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Citation: Takeda, T.; Yamada, T.;
Kunimatsu, Y.; Tanimura, K.;
Morimoto, K.; Shiotsu, S.; Chihara, Y.;
Okada, A.; Horiuchi, S.; Hibino, M.;
et al. Age-Stratified Analysis of
First-Line Chemoimmunotherapy for
Extensive-Stage Small Cell Lung
Cancer: Real-World Evidence from a
Multicenter Retrospective Study.
Cancers 2023,15, 1543. https://
doi.org/10.3390/cancers15051543
Academic Editor: David Wong
Received: 2 February 2023
Revised: 23 February 2023
Accepted: 27 February 2023
Published: 28 February 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
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4.0/).
cancers
Article
Age-Stratified Analysis of First-Line Chemoimmunotherapy for
Extensive-Stage Small Cell Lung Cancer: Real-World Evidence
from a Multicenter Retrospective Study
Takayuki Takeda 1, * , Tadaaki Yamada 2, Yusuke Kunimatsu 1, Keiko Tanimura 1, Kenji Morimoto 2,
Shinsuke Shiotsu 3, Yusuke Chihara 4, Asuka Okada 5, Shigeto Horiuchi 6, Makoto Hibino 6, Kiyoaki Uryu 7,
Ryoichi Honda 8, Yuta Yamanaka 9, Hiroshige Yoshioka 9, Takayasu Kurata 9and Koichi Takayama 2
1Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto 602-8026, Japan
2Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University
of Medicine, Kyoto 602-8566, Japan
3Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 605-0981, Japan
4Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Kyoto 611-0041, Japan
5Department of Respiratory Medicine, Saiseikai Suita Hospital, Osaka 564-0013, Japan
6Department of Respiratory Medicine, Shonan Fujisawa Tokushukai Hospital, Kanagawa 251-0041, Japan
7Department of Respiratory Medicine, Yao Tokushukai General Hospital, Osaka 581-0011, Japan
8Department of Respiratory Medicine, Asahi General Hospital, Chiba 289-2511, Japan
9Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka 573-1191, Japan
*Correspondence: dyckw344@yahoo.co.jp; Tel.: +81-75-231-5171
Simple Summary:
Chemoimmunotherapy improved overall survival (OS) and progression-free
survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) in two phase III trials,
which set the age-stratified subgroup analyses at 65 years. Considering the super-aged society of
Japan, treatment efficacy and safety in elderly patients
≥
75 years with ES-SCLC should be validated
through real-world Japanese evidence. Consecutive 225 Japanese patients with SCLC were evaluated,
and 155 received chemoimmunotherapy (98 non-elderly and 57 elderly patients). The dose reduction
at initiating the first cycle was significantly higher in the elderly (47.4%) than in the non-elderly
(20.4%) patients (p= 0.03). The median PFS and OS in the non-elderly and the elderly were 5.1
and 14.1 months and 5.5 and 12.0 months, respectively, without significant differences. Multivariate
analyses revealed that age, the baseline Eastern Cooperative Oncology Group performance status, and
dose reduction at initiating the first chemoimmunotherapy cycle were not correlated with PFS or OS.
Abstract:
Chemoimmunotherapy improved overall survival (OS) and progression-free survival
(PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) in two phase III trials. They
set the age-stratified subgroup analyses at 65 years; however, over half of the patients with lung
cancer were newly diagnosed at
≥
75 years in Japan. Therefore, treatment efficacy and safety in
elderly patients
≥
75 years with ES-SCLC should be evaluated through real-world Japanese ev-
idence. Consecutive Japanese patients with untreated ES-SCLC or limited-stage SCLC unfit for
chemoradiotherapy between 5 August 2019 and 28 February 2022 were evaluated. Patients treated
with chemoimmunotherapy were divided into the non-elderly (<75 years) and elderly (
≥
75 years)
groups, and efficacy, including PFS, OS, and post-progression survival (PPS) were evaluated. In total,
225 patients were treated with first-line therapy, and 155 received chemoimmunotherapy (98 non-
elderly and 57 elderly patients). The median PFS and OS in non-elderly and elderly were 5.1 and
14.1 months and 5.5 and 12.0 months, respectively, without significant differences. Multivariate
analyses revealed that age and dose reduction at the initiation of the first chemoimmunotherapy
cycle were not correlated with PFS or OS. In addition, patients with an Eastern Cooperative Oncology
Group performance status (ECOG-PS) = 0 who underwent second-line therapy had significantly
longer PPS than those with ECOG-PS = 1 at second-line therapy initiation (p< 0.001). First-line
chemoimmunotherapy had similar efficacy in elderly and non-elderly patients. Individual ECOG-PS
maintenance during first-line chemoimmunotherapy is crucial for improving the PPS of patients
proceeding to second-line therapy.
Cancers 2023,15, 1543. https://doi.org/10.3390/cancers15051543 https://www.mdpi.com/journal/cancers
Cancers 2023,15, 1543 2 of 17
Keywords:
age-stratified analysis; chemoimmunotherapy; elderly patient; post-progression survival
(PPS); prognostic nutritional index (PNI); small cell lung cancer
1. Introduction
Lung cancer is the leading cause of mortality in cancer patients, of which, small cell
lung cancer (SCLC) accounts for approximately 10–15% [
1
]. Due to SCLC’s aggressive
and devastating nature, approximately two-thirds of patients present with extensive-stage
SCLC (ES-SCLC), whose treatment goal is to prolong overall survival (OS) without expect-
ing a complete cure [
2
]. The standard treatment has been platinum doublet chemotherapy
with an OS of 9.3–12.8 months [
3
–
5
]. However, introducing immune checkpoint inhibitors
(ICIs), especially anti-programmed cell death ligand 1 (PD-L1) monoclonal antibodies,
has changed ES-SCLC outcomes. Chemoimmunotherapy consisting of atezolizumab com-
bined with carboplatin (CBDCA) and etoposide (ETP) significantly improved OS and
progression-free survival (PFS) compared to the placebo plus CBDCA and the ETP group
in the IMpower133 phase III trial reported in 2018 [
6
]. Another chemoimmunotherapy
consisting of durvalumab plus cisplatin (CDDP) or CBDCA and ETP significantly improved
OS and PFS in the CASPIAN phase III trial [7].
