Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non–small cell lung cancer to the brain: a matched cohort study

Matthew J. Shepard Departments of Neurological Surgery;

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Zhiyuan Xu Departments of Neurological Surgery;

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Joseph Donahue Neuroradiology;

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Thomas J. Eluvathingal Muttikkal Neuroradiology;

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Diogo Cordeiro Departments of Neurological Surgery;

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Leslie Hansen Departments of Neurological Surgery;

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Nasser Mohammed Departments of Neurological Surgery;

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Ryan D. Gentzler Medicine, Division of Hematology–Oncology;

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James Larner Radiation Oncology; and

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Camilo E. Fadul Neurology, Division of Neuro-Oncology, University of Virginia Health System, Charlottesville, Virginia

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Jason P. Sheehan Departments of Neurological Surgery;

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OBJECTIVE

Immune checkpoint inhibitors (ICIs) improve survival in patients with advanced non–small cell lung cancer (NSCLC). Clinical trials examining the efficacy of ICIs in patients with NSCLC excluded patients with untreated brain metastases (BMs). As stereotactic radiosurgery (SRS) is commonly employed for NSCLC-BMs, the authors sought to define the safety and radiological and clinical outcomes for patients with NSCLC-BMs treated with concurrent ICI and SRS.

METHODS

A retrospective matched cohort study was performed on patients who had undergone SRS for one or more NSCLC-derived BMs. Two matched cohorts were identified: one that received ICI before or after SRS within a 3-month period (concurrent ICI) and one that did not (ICI naive). Locoregional tumor control, peritumoral edema, and central nervous system (CNS) adverse events were compared between the two cohorts.

RESULTS

Seventeen patients (45 BMs) and 34 patients (92 BMs) composed the concurrent-ICI and ICI-naive cohorts, respectively. There was no statistically significant difference in overall survival (HR 0.99, 95% CI 0.39–2.52, p = 0.99) or CNS progression-free survival (HR 2.18, 95% CI 0.72–6.62, p = 0.11) between the two groups. Similarly, the 12-month local tumor control rate was 84.9% for tumors in the concurrent-ICI cohort versus 76.3% for tumors in the ICI-naive cohort (p = 0.94). Further analysis did reveal that patients receiving concurrent ICI had increased rates of CNS complete response for BMs treated with SRS (8/16 [50%] vs 5/32 [15.6%], p = 0.012) per the Response Assessment in Neuro-Oncology (RANO) criteria. There was also a shorter median time to BM regression in the concurrent-ICI cohort (2.5 vs 3.1 months, p < 0.0001). There was no increased rate of radiation necrosis or intratumoral hemorrhage in the patients receiving concurrent ICI (5.9% vs 2.9% in ICI-naive cohort, p = 0.99). There was no significant difference in the rate of peritumoral edema progression between the two groups (concurrent ICI: 11.1%, ICI naive: 21.7%, p = 0.162).

CONCLUSIONS

The concurrent use of ICI and SRS to treat NSCLC-BM was well tolerated while providing more rapid BM regression. Concurrent ICI did not increase peritumoral edema or rates of radiation necrosis. Further studies are needed to evaluate whether combined ICI and SRS improves progression-free survival and overall survival for patients with metastatic NSCLC.

ABBREVIATIONS

ALC = absolute lymphocyte count; BM = brain metastasis; CNS = central nervous system; ICI = immune checkpoint inhibitor; KPS = Karnofsky Performance Status; NSCLC = non–small cell lung cancer; OS = overall survival; PACS = picture archiving and communication system; PD-1 = programmed death receptor 1; PD-L1 = programmed death ligand 1; PEV = peritumoral edema volume; PFS = progression-free survival; RANO = Response Assessment in Neuro-Oncology; RPA = recursive partitioning analysis; SRS = stereotactic radiosurgery.

OBJECTIVE

Immune checkpoint inhibitors (ICIs) improve survival in patients with advanced non–small cell lung cancer (NSCLC). Clinical trials examining the efficacy of ICIs in patients with NSCLC excluded patients with untreated brain metastases (BMs). As stereotactic radiosurgery (SRS) is commonly employed for NSCLC-BMs, the authors sought to define the safety and radiological and clinical outcomes for patients with NSCLC-BMs treated with concurrent ICI and SRS.

METHODS

A retrospective matched cohort study was performed on patients who had undergone SRS for one or more NSCLC-derived BMs. Two matched cohorts were identified: one that received ICI before or after SRS within a 3-month period (concurrent ICI) and one that did not (ICI naive). Locoregional tumor control, peritumoral edema, and central nervous system (CNS) adverse events were compared between the two cohorts.

RESULTS

Seventeen patients (45 BMs) and 34 patients (92 BMs) composed the concurrent-ICI and ICI-naive cohorts, respectively. There was no statistically significant difference in overall survival (HR 0.99, 95% CI 0.39–2.52, p = 0.99) or CNS progression-free survival (HR 2.18, 95% CI 0.72–6.62, p = 0.11) between the two groups. Similarly, the 12-month local tumor control rate was 84.9% for tumors in the concurrent-ICI cohort versus 76.3% for tumors in the ICI-naive cohort (p = 0.94). Further analysis did reveal that patients receiving concurrent ICI had increased rates of CNS complete response for BMs treated with SRS (8/16 [50%] vs 5/32 [15.6%], p = 0.012) per the Response Assessment in Neuro-Oncology (RANO) criteria. There was also a shorter median time to BM regression in the concurrent-ICI cohort (2.5 vs 3.1 months, p < 0.0001). There was no increased rate of radiation necrosis or intratumoral hemorrhage in the patients receiving concurrent ICI (5.9% vs 2.9% in ICI-naive cohort, p = 0.99). There was no significant difference in the rate of peritumoral edema progression between the two groups (concurrent ICI: 11.1%, ICI naive: 21.7%, p = 0.162).

