Articles

Adebrelimab or placebo plus carboplatin and etoposide as

first-line treatment for extensive-stage small-cell lung
cancer (CAPSTONE-1): a multicentre, randomised,
double-blind, placebo-controlled, phase 3 trial
Jie Wang, Caicun Zhou, Wenxiu Yao, Qiming Wang, Xuhong Min, Gongyan Chen, Xingxiang Xu, Xingya Li, Fei Xu, Yong Fang, Runxiang Yang,
Guohua Yu, Youling Gong, Jun Zhao, Yun Fan, Quan Liu, Lejie Cao, Yu Yao, Yunpeng Liu, Xiaoling Li, Jingxun Wu, Zhiyong He, Kaihua Lu,
Liyan Jiang, Chengping Hu, Wenhua Zhao, Ben Zhang, Wei Shi, Xiaojing Zhang, Ying Cheng, for the CAPSTONE-1 Study Group*

Summary
Background Extensive-stage small-cell lung cancer (ES-SCLC) is associated with poor prognosis and treatment options Lancet Oncol 2022
are scarce. Immunotherapy has shown robust clinical activity in ES-SCLC in previous phase 3 trials. We aimed to Published Online
assess the efficacy and safety of adebrelimab (SHR-1316), a novel anti-PD-L1 antibody, with standard chemotherapy as May 13, 2022
https://doi.org/10.1016/
a first-line treatment for ES-SCLC.
S1470-2045(22)00224-8
See Online/Comment
Methods The CAPSTONE-1 study was a randomised, double-blind, placebo-controlled, phase 3 trial, done in 47 tertiary https://doi.org/10.1016/
hospitals in China. Key inclusion criteria were patients aged 18–75 years, with previously untreated histologically or S1470-2045(22)00288-1
cytologically confirmed ES-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. For a Chinese translation of the
Eligible patients were randomly assigned (1:1) to receive four to six cycles of carboplatin (area under the curve of summary see Online for
5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m² of body-surface area, on days 1–3 of each cycle) with appendix 1

either adebrelimab (20 mg/kg, day 1 of each cycle) or matching placebo, followed by maintenance therapy with *Investigators are listed in the
appendix 2 (p 4)
adebrelimab or placebo. All treatments were given intravenously in 21-day cycles. Randomisation was done using a
Department of Medical
centralised interactive web response system with a block size of four, stratified by liver metastases, brain metastases,
Oncology, National Cancer
and lactate dehydrogenase concentration. The primary endpoint was overall survival in patients who received at least Center, National Clinical
one dose of study medication. Safety was analysed in the as-treated population. This study is complete and registered Research Center for Cancer,
with ClinicalTrials.gov, NCT03711305. Cancer Hospital, Chinese
Academy of Medical Sciences &
Peking Union Medical College,
Findings Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were enrolled and randomly assigned: Beijing, China (Prof J Wang MD);
230 (50%) patients received adebrelimab plus chemotherapy (adebrelimab group) and 232 (50%) patients received Department of Medical
placebo plus chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was 13·5 months Oncology, Shanghai Pulmonary
Hospital, Shanghai, China
(IQR 8·9–20·1). Median overall survival was significantly improved in the adebrelimab group (median 15·3 months (Prof C Zhou MD); Department
[95% CI 13·2–17·5]) compared with the placebo group (12·8 months [11·3–13·7]; hazard ratio 0·72 [95% CI of Thoracic Oncology, Sichuan
0·58–0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4 adverse events were decreased Cancer Hospital & Institute,
neutrophil count (174 [76%] patients in the adebrelimab group and 175 [75%] patients in the placebo group), decreased Chengdu, China
(Prof W Yao PhD); Department
white blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%] and 78 [34%]), and anaemia of Internal Medicine, Henan
(64 [28%] and 66 [28%]). Treatment-related serious adverse events occurred in 89 (39%) patients in the adebrelimab Cancer Hospital, Affiliated
group and 66 (28%) patients in the placebo group. Four treatment-related deaths were reported: two each in the Cancer Hospital of Zhengzhou
adebrelimab group (respiratory failure and interstitial lung disease and pneumonia) and placebo group (multiple University, Zhengzhou, China
(Prof Q Wang, MD); Department
organ dysfunction and unknown cause of death). of Tumor Radiotherapy, Anhui
Chest Hospital, Hefei, China
Interpretation Adding adebrelimab to chemotherapy significantly improved overall survival with an acceptable safety (X Min BS); Department of
profile in patients with ES-SCLC, supporting this combination as a new first-line treatment option for this population. Respiratory Medicine, Harbin
Medical University Cancer
Hospital, Harbin, China
Funding Jiangsu Hengrui Pharmaceuticals. (Prof G Chen, MD); Department
of Respiratory Medicine,
Northern Jiangsu People’s
Copyright © 2022 Elsevier Ltd. All rights reserved.
Hospital, Yangzhou, China
(Prof X Xu MD); Department of
Introduction patients first diagnosed at the extensive stage.4 Despite Medical Oncology, The First
Globally, lung cancer is the leading cause of cancer death the substantial efforts into the development of new Affiliated Hospital of
Zhengzhou University,
and the second most diagnosed cancer.1 Small-cell lung treatment regimens, for decades platinum-based (with
Zhengzhou, China
cancer (SCLC), which accounts for about 15% of all lung etoposide or irinotecan) chemotherapy remained the (Prof Xin Li MD); Department of
cancers, is an aggressive neuroendo­crine malignancy.2,3 standard first-line treatment for extensive stage SCLC Respiratory Medicine, The First
SCLC is characterised by rapid growth and early (ES-SCLC), which provides a median overall survival of Affiliated Hospital of
Nanchang
occurrence of metastases, with approximately 70% of 9–11 months.5

www.thelancet.com/oncology Published online May 13, 2022 https://doi.org/10.1016/S1470-2045(22)00224-8 1

