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ORIGINAL ARTICLE
Phase 1b Study of Sintilimab Plus Anlotinib as
First-line Therapy in Patients With Advanced
NSCLC
Tianqing Chu, MD,
a
Runbo Zhong, MD,
a
Hua Zhong, MD,
a
Bo Zhang, MD,
a
Wei Zhang, MD,
a
Chunlei Shi, MD,
a
Jialin Qian, MD,
a
Yanwei Zhang, MD,
a
Qing Chang, MD,
a
Xueyan Zhang, MD,
a
Yu Dong, MD,
a
Jiajun Teng, MD,
a
Zhiqiang Gao, MD,
a
Huiping Qiang,
a
Wei Nie, MD,
a
Yiming Zhao, PhD,
a
Yuchen Han, PhD,
b
Ya Chen,
a
Baohui Han, MD
a,
*
a
Respiratory Department, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China
b
Pathology Department, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China
Received 20 October 2020; revised 15 November 2020; accepted 20 November 2020
Available online - 29 January 2021
ABSTRACT
Introduction: Although the interaction between tumor
immune microenvironment and angiogenesis has been well
established, evidence supporting the chemo-free combina-
tion of immune checkpoint inhibitors plus antiangiogenic
tyrosine kinase inhibitors in treatment-naive patients with
advanced NSCLC is insufficient. This report provides the
efficacy and safety of sintilimab combined with anlotinib as
first-line therapy for advanced NSCLC from a phase 1b trial
(NCT03628521).
Methods: Eligible patients who were treatment-naive and
had unresectable stage IIIB/C or IV NSCLC without EGFR/
ALK/ROS1 mutations received sintilimab (200 mg, day 1)
and anlotinib (12 mg, day 1–14) every 3 weeks till disease
progression or unacceptable toxicity. Baseline programmed
death-ligand 1 expression and tumor mutation burden
status was assessed in all patients. The primary end points
were objective response rate and safety.
Results: A total of 22 patients received sintilimab and
anlotinib. Median follow-up was 15.8 months (range: 8.3–
19.3). Sixteen patients achieved confirmed partial response
with an objective response rate of 72.7% (95% confidence
interval [CI]: 49.8%–89.3%) and disease control rate of
100% (95% CI: 84.6%–100%). Median progression-free
survival was 15 months (95% CI: 8.3 m, not reached), and
the 12-month progression-free survival rate was 71.4%
(95% CI: 47.2%–86.0%). The incidence rate of grade 3 or
higher treatment-related adverse events was 54.5%, and
grade 3 hypertension was predominant (two of 22, 9.1%).
No grade 4 treatment-related adverse events were
observed, and one case of grade 5 immune-related pneu-
monitis occurred.
Conclusions: To the best of our knowledge, this is the first
study that assessed an anti–programmed cell death protein
1 antibody combined with a multitarget antiangiogenic
tyrosine kinase inhibitor in the frontline setting for patients
with NSCLC. In view of its encouraging efficacy, durability,
and safety profile, sintilimab plus anlotinib represents a
novel chemotherapy-free regimen in this patient population.
2020 Published by Elsevier Inc. on behalf of International
Association for the Study of Lung Cancer.
Keywords: Non–small cell lung cancer; First-line; Anti–PD-1;
Antiangiogenic TKIs; Chemotherapy-free
Introduction
Immune checkpoint inhibitors (ICIs) have emerged in
first- and second-line therapy for NSCLC and become a
dynamic field in which new combinations are constantly
being evaluated. Whereas antiangiogenic therapy has
exhibited the potential to directly or indirectly alleviate
immunosuppression,
1
conversely, ICIs can prompt tu-
mor vessel normalization.
2
This suggests that immuno-
therapy and antiangiogenesis may have synergistic
*Corresponding author.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Baohui Han, MD, Respiratory Department,
Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, Peo-
ple’s Republic of China. E-mail: 18930858216@163.com
ª2020 Published by Elsevier Inc. on behalf of International
Association for the Study of Lung Cancer.
ISSN: 1556-0864
https://doi.org/10.1016/j.jtho.2020.11.026
Journal of Thoracic Oncology Vol. 16 No. 4: 643-652
antitumor effects. The clinical benefits of combining ICIs
and antiangiogenic agents have been reported in a va-
riety of clinical studies of solid tumors.