CONCLUSIONS

The concurrent use of ICI and SRS to treat NSCLC-BM was well tolerated while providing more rapid BM regression. Concurrent ICI did not increase peritumoral edema or rates of radiation necrosis. Further studies are needed to evaluate whether combined ICI and SRS improves progression-free survival and overall survival for patients with metastatic NSCLC.

In Brief

Immune checkpoint inhibitors (ICIs) are becoming increasingly used in patients with advanced non–small cell lung cancer (NSCLC); however, their efficacy for treating brain metastases in conjunction with stereotactic radiosurgery (SRS) has not been studied. In this retrospective matched cohort study, the authors found that the concurrent use of ICI and SRS appeared to improve local control of NSCLC-derived brain metastases. This strategy did not increase rates of radiation necrosis, peritumoral edema, or intratumoral hemorrhage.

Activation of co-inhibitory receptors on cytotoxic lymphocytes (programmed death receptor 1 [PD-1] and cytotoxic T-lymphocyte–associated protein 4 [CTLA-4]) by cancer cells is recognized as a fundamental mechanism of tumor-induced anergy.32 For patients with advanced non–small cell lung cancer (NSCLC), several randomized clinical trials have shown an increase in overall survival (OS) associated with blocking the interaction of PD-1 and its ligand (PD-L1) on tumor cells by using nivolumab, pembrolizumab, and atezolizumab.4,5,24,25 Given the poor prognosis of patients with brain metastases (BMs) and low drug penetration to the central nervous system (CNS), patients with untreated BMs were often excluded from these clinical trials.4,5,19,24,25 Nevertheless, an open-label phase 2 clinical trial found that 33% of patients with untreated NSCLC-BMs had an objective response to systemic immune checkpoint inhibitors (ICIs).11

Recently, patients with NSCLC treated with pembrolizumab who also received extracranial radiotherapy demonstrated improved OS and progression-free survival (PFS).28 This raises the possibility that radiation and ICI may be synergistic. Preclinical studies have suggested that radiation may increase the density of tumor-infiltrating lymphocytes, increase antigen release from metastases, and increase antigen-presenting cell activity.27 Whether or not these preclinical data translate into improved outcomes for patients has not been adequately investigated. Singh et al. suggested that the combination of ICIs and stereotactic radiosurgery (SRS) did not improve OS or PFS for patients with NSCLC-BMs.30 In their analysis, patients treated with ICIs had an increased number of BMs, more BMs treated with SRS, and tended to have worse Karnofsky Performance Status (KPS) scores, potentially confounding their results. We, therefore, performed a retrospective matched cohort study to examine the radiological and clinical outcomes as well as CNS safety in patients with NSCLC-BMs treated with concurrent ICI and SRS.

Methods

Study Design

A retrospective cohort study was performed at a single institution. Patients with histologically confirmed squamous cell carcinoma or adenocarcinoma of the lung treated with SRS for one or more BMs between January 1, 2012, and January 31, 2018, were identified from an institutional review board–approved database. Patients who had previously undergone SRS were excluded. Patients who had received prior whole-brain radiation or fractionated radiation to a different BM were eligible for analysis. All patients gave informed consent prior to undergoing SRS.

The use of ICIs for patients with NSCLC was restricted to nivolumab, pembrolizumab, and atezolizumab. Until 2016, NSCLC samples were not routinely tested for PD-L1 status. After 2016, positive PD-L1 levels were required only for patients who were receiving pembrolizumab as first-line therapy.7 We did not set strict PD-L1 level criteria for this study as PD-L1 levels are not required for administering nivolumab, pembrolizumab, or atezolizumab as second-line treatment.7 Patients receiving other targeted therapies were excluded from our analysis.

A chart review was performed to identify two cohorts of patients: one that received ICIs within 3 months of SRS (concurrent ICI) and one that did not (ICI naive). Initially, we identified 17 patients in the concurrent-ICI cohort and 101 patients in the ICI-naive group. A 1:2 propensity score “nearest” matching algorithm was used to determine the matched cohorts. Patients were matched in terms of age, sex, recursive partitioning analysis (RPA) scores, and number of treated BMs by using the R package “Matching” (R Foundation for Statistical Computing).10 The caliper was 0.2 and replacement was set as false. Before matching, the minimum p value was 0.018; it changed to 0.323 after matching. Seventeen patients composed the concurrent-ICI cohort and 34 patients composed the ICI-naive cohort after matching. Overall survival was defined as the interval between SRS and date of death. Data were censored as of April 20, 2018. Upon completion of generating the matched cohorts, chart review was performed to extract basic demographic information and radiosurgical parameters at the time of SRS.

SRS Technique and Follow-Up

Single-session SRS for BM was performed as previously described.26 Patients were placed in a Leksell model G stereotactic frame, and a thin-slice CT scan was acquired and merged with a preplanning thin-slice postcontrast MR image of the brain. Treatment plans were generated on Gamma Knife software (Elekta). Patients were typically followed clinically and radiologically with serial MRI every 2–3 months. All patients were imaged consistently on a 1.5-T or 3.0-T MRI unit. Standard dosing of contrast was used for all patients. Typically, patients underwent 2- to 3-month interval posttreatment MRI.

