Proton therapy may reduce the risk of cancer progression during immune checkpoint inhibitor therapy: a propensity score-matched analysis of intensity-modulated proton versus photon radiotherapy.

Purpose: Intensity-modulated proton radiotherapy (IMPT) may preserve the immune response more effectively than intensity-modulated photon radiotherapy (IMRT) owing to its dosimetric advantages, making it a potentially superior modality in immunotherapy. This study aimed to evaluate the clinical benefits of IMPT versus IMRT during immune checkpoint inhibitors (ICIs) treatment.

Methods and materials: We retrospectively analyzed the data of 466 patients (IMPT group, n=109; IMRT group, n=357) who received radiotherapy (RT) during ICI therapy between July 2022 and September 2024. Propensity score matching (PSM) was applied to balance clinical characteristics. The primary endpoint was the duration of response (DoR). Secondary endpoints included progression-free survival (PFS) and post-RT adverse events. Kaplan-Meier and Cox proportional hazards regression were used to calculate survival curves and identify independent prognostic factors. The threshold used to dichotomize post-RT lymphocyte count was 0.5 × 10⁹/L.

Results: Baseline clinical characteristics were balanced after PSM. The IMPT group showed significantly longer median DoR (17.7 vs. 5.7 months, p=0.0001) and PFS (18.8 vs. 6.8 months, p<0.0001) than the IMRT group. Multivariable regression revealed IMPT to be an independent predictor of improved DoR (hazard ratio [HR] 0.34; 95% confidence interval [CI]: 0.21-0.55; p<0.0001) and PFS (HR 0.36; 95% CI: 0.25-0.52; p<0.0001). Subgroup analyses suggested greater benefit of IMPT over IMRT in patients with a Charlson Comorbidity Index ≥4, lung cancer, advanced-stage disease, or those receiving palliative, thoracic, or abdominal/pelvic RT. Higher post-RT lymphocyte counts in the IMPT group showed potential correlation with improved DoR and PFS. Additionally, the IMPT group had fewer grade ≥2 post-RT adverse events (p=0.012).

Conclusions: IMPT is linked to enhanced efficacy of ICIs, compared to IMRT, by improving DoR and PFS with tolerable adverse effects. Higher post-RT lymphocyte counts may be associated with improved survival in patients receiving IMPT during ICI therapy. These findings suggest that IMPT may be a preferable option for preserving immune function, thereby optimizing outcomes during immunotherapy.