Lung cancer is the second most common cancer type in terms of incidence rate (T: 228820, 12.7%; M: 116, 300 13%; F: 112, 520 12%), and is the leading cause of death (T: 135720, 22%; M: 72,500 23%; F: % 63220 22%) in both sexes according to newly estimated new cancer cases and deaths by sex in the United States in 2020 (1). Non-small cell lung carcinoma (NSCLC) accounts for 85% of lung cancer cases and is the most frequent primary site for brain metastasis (BM) (1–3). The relative incidence of BMs accounts for 40% of all NSCLC patients and is increasing with the development of advanced imaging technology, targeted agents, and immunotherapy (IT) (3–5). Radiation therapy (RT) has been predominantly used for the management of BMs (5–13).

BM patients with a high intracranial burden are primarily offered whole brain radiation therapy (WBRT). Generally, stereotactic radiosurgery (SRS) has been restricted to patients with up to 3 BMs. However, recent trends indicate that SRS/stereotactic radiotherapy (SRT) has been increasingly offered to patients with >3 BMs with WBRT used as salvage therapy (5, 9, 10, 12). In BM patients with NSCLC, a combination of the two may result in improved outcomes compared to being treated with either of the two (5, 7–12). Next-generation tyrosine kinase inhibitors (TKIs) and immune checkpoint blockades (ICBs) have shown efficacy in treating BMs (14, 15). The addition of up-front radiotherapy to TKIs may improve outcomes compared with TKI alone in EGFR-mutated NSCLC (14). Despite increased usage of SRS in recent times, BM patients are still managed with WBRT alone because of multiple brain lesions at presentation and the feasibility of SRS treatment (13).

ICB targeting the CTLA-4 and PD-1 checkpoint pathways has shown significant improvement in the survival of NSCLC patients (16). As a result, anti-PD-1/PD-L1 therapy has been approved as a first-line or second-line monotherapy treatment or given in combination with chemotherapy (16). Anti-PD-1 monoclonal antibodies (nivolumab/pembrolizumab) as monotherapy have also displayed an intracranial response with an objective response rate (ORR) of 9–30% in patients with NSCLC BMs (15, 17, 18). A rationale has been developed for the combination of immune checkpoint inhibitors (ICIs) and RT to seek synergistic anti-cancer responses (19). So far, there are limited reports of improvement in outcome with a combination of the two treatments (20–25). Hence, we are attempting to conduct a retrospective review involving NSCLC patients with BM to analyze the addition of anti-PD-1 therapy to WBRT compared to RT alone.

Lung cancer is often diagnosed at an advanced stage, with a 5-year survival rate of 5% (1). Advanced stage NSCLC patients lacking molecular markers are offered chemotherapy alone or chemotherapy in combination with immune checkpoint inhibitors (ICIs) as first-line treatment (16). Moreover, the addition of stereotactic ablative radiotherapy (SABR) to IT has also been tested in metastatic NSCLC (30, 31). This combination has demonstrated abscopal responses in metastatic sites and delayed disease progression (30, 31). In fact, multiple-lesion radiotherapy has shown to enhance the efficacy of PD-1 checkpoint inhibitors as compared to single-lesion receiving radiotherapy indicating synergism (32). However, the efficacy of this combination of RT and ICI in the brain remains to be elucidated. Our retrospective analysis of 70 NSCLC patients with multiple BMs (>3) revealed a better PFS (though not significant) and significantly improved OS in patients receiving concurrent treatment without any increase in toxicity.