3-7
In particular,
the IMpower150 trial has reported an enhanced efficacy
of atezolizumab and bevacizumab in combination with
chemotherapy in chemotherapy-naive patients, making
this regimen one of the current standard of care treat-
ments for advanced nonsquamous NSCLC.
8
Despite the
observed efficacy in the IMpower150 study, this
chemotherapy-containing four-drug regimen led to a
high incidence of grade 3 or 4 treatment-related adverse
events (TRAEs).
8
Given that severe AEs may deteriorate
treatment compliance, performance status and quality of
life, and even subsequent treatment eligibility, there is
an unmet need for a more tolerable regimen with com-
parable efficacy for patients with NSCLC. Meanwhile,
some nonchemotherapy trials have found good tolera-
bility and efficacy across multiple tumor types, which
suggest the worth of investigating ICIs plus anti-
angiogenic agents in the frontline setting for advanced
NSCLC.
3-7,9
Sintilimab is a fully-humanized immunoglobulin G4
anti–programmed cell death protein 1 (PD-1) mono-
clonal antibody with encouraging antitumor activity in
advanced NSCLC.
9-12
Anlotinib blocks tumor angiogen-
esis and proliferation by inhibiting the vascular endo-
thelial growth factor (VEGF) receptors (1/2/3) and other
major tyrosine kinase receptors, such as FGFR1-4,
PDGFR a/b, c-Kit, and FLT3.
13
In phase 3 ALTER 0303
trial, anlotinib substantially prolonged progression-free
survival (PFS) and overall survival (OS) in patients
with advanced NSCLC who failed at least second-line
therapy.
14
On the basis of such favorable results, we
conducted this phase 1b study to evaluate the efficacy
and safety of the combination of sintilimab and anlotinib
as a chemotherapy-free regimen in the first-line treat-
ment for patients with advanced NSCLC.
Materials and Methods
Design and Patients
This was a single-center, open-label, phase 1b trial
conducted in Shanghai Chest Hospital. It was a part of
the NCT03628521 trial (cohort C), which evaluated
anlotinib-based combination therapy as a first-line
treatment for advanced NSCLC. The results of each
cohort of the study will be reported separately. The
study was conducted in accordance with the Declaration
of Helsinki and Good Clinical Practice guidelines. The
study protocol was reviewed and approved by the
institutional review board and ethics committee at
Shanghai Chest Hospital. All patients provided written
informed consent before enrollment.
Eligible patients had the following inclusion criteria:
(1) 18 to 75 years of age; (2) histologically confirmed
NSCLC at the clinical stage of IIIB/IIIC (inoperable or not
suitable for definitive concurrent chemoradiotherapy) or
stage IV, as defined by American Joint Committee on
Cancer, eighth edition; (3) without EGFR/ALK/ROS1
mutations; (4) Eastern Cooperative Oncology Group
performance status score of 0 to 1; and (5) no previous
systemic therapy for advanced diseases. The main
exclusion criteria were the following: (1) SCLC
(including patients with mixed small cell and non-small
cell tumors); (2) symptomatic or had uncontrolled brain
metastases (BMs); (3) central squamous cell carcinoma
with a cavity; (4) and with active hemorrhage or at the
risk of hemorrhage.
Treatment
Sintilimab (200 mg, Innovent [Suzhou] Biopharma-
ceutical Co., Ltd.) was intravenously administered on day
1 of 3-week cycles, and anlotinib (12 mg, Chia Tai
Tianqing Pharmaceutical Group Co., Ltd.) was orally
administered once daily on day 1 to 14 per cycle. The
combination of sintilimab plus anlotinib would be
assessed for safety in 10 patients in the first cycle before
accruing the additional patients targeted for study entry.
If any of those 10 patients experienced intolerable AEs,
which were defined as grade 3 hematologic toxicity for
more than 7 days, grade 4 hematologic toxicity, or higher
than grade 3 nonhematologic toxicity, patients subse-
quently enrolled would receive a reduced dose of anlo-
tinib at 10 mg or 8 mg. Treatment continued until
disease progression, intolerance, or patients’withdrawal
of consent. No other antitumor therapy was allowed
before disease progression. Patients with intolerable AEs
that lead to delay or discontinuation of one drug
continued the treatment with the other study drug.
