Introduction
Lung cancer has the highest morbidity and mortality worldwide.[ 1 ] Brain metastasis is generally associated with poor survival outcomes and low quality of life.[ 2 ] The probability of detecting brain metastasis at initial diagnosis is approximately 10% in patients with advanced non-small cell lung cancer (NSCLC).[ 3–5 ] Strategies for prolonging the survival of NSCLC patients with brain metastasis have long been the focus of research efforts. In recent years, targeted therapy has improved the survival and quality of life of patients with driver gene-positive NSCLC, even those with brain metastasis at initial diagnosis.[ 6–11 ] However, treatment remains challenging for patients with driver gene-negative NSCLC who present with brain metastasis . Evidence supporting the efficacy of immune checkpoint inhibitors (ICIs) in patients with NSCLC with brain metastasis is still limited due to the exclusion or limited inclusion of those with untreated or active brain metastasis in clinical trials. For instance, only 108 (17.5%) and 48 (7.9%) patients with brain metastasis were enrolled in the KEYNOTE-189 and KEYNOTE-407 studies, respectively.[ 12,13 ] One study that pooled cohorts with brain metastasis from three KEYNOTE studies, namely, KEYNOTE-021, KEYNOTE-189, and KEYNOTE-407, revealed that pembrolizumab plus platinum-based histology-specific chemotherapy improved the clinical outcomes of patients with or without brain metastasis compared with chemotherapy alone.[ 14 ] In addition, a phase II study suggested that pembrolizumab shows efficacy for NSCLC patients with brain metastasis with at least 1% expression of programmed death-ligand 1 (PD-L1) protein.[ 15 ] Moreover, the IMPOWER 150 study demonstrated a prolonged time to brain progression in the population receiving atezolizumab compared with the population receiving standard of care bevacizumab plus carboplatin plus paclitaxel (BCP).[ 16 ] Nevertheless, few large-scale clinical data have been reported on the efficacy and safety of ICIs in NSCLC patients with brain metastasis at initial diagnosis. Hence, this retrospective study aimed to explore the efficacy and safety of ICI-based regimens in a real-world population of patients with NSCLC presenting with brain metastasis at initial diagnosis and to provide a basis for the treatment of these patients.
Methods
Ethical approval All procedures were conducted in accordance with the ethical standards of the institutional and national research committees and the 2013 revision of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Hunan Cancer Hospital (No: 2019YYQ-SSB-174). A waiver of written informed consent was approved by the institutional review board.
Patients We retrospectively screened 3124 patients with newly diagnosed stage IV NSCLC at Hunan Cancer Hospital between January 1, 2019 and September 30, 2021, for identifing measurable brain metastases and lung lesions. A measurable lesion was defined as a lesion that could be accurately measured in at least one dimension with the largest diameter >10 mm by either magnetic resonance imaging (MRI) or computed tomography (CT). Our study cohort excluded patients with actionable driver genes (i.e., EGFR sensitizing mutations, ALK fusion, ROS1 fusion, RET fusion, BRAF V600E, KRAS G12C, or MET skipping mutations) and those receiving best supportive care. The cohort was stratified according to the treatment regimen received as first-line therapy. Patients who received chemotherapy combined with ICI as first-line therapy were grouped into the ICI + chemo group; patients who received chemotherapy as first-line therapy were grouped into the chemotherapy group. The evaluable population included all patients who received at least two cycles of treatment and underwent at least one tumor assessment.
Inclusion and exclusion criteria The main inclusion criteria were as follows: (1) histologically or cytologically confirmed advanced NSCLC; (2) stage IV disease based on either the American Joint Committee on Cancer (AJCC) 7th edition or the International Association for the Study of Lung Cancer (IASLC) 7th edition tumor-node-metastasis classification; and (3) a radiologically confirmed brain lesion (at least one measurable lesion) measured using cranial MRI and/or enhanced CT. Patients who received local therapy (i.e., whole-brain radiotherapy [WBRT], stereotactic radiosurgery [SRS], or surgery) were excluded from the study. The main exclusion criteria were as follows: (1) leptomeningeal metastasis; (2) history of cranial radiotherapy or surgery; (3) without measurable lung and brain lesions; (4) actionable driver gene mutations and eligible to receive targeted therapy, including EGFR sensitizing mutations, ALK fusion, ROS1 fusion, RET fusion, BRAF V600E, KRAS G12C, or MET skipping mutations; (5) unmanageable intracranial hypertension or edema; and (6) presenting with neurologic symptoms at baseline.