The benefit in response can be explained based on preclinical and clinical evidence. Clinical response to ICIs is predicated on PD-L1 expression and the density of tumor-infiltrating lymphocytes (TILs), with a correlation between the primary tumor and BMs in lung adenocarcinoma (33–37). Moreover, RT promotes PD-L1 expression in metastatic sites by improving antigen presentation and tumor-specific immunity, which could be further augmented by ICIs to overcome the acquired resistance to RT (38–40). Third, local damage caused to the blood-brain-barrier during RT could also provide a window for IT drugs to be effective in the brain (41). For example, secondary analysis of the KEYNOTE-001 phase I trial demonstrated a comparatively superior PFS (median PFS: 4.4 vs. 2.1 months) and OS (median OS: 10.7 vs. 5.3 month) in the cohort that had previously received RT to the brain or extracerebral in addition to pembrolizumab, as compared to pembrolizumab alone (21). Moreover, the two concurrently administered treatments showed superior efficacy compared to use of only one of either treatment. In a retrospective study of BM patients (n=260) with primary tumor sites such as NSCLC, melanoma, and renal cell carcinoma (RCC), the use of ICIs with SRS/SRT (n=79) improved the median OS compared to SRS/SRT alone (14.5 vs. 12 months) (22). The improvement in OS (24.7 months) was significantly higher for the concurrent (within 2 weeks) IT (CI) cohort (n=28) than in the non-concurrent IT (nCI) cohort (HR 2.40, p=0.006) and SRS/SRT alone group (HR 2.69, p=0.002) (22). The median survival for concurrent group (n=28, median OS= 24.7 months) reported in the study by Chen et al. was similar to our study (n=29, median OS=27 months) (22). Likewise, no statistical difference in PFS (PFS: CI=2.3 vs. nCI=2.3 vs. SRS alone=3.7 months) was revealed between the cohorts (7 vs. 12 months, p=0.264) (22). However, the melanoma patients were prevalent in concurrent group (83%) in their study, which was also significant predictor of survival on multivariate analysis (HR 2.7, 95% CI: 1.6–4.7 for NSCLC; 3.6, 95% CI: 1.4–8.3 for RCC) (22). Melanoma BM patients (n=48, median OS=394 days) were also a significant driver of OS from the first anti-PD-1 therapy in comparison to NSCLC (n=79, median OS=192 days) and RCC (n=10, median OS=121 days) in a retrospective study by Pike et al. (23). In their study, among 59 BM patients who received RT following PD-1 inhibition, 25 continued to receive anti-PD-1 therapy for a median of 179 days and showed an improved median survival (additional 238 days) (23). In another retrospective matched cohort study of NSCLC-derived BM, the concurrent use of ICI (n=17, BMs=45) within 3-months of SRS provided a significantly rapid regression of BM (2.5 vs. 3.1 months, p<0.0001) and improved CNS complete response (CR) [8/16 (50%) vs. 5/32 (15.6%), p=0.012] compared to SRS alone (n=34, BM =92) (24). However, this benefit was not translated clinically in terms of PFS (HR 2.18; 95% CI, 0.72–6.62; p=0.11) and OS (HR 0.99, 95% CI: 0.39–2.52, p=0.99). Similarly, no statistical difference in median survival was found between the IT group (n=39) and CT group (n=46) in a retrospective study of 85 NSCLC patients with BMs (median OS: 10 vs. 11.6 months, p=0.23) (25). However, lesion shrinkage was significantly higher in the IT group than in the CT group in a subset of patients with lesion volume > 500 mm³ (90% vs. 47.8%, p=0.001). In both of these studies, even though no survival advantage was achieved, intracranial responses were observed with the combined approach. Similarly, the 6-month distant brain control rate for the before/concurrent cohort was significant compared to the post-RT cohort (57% vs. 0%, p=0.05) in a small cohort of NSCLC BM patients (n=17) receiving anti-PD-1 (nivolumab/durvalumab) and/or SRS/fractionated stereotactic radiation therapy (42). The timing (before/concurrent vs. after) was also significant for OS on univariate analysis (HR 9.2, 95% CI: 1.9–65.3, p=0.006) but not on multivariate analysis (HR 3.6; 95% CI, 0.74–26.9; p=0.11) (42). Another retrospective study on metastatic NSCLC patients revealed that delivering radiation before (6 months) or during/after (3 months) nivolumab administration was not associated with better OS or PFS (43). These outcomes endorse the observation that a window of at least 14 days was essential for palliative RT prior to the administration of nivolumab to take advantage of the RT-induced tumor antigenic stimulation effect (44, 45). Preclinical evidence also suggests that concurrent RT/anti-PD-1 inhibition may induce better anti-cancer effects compared to RT undertaken prior to PD-1 inhibition (30). Therefore, the literature implies that these patients may benefit from a combination of both treatments.