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University, Nanchang, China
(Prof F Xu MD); Department of
Medical Oncology,
Sir Run Run Shaw Hospital
Zhejiang University School of
Medicine, Hangzhou, China
(Prof Y Fang MD); Department
of Internal Medicine, Yunnan
Cancer Hospital, Kunming,
China (Prof R Yang MM);
Department of Medical
Oncology, Weifang People’s
Hospital, Weifang, China
(Prof G Yu BS); Department of
Thoracic Oncology, West China
Hospital, Sichuan University,
Chengdu, China
(Prof Y Gong PhD); Department
of Thoracic Oncology, Beijing
Cancer Hospital, Beijing, China
(Prof J Zhao MD); Department
of Thoracic Oncology, Zhejiang
Cancer Hospital, Hangzhou,
China (Prof Y Fan MD);
Department of Oncology,
Affiliated Hospital of Jiangnan
University, Wuxi, China
(Prof Q Liu MD); Department of
Respiratory Medicine,
Affiliated Hospital of
University of Science and
Technology of China, Anhui
Provincial Hospital, Hefei,
China (Prof L Cao MD);
Department of Oncology,
The First Affiliated Hospital of
Xi’an Jiaotong University,
Xi’an, China (Prof Y Yao MD);
Department of Oncology,
The First Hospital of China
Medical University, Shenyang,
China (Prof Y Liu MD);
Department of Thoracic
Surgery, Liaoning Cancer
Hospital & Institute, Shenyang,
China (Prof Xia Li MD);
Department of Oncology,
The First Affiliated Hospital of
Xiamen University, Xiamen,
China (Prof J Wu MD);
Department of Thoracic
Medical Oncology, Fujian
Medical University Cancer
Hospital/Fujian Cancer
Hospital, Fuzhou, China
(Prof Z He MM); Department of
Oncology, Jiangsu Province
Hospital, Nanjing, China
(Prof K Lu MD); Department of
Pulmonary Medicine, Shanghai
Chest Hospital, Shanghai,
China (Prof L Jiang PhD);
Department of Respiratory
Medicine, Xiangya Hospital of
Central South University,
Changsha, China
(Prof C Hu PhD); Department of
Respiratory Oncology, Guangxi
Medical University Affiliated
Tumour Hospital, Nanning,
China (W Zhao MD); Jiangsu
2 www.thelancet.com/oncology Published online May 13, 2022 https://doi.org/10.1016/S1470-2045(22)00224-8
Research in context
Evidence before this study
We searched PubMed and abstracts from major international
oncology and lung cancer congresses, including the American
Society of Clinical Oncology Annual Meetings, the European
Society for Medical Oncology Congress, the World Conference
on Lung Cancer, the European Lung Cancer Congress, and the
American Association for Cancer Research Annual Meeting
using the search terms “small-cell lung cancer” OR “SCLC” AND
“extensive-stage” OR “extensive-disease” AND
“immunotherapy” OR “PD-1” OR “PD-L1” for phase 3 clinical
trials published in English between Jan 1, 2016,
and Jan 1, 2022. We identified three phase 3 studies assessing
the combination of PD-1 or PD-L1 blockade and chemotherapy
in first-line treatment of extensive-stage small-cell lung cancer
(ES-SCLC): the IMpower133 trial, a study of atezolizumab plus
carboplatin and etoposide; the CASPIAN trial, a study of
durvalumab (with or without tremelimumab) plus platinum
and etoposide; and the KEYNOTE-604 trial, a study of
pembrolizumab plus platinum and etoposide. Significant
improvement in overall survival was observed in the
Because of the promising efficacy of PD-1–PD-L1
blockade in other tumour types and the high frequency
of somatic mutations found in SCLC, which favours
the development of immunogenic tumour clones
and the elicitation of adaptive immune response,6,7
immune-checkpoint inhibitors targeting the PD-1–PD-L1
path­way have been investigated in SCLC. Two phase 3
trials evaluated the PD-L1 inhibitors atezolizumab
(IMpower133)8,9 and durvalumab (CASPIAN)10,11 and a
third evaluated the PD-1 inhibitor pembrolizumab
(KEYNOTE-604)12 in combination with chemotherapy as
a first-line treatment for ES-SCLC, and showed different
efficacy outcomes. Only the addition of atezolizumab or
durvalumab to chemotherapy resulted in significantly
improved overall survival. These combinations were
subsequently approved as new first-line therapeutic
options and changed the treatment framework for
ES-SCLC.
Adebrelimab (SHR-1316) is a novel humanised IgG4
monoclonal antibody against PD-L1 (appendix 2 p 3). In a
phase 1 trial in patients with solid advanced tumours,
adebrelimab showed preliminary antitumour activity and
acceptable safety, with no dose limiting toxicity reported
up to a dose of 20 mg/kg every 3 weeks; in addition,
dose-proportional exposure was observed at the dose
range of 3–20 mg/kg, every 3 weeks (NCT03474289;
Xichun Hu, Fudan University Shanghai Cancer Center,
Shanghai, China; unpublished data; data on file with
Jiangsu Hengrui Pharmaceuticals, Shanghai, China). In
a phase 2 trial of oesophageal squamous cell cancer, the
clinical efficacy and tolerability of adebrelimab was
shown in combination with chemotherapy.13 In this
phase 3 trial, we aimed to evaluate the efficacy and safety
IMpower133 and CASPIAN trials, but not in the KEYNOTE-604
trial with the addition of a PD-1 or PD-L1 inhibitor to
chemotherapy.
Added value of this study
In the phase 3 CAPSTONE-1 trial, the combination of
adebrelimab, a novel and potent humanised IgG4 anti-PD-L1
monoclonal antibody, and carboplatin and etoposide led to a
significant improvement in overall survival by 2·5 months
compared with placebo plus chemotherapy in untreated
patients with ES-SCLC. The survival benefits with adebrelimab
persisted despite a high rate of patients receiving a subsequent
therapy, particularly in the chemotherapy control group.
Implications of all the available evidence
Our study, together with previous studies, provide strong
evidence for PD-L1 inhibitor plus chemotherapy as a standard
first-line treatment for ES-SCLC. With the expansion of
treatment options, physicians and patients could have the
flexibility to select treatment regimen based on efficacy, safety,
and accessibility in clinical practice.
of adebrelimab versus placebo in combination with
carboplatin and etoposide as a first-line treatment for
ES-SCLC.
Methods
Study design and participants
The CAPSTONE-1 study was a multicentre, randomised,
double-blind, placebo-controlled, phase 3 trial done in
47 tertiary hospitals in China (appendix 2 p 4). Eligible
patients were 18–75 years old with histologically or
cytologically confirmed ES-SCLC per Veterans Admin­
istration Lung Study Group staging system; had no
previous systemic treatment for ES-SCLC; had an Eastern
Cooperative Oncology Group (ECOG) performance
status score of 0 or 1; had measurable disease per
Response Evaluation Criteria in Solid Tumours (RECIST;
version 1.1); had a life expectancy of at least 3 months;
and had adequate haematological (white blood cell count
of ≥3  × 
10⁹ per L, absolute neutrophil count of
≥1·5 × 10⁹ per L, platelets of ≥100 × 10⁹ per L, haemoglobin
of ≥9·0 g per dL, and no blood transfusion or correction
with haemato­poietic stimulating factors within 14 days),
hepatic (aspartate amino­ transferase and alanine
aminotransferase ≤2·5 times the upper limit of normal
[ULN] in patients without liver metastasis and ≤5 times
the ULN in those with liver metastasis; serum total
bilirubin ≤1·5 times the ULN), renal (serum creatinine
≤1·5 times the ULN or serum creatinine clearance as
assessed by Cockcroft-Gault of ≥50 mL per min), and
coagulation (activated partial thromboplastin time and
international normalised ratio ≤1·5 times the ULN)
function. Patients with brain metastases were eligible if
they were asymptomatic, had disease limited to the

