(2024) 22:344
Tian et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03564-z

BMC Medicine

RESEARCH

Open AccessCamrelizumab plus apatinib in patientswith advanced or recurrent endometrial cancer
after failure of at least one prior systemic
therapy (CAP 04): a single‑arm phase II trial
Wenjuan Tian1,2†, Yulan Ren1,2†, Jing Lu2,3, Chuyu Jing1,2, Wei Zhang1,2, Haiming Li2,3, Tingting Wang4,5,
Zhiguo Hou6, Ting Yang6, Wenqing Zhu6, Yi Zhang2,7, Boer Shan1,2, Huijuan Yang1,2, Xi Cheng1,2 andHuaying Wang1,2*

Abstract
Background The combination of anti-programmed death 1 (PD-1) inhibitors and tyrosine kinase inhibitors
is an effective treatment strategy in endometrial cancer. We aimed to explore the efficacy and safety of camrelizumab
plus apatinib as an alternative therapeutic option in patients with previously treated endometrial cancer.
Methods This single-arm Simon’s two-stage phase II trial was conducted at the Fudan University Shanghai Cancer
Center. Patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy
were screened for potential participation. Eligible patients were treated with intravenous camrelizumab (200 mg
d1 q2w) and oral apatinib (250 mg qd) every 4 weeks. The primary end point was the objective response rate (ORR)
per RECIST v1.1 in the intention-to-treat principle.
Results Between January 20, 2020, and October 14, 2022, 36 patients (29 with microsatellite stability/mismatch repair
proficient [MSS/pMMR] tumors; two with microsatellite instability-high/mismatch repair deficient [MSI-H/dMMR]
tumors) were enrolled and treated. The confirmed ORR was 44.4% (95% CI: 27.9, 61.9) and the disease control rate
was 91.7% (95% CI: 77.5, 98.2). The median duration of response was 9.3 (95% CI: 4.3, not reached) months, the medianprogression-free survival was 6.2 (95% CI: 5.3, 11.1) months, and the median overall survival was 21.0 (95% CI: 13.4,
not reached) months during a median follow-up of 14.2 (interquartile range: 10.3, 27.6) months. Treatment-related
adverse events of grade 3 or 4 occurred in 20 (55.6%) patients, with the most common being increased γ-glutamyltransferase (27.8%), alanine aminotransferase (16.7%) and aspartate aminotransferase (13.9%), and hypertension(11.1%). No treatment-related death occurred.
Conclusions Camrelizumab plus apatinib showed promising antitumor activity with manageable toxicity in patientswith advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy. The findings of thisstudy support further investigation of camrelizumab plus apatinib as an alternative therapeutic option, especiallyfor patients with MSS/pMMR tumors.
†

Wenjuan Tian and Yulan Ren contributed equally to this work.

*Correspondence:
Huaying Wangwanghuayingfducc@163.com
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Tian et al. BMC Medicine(2024) 22:344

Page 2 of 11

Trial registration This trial was retrospectively registered with ChiCTR.org.cn, number ChiCTR2000031932.
Keywords Endometrial cancer, Immune checkpoint inhibitors, Anti-programmed death 1 (PD-1) inhibitors,
Antiangiogenic agents

Background
Endometrial cancer is the sixth most commonly diagnosed cancer in women [1], with an ever-increasing
incidence of 0.69% per year globally [2]. In China, theage-standardized incidence rate of endometrial cancer has increased by 3.4% per year from 2000 to 2018 infemales [3]. Although most patients with endometrial
cancer are diagnosed at an early stage, approximately 30%
of patients present with advanced disease with regional
or distant metastases [4, 5] and more than half of themdeveloped tumor recurrences after first-line therapy [6].
Platinum-based chemotherapy is the cornerstone for thetreatment of advanced or recurrent endometrial cancer[7]. However, the treatment options have been historically limited, especially after prior systemic therapy.
Immunotherapy has been changing the treatment landscape of endometrial cancer. Several anti-programmed
death 1 (PD-1) or its ligand (PD-L1) inhibitors (pembrolizumab, dostarlimab, avelumab, and nivolumab) havebeen recommended for the treatment of patients withmicrosatellite instability-high/mismatch repair-deficient(MSI-H/dMMR) advanced or recurrent endometrial cancer in the second-line or beyond [8, 9]. However, only
17–33% of patients with advanced or recurrent endometrial cancer are MSI-H/dMMR [10, 11]. Immune checkpoint inhibitors combined with antiangiogenic agents
showing synergistic therapeutic effects could be a potential antitumor strategy. To that end, the combination of
pembrolizumab and lenvatinib has been investigated anddemonstrated promising activity in patients with previously treated advanced or recurrent endometrial cancer[12–15]. Pembrolizumab in combination with lenvatinib
was first approved by the Food and Drug Administration
for the treatment of patients with non-MSI-H or MMR
proficient (pMMR) advanced endometrial cancer whose
disease has progressed on or following prior systemic
therapy, by the National Medical Products Administration (NMPA) for the same indication, and also by theEuropean Medicines Agency for the same indication
except for no restriction on MMR status.
Camrelizumab is a humanized anti-PD-1 monoclonal
antibody that can block the interaction between PD-1
and its ligand (PD-L1). Apatinib is a highly selective
tyrosine kinase inhibitor of vascular endothelial growth
factor receptor 2 (VEGFR2). Combining camrelizumab
with apatinib produced synergistic antitumor activity ina preclinical study. The potential mechanism involved the