Radiographic Assessments

Two independent neuroradiologists who were blinded to ICI administration reviewed the brain MRI before and after SRS. For each follow-up MRI study, they applied the Response Assessment in Neuro-Oncology (RANO) criteria for BM.18 Disease progression was noted to occur in field (in one of the tumors treated with SRS) or out of field (new BM or leptomeningeal disease). Both neuroradiologists agreed on the RANO assessments. The interval between SRS and RANO-designated progressive disease and/or the development of a new BM was defined as PFS.

Tumor volumes were determined at the time of SRS and at each follow-up MRI by using the picture archiving and communication system (PACS) polygon method (Centricity PACS 4.0 SP3, GE Healthcare).31 Tumor growth or regression was defined as volumetric changes of ≥ 20% enlargement or ≥ 20% reduction, respectively, following SRS. Tumor stability was defined as a < 20% change in tumor volume from the time of SRS. We defined tumor control as either tumor stability or tumor regression.

Radiation necrosis was defined as a progressive increase in the volume of a specific BM on postcontrast T1-weighted images with concurrent increasing FLAIR signal changes that resolved or dramatically improved over time.22

The volume of peritumoral edema (if present) was determined for each BM prior to SRS and at each follow-up MRI using the PACS polygon method. The volume of the BM was excluded from the calculated peritumoral edema volume (PEV). Peritumoral edema was defined as the presence of hyperintense signal change surrounding each BM on T2 or FLAIR sequences. Edema progression or regression was defined as T2 or FLAIR volumetric changes of > 20% or < 20%, respectively, following SRS.

Statistical Analysis

Univariate analysis was performed using the t-test and chi-square test for continuous and categorical variables, respectively. Log-rank analysis was used to compare survivorship and time-dependent outcomes between the two cohorts. As patient death and tumor progression were competing risks, we calculated the cumulative probability of the target and nontarget tumor progression following SRS using the Gray and Fine subdistribution model.12 All tests were two-sided. A p value < 0.05 was considered statistically significant. Statistical analysis was performed using Prism statistical software (version 7.0b) and R (R Foundation for Statistical Computing).

Results

Patient and Tumor Characteristics

Following propensity score matching, 34 patients with 92 BMs were included in the ICI-naive cohort and 17 patients with 45 BMs were included in the concurrent-ICI cohort. Baseline demographic information is summarized in Table 1. Patients were similar with respect to age, RPA scores, mean number of BMs treated with SRS (2.7 for each cohort), use of corticosteroids at SRS (61.8% of patients in ICI-naive cohort vs 58.8% in concurrent-ICI cohort, p = 0.84), and prior treatments for BM. At the time of SRS, patients in the ICI cohort had reduced absolute lymphocyte counts (ALCs) compared to those in the ICI-naive group (1087 ± 453 vs 1673 ± 919 no./μl, p < 0.02). Patients in the ICI-treated group were more likely to have metastatic disease at lung cancer diagnosis (76.5% vs 55.9%, p = 0.15) and generally received systemic therapy (cisplatin or carboplatin) at the first diagnosis more often than their ICI-naive counterparts (88.2% vs 61.8%, p = 0.05). The incidence of synchronous BMs was similar between the two cohorts (concurrent ICI: 6/17 [35.3%], ICI naive: 13/34 [38.2%]). The interval between SRS and the first posttreatment MRI was also similar between the two cohorts (3.0 vs 3.1 months, p = 0.16).

TABLE 1.

Demographic information for patients treated with SRS for NSCLC

VariableICI-Naive CohortConcurrent-ICI Cohortp Value
No. of patients3417
Age at NSCLC Dx in yrs64.1 ± 10.264.4 ± 8.60.90
Female14 (41.2%)6 (35.3%)0.69
Metastatic disease at Dx19 (55.9%)13 (76.5%)0.15
Systemic treatment at Dx21 (61.8%)15 (88.2%)0.05
Resection of lung tumor10 (29.4%)3 (17.6%)0.36
Prior lung radiation15 (44.1%)4 (23.5%)0.15
Interval btwn NSCLC Dx & SRS in mos8 (0.8–34.6)9 (1–28.7)0.46
No. of BMs treated w/ SRS2.7 ± 2.42.7 ± 2.50.94
Prior BM treatment
 WBRT4 (11.8%)1 (5.9%)0.47
 Surgery*10 (29.4%)5 (29.4%)0.99
 Fractionated radiation0 (0%)1 (5.9%)0.15
Interval btwn surgery & SRS in mos0.7 (0.3–2.3)0.9 (0.5–10.5)0.13
RPA score at SRS
 16 (17.6%)0 (0%)
 227 (79.4%)17 (100%)
 31 (2.9%)0 (0%)0.13
Steroids Rx at SRS21 (61.8%)10 (58.8%)0.84
ALC at SRS in no./μl1673 ± 9191087 ± 4530.02
Radiographic FU in mos10.4 ± 9.97.0 ± 8.40.05

Dx = diagnosis; FU = follow-up; Rx = prescription; WBRT = whole-brain radiation therapy.

Data are presented as mean ± standard deviation (SD), median (interquartile range [IQR]), or frequency (%), unless indicated otherwise.

Time from prior cranial surgery.

Data available for 29/34 patients.

