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Outcome of Patients with Non–Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors

Open ArchivePublished:February 16, 2019DOI:https://doi.org/10.1016/j.jtho.2019.02.009

      Abstract

      Introduction

      Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.

      Methods

      Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.

      Results

      A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0–1, 58.5% with a score of 1.5–2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5–2.1) and 2.1 (95% CI: 1.9–2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p < 0.001]). The median OS times were 8.6 months (95% CI: 6.8–12.0) with BM and 11.4 months (95% CI: 8.6–13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48–0.52) were associated with improved OS.

      Conclusion

      In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis.

      Keywords

      Introduction

      In up to 40% of molecularly unselected patients with NSCLC, brain metastases (BMs) are diagnosed during the course of their disease.
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      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
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      Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.
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      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
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      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
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      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
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      the survival of patients with BMs was not significantly superior with ICI treatment versus with chemotherapy. Conversely, in the first-line KEYNOTE-189 trial (pembrolizumab platinum-doublet chemotherapy versus platinum-doublet chemotherapy)
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      or the optimal timing of cranial irradiation, remain unsolved.
      In this study, we aimed to compare outcome of less-selected patients with ICI-treated NSCLC and BMs with outcome of patients without BMs and to identify prognostic factors.

      Patients and Methods

      Prospectively collected lists of patients with advanced NSCLC that started between November 2012 and May 2018 with ICI treatment in six European centers (five French and one Dutch) were merged. All consecutive patients with advanced NSCLC were included when they were treated with programmed cell death 1 (PD-1)/PD-L1 inhibitors with or without anti–cytotoxic T-lymphocyte antigen 4 within routine clinical care, EAPs, compassionate use programs, and clinical trials. Patients were excluded when they were treated with a concurrent combination of anti–PD-1/PD-L1 therapy and chemotherapy. Patients with leptomeningeal metastases (LMs) were excluded, as the prognosis of patients with LMs is usually poorer than that of patients with BMs.
      • Turkaj A.
      • Morelli A.M.
      • Vavala T.
      • Novello S.
      Management of leptomeningeal metastases in non-oncogene addicted non-small cell lung cancer.
      These patients will be reported separately.
      Data on demographics and clinical, pathological, and molecular data were retrospectively extracted from the medical records between November 2017 and April 2018. For patients with a diagnosis of central nervous system metastases, ds-GPA score at the start of ICI treatment was also collected. The ds-GPA scores were grouped according to Sperduto et al. as follows: 0 to 1 (worst prognostic group), 1.5 to 2.5, 3, and 3.5 to 4 (best group).
      • Sperduto P.W.
      • Chao S.T.
      • Sneed P.K.
      • et al.
      Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients.
      Active BMs were defined as newly diagnosed and nonirradiated lesions and/or growing lesions (investigator/local radiologist–assessed) on brain imaging (including treated lesions that secondarily progressed) without any subsequent local treatment before the start of ICI treatment (compare with Goldberg et al.
      • Goldberg S.B.
      • Gettinger S.N.
      • Mahajan A.
      • 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.
      ). Stable BMs were defined as those that had been treated (with radiotherapy or surgery) before ICI treatment and showed no progression on brain imaging no more than 6 weeks before the start of ICI treatment. Treated patients with BMs who were symptomatic but had stable or decreasing symptoms at the start of ICI treatment were classified as stable.
      Data for local assessment of PD-L1 expression were analyzed on tumor cells by immunohistochemistry. Expression of at least 1% was considered positive. Radiological assessments of brain and extracranial disease were performed (usually every 6–9 weeks), and response was determined locally at each institution by the investigator.
      This study was approved by the institutional review board of Gustave Roussy (Institutional Review Board) and the ethical committee of Maastricht University Medical Center+ (No. 2018-0530). Informed consent was not necessary, as clinical and imaging data were retrospectively added.

      Statistical Analysis

      Comparisons between patient characteristics were performed by using the chi-square or Fisher exact test for discrete variables and the unpaired t test, Wilcoxon signed rank test, or analysis of variance for continuous variables when applicable. Disease control rate (DCR) was defined as complete plus partial response plus stable disease, and ORR as complete response plus partial response. OS was calculated from the date of first administration of immunotherapy until death due to any cause. Progression-free survival (PFS) was calculated from the date of first administration of immunotherapy until progressive disease (PD) or death due to any cause. A Cox proportional hazards regression model was used to evaluate factors independently associated with OS and PFS. Variables included in the final multivariate model were selected according to their clinical relevance and statistical significance in a univariate analysis (cutoff p = .10).
      The proportional hazard hypothesis was verified by using the Schoenfeld residual method. Correlation between variables was verified before construction of the multivariate models to deal with potential colinearity. Statistical analyses were performed with RStudio software.