optimization of the immunosuppressive tumor microenvironment induced by low-dose apatinib [16]. Clinically,
camrelizumab in combination with apatinib has demonstrated survival benefits in patients with unresectable
hepatocellular carcinoma and has been approved by the
NMPA in China [17]. Moreover, this combination has
shown encouraging antitumor activity in various typesof solid tumors, with a manageable safety profile [18–22].
However, their combination effect in endometrial cancer has not been investigated. We conducted the CAP 04
trial to evaluate the efficacy and safety of camrelizumab
plus apatinib in patients with advanced or recurrent
endometrial cancer who had failed at least one prior systemic therapy.

Methods
Study design and patients

CAP 04 was a single-arm, open-label phase II trial (www.​chictr.​org.​cn, No. ChiCTR2000031932) enrolled patientsfrom the Fudan University Shanghai Cancer Center. Eligible patients were aged 18 years or older and had histologically confirmed advanced endometrial cancer that
had progressed on or following at least one prior systemic therapy. Other inclusion criteria were an Eastern
Cooperative Oncology Group (ECOG) performance status score of 0 ~ 1, measurable disease according to the
Response Evaluation Criteria In Solid Tumors version
1.1 (RECIST v1.1), adequate major organ function, and alife expectancy of at least 12 weeks. Patients were staged
according to the International Federation of Gynecology
and Obstetrics (FIGO) 2009 staging system. MSI/MMR
status was not required for patient enrollment. Patientswere excluded if they had a history of or active autoimmune disease; immunosuppressive therapy or systemic
steroid therapy (≥ 10 mg daily of prednisone equivalent)within 2 weeks before enrollment; known central nervous system metastases; uncontrolled hypertension orheart disease; previous thromboembolic events within
6 months before enrollment; were at risk of developing
hemorrhage or thrombosis; had an active infection; or
had previously received any immune checkpoint inhibitors. Full eligibility criteria can be found in the study
protocol.
Procedures

Patients received camrelizumab (200 mg) intravenously
on day 1 every 2 weeks and apatinib (250 mg) orally once

Tian et al. BMC Medicine(2024) 22:344

daily in 4-week cycles. Treatment could be continued
until disease progression, intolerable toxicity, patient’s
request, investigator’s decision, or for up to 2 years.
Treatment beyond RECIST v1.1 defined disease progression was allowed if the patient was deemed to benefit by
the investigators. Toxicity was managed by supportive
care, dose reduction, and/or treatment delay or discontinuation. Apatinib could be reduced from once daily tofive continuous days per week, or even every other day.
The reduced dose of apatinib could not be re-escalated.
All patients were followed up monthly after the end of
the study treatment for survival and subsequent antitumor treatment.
Tumor response was assessed every 8 weeks for the first48 weeks and every 12 weeks thereafter according to the
RECIST v1.1. Adverse events were monitored throughout the study treatment and continued for an additional
30 days after the last dose of study treatment. All adverse
events were graded according to the Common Terminology Criteria for Adverse Events version 5.0. Tumor
specimens or biopsies were obtained at baseline after
informed consent for exploratory biomarker analyses.
End points

The primary end point was the objective response rate(ORR), defined as the percentage of patients achieving complete response (CR) or partial response (PR) per
RECIST v1.1. All responses were confirmed at least 4(+ 7 days) weeks later. Secondary end points were disease
control rate (DCR, defined as the percentage of patientswith CR, PR, or stable disease [SD]), time to response(TTR, defined as the time from the date of treatment initiation to the date of first documented CR or PR), duration of response (DoR, defined as the time from the dateof first documented CR or PR to the date of first recorded
disease progression), time to treatment failure (TTF,
defined as the time from the date of treatment initiation
to the date of treatment discontinuation for any reason),progression-free survival (PFS, defined as the time fromthe date of treatment initiation to the date of disease progression or death, whichever occurred first), overall survival (OS, defined as the time from the date of treatment
initiation to the date of death), and safety (treatmentrelated adverse events [TRAEs], immune-related adverse
events [irAEs]). Exploratory endpoints were ORR andPFS stratified by MSI/MMR and PD-L1 expression.
Exploratory biomarker