Immune checkpoint inhibitors (IC) induce paradoxical progression in a subset of non-small cell lung cancer (NSCLC)

Abstract

Background: Immune Checkpoint inhibitors (IC) represent a major step forward in treating advanced NSCLC by improving survival and clinical outcomes. In patients (pts) with non-squamous NSCLC PDL1 negative NSCLC, IC increases the risk of early death compared to docetaxel. Risks later reversed for the two study groups to increasingly favor IC, as reflected in the eventual crossing of the Kaplan-Meier curves. Tumor Growth Rate (TGR) integrates tumoral dynamics and kinetics. Therefore, TGR gives additional information vs RECIST criteria. We hypothesized that TGR could identify a subset of pts in which IC could accelerate tumor progression, leading to early death. Methods: We performed a clinical and radiological retrospective case study of all NSCLC pts treated by IC in a single institution between Dec. 12 and Feb. 16. For each patient, CT scan during immunotherapy and previous treatment were centrally reviewed by a senior radiologist and assessed according to RECIST criteria. We calculated TGR at baseline of IC (baseline CTscan (n) vs n-1 CTscan) and TGR during IC (n + 2 CTscan vs n + 1 CTscan). We further estimated the difference (deltaTGR) between TGR during IC and TGR at baseline. deltaTGR<0 means that the treatment slows down tumor progression whereas deltaTGR>0 means that the treatment speeds up tumor growth. Results: 89 pts were eligible. 58% were male, median age 60 (41-78); 15% never smokers. 62 pts had adenocarcinoma, 21 squamous and 6 other histologies. Mutational status was unknown for 14 pts; 36% wild type, 9 pts EGFRmut, 25 pts KRASmut. PDL1 expression was positive in 25 pts, unknown in 57 pts. 52 pts (58%) received nivolumab, 25 pembrolizumab and 12 atezolizumab. During IC, deltaTGR was <0 in 79 pts and >0 in 20 pts. Among the 20 pts with deltaTGR > 0, 9 had a deltaTGR > 50%, meaning that tumor growth, expressed as percent increase in tumor volume per month, increased by at least 50% during IC. Clinical characteristics (age, sex, smoking status, pathology) of the 9 pts were not different from other pts. Conclusions: Our results suggest that IC increased tumor progression in around 10% pts and thus could illustrate a deleterious effect in this subset of pts. Further work is needed to confirm this finding and characterize this population.