Background: Immune checkpoint inhibitors (ICI)s were recently approved for the treatment of advanced non-small cell lung cancer (NSCLC). Whereas brain metastases (BM) are frequent in NSCLC patients, data are missing regarding ICIs intracranial efficacy and tolerance in patients with BM from NSCLC. Methods: This retrospective study was performed in the Multidisciplinary Oncology and Therapeutic Innovation department, Marseille, France between April 2013 and February 2016. Data from patients with NSCLC with at least one BM, and treated with ICIs (anti-PD1, anti-PDL1 or anti-CTL4) were analyzed. Clinical, biological data and outcomes were retrieved from electronic patients’ records. We assessed ICIs intracranial efficacy and tolerance. Results: Data from 55 patients were analyzed. Objective Response Rate (ORR) and Disease Control Rate (DCR) were respectively of 1.8 and 36.4%. Median overall survival was 17.2 months and median progression free survival was 2.9 months. Intracranial ORR (icORR) and intracranial DCR (icDCR) were respectively 16.4% and 45.5%. Both were independent of smoking status, intracranial treatment, performance status, pathology, molecular profile and the presence or number of BM at diagnosis. However, there was a trend towards an association between icORR and ECOG PS (p = 0.05), tobacco status (p = 0.057) and intracranial treatment. Adverse events were seen in 38.2% patients without identified predictive factor. Neurological symptoms appeared in 5.5% patients during immunotherapy and improved in 3.63% patients. Conclusions: ICIs can be used safely on patients with BM from NSCLC. However, intracranial response is heterogeneous in such patients and we showed ECOG PS, tobacco smoking and intracranial treatment to be associated with an improved icORR. This is the first study looking for predictive factors of intracranial response of ICIs in patients with BM from NSCLC.
Lung cancer is the leading cause of brain metastases (BM): 40% to 50% of BMs come from lung cancers [
Recently, immunotherapy has become part of advanced NSCLC treatment strategy. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting anti-tumor immunity. Programmed cell death 1 (PD-1) is expressed by T cells while its ligand, programmed death-ligand 1 (PD-L1), is expressed by tumor cells. They both participate in anti-tumor immunity inhibition signal [
Until recently, BBB was thought to be responsible for brain poor immunogenicity [
As the use of ICIs for the treatment of advanced NSCLC is growing and because of the high prevalence of BM in this disease, there is a real need for data regarding predictive factors of ICIs intracranial efficacy, neurotoxicity and interaction with brain local treatment.
In this study, we tried to identify predictive factors of intracranial efficacy and tolerance of immunotherapy in patients with brain metastasis from NSCLC.
This retrospective single-center study was performed in the Multidisciplinary Oncology and Therapeutic Innovation department, Marseille, France. Patients were selected as follows: advanced NSCLC, at least one brain metastasis diagnosed before immunotherapy, at least one cycle of immunotherapy with ICIs between April 2013 and February 2016. The study protocol was approved by a national ethical committee, the Institutional Review Board of the French learned society for respiratory medicine -Société de Pneumologie de Langue Française- on June 27, 2016, with reference number CEPRO 2016-024. All patients signed a consent form allowing the use of clinical, biological and radiological data collected during routine care for research purposes.
Data were retrieved from the electronic patient records. The following data were collected: patients background characteristics (age, sex, smoking history), disease characteristics (pathology, stage at diagnosis, molecular profile, number of brain metastases at diagnosis), treatment data (ECOG performance status PS at the beginning of immunotherapy, brain local treatment, adverse events, neurological symptoms) and outcome data (disease control rate DCR, intracranial disease control rate icDCR, objective response rate ORR, intracranial objective response rate icORR, progression-free survival PFS and overall survival OS).
ORR and DCR were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CT-scan was used instead of magnetic resonance imaging (MRI) to evaluate brain response because CT-scan was performed routinely to assess disease response to ICIs and because MRI was only available for patients treated with brain local treatment. The first assessment was performed 6 to 8 weeks after the beginning of immunotherapy.
icORR was defined by complete response or partial response of brain metastases and icDCR was defined by complete response, partial response or stable disease in the brain.