BMs in the ICI cohort were smaller than those treated in the ICI-naive cohort (mean diameter 1.0 ± 0.8 vs 1.2 ± 0.9 cm), but the difference was not significant (p = 0.12; Table 2). The mean radiographic follow-ups for the ICI-naive and concurrent-ICI groups were 10.4 and 7.0 months, respectively (p = 0.054; Table 1). The mean clinical follow-up was 16.0 and 10.0 months, respectively (p = 0.143).

TABLE 2.

BM characteristics and radiosurgical parameters in patients with NSCLC

VariableICI-Naive CohortConcurrent-ICI Cohortp Value
No. of BMs9245
Tumor diameter in cm1.2 ± 0.91.0 ± 0.80.12
Tumor vol in cm31.45 ± 3.39*0.60 ± 1.130.11
Vol treated in cm32.5 ± 4.91.7 ± 3.40.38
Margin dose in Gy19.3 ± 2.518.4 ± 2.30.05
Max dose in Gy30.0 ± 8.826.6 ± 7.50.03
No. of isocenters4.1 ± 5.33.3 ± 4.90.38
Isodose line68% (30%–97%)80% (50%–97%)0.39

Data are presented as mean ± SD or median (range), unless indicated otherwise.

Data for 91 evaluable tumors.

Data for 44 evaluable tumors.

PD-L1 Levels and Use of ICIs

Nivolumab, pembrolizumab, or atezolizumab was used in 58.8% (10/17), 29.4% (5/17), and 11.8% (2/17) of cases, respectively. The median number of cycles of ICI was 7 (range 3–36 cycles). The median duration between first receiving ICI and SRS was 23.5 days (range 1–76 days). Ten (58.8%) of 17 patients received ICIs within a month of SRS.

Of the 17 patients treated with ICI, 14 (82.4%) underwent PD-L1–level testing on immunohistochemistry. Four (28.6%) of the 14 had PD-L1 levels greater than 50%, 6/14 (42.9%) had PD-L1 levels between 1% and 49%, and 4/14 (28.6%) had PD-L1 levels less than 1%.

Radiosurgical Parameters

The radiosurgical parameters are listed in Table 2. For the concurrent-ICI cohort, the mean margin dose was 18.4 ± 2.3 Gy applied to a median isodose line of 80% (range 50%–97%). In comparison, for the ICI-naive cohort, the mean margin dose was 19.3 ± 2.5 Gy applied to a median isodose line of 68% (range 30%–97%). While there was a clear trend toward a reduced margin dose in the concurrent-ICI cohort, the difference between the two groups was not statistically significant (p = 0.05). However, the maximum treatment dose was significantly less in the concurrent-ICI cohort (26.6 ± 7.5 vs 30.0 ± 8.8 Gy, p = 0.03). There was no statistical difference in the treatment volume or number of isocenters.

Overall Survival

There was no statistically significant difference in OS following SRS for BM between the ICI-naive and concurrent-ICI cohorts (HR 0.99, 95% CI 0.39–2.52, p = 0.99). Median survival after SRS for the ICI-naive cohort was 15.9 months, while median survival for the concurrent-ICI cohort was not reached. For patients receiving concurrent ICI, survival following SRS was 100%, 55%, and 55% at 3, 6, and 12 months, respectively. Meanwhile, actuarial survival for those who did not receive ICI was 93.4%, 84.2%, and 62% at 3, 6, and 12 months, respectively.

Intracranial Disease Control

Sixteen patients in the concurrent-ICI cohort and 32 patients in the ICI-naive cohort were evaluable for assessing post-SRS tumor control per the RANO criteria.18 One patient in each cohort had received SRS to a BM resection cavity, and 1 patient in the ICI-naive cohort had not been able to receive intravenous contrast on post-SRS MRI studies. These patients were excluded from this analysis.

The results of intracranial tumor control after SRS are summarized in Table 3. Per the RANO criteria, the 12-month local control rate was similar between the concurrent-ICI and ICI-naive groups (100% vs 85.2%, p = 0.31). Patients receiving concurrent ICI had a statistically increased rate of complete response for BMs treated with SRS compared to their ICI-naive counterparts (8/16 [50%] vs 5/32 [15.6%], p = 0.012). No patient in the concurrent-ICI cohort developed disease progression of their treated BMs per the RANO criteria, whereas 3 patients (9.4%) in the ICI-naive group did (p = 0.21). At the last follow-up, the partial/complete response rate was 100% for patients receiving concurrent ICI versus 53.1% for the ICI-naive group (p = 0.001).

TABLE 3.

Patient-level intracranial control of BMs following SRS

VariableICI-Naive CohortConcurrent-ICI Cohortp Value
12-mo local control*85.2%100%0.31
Incidence of complete response at any FU5 (15.6%)8 (50.0%)§0.01
Time to complete response in mos3.7 (3.0–6.1)6.2 (3.1–13.4)0.20
Incidence of partial response19 (59.4%)12 (75.0%)§0.29
Time to partial response in mos3.4 (3.0–5.2)2.5 (2.3–3.2)0.08
Incidence of local progression3 (9.4%)0 (0.0%)§0.21
Time to local progression in mos5.5 (3.9–7.8)NANA
Out-of-field progression8 (23.5%)7 (41.2%)0.19
Time to out-of-field progression in mos5.1 (3.1–8.5)3.1 (1.8–4.6)0.14
Status of treated BM at last radiographic FU
 Complete response4 (12.5%)8 (50.0%)§
 Partial response13 (40.6%)8 (50.0%)§0.003
 Stable disease12 (37.5%)0 (0.0%)§
 Progressive disease3 (9.4%)0 (0.0%)§

NA = not applicable.