Biomarker Analysis
Before the treatment, the patients’tumor tissue
samples would be collected for programmed death-
ligand 1 (PD-L1) expression evaluation and tumor mu-
tation burden (TMB) assessment. PD-L1 expression was
measured by 22C3 pharmDx assay (Agilent Technolo-
gies, Carpinteria, CA), and PD-L1–positive (PD-L1
þ
) was
defined as PD-L1 tumor proportion score greater than or
equal to 1%. The TMB was measured by the Founda-
tionOne CDx assay (Foundation Medicine, Cambridge,
MA), and TMB-high (TMB-H) was defined as greater than
or equal to 10 mutations per Mb. Blood samples would
be collected at baseline, before and after the treatment
for subsequent exploratory studies, such as T-cell re-
ceptor dynamics during the treatment.
644 Chu et al Journal of Thoracic Oncology Vol. 16 No. 4
Assessment
Tumor response was assessed by investigators per
Response Evaluation Criteria in Solid Tumors 1.1 every 6
weeks (±7 d). Complete response (CR) or partial
response (PR) would be confirmed in subsequent
radiographic assessments at least 4 weeks later. Patients
with first radiologic evidence of progressive disease (PD)
would continue on treatment until disease progression
was confirmed in subsequent examinations provided
that they would benefit from continuous treatment. All
patients underwent brain magnetic resonance imaging at
baseline, and for those with BMs, the intracranial
response would be evaluated per Response Evaluation
Criteria in Solid Tumors 1.1 concurrently at scheduled
tumor assessments. All patients would be followed up
every 2 months for survival after PD.
Safety was assessed throughout the study. AEs were
graded according to the U.S. National Cancer Institute’s
Common Terminology Criteria for Adverse Events
(version 4.0) and recorded from enrollment until 90
days after the last dose of study drugs.
End Point
The primary end points were objective response rate
(ORR) (defined as the proportion of patients with CR
plus PR) and safety. The secondary end points included
disease control rate (DCR) (defined as the proportion of
patients with CR, PR, and stable disease maintained 6
wk), duration of response (DOR), PFS, and OS. DOR was
defined as the time from first documented CR or PR to
disease progression or death. PFS was defined as the
time from the first dose of either drug to investigator-
assessed radiologic PD or death from any cause and
would be censored at the time of last tumor assessment.
OS was defined as the time from patient enrollment to
death from any cause.
Statistics
Efficacy and safety were evaluated in all patients who
received at least one dose of the study drugs. The data
were analyzed by descriptive statistical analyses. Contin-
uous data were expressed as mean (±SD) or median with
an interquartile range as appropriate. Categorical data
were expressed in numbers and percentages. ORR and
DCR were calculated with corresponding two-sided 95%
confidence intervals (CIs) using the Clopper-Pearson
method. The Kaplan-Meier method was used for the
analysis of PFS and OS. All data analysis was done with
Statistical Analysis System version 9.4 software.
Results
Patient Enrollment and Baseline Characteristics
Between September 2018 and February 2019, a
total of 24 patients were enrolled. Among them, 22
received at least one dose of study treatment
(Supplementary Fig. 1) and were included in the effi-
cacy and safety analysis. Two were excluded before
the treatment owing to the lack of measurable lesions
and inadequate biopsy tissue. Patients were predomi-
nately men (95.5%) and with an Eastern Cooperative
Oncology Group performance status score of 1
(95.5%). A total of 13 patients (59.1%) had stage IV
disease, and patients at stage IIIB/IIIC were all N3
with supraclavicular lymph node metastases. A total of
12 (54.5%) had squamous cell carcinomas, nine
(40.1%) had adenocarcinomas, and one was diagnosed
as not otherwise specified. Among the 13 stage IV
patients, four had BM, and two had liver metastasis at
baseline. PD-L1 expression and TMB status were
assessed in all 22 patients. Because of tissue sample
disqualification, three were not evaluable for TMB, and
one was not assessable for neither TMB nor PD-L1.
Among the patients with evaluable biomarkers, 13
(59.1%) were PD-L1
þ
, and seven (31.8%) were TMB-
H. The detailed baseline characteristics of the partici-
pants are illustrated in Table 1. At the time of data
cutoff (April 30, 2020), the median follow-up time was
15.8 months (range: 8.3–19.3), and nine patients were
still under the study of treatment. The treatments
paused in 10 patients during the lockdown for coro-
navirus disease 2019, and the median pause time was
3 weeks (range: 2–6). All patients resumed the treat-
ment after being radiologically confirmed as progres-
sion-free.