Toxicity was evaluated according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.
The primary objective of the study was to identify predictive factors for ICIs intracranial efficacy in terms of icDCR and icORR. Secondary objectives were the identification of predictive factors for ICIs intracranial efficacy in terms of OS, intracranial progression-free survival (icPFS) and tolerance.
Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 20.0 (IBM SPSS Inc., Chicago, IL, United States of America (USA)). Comparisons of mean values between two groups were performed using student t-test or Mann-Whitney U test. Comparisons of percentages were performed using Chi-Square test or Fisher’s exact test, as appropriate. Time-to-event endpoints were estimated by the Kaplan-Meier method and compared using the log-rank test. OS was defined as the time from the beginning of immunotherapy to death from any cause, censored at the date of the last follow-up. PFS was defined as the time from the beginning of immunotherapy to documented disease progression or death, censored at the date of the last follow-up. Medians were reported with 95% confidence interval.
A total of 117 patients who received at least one cycle of immunotherapy for advanced NSCLC between April 2013 and February 2016 were retrieved from the database. Among them, 55 patients had BM (
Patients’ main characteristics were summarized in
Characteristics | N | % |
---|---|---|
Sex Male Female | 38 17 | 69.1 30.9 |
Tobacco smoking Never smoker Smoker Former smoker | 6 21 28 | 10.9 38.2 50.9 |
Pathology Non-squamous Squamous | 46 9 | 83.6 16.4 |
Mutation status No molecular alteration Molecular alteration | 25 17 | 45.5 30.9 |
Disease stage I, II, IIIA IIIB, IV | 7 48 | 12.7 87.3 |
Brain metastases Synchronous Metachronous | 26 29 | 47.3 52.7 |
Number of brain metastases at diagnosis 0 1 to 5 >5 | 29 19 7 | 52.7 34.5 12.7 |
Brain metastases treatment Surgery or radiosurgery Whole brain radiation therapy None | 42 7 6 | 76.4 12.7 10.9 |
Immunotherapy type Anti-PD-1 Anti-PD-L1 Anti-CTLA-4 | 47 5 3 | 85.5 9.0 5.5 |
ECOG PS 0 - 1 ≥2 | 45 10 | 81.8 18.2 |
carcinoma in 9 patients (16.4%) and non-squamous NSCLC in 46 patients (83.6%). A genomic alteration was found in 17 (30.9%) patients: 1 patient had an ALK-rearranged tumor, 2 patients had EGFR-mutant tumors, 13 patients had KRAS-mutant tumors and 1 patient had a MET-amplified tumor.
BMs were present at the diagnosis of NSCLC in 26 (47.3%) patients. Thirty- two (58.2%) patients had active BM at the beginning of immunotherapy. The other 23 patients (41.8%) had previously treated BMs at the beginning of immunotherapy.
Forty-seven (76.4%) patients received anti-PD-1 treatment, five (9%) patients received anti-PD-L1 and 3 (5.5%) received anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) treatments.
Brain local treatment was performed for 49 patients (89.1%); among them, 42 had surgery or SRS and 7 had WBRT. Forty-seven patients (85.5%) were treated with PD-1 inhibitors while 8 (14.5%) patients received anti-PD-L1 or anti-CTAL-4 inhibitors.
Regarding systemic response to immunotherapy, only one patient (1.8%) had a partial response (PR) while 19 patients (34.6%) had a stable disease (SD) and 29 patients (52.7%) had a progressive disease (PD) as the best response. Response assessment was missing for six patients mainly because of clinical progression or death before the first radiological assessment.