Data are presented as median (IQR) or frequency (%), unless indicated otherwise.

Local control was defined as complete response, partial response, or stable disease per the RANO criteria of treated BM.

Per the RANO criteria.

Of 32 evaluable patients (excluded 1 patient without postcontrast imaging available and 1 patient receiving postoperative SRS to resection cavity).

Of 16 evaluable patients (excluded 1 patient who received postoperative SRS to resection cavity).

Concurrent ICI did not prevent the development of out-of-field BM (new BM or leptomeningeal disease). Eight patients (23.5%) in the ICI-naive group developed distant CNS BMs versus 7 (41.2%) in the concurrent-ICI cohort (p = 0.19). Five (71.4%) of the 7 patients who developed out-of-field progression did so after ICIs were discontinued. The 12-month CNS distant control rate was 47.5% for the concurrent-ICI group versus 66.5% for the ICI-naive cohort (p = 0.061).

Progression-Free Survival

There was no difference in intracranial PFS following SRS between the two treatment groups (HR 2.18, 95% CI 0.72–6.62, p = 0.11; Fig. 1A). Median PFS for the concurrent-ICI cohort was 6.6 months. Median PFS for the ICI-naive cohort was not reached. The actuarial PFS rate for the concurrent-ICI cohort was 81.4%, 57.1%, and 47.6% at 3, 6, and 12 months. For the ICI-naive cohort, actuarial PFS was 97.1%, 79.4%, and 63.4% at 3, 6, and 12 months. One patient (2.9%) from the ICI-naive group developed leptomeningeal metastases. After adjusting for patient death as a competing risk, there was no difference in the cumulative likelihood of tumor progression between the groups (p = 0.42).

FIG. 1.
FIG. 1.

Kaplan-Meier analysis of patients and their treated BMs following SRS. A: There was no statistically significant difference in PFS between patients receiving concurrent ICI and those who did not (p = 0.11, log-rank test). The 12-month actuarial PFS rate for the concurrent-ICI cohort (dashed line) was 47.6% versus 63.4% for the ICI-naive cohort (solid line). B: The median time to individual BM regression was shorter in patients receiving ICIs (2.5 months) than in those who did not (3.1 months; p < 0.0001, log-rank test). C: BMs with peritumoral edema had a shorter median time to edema regression in patients who received ICI (2.4 vs 3.1 months; p < 0.001, log-rank test).

Factors Associated With Distant CNS Tumor Progression

Seven patients (41.2%) in the concurrent-ICI cohort developed new BMs during follow-up. Age, ALC, corticosteroid use at SRS, number of metastases, and KPS scores were similar between patients who developed out-of-field progression and those who did not (Table 4). Administration of ICIs prior to SRS was associated with a decrease in the rate of distant CNS BM development (ICI before SRS: 0% [0/6], ICI after SRS: 63.6% [7/11], p = 0.011).

TABLE 4.

Univariate analysis of factors associated with local or distant CNS progression for patients treated with ICIs

VariableNo ProgressionLocal or Distant CNS Progressionp Value
No. of patients107
Age in yrs64.9 ± 6.863.7 ± 11.20.79
Uncontrolled primary disease at SRS4 (40.0%)5 (71.4%)0.20
ALC at SRS (no./μl)1005 ± 5221204 ± 3350.39
Steroid use at time of SRS6 (60.0%)4 (57.1%)0.91
Presence of extracranial metastasis at SRS6 (60.0%)5 (71.4%)0.63
No. of treated BMs2.9 ± 3.22.3 ± 0.80.63
KPS score <808 (80.0%)6 (85.7%)0.76
Duration btwn SRS & last cycle of ICI in days20.3 ± 12.833.9 ± 31.20.23
ICI prior to SRS6 (60.0%)0 (0.0%)0.01

Data are presented as mean ± SD or frequency (%), unless indicated otherwise.

Individual Tumor Control

In addition to examining treatment response at the patient level, we investigated the effect of concurrent ICI use on individual tumor responses following SRS (Table 5). Of the 45 tumors in the concurrent-ICI cohort, 44 were evaluable for regression (1 tumor resection cavity treated with SRS was excluded). In the ICI-naive cohort, 88 of the 92 treated tumors were evaluable (excluded 1 tumor resection cavity and 1 patient with 3 treated BMs as she was unable to receive contrast on follow-up MRI). Tumor regression occurred in 86.4% (38/44) and 87.5% (77/89) of treated tumors in the concurrent-ICI and ICI-naive cohorts (p = 0.85), respectively. The median time to tumor regression was shorter in the concurrent-ICI cohort than in the ICI-naive cohort (2.5 vs 3.1 months, p < 0.0001; Fig. 1B). The median time to BM progression was similar in the two groups (concurrent ICI 3.0 vs ICI-naive 3.9 months, p = 0.18). As we included patients who could receive ICIs up to 3 months from SRS, we performed a sensitivity analysis excluding those who received ICIs more than 2 months from the time of SRS. Here, we still found that the median time to tumor regression was shorter in the concurrent-ICI cohort (2.8 vs 3.1 months, p < 0.0001).

TABLE 5.