Efficacy
Out of 22 patients, 16 achieved confirmed PR, and the
ORR was 72.7% (Table 2). DCR was 100%, and all pa-
tients achieved tumor shrinkage (Fig. 1A). The median
time to response was 1.6 months (95% CI: 1.4–2.9). The
responses were durable, with a median DOR not reached
(NR) (95% CI: 3.2–NR) (Table 2 and Fig. 1B). Objective
responses were noted in eight of nine patients (88.9%)
with adenocarcinoma and seven of 12 (58.3%) patients
with squamous cell carcinomas. Patients had a consis-
tent ORR cross the stage subgroups (stage IIIB/IIIC, six
of nine, 66.7% versus stage IV, 10 of 13, 76.9%). The
benefit of sintilimab plus anlotinib combination, in terms
of ORR, was regardless of PD-L1 expression level (PD-
L1
þ
versus PD-L1
–
, 69.2% versus 75.0%) or TMB
(TMB-H versus TMB-low, 85.7% versus 63.6%). Among
the four patients with BM, three achieved overall PR, and
the intracranial responses were all CR. Till the last follow-
up, two PR patients had sustained intracranial and sys-
temic responses. One PR patient had disease progression
at primary lesion after 6.7 months. The patient who
achieved stable disease had disease progression at both
intracranial and primary sites after 4.2 months. Till the
April 2021 Sintilimab Plus Anlotinib in First Line NSCLC 645
cutoff date, no newly developed brain metastases were
observed in patients without BM at baseline.
PFS events occurred in nine patients (40.9%), and
the 12-month PFS rate was 71.4% (95% CI: 47.2%–
86.0%). The median PFS was 15 months (95% CI: 8.3
mo–NR) (Fig. 2 and Supplementary Table 1). In sub-
group analyses, the 12-month PFS rates were similar
between the patients with squamous cell carcinoma and
those with adenocarcinoma (72.7% versus 66.7%). The
median PFS was 13 months in the squamous cell car-
cinoma subgroup, whereas it was NR in the adenocar-
cinoma subgroup. Patients at stage IIIB/IIIC had a
similar median PFS with stage IV (15 versus 14 mo). The
12-month PFS rate of patients without BM was 76.5%
(95% CI: 48.8%–90.4%), and the median PFS was 15
months. The 12-month PFS rate of patients with BM was
50.0% (95% CI: 5.78%–84.5%), whereas the median
PFS was NR (Supplementary Fig. 2 and Supplementary
Table 1). Compared with PD-L1
patients, PD-L1
þ
pa-
tients had a longer median PFS (NR versus 14 mo) and a
higher 12-month PFS rate (76.9% versus 62.5%). No
disease progression was observed in all seven TMB-H
patients until the end of the follow-up period, and the
12-months PFS rate was 60.0% for TMB-low patients.
OS data was immature owing to the limited occurrence
of death (n ¼3) at the time of data cutoff, and the
estimated 12-month OS rate was 95.5% (95% CI:
71.9%–99.3%).
Figure 1. Best overall response and drug exposure. (A) Best overall response. (B) Duration of drug exposure. BM, brain
metastases; EOT, end of treatment; NA, not applicable; PD, progressive disease; PD-L1, programmed death-ligand 1; PR,
partial response; TMB, tumor mutation burden.
646 Chu et al Journal of Thoracic Oncology Vol. 16 No. 4
Safety
The median treatment duration was 14.6 months
(range: 3.7–19.3) for combination therapy, 14.1 months
(range: 2.9–19.3) for sintilimab, and 14.0 months (range:
3.7–19.3) for anlotinib, respectively. No AEs higher than
grade 2 were observed in the first 10 patients during the
first cycle; therefore, all enrolled patients started with
anlotinib at the dose of 12 mg. Five (22.7%) patients
required a dose reduction of anlotinib (n ¼4–10 mg and
n¼1–8 mg) owing to intolerable toxicities during the
study period. One patient discontinued anlotinib (owing
to grade 3 cerebral infarction), one discontinued sintili-
mab (owing to grade 1 immune-mediated pneumonitis),
and one discontinued both drugs (owing to grade 3
rash).
TRAEs occurred in all patients, and the most common
TRAEs were hemorrhage (59.1%), hypothyroidism
(50.0%), and increased uric acid (40.9%) (Table 3).