supratentorial region and cerebellum, had no evidence of
CNS progression after stereotactic treatment or whole
brain radiotherapy (treatment completed at least 14 days
before the first dose of study medication), and were
stable off steroids. Key exclusion criteria included active
or previous autoimmune disorders, active serious
infections, corticosteroid use within 14 days before the
first study dose, and previous treatment with a T cell
costimulation inhibitor or immune checkpoint inhibitor.
The full eligibility criteria are listed in the protocol in
appendix 2.
The trial was done in compliance with Good Clinical
Practice guidelines and the Declaration of Helsinki. The
trial protocol and all amendments were approved by the
independent review boards or ethics committees at each
participating site. All patients provided written, informed
consent before enrolment.
Randomisation and masking
Patients were randomly assigned (1:1) to receive
adebrelimab plus chemotherapy (adebrelimab group) or
placebo plus chemotherapy (placebo group) by a
centralised interactive web-response system with a block
size of four. Random assignment was stratified by the
presence of liver metastases (yes vs no), brain metastases
(yes vs no), and lactate dehydrogenase concentration
(normal vs elevated) at baseline according to local
reference values. An investigator at each site registered
patients via the web response system and assigned them
according to the randomisation sequences generated by
an independent third-party. All patients, investigators,
study site personnel, and the sponsor were masked to
treatment assignment. Masking was ensured by using
identical packaging for adebrelimab and placebo.
Procedures
All treatment was administered intravenously in 21-day
cycles. Patients were given four to six cycles of carboplatin
(area under the curve of 5 mg/mL per min on day 1 of
each cycle) and etoposide (100 mg/m² of body-surface
area on days 1–3 of each cycle) with either adebrelimab
(20 mg/kg on day 1 of each cycle) or matching placebo,
followed by maintenance therapy with adebrelimab
(20 mg/kg) or placebo, respectively. The dose of
adebrelimab was based on the phase 1 trial of adebrelimab
in patients with advanced solid tumours (unpublished
data; appendix 2 p 2). We used a placebo plus chemo­
therapy control group because at the time of study
design, chemotherapy was the standard first-line treat­
ment for ES-SCLC in China (atezolizumab with chemo­
therapy was approved in February, 2020).
During the maintenance phase, patients were allowed to
receive prophylactic cranial irradiation as per local
standard practice, but not thoracic radiotherapy. Treat­
ment continued until disease progression, unacceptable
toxicity, patient withdrawal, investigator decision, or up to
2 years of treatment with adebrelimab or placebo. In the
www.thelancet.com/oncology Published online May 13, 2022 https://doi.org/10.1016/S1470-2045(22)00224-8 3
Articles
absence of intolerable toxicity or cancer-related clinical Hengrui Pharmaceuticals,
deterioration, patients could continue to receive Shanghai, China (B Zhang Ms,
W Shi MD, X Zhang MD);
adebrelimab or placebo beyond RECIST-defined pro­ Department of Thoracic
gression at the investigator’s discretion. Because there is Oncology, Jilin Cancer Hospital,
no proven effective second-line immunotherapy for Changchun, China
ES-SCLC,14 as detailed in the protocol, patients allocated to (Prof Y Cheng, MD)
placebo plus chemotherapy were not allowed to crossover Correspondence to:
Prof Ying Cheng, Department of
to receive adebrelimab after disease progression. Dose Thoracic Oncology, Jilin Cancer
reduction was permitted for carboplatin and etoposide, Hospital, Changchun 130012,
but not for adebrelimab or placebo. The details on dose China
modifications are reported in the protocol (appendix 2). jl.cheng@163.com
Tumour imaging (using CT or MRI) was done at See Online for appendix 2
baseline, every 6 weeks until week 48, and then every
9 weeks until disease progression. Response was
assessed by the investigators and blinded independent
central review (BICR) in accordance with RECIST
version 1.1. Complete and partial response had to be
confirmed with a subsequent scan at least 4 weeks after
the initial documentation. Overall survival was assessed
every 30 days during follow-up. Safety was monitored
with adverse events and laboratory examinations from
the time of informed consent to 90 days after the last
administration of study medication. Electrocardiograms,
haematological examination, and liver and renal function
tests were done on day 1 of each cycle; coagulation and
thyroid function tests were done on day 1 of every other
cycle. Data on immune-mediated adverse events were
also collected as prespecified in the protocol (appendix 2).
Adverse events were graded by the investigators
according to National Cancer Institute Common
Terminology Criteria for Adverse Events (version 5.0).
PD-L1 expression was centrally measured in formalin
fixed, paraffin-embedded tumour tissue using a PD-L1
immunohistochemistry kit (clone, E1L3N; Xiawei
Biotechnology, Shanghai, China) and determined as the
proportion of viable tumour cells showing membrane
staining of any intensity (tumour proportion score).
Outcomes
The primary endpoint was overall survival, defined as
time from randomisation to death from any cause.
Secondary endpoints were progression-free survival
(time from randomisation to RECIST-defined disease
progression or death, whichever occurred first), objective
response rate (proportion of patients with confirmed
complete or partial response), duration of response (time
from first complete or partial response to first disease
progression or death), disease control rate (proportion of
patients with complete or partial disease or stable disease
lasting for at least 4 weeks), progression-free survival at
6 months and 12 months (all as assessed by the BICR
and investigator), overall survival at 12 months and
24 months, and safety.
Statistical analysis
Assumptions for sample size calculation included a
median overall survival of 9 months for the placebo
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659 patients assessed for eligibility