Median PFS calculated from the beginning of immunotherapy was 86 days (2.9 months) and median OS calculated from the beginning of immunotherapy was 515 days (17.2 months) (
Regarding intracranial efficacy, 5 patients (9.1%) had complete intracranial response icCR, 4 (7.3%) had intracranial partial response icPR, 16 (29.1%) had intracranial stable disease icSD and 29 (41.8%) had intracranial progressive disease icPD. Intracranial response data were missing for seven patients. Intracranial Overall Response Rate was 16.4% (n = 9) and intracranial Disease Control Rate was 45.5% (n = 25). Intracranial response is shown in
Fifty percent of patients with poor ECOG PS (≥ 2) at the beginning of immunotherapy (N = 10) had an intracranial response (p = 0.05). On the contrary, patients with PS < 2 (N = 45) had lower icORR. No difference was found regarding icDCR according to ECOG PS (p = 0.242).
A significant difference in icORR, but not in icDCR, was found depending on the type of immunotherapy: patients treated with anti-PD-L1 had better icORR than patients treated with anti-PD-1 (p = 0.035) or anti-CTLA-4.
Tobacco status was not significantly associated with icDCR (p = 0.560), however, there was a trend towards better icORR for current smokers in comparison with non-smokers (p = 0.057).
Previous brain local treatment was not significantly associated with intracranial efficacy. However, 20% of patients who received surgery or radiosurgery had intracranial objective response whereas 0% of patients who received whole brain radiation therapy (WBRT) or no local treatment had intracranial objective response.
There was no significant association between icORR/icDCR and pathology (p = 0.990/p = 0.466), mutation status (p = 0.990/0.549) and number of brain metastasis at diagnosis (p = 0.477/p = 0.089) (
Characteristics | Objective Response Rate | Disease Control Rate | ||
---|---|---|---|---|
% | p Value | % | p Value | |
Tobacco smoking Never smoker Smoker Former smoker | 0.0 37.5 11.5 | 0.060 | 50.0 62.5 46.2 | 0.560 |
Brain local treatment Surgery or radiosurgery Whole brain radiation therapy None | 25.0 0.0 0.0 | 0.246 | 58.3 50.0 16.7 | 0.224 |
Immunotherapy type Anti-CTLA-4 Anti-PD-1 Anti-PD-L1 | 0.0 15.0 60.0 | 0.056 | 33.3 52.5 60.0 | 0.866 |
ECOG PS 0 - 1 ≥2 | 14.3 50.0 | 0.071 | 50.0 66.7 | 0.668 |
Pathology Non-squamous Squamous | 17.9 22.2 | 0.990 | 48.7 66.7 | 0.466 |
Mutation status Mutation No mutation | 17.4 15.4 | 0.990 | 43.5 53.8 | 0.549 |
Brain metastases Synchronous Metachronous | 23.8 14.8 | 0.477 | 66.7 40.7 | 0.089 |
Number of brain metastases at diagnosis 0 1 to 5 >5 | 14.8 25.0 20.0 | 0.660 | 40.7 62.5 80.0 | 0.170 |
In our population, twenty-one patients developed immunotherapy-induced adverse events. Endocrine toxicity was the most common and 10 patients (18.2%) had hypo or hyperthyroidism. Six patients had diarrhea (10.9%), lung and skin effects were seen in 2 patients (3.6%), and only 1 (1.8%) patient reported arthritis.
Regarding neurological toxicity, 3 patients had increased or new neurological symptoms during immunotherapy: 1 had vertigo, 1 had sensitive deficiency and 1 had motor deficiency. Among them one patient had intracranial progressive disease.
On the contrary, 2 patients described an improvement of neurological symptoms during immunotherapy, one of them with intracranial partial response and the other with intracranial stable disease.
No patient had any grade 3 or 4 neurological side effect during immunotherapy.
