Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting Subgroups.

While immune checkpoint inhibitors (ICIs) in combination with radiotherapy (RT) are widely used for patients with brain metastasis (BM), markers that predict treatment response for combined RT and ICI (RT-ICI) and their optimal dosing and sequence for the best immunogenic effects are still under investigation. The aim of this study was to evaluate prognostic factors for therapeutic outcome and to compare effects of concurrent and non-concurrent RT-ICI. We retrospectively analyzed data of 93 patients with 319 BMs of different cancer types who received PD-1 inhibitors and RT at the University Hospital Cologne between September/2014 and November/2020. Primary study endpoints were overall survival (OS), progression-free survival (PFS), and local control (LC). We included 66.7% melanoma, 22.8% lung, and 5.5% other cancer types with a mean follow-up time of 23.8 months. Median OS time was 12.19 months. LC at 6 months was 95.3% (concurrent) vs. 69.2% (non-concurrent; p = 0.008). Univariate Cox regression analysis detected following prognostic factors for OS: neutrophil-to-lymphocyte ratio NLR favoring <3 (low; HR 2.037 (1.184-3.506), p = 0.010), lactate dehydrogenase (LDH) favoring ≤ULN (HR 1.853 (1.059-3.241), p = 0.031), absence of neurological symptoms (HR 2.114 (1.285-3.478), p = 0.003), RT concept favoring SRS (HR 1.985 (1.112-3.543), p = 0.019), RT dose favoring ≥60 Gy (HR 0.519 (0.309-0.871), p = 0.013), and prior anti-CTLA4 treatment (HR 0.498 (0.271-0.914), p = 0.024). Independent prognostic factors for OS were concurrent RT-ICI application (HR 0.539 (0.299-0.971), p = 0.024) with a median OS of 17.61 vs. 6.83 months (non-concurrent), ECOG performance status favoring 0 (HR 7.756 (1.253-6.061), p = 0.012), cancer type favoring melanoma (HR 0.516 (0.288-0.926), p = 0.026), BM volume (PTV) favoring ≤3 cm 3 (HR 1.947 (1.007-3.763), p = 0.048). Subgroups with the following factors showed significantly longer OS when being treated concurrently: RT dose <60 Gy ( p = 0.014), PTV > 3 cm 3 ( p = 0.007), other cancer types than melanoma ( p = 0.006), anti-CTLA4-naïve patients ( p < 0.001), low NLR ( p = 0.039), steroid intake ≤4 mg ( p = 0.042). Specific immune responses, such as abscopal effects (AbEs), pseudoprogression (PsP), or immune-related adverse events (IrAEs), occurred more frequently with concurrent RT-ICI and resulted in better OS. Other toxicities, including radionecrosis, were not statistically different in both groups. The concurrent application of RT and ICI, the ECOG-PS, cancer type, and PTV had an independently prognostic impact on OS. In concurrently treated patients, treatment response (LC) was delayed and specific immune responses (AbE, PsP, IrAE) occurred more frequently with longer OS rates. Our results suggest that concurrent RT-ICI application is more beneficial than sequential treatment in patients with low pretreatment inflammatory status, more and larger BMs, and with other cancer types than melanoma.