Treatment regimens Chemotherapy with either a pemetrexed–carboplatin regimen or a paclitaxel–carboplatin regimen was administered intravenously. Pemetrexed was given at a dose of 500 mg/m2 , plus carboplatin, with a target area under the curve of 5–6 mg∙mL-1 ∙min-1 . Paclitaxel was administered at a dose between 135 mg/m2 and 175 mg/m2 . Pembrolizumab or sintilimab were injected at a fixed dose of 200 mg. Treatment regimens were administered until progressive disease (PD) or unacceptable toxicity was confirmed. For patients who were administered chemotherapy only, those who experienced toxicity were managed by dose reduction or discontinuation based on the physician's discretion.
Tumor responses and data collection The best response was assessed by the investigators based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Treatment responses were evaluated using CT or MRI at baseline (Day 0) and thereafter every 2 cycles (approximately 45–50 days); the radiological images were independently reviewed by two radiologists.
The objective response rate (ORR) was calculated as the proportion of patients who achieved complete response (CR) or partial response (PR). The disease control rate (DCR) was calculated as the proportion of patients with CR, PR, and stable disease (SD). Progression-free survival (PFS) was defined as the time from the start of treatment until PD or death due to any cause. Clinical outcomes were assessed as systemic and intracranial outcomes. Systemic PFS (sPFS) refers to disease progression in the primary lesion as well as intracranial or other metastatic lesions; intracranial PFS (iPFS) refers to progression limited to only intracranial lesions. Overall survival (OS) was defined as the time from the start of treatment until death. The data cutoff date was November 1, 2021.
Statistical analysis Continuous variables were compared using an unpaired t -test or Wilcoxon rank sum test, as appropriate, and are presented as the mean and standard deviation or median and range. Categorical variables were compared using the chi-squared or Fisher's exact test, as appropriate, and are presented as frequencies and percentages. Kaplan-Meier analysis was used to estimate the survival outcomes and the log-rank test to determine differences in survival outcomes. Multivariable survival analysis was performed using the Cox proportional hazards model, with all factors included for analysis. The proportional hazards assumption was checked using Schoenfeld residuals. All tests were statistically significant at P -value <0.05. All statistical analyses were performed as two-sided tests using SPSS software (version 22; IBM, Chicago, IL, USA) or GraphPad Prism (version 8.3.0; Dotmatics, San Diego, CA, USA).
Results
Patient characteristics We screened a total of 3124 patients diagnosed with stage IV NSCLC. Of the screened population, 332 had brain metastasis at initial diagnosis, accounting for 10.6% of all patients diagnosed with stage IV NSCLC. A total of 121 patients were excluded due to detected actionable mutations (n = 73), history of local treatment before receiving a first-line systemic regimen (n = 25), or no measurable lung or brain lesions (n = 23). Overall, 211 patients were included in our study. Of them, 102 received ICI combined with chemotherapy as first-line treatment and were grouped into the ICI + chemo group; 109 received first-line chemotherapy and were grouped into the chemotherapy group [Figure 1 ]. Among the 211 patients, the majority were male (67.3%, n = 142), and their median age was 59 years (range, 28–78 years). Most patients were smokers (63.5%, n = 134), had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0–1 (93.8%; n = 198), were diagnosed with adenocarcinoma (71.6%; n = 151), and had extracranial metastasis at baseline (65.4%; n = 138). MRI was the preferred diagnostic modality for brain imaging at baseline (89.6%; n = 189) [Table 1 ]. Baseline clinical characteristics were statistically similar between the two groups [Table 1 ]. The somatic mutation profiles of the ICI + chemo cohort and chemotherapy cohort are summarized in Supplementary Figures 1 and 2, https://links.lww.com/CM9/B583
Figure 1: Flow chart for the study. ICI: Immune checkpoint inhibitor ; NSCLC: Non-small cell lung cancer ; iORR: Intracranial objective response rate; iPFS: Intracranial progression-free survival ; sORR: Systemic objective response rate; sPFS: Systemic progression-free survival .
