Tumour growth rate as a tool for response evaluation during PD-1 treatment for non-small cell lung cancer: a retrospective analysis

Abstract

Background: Immune checkpoint inhibitors have emerged as a standard of care treatment for non-small cell lung cancer (NSCLC). To get insight into variations in tumour growth kinetics and their potential predictive values for outcome, we evaluated tumour growth rate (TGR) in patients receiving programmed cell death 1 (PD-1) checkpoint inhibitors.

Patients and methods: Differences in TGR before and after the start of treatment were calculated by entering the sum of the longest diameters from computer tomography scans before and after the initiation of therapy into a formula that assumes volumetric exponential tumour growth. TGR variations, possible predictors for TGR changes and its relationship to overall survival (OS) were studied. For comparison, tumour response was assessed using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

Results: Among the 58 evaluable patients, 37 patients (64%) showed deceleration of TGR and 16 patients (27%) showed an acceleration of TGR after initiation of therapy, with a significant difference in median OS of 18.0 months versus 6.0 months (hazard ratio 0.35, 95% CI 0.18-0.71) between these groups. Four patients (7%) were defined as having hyperprogressive disease. In five patients (9%), tumour growth remained stable. These TGR categories were not significantly different according to age, sex, histology, smoking or previous radiotherapy. Of the patients defined as having progressive disease by RECIST version 1.1 at first follow-up, 40% showed response to checkpoint inhibitors by a decrease in TGR.

Conclusion: Tumour growth kinetics can be used as a clinically relevant predictor for OS in anti-PD-1-treated patients with NSCLC, and may provide additional information to RECIST measurements.

FIGURE 1

a) Patient selection flow chart. b) Reviewed computed tomography (CT) scan moments. PREBA (pre-baseline to baseline): time between pre-baseline and baseline CT scan; BAFFU (baseline to first follow-up): time between baseline and first follow-up CT; red marked area: time between baseline CT and start of nivolumab, which was <2 weeks. RECIST: Response Evaluation Criteria in Solid Tumours.

FIGURE 2

Response Evaluation Criteria in Solid Tumours (RECIST) categories at first follow-up and hyperprogressive disease (HPD). a) Tumour growth in sum of the longest diameters (SLD) difference (diff) between baseline and first follow-up. b) SLDdiff before and after baseline. c) Tumour growth in tumour growth rate (TGR) before and after baseline. d) Overall survival (OS) when differentiated according to RECIST response categories (log-rank p=0.004). e) OS according to HPD (log-rank p=0.041). True-HPD (black): HPD defined as PD at the first evaluation with a twofold or greater increase in TGR from baseline; no HPD (yellow): patients not showing HPD at first follow-up. PREBA: pre-baseline period; BAFFU: period from baseline to first follow-up; PR: partial remission; SD: stable disease; PD: progressive disease; FU: follow-up.

FIGURE 3

a) Tumour growth rate (TGR) acceleration versus deceleration after start of therapy. b) Patients showing growth before the start of therapy grouped according to change in growth pattern after start of therapy. c) Overall survival (OS) according to increase versus decreased TGR after start of therapy (log-rank p=0.002). d) OS according to change in TGR after initiation of therapy (log-rank: p<0.001). SLD: sum of the longest diameters; diff: difference; PREBA: pre-baseline period; BAFFU: period from baseline to first follow-up; FU: follow-up.

FIGURE 4

Overall survival plotted against the sum of the longest diameters (SLD) difference (diff) at 6 weeks after the start of checkpoint inhibition in the patients that showed tumour growth before the start of therapy. The patients were divided into groups according to tumour growth rate (TGR) change. Patients showing tumour growth with an increased growth rate (red) as well as with a decreased growth rate (yellow) go over the 20% growth line, defining progressive disease at first follow-up.