The rechallenge benefit score: A clinical decision tool for patients progressing after immunotherapy

Most patients with advanced Non-Small-Cell Lung Cancer (NSCLC) receive an immune checkpoint inhibitor (ICI) as first-line treatment. Upon progression, therapeutic options are limited, making ICI rechallenge a relevant strategy. However, identifying patients who may benefit remains challenging. This study presents a predictive score to guide treatment decisions.

Seventeen routine blood tests performed before the first two ICI cycles were analyzed in 80 NSCLC patients rechallenged across 16 French centers. Using a robust machine learning approach, we identified biological parameters associated with progression-free survival during rechallenge (rPFS) and developed an integrative score able to stratify patients according to rPFS. Its predictive value was assessed in relation to patients treated with chemotherapy after ICI (n = 82) and to their outcomes evaluated during first-line immunotherapy (n = 252).

Our findings indicate that clinical characteristics alone are insufficient to reliably identify patients who are likely to respond to ICI rechallenge. We identify the Rechallenge Benefit Score (RBS), which identifies patients likely to achieve longer clinical benefit from ICI rechallenge (C-index 0.79), regardless of clinical characteristics. Median rPFS was significantly longer in patients with low versus high RBS (6.4 and 1.9 months respectively; p < 0.0001, HR=0.31, 95 % CI:0.17-0.55). Notably, the RBS is specific, as it does not predict benefit in Chemotherapy or first-line ICI cohorts.

We identified and validated the RBS score to select patients likely to benefit from ICI rechallenge. Since clinical features alone are insufficient, our findings may guide treatment strategies for patients who experienced disease progression during prior ICI treatment.