Adebrelimab group Placebo group
(n=230) (n=232)
Age, years
197 ineligible Median (IQR) 62 (55–66) 62 (56–67)
162 did not meet eligibility criteria
32 withdrew consent <65 155 (67%) 147 (63%)
3 investigator decision ≥65 75 (33%) 85 (37%)
Sex

462 randomly assigned Male 184 (80%) 188 (81%)

Female 46 (20%) 44 (19%)
ECOG performance status
0 33 (14%) 30 (13%)
230 assigned to adebrelimab plus chemotherapy 232 assigned to placebo plus chemotherapy 1 197 (86%) 202 (87%)
Smoking history
213 discontinued treatment 229 discontinued treatment Never smoked 50 (22%) 53 (23%)
158 radiographic progression 180 radiographic progression Former smoker 180 (78%) 178 (77%)
19 withdrew consent* 22 withdrew consent*
11 died 7 adverse events Current smoker 0 1 (<1%)
8 maximum treatment duration 7 investigator decision Disease stage
for adebrelimab reached without 5 clinical progression
radiographic progression† 4 died III 8 (3%) 6 (3%)
7 investigator decision 2 maximum treatment duration IV 222 (97%) 226 (97%)
6 adverse events for placebo reached without
Lactate dehydrogenase at enrolment
4 clinical progression radiographic progression†
1 protocol deviation ≤ULN 116 (50%) 115 (50%)
1 patient decision‡ >ULN 114 (50%) 117 (50%)
Brain metastases
17 treatment ongoing 3 treatment ongoing Yes* 5 (2%) 5 (2%)
No 225 (98%) 227 (98%)
Liver metastases
230 included in the full analysis and safety sets 232 included in the full analysis and safety sets
Yes 73 (32%) 74 (32%)
No 157 (68%) 158 (68%)
Figure 1: Trial profile
PD-L1 tumour proportion score
*Five (2%) patients in the adebrelimab group and seven (3%) patients in the placebo group withdrew due to
the COVID-19 pandemic. †The maximum duration of treatment allowed for adebrelimab or placebo was 2 years <1% 196 (85%) 200 (86%)
per protocol. ‡Started new antitumour treatment at local hospital without confirmed evidence of ≥1% 24 (10%) 20 (9%)
radiographical progression. Not evaluable 10 (4%) 12 (5%)

group, a hazard ratio (HR) of 0·70 for overall survival, a
randomisation ratio of 1:1, an accrual period of 16 months,
a follow-up period of 20 months, and a dropout rate of 5%
per year. The trial planned to enrol 430 patients to obtain
332 overall survival events, which would provide
89% power (using EAST [version 6.5]) to detect the
superiority of adebrelimab over placebo at an overall one-
sided α level of 0·025.
The initial sample size planned was 396 patients with
280 overall survival events. However, on the basis of
survival outcomes in contemporary clinical trials
published during the study,8,10 the sample size was
increased to 430 patients with 332 overall survival events
to increase the power of the overall survival analysis. The
sample size increase was based on the external study
outcome while this double-blind trial was ongoing, and it
was approved by the China Center for Drug Evaluation
(protocol amendment on Oct 17, 2019).
An interim analysis for overall survival was planned
when approximately 258 (77·7%) of the 332 expected
deaths had occurred. The final analysis was planned
when 332 deaths had occurred; the corresponding one-
sided α level was calculated using the Lan-Demets
Data are n (%) or median (IQR). ECOG=Eastern Cooperative Oncology Group.
ULN=upper normal limit. *In each group, three (60%) of five patients with brain
metastases received radiotherapy and two (40%) received surgery at diagnosis.
Table 1: Baseline characteristics
α spending function approximating O’Brien-Fleming
boundary. At the time of actual interim analysis (data
cutoff March 31, 2021), 277 (83·4%) of total expected
deaths were observed (significance level, one-sided
p≤0·01413). At the interim analysis, the HR for death was
0·77 (95% CI 0·61–0·97; one-sided p=0·0144) for the
adebrelimab group versus the placebo group and the
predefined superiority boundary was not met. On
the basis of these results, the independent data
monitoring committee recommended continuation of
the trial in a double-blind manner. As of Oct 8, 2021,
336 deaths occurred and the final analysis for overall
survival was done; the nominal significance level (one-
sided) for the analysis was 0·0207. We report findings
from the final analysis in this Article.
Efficacy was analysed in the full analysis set, which
included all randomly assigned patients who received at
least one dose of study medication. Safety was analysed in

4 www.thelancet.com/oncology Published online May 13, 2022 https://doi.org/10.1016/S1470-2045(22)00224-8

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the as-treated population. Overall survival, progression- A

free survival, and duration of response was estimated Median overall
survival, months
using the Kaplan-Meier method, with the 95% CIs 100
calculated with the Brookmeyer-Crowley method. Between- Adebrelimab group 15·3 (95% CI 13·2–17·5)
80 Placebo group 12·8 (95% CI 11·3–13·7)
group comparison in overall survival and progression-free