Grade 3 TRAEs occurred in 12 patients (54.5%). Except
for two cases of hypertension (Table 3), most of the
grade 3 TRAEs occurred only once.
The most common antiangiogenetic therapy–related
AEs were hemorrhage (59.1%), hypertension (31.8%),
and proteinuria (18.2%). Among the 84.6% (11 of 13)
patients, hemorrhage events were grade 1, with three
patients experiencing transient grade 1 hemoptysis. Only
one patient with grade 2 urinary occult blood required
medication. No higher than grade 3 hemorrhage
occurred, and no treatment was interrupted or dis-
continued owing to hemorrhage events. The incidence
rate of hemorrhage was similar between patients with
squamous cell carcinoma and adenocarcinoma (66.7%
versus 55.6%). The most common immune-related AE
were hypothyroidism (50%), pneumonitis (13.6%),
myositis (4.5%), and adrenal insufficiency (4.5%). Only
one patient experienced both grade 3 myositis and ad-
renal insufficiency. No grade 4 AEs were observed.
One patient with grade 5 immune-related AE was
recorded, who had developed grade 2 immune-related
pneumonitis after eight cycles of treatment and
improved after intravenous methylprednisolone and
anti-infective medication. The patient died 2 months
later from unexplained acute respiratory failure. How-
ever, the radiographic assessment did not reveal subse-
quent pneumonitis deterioration; therefore, it was
unlikely that the cause of death was associated with
immune-related pneumonitis.
Discussion
In this phase 1b trial, sintilimab plus anlotinib as the
first-line therapy has exhibited favorable efficacy, dura-
bility, and tolerability in treatment-naive patients with
advanced NSCLC without sensitive mutations. The clin-
ical benefits were consistent across different stage, his-
tologic, or molecular subgroups. It is noteworthy that,
despite the different clinical settings, patients receiving
this combined regimen had a highly superior ORR
(72.7%) compared with anlotinib (9.2%) or sintilimab
(20%) alone.
12,14
Besides, such response was compara-
ble to that of sintilimab-based chemotherapy in first-line
advanced or metastatic NSCLC (68.4% and 64.7% in
nonsquamous and squamous, respectively) in a phase 1b
study.
9
Thus, sintilimab plus anlotinib could represent a
promising chemotherapy-free option for treatment-naive
patients with advanced NSCLC.
There have been several promising clinical outcomes
with ICIs plus antiangiogenic antibodies in advanced
NSCLC
15
; however, more effective combinations remain
to be developed. In the phase I JVDF trial, the combina-
tion of pembrolizumab and ramucirumab exhibited an
ORR of 42.3% and a 12-month PFS rate of 45% in
Table 1. Baseline Patient Characteristics
Characteristics
Sintilimab Plus
Anlotinib (n ¼22)
Median age, y (range) 64.5 (47–74)
Sex
Male 21 (95.5)
Female 1 (4.5)
Smoking history
Yes 14 (63.6)
No 8 (36.4)
ECOG PS
0 1 (4.5)
1 21 (95.5)
Stage
IIIb 4 (18.2)
IIIc 5 (22.7)
IV 13 (59.1)
BM
Yes 4 (18.2)
No 18 (81.8)
Histology type
Adenocarcinoma 9 (40.9)
Squamous 12 (54.5)
NOS 1 (4.5)
PD-L1 TPS, %
<1 8 (36.4)
1–49 5 (22.7)
50 8 (36.4)
NE 1 (4.5)
TMB Status
10 Muts/Mb 7 (31.8)
<10 Muts/Mb 11 (50.0)
NE 4 (18.2)
Note. Data are No. (%), unless otherwise noted.
BM, brain metastasis;ECOG PS, Eastern Cooperative Oncology Group per-
formance status; Muts/Mb, mutations per Mb; NE, not evaluable; NOS, not
otherwise specified; PD-L1, programmed death-ligand 1; TMB, tumor mu-
tation burden; TPS, tumor proportion score.
April 2021 Sintilimab Plus Anlotinib in First Line NSCLC 647
treatment-naive patients with advanced NSCLC.
16
Given
that anlotinib targets multiple factors involving tumor
proliferation, vasculature, and tumor microenvironment,
potentially, it could render more benefits than VEGF/
VEGF receptor antibodies. More data are being awaited
to confirm this preliminary observation.