      Results

      Population with BMs

      Data on 1052 patients were collected. Of these patients, 11 were excluded because of combination anti–PD-1/PD-L1 with chemotherapy and 16 were excluded because of LMs (with or without BMs) at the start of ICI treatment, resulting in 1025 included patients (CONSORT diagram [Fig. 1]). The median follow-up time was 15.8 (95% confidence interval [95% CI]: 14.6–17.0) months. A total of 534 patients (52.1%) had brain imaging no more than 6 weeks before the start of ICI treatment; 172 (32.2%) underwent magnetic resonance imaging, whereas the others underwent computed tomography. Reasons for brain imaging were screening, follow-up of known BMs, and neurological symptoms.
      Figure thumbnail gr1
      Figure 1CONSORT diagram: patient inclusion. ICI: immune checkpoint inhibitor; LM: leptomeningeal metastasis; BM: brain metastasis.
      In all, 255 patients (24.9%) had BMs at the start of ICI treatment. Baseline characteristics for those with and without BM are presented in Table 1. Compared with patients without BMs, those with BMs were significantly younger, had the adenocarcinoma histologic type more often, had a WHO performance status (PS) of 2 or higher, had used corticosteroids at the start of ICI treatment more frequently, and had a higher median number of organs with metastases.
      Table 1Baseline Characteristics Overall and Brain Metastases Subgroups
      CharacteristicTotal Population (N = 1025)Patients without Baseline Brain Metastases (n = 770)Patients with Baseline Brain Metastases (n = 255)p Value
      Patients with and without brain metastases are compared.
      Sex, n (%)
       Male646 (63.0)488 (63.4)158 (62.0)0.685
      Median age at start of ICI treatment, y (range)64.3 (30.2–92.8)65.4 (30.7–92.8)61.5 (30.2–80.8)<0.001
      Smoking status at start of ICI treatment, n (%)
       Current402 (41.6)299 (41.2)103 (42.7)0.666
       Former488 (50.5)366 (50.4)122 (50.7)
       Never77 (8.0)61 (8.4)16 (6.6)
       Unknown584414
      Histologic type, n (%)
       Adenocarcinoma681 (66.4)482 (62.6)199 (78.0)<0.001
       Squamous carcinoma268 (26.2)230 (29.9)38 (14.9)
       NSCLC, other76 (7.4)58 (7.5)18 (7.1)
      Molecular alteration,
      Percentage computed for patients with known results, numbers tested (positive or negative) after each molecular alteration.
      n (%)
      EGFR mutation (737 tested)39 (5.3)29 (5.3)10 (5.2)0.921
      ALK rearrangement (713 tested)6 (0.8)5 (1.0)1 (0.5)1.00
      KRAS mutation (708 tested)241 (34.0)174 (33.6)67 (35.3)0.677
      BRAF mutation (613 tested)23 (3.8)19 (4.3)4 (2.4)0.346
      ROS1 rearrangement (439 tested)0 (0.0)0 (0.0)0 (0.0)1.00
      PD-L1 status, n (%)
       Positive230 (64.1)179 (64.9)51 (61.5)0.57
       Negative129 (35.9)97 (35.1)32 (38.5)
       Unknown666494172
      Performance status (WHO)
       0–1823 (82.2)630 (84.0)197 (77.2)0.011
       ≥2178 (17.8)120 (16.0)58 (25.8)
       Unknown24200
      Corticosteroid use at start of ICI treatment, n (%)
       Yes141 (13.9)72 (9.4)69 (27.4)<0.001
       No875 (86.1)692 (90.6)183 (72.6)
       Unknown963
      Brain imaging ≤6 weeks of start of ICI treatment, n (%)534 (52.1)328 (42.6%)206 (80.8)<0.001
       MRI172 (32.2)68 (20.7%)104 (50.5)<0.001
       CT362 (67.8)260 (79.35)102 (49.5)
      Median No. of organs with metastases at start of ICI treatment (range)2 (1–10)2 (1–9)3 (1–10)<0.001
      Median line of ICI treatment (range)2 (1–12)2 (1–12)2 (1–8)0.555
      PD-1/PD-L1 inhibitor as monotherapy, n (%)963 (94.0)721 (93.6)242 (94.9)0.541
       PD-1 inhibitor927 (96.3)687 (95.3)240 (99.2)0.003
       PD-L1 inhibitor36 (3.7)34 (4.7)2 (0.8)
      ICI, immune checkpoint inhibitor; ALK, ALK receptor tyrosine kinase gene; PD-L1, programmed death ligand 1; MRI, magnetic resonance imaging; CT, computed tomography; PD-1, programmed cell death 1.
      a Patients with and without brain metastases are compared.
      b Percentage computed for patients with known results, numbers tested (positive or negative) after each molecular alteration.
      Details on patients with BMs are shown in Table 2. In all, 37 patients (14.3%) had symptomatic BMs at the start of ICI treatment and 69 (27.4%) received corticosteroids.
      Table 2Baseline Characteristics of Patients with Stable versus Active Brain Metastases
      CharacteristicPatients with Baseline Brain Metastases (n = 255)Patients with Active Baseline Brain Metastases (n = 100)Patients with Stable Baseline Brain Metastases (n = 121)p Value
      Patients with stable and active brain metastases are compared.
      Median time between first diagnosis of brain metastases and start of ICI treatment, mo (range)5.8 (0–68.8)4.7 (0–41.1)6.0 (0.1–68.8)0.248
      Brain surgery before start of ICI treatment, n (%)36 (14.1)9 (9.0)23 (19.0)0.035
      Brain radiotherapy before start of ICI treatment, n (%)173 (68.1)43 (43.0)110 (90.9)< 0.001
       WBRT72 (41.6)18 (41.9)44 (40.0)0.664
       SRT99 (57.2)24 (55.8)65 (59.1)
       WBRT + boost SRT2 (1.2)1 (2.3)1 (0.9)
      Median time between end of last brain radiotherapy and start of ICI treatment, mo (range)3.6 (0–66.3)5.2 (1.7–38.9)1.4 (0–66.3)<0.001
      Brain imaging before start of ICI treatment, n (%)206 (80.8)96 (87.3)121 (100.0)< 0.001
       MRI104 (50.5)53 (53.0)59 (48.8)0.316
       CT102 (49.5)47 (47.0)59 (48.8)
       Unknown CT or MRI003 (2.5)
      Brain metastases at start of ICI treatment, n (%)
       ≤2120 (47.1)52 (52.0)57 (47.1)0.769
       3–549 (19.2)18 (18.0)24 (19.8)
       ≥686 (33.7)30 (30.0)40 (33.1)
      Brain metastases symptomatic at start of ICI treatment, n (%)
       Yes37 (14.7)12 (12.0)22 (18.5)0.187
       No214 (85.3)88 (88.0)97 (81.5)
       Unknown402
      Corticosteroid use at start of ICI treatment, n (%)69 (27.4)22 (22.0)39 (32.2)0.100
       ≤10 mg of prednisolone equivalent/d20 (33.3)6 (31.6)10 (29.4)0.869
       >10 mg of prednisolone equivalent/d40 (66.7)13 (68.4)24 (70.6)
       Unknown dose935
      WHO PS at start of ICI treatment, n (%)
       0–1197 (77.3)73 (73.0)98 (81.0)0.158
       ≥258 (22.7)27 (27.0)23 (19.0)
      ds-GPA at start of ICI treatment, n (%)
       0–186 (35.7)33 (33.3)43 (36.8)0.869
       1.5–2.5141 (58.5)60 (60.6)67 (57.2)
       314 (5.8)6 (6.1)7 (6.0)
       3.5–40 (0)(0)(0)
       Unknown1414
      ICI, immune checkpoint inhibitor; WBRT, whole brain radiotherapy; SRT, stereotactic radiotherapy; MRI, magnetic resonance imaging; CT, computed tomography; PS, performance status; ds-GPA, disease-specific Graded Prognostic Assessment.
      a Patients with stable and active brain metastases are compared.
      ds-GPA classification was available for 241 of 255 patients (94.5%); and was 0 to 1 in 86 patients (35.7%), 1.5 to 2.5 in 141 (58.5%), and 3 in 14 (5.8%). None of the patients had a score of 3.5 or 4. Patients with a lower ds-GPA classification used corticosteroids at the start of ICI treatment significantly more often (38.8% with a ds-GPA classification of 0 to 1, 23.4% with a ds-GPA classification of 1.5–2.5, and 0% with a ds-GPA classification of 3 [p = 0.003]). Of the 255 patients, 100 (39.2%) had active BMs at the start of ICI treatment, 121 (47.5%) had stable BMs, and BM status (i.e., active or not) was unknown for 34 (13.3%).