Table 1 -
Baseline characteristics of included patients with chemotherapy or ICI combined with chemotherapy as first-line treatment.
Items
Total (n = 211)
First-line ICI + chemo (n = 102)
First-line chemo (n = 109)
Statistical
values
P -value
Age (years)
59 (28–78)
59 (28–78)
58 (29–77)
1.425*
0.114
Sex
0.036†
0.884
Female
69 (32.7)
34 (33.3)
35 (32.1)
Male
142 (67.3)
68 (66.7)
74 (67.9)
Smoking history
1.460†
0.254
Smoker
134 (63.5)
69 (67.6)
65 (59.6)
Never smoker
77 (36.5)
33 (32.4)
44 (40.4)
ECOG PS
0.027†
1.000
Good (0–1)
198 (93.8)
96 (94.1)
102 (93.6)
Poor (2–3)
13 (6.2)
6 (5.9)
7 (6.4)
Histology
0.094†
0.763
Squamous cell carcinoma
60 (28.4)
28 (27.5)
32 (29.4)
Adenocarcinoma
151 (71.6)
74 (72.5)
77 (70.6)
Presence of extracranial metastasis
0.439†
0.563
With
138 (65.4)
69 (67.6)
69 (63.3)
Without
73 (34.6)
33 (32.4)
40 (36.7)
Diagnostic methods
2.859 ‡
0.224
CT
8 (3.8)
6 (5.9)
2 (1.8)
MRI
189 (89.6)
88 (86.3)
101 (92.7)
PET-CT
14 (6.6)
8 (7.8)
6 (5.5)
Data are presented as the n (%), except for age, which is presented as the median and range. * U values; † χ 2 values; ‡ χ 2 values obtained by Fisher' s exact test. CT: Computer tomography; ECOG PS: Eastern Cooperative Oncology Group performance score; ICI + chemo: Immune checkpoint inhibitor combined with chemotherapy; MRI: Magnetic resonance image; PET-CT: Positron emission tomography-computer tomography.
Efficacy Compared with the chemotherapy group, a significantly higher intracranial ORR (iORR, 44.1% [45/102] vs . 28.4% [31/109], P = 0.013, Table 2 ) and systemic ORR (sORR, 49.0% [50/102] vs . 33.9% [37/109], P = 0.019, Table 2 ) were observed in the ICI + chemo group. Patients in the ICI + chemo group also had a significantly longer median iPFS (11.0 months vs . 7.0 months, hazard ratio [HR] = 0.55, 95% confidence interval [CI]: 0.40–0.76, P <0.001, Figure 2A ) and sPFS (9.0 months vs . 5.0 months, HR = 0.56, 95% CI: 0.42–0.76, P <0.001, Figure 2B ) than patients in the chemotherapy group. Univariable and multivariable analyses consistently revealed that the use of a first-line ICI-containing regimen was independently associated with prolonged iPFS (univariable analysis: HR = 0.54, 95% confidence intervals [CI]: 0.39–0.75, P <0.001; multivariable analysis: HR = 0.52, 95% CI: 0.37–0.73, P <0.001, Figure 3A ), and sPFS (univariable analysis: HR = 0.54, 95% CI: 0.40–0.73, P <0.001; multivariable analysis: HR = 0.48, 95% CI: 0.35–0.66, P <0.001, Figure 3B ).
Table 2 -
Comparison of reatment outcomes in advanced NSCLC patients with chemotherapy or ICI plus chemotherapy as first-line treatment.
