Predicting Clinical Outcomes of Patients with Stage III Non-Small-Cell Lung Cancer Treated with Concurrent Chemoradiation with and without PD-1/PD-L1 Inhibitors Using Cone Beam Computed Tomography

Abstract

Currently, there are no standardized biomarkers that predict response to consolidative therapy with Programmed cell Death receptor -1(PD-1) or Programmed cell Death receptor -Ligand 1 (PD-L1) inhibitors used after concurrent chemoradiation therapy (CCRT) for patients with stage III unresectable locally advanced non-small-cell lung cancer (LA-NSCLC).We hypothesized that tumor volume reduction during CCRT may be predictive of response to consolidative PD-1/PDL-1 inhibitors. We retrospectively reviewed the medical records of patients treated with definitive CCRT, both with and without consolidative PD-1/PD-L1 inhibitors. CCRT consisted of 60Gy in 30 fractions with platinum-based chemotherapy doublet. Primary gross tumor volumes (GTV) of all patients were contoured on set-up cone-beam computed tomography (CBCT) scans acquired on day 1, 15, 29, and 43 of CCRT, as well as on follow-up CT at 1 month. GTV reduction was quantified as the percent difference in volume on each CBCT and follow-up CT, relative to CBCT Day 1. Mid-treatment shrinkage (MTS) and End of Treatment Tumor Shrinkage (ETTS) were defined at day 29 and 43, respectively. Progression-free survival (PFS) was calculated using Kaplan-Meier curves and the log-rank test was used for statistical evaluation. 93 LA-NSCLC patients completed definitive CCRT, of which 24 received consolidative PD-1/PD-L1 inhibitors. For the entire cohort, the median age was 66.5 years (range: 51-84 years) and 54% were males. Adenocarcinoma represented 51%, squamous cell carcinoma 40% and undifferentiated histology 9%. 32% had stage IIIA and 68% had stage IIIB (AJCC 7th edition). Median follow-up was 43 months (range: 36-53 months). Patients who received PD-1/PD-L1 inhibitors achieved significantly longer PFS than CCRT-only group (22.5 vs. 9.5 months, p = 0.014). For the 93 patients, median ETTS was 40.6% (range: 39.3-50.3). Median ETTS was comparable between PD-1/PD-L1 inhibitors and CCRT-only group (41.2% vs. 40%). Patients who received PD-1/PD-L1 inhibitors and achieved ETTS > 35% demonstrated a trend toward improved PFS compared to those who had ETTS ≤ 35% (median PFS was not reached vs. 11.03 months, p = 0.059). Similarly, patients who received PD-1/PD-L1 inhibitors and achieved MTS of > 35% were associated with numerically better PFS compared to patients who did not achieve the same cut off (median PFS was not reached vs. 13.15 months, p = 0.059). Patients who achieved a significant reduction in their tumor volume during CCRT are more likely to benefit from consolidative PD-1/PD-L1 inhibitors. Measuring tumor volume dynamics using the readily available CBCT images acquired during CCRT may serve as a potential biomarker to predict response to PD-1/PD-L1 inhibition therapy.