Overall survival (%)

survival (per BICR and investigator) was tested using a Stratified HR 0·72 (95% CI 0·58–0·90);
60 log-rank p=0·0017
stratified log-rank test; HR and the associated 95% CIs
were calculated using a Cox proportional hazards model 40
stratified by brain or liver metastases (yes vs no; due to the
small number of patients with brain metastases, the 20

two randomisation stratification factors brain metastases

0
[yes or no] and liver metastases [yes or no] were grouped 0 4 8 12 16 20 24 28 32
into one factor) and lactate dehydrogenase concentration Time since randomisation (months)
Number at risk
(normal vs elevated) at baseline. The proportional hazards (number censored)
assumption for the Cox analysis was examined by the Adebrelimab group 230 (0) 215 (0) 180 (1) 144 (1) 101 (10) 72 (19) 37 (44) 8 (71) 1 (78)
Placebo group 232 (0) 221 (0) 185 (1) 120 (1) 70 (10) 44 (14) 21 (29) 1 (46) 0 (47)
Grambsch–Therneau test and Schoenfeld residuals. A
prespecified sensitivity analysis for overall survival using B
restricted mean survival time was also done. Overall Events/number of patients HR (95% CI)
survival and progression-free survival rates were calculated Adebrelimab Placebo
with the Kaplan-Meier method, with the 95% CIs estimated group group
using normal approxi­ mation. Prespecified subgroup Sex
analysis for overall survival and progression-free survival Male 126/184 152/188 0·72 (0.57–0.92)
(per BICR and investigator) was done using an unstratified Female 25/46 33/44 0·62 (0·37–1·05)
Cox proportional hazards model according to age, sex, Age
ECOG performance status, smoking history, lactate <65 years 101/155 116/147 0·71 (0·54–0·93)
dehydrogenase concentration, brain metastases, liver ≥65 years 50/75 69/85 0·70 (0·48–1·00)
metastases, disease stage, and PD-L1 expression. Objective ECOG performance status
response rate and disease control rate as assessed by BICR 0 21/33 22/30 0·83 (0·46–1·52)
and investigator were calculated in the full analysis set, 1 130/197 163/202 0·69 (0·55–0·87)

with the 95% CIs estimated using the Clopper–Pearson Smoking history
Current or former smoker 122/180 143/179 0·75 (0·59–0·95)
method. Patients not assessable were defined as those who
Never smoked 29/50 42/53 0·59 (0·37–0·95)
did not have a tumour response assessment after baseline.
LDH concentration at enrolment
All statistical analyses were done using SAS
≤ULN 63/116 86/115 0·59 (0·42–0·82)
(version 9.4). The trial is registered with ClinicalTrials.gov, >ULN 88/114 99/117 0·83 (0·62–1·11)
NCT03711305. Liver metastases
Yes 62/73 65/74 0·92 (0·65–1·31)
Role of the funding source No 89/157 120/158 0·61 (0·46–0·81)
The funder of the study participated in study design, data Brain metastases
collection, data analysis, data interpretation, and writing No 146/225 181/227 0·68 (0·55–0·85)
of the report. Disease stage
IV 146/222 179/226 0·72 (0·58–0·90)
Results PD-L1 tumour proportion score
<1% 131/196 168/200 0·66 (0·52–0·83)
Between Dec 26, 2018, and Sept 4, 2020, 659 patients were
≥1% 12/24 13/20 0·72 (0·33–1·59)
screened for inclusion, of whom 462 (70%) were eligible
Overall 151/230 185/232 0·72 (0·58–0·90)
for inclusion: 230 (50%) were randomly assigned to the
adebrelimab group and 232 (50%) were assigned to the 0·2 0·5 1·0 2·0 5·0
placebo group. All randomly assigned patients received at Favours adebrelimab Favours placebo
least one dose of study treatment and were included in the
efficacy and safety analyses (figure 1). At data cutoff Figure 2: Overall survival
(A) Kaplan-Meier curve of overall survival. Crosses denote censored patients. (B) Forest plot of subgroup analysis of
(Oct 8, 2021), median follow-up for overall survival
overall survival. Subgroups with a sample size of less than ten patients in either study group are not shown.
was 13·5 months (IQR 8·9–20·1) for all patients ECOG=Eastern Cooperative Oncology Group. HR=hazard ratio. LDH=lactate dehydrogenase. ULN=upper normal limit.
(14·4 months [8·7–21·0] in the adebrelimab group
and 12·8 months [9·0–17·3] in the placebo group) and 229 (99%) patients in the placebo group discontinued
22·5 months (IQR 18·7–25·9) for those still alive study treatment; of whom, 135 (59%) patients in the
(22·7 months [20·1–26·1] in the adebrelimab group adebrelimab group and 162 (70%) patients in the placebo
and 22·3 months [16·9–25·5] in the placebo group). group received at least one subsequent systemic anticancer
213 (93%) patients in the adebrelimab group and therapy (appendix 2 pp 5–6). 55 (24%) patients in the

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Baseline characteristics are reported in table 1. Overall,

A
100 Median progression-
median age was 62 years (IQR 56–66), and most patients
free survival, months were men (372 [81%] of 462), former smokers (358 [77%]),
Progression-free survival (%)