The pre-specified age-stratified subgroup analyses in these phase III trials were set at
65 years, and the observed adverse events (AEs) and immune-related AEs (irAEs) were toler-
able among patients aged
≥
65 years [
6
,
7
]. However, an exponential increase in the number
of elderly patients with lung cancer has been noticed worldwide in recent years owing to
population aging in developed countries, which is the cardinal risk of malignancy. In the
United States, the median age of those patients diagnosed with lung cancer is 70 years [
8
],
and over 35% of patients diagnosed with lung cancer are aged > 75 years in the U.S. based
on the Surveillance, Epidemiology, and End Results (SEER) database [
9
]. In Japan, the
super-aged society is becoming the oldest worldwide, with 28.4% aged
≥
65 and 14.7%
≥
75 [
10
]. Over half of the newly diagnosed lung cancer patients were >75 years [
11
].
Thus, the efficacy and safety of chemoimmunotherapy for elderly patients with ES-SCLC
aged
≥
75 should be validated through real-world Japanese evidence because there are no
prospective phase III trials in this population. Only one prospective observational study
with a small sample size has assessed this population [12].
The limited efficacy of ICIs and the increased risk of irAEs among elderly patients with
non-small cell lung cancer (NSCLC) have been reported [
13
]. The accumulated evidence
of the restricted efficacy of ICIs among elderly patients with NSCLC [
14
] could be partly
explained by immunosenescence [
13
,
15
]. In contrast, there is scarce evidence regarding
the efficacy and safety of ICIs in elderly patients with ES-SCLC. Therefore, exploring
whether elderly patients aged
≥
75 with ES-SCLC would benefit from the standard first-
line treatment of chemoimmunotherapy equivalent to their younger counterparts is useful.
Furthermore, biomarkers for predicting OS and PFS in patients with ES-SCLC during
chemoimmunotherapy remain scarce. The pretreatment platelet-to-lymphocyte ratio (PLR)
in patients with ES-SCLC receiving first-line chemotherapy reportedly correlated with
OS and PFS in a phase II trial cohort [
16
]. Similarly, some immunological and nutritional
markers during platinum doublet chemotherapy have correlated with ES-SCLC prognosis,
including the neutrophil-to-lymphocyte ratio (NLR) in a meta-analysis [
17
] and a single
institute [18], the prognostic nutritional index (PNI) in a meta-analysis [19], PNI in combi-
nation with neuron-specific enolase [
20
], and the systemic immune-inflammation index
(SII) in a single institute [
21
]. However, a contradictory report from a single institute exists
where NLR did not correlate with OS in patients with SCLC [22].
Thus, this multicenter retrospective study aimed to investigate the efficacy and safety
of first-line chemoimmunotherapy for patients
≥
75 years with ES-SCLC compared to their
younger counterparts and identify baseline characteristics and immunological and nutri-
tional markers that could predict OS and PFS. This study also evaluated post-progression
Cancers 2023,15, 1543 3 of 17
survival (PPS) after first-line chemoimmunotherapy, which was highly correlated with OS
compared to PFS in patients with ES-SCLC who were treated with chemoimmunother-
apy [
23
]. PPS evaluation was added to elucidate the efficacy of second-line or later therapy
in patients with ES-SCLC. To our knowledge, this is the first study on the age-stratified
analysis of chemoimmunotherapy in patients with ES-SCLC aged ≥75.
2. Materials and Methods
2.1. Patients
This multicenter retrospective study evaluated consecutive Japanese patients with
untreated ES-SCLC or limited-stage SCLC (LS-SCLC) who were unfit for chemoradiother-
apy at nine hospitals in Japan between 5 August 2019 (the approval date of the first-line
CBDCA plus ETP combined with atezolizumab in Japan) and 28 February 2022. The data
cut-off date was 31 August 2022, with a minimum follow-up of 6 months after the final
enrolment date.
The inclusion criteria were: (1) cytologically or histologically diagnosed ES-SCLC or
LS-SCLC unfit for curative radiotherapy and (2) patients treated with first-line chemoim-
munotherapy (CBDCA + ETP + atezolizumab, CBDCA+ ETP + durvalumab, CDDP + ETP +
durvalumab) or platinum doublet chemotherapy (CBDCA + ETP, CDDP + ETP, and CDDP
+ irinotecan), without treatment history.
This study aimed to elucidate the efficacy and safety of chemoimmunotherapy for
elderly patients with ES-SCLC. The chemoimmunotherapy group was divided into non-
elderly (<75 years) and elderly (
≥
75) groups. The data of patients treated with platinum
doublet chemotherapy were not compared with the chemoimmunotherapy counterparts
because those who did not receive chemoimmunotherapy may have some characteristics
unfit for ICIs, leading to bias and strong confounding. Therefore, the reasons they did
not receive chemoimmunotherapy were recorded in the platinum doublet group, and
age-stratified analyses were conducted among the chemoimmunotherapy group.
The study protocol was in accordance with the Declaration of Helsinki and was ap-
proved by the Ethics Committees of the Japanese Red Cross Kyoto Daini Hospital (5 August
2022; S2022-16) and of each participating hospital. The requirement for informed consent
was waived based on the retrospective analysis of anonymized patient data. Patients were
allowed to opt out of their data use, and the relevant information was publicly available on
each hospital’s website.
2.2. Treatment with First-Line Chemoimmunotherapy and Response Evaluation
All patients were treated with 1–6 cycles of induction chemoimmunotherapy, followed
by maintenance therapy with the relevant anti-PD-L1 antibody until disease progression,
death, or unacceptable toxicity. The administered regimens were: (1) ETP (80–100 mg/m
2
body surface area, administered intravenously on days 1–3 of each cycle), CBDCA (area
under the curve of 5–6 mg/mL per min, administered intravenously on day 1 of each
cycle), and atezolizumab (fixed dose of 1200 per body, administered intravenously on
day 1 of each cycle), followed by maintenance atezolizumab 1200 mg every three weeks;
(2) platinum-ETP consisting of ETP (80–100 mg/m
2
on days 1–3 of each cycle) combined
with the physicians’ choice of CBDCA (area under the curve of 5–6 mg/mL per min) or
CDDP (75–80 mg/m
2
) intravenously administered on day 1 of each cycle, and durvalumab
(fixed dose of 1500 mg per body, administered intravenously on day 1 of each cycle),
followed by maintenance durvalumab 1500 mg every 4 weeks. The standard dosage of ETP,
CBDCA, and CDDP had been previously defined at each participating hospital, and dose
reduction was each treating physician’s choice.