Items
Intracranial response
Systemic response
ICI + chemo
(n = 102)
Chemotherapy
(n = 109)
χ
2 values
P -value
ICI + chemo
(n = 102)
Chemotherapy (n = 109)
χ
2 values
P -value
CR
0 (0)
0 (0)
–
–
0 (0)
0 (0)
–
–
PR
45 (44.1)
31 (28.4)
5.620
0.013
50 (49.0)
37 (33.9)
4.942
0.019
SD
49 (48.1)
62 (56.9)
1.652
0.216
37 (36.3)
56 (51.4)
4.875
0.037
PD
8 (7.8)
16 (14.7)
2.442
0.133
15 (14.7)
16 (14.7)
0
1.000
ORR
45 (44.1)
31 (28.4)
5.620
0.013
50 (49.0)
37 (33.9)
4.942
0.019
DCR
94 (92.2)
93 (85.3)
2.442
0.133
87 (85.3)
93 (85.3)
0
1.000
Data are presented as n (%). CR: Complete response; DCR: Disease control rate; ICI + chemo: Immune checkpoint inhibitor combined with chemotherapy; NSCLC: Non-small cell lung cancer ; ORR: Objective response rate; PD: Progressive disease; PR: Partial response; SD: Stable disease. –: Not applicable
Figure 2: Immunotherapy combined with chemotherapy prolongs intracranial and systemic PFS in patients with brain metastasis at initial diagnosis compared with chemotherapy. Kaplan-Meier survival curves comparing intracranial (A) and systemic (B) PFS between patients who received first-line immune checkpoint inhibitors (ICIs) with chemotherapy and those who received chemotherapy. Tick marks denote censored data. Chemo: Chemotherapy; CI: Confidence interval; HR: Hazard ratio; ICIs: Immune checkpoint inhibitors; mPFS: Median progression-free survival ; PFS: Progression-free survival .
Figure 3: The first-line ICIs-containing regimen received by patients with brain metastasis at initial diagnosis is a factor for significantly prolonging systemic and intracranial progression-free survival (PFS). Forest plots summarizing univariable and multivariable analyses of the effect of clinical variables on intracranial (A) and systemic (B) PFS. Chemo: Chemotherapy; CI: Confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; HR: Hazard ratio; ICI: Immune checkpoint inhibitor ; PFS: Progression-free survival .
Next, we performed subgroup analysis for our study population. First-line ICI combined with chemotherapy led to significantly favorable iPFS in males (HR = 0.49, 95% CI: 0.30–0.80, P = 0.004), smokers (HR = 0.43, 95% CI: 0.26–0.72, P = 0.001), those with ECOG PS 0–1 (HR = 0.64, 95% CI: 0.43–0.94, P = 0.023), those with adenocarcinoma (HR = 0.47, 95% CI: 0.20–0.73, P = 0.001), and those with extracranial metastasis (HR = 0.55, 95% CI: 0.34–0.89, P = 0.016; Supplementary Figure 3, https://links.lww.com/CM9/B583 https://links.lww.com/CM9/B583
Considering that PD-L1 positivity was found in previous reports to be associated with good outcomes with ICI + chemotherapy, we also analyzed 71 patients in the ICI + chemotherapy group with available data for PD-L1 expression. Of them, 18 patients were negative for PD-L1 expression; 53 patients had a PD-L1 tumor proportion score ≥1% and were considered PD-L1 positive. Patients who were PD-L1 positive had a significantly longer median sPFS than those who were PD-L1 negative (13.0 months vs . 8.0 months, HR = 0.45, 95% CI: 0.21–0.97, P = 0.041, Supplementary Figure 5, https://links.lww.com/CM9/B583
Moreover, we compared OS outcomes between patients in the ICI + chemo and chemotherapy groups. It should be noted that the OS of the ICI + chemo group was immature, and 68.6% (70/102) of the patients were still receiving treatment at the data cutoff date and 32 of the patients died. Additionally, 63 patients in the chemotherapy group had died, with 46 patients remaining on treatment. The median OS was significantly longer in the ICI + chemo group than that in the chemotherapy group (41.0 months vs . 15.0 months, HR = 0.56, 95% CI: 0.37–0.84, P = 0.006, Supplementary Figure 6, https://links.lww.com/CM9/B583
Adverse events (AEs) In the ICI + chemo group, 57 patients (55.9%) experienced AEs, whereas 67 patients (61.5%) in the chemotherapy group experienced AEs, with no significant difference between the groups (P = 0.484). Grade 3–4 AEs occurred in 12 patients (11.8%) treated with ICI + chemo and 13 patients (11.9%) treated with chemotherapy. The frequency of grade 3–4 AEs between these groups was not significantly different (P = 0.685). Anemia, elevated transaminases, and leukopenia were the most frequent AEs in both groups. Among the grade 1–2 AEs, hypothyroidism occurred more frequently in the ICI + chemo group, whereas nausea, vomiting, and peripheral neuropathy occurred more frequently in the chemotherapy group. Rash, hypothyroidism, immune-related pneumonia, enteritis, and myositis did not occur in the chemotherapy cohort [Table 3 ]. The AEs associated with ICI combined with chemotherapy regimens were comparable to those related to chemotherapy-based regimens [Table 3 ]. Overall, treatment-emergent AEs were manageable for both groups.