80
Adebrelimab group 5·8 (95% CI 5·6–6·9)
with an ECOG score of one (399 [86%]), and had stage IV
Placebo group 5·6 (95% CI 5·5–5·7) disease (448 [97%]). 147 (32%) patients had liver
60 metastases, 231 (50%) had increased lactate dehydro­
Stratified HR 0·67 (95% CI 0·54-0·83);
log-rank p<0·0001 genase concentration, and 396 (86%) had a PD-L1 tumour
40
proportion score of less than 1%.
20 At data cutoff, 151 (66%) of 230 patients in the
adebrelimab group and 185 (80%) of 232 patients in the
0 placebo group had died. Median overall survival was
0 4 8 12 16 20 24 28 32
significantly longer in the adebrelimab group
Time since randomisation (months)
Number at risk (15·3 months [95% CI 13·2–17·5]) than in the placebo
(number censored)
Adebrelimab group 230 (0) 175 (18) 67 (24) 37 (27) 30 (31) 21 (37) 11 (45) 1 (54) 0 (55)
group (12·8 months [11·3–13·7]; HR 0·72 [95% CI
Placebo group 232 (0) 174 (19) 34 (31) 9 (35) 6 (37) 3 (39) 2 (39) 0 (41) ·· 0·58–0·90]; one-sided p=0·0017; figure 2A); the overall
survival rates were 62·9% (95% CI 56·3–68·8) in the
B adebrelimab group versus 52·0% (45·4–58·2) in the
Events/number of patients HR (95% CI)
placebo group at 12 months and 31·3% (24·9–37·9) in
Adebrelimab Placebo
group group
the adebrelimab group versus 17·2% (12·1–23·0) in
the placebo group at 24 months (figure 2A). As the
Sex proportional hazards assumption was not met for the
Male 143/184 156/188 0·72 (0·57–0·90)
analysis of overall survival (appendix 2 p 12), a restricted
Female 32/46 35/44 0·55 (0·33–0·90)
mean survival time analysis was done. With a cutoff at
Age
28·6 months (the minimum of the longest follow-up
<65 years 119/155 121/147 0·70 (0·54–0·91)
≥65 years 56/75 70/85 0·62 (0·43–0·89)
time for a patient in either group), the restricted mean
ECOG performance status
survival time was 16·8 months (95% CI 15·6–18·0) in the
0 23/33 24/30 0·62 (0·35–1·10) adebrelimab group and 14·5 months (13·5–15·5)
1 152/197 167/202 0·69 (0·56–0·87) in the placebo group. Overall survival results across
Smoking history predefined subgroups are shown in figure 2B.
Current or former smoker 137/180 149/179 0·76 (0·60–0·96) According to the assessment of progression-free
Never smoked 38/50 42/53 0·44 (0·27–0·71) survival according to BICR, 175 (76%) of 230 patients in
LDH concentration at enrolment the adebrelimab group and 191 (82%) of 232 patients in
≤ULN 83/116 91/115 0·70 (0·52–0·95) the placebo group had disease progression or died. The
<ULN 92/114 100/117 0·64 (0·48–0·85) progression-free survival rate was 49·4% (95% CI
Liver metastases
42·4–56·0) in the adebrelimab group versus 37·3%
Yes 60/73 61/74 0·74 (0·51–1·07)
(30·7–43·9) in the placebo group at 6 months and 19·7%
No 115/157 130/158 0·64 (0·50–0·83)
(14·5–25·5) versus 5·9% (3·1–10·1) at 12 months
Brain metastases
No 171/225 188/227 0·65 (0·53–0·81)
(figure 3A). Analyses of progression-free survival by the
Disease stage
investigators were similar to the findings of the BICR
IV 168/222 187/226 0·68 (0·55–0·83) assessment (appendix 2 p 13). Progression-free survival
PD-L1 tumor proportion score across predefined subgroups is shown in figure 3B.
<1% 150/196 169/200 0·68 (0·54–0·85) 162 (70·4%; 95% CI 64·1–76·3) of 230 patients in the
≥1% 17/24 14/20 0·70 (0·34–1·45) adebrelimab group and 153 (65·9%; 59·5–72·0) of
Overall 175/230 191/232 0·67 (0·54–0·83) 232 patients in the placebo group had confirmed objective
0·2 0·5 1·0 2·0 5·0
response according to BICR (appendix 2 p 7). Of the
responders, median duration of response was 5·6 months
Favours adebrelimab Favours placebo
(95% CI 4·6–6·7) in the adebrelimab group versus
Figure 3: Progression-free survival as assessed by the blinded independent central review 4·6 months (4·3–5·5) in the placebo group. 32 (20%) of
(A) Kaplan-Meier curve of progression-free survival. Crosses denote censored patients. (B) Forest plot of subgroup 162 patients in the adebrelimab group and six (4%) of
analysis of progression-free survival. Subgroups with a sample size of less than ten patients in either group are not 153 patients in the placebo group had an ongoing
shown. ECOG=Eastern Cooperative Oncology Group. HR=hazard ratio. LDH=lactate dehydrogenase. ULN=upper
normal limit.
response at 12 months. Results of tumour response
according to investigator assessment are reported in the
adebrelimab group and 70 (30%) patients in the placebo appendix 2 (p 7). Disease control rate per BICR and
group received anti­angiogenic drugs. Four (2%) patients investigator are also shown in the appendix 2 (p 7).
in the adebrelimab group and two (1%) patients in the Median duration of treatment was 27·4 weeks
placebo group received prophylactic cranial irradiation (IQR 18·1–41·1) in the adebrelimab group and 25·2 weeks
during the study (total dose range 20–30 Gy). (18·8–33·5) in the placebo group; the median cycle

6 www.thelancet.com/oncology Published online May 13, 2022 https://doi.org/10.1016/S1470-2045(22)00224-8

 Articles

Adebrelimab group (n=230) Placebo group (n=232)

Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
Any treatment-related adverse event 32 (14%) 85 (37%) 110 (48%) 2 (1%) 32 (14%) 110 (47%) 85 (37%) 2 (1%)
Neutrophil count decreased 44 (19%) 82 (36%) 92 (40%) 0 45 (19%) 103 (44%) 72 (31%) 0
White blood cell count decreased 111 (48%) 99 (43%) 7 (3%) 0 127 (55%) 78 (34%) 10 (4%) 0
Platelet count decreased 103 (45%) 65 (28%) 23 (10%) 0 113 (49%) 56 (24%) 22 (9%) 0
Alanine aminotransferase increased 90 (39%) 5 (2%) 0 0 69 (30%) 4 (2%) 0 0
Aspartate aminotransferase increased 78 (34%) 2 (1%) 1 (<1%) 0 56 (24%) 4 (2%) 0 0
γ-glutamyltransferase increased 24 (10%) 4 (2%) 0 0 22 (9%) 1 (<1%) 0 0
Anaemia 131 (57%) 63 (27%) 1 (<1%) 0 141 (61%) 66 (28%) 0 0
Nausea 90 (39%) 2 (1%) 0 0 107 (46%) 0 0 0
Vomiting 58 (25%) 2 (1%) 0 0 53 (23%) 1 (<1%) 0 0
Constipation 40 (17%) 0 0 0 42 (18%) 0 0 0
Alopecia 102 (44%) 0 0 0 98 (42%) 0 0 0
Decreased appetite 63 (27%) 5 (2%) 0 0 60 (26%) 2 (1%) 0 0
Hypoalbuminaemia 26 (11%) 0 0 0 24 (10%) 0 0 0
Asthenia 41 (18%) 1 (<1%) 0 0 44 (19%) 1 (<1%) 0 0
Hypothyroidism 28 (12%) 0 0 0 21 (9%) 0 0 0
Hyponatraemia 13 (6%) 3 (1%) 2 (1%) 0 8 (3%) 4 (2%) 2 (1%) 0
Hypertension 6 (3%) 6 (3%) 0 0 2 (1%) 2 (1%) 0 0
Hypokalaemia 6 (3%) 2 (1%) 2 (1%) 0 11 (5%) 0 0 0
Pneumonia 7 (3%) 3 (1%) 0 0 2 (1%) 1 (<1%) 0 0
Lymphocyte count decreased 4 (2%) 3 (1%) 2 (1%) 0 4 (2%) 1 (<1%) 3 (1%) 0
Febrile neutropenia 0 3 (1%) 2 (1%) 0 0 0 2 (1%) 0
Myelosuppression 0 0 2 (1%) 0 1 (<1%) 0 3 (1%) 0

Data are n (%). Treatment-related adverse events of grade 1–2 occurring in at least 10% of patients or of grade 3–5 occurring in at least 1% of patients across both groups
are reported.

