indicated a “moderate” correlation between ORR and 12-month OS (r=0.65). 

And analysis of 65 RCTs comparing ICI versus a control therapy showed a “moderate” correlation between PFS and OS hazard ratios (r=0.54), as did analysis of 66 RCTs for a correlation between ORR risk ratio and OS hazard ratio. 

Subgroup analysis for the ORR model revealed a stronger correlation between ORR and 12-month OS for trial arms of ICI therapy only than for ICIs used in combination with a tyrosine kinase inhibitor or chemotherapy (r=0.80 vs 0.38), as well as in second- or later-line usage versus first-line treatment (r=0.66 vs 0.37).  

These data were used to refine the ORR estimation model and validation is now ongoing, the authors remark. 

“Where phase 3 RCTs are not feasible owing to limitations, such as small sample size in rare cancers, 6-month PFS results that estimate for promising 12-month OS outcomes may assist regulators, policy makers, and funding bodies to better assess treatment efficacy even if evidence is limited to smaller, non-randomized trials”, say Peey-Sei Kok et al.

“Importantly, our work may serve as a platform for future estimation models that incorporate multiple surrogate end points, including molecular surrogates and pharmacodynamic markers for a more sophisticated estimation of OS with ICI therapy.” 

Reference  

Kok P-S, Cho D, Yoon W-H, et al. Validation of progression-free survival rate at 6 months and objective response for estimating overall survival in immune checkpoint inhibitor trials. A systematic review and meta-analysis. JAMA Netw Open; 3: e2011809. doi:10.1001/jamanetworkopen.2020.11809