Table 3 -
AEs comparison in patients who received first-line ICIs combined with chemotherapy and those who received chemotherapy alone.
AEs
CTCAE Grade 1–2
CTCAE Grade 3–4
ICI + chemo (n = 102)
Chemo (n = 109)
P -value
ICI + chemo (n = 102)
Chemo (n = 109)
P -value
Total
79
102
<0.001
12
16
0.550
Elevated transaminases
18
13
0.251
3
2
0.675
Rash
4
0
0.053
0
0
–
Asthenia
11
7
0.326
0
0
–
Hyporexia
4
8
0.377
0
0
–
Anemia
15
23
0.283
3
1
0.355
Thrombocytopenia
2
1
0.611
2
5
0.447
Leukopenia
12
16
0.550
2
1
0.611
Hypothyroidism
9
0
0.001
0
0
–
Immune-related pneumonia
1
0
0.483
0
0
–
Myositis
1
0
0.483
0
0
–
Enteritis
0
0
–
2
0
0.232
Vomiting
1
13
0.001
0
1
1.000
Alopecia
1
2
1.000
0
0
–
Peripheral neuropathy
0
6
0.030
0
0
–
Proteinuria
0
5
0.060
0
0
–
Nausea
0
6
0.030
0
1
1.000
Hiccup
0
1
1.000
0
1
1.000
Arrhythmia
0
0
–
0
1
1.000
Thrombus
0
1
1.000
0
0
–
Diarrhea
0
0
–
0
2
0.498
Hypertension
0
0
–
0
1
1.000
Data are presented as n . AEs: Adverse events; chemo: Chemotherapy; CTCAE: Common terminology criteria for adverse events; ICI + chemo: Immune checkpoint inhibitor combined with chemotherapy. –: Not applicable
Discussion
Brain metastasis is one of the poor prognostic factors in lung cancer, particularly for patients with driver gene mutation-negative NSCLC due to the lack of opportunity to receive blood-brain barrier-permeable targeted therapies.[ 2,3 ] ICIs have been regarded as an important breakthrough in the treatment of cancer. However, patients with untreated or active brain metastasis are often excluded from ICI-related clinical studies owing to poor survival outcomes. Hence, there are currently few large-scale phase III clinical data that demonstrate the efficacy of ICIs for patients with NSCLC presenting with brain metastasis . Our study provides real-world clinical evidence for the efficacy of ICI-chemotherapy combination therapy in patients with advanced NSCLC who present with asymptomatic brain metastasis at initial diagnosis. Our findings demonstrate improved intracranial and systemic ORRs and prolonged PFS for patients who received ICI-chemotherapy combination therapy compared with those who received chemotherapy. These findings provide an alternative option for treating patients with driver gene-negative NSCLC harboring asymptomatic but measurable brain metastasis and can inform future clinical studies on treatment strategies for these patients. The frequency of detecting brain metastasis at initial diagnosis is 10.2% among those diagnosed with advanced NSCLC in our center, consistent with historical data.[ 3,5 ] Pooled analysis of three KEYNOTE studies–KEYNOTE-021, KEYNOTE-189, and KEYNOTE-407 has revealed that NSCLC patients with baseline brain metastasis who received platinum doublet chemotherapy plus pembrolizumab had a better ORR (39.0%) and longer PFS (6.9 months) than those who only received chemotherapy.[ 15 ] However, intracranial response status was not evaluated in this pooled analysis. A real-world study reported similar ORR and median PFS between ICI-treated NSCLC patients with (ORR, 20.6%; PFS, 1.7 months) and without (22.7%; PFS, 2.1 months) brain metastasis .[ 17 ] Interestingly, this multivariate analysis also revealed that patients with stable brain metastasis without baseline corticosteroid use and a good disease-specific graded prognostic assessment score had better prognoses than patients with active brain metastasis .[ 17 ]