Individual tumor control

VariableICI-Naive CohortConcurrent-ICI Cohortp Value
Incidence of BM regression77 (87.5%)*38 (86.4%)0.85
Time to tumor regression in mos3.1 (2.8–3.4)2.5 (2.3–3.1)<0.0001
Incidence of BM progression15 (16.9%)4 (8.9%)§0.21
Time to BM progression in mos3.9 (2.7–3.4)3 (2.7–3.1)0.18
BM control at last FU
 Regressed70 (78.7%)37 (82.2%)§0.44
 Stable7 (7.9%)5 (11.1%)§
 Progressed12 (13.5%)3 (6.7%)§
Relative tumor vol change−0.07 ± 2.3*−0.7 ± 0.50.012
12-mo local tumor control rate76.3%84.9%0.94

Data are presented as frequency (%), median (IQR), or mean ± SD, unless indicated otherwise.

Of 88 evaluable tumors (excluded 1 tumor resection cavity treated with SRS and 1 patient with 3 treated BMs as she was unable to receive contrast following SRS).

Of 44 evaluable tumors (excluded 1 tumor resection cavity treated with SRS).

Of 89 evaluable tumors (excluded 1 patient with 3 treated BMs as she was unable to receive contrast following SRS).

Of 45 evaluable tumors.

(Final tumor volume – pretreatment volume)/final tumor volume.

There was no statistical difference in the individual tumor control rate between the two groups. The 12-month local tumor control rate was 84.9% for tumors in the concurrent-ICI cohort versus 76.3% for tumors in the ICI-naive cohort (p = 0.94). At the last follow-up, the relative volumetric change in all treated tumors was greater in the concurrent-ICI cohort (−0.7 vs −0.07, p = 0.012).

Peritumoral Edema

Some studies suggest that combining SRS with ICI may aggravate peritumoral edema.9,20 Therefore, we investigated the degree of PEV before and after SRS in both cohorts (Table 6). Measurable peritumoral edema was evident in 45.7% (42/92) of BMs in the ICI-naive cohort and 55.6% (25/45) of BMs in the concurrent-ICI cohort. Baseline PEV in each cohort was similar (ICI naive: 10.8 cm3, concurrent ICI: 6.7 cm3, p = 0.36). At the last follow-up, there was no difference in PEV between the groups; however, the relative change in PEV at the last follow-up was decreased in the concurrent-ICI group (−3.1 ± 8.4 vs −0.2 ± 7.3 in ICI-naive group, p = 0.039). There was no difference in the rate of peritumoral edema regression between the two groups (ICI naive: 76.2% [32/42], concurrent ICI: 88% [22/25], p = 0.342). BMs with peritumoral edema had a shorter median time to edema regression when treated with ICI, as shown in Fig. 1C (2.4 vs 3.1 months, p < 0.001).

TABLE 6.

Peritumoral edema volumes following SRS

VariableICI-Naive CohortConcurrent-ICI Cohortp Value
Baseline PEV in cm310.8 ± 26.6*6.7 ± 18.20.36
1–3 mos post-SRS PEV in cm33.7 ± 12.41.1 ± 2.90.16
PEV at last FU in cm36.2 ± 18.81.0 ± 2.30.07
Relative PEV change at 1–3 mos−0.9 ± 8.7−3.1 ± 8.40.16
Relative PEV change at last FU−0.2 ± 7.3−3.1 ± 8.40.04
PTE progression20 (21.7%)5 (11.1%)0.16
Time to PTE progression in mos3.3 (2.8–7.6)3.4 (3.1–6.8)0.65
PTE regression32 (76.2%)*22 (88.0%)0.34
Time to PTE regression in mos3.1 (2.9–3.6)2.4 (2.3–3.1)0.006

PTE = peritumoral edema.

Data presented as mean ± SD, median (IQR), or frequency (%), unless indicated otherwise.

Of 42 BMs with measurable peritumoral edema prior to SRS.

Of 25 BMs with measurable peritumoral edema prior to SRS.

Relative FLAIR change = change in FLAIR volume/treatment volume.

Adverse Events

There was one instance of radiation necrosis in the ICI-naive cohort (2.9%) and none in the concurrent-ICI cohort. The patient who developed radiation necrosis became symptomatic and required resection with pathological confirmation of radiation necrosis. One patient in the concurrent-ICI cohort (5.9%) had radiographic evidence of hemorrhage within one of the treated BMs, though the patient was asymptomatic. No patient in the ICI-naive cohort developed intratumoral hemorrhage.

Discussion

The use of systemic ICIs is a promising treatment strategy for patients with advanced NSCLC.4,5,19,25 Approximately half of patients with NSCLC will develop BMs, and the majority of this half will undergo intracranial radiotherapy. As SRS remains the treatment strategy of choice for patients with multiple BMs, understanding the safety and efficacy of concurrent SRS and ICI administration is imperative.6

Most of the literature on SRS and ICI for BMs has been derived from the study of melanoma.2,3,8,9,14,15,21,23,29 Indeed, only a few studies have reported on patients with NSCLC-BMs treated with SRS and ICIs.1,8,13,16,20,30 Ahmed et al. published clinical and radiographic outcome data specific to NSCLC-BMs.1 In their study, a control arm that did not receive ICI was not included, and the timing between ICI and SRS was not defined. Recently, Singh et al. reported a retrospective series of patients treated with ICIs for NSCLC and compared their outcomes to those of historical controls.30 As in our study, the concurrent use of ICI and SRS for NSCLC did not improve OS or PFS. In their analysis, patients treated with ICIs were not matched with patients who received conventional chemotherapy. As a result, the patients who received ICI had more BMs and improved Graded Prognostic Assessment (GPA) scores compared to the patients receiving conventional therapy. Furthermore, historical controls in their study were composed of patients treated with SRS between 2006 and 2009, whereas the ICI cohort received SRS between 2013 and 2016. Thus, differences in systemic therapy and/or radiographic imaging may have confounded their results. In the current study, we sought to create a more homogeneous population of those patients receiving ICI and those who did not.