No significant association was found between immune-related adverse events and tobacco status (p = 0.164 for smokers and p = 0.054 for former smokers in comparison with never-smokers), brain local treatment (p = 0.694 for WBRT and p = 0.186 for SRS in comparison with surgery), the type of immunotherapy (p = 0.900 for PD-1 and p = 0.472 for PD-L1), ECOG PS (p = 0.428 for ECOG PS ≥ 2 in comparison with ECOG PS 0 - 1) at the beginning of immunotherapy, pathology (p = 0.273 for squamous versus non-squamous NSCLC), mutation status (p = 0.530), the presence of BM at diagnosis (p = 0.620 for synchronous BM versus metachronous BM) or the number of brain metastasis at diagnosis (p = 0.252 for 1 - 5 BM and p = 0.295 for >5 BM in comparison with no BM) (
Characteristics | Adverse Events (%) | OR | 95% Confidence Interval | p Value |
---|---|---|---|---|
Tobacco smoking Never smoker Smoker Former smoker | 80.0 42.9 28.6 | Ref 0.188 0.100 | 0.018 - 1.977 0.010 - 1.038 | 0.164 0.054 |
Brain local treatment Surgery or radiosurgery Whole brain radiation therapy None | 50.0 41.5 14.3 | Ref 0.708 0.167 | 0.127 - 3.943 0.012 - 2.368 | 0.694 0.186 |
Immunotherapy type Anti-CTLA-4 Anti-PD-1 Anti-PD-L1 | 33.3 37.0 60.0 | Ref 1.172 3.000 | 0.099 - 13.916 0.150 - 59.890 | 0.900 0.472 |
ECOG PS 0 - 1 ≥2 | 36.4 50.0 | Ref 1.750 | 0.439 - 6.980 | 0.428 |
Pathology Non-squamous Squamous | 42.2 22.2 | Ref 0.391 | 0.073 - 2.096 | 0.273 |
Mutation status No molecular alteration Molecular alteration | 40.0 50.0 | Ref 1.500 | 0.423 - 5.315 | 0.530 |
Brain metastases Synchronous Metachronous | 42.3 35.7 | 1.320 Ref | 0.441 - 3.953 | 0.620 |
Number of brain metastases at diagnosis 0 1 to 5 >5 | 35.7 52.6 14.3 | Ref 2.000 0.300 | 0.610 - 6.553 0.032 - 2.857 | 0.252 0.295 |
ICIs have revolutionized treatment strategies of advanced NSCLC, but data are missing regarding their efficacy and tolerance in patients with brain metastasis, and no predictive factors are available to better select patients before immunotherapy. Our study is the first and largest series reporting factors associated with favorable outcomes in patients with BM from NSCLC treated with ICIs.
In a population of 55 patients, we have shown that intracranial disease control was achieved in nearly half patients, regardless of local brain treatments received previously. However, intracranial efficacy was heterogeneous, with new BM appearing during immunotherapy treatment in 16 patients, highlighting the need for predictive markers of intracranial efficacy. Furthermore, ICIs were well tolerated with a weak proportion of patients with neurological symptoms and no serious (grade 3 or 4) neurological adverse event.
Our data were collected from a daily-practice population of patients with BM from NSCLC receiving immunotherapy whereas patients enrolled in immunotherapy trials are over-selected regarding ECOG performance status, comorbidities or brain metastases control before enrollment.