Encouraging clinical activity has been observed with
regimens combing ICIs and antiangiogenic tyrosine ki-
nase inhibitors (TKIs) in various advanced solid tumors,
such as pembrolizumab plus axitinib in advanced renal
cell carcinoma,
3
and pembrolizumab plus lenvatinib in
first-line treatment of advanced liver cancer.
17
A recent
Table 2. Tumor Response
Response
Overall
(n ¼22)
Adenocarcinoma
(n ¼9)
Squamous
(n ¼12)
PD-L1þ
(n ¼13)
PD-L1
(n ¼8)
High TMB
(n ¼7)
Low TMB
(n ¼11)
BOR, n (%)
CR 00 00000
PR 16 (72.7) 8 (88.9) 7 (58.3) 9 (69.2) 6 (75.0) 6 (85.7) 7 (63.6)
Stable disease 6 (27.3) 1 (11.1) 5 (41.7) 4 (30.8) 2 (25.0) 1 (14.3) 4 (36.4)
PD 00 00000
ORR, n (%) 16 (72.7) 8 (88.9) 7 (58.3) 9 (69.2) 6 (75.0) 6 (85.7) 7 (63.6)
95% CI (49.8–89.3) (51.8–99.7) (27.7–84.8) (38.6–90.9) (34.9–96.8) (42.1–99.6) (30.8–89.1)
DCR, n (%) 22 (100) 9 (100) 12 (100) 13 (100) 8 (100) 7 (100) 11 (100)
95% CI (84.6–100) (73.5–100) (66.4–100) (75.3–100) (63.1–100) (59.0–100) (71.5–100)
TTR, mo (95% CI) 1.6 (1.4–2.9) 1.7 (1.2–3.2) 1.6 (1.4–3.1) 1.6 (1.2–2.9) 1.6 (1.4–4.2) 1.7 (1.2–3.2) 1.5 (1.4–2.4)
DOR, mo (95% CI) NR (3.2–NR) NR (2.5–NR) NR (3.2–NR) NR (3.2–NR) NR (2.5–NR) NR (NR–NR) NR (2.9–NR)
PD-L1þwas defined as PD-L1 expression greater than or equal to 1% (Dako 22C3). High TMB was defined as greater than or equal to 10 Mutations/Mb (Foundation
One).
BOR, best overall response; CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; NR, not reached; ORR,
objective response rate; PD, progressive disease; PD-L1, programmed death-ligand 1; PD-L1þ, PD-L1-positive; PR, partial response; TMB, tumor mutation
burden; TTR, time to response.
Figure 2. PFS. (A) All patients. (B) Nonsquamous versus squamous. (C) By PD-L1 status (positive versus negative). (D) by TMB
status (high versus low). PD-L1–positive was defined as PD-L1 expression greater than or equal to 1% (22C3 pharmDx assay).
TMB-H was defined as greater than or equal to 10 Muts/Mb (FoundationOne CDx assay). Adeno, adenocarcinoma; Muts/Mb,
mutations per Mb; PD-L1, programmed death-ligand 1; TMB, tumor mutation burden; TMB-H, TMB-high.
648 Chu et al Journal of Thoracic Oncology Vol. 16 No. 4
phase 1 study reported a 33% ORR in patients with
advanced NSCLC treated with pembrolizumab plus len-
vatinib, in which most patients (18 of 21) enrolled had
received at least one line systemic treatment and 52%
had received previous immunotherapy.
6
This study,
however, enrolled treatment-naive patients only, aiming
to bring this combination strategy in the frontline setting
by reactivating the immunity and remodeling the tumor
microenvironment in the first place to maximize the
antitumor activity. Our sintilimab plus anlotinib regimen
is the first combination of an ICI and a multitarget
antiangiogenic TKI as first-line therapy for patients with
advanced NSCLC, and the efficacy observed was
promising. In addition, because the pembrolizumab/
lenvatinib trial enrolled only non-Asian patients, our
study provided additional evidence for applying this new
strategy in the Chinese population.
In line with the previous reports that immune acti-
vation can lead to durable responses and prolonged
survival in patients with solid tumors,
18-21
a better DOR
and PFS were observed in our study. In a pooled anal-
ysis, the tumor shrinkage rate was suggested to be
positively correlated with PFS and OS in patients with
metastatic NSCLC treated with anti–PD-1,
22
and patients
with tumor shrinkage greater than 50% seemed to
benefit more. Considering that all patients in this study
have achieved tumor shrinkage and 36.4% (eight of 22)
patients have achieved greater than 50% tumor reduc-
tion, we anticipate that this regimen will render long-
term benefits to the patients.