Our work suggests that combining ICI and SRS does not necessarily lead to improved OS or PFS in patients with NSCLC-BM. There was no statistical difference in OS or PFS at the patient level between the concurrent-ICI and ICI-naive cohorts. Likewise, the 12-month local control rate per the RANO criteria was similar between the two groups (concurrent ICI: 100%, ICI naive: 85.2%, p = 0.305). Nevertheless, our data indicated that combining ICI and SRS for these patients does not increase the risk of radiation necrosis, intratumoral hemorrhage, or peritumoral edema. However, our data did hint that there may be some synergism when combining ICI and SRS. In our study, patients who received ICIs within 3 months of SRS were more likely to attain a complete response from their treated BMs per the RANO criteria. Furthermore, individual BMs treated with SRS in the concurrent-ICI cohort had a shorter median time to tumor regression. Fifty percent of patients in the concurrent-ICI cohort met criteria for complete treatment response as gauged by RANO criteria, compared to just 15.6% of patients in the ICI-naive cohort (p = 0.012). At the tumor level, there was a greater magnitude of relative tumor volume change (concurrent ICI: −0.7, ICI naive: −0.07, p = 0.012). Given the retrospective nature of our study, however, these data should be interpreted with caution and should be considered hypothesis generating.

The present study is one of first to compare the clinical outcomes of patients receiving concurrent ICI and SRS versus isolated SRS for the treatment of NSCLC-BM. While some studies have suggested improved OS for patients receiving concurrent ICI and SRS for the treatment of melanoma-BM,2,9,14,15,29 others have not.3,21,23 Although a recent meta-analysis suggested that the concurrent administration of ICIs and (within 1 month of) SRS to BMs may improve survival, most of the patients included in that analysis had metastatic melanoma and many patients were treated with ipilimumab, an ICI targeting CTLA-4, which is not used in the NSCLC population.17 In our study, the 12-month OS rate following SRS was 55%, which is notably longer than the 12-month actuarial survival rate reported in the only other study to examine survival following combined SRS and ICI for NSCLC.1 Thus, further studies are needed to determine whether combining ICIs and SRS for patients with NSCLC-BMs affects OS.

Radiation necrosis in ICI-exposed patients was higher in previous reports than in our study.17,20 The incidence of radiation necrosis seems to be higher in patients with melanoma who receive ipilimumab.17,20 Individuals with NSCLC who receive ICIs targeting PD-1/PD-L1 do not appear to have high rates of radiation necrosis, which is consistent with the results reported herein.13

While other studies have suggested a possible abscopal effect when combining ICI and SRS, our study did not.14 The 12-month distant control rate was 47.5% for the concurrent-ICI cohort and 66.5% for the ICI-naive cohort (p = 0.061). The reasons for the poor regional control rates in the patients receiving concurrent ICI may be numerous. First, while patients in each cohort were matched with regard to RPA scores and number of treated BMs, patients in the concurrent-ICI cohort tended to have more advanced disease at first diagnosis and to have lower ALCs. We did not examine previous systemic treatment history; therefore, imbalances in patients with multiple lines of prior systemic therapy or those with cancer that was refractory to treatment may account for differences in regional failure. During the time frame examined, many patients exposed to ICIs were treated in the second-line or later setting for metastatic disease as first-line immunotherapy in NSCLC is a more recent treatment option. Those in the ICI-naive cohort may have been more likely to be newly diagnosed or to have good systemic control with first-line chemotherapy. Furthermore, lower ALCs are associated with an increased risk of intracranial recurrence in patients with melanoma-BMs treated with SRS and ipilimumab.3 Those with multiple lines of prior cytotoxic chemotherapy would be expected to have lower ALCs than a treatment-naive patient. Second, we defined concurrent ICI as the receipt of ICIs within 3 months of SRS. Other studies examining melanoma-BMs treated with concurrent ICIs have defined this differently.3,8,23 It is certainly possible that improved regional control may only be observed when ICIs and SRS are combined within a few weeks of one another, as suggested by Kiess et al.14 Further studies are needed to clarify whether concurrent ICI and SRS can decrease out-of-field disease progression for patients with NSCLC-BM.

In this study, we did not use minimum levels of PD-L1 expression for inclusion. As a result, there was significant heterogeneity of PD-L1 expression in the tested NSCLC tissues. While some studies have suggested that increasing PD-L1 expression may be associated with an improved response to ICIs, this has not been a universal finding.4,5,24 Furthermore, it has been well described that PD-L1 levels can change significantly during the course of treatment, have significant heterogeneity within a given biopsied tumor, and can be affected by the specific antibody used during immunohistochemistry.7 Thus, by incorporating a broad range of PD-L1 expression levels in this analysis, we increased the generalizability of the results to many patients who are considered candidates for ICI. Further studies are needed to determine if PD-L1 levels correlate with improved locoregional control following combined ICI and SRS.

