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Corresponding author. Address for correspondence: Lizza E.L. Hendriks, MD, PhD, Department of Pulmonary Diseases, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
Department of Medical Oncology, Gustave Roussy Cancer Campus, Institut d’Oncologie Thoracique, Gustave Roussy, Université Paris-Saclay, Villejuif, FranceDepartment of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Medical Oncology, Gustave Roussy Cancer Campus, Institut d’Oncologie Thoracique, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Department of Medical Oncology, Gustave Roussy Cancer Campus, Institut d’Oncologie Thoracique, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Department of Medical Oncology, Gustave Roussy Cancer Campus, Institut d’Oncologie Thoracique, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Department of Radiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceImagerie par Résonance Magnétique Médicale et Multi-Modalités, IR4M, CNRS, Université Paris-Sud, Université Paris-Saclay, Orsay, France
Department of Medical Oncology, Gustave Roussy Cancer Campus, Institut d’Oncologie Thoracique, Gustave Roussy, Université Paris-Saclay, Villejuif, FranceDepartment of Drug Development, Gustave Roussy Cancer Campus, Villejuif, France
Department of Medical Oncology, Gustave Roussy Cancer Campus, Institut d’Oncologie Thoracique, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Department of Radiation Oncology, MAASTRO Clinic, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Medical Oncology, Gustave Roussy Cancer Campus, Institut d’Oncologie Thoracique, Gustave Roussy, Université Paris-Saclay, Villejuif, FranceParis-Sud University, Orsay, France
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.
Despite this high incidence, patients with untreated and/or unstable BMs, or even all BMs, were excluded from most pivotal immune checkpoint inhibitor (ICI) trials.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
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].
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].
Use of corticosteroids (which might abrogate an immune response), the probable inability to cross the blood-tumor barrier (although the peripherally activated T cell can cross the blood-tumor barrier), and the risk of brain pseudoprogression were possible reasons to exclude these patients.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
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].
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)
Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer.
patients with ICI-treated BMs had a longer overall survival (OS) than did patients with chemotherapy-treated BMs. So far, only one prospective phase II trial with pembrolizumab has specifically addressed the question of ICI efficacy for patients with BMs: a 29.4% intracranial objective response rate (ORR) was observed in the programmed death ligand 1 (PD-L1)-positive cohort (n = 34), which was similar to the extracranial ORR.
Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab [abstract].
Therefore, ICI treatment might also result in favorable outcomes for patients with NSCLC and BMs, but data on larger, less-selected cohorts are needed.
Available series on patients with BMs treated with an ICI in daily practice mainly come from expanded access programs (EAPs) or from small retrospective series.
Severe exacerbation or manifestation of primary disease related to nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases.
Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
As a result, many questions, such as the prognostic value of the disease-specific Graded Prognostic Assessment (ds-GPA) classification (Supplementary Table 1)
Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients.
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.
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).
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.
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.
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
Characteristic
Total Population (N = 1025)
Patients without Baseline Brain Metastases (n = 770)
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
Characteristic
Patients with Baseline Brain Metastases (n = 255)
Patients with Active Baseline Brain Metastases (n = 100)
Patients with Stable Baseline Brain Metastases (n = 121)
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 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
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
Factor
PFS HR (95% CI)
p Value
OS HR (95% CI)
p Value
Sex, male vs. female
0.95 (0.68–1.33)
0.765
1.42 (0.94–2.16)
0.100
Smoking, yes vs. no
0.81 (0.40–1.64)
0.561
0.74 (0.34–1.64)
0.464
Histologic type
Squamous vs. adeno
0.97 (0.60–1.57)
0.99
1.09 (0.63–1.90)
0.750
NSCLC, other vs. adeno
0.98 (0.53–1.83)
0.79 (0.38–1.65)
No. of organs with metastases, >2 vs. ≤2
1.72 (1.15–2.57)
0.009
1.39 (0.87–2.22)
0.174
ICI treatment line, >2 vs. ≤2
0.98 (0.70–1.39)
0.922
1.09 (0.73–1.65)
0.671
Use of corticosteroids at start of ICI treatment, yes vs. no
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).
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
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].
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].
Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
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%)
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
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].
Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
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.
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),
Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab [abstract].
Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
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.
Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab [abstract].
Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
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,
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.
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
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.
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.
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.
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,
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).
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).
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.
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).
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
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].
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].
Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer.
Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab [abstract].
Severe exacerbation or manifestation of primary disease related to nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases.
Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy.
Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients.
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.
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.
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).
Disclosure: Dr. Hendriks reports research funding from Roche and Boehringer Ingelheim (both to her institution), fees for participation in advisory boards of Boehringer Ingelheim (to her institution) and BMS (to her institution and to her personally), travel/conference reimbursement from Roche and BMS (to her personally), participation in a mentorship program with key opinion leaders that was funded by AstraZeneca, and fees for educational webinars from Quadia outside of the submitted work. Dr. Audigier-Valette reports fees for being the principal investigator of industry trials for AstraZeneca, Boehringer Ingelheim, BMS, Novartis, and Roche; fees for service on advisory boards of AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche; and fees for speaker bureau participation from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche. Dr. Duchemann has received payments for expert testimony from BMS and Roche and reimbursement for travel, accommodations, and expenses from BMS and Roche. Dr. Mazieres has received institutional research funding from Roche, Bristol-Myers Squibb, and AstraZeneca; fees for consulting/advisory roles for Novartis, Roche/Genentech, Pfizer, Bristol-Myers Squibb, Lilly/ImClone, MSD, and AstraZeneca; and reimbursement for travel and accommodation expenses from Pfizer, Roche, and Bristol-Myers Squibb. Dr. Mezquita has received payments from BMS for serving as a speaker and from Roche Diagnostics for advisory board participation. Dr. le Pechoux has received payment from AstraZeneca for advisory board participation outside the submitted work. Dr. Dingemans has received payments from BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim for advisory board participation (all to her institution) and a research grant from BMS (to her institution) outside the submitted work. Dr. Besse has received institutional grants for clinical and translational research from Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma (all outside the submitted work). Dr. de Ruysscher reports fees for participation on advisory boards of Bristol-Myers-Squibb, Astra Zeneca, Roche/Genentech, Merck/Pfizer and Celgene (all to his institution), as well as research grants from Bristol-Myers Squibb and Boehringer Ingelheim (all to his institution). The remaining authors declare no conflict of interest.
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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