      Outcome with ICI Treatment

      Responses

      Overall ORR was not significantly different for patients with (n = 255) and without (n = 770) BMs: 20.6% versus 22.7% (p = 0.484), but DCR was significantly lower in patients with BMs: 43.9% versus 52.0% (p = 0.024). Of 100 patients with active BMs, 73 (73.0%) underwent brain imaging during ICI treatment. The intracranial ORR was 27.3%, and intracranial DCR was 60.3%. For 23 patients with active BMs with baseline brain imaging and comparable brain imaging available during ICI treatment (31.5% [i.e., only magnetic resonance imaging or only computed tomography]), PD-L1 status was available; 14 patients (60.9%) had a PD-L1 expression level of 1% or higher, with an ORR of 35.7% versus 11.1% in PD-L1–negative patients. Of the 27 patients with active BMs, three (11.1%) without brain imaging during ICI treatment died with neurological deterioration during ICI treatment.
      Only two patients with BMs (0.8%) experienced pseudoprogression in the brain (growing and/or new BMs on imaging, with subsequent shrinkage on imaging). Nine patients with BMs had resection of a BM during ICI treatment because of symptomatic growth. For one patient, radiological growth was comparable with radiation necrosis, and this was histologically confirmed. For five patients, only vital tumor tissue was found; for the others, a mixture of vital tumor tissue and necrosis was found (example in Supplementary Fig. 1).