In our study, ICIs combined with chemotherapy as a first-line regimen had a sPFS of 7.0 months and an iPFS of 11.0 months. The sORR was 44.1%, and the iORR was 33.9%. These treatment outcomes observed for ICI combined with chemotherapy were superior to those of chemotherapy. Similar to our results, updated data from the Atezo-Brain study presented at the recent American Society of Clinical Oncology (ASCO) meeting reported promising survival outcomes with atezolizumab plus carboplatin with pemetrexed in patients with stage IV NSCLC without EGFR or ALK alterations and untreated brain metastasis .[ 18 ] In addition, the Atezo-Brain study reported an iORR of approximately 45%, a median iPFS of 6.9 months (95% CI: 4.7–11.9 months), an sPFS of 8.9 months (95% CI: 6.7–13.8 months), a median OS of 13.6 months (95% CI: 9.7–not reached), and an estimated 2-year OS rate of 30.5% with atezolizumab plus chemotherapy.[ 18 ] The iPFS in our study was slightly longer than the outcome from Atezo-Brain, possibly due to our exclusion of patients with actionable oncogenic driver gene mutations. Combined use of ICIs and chemotherapy dramatically improves efficacy, possibly due to chemotherapy-mediated enhancement of T-cell responses and suppression of tumor-activated macrophages (TAMs).[ 19 ]
PD-L1 expression is an important biomarker often used to predict the efficacy of ICIs in NSCLC.[ 20–22 ] In our cohort, we observed that patients with PD-L1-positive NSCLC brain metastasis benefited more from ICI plus chemotherapy, as shown by the significantly longer PFS of these patients than those with PD-L1-negative status. Our findings are consistent with previously reported studies on the role of PD-L1 positivity in predicting better outcomes with ICI therapy.[ 15,23,24 ] Interestingly, in the Atezo-Brain study, patients with PD-L1-positive NSCLCs exhibited a trend of better OS with first-line atezolizumab plus chemotherapy than those with PD-L1-negative status; however, the difference was not statistically significant due to limited statistical power.[ 18 ]
In terms of treatment safety, the overall AE rate in the ICI + chemo group was 55.9%, with a 11.8% grade 3–4 AE rate. No new or unexpected safety signals were observed, and all AEs in both groups were manageable.
Our study is limited by its retrospective nature, with some data not being available for analysis, such as the expression levels of PD-L1. Further prospective, controlled clinical trial data are needed to validate the safety and efficacy of this combination regimen as standard of care for patients with brain metastasis . It would also be clinically relevant to investigate the impact of first-line ICI-chemotherapy combination therapy in extending OS outcomes as well as the utility of PD-L1 expression status as a biomarker in predicting treatment outcomes in these patients.
In summary, our study provides real-world clinical evidence that compared with chemotherapy, first-line ICI combined with platinum-based chemotherapy is associated with better intracranial and systemic clinical outcomes in patients with advanced NSCLC with no actionable mutations and asymptomatic, measurable brain metastasis at initial diagnosis. ICI combined with chemotherapy may be considered a treatment option in first-line treatment of these patients.
Acknowledgments The authors would like to thank Dr. Analyn Lizaso for editing assistance.
Funding This work received financial support from the National Natural Science Foundation of China (Nos. 82003206 and 82173338) and Natural Science Foundation of Hunan Province (Nos. 2020SK2031, 2020SK2030, 2021RC4040, and 2020JJ3025). The funding agencies had no role in the study design, data collection, analysis, interpretation, manuscript writing, or decision to submit the article for publication.
Conflicts of interest None.
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