Investigation of factors affecting OS or PFS revealed no impact for several factors including age, gender, smoking, pathology, KPS, and the presence of EGFR mutation and extracranial metastases. Nonetheless, histopathologic differentiation showed slight association with worst PFS and OS. Likewise, smoking and KPS have also shown to negatively impact PFS on univariate and/or multivariate analysis. Importantly, WBRT alone group had more EGFR-positive participants, which may have confounded survival advantage as EGFR inhibitor plus WBRT treatment yields better survival compared to WBRT alone in NSCLC BM patients (14). For this reason, subgroup analysis was performed which revealed a significant improvement in PFS and OS for EGFR negative NSCLC patients. This result in concordance to a previously published meta-analysis comprising seven randomized controlled trials, in which immune checkpoint blockade had resulted in significantly better PFS and OS as compared to chemotherapy in EGFR wild-type stage IV NSCLC patients (PFS: HR 0.83, 95% CI 0.73-0.95); OS: HR 0.67, 95% CI 0.60-0.76; p<00001) (46). In this meta-analysis, EGFR mutant responded better to chemotherapy as opposed to immunotherapy in terms of PFS and OS. Likewise, no significant improvement in PFS and OS was found in EGFR positive patients in our study. Nonetheless, the cohort for combined treatment (n=5) was very small and further investigation would be required to establish presence or lack of benefit for the combined treatment in EGFR positive NSCLC patients with brain metastases.

Our study showed the safety of the combined approach with no increase in toxicity. Other studies have also revealed that the combination of ICIs and RT does not lead to an increase in toxicity compared to RT alone or ICI alone (47). In a single-center secondary analysis of a phase 1/2 trial (n=10), a combination of palliative RT (3DCRT, 79% and SRS–SRT, 21%; 28 Gy/5 fraction) plus durvalumab (10 mg/kg every 2 weeks via intravenous infusion) led to no grade 3 RT-related adverse events (AEs) (NCT01693562) (47). All AEs were transient and manageable according to the standard guidelines (47). Concurrent ICI (nivolumab within 3-month of RT) was also not associated with any increase in the rate of radiation necrosis or intratumoral hemorrhage in NSCLC-derived BM patients (5.9% vs. 2.9% in ICI-naive cohort, p=0.99) (24). There were no significant differences in the rates of all-grade AEs and grade ≥3 AEs between the ICI-naive (n=113) and ICI-treated NSCLC BM patients (n=50) across different cranial RT types (grade ≥3 AEs in 8% vs. 9% for SRS, p=1.00; 8% vs. 10% for WBRT, p=0.71) (48). Additionally, there was no difference in AE rates based on the timing of ICI administration with respect to RT.

Our study is limited by inherent biases of retrospective research design, which include selection, information, recall, and/or observation biases (49). The small sample size also limits our study. There is also chronological bias since WBRT alone participants were diagnosed earlier, whereas the PD-1 inhibition therapy group participants were diagnosed later. Moreover, certain outcomes were not reported such as intracranial response rate and subsequent therapies undertaken after completion or withdrawal from either treatment.

Our results indicate that concurrent WBRT and anti-PD-1 therapy may enhance OS in NSCLC patients with BM particularly in EGFR negative patients. The addition of anti-PD-1 therapy to RT may not increase the toxicity. Further studies are warranted to validate and elucidate the effect of using the treatments in combination.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

Ethics approval was obtained from the Ethical review board of “Shenzhen People’s Hospital, The First Affiliated Hospital Of Southern University Of Science And Technology, Shenzhen, China”, and “The First Affiliated Hospital Of Wenzhou Medical University, Wenzhou, China. The patients/participants provided their written informed consent to participate in this study.

GXL and GL provided the data. GXL and MK wrote the manuscript. All authors approved the design, data collection, data analysis, and final manuscript for publication.

The Natural Science Foundation of Shenzhen (No.JCYJ2017 0307095828424); Shenzhen Health and Family Planning System Research Project (No.SZBC2017024) were providing support for this work.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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