      PFS

      Of the 255 patients with BMs, 204 (80%) progressed, whereas 589 of 770 patients without BMs (76.5%) progressed (p = 0.246). The median PFS times for patients with and without BMs were 1.7 months (95% CI: 1.5–2.1) and 2.1 months (95% CI: 1.9–2.5), respectively (p = 0.009) (Fig. 2A). The patients with BMs had brain PD significantly more often than did those without (46.3% versus 11.4% [p < 0.001]). The patients with active BMs had brain PD (with or without extracranial PD) significantly more often than did those with stable BMs (54.2% versus 30% [p < 0.001]).
      Figure thumbnail gr2
      Figure 2Kaplan-Meier curves for progression-free survival (A) and overall survival (B) according to presence of brain metastases. met, metastasis.
      Patterns of progression are depicted in Supplementary Figure 2. In the subgroup of patients with BMs, 26 of 204 progressing patients (12.7%) had a dissociated central nervous system and extracranial response (i.e., six of 24 patients [25.0%] had brain-only PD with an extracranial response at that time, and 20 of 97 patients had only extracranial PD but had a cranial response at that time [seven (35.0%) of these had undergone cranial radiotherapy less than 3 months before starting ICI treatment]).
      In multivariate analysis for PFS, smoking was associated with an improved PFS, whereas more than two organs with metastases, a WHO PS of 2 or higher, and use of corticosteroids at the start of ICI treatment were associated with a decreased PFS (Table 3). The results regarding presence of BM (not associated with PFS) did not change significantly when we analyzed the subgroup with baseline brain imaging only (Supplementary Table 2)
      Table 3Multivariate Analysis of PFS and OS of the Overall Population
      FactorPFS HR (95% CI)p ValueOS HR (95% CI)p Value
      Age, >65 y vs. ≤65 y1.03 (0.89–1.20)0.6671.11 (0.93–1.33)0.26
      Smoking, yes vs. no0.52 (0.41–0.67)<0.00010.79 (0.59–1.06)0.112
      Histologic type
       Squamous vs. adeno1.04 (0.87–1.24)0.861.18 (0.95–1.45)0.28
       NSCLC, other vs. adeno1.06 (0.80–1.42)1.14 (0.81–1.60)
      No. of organs with metastases, >2 vs. ≤21.29 (1.10–1.50)0.0011.42 (1.18–1.71)<0.0001
      ICI line, >2 vs. ≤21.01 (0.87–1.18)0.8811.07 (0.90–1.29)0.44
      WHO PS, ≥2 vs. 0–12.29 (1.89–2.77)<0.00013.37 (2.72–4.16)<0.0001
      Use of corticosteroids, yes vs. no1.31 (1.07–1.62)0.011.46 (1.16–1.84)0.001
      Brain metastases, yes vs. no1.10 (0.92–1.31)0.280.99 (0.81–1.23)0.96
      PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival; adeno, adenocarcinoma; ICI, immune checkpoint inhibitor; PS, performance status.
      For ds-GPA classifications of 0 to 1, 1.5 to 2.5, and 3, the median PFS times were 1.4 months (95% CI: 1.2–1.6), 2.4 months (95% CI: 1.5–3.3), and 5.5 months (95% CI: 0.1–11.8), respectively. The median PFS was significantly longer for ds-GPA classifications of 1.5 to 2.5 (p < 0.001) and 3 (p = 0.023) than for classification of 0 to 1. In multivariate analysis for the BM subgroup, more than two organs with metastases, and use of corticosteroids at the start of ICI treatment were associated with poorer PFS, whereas stable BM and a higher ds-GPA score were associated with improved PFS (Table 4). Previous cranial radiotherapy (yes versus no) was not associated with PFS in univariate analysis (HR = 0.80, 95% CI: 0.60–1.08, p = 0.144) and as such was not carried forward to multivariate analysis.
      Table 4Multivariate Analysis of PFS and OS in the BM Subgroup
      FactorPFS HR (95% CI)p ValueOS HR (95% CI)p Value
      Sex, male vs. female0.95 (0.68–1.33)0.7651.42 (0.94–2.16)0.100
      Smoking, yes vs. no0.81 (0.40–1.64)0.5610.74 (0.34–1.64)0.464
      Histologic type
       Squamous vs. adeno0.97 (0.60–1.57)0.991.09 (0.63–1.90)0.750
       NSCLC, other vs. adeno0.98 (0.53–1.83)0.79 (0.38–1.65)
      No. of organs with metastases, >2 vs. ≤21.72 (1.15–2.57)0.0091.39 (0.87–2.22)0.174
      ICI treatment line, >2 vs. ≤20.98 (0.70–1.39)0.9221.09 (0.73–1.65)0.671
      Use of corticosteroids at start of ICI treatment, yes vs. no2.78 (1.90–4.08)<0.00012.37 (1.54–3.63)<0.0001
      BMs stable at start ICI, yes vs. no0.62 (0.44–0.88)0.0070.62 (0.41–0.93)0.019
      ds-GPA, 1.5–2.5 vs. 0–10.55 (0.38–0.78)0.0040.48 (0.31–0.72)0.002
      ds-GPA, 3 vs. 0–10.65 (0.31–1.35)0.54 (0.22–1.32)
      BM, brain metastasis; PFS, progression free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival; ICI, immune checkpoint inhibitor; ds-GPA, disease-specific Graded Prognostic Assessment.