Table 2: Treatment-related adverse events

number was six (4–6) for carboplatin and etoposide in
both groups (appendix 2 p 8). Adverse events related to
any component of the trial regimen occurred in
229 (100%) patients in the adebrelimab group and
229 (99%) patients in the placebo group; grade 3 or worse
treatment-related events occurred in 197 (86%) patients
in the adebrelimab group and 197 (85%) patients in the
placebo group (table 2). The most common grade 3 or 4
treatment-related adverse events in both groups were
haematological adverse events, including decreased
neutrophil count (174 [76%] patients in the adebrelimab
group and 175 [75%] in the placebo group), decreased
white blood cell count (106 [46%] vs 88 [38%]), decreased
platelet count (88 [38%] vs 78 [34%]), and anaemia
(64 [28%] vs 66 [28%]). Treatment-related adverse events
led to discontinuation of any treatment component in
12 (5%) patients in the adebrelimab group and
nine (4%) patients in the placebo group, with decreased
platelet count being the most common reason in both
groups (three [1%] patients in the adebrelimab group and
two [1%] patients in the placebo group; appendix 2 p 9).
Treatment-related serious adverse events occurred in
89 (39%) patients in the adebrelimab group and
66 (28%) patients in the placebo group; all events with an
incidence of 2% or more (in either group) were
haematological adverse events and hepatic function test
abnormalities (appendix 2 p 10). Fatal adverse events
possibly related to study treatment were reported in
two (1%) patients in the adebrelimab group (respiratory
failure and interstitial lung disease or pneumonia) and
two (1%) patients in the placebo group (multiple organ
dysfunction and unknown cause of death).
Immune-mediated adverse events of any grade were
reported in 64 (28%) patients in the adebrelimab group
and 40 (17%) patients in the placebo group; the most
frequent events were hypothyroidism (21 [9%] patients in
the adebrelimab group and 13 [6%] in the placebo group),
and hepatic laboratory abnormalities (17 [7%] patients in
the adebrelimab group and 12 [5%] patients in the placebo
group; appendix 2 p 11). Grade 3 or worse immune-
mediated adverse events occurred in 11 (5%) patients in
the adebrelimab group and seven (3%) patients in the
placebo group; hepatic laboratory abnormalities and
pneumonitis (four [2%] patients each) occurred in 1% or
more of patients in the adebrelimab group.
Discussion
Our findings suggest that adebrelimab plus chemo­
therapy significantly improved overall survival compared
with placebo plus chemotherapy in previously untreated

www.thelancet.com/oncology Published online May 13, 2022 https://doi.org/10.1016/S1470-2045(22)00224-8 7

 Articles
patients with ES-SCLC. The addition of adebrelimab to
chemotherapy improved overall survival by 2·5 months.
Of note, overall survival rate was higher in the
adebrelimab group than the placebo group at both
12 and 24 months. Moreover, the adebrelimab group
showed reduced risk of progression or death, higher
objective response rate, and more durable response. The
safety profile of the adebrelimab and chemotherapy
combination was manageable, with a low incidence of
treatment discontinuation owing to adverse events.
To date, to our knowledge, three global, randomised,
phase 3 trials have reported the effects of a PD-1 and PD-L1
inhibitors in combination with chemotherapy as first-
line treatment for ES-SCLC. In the IMpower1338,9 and
CASPIAN10,11 trials, atezolizumab (HR 0·70 [95% CI
0·54–0·91]) or durvalumab (0·73 [0·59–0·91]) combined
with chemotherapy significantly improved overall survival
versus chemotherapy alone.8–11 In the KEYNOTE-604 trial,12
the addition of pembrolizumab to chemotherapy led to a
statistically significant benefit in progression-free survival
(HR 0·75 [0·61–0·91]), but in not overall survival (HR 0·80
[0·64–0·98]), compared with placebo plus chemotherapy.
Compared with these phase 3 trials, the proportion of male
patients, former and never smokers, and patients with an
ECOG score of one were higher in our study, whereas the
proportion of patients aged 65 years or older and brain
metastases at baseline were slightly lower. The prevalence
of never-smokers in Chinese patients with SCLC has
reportedly increased over the past decade, and the
population of patients who had never smoked (103 [22%]
of 462 patients) in our study was in accordance with recent
clinical trials and large-scale observational studies
(range 22–37%) from China.15–18 The magnitude (HR 0·72
[95% CI 0·58–0·90]) and scope (across all clinically
relevant subgroups) of benefit in overall survival with the
addition of adebrelimab to chemotherapy was generally
consistent with those reported for atezolizumab and
durvalumab. The Kaplan-Meier curves of overall survival
separated in favour of the adebrelimab group at about
9 months, with separation maintained over the evaluation
period. Of note, subsequent systemic anticancer therapy
was more frequently administered in our study compared
with the IMpower133, CASPIAN, and KEYNOTE-604
trials (treatment groups 59% vs 46–52·9%; control groups
70% vs 46–65·5%);8–12 parti­cularly, antiangiogenic therapy
(primarily anlotinib, a VEGFR inhibitor approved as a
third-line or later treatment for SCLC in China in 201915)
was received by 24% of patients in the adebrelimab group
and 30% in the placebo group. This difference might
partly account for the longer median overall survival
observed for the chemotherapy control group in our study
(12·8 months) than in other studies in the same context
(9·7–10·3 months).8–12 However, despite the less frequent
admin­istration of post-study treatment in the adebrelimab
group versus the placebo group, overall survival benefit
was sustained, supporting the clinical benefits of the
adebrelimab combination regimen.
8 www.thelancet.com/oncology Published online May 13, 2022 https://doi.org/10.1016/S1470-2045(22)00224-8
Similar to the findings of overall survival, progression-
free survival was improved in the adebrelimab group
than in the placebo group, with benefits consistently
shown across subgroups. The risk for progression or
death was 33% lower in the adebrelimab group per BICR,
similar to the reduced risk of 23% with atezolizumab,8,9
22% with durvalumab,10,11 and 25% with pembrolizumab12
for treatment of ES-SCLC in the first-line setting. In our
study, the maximum treatment exposure of adebrelimab
was restricted to 2 years, which was based on the low rate
of relapse after treatment discontinuation in patients
with other tumour types who derived durable response
and the concerns regarding immune-mediated adverse
events and financial burden for patients from prolonged
treatment.19 The Kaplan-Meier curve of progression-free
survival for the adebrelimab group appeared to be flat
after 2 years, supporting the treatment cessation strategy.
Nevertheless, the optimal treatment cessation time will
have to be investigated in larger-scale, longer-term
studies. In addition, markers for treatment interruption
could be explored, which could help avoid adverse
events from prolonged treatment and maximise the
clinical benefit.
The safety profile of the two treatment groups were
generally similar, except for a mildly increased rate of
laboratory abnormalities in the adebrelimab group. The
most common grade 3 or worse treatment-related adverse
events were haematological toxicities in both groups, with
a frequency higher than previously reported in studies
involving other immunochemotherapy regimens.8–12,20
This finding might be attributed, in part, to the higher
susceptibility to haematological adverse events from
chemotherapy in Asian patients21 and the higher exposure
to chemotherapy in the immunochemotherapy group in
our study (median six cycles) than in other studies of
SCLC (median four cycles). These haematological adverse
events were effectively managed with standard supportive
care and rarely led to treatment discontinuation. Immune-
mediated adverse events with adebrelimab plus chemo­
therapy were mostly of grade 1–2 severity and the
spectrum was in line with other combinations of PD-L1
inhibitor and chemotherapy.8–11 Two deaths were deemed
possibly related to the adebrelimab combination; these
patients either had disease progression and started new
anticancer treatment (patient with respiratory failure) or
had respiratory conditions at baseline (patient with
interstitial lung disease and pneumonia).
The main limitation of the study was that all patients
were enrolled from China. The efficacy and safety profile
with adebrelimab plus chemotherapy in patients of
other ethnicities remain to be confirmed. Additionally,
the recruitment rate of patients with brain metastases at
diagnosis was low (2%). The prevalence of brain meta­
stases at enrolment ranged from 9% to 12% in the
IMpower133, CASPIAN, and KEYNOTE-604 trials.8–12
Generally, these studies showed that patients with brain
metastases was an under-represented population in

