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

Abstract

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 cm3 (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 cm3 (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.

Patterns of Care and Survival in Cancer Patients with Brain Metastases Receiving Immune Checkpoint Inhibitors

“…In a multicenter study of melanoma patients with previously untreated brain metastases, the addition of radiotherapy (SRS or other regimes) resulted in a favorable OS on systemic therapy [31]. A German group retrospectively analyzed data of 93 patients with 319 distinct brain metastases from different cancer types (67% malignant melanoma) who received PD-1 inhibitors and radiotherapy between 2014 and 2020 [32]. Median OS was 12.2 months (13 months in the present study).…”

Management of initial and recurrent radiation-induced contrast enhancements following radiotherapy for brain metastases: Clinical and radiological impact of bevacizumab and corticosteroids

“…However, patients with extracranial progressive disease at the time point of first diagnosis of RICE had an inferior improvement in imaging results. Prior analyses exploring the impact of blood–brain barrier penetration of substances on toxicities are quite controversial and increased rates of RICE development up to 16.9% after chemotherapy, 25.0% after targeted and 37.5% after immunotherapy have been reported [6] , [38] . While simultaneous or combined application of systemic therapies might also lead to a deterioration of RICE/RNI outcomes, we were not able to detected specific high-risk substances, which might have been to the high amount of various substances, and combination therapy concepts that were applied in our cohort.…”

Effect and Tolerability of Immunotherapy in Patients with NSCLC with or without Brain Metastasis

“…Current data on patients with NSCLC and BM receiving ICI come from RCTs, single arm phase I/II trials, or expanded access programs, all of which have included pre-selected patients, resulting in almost no data on patients with active and/or symptomatic BM [ 18 , 35 , 36 ]. The only present data comparable to the everyday clinical patient come from retrospective studies [ 32 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ], and prospective data within this area are warranted [ 20 ]. In line with these retrospective studies in patients with advanced NSCLC, our study report that patients with BM are younger and more often have a histology of adenocarcinoma than those without BM [ 32 , 37 ].…”