The response was evaluated according to the best overall treatment response using the
response evaluation criteria in solid tumours version 1.1 [
24
]. The treating physicians and
radiologists used chest radiography, computed tomography, and brain magnetic resonance
imaging with contrast enhancement to evaluate the treatment response. The responses were
Cancers 2023,15, 1543 4 of 17
classified as complete response (CR), partial response (PR), stable disease (SD), progressive
disease (PD), and not evaluable (NE).
The PPS was the period from PD for first-line chemoimmunotherapy to any-cause
death or the last follow-up in censored cases without death. The correlations between PFS,
OS, PPS, and OS were evaluated.
The patient’s Eastern Cooperative Oncology Group performance status (ECOG-PS)
was documented at baseline, at the time of disease progression, and at second-line therapy
initiation if available. The relationship between ECOG-PS at the time of disease progression
and PPS after chemoimmunotherapy was investigated. Thereafter, the correlation between
ECOG-PS at second-line therapy initiation and PPS after chemoimmunotherapy was also
investigated to indirectly elucidate the importance of maintaining ECOG-PS during the
first-line chemoimmunotherapy.
Treatment beyond disease progression was allowed when there was a clinical benefit,
where the PPS was estimated from the end of beyond disease progression. Prophylactic
cranial irradiation was allowed at the physician’s discretion.
2.3. Data Collection
Baseline characteristics, namely, age, sex, smoking history, ECOG-PS score, comorbidi-
ties, height, body weight, histology, blood investigations, systemic corticosteroid adminis-
tration at baseline, regimen administered, dosage (standard or reduced) at initiating the first
induction chemoimmunotherapy cycle, dose reduction during subsequent cycles, usage of
granulocyte colony-stimulating factor (G-CSF), efficacy including objective response rate
(ORR), disease control ratio (DCR), PFS, OS, and PPS, were reasons for discontinuation
of first-line chemoimmunotherapy, observed AEs including irAEs. Subsequent therapy
options were collected from electronic medical records. AEs were evaluated using the
common terminology criteria for adverse events (version 5.0).
2.4. Study Variables
Previous reports were used to define cut-off values for the following immunological
and nutritional markers: PLR [
16
,
25
,
26
], NLR [
17
,
18
,
21
,
22
,
26
,
27
], PNI [
19
,
20
,
26
,
28
], and
SII [
21
,
29
,
30
]. PLR was the ratio of absolute platelet count (/
µ
L) divided by absolute
lymphocyte count (/
µ
L) and grouped based on PLR < 250 or
≥
250. NLR was the ratio of
absolute neutrophil count (/
µ
L) to lymphocyte count (/
µ
L) and grouped using NLR < 5 or
≥
5. The PNI was calculated as 10
×
albumin (g/dL) + 0.005
×
absolute lymphocyte count
(/
µ
L), and grouped using PNI
≥
40 or <40. The SII values were calculated as absolute
platelet count (/L) ×NLR and grouped according to SII values of <1000 or ≥1000.
These markers were evaluated at baseline for associations with PFS and OS.
2.5. Statistical Analysis
Statistical analyses were performed using EZR [
31
], a graphical user interface for R
software (The R Foundation for Statistical Computing, Vienna, Austria). Baseline character-
istics were compared using Pearson’s Chi-square test. Median PFS and OS intervals with
corresponding 95% confidence intervals (CIs), ORR, and DCR were calculated. Curves for
PFS and OS were illustrated using the Kaplan–Meier method and log-rank tests. Univariate
and multivariate analyses were performed for each potential marker or baseline character-
istic using Cox proportional hazards regression analyses, in which hazard ratios (HR) and
95% CIs were estimated. Spearman’s rank correlation and linear regression analyses were
used to evaluate the correlations between PFS or PPS and OS via a correlation coefficient
(r
s
value), p-value, and linear regression (R
2
value). Differences were considered significant
at p< 0.05.
Cancers 2023,15, 1543 5 of 17
3. Results
3.1. Patient Selection Diagram (Figure 1) and the Characteristics of Patients Treated with Platinum
Doublet Chemotherapy (Table 1)
In total, 225 patients with ES-SCLC were treated with first-line chemoimmunotherapy
or platinum doublet chemotherapy, including 178 males and 47 females with a median
age of 73 (range: 43–87). Among the 225 patients, 70 were treated with platinum doublet
chemotherapy, and 155 received first-line chemoimmunotherapy.
Figure 1. Diagram presenting patient selection among 225 consecutive patients with small cell lung
cancer who underwent first-line therapy between 5 August 2019 and 28 February 2022; 155 of them
received chemoimmunotherapy. Age-stratified analyses were conducted to compare non-elderly
patients aged <75 (n= 98) and elderly patients aged ≥75 (n= 57).
The 70 patients in the chemotherapy group included 53 males and 17 females, and 26
non-elderly and 44 elderly patients with a median age of 76 (range: 61–86); 6 (23.1%) out of
26 non-elderly patients received CDDP-based regimens which were not administered in
elderly patients (p= 0.04). On the other hand, all elderly patients received CBDCA plus
ETP, which was selected in 20 out of 26 non-elderly patients (p= 0.002). There was no
significant difference in the baseline characteristics between the non-elderly and elderly
patients. The dominant reasons why chemoimmunotherapy was considered unfit and
chemotherapy was adopted were underlying interstitial lung disease, poor ECOG-PS, age,
patient preference, and underlying autoimmune disease (Table 1).
Table 1. Characteristics of patients treated with platinum doublet chemotherapy.
