Brain metastases, patterns of intracranial progression, and the clinical value of upfront cranial radiotherapy in patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors

Abstract

Background: Despite the emergence of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases (BMs), knowledge gaps remain regarding the impact and timing of cranial radiotherapy for patients receiving anti-PD-1/PD-L1 therapy.Methods: Data were collected from 461 consecutive patients who received anti-PD-1/PD-L1 therapy for metastatic NSCLC at three institutions between June 2017 and September 2020. Intracranial progressive disease (PD) at the original disease sites, new sites, or both sites were classified as original-site PD (OPD), new-site PD (NPD), and original-and-new-site PD (ONPD), respectively. Patients with baseline BMs were categorized based on whether they received upfront cranial radiotherapy (uCRT) at any time point between the introduction of anti-PD-1/PD-L1 therapy and the first subsequent progression.Results: Of the 461 patients enrolled, 110 (23.9%) had BMs at baseline. The presence of BMs did not show independent prognostic value for progression-free survival (PFS) or overall survival (OS). During a median follow-up of 13.2 months, 96 patients with BMs developed PD, of whom 53 (55.2%) experienced intracranial PD. OPD, NPD, and ONPD were observed in 50.9%, 18.9%, and 30.2% of patients, respectively. Patients who received uCRT exhibited a longer median OS than those with BMs who did not receive uCRT (25.4 vs. 14.6 months, HR: 0.52, 95% CI: 0.29-0.91, P=0.041); this survival advantage was more prominent in patients with 1-4 BMs (median OS, 25.4 vs. 17.0 months, HR: 0.42, 95% CI: 0.22-0.81, P=0.024), and uCRT was independently associated with OS among these patients. Conclusions:The presence of BMs at baseline was not associated with poorer OS in patients with metastatic NSCLC treated with anti-PD-1/PD-L1 therapy. Intracranial progression on PD-l/PD-L1 inhibitors predominately occurred at the original BM sites. The use of uCRT may improve OS, especially in NSCLC patients with 1-4 BMs.

Efficacy and safety of immune checkpoint inhibitors with or without radiotherapy in metastatic non-small cell lung cancer: A systematic review and meta-analysis

“…After excluding 139 studies because the article type was not suitable for inclusion (including 13 case studies, 4 meta-analyses, 13 single-arm studies, 17 studies on other tumor types, 22 conference papers with abstracts only, 12 phase I studies, 15 ongoing studies, 42 reviews, and 1 comment), 3 RCTs and 12 NRCTs remained. A total of 15 clinical studies were reported in 16 publications ( Figure 1 ) ( Kataoka et al, 2017 ; Shaverdian et al, 2017 ; Tamiya et al, 2017 ; Fiorica et al, 2018 ; Theelen et al, 2019 ; Welsh et al, 2020 ; Hosokawa et al, 2021 ; Metro et al, 2021 ; Samuel et al, 2021 ; Sheng et al, 2021 ; Theelen et al, 2021 ; Öjlert Å et al, 2021 ; Guo et al, 2022 ; Qiang et al, 2022 ; Schoenfeld et al, 2022 ; Wang et al, 2022 ).…”

RT-based combination therapy for brain metastasis from NSCLC with non-EGFR mutation/ALK gene rearrangement: A network meta-analysis

“…After excluding studies, such as conference abstracts, non-English papers, and non-related interventions, 28 papers, including 12 randomized controlled trials, were finally included in the Bayesian network meta-analysis. A total of 3703 patients received at least one of the five treatment strategies ( Table 1 ) ( 15 – 42 ).…”

“…6 studies recruited less than expected ( 32 , 34 , 35 , 39 – 41 ), 9 studies did not mention random sequence generation ( 32 , 33 , 35 , 37 – 42 ), 3 studies did not mention study blinding design ( 31 – 33 ), and other aspects were assessed as high quality. Table 2 | Of the cohort studies, 12 studies did not specify whether subjects had developed the focused disease ( 15 , 16 , 18 , 20 , 23 , 24 , 26 – 30 , 36 ), and were rated as high risk, 25 studies only mentioned part follow-up related data ( 15 – 21 , 23 , 25 – 30 ), which is not enough to judge the completeness of the follow-up data, and were rated as high risk, and the rest included studies were low risk. We rated articles with a score of ≥ 6 as high quality, and all included studies were high quality.…”

“…All included studies reported adverse effects. 10 studies reported no 3/4 grade or higher adverse effects (15,20,(22)(23)(24)(25)(26)(27), and the remaining 18 studies reported 839 adverse events, The ICIs combined RT intervention accounted for 65 cases. The reported adverse effects involved different systems and symptoms.…”

“…6 studies recruited less than expected(32, 34, 35,(39)(40)(41), 9 studies did not mention random sequence generation(32,33, 35,(37)(38)(39)(40)(41)(42), 3 studies did not mention study blinding design(31)(32)(33), and other aspects were assessed as high quality. Table2| Of the cohort studies, 12 studies did not specify whether subjects had developed the focused disease(15, 16,18,20,23, 24,(26)(27)(28)(29)(30)36), and were rated as high risk, 25…”