      OS

      The median OS times were 8.6 months (95% CI: 6.8–12.0) for patients with BMs and 11.4 months (95% CI: 8.6–13.8) for patients without BMs, respectively (p = 0.035) (Fig. 2B). Except for smoking, the same factors associated with PFS in multivariate analysis were identified for OS. Presence of BMs was not associated with OS in multivariate analysis (see Table 3). The results did not change significantly regarding presence of BMs when we analyzed the subgroup with baseline brain imaging only (see Supplementary Table 2). Because of the large number of patients with unknown PD-L1 status (65.0%), PD-L1 status was not evaluated in the multivariate analysis.
      The median OS times were 4.4 months (95% CI: 2.0–6.7), 13.7 months (95% CI: 10.2–17.2), and 13.7 months (95% CI: 1.5–26.1) for ds-GPA classifications of 0 to 1, 1.5 to 2.5, and 3, respectively. The median OS was significantly longer with ds-GPA classifications of 1.5 to 2.5 (p < 0.001) and 3 (p = 0.010) than with classifications of 0 to 1. In multivariate analysis for the BM subgroup, use of corticosteroids at the start of ICI treatment was associated with poorer PFS, whereas stable BMs and a higher ds-GPA score were associated with improved PFS (see Table 4). Previous cranial radiotherapy (yes versus no) was not associated with survival in univariate analysis (HR = 0.80, 95% CI: 0.57–1.13, p = 0.204) and as such was not carried forward to multivariate analysis.