Characteristics Total: n= 70 Non-Elderly Patients
(<75 Years): n= 26
Elderly Patients
(≥75 Years): n= 44 p-Value
Sex: male/female 53 (75.7%)/17 (24.3%) 16 (61.5%)/10 (38.5%) 37 (84.1%)/7 (15.9%) 0.05
Age (years): median (range) 76 (61–86) 70 (61–73) 78 (75–86) N/A
ECOG-PS: 0/1/2/3/4 7 (10.0%)/40 (57.1%)/
11 (15.7%)/12 (17.1%)/0 3 (11.5%)/13 (50.0%)/
2 (7.7%)/8 (30.8%)/0 4 (9.1%)/27 (61.4%)/
9 (20.5%)/4 (9.1%)/0 0.09
Regimen
CBDCA + etoposide 64 (91.4%) 20 (76.9%) 44 (100%) 0.002
CDDP + etoposide 3 (4.3%) 3 (11.5%) 00.04
CDDP + irinotecan 3 (4.3%) 3 (11.5%) 00.04
Reasons for adopting chemotherapy
Patient’s preference 5 (7.1%) 5 (19.2%) 00.005
Interstitial lung disease 33 (47.1%) 11 (42.3%) 22 (50.0%) 0.62
Poor ECOG-PS 13 (18.6%) 6 (23.1%) 7 (15.9%) 0.53
Age 8 (11.4%) 1 (3.8%) 7 (15.9%) 0.24
Rheumatoid arthritis 2 (2.9%) 2 (7.7%) 0 0.14
IgA nephritis 1 (1.4%) 1 (3.8%) 0 0.37
Dermatomyositis 1 (1.4%) 01 (2.3%) 1.00
Congestive heart failure 3 (4.3%) 03 (6.8%) 0.29
Sick sinus syndrome 1 (1.4%) 01 (2.3%) 1.00
Cognitive impairment 1 (1.4%) 01 (2.3%) 1.00
Liver dysfunction 1 (1.4%) 01 (2.3%) 1.00
Renal dysfunction 1 (1.4%) 01 (2.3%) 1.00
The bold and underline in the tables means the statistical significance.
Cancers 2023,15, 1543 6 of 17
3.2. Characteristics of Patients Treated with Chemoimmunotherapy (Table 2)
The 155 patients treated with chemoimmunotherapy included 98 non-elderly and
57 elderly patients, with a median age of 72 (Table 2). The dose reduction at initiating the
first cycle was significantly higher in the elderly (47.4%) than in the non-elderly (20.4%)
patients (p= 0.03). Among the 155 patients, 13 (8.4%) were still on the first-line chemoim-
munotherapy at the data cut-off, 99 (63.9%) underwent subsequent second-line treatment,
and 43 (27.7%) selected the best supportive care without receiving second-line treatment.
3.3. Objective Response Rate, Progression-Free Survival, and Overall Survival Outcomes
(Figures 2and 3)
The median follow-up for the entire study population was 11.5 months
(range: 6.0–37.3)
.
The treatment responses to chemoimmunotherapy in the 155 patients were classified as
CR in 2 (1.3%), PR in 124 (80.0%), SD in 20 (12.9%), PD in 5 (3.2%), and NE in 4 (2.6%)
patients, resulting in an ORR of 81.3% and DCR of 94.2% (Supplementary Table S1). The
median PFS and OS were 5.2 months (95% CI: 4.8–5.5) and 13.2 months (95% CI: 11.7–15.5),
respectively (Figure 2).
Next, we performed age-stratified analyses. The treatment responses in 98 non-elderly
patients were CR in 2 patients (2.0%), PR in 77 (78.6%), SD in 14 (14.3%), PD in 4 (4.1%), and
NE in 1 (1.0%), resulting in an ORR of 80.6% and DCR of 94.9%. In contrast, the 57 elderly
patients had CR in 0, PR in 47 (82.5%), SD in 6 (10.5%), PD in 1 (1.8%), and NE in 3 (5.3%)
patients, resulting in an ORR of 82.5% and DCR of 93.0%. The median PFS in non-elderly
and elderly patients was 5.1 months (95% CI: 4.7–5.5) and 5.5 months (95% CI: 4.6–6.4),
respectively. The median OS in non-elderly and elderly patients was 14.1 months (95%
CI: 11.7–17.0) and 12.0 months (95% CI: 8.3–16.9), respectively. There were no significant
differences between both groups regarding ORR (p= 0.83), DCR (p= 0.73), PFS (p= 0.19),
and OS (p= 0.59).
Figure 2.
Kaplan-Meier estimates of (
A
) progression-free survival (PFS) and (
B
) overall survival (OS)
in 155 patients who received first-line chemoimmunotherapy. The median PFS and OS were 5.2 and
13.2 months, respectively.
Cancers 2023,15, 1543 7 of 17
Table 2. Characteristics of patients treated with chemoimmunotherapy.
Characteristics Total: n= 155 Non-Elderly Patients
(<75 Years): n= 98
Elderly Patients
(≥75 Years): n= 57 p-Value
Sex: male/female 125 (80.6%)/30 (19.4%) 74 (75.5%)/24 (24.5%) 51 (89.5%)/6 (10.5%) 0.04
Age (years): median (range) 72 (43–87) 69 (43–74) 79 (75–87)
ECOG-PS: 0/1/2/3/4 39 (25.2%)/94 (60.6%)/
17 (11.0%)/5 (3.2%)/0
32 (32.7%)/52 (53.1%)/
11 (11.2%)/3 (3.1%)/0
7 (12.3%)/42 (73.7%)/
6 (10.5%)/2 (3.5%)/0 0.03
Smoking: current/former/never 54 (34.8%)/96 (61.9%)/5 (3.2%) 38 (38.8%)/55 (56.1%)/5 (5.1%) 16 (28.1%)/41 (71.9%)/0 0.04
Stage: III/IVA/IVB/recurrence
9 (5.8%)/40 (25.8%)/103 (66.5%)/3 (1.9%)
5 (5.1%)/22 (22.4%)/68 (69.4%)/3 (3.1%)
4 (7.0%)/18 (31.6%)/35 (61.4%)/0 0.35
Brain metastasis at baseline: (+)/(−) 33 (21.3%)/122 (78.7%) 25 (25.5%)/73 (74.5%) 8 (14.0%)/49 (86.0%) 0.11
Liver metastasis at baseline: (+)/(−) 37 (23.9%)/118 (76.1%) 24 (24.5%)/74 (75.5%) 13 (22.8%)/44 (77.2%) 0.85
ILD at baseline: (+)/(−) 6 (3.9%)/149 (96.1%) 2 (2.0%)/96 (98.0%) 4 (7.0%)/53 (93.0%) 0.19
Autoimmune disease: (+)/(−) 2 (1.3%)/153 (98.7%) 1 (1.0%)/97 (99.0%) 1 (1.8%)/56 (98.2%) 1.00
Steroid treatment at baseline: (+)/(−) 7 (4.5%)/148 (95.5%) 7 (7.1%)/91 (92.9%) 0/57 (100%) 0.04
Cycles of induction: 1–2/3/4/5–6
