Patient outcomes
The main clinical and pathological characteristics of the cohorts are shown in Table 1. Mean age at the time of diagnosis was 67 years, and most of the patients were of male sex (72.5%) and had adenocarcinoma (555.8%). A total of 52 patients (37.7%) were presented with a PD-L1 expression≥ 50%. More than half of the patients had smoking history (72.5%). Here, PD-L1 level was significantly associated with age and TMB status. 50 out of 52 patients with PD-L1≥50% were adminstrated with combined chemo- and immuno- therapy, while 14 out of 86 patients with PD-L1<50% underwent mono- chemotherapy.
Table 1. Demographics and characteristics for patients with PD-L1≥50% and PD-L1<50% in 138 NSCLC patients
|
All Patients (n=138)
|
PD-L1≥50% (High) (n=52)
|
PD-L1<50% (Low) (n=86)
|
P Value
|
Age,median(range)
|
|
|
|
p<0.05
|
<65
|
55
|
15
|
40
|
|
≥65
|
83
|
37
|
46
|
|
TMB status
|
|
|
|
p<0.05
|
<5/MB
|
62
|
19
|
43
|
|
5-10/MB
|
33
|
10
|
23
|
|
>10MB
|
43
|
23
|
20
|
|
Gender
|
|
|
|
0.9
|
Male
|
100
|
38
|
62
|
|
Femal
|
38
|
14
|
24
|
|
Smoking history
|
|
|
|
0.192
|
No
|
38
|
11
|
27
|
|
Yes
|
100
|
41
|
59
|
|
Histological type
|
|
|
|
0.4534
|
ADC
|
77
|
29
|
48
|
|
SCC
|
43
|
19
|
24
|
|
Sarcomatoid carcinoma
|
14
|
3
|
11
|
|
Mixed adenosquamous carcinoma
|
4
|
1
|
3
|
|
PD-L1, programmed death receptor ligand 1 (PD-L1); TMB, tumor mutational burden; ADC, lung adenocarcinoma, SCC, lung squamous cell carcinoma.
Mutation mapping for PD-L1≥50% and PD-L1<50%
The most common genomic alterations in PD-L1≥50% and PD-L1<50% are summarized in Table 2. TP53 is the most frequently altered gene across both groups. The PD-L1≥50% cohort bear mutations of KRAS, NOTCH1, and FAT, while PD-L1<50% group exhibited mutations of EGFR, PTEN, or LATS1/2.
Table 2. DNA alterations in PD-L1≥50% and PD-L1<50%.
Variants
|
PD-L1≥50% (High) (n=52)
|
PD-L1<50% (Low) (n=86)
|
p Value
(Chi-Square)
|
Cell cycle control
|
|
|
|
TP53
|
45
|
65
|
0.1209
|
RB1
|
7
|
9
|
0.5942
|
MYC
|
3
|
7
|
0.6027
|
SRC
|
2
|
1
|
0.2949
|
CDKN2A
|
8
|
17
|
0.5171
|
CDKN2B
|
1
|
1
|
0.7172
|
CCND1
|
2
|
7
|
0.3222
|
RTK
|
|
|
|
EGFR
|
8
|
28
|
p<0.05
|
FGFR1/2/3
|
2
|
9
|
0.1642
|
DDR2
|
0
|
3
|
0.1733
|
ERBB2
|
1
|
10
|
0.0414
|
IGF1R
|
1
|
4
|
0.4059
|
EPHA2
|
2
|
1
|
0.2949
|
MET
|
2
|
4
|
0.8222
|
MAPK-PI3K pathway
|
|
|
|
KRAS
|
15
|
9
|
p<0.01
|
BRAF
|
1
|
1
|
0.7172
|
MAPK1
|
1
|
1
|
0.7172
|
NF1
|
9
|
9
|
0.2474
|
PIK3CA
|
11
|
19
|
0.8969
|
PTEN
|
1
|
11
|
p<0.05
|
RICTOR
|
1
|
6
|
0.1898
|
Cell death
|
|
|
|
CASP8
|
0
|
3
|
0.1733
|
BCL2L1
|
2
|
1
|
0.2949
|
Cell differentiation
|
|
|
|
TP63
|
1
|
1
|
0.7172
|
NOTCH1
|
18
|
9
|
p<0.01
|
MAML1
|
0
|
1
|
0.4351
|
Transscriptional regulation
|
|
|
|
EP300
|
0
|
2
|
0.268
|
KMT2D
|
7
|
17
|
0.3436
|
NSD1
|
1
|
2
|
0.8751
|
MED1
|
1
|
2
|
0.8751
|
Oxidative stress
|
|
|
|
NFE2L2
|
5
|
5
|
0.4039
|
KEAP1
|
7
|
8
|
0.4468
|
CUL3
|
1
|
1
|
0.7122
|
Hippo-YAP related pathway
|
|
|
|
FAT1/2/3/4
|
19
|
9
|
p<0.01
|
LATS1/2
|
0
|
7
|
p<0.05
|
YAP1
|
1
|
1
|
0.7172
|
NF2
|
1
|
1
|
0.7122
|
DNA alterations include somatic mutations and copy number alterations; EGFR mutations exclude traditional targeted sites.
Gene Enrichment Analysis of PD-L1≥50% and PD-L1<50%
Gene enrichment analysis (GEA) was constructed to analyze all gene alterations in PD-L1≥50% and PD-L1<50% groups. As shown in Figure 2A, we found that hsa05200 (Pathways in cancer), WP2261 (Glioblastoma signaling pathways), GO:0007167 (enzyme-linked receptor protein signaling pathway), GO:0006974 (DNA damage response), and WP5087 (Malignant pleural mesothelioma) were remarkably correlated with a high PD-L1 expression, whereas GO:0006468 (protein phosphorylation), WP5087 (Malignant pleural mesothelioma), GO:0006974 (DNA damage response), GO:0008283 (cell population proliferation) were predominantly associated with a PD-L1 expression <50% (Figure 2B). Interestingly, the study revealed that Hippo siganling was closely connected with the high expression of PD-L1.
Prognostic variables for PFS in patients with PD-L1 expression≥50% and PD-L1<50%
The follow-up period ranged from 175 to 719 days, with a median follow-up time for censored patients of 298 days. When we correlated the PD-L1 status with PFS (Figure 3), it revealed that there was no statistical significance between the two cohorts. Medium PFS in patients with a PD-L1 expression≥50% and PD-L1<50% were 11.0 months and 9.6 months, respectively.
irAEs in patients with PD-L1 expression≥50% and PD-L1<50%
A total of 34 irAEs were observed in 27.9% of patients (29/122) and the median time from ICIs initiation to the onset of the first irAE was 37 days. Of which, we observed 22 irAEs in 50 patients with a PD-L1 expression ≥50% compared to 12 out of 72 with PD-L1 expression <50% (Supplement Table 1). The most common grade 1-5 irAEs distributed on the endocrine system (8.0%, 9/122), pulmonary (4.3%, 6/122), and skin (3.6%, 5/122) organs. Here, distribution of ≥grade 3 irAEs were shown in Figure 4. 9 irAEs led to discontinuation, including four from pneumonitis, two from liver failure, two from renal failure, and one from colitis.