      Discussion

      BMs are frequent in NSCLC, but patients with BMs are often fully excluded from clinical trials, or only selected patients are included, resulting in underrepresentation of these patients in clinical trials (6.2%–17.5% of included patients had BMs).
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      Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
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      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
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      IMpower131:pPrimary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC [abstract].
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      Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (chemo) with or without pembrolizumab (pembro) for patients (pts) with metastatic squamous (sq) non-small cell lung cancer (NSCLC) [abstract].
      EAPs also allowed only selected patients with BMs.
      • Crino L.
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      • Roila F.
      • et al.
      Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
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      Intracerebral efficacy and tolerance of nivolumab in non-small-cell lung cancer patients with brain metastases.
      As data on ICI efficacy in less-selected patients with BMs are lacking, we performed the current study to evaluate response and survival of patients with BMs treated with ICIs.
      In this large, multicenter cohort of patients with advanced ICI-treated NSCLC, 255 (24.9%) had BMs at the start of ICI treatment. This percentage is higher than that reported in clinical trials (6.2%–17.5%) but comparable with the rates reported in other, mostly smaller retrospective ICI series (10.2%–31%)
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      • Brahmer J.
      • Reckamp K.L.
      • Baas P.
      • et al.
      Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.
      • Reck M.
      • Rodriguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      • Herbst R.S.
      • Baas P.
      • Kim D.W.
      • et al.
      Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
      • Rittmeyer A.
      • Barlesi F.
      • Waterkamp D.
      • et al.
      Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      • Paz-Ares L.
      • Luft A.
      • Tafreshi A.
      • et al.
      Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (chemo) with or without pembrolizumab (pembro) for patients (pts) with metastatic squamous (sq) non-small cell lung cancer (NSCLC) [abstract].
      • Dudnik E.
      • Yust-Katz S.
      • Nechushtan H.
      • et al.
      Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases.
      • Crino L.
      • Bidoli P.
      • Roila F.
      • et al.
      Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
      • Molinier O.
      • Audigier-Valette C.
      • Cadranel J.
      • et al.
      OA 17.05 IFCT-1502 CLINIVO: real-life experience with nivolumab in 600 patients (Pts) with advanced non-small cell lung cancer (NSCLC).
      • Henon C.
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      • et al.
      P2.07-005 Impact of baseline leptomeningeal and brain metastases on immunotherapy outcomes in advanced non-small cell lung cancer (NSCLC) patients.
      and in line with what is expected in this patient population (25%–40% with BMs).
      • Sorensen J.B.
      • Hansen H.H.
      • Hansen M.
      • Dombernowsky P.
      Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis.
      • Yawn B.P.
      • Wollan P.C.
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      • Mehta M.
      Temporal and gender-related trends in brain metastases from lung and breast cancer.
      To the best of our knowledge, only two large EAP series on patients with NSCLC and BMs treated with ICIs have previously been reported,
      • Crino L.
      • Bidoli P.
      • Roila F.
      • et al.
      Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
      • Molinier O.
      • Audigier-Valette C.
      • Cadranel J.
      • et al.
      OA 17.05 IFCT-1502 CLINIVO: real-life experience with nivolumab in 600 patients (Pts) with advanced non-small cell lung cancer (NSCLC).
      with 26% (409 of 1588) and 22% (197 of 902) of patients with BMs included, respectively. Important factors for patients with BMs such as ds-GPA score, use of steroids and classification of BM (active or not) were not mentioned. In our study, 39.2% of patients with BMs had active BMs, 14.7% had symptomatic BMs, 22.7% had a WHO PS of 2 or higher, and 15.7% had corticosteroid doses higher than 10 mg of prednisolone equivalent/day (all exclusion criteria in EAP or clinical trial).
      The overall ORR of 20.6% (with BMs) to 22.7% (no BMs) in our series is comparable with that in the existing literature.
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      • Brahmer J.
      • Reckamp K.L.
      • Baas P.
      • et al.
      Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.
      • Rittmeyer A.
      • Barlesi F.
      • Waterkamp D.
      • et al.
      Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
      The 27.3% intracranial ORR of the patients with active BMs is similar to that of the PD-L1–positive patients included in the phase II trial of Goldberg et al. (none of the PD-L1–negative patients responded in this trial),
      • Goldberg S.
      • Gettinger S.
      • Mahajan A.
      • et al.
      Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab [abstract].
      and is slightly higher than that reported in retrospective series.
      • Cortinovis D.
      • Delmonte A.
      • Chiari R.
      • et al.
      P3.02c-094. Italian Nivolumab Advanced Squamous NSCLC Expanded Access Program: efficacy and safety in patients with brain metastases.
      • Crino L.
      • Bidoli P.
      • Roila F.
      • et al.
      Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
      • Henon C.
      • Mezquita L.
      • Auclin E.
      • et al.
      P2.07-005 Impact of baseline leptomeningeal and brain metastases on immunotherapy outcomes in advanced non-small cell lung cancer (NSCLC) patients.
      Furthermore, patients with BMs progressed more often in the brain than did patients without preexisting BMs. As severe neurological symptoms can develop in these patients because of their brain progression, careful monitoring, especially of active BM, during the first months of ICI treatment seems needed. In general, a growing BM indicates real PD, as pseudoprogression was rare (0.8%) in our BM cohort.
      The median PFS and OS times of patients with BM in our study are comparable with those in other, mostly smaller ICI series.
      • Goldberg S.
      • Gettinger S.
      • Mahajan A.
      • et al.
      Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab [abstract].
      • Cortinovis D.
      • Delmonte A.
      • Chiari R.
      • et al.
      P3.02c-094. Italian Nivolumab Advanced Squamous NSCLC Expanded Access Program: efficacy and safety in patients with brain metastases.
      • Watanabe H.
      • Kubo T.
      • Ninomiya T.
      • et al.
      The effect of nivolumab treatment for central nervous system metastases in non-small cell lung cancer.
      • Dudnik E.
      • Yust-Katz S.
      • Nechushtan H.
      • et al.
      Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases.
      • Crino L.
      • Bidoli P.
      • Roila F.
      • et al.
      Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
      • Gauvain C.
      • Vauleon E.
      • Chouaid C.
      • et al.
      Intracerebral efficacy and tolerance of nivolumab in non-small-cell lung cancer patients with brain metastases.
      • Molinier O.
      • Audigier-Valette C.
      • Cadranel J.
      • et al.
      OA 17.05 IFCT-1502 CLINIVO: real-life experience with nivolumab in 600 patients (Pts) with advanced non-small cell lung cancer (NSCLC).
      The median PFS and OS times were shorter for patients with BMs than for those without BMs, but in multivariate analysis presence of BMs (when compared with absence of BMs) was not significantly associated with a poorer survival with ICI treatment. This finding is in contrast to the findings of the French EAP series, but in the French series there was no adjustment for corticosteroid use or number of organs with metastases in multivariate analysis,
      • Molinier O.
      • Audigier-Valette C.
      • Cadranel J.
      • et al.
