Modeling Survival Outcomes of Immune Checkpoint Inhibitors on Locally Advanced Non-Small Cell Lung Cancer Following Concurrent Chemoradiotherapy

Abstract

<h3>Purpose/Objective(s)</h3> Immune checkpoint inhibitors (ICI) have shown significant improvement in overall survival in locally advanced non-small cell lung cancer (LA-NSCLC), when combined with concurrent chemoradiotherapy (cCRT). The best schedule of cCRT ICI combination is still uncertain. We aim to develop a novel prediction survival model and investigate dose-relationship following cCRT and ICI combinations for LA-NSCLC. <h3>Materials/Methods</h3> ICI and cCRT studies between 2010 and 2021 were collated. ICI were intended to be delivered to 12 months. We modelled the 2-year overall survival (OS_2-yr) through sigmoidal TCP and NTCP, where EQD₂ of tumor control were modified to quantify immune-related survival gain as dose effects via adding an immune related term "<i>I</i>" – potentially dependent on the ICI doses and duration. Models were fitted using maximum likelihood estimation with 100 times bootstrapping, comparing fits via Akaike Information Criteria and likelihood ratio test. Dose-responses of OS_2-yr were plotted for 60 – 74Gy cCRT given in 6 weeks and standard 2Gy-per-fraction (F). <h3>Results</h3> The data comprised 1001 NSCLC patients from 6 trials. All treated with 2Gy F cCRT, 60 – 66Gy in 30 – 33 fractions. ICI were PD-1/PD-L1 inhibitors 17 doses (range: 13 – 22). 301 patients had cCRT only, 592 patients had ICI sequentially, 108 patients concurrently with cCRT. OS_2-yr was 48% (range: 41% – 55%) using cCRT, 67% (range: 44% – 87%) using cCRT ICI. In the generalized model, <i>I</i> was 0.37Gy/ICI-dose (95% CI: 0.12 – infinite), indicating that ICI augmented equivalent 5.6Gy or 7.4Gy EQD₂ dose escalation per 15 or 20 ICI doses respectively. The fitting efficacy improved significantly after incorporating ICI (p = 1.5*10⁻⁵). The best modelling OS_2-yr for cCRT was 63% (95% CI: 53% – 75%) for stage IIIA and 54% (33% – 69%) for stage IIIB/C; while it raised to 75% (66% – 86%) for stage IIIA and 67% (51% – 79%) for stage IIIB/C using cCRT ICI. Once ICI were added, best OS_2-yr occurred using radiation dose of 60Gy, and dose-escalation did not improve further outcomes. (table) <h3>Conclusion</h3> The model suggests that ICI increase the OS_2-yr by ∼12% for stage IIIA and ∼13% for stage IIIB/C following the cCRT treatment of LA-NSCLC at 60Gy biological dose regardless of fractionation.