Study Limitations

This study is limited by the inherent biases of all retrospective studies, including the possibility of recall or observation biases. Given rapidly changing treatment paradigms for systemic therapy for NSCLC, there is also chronological bias based on the year when patients were diagnosed and/or treated. Furthermore, while no statistical difference in the demographic information was noted between the two cohorts, the BMs treated with concurrent ICI were smaller. We hypothesize that this is why there was a trend toward a decreased margin dose in the concurrent-ICI cohort. Therefore, the trend toward improved local control in this study may also be confounded by the smaller tumor size. Nevertheless, by generating a matched cohort, we attempted to isolate patients with similar baseline characteristics that could be adequately compared.

Conclusions

Concurrent ICI and SRS decreased the time to tumor and peritumoral edema regression. While OS and PFS control rates were not necessarily increased with the addition of ICIs, the 12-month local tumor control was excellent (84.9%). There does not appear to be an increased rate of post-SRS adverse events with concurrent ICI. Further studies are needed to corroborate these findings.

Disclosures

Dr. Gentzler is a consultant for AstraZeneca, Merck, Takeda (Ariad), Bristol Myers Squibb, and Clovis Oncology and has received research funding from Merck, Bristol Myers Squibb, Helsinn, and Takeda for the study described.

Author Contributions

Conception and design: Sheehan, Shepard, Gentzler, Larner. Acquisition of data: Sheehan, Shepard, Xu, Donahue, Eluvathingal Muttikkal, Cordeiro, Hansen, Mohammad, Gentzler. Analysis and interpretation of data: all authors. Drafting the article: Sheehan, Shepard, Xu, Donahue, Eluvathingal Muttikkal. Critically revising the article: all authors. Reviewed submitted version of manuscript: Sheehan, Shepard, Xu, Donahue, Gentzler, Larner, Fadul. Approved the final version of the manuscript on behalf of all authors: Sheehan. Statistical analysis: Shepard, Xu. Administrative/technical/material support: Sheehan, Donahue. Study supervision: Sheehan, Shepard, Donahue, Gentzler, Larner, Fadul.

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    Lehrer EJ, Peterson J, Brown PD, Sheehan JP, Quiñones-Hinojosa A, Zaorsky NG, et al.: Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: an international meta-analysis of individual patient data. Radiother Oncol 130:104112, 2019

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  • Collapse
  • Expand

Illustration from Bernstock et al. (pp 655–663). Copyright Joshua D. Bernstock, NIH/NINDS. Published with permission.

  • FIG. 1.

    Kaplan-Meier analysis of patients and their treated BMs following SRS. A: There was no statistically significant difference in PFS between patients receiving concurrent ICI and those who did not (p = 0.11, log-rank test). The 12-month actuarial PFS rate for the concurrent-ICI cohort (dashed line) was 47.6% versus 63.4% for the ICI-naive cohort (solid line). B: The median time to individual BM regression was shorter in patients receiving ICIs (2.5 months) than in those who did not (3.1 months; p < 0.0001, log-rank test). C: BMs with peritumoral edema had a shorter median time to edema regression in patients who received ICI (2.4 vs 3.1 months; p < 0.001, log-rank test).

  • 1

    Ahmed KA, Kim S, Arrington J, Naghavi AO, Dilling TJ, Creelan BC, et al.: Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases. J Neurooncol 133:331338, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Ahmed KA, Stallworth DG, Kim Y, Johnstone PAS, Harrison LB, Caudell JJ, et al.: Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol 27:434441, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    An Y, Jiang W, Kim BYS, Qian JM, Tang C, Fang P, et al.: Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiother Oncol 125:8088, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al.: Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:16271639, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al.: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123135, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, et al.: Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA 316:401409, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Büttner R, Gosney JR, Skov BG, Adam J, Motoi N, Bloom KJ, et al.: Programmed death-ligand 1 immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. J Clin Oncol 35:38673876, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Chen L, Douglass J, Kleinberg L, Ye X, Marciscano AE, Forde PM, et al.: Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma. Int J Radiat Oncol Biol Phys 100:916925, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Cohen-Inbar O, Shih HH, Xu Z, Schlesinger D, Sheehan JP: The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab. J Neurosurg 127:10071014, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al.: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745751, 1997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al.: Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 17:976983, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:11411154, 1988

  • 13

    Hubbeling HG, Schapira EF, Horick NK, Goodwin KEH, Lin JJ, Oh KS, et al.: Safety of combined PD-1 pathway inhibition and intracranial radiation therapy in non-small cell lung cancer. J Thorac Oncol 13:550558, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Kiess AP, Wolchok JD, Barker CA, Postow MA, Tabar V, Huse JT, et al.: Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys 92:368375, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Knisely JPS, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VLS: Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg 117:227233, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Kotecha R, Kim JM, Miller JA, Juloori A, Chao ST, Murphy ES, et al.: The impact of sequencing PD-1/PD-L1 inhibitors and stereotactic radiosurgery for patients with brain metastasis. Neuro Oncol [epub ahead of print], 2019

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Lehrer EJ, Peterson J, Brown PD, Sheehan JP, Quiñones-Hinojosa A, Zaorsky NG, et al.: Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: an international meta-analysis of individual patient data. Radiother Oncol 130:104112, 2019

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al.: Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 16:e270e278, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al.: Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 30:20462054, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Martin AM, Cagney DN, Catalano PJ, Alexander BM, Redig AJ, Schoenfeld JD, et al.: Immunotherapy and symptomatic radiation necrosis in patients with brain metastases treated with stereotactic radiation. JAMA Oncol 4:11231124, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
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  • 21

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