13 (8.4%)/13 (8.4%)/126 (81.3%)/3 (1.9%)
4 (4.1%)/9 (9.2%)/83 (84.7%)/2 (2.0%) 9 (15.8%)/4 (7.0%)/43 (75.4%)/1 (1.8%) 0.08
Reduced dose at 1st cycle: (+)/(−) 45 (29.0%)/110 (71.0%) 20 (20.4%)/78 (79.6%) 25 (43.9%)/32 (56.1%) 0.003
Dose reduction during Tx.: (+)/(−) 62 (40.0%)/93 (60.0%) 35 (35.7%)/63 (64.3%) 27 (47.4%)/30 (52.6%) 0.18
G-CSF during induction Tx.: (+)/(−) 91 (58.7%)/64 (41.3%) 58 (59.2%)/40 (40.8%) 33 (57.9%)/24 (42.1%) 1.00
Reason for discontinuation of 1st-line
Disease progression 112 (72.3%) 80 (81.6%) 32 (56.1%) <0.001
Adverse events 3 (1.9%) 1 (1.0%) 2 (3.5%) 0.55
Immune-related adverse events 9 (5.8%) 5 (5.1%) 4 (7.0%) 0.73
Others 18 (11.6%) 5 (5.1%) 13 (22.8%) 0.001
Ongoing Tx. 13 (8.4%) 7 (7.1%) 6 (10.5%) 0.55
2nd-line Tx.: (+)/(−)/on 1st-line Tx. 99 (63.9%)/43 (27.7%)/13 (8.4%) 70 (71.4%)/21 (21.4%)/7 (7.1%) 29 (50.9%)/22 (38.6%)/6 (10.5%) 0.04
The bold and underline in the tables means the statistical significance.
Cancers 2023,15, 1543 8 of 17
The Kaplan–Meier curves for PFS and OS in each group are illustrated in Figure 3A,B,
respectively.
Figure 3.
Age-stratified survival of patients treated with first-line chemoimmunotherapy. The Kaplan-
Meier estimates of (
A
): progression-free survival (PFS) and (
B
): overall survival (OS) in non-elderly
patients < 75 years (n= 98) and elderly patients aged
≥
75 (n= 57) are illustrated. The median PFS
and OS are presented with a 95% confidence interval (95% CI).
3.4. Relationship between Overall Survival and Progression-Free Survival or Post-Progression
Survival after First-Line Chemoimmunotherapy (Figure 4)
The correlation between PFS and OS is presented in Figure 4A, and that between PPS
and OS is indicated in Figure 4B. Spearman’s rank correlation analysis revealed a moderate
correlation between PFS and OS (r
s
= 0.60, p< 0.001, R
2
= 0.48), whereas PPS and OS
displayed a significantly higher correlation (rs= 0.86, p< 0.001, R2= 0.73).
Figure 4.
The Spearman’s rank correlation analysis and linear regression analysis to reveal (
A
) a
correlation between progression-free survival (PFS) and overall survival (OS); (
B
) a correlation
between post-progression survival (PPS) and OS. The r
s
value and the R
2
value represent Spearman’s
rank correlation coefficient and linear regression, respectively.
Cancers 2023,15, 1543 9 of 17
3.5. Adverse Events and Dose Reduction during Induction Therapy
AEs of any grade were observed in 143 patients (92.3%), including 90 non-elderly
(91.8%) and 53 elderly (93.0%) patients (Supplementary Table S2). In total, 12 patients (7.7%)
of the total study population experienced adverse events leading to treatment withdrawal,
including 6 non-elderly (6.1%) and 6 elderly (10.5%) patients. The most common AE was
neutropenia, occurring in 114 (73.5%) of the total population, in 68 (69.4%) non-elderly and
46 (80.7%) elderly patients.
IrAEs of any grade were observed in 30 patients (19.4%). Adrenal insufficiency
(grade 1) and colitis (grade 1) were observed in the same elderly patient. All irAEs of
≥
grade 3, excluding hyperthyroidism, and one patient who experienced grade 2 pneu-
monitis led to treatment withdrawal: one with grade 2, two with grade 3, and one with
grade 4 pneumonitis, one with grade 4 myasthenia gravis, one with grade 3 encephalopathy,
and one with grade 3 vasculitis. No grade 5 AE was observed.
There was no difference between the groups regarding AEs of all grades (p= 0.78),
AEs
≥
grade 3 (p= 0.11), and those leading to discontinuation (p= 0.36), and between both
groups in dose reduction during induction (p= 0.176).
3.6. Relationship between the Baseline Characteristics or Candidate Predictive Biomarkers and
Progression-Free Survival or Overall Survival among 155 Patients (Table 3), Elderly Patients Aged
≥75 (Table 4), and Non-Elderly Patients < 75 Years (Table 5)
Univariate analyses were performed to predict PFS and OS using baseline character-
istics and predictive markers (Table 3). PFS outcomes were significantly associated with
a baseline PNI of
≥
40 vs. <40 (HR: 0.64 [95% CI: 0.45–0.92], p= 0.02) and the number of
induction chemoimmunotherapy cycles (4–6 vs. 1–3 cycles; HR: 0.38 [95% CI: 0.25–0.95],
p< 0.001). OS outcomes were significantly associated with ECOG-PS of 0–1 vs.
≥
2 (HR: 0.43
[95% CI: 0.25–0.74], p= 0.002), NLR of <5 vs.
≥
5 (HR: 0.65 [95% CI: 0.43–0.98], p= 0.04), PNI
of
≥
40 vs. <40 (HR: 0.38 [95% CI: 0.25–0.57], p< 0.001), and the number of induction cycles
(4–6 vs. 1–3 cycles; HR: 0.30 [95% CI: 0.19–0.49], p< 0.001). Meanwhile, the dose reduction
at initiating the first chemoimmunotherapy cycle did not reveal a significant correlation
with PFS (HR: 1.04 [95% CI: 0.71–1.51], p= 0.84) or OS (HR: 1.21 [95% CI: 0.79–1.85], p= 0.39)
as shown in Table 3.