      OA 17.05 IFCT-1502 CLINIVO: real-life experience with nivolumab in 600 patients (Pts) with advanced non-small cell lung cancer (NSCLC).
      which were both associated with poorer PFS and OS in our and in other series.
      • Arbour K.C.
      • Mezquita L.
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      Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer.
      • Mezquita L.
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      Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer.
      Patients with stable BMs had PFS and OS times superior to those of patients with active BMs; use of corticosteroids at the start of ICI treatment was associated with worse PFS and OS. Furthermore, symptomatic BMs were associated with worse PFS and OS in univariate analysis (for PFS, HR = 1.90, 95% CI: 1.30–2.77, p = 0.001; and for OS, HR = 2.03, 95% CI: 1.33–3.11, p = 0.001). Corticosteroid use at the start of ICI treatment was already described as deleterious.
      • Arbour K.C.
      • Mezquita L.
      • Long N.
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      Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer.
      • Scott S.C.
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      Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab.
      However, as there was colinearity with symptomatic BMs and use of corticosteroids and use of corticosteroids was more significant, only the latter was carried forward to the multivariate analysis. Interestingly, ds-GPA score is prognostic not only patients with in newly diagnosed BMs
      • Sperduto P.W.
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      Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients.
      but also in patients with previously diagnosed BMs who start ICI treatment. ds-GPA score combined with use of corticosteroids, symptoms, BM status (active versus stable), and PD-L1 status could be used in the decision regarding whether to administer ICI to a patient with BM.
      In our study, cranial radiotherapy before start of ICI treatment (yes versus no) was not associated with OS in the BM subgroup in univariate analysis (HR = 0.80, 95% CI: 0.57–1.13, p = 0.204); however, this analysis did not take into account time from cranial radiotherapy to start of ICI treatment, or brain PD after cranial irradiation before the start of ICI treatment. Indeed, patients with stable BMs (i.e., locally treated [mostly with radiotherapy] and no radiological progression or new BMs at the start of ICI treatment) had a better OS than did those with active BM. In a retrospective, single-center (N = 98) analysis of the KEYNOTE-001 trial, patients who were treated with any radiotherapy (n = 42) or extracranial radiotherapy (n = 38) before the start of ICI treatment had a survival superior to that of patients who were not treated with radiotherapy.
      • Shaverdian N.
      • Lisberg A.E.
      • Bornazyan K.
      • et al.
      Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.
      However, an updated analysis including all patients included in the KEYNOTE-001 trial did not demonstrate this benefit anymore.
      • Felip E.
      • Hellmann M.
      • Hui R.
      • et al.
      4-year overall survival for patients with advanced NSCLC treated with pembrolizumab: results from KEYNOTE-001 [abstract].
      As it is possible that recent cranial irradiation before the start of ICI treatment improves the survival of patients with BMs treated with ICIs owing to improved local control, we divided (in an exploratory analysis) the stable BM group (i.e., those with local brain therapy before the start of ICI treatment, regardless of timing of local treatment before ICI treatment, but without brain progression on brain imaging before ICI) into (1) stable patients without cranial irradiation within 3 months of ICI treatment and (2) stable patients who received cranial irradiation within 3 months of ICI treatment. When compared to active BMs, cranial irradiation within 3 months of the start of ICI treatment was associated with a superior survival (HR = 0.52, 95% CI: 0.30–0.72, p = 0.04), whereas no cranial irradiation within 3 months of the start of ICI treatment was not (Supplementary Table 3).
      The drawbacks of the current study are inherent to the retrospective data collection, although the overview of patients who received an ICI was prospectively collected. Not all patients underwent baseline brain imaging, and the reasons for brain imaging varied. However, when we analyzed the subgroup with baseline brain imaging only, the results did not change significantly. Furthermore, follow-up was not standardized, and imaging was not reviewed according to the Response Criteria in Solid Tumors 1.1/Response Assessment in Neuro-oncology BM criteria (the differences between response assessment methods are summarized in El Rassy et al.
      • El Rassy E.
      • Botticella A.
      • Kattan J.
      • Le Péchoux C.
      • Besse B.
      • Hendriks L.
      Non-small cell lung cancer brain metastases and the immune system: from brain metastases development to treatment.
      ). The definition of active BM was according to Goldberg et al.,
      • Goldberg S.B.
      • Gettinger S.N.
      • Mahajan A.
      • 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.
      but the decision to administer local treatment for BM before ICI treatment was according to the treating physician, making the stable BM group more heterogeneous. The number of patients with active BMs who had cranial response evaluation during ICI treatment was small, and for most of these patients PD-L1 status was unknown, making further subgroup analysis of the active BM group difficult. Moreover, additional data such as steroid dosage or type and severity of neurological symptoms would have enabled further subgroup analyses. As whether neurological adverse events were to be attributed to immunotherapy, previous cranial radiotherapy, or brain progression was not always clear, we choose not to report these events. Cause of death (cranial versus extracranial progression) was not documented for most patients. We could not evaluate the possible different efficacy of PD-1/PD-L1 inhibitors in relation to BMs, as only two patients with BMs were treated with PD-L1 inhibition monotherapy. Lastly, we did not use the update of the ds-GPA for lung cancer (the molecular GPA,
      • Sperduto P.W.
      • Yang T.J.
      • Beal K.
      • et al.
      Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA).
      also incorporating the presence of EGFR and ALK receptor tyrosine kinase gene [ALK] drivers in the nonsquamous subgroup). However, this molecular GPA was validated in patients with newly diagnosed BMs. Patients with driver mutations included in the molecular GPA analysis would have had the option of receiving effective targeted therapy, improving their OS (patients with driver mutations had the best survival in the molecular GPA).
      • Sperduto P.W.
      • Yang T.J.
      • Beal K.
      • et al.
      Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA).
      In contrast, patients with driver mutations often have a poor survival when treated with an ICI.
      • Lee C.K.
      • Man J.
      • Lord S.
      • et al.
      Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-a meta-analysis.
      • Mazieres J.
      • Drilon A.
      • Mhanna L.
      • et al.
      Efficacy of immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) patients harboring activating molecular alteriations (ImmunoTarget) [abstract].
      • Remon J.
      • Hendriks L.E.
      • Cabrera C.
      • Reguart N.
      • Besse B.
      Immunotherapy for oncogenic-driven advanced non-small cell lung cancers: is the time ripe for a change?.
      Therefore, we choose to use the ds-GPA instead of the molecular GPA.
      In conclusion, in multivariate analysis, the presence of BM was not associated with response and survival when treated with an ICI. Patients with (untreated) BM, a good ds-GPA classification, and no requirement for corticosteroids should not be excluded from clinical trials, although especially those patients with active BM should undergo regular brain imaging, as brain progression occurs more frequently in this subgroup of patients. Future studies should also focus on the timing of cranial irradiation, as cranial irradiation within 3 months of the start of ICI treatment was associated with improved OS compared with cranial irradiation more than 3 months before the start of ICI treatment.