PD-L1 expression level has exhibited a positive cor-
relation with tumor response in previous studies of ICIs
monotherapies.
23,24
Interestingly, in this study, the
response was high regardless of the PD-L1 expression
level, consistent with the observation from the pem-
brolizumab/lenvatinib phase 1b study.
6,23-25
These
findings suggested that the efficacy of anti–PD-1 in
combination with antiangiogenic TKIs could be PD-L1
expression–independent.
The U.S. Food and Drug Administration recently
approved pembrolizumab for patients with previously
treated unresectable or metastatic TMB-H (10 muta-
tions per Mb) solid tumors who had no satisfactory
alternative treatment options. In our study, TMB-H pa-
tients had an impressive ORR of 85.7%, and no case of
disease progression was reported at the time of data
cutoff, suggesting that the addition of antiangiogenic
TKIs to anti–PD-1 immunotherapy may favor the pa-
tients with high genomic instability more. Nevertheless,
the prognostic value of TMB in patients receiving this
regimen should be further verified by larger clinical
studies.
In this study, nine patients (40.9%) developed tumor
cavities, including five of six patients who achieved sta-
ble disease (Supplementary Figs. 3 and 4). Cavitation is
common in treatment with antiangiogenetic in-
hibitors,
26,27
yet the incidence of the intratumor cavity
with sintilimab and anlotinib is higher than other
antiangiogenic-based therapies (14%–24%).
26,27
It is
clear now that both anlotinib and sintilimab can modu-
late the immune-suppressive microenvironment in tu-
mors.
28,29
Thus, sintilimab plus anlotinib may
synergistically enhance the antitumor activity, and is
more likely to lead to the development of tumor cavi-
tation. A study of anlotinib in NSCLC indicated that pa-
tients with tumor cavities had a better prognosis than
those without cavities.
30
In our study, nine patients
Table 3. TRAEs
AEs
Any Grade
No. (%)
Grade 3
No. (%)
Hemorrhage 13 (59.1) 0 (0.0)
Urinary occult blood 10 (45.5) 0 (0.0)
Hemoptysis 3 (13.6) 0 (0.0)
Fecal occult blood 2 (9.1) 0 (0.0)
Epistaxis 1 (4.5) 0 (0.0)
Gingival bleeding 1 (4.5) 0 (0.0)
Hypothyroidism 11 (50.0) 0 (0.0)
Uric acid increased 9 (40.9) 0 (0.0)
Hand-foot skin reaction 8 (36.4) 1 (4.5)
Hypoalbuminemia 8 (36.4) 0 (0.0)
Hypertension 7 (31.8) 2 (9.1)
ALT increased 7 (31.8) 0 (0.0)
Direct bilirubin increased 7 (31.8) 0 (0.0)
Rash 5 (22.7) 1 (4.5)
Pneumonitis 5 (22.7) 0 (0.0)
Immune-related pneumonitis
a
3 (13.6) 0 (0.0)
Fever 5 (22.7) 0 (0.0)
Total bilirubin increased 5 (22.7) 0 (0.0)
Hyponatremia 4 (18.2) 1 (4.5)
Proteinuria 4 (18.2) 1 (4.5)
Diarrhea 4 (18.2) 1 (4.5)
Hypochloremia 4 (18.2) 0 (0.0)
Fatigue 4 (18.2) 0 (0.0)
Oral ulcer 4 (18.2) 0 (0.0)
AST increased 4 (18.2) 0 (0.0)
Hoarseness 4 (18.2) 0 (0.0)
Anorexia 4 (18.2) 0 (0.0)
Gum pain 4 (18.2) 0 (0.0)
Lipase elevation 3 (18.2) 1 (4.5)
Amylase increased 2 (9.1) 1 (4.5)
Immune-related myositis
b
1 (4.5) 1 (4.5)
Cerebral infarction 1 (4.5) 1 (4.5)
Blood cortisol decreased 1 (4.5) 1 (4.5)
Adrenal insufficiency
b
1 (4.5) 1 (4.5)
TRAEs occurring at any grade in more than 15% of patients or grade 3 or worse
in more than 1% of patients in the safety population are illustrated in this
table.
a
One grade 5 event was observed (immune-related pneumonitis).
b
Immune-related myositis and adrenal insufficiency occurred in the same
patient. No grade 4 events were observed.