As shown in Table 4, PFS outcomes among patients aged
≥
75 were significantly
associated with the number of induction chemoimmunotherapy cycles (4–6 vs. 1–3 cycles;
HR: 0.35 [95% CI: 0.18–0.69], p= 0.003), and OS outcomes were significantly associated
with ECOG-PS of 0–1 vs.
≥
2 (HR: 0.38 [95% CI: 0.16–0.90], p= 0.03), NLR of <5 vs.
≥
5
(HR: 0.40 [95% CI: 0.20–0.82], p= 0.01), PNI of
≥
40 vs. <40 (HR: 0.28 [95% CI: 0.14–0.55],
p< 0.001), and the number of induction cycles (4–6 vs. 1–3 cycles; HR: 0.25 [95% CI: 0.12–
0.52], p< 0.001). On the other hand, OS outcomes among non-elderly patients (Table 5)
were significantly associated with ECOG-PS of 0–1 vs.
≥
2 (HR: 0.48 [95% CI: 0.24–0.96],
p= 0.03), the number of induction chemoimmunotherapy cycles (4–6 vs. 1–3 cycles; HR:
0.37 [95% CI: 0.20–0.70], p= 0.002), and PNI of
≥
40 vs. <40 (HR: 0.45 [95% CI: 0.27–0.76],
p= 0.002), whereas PFS outcomes were significantly associated the number of induction
chemoimmunotherapy cycles (4–6 vs. 1–3 cycles; HR: 0.41 [95% CI: 0.23–0.75], p= 0.003).
Multivariate analyses demonstrated that age (<75 vs.
≥
75), sex, smoking status, base-
line ECOG-PS, and dose reduction at initiating the first chemoimmunotherapy cycle did
not correlate with PFS or OS. In contrast, the number of induction cycles (4–6 vs. 1–3 cycles;
HR: 0.45 [95% CI: 0.27–0.73], p= 0.001) was associated with PFS. Moreover, baseline PNI of
≥
40 vs. <40 (HR: 0.36 [95% CI: 0.22–0.59], p< 0.001) and the number of induction cycles
(4–6 vs. 1–3 cycles; HR: 0.31 [95% CI: 0.18–0.54], p< 0.001) were related to OS (Table 3).
Cancers 2023,15, 1543 10 of 17
Table 3. Univariate and multivariate analyses to predict progression-free survival and overall survival among 155 patients treated with chemoimmunotherapy.
Progression-Free Survival Overall Survival
Univariate Analysis Multivariate Analysis Univariate Analysis Multivariate Analysis
Variables HR 95% CI p-Value HR 95% CI p-Value HR 95% CI p-Value HR 95% CI p-Value
Age (<75/≥75) 0.79 0.56–1.12 0.19 0.81 0.55–1.19 0.28 1.12 0.75–1.66 0.58 1.18 0.76–1.84 0.47
Sex (female/male) 1.25 0.82–1.90 0.31 1.18 0.73–1.91 0.49 1.23 0.73–2.06 0.45 1.05 0.60–1.85 0.86
Smoking (−/+) 1.21 0.49–2.95 0.68 1.53 0.50–4.72 0.45 1.68 0.61–4.59 0.31 1.92 0.58–6.34 0.29
ECOG-PS (<2/≥2) 0.94 0.58–1.54 0.82 0.75 0.42–1.32 0.32 0.43 0.25–0.74 0.002 0.55 0.30–1.03 0.06
Reduced dose at 1st cycle (−/+) 1.04 0.71–1.51 0.84 0.94 0.63–1.39 0.75 1.21 0.79–1.85 0.39 0.97 0.62–1.54 0.90
Cycles of induction (≥4/<4) 0.38 0.25–0.59 <0.001 0.45 0.27–0.73 0.001 0.30 0.19–0.49 <0.001 0.31 0.18–0.54 <0.001
PLR (<250/≥250) 0.92 0.65–1.30 0.62 0.88 0.59–1.32 0.55
NLR (<5/≥5) 0.72 0.50–1.02 0.07 0.84 0.55–1.30 0.44 0.65 0.43–0.98 0.04 0.96 0.58–1.58 0.84
PNI (≥40/<40) 0.64 0.45–0.92 0.02 0.70 0.46–1.07 0.10 0.38 0.25–0.57 <0.001 0.36 0.22–0.59 <0.001
SII (<1000/≥1000) 0.77 0.55–1.08 0.13 0.89 0.61–1.30 0.55
The bold and underline in the tables means the statistical significance.
Cancers 2023,15, 1543 11 of 17
Table 4.
Univariate analysis to predict progression-free survival and overall survival among elderly
patients aged ≥75.
Univariate Analysis (≥75 Years)
Progression-Free Survival Overall Survival
Variables HR 95% CI p-Value HR 95% CI p-Value
Sex (female/male) 1.24 0.49–3.14 0.65 1.68 0.51–5.47 0.39
ECOG-PS (<2/≥2) 0.79 0.35–1.78 0.57 0.38 0.16–0.90 0.03
Reduced dose at 1st cycle (−/+) 1.06 0.60–1.87 0.85 1.07 0.56–2.05 0.84
Cycles of induction (≥4/<4) 0.35 0.18–0.69 0.003 0.25 0.12–0.52 <0.001
PLR (<250/≥250) 0.92 0.51–1.68 0.79 0.87 0.44–1.71 0.68
NLR (<5/≥5) 0.59 0.32–1.09 0.09 0.40 0.20–0.82 0.01
PNI (≥40/<40) 0.58 0.32–1.05 0.07 0.28 0.14–0.55 <0.001
SII (<1000/≥1000) 0.93 0.52–1.65 0.79 0.84 0.44–1.59 0.59
The bold and underline in the tables means the statistical significance.
Table 5.
Univariate analysis to predict progression-free survival and overall survival among non-
elderly patients < 75 years.