clinical trials and investigations are needed (possibly in a
real-world setting). Moreover, only PD-L1 expression was
assessed as a biomarker. Consistent with previous trials
of PD-L1 inhibitor plus chemotherapy as first-line
therapy in ES-SCLC, PD-L1 expression did not appear to
be a predictive biomarker for treatment outcome in our
study. Given the clear long-term clinical benefits
observed with adebrelimab plus chemotherapy in a
subset of patients with ES-SCLC, additional studies are
warranted to explore potential biomarkers for survival
and durable response. Finally, the Cox proportional
hazards assumption was not met for survival analysis.
The restricted mean survival time analysis confirmed
the overall survival benefit with adebrelimab plus
chemotherapy.
In conclusion, the final analysis of this phase 3 trial
showed that adebrelimab combined with carboplatin and
etoposide significantly improved overall survival in
patients with ES-SCLC. These findings, along with an
acceptable safety profile, support adebrelimab plus
chemo­therapy as a new first-line treatment option for
ES-SCLC. With the expansion of treatment options,
physicians and patients are offered the flexibility to select
treatment regimen based on efficacy, safety, and
accessibility in clinical practice.
Contributors
YC and JW conceived and designed this study. YC, JW, CZ, WY, QW,
XM, GC, XX, XinL, FX, YoF, RY, GY, YG, JZ, YuF, QL, LC, YY, YL, XiaL,
JW, ZH, KL, LJ, CH, and WZ enrolled patients and collected the data.
BZ was responsible for statistical analysis, and all authors participated in
data interpretation. The manuscript was drafted by YC and JW and was
reviewed and revised by all authors. YC, JW, BZ, and WS had access to
and verified the data. All authors had full access to all the data in the
manuscript and approved the decision to submit for publication.
Declaration of interests
CZ reports honoraria as a speaker from Roche, Lily China, Boehringer
Ingelheim, Merck, Hengrui, Qilu, Sanofi, Merck Sharp & Dohme,
Innovent Biologics, C-Stone, Luye Pharma, TopAlliance Biosciences,
and Amoy Diagnositics; and advisor fees from Innovent Biologics,
Hengrui, Qilu, and TopAlliance Biosciences. BZ, WS, and XZ are
employees of Hengrui Pharmaceuticals. All other authors declare no
competing interests.
Data sharing
Individual deidentified participant data that underlie the results reported
in this Article can be requested 24 months after study completion.
Researchers should submit a proposal to the corresponding author
outlining the reasons for requiring the data. The leading clinical site and
sponsor will check whether the request is subject to any intellectual
property or confidentiality obligations. A signed data access agreement
with the sponsor is required before accessing shared data. The study
protocol and statistical analysis plan are provided in appendix 2.
Acknowledgments
This study was funded by Jiangsu Hengrui Pharmaceuticals. We are
grateful to all patients and their families and all members of the
collaborative group participating the study. We also would like to thank
Xichun Hu (Fudan University Shanghai Cancer Center), Wen Jing
(Hengrui Pharmaceuticals), and Yanyan Zhang (Hengrui
Pharmaceuticals) for reviewing content on the unpublished data from
the phase 1 trial of adebrelimab; and Ke Ma (Hengrui Pharmaceuticals)
for data verification. Medical writing support was provided by Xiuzhi Wu
(Hengrui Pharmaceuticals) according to Good Publication Practice
Guidelines.
www.thelancet.com/oncology Published online May 13, 2022 https://doi.org/10.1016/S1470-2045(22)00224-8 9
Articles
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