We tried to identify predictive factors associated with intracranial response. A significant difference was found regarding ECOG PS, patients with poor PS having a better icORR than patients with ECOG PS 0 or 1. These results show that ICIs can be used in patients with brain metastasis even if they have poor ECOG PS (≥2). In addition, tobacco status seemed to be associated with intracranial efficacy in our study. Current smokers had a trend towards better icORR than former or never smokers. This result can be explained by the association between tobacco smoking and higher tumor mutational burden potentially responsible for better response to ICIs. Moreover, whereas no significant difference was shown in icORR or icDCR regarding brain local treatment, only patients who received surgery or radio surgery (22%) had an intracranial objective response. Patients who did not receive brain local treatment had a trend towards worst icDCR than patients who received surgery, radiosurgery or WBRT, highlighting a potential association between brain local treatment and a better intracranial response to ICIs. It is still unclear whether this difference was explained by immunotherapy efficacy on brain metastasis independently from brain local treatment or by surgery or radiosurgery efficacy on brain metastasis independently from immunotherapy, or by an interaction between immunotherapy and brain local treatment. Some studies reported a potential benefit on safety and efficacy of concurrent cranial radiation therapy and immunotherapy [
Our survival results are consistent with randomized phase III trials of anti-PD-1 treatments for second or third-line treatment of advanced NSCLC regardless PD-L1 expression: PFS was 2.9 months in our study versus 2.3 months in the CheckMate 057 trial and 3.5 months in the CheckMate 017 trial [
Disease response or control rate was not dependent on any clinical criteria, but we found a trend towards an association between tobacco status and response (p = 0.06), with better responses in smokers than in non-smokers. These results are consistent with the CheckMate 057 study [
In addition, whereas intracranial response to ICIs in our study was not significantly associated with prior intracranial treatment, patients previously treated with surgery or radiosurgery seemed to have better intracranial response than patients who did not receive any intracranial treatment. However, data are missing regarding potential interaction between ICIs and brain local treatments such as surgery, SRS or WBRT. In a retrospective study, Choong ES et al. [
Other studies have already tried to assess intracranial efficacy of ICIs, mainly assessing melanoma patients. Goldberg et al. provided in a phase 2-trial, an evidence of intra-cranial activity of pembrolizumab on thirty-six patients with untreated or progressive brain metastasis from melanoma and NSCLC. Only NSCLC with PDL-1 expression ≥ 1% were included. Patients had no neurological symptoms, steroids treatment or local brain treatment. Response was achieved on four patients with melanoma and six with NSCLC. These results showed an effect of immunotherapy on brain metastasis in NSCLC but only for patients with PDL-1 positive tumors. However, there were no data available regarding potential predictive factors for intracranial response [
All these studies assessed ICIs efficacy on brain metastasis. However, our study is the largest one to report predictive factors of ICIs efficacy and tolerance in patients with NSCLC metastatic to the brain treated in a daily routine practice. In all these publications, ICIs were well tolerated, with no severe (grade 3 or more) neurologic adverse events. Cohen et al. however reported the case of a patient with brain pseudo-progression after pembrolizumab treatment for metastatic melanoma [
Furthermore, several studies tried to find better criteria to assess BM response for patients treated with ICIs. Qian JM et al. [
The main limitation of the study is its retrospective design with fifty-five patients analyzed. However, this is the largest series studying brain response to ICIs in patients with NSCLC.
Despite these encouraging results, BMs from NSCLC are still correlated with a poor prognosis and a better knowledge of BM microenvironment and immunogenicity would help physicians to improve the outcomes and treatments of patients with BM. In a review by Hamilton A et al. [
In our study, PD-1, PD-L1 or CTLA-4 expression was absent for most patient because when data were collected, we did not search these expressions systematically, and we can think that it can maybe change intracranial response.
In conclusion, we have shown that ICIs can be used safely for patients with BM from NSCLC, including patients with poor ECOG PS, and that intracranial response may be associated with current tobacco smoking and previous brain local treatment but it is still necessary to discuss each case in a multidisciplinary tumor boards (MTB) dedicated to the treatment of BMs [
Lung cancer is one of the leading causes of brain metastasis and they are associated with a poor prognosis. Immune checkpoint inhibitors (ICIs) use is rising in this disease and their consequence on brain metastases is still unclear. This is the largest case series of non-small cell lung cancer patients with brain metastases providing data about potential predictive factors of efficacy and tolerance of ICIs on brain metastases.
The authors declare no conflicts of interest regarding the publication of this paper.
Bermudez, J., Mascaux, C., Trigui, Y., Biemar, J., Boucekine, M., Greillier, L., Barlesi, F. and Tomasini, P. (2019) Predictive Factors of Intracranial Response of Immune Checkpoint Inhibitors in Patients with Brain Metastasis from Non-Small Cell Lung Cancer. Journal of Cancer Therapy, 10, 692-707. https://doi.org/10.4236/jct.2019.108057