Univariate Analysis (<75 Years)
Progression-Free Survival Overall Survival
Variables HR 95% CI p-Value HR 95% CI p-Value
Sex (female/male) 1.29 0.80–2.09 0.30 1.05 0.58–1.90 0.88
ECOG-PS (<2/≥2) 1.28 0.70–2.35 0.43 0.48 0.24–0.96 0.03
Reduced dose at 1st cycle (−/+) 0.99 0.57–1.71 0.98 1.26 0.68–2.33 0.46
Cycles of induction (≥4/<4) 0.41 0.23–0.75 0.003 0.37 0.20–0.70 0.002
PLR (<250/≥250) 1.18 0.76–1.81 0.46 0.91 0.55–1.49 0.70
NLR (<5/≥5) 0.80 0.51–1.24 0.32 0.83 0.50–1.39 0.48
PNI (≥40/<40) 0.77 0.49–1.19 0.24 0.45 0.27–0.76 0.002
SII (<1000/≥1000) 1.48 0.97–2.27 0.07 1.36 0.84–2.21 0.21
The bold and underline in the tables means the statistical significance.
3.7. Relationship between Eastern Cooperative Oncology Group Performance Status at Disease
Progression or at Second-Line Therapy Initiation and the Post-Progression Survival after First-Line
Chemoimmunotherapy (Figure 5)
Among 155 patients, 112 (72.3%) experienced disease progression, and ECOG-PS at
disease progression was available in 96 patients. The number of patients with ECOG-PS of
0, 1, 2, and 3–4 was 15, 52, 9, and 20, respectively. The median PPS of those who experienced
disease progression with ECOG-PS of 0–1, 2, and 3–4 was 10.7 (95% CI: 9.0–13.8), 2.1 (95%
CI: 0.4–8.6), and 2.1 months (95% CI: 1.1–2.8), respectively (p< 0.001).
Among the 112 patients, 99 (88.4%) underwent subsequent second-line therapy. The
ECOG-PS at the second-line therapy initiation was available in 79 patients; the number
of patients with ECOG-PS of 0, 1, 2, and 3–4 was 15, 52, 9, and 3, respectively. The PPS of
patients who underwent second-line therapy with ECOG-PS of 0, 1, 2, and 3–4 was 16.4
(95% CI: 10.1-not applicable), 9.0 (95% CI: 7.9–12.5), 2.1 (95% CI: 0.4–8.6), and 2.8 months
(95% CI: 1.6-not applicable), respectively (p< 0.001). There was a substantial difference in
the PPS between those with an ECOG-PS of 0 and 1 at the second-line therapy initiation.
In total, 15 patients with an ECOG-PS of 0 at the second-line therapy initiation in-
cluded 4 elderly patients. Dose reduction at first-line chemoimmunotherapy initiation
was performed in 3 elderly patients (75.0%), whereas all 11 non-elderly patients were
treated without dose reduction. On the other hand, 52 patients with an ECOG-PS of 1
included 18 elderly patients, in which preliminary dose reduction at the first-line therapy
initiation was conducted in only eight patients (44.4%). The preliminary dose reduction at
Cancers 2023,15, 1543 12 of 17
the first-line therapy initiation in elderly patients might have led to a reduction in AEs and
the preservation of ECOG-PS at second-line therapy initiation, resulting in prolonged PPS.
Figure 5.
The Kaplan-Meier estimates of post-progression survival (PPS) according to the Eastern
Cooperative Oncology Group performance status (ECOG-PS) at the disease progression of first-line
chemoimmunotherapy (A), and at the start of second-line therapy (B).
4. Discussion
Age is not considered a prognostic factor in several randomized NSCLC studies [
32
–
35
].
However, early death within 6 months after first-line chemotherapy in elderly patients with
cancer aged > 70 years is associated with malnutrition and poor mobility [
36
]. Furthermore,
a functional decline in daily activities occurs in 16.7% [
37
] and 19.9% [
38
] of the patients
after first-line chemotherapy. Similar results have been reported for lung cancer, with 23%
of elderly patients aged
≥
70 years experiencing a functional decline in daily activities after
first-line chemotherapy [
39
]. Therefore, phase III trial results cannot be routinely applied to
the daily clinic of elderly patients with cancer without modification.
A geriatric assessment (GA) is recommended to identify the vulnerabilities of patients
aged
≥
65 to overcome this age-related obstacle. CARG or Chemotherapy Risk Assess-
ment Scale for High-Age Patients (CRASH) scoring tools are also recommended to predict
chemotherapy toxicity risk [
40
,
41
]. A cluster-randomized study revealed that GA inter-
vention reduced grade 3–5 toxicity without shortening the 6-month OS [
42
]. However, no
tool is available for the prediction of the irAE risk in elderly patients, and the validity of
chemoimmunotherapy in elderly patients with ES-SCLC remains unclear.
The introduction of ICIs has revolutionized the treatment strategy for ES-SCLC. Anti-
PD-L1 antibodies of atezolizumab (IMpower133 trial) or durvalumab (CASPIAN trial)
with platinum plus ETP regimens have improved PFS and OS compared to platinum plus
ETP regimens [
6
,
7
]. In contrast, adding anti-programmed cell death 1 (PD-1) antibody to
pembrolizumab in the KEYNOTE-604 trial improved PFS more compared to the placebo.
However, it did not improve OS [
43
]. Although irAE risk is unpredictable, chemoim-
munotherapy’s favourable effects on cancer-related symptoms and quality of life (QOL)
in patients with ES-SCLC have been demonstrated in IMpower133 [
44
] and CASPIAN
trials [
45
]. Thus, it is crucial to understand whether chemoimmunotherapy could improve
PFS, OS, cancer-related symptoms, and QOL in elderly patients with ES-SCLC.
Cancers 2023,15, 1543 13 of 17
This multicenter retrospective study elucidated that the same efficacy of chemoim-
munotherapy could be expected in elderly and non-elderly patients regarding ORR, PFS,
OS, and PPS. Furthermore, AEs and irAEs did not exhibit a higher increase in elderly
patients compared with those in non-elderly patients. Thus, chemoimmunotherapy for
ES-SCLC would benefit elderly patients aged
≥
75. This information can facilitate the
administration of chemoimmunotherapy in elderly patients with ES-SCLC, especially in
those who avoided chemoimmunotherapy due to age and patient preference.
