Progression-free survival (PFS)
The measure for time to progression
Clinical trials in advanced NSCLC are increasingly designed to evaluate PFS or time to progression as a clinical endpoint of interest, based on anatomical measurement of tumor size, upon which efficacy conclusions are drawn.1
PFS is influenced by the frequency of follow-up after baseline evaluation.1 The RECIST guidelines do not define a standard follow-up frequency, since many parameters, such as disease types and stages, anticipated time required for treatment response, cost, and patient convenience, should be factored in.1,2 However, the latest update and clarification to the RECIST criteria notes that follow-up every 6–8 weeks is reasonable in the context of phase II trials, where treatment benefit is unknown.2
PFS and HR
HR is the most appropriate way of summarizing PFS and expressing the intervention effect. The use of HR enables the measurement of instantaneous risk and describes how many more times likely a patient is to suffer an event with the experimental intervention rather than with the comparator.3
Trials with molecularly selected patients have exhibited greater PFS-HR compared with
all-comer trials (0.4 vs 1.01, P<0.01), distinguishing molecularly selected patients as 60% less likely to experience disease progression.4 The PFS-HR cut-off of 0.6 was shown to better detect the clinical benefit of molecularly targeted therapies compared to the OS endpoint.4
Median PFS
Median PFS describes the time at which disease progression has occurred in 50% of patients.5 Because survival times are usually skewed, median PFS is considered to be a better measure of centrality than mean.6 Median PFS is not currently used as a surrogate for median OS, as no correlation between the two endpoints has been established.7
Intracranial PFS8
In patients with NSCLC and brain metastases, a clear distinction between intracranial PFS, extracranial PFS and overall PFS is needed. However, intracranial PFS has limited value as a primary endpoint due to treatment-related changes.8
To assess efficacy in the prevention of CNS metastases, there are three prerequisites:8
- Identification of patient subgroups with NSCLC at high risk of brain metastases
- Therapeutic agent able to cross the blood-brain barrier
- Use of clinical endpoints, such as incidence of brain metastases and intracranial PFS
MRI surveillance is used to assess intracranial PFS in patients at high risk of brain metastases.8
CNS: central nervous system; HR: hazard ratio; MRI: magnetic resonance imaging; NSCLC: non-small-cell lung cancer; PFS: progression-free survival. RECIST: Response Evaluation Criteria In Solid Tumors.
1. Eisenhauer EA, et al. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45:228–47.
2. Schwartz LH, et al. RECIST 1.1 – Update and clarification: From the RECIST committee. Eur J Cancer. 2016;62:132–7.
3. Higgins JPT, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.1 (updated September 2020). Cochrane, 2020. Available from www.training.cochrane.org/handbook. Accessed September 2020.
4. Hotta K, et al. Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. PLoS ONE. 2015;10:e0121211.
5. Singh R, Mukhopadhyay K. Survival analysis in clinical trials: basics and must know areas. Perspect Clin Res. 2011;2:145–8.
6. Dudley WN, et al. An introduction to survival statistics: Kaplan-Meier analysis. J Adv Pract Oncol. 2016;7:91–100.
7. Zhao S, et al. Progression-free survival and one-year milestone survival as surrogates for overall survival in previously treated advanced non-small cell lung cancer. Int J Cancer. 2019;144:2854–66.
8. Soffietti R, et al. Imaging and clinical end points in brain metastases trials. CNS Oncol. 2017;6:243–6.