AE, adverse event; AST, aspartate aminotransferase; ALT, alanine amino-
transferase; TRAE, treatment-related AE.
April 2021 Sintilimab Plus Anlotinib in First Line NSCLC 649
developed tumor cavities, and they tended to have du-
rable responses (Supplementary Fig. 4). Of note, only
one experienced grade 1 hemoptysis among these pa-
tients, and no other pulmonary hemorrhage events were
observed.
Unlike the IMpower150 phase 3 study,
8
which only
enrolled patients with nonsquamous NSCLC, 54.5% of
patients in this study had squamous cell carcinomas.
Therefore, a significant clinical advantage noted with
sintilimab plus anlotinib is that it can benefit both his-
tologic subgroups. This is consistent with the previous
conclusions that the benefits of anlotinib monotherapy
or sintilimab-based chemotherapy are regardless of
NSCLC histology type.
9,14
Among the four patients with BM at baseline, three
achieved overall PR, and one achieved stable disease.
The observed intracranial and systemic responses were
comparable, indicating that the regimen of sintilimab
plus anlotinib had synergistic effects in the brain. This
finding was consistent with the phase 2 trial of patients
with NSCLC with BM
31
and the KEYNOTE-189 posthoc
analysis.
32
Safety was found to be consistent with known safety
profiles of either sintilimab or anlotinib alone.
12,14
No
new safety signal was identified.
10,11,33
Grade 3 or higher
TRAEs occurred in 54.5% of patients, whereas the inci-
dence of grade 3 or higher TRAEs was generally above
60% in chemotherapy-containing immunother-
apies.
8,34,35
Except for two cases of grade 3 hyperten-
sion, most grade 3 TRAEs occurred only once. Five
patients experienced grade greater than or equal to 3
TRAEs 1 year after the treatment, which might be
associated with the long treatment duration. Although
hypothyroidism occurred in half of the patients in this
study, most subjects had grade 1 to 2 and recovered
without medication. A similar hypothyroidism incidence
was observed in patients treated with pembrolizumab
plus lenvatinib (47%) or axitinib (35.4%).
3,36
The major limitation of this hypothesis-generating,
single-center study is the relatively small sample size.
To further evaluate this hypothesis, a multicenter, ran-
domized, phase 2 trial (NCT04124731) is underway to
generate more clinical evidence on efficacy, safety,
quality of life, and translational biomarkers. We also
noted that some of the baseline characteristics in this
study were not representative of the prevalence of pa-
tients with advanced NSCLC in the People’s Republic of
China, with men and squamous cell carcinoma histology
type predominating in the enrolled patients. The most
likely reason for this was the exclusion of EGFR muta-
tions, which were more common in Asian women and
adenocarcinoma types than in men and squamous types.
In summary, the combination of sintilimab plus
anlotinib has exhibited encouraging efficacy, durability,
and tolerability in this phase 1b clinical trial, making it a
promising chemotherapy-free option for first-line treat-
ment in patients with advanced NSCLC. This novel
combination has potential efficacy for a broader range of
patients with NSCLC, regardless of histologic subtype or
PD-L1 status. In addition, its favorable and manageable
safety profile may provide an improved quality of life
and offer potential opportunities for subsequent treat-
ments. These preliminary findings have exhibited the
worthiness of the development of sintilimab plus anlo-
tinib in first-line advanced NSCLC.
Acknowledgments
This study was supported by the Western Medicine
Guidance Project of Shanghai Science and Technology
Commission (No. 18411968500), the Multicenter Clin-
ical Research Project of Shanghai Jiao Tong University
Medical School (No. DLY201816), and the Cooperative
Innovation Project of Shanghai Chest Hospital (No.
YJXT20190102). The study drugs of sintilimab and
anlotinib were provided by Innovent (Suzhou) Biophar-
maceutical Co., Ltd. and Chia Tai Tianqing Pharmaceu-
tical Group Co., Ltd., respectively. The authors would like
to thank all patients who participated in the study and
the clinical personnel involved in data collection. The
funders have no role in study design; in the collection,
analysis, and interpretation of data; in the writing of the
report; and in the decision to submit the article for
publication.
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