Whereas dose reduction at the first cycle initiation was more frequent in elderly pa-
tients (p= 0.03), the efficacy of chemoimmunotherapy was similar in non-elderly patients,
suggesting that the physician’s cautious patient-specific dose reduction would not nega-
tively affect these outcomes. Four or more chemoimmunotherapy induction cycles were
associated with prolonged PFS (HR: 0.45) and OS (HR: 0.31). This finding suggests the
importance of platinum plus ETP treatment in managing ES-SCLC. Moreover, substantial
tumour reduction before continuing maintenance therapy with an anti-PD-L1 antibody
could improve PFS and OS, considering the aggressive nature of SCLC. Thus, the results
revealed that the standard four-cycle induction chemoimmunotherapy would be optimal
for treating ES-SCLC.
The significantly high correlation between PPS and OS compared to the correlation
between PFS and OS was also demonstrated in this study. The PPS of patients who
experienced disease progression with an ECOG-PS of 0–1 was significantly longer than that
of patients with ECOG-PS
≥
2 (p< 0.001). Furthermore, the PPS of patients who underwent
second-line therapy was significantly longer with an ECOG-PS of 0 at second-line therapy
initiation than in those with an ECOG-PS of 1 (p< 0.001).
These results suggest that reducing AEs and maintaining the ECOG-PS during first-line
chemoimmunotherapy by appropriate individual management, including dose reduction
and supportive care, is crucial for PPS improvement in patients who proceed to second-
line therapy.
Immunological and nutritional markers are considered to reflect the close relationship
between cancer treatment and local or systemic host–tumour interactions. Thus, these
markers were also investigated as candidate biomarkers for predicting treatment outcomes.
PLR [
16
], NLR [
17
,
18
], PNI [
19
,
20
], and SII [
21
] are predictive of OS in patients with ES-
SCLC. NLR and PNI significantly correlated with OS in this study. However, univariate
analyses among elderly and non-elderly patients did not show any age-specific markers.
The higher rate of receiving second-line therapy after disease progression (88.4%) was
a significant feature in this study, compared to the previously reported real-world evidence
in Canada where only 8.7% of the patients underwent second-line therapy [
46
]. The data
in Canada were collected before the introduction of chemoimmunotherapy for ES-SCLC,
and a real-world evaluation of atezolizumab in combination with platinum-etoposide
chemotherapy in Canada reported that 27% of patients treated with chemoimmunotherapy
received second-line therapy, whereas 15% of patients treated with chemotherapy pro-
ceeded to second-line therapy [
47
]. Thus, the treatment strategy could be evolving after the
introduction of chemoimmunotherapy. In addition, the observed feature could be partly
explained by the national traits.
This study had several limitations. First, its retrospective design was prone to bias.
Second, despite the relatively large sample size, it was insufficient for category-stratified
analysis, especially in the ECOG-PS status at disease progression or at second-line therapy
initiation. Univariate analyses were used to assess the age-stratified analysis of PFS and
OS outcomes, which is another potential source of bias. Third, we selected cut-off values
for various predictive biomarkers from previous reports. Therefore, using biomarkers
and optimal cut-off values should be clarified in large prospective studies. Finally, this
study evaluated the age-stratified PFS and OS outcomes among the patients treated with
chemoimmunotherapy, which resulted in an indirect comparison between elderly and non-
elderly patients. Because it is difficult to retrospectively compare the chemoimmunotherapy
and chemotherapy groups, the indirect comparison was used in this study.
Cancers 2023,15, 1543 14 of 17
5. Conclusions
This study revealed that chemoimmunotherapy would benefit elderly patients with
ES-SCLC aged
≥
75 years, with PFS and OS improvement similar to that in non-elderly
patients. The observed AEs and irAEs were tolerable in elderly patients, facilitating
chemoimmunotherapy application in elderly patients. An ECOG-PS of 0 at subsequent
second-line therapy initiation predicted a substantially longer PPS than an ECOG-PS of 1.
This suggests that ECOG-PS maintenance by appropriate individual management during
first-line chemoimmunotherapy is crucial in the management of ES-SCLC. Thus, elderly
patients with ES-SCLC should be cautiously treated to improve outcomes.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/cancers15051543/s1, Table S1. Response to treatment, Table S2.
Treatment-related adverse events.
Author Contributions:
Each author made a significant contribution to the manuscript and has
approved the submitted version. T.T.: conceptualization, data curation, methodology, project ad-
ministration, and writing original draft; T.Y.: data curation, project administration, and validation;
Y.K.: formal analysis, methodology, and validation; K.T. (Keiko Tanimura): data curation, formal
analysis; K.M.: data curation, resources, and validation; S.S.: data curation, resources, and validation;
Y.C.: data curation, resources, and validation; A.O.: data curation, resources, and validation; S.H.:
data curation, resources, and validation; M.H.: data curation, resources, and validation; K.U.: data
curation, resources, and validation; R.H.: data curation, resources, and validation; Y.Y.: data curation,
resources, and validation; H.Y.: data curation, resources, and validation; T.K.: data curation, resources,
supervision, and validation; K.T. (Koichi Takayama): project administration, supervision, validation,
and writing—review and editing. All authors commented on previous versions of the manuscript.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement:
The study protocol complied with the Declaration of Helsinki
and was approved by the Ethics Committees of the Japanese Red Cross Kyoto Daini Hospital
(5 August 2022; S2022-16) and each participating hospital.
Informed Consent Statement:
The requirement for informed consent was waived because this was a
retrospective analysis of anonymized patient data. Patients were allowed to opt out of the research’s
use of their data, and the related information was publicly available on each hospital’s website.
Data Availability Statement:
The datasets generated during the current study are available from the
corresponding author on reasonable request.
Conflicts of Interest:
Takayasu Kurata received grants from MSD, Astra Zeneca, Amgen, Boehringer
Ingelheim, Daiichi Sankyo pharmaceutical, Takeda pharmaceutical, and Bristol Myers Squibb, and
honoraria for lecture from Astra Zeneca, Ono pharmaceutical, MSD, Nippon Kayaku, Takeda phar-
maceutical, Eli Lilly, Bristol Myers Squibb, Chugai pharmaceutical, and Pfizer. Hiroshige Yoshioka
received honoraria for lecture fees from Boehringer Ingelheim, Chugai pharmaceutical, Nippon
Kayaku, Taiho pharmaceutical, Eli Lilly, Takeda pharmaceutical, and Bristol Myers Squibb. The other
authors declare no conflict of interest.
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