      Acknowledgments

      Dr. Hendriks was the recipient of a European University Diploma for Translational and Clinical Research in Oncology grant for 2017–2018.

      Supplementary Data

      • Figure S1

        resection specimen of brain metastasis progressing on immunotherapy

        Legends: MRI showing the reassessment of the brain metastasis during ICI. (A) Hematoxylin-phloxine-saffron (HPS) stained specimen of the lesion on Gd-MRI of the same patient. The histological correlate to the MRI solid component typically shows an invasive adenocarcinoma (↑) while large areas of necrosis (↑↑) lead to the cystic component (bar =500 μm). The tumor extends to the meninges (*). (B) The higher magnification demonstrates sheets of large epithelial tumor cells with irregular nuclei, numerous mitosis (↑) and necrosis (↑↑) (bar = 50 μm). (C) Tumor cells infiltrate the cortex closely aligned to the external surface of blood vessels (*). (bar = 50 μm).

      • Figure S2

        patterns of progression on immunotherapy

        Legends: BM: brain metastases; N: number; PD: progressive disease; ECR: extracranial; SD: stable disease

        *: other patients were not evaluated for response in other sites

        **: investigator assessed as PD without imaging, e.g. clinical deterioration or growing palpable node

      • Table S1

        disease specific Graded Prognostic Assessment for lung cancer

        Legends: Ds-GPA: disease specific Graded Prognostic Assessment; KPS: Karnofsky Performance Score; ECM: extracranial metastases; No: number; BM: brain metastases

        *Sperduto et al. Int J Radiat Oncol Biol Phys 2010;77(3):655-661

      • Table S2

        multivariate analysis PFS and OS subgroup overall population with baseline brain imaging

        Legends: PFS: progression free survival; HR: hazard ratio; OS: overall survival; NSCLC: non-small cell lung cancer; nr: number; vs: versus; ICI: immune checkpoint inhibitor; WHO PS: world health organization performance status;

      • Table S3

        multivariate analysis PFS and OS for the brain metastases subgroup according to timing of cranial irradiation before start of immunotherapy

        Abbreviations: PFS: progression free survival; OS: overall survival; HR: hazard ratio; NSCLC: non-small cell lung cancer; adeno: nr: number; vs: versus; ICI: immune checkpoint inhibitor; BM: brain metastases; RT: radiation; ds-GPA: disease specific Graded Prognostic Assessment

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      Linked Article

      • Immunotherapy for NSCLC With Brain Metastases: What Can We Learn From Real-World Data?
        Journal of Thoracic OncologyVol. 14Issue 7
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          Brain metastases (BMs) are common among patients with lung cancer, melanoma, and breast cancer. The treatment of metastatic brain tumor is crucial for better symptom control and for improving survival. Historically, local therapies, such as whole-brain radiation therapy, stereotactic radiosurgery, and surgical resection have been the cornerstone of these therapies. The addition of stereotactic radiosurgery to whole-brain radiation therapy has been compared with whole-brain radiation therapy alone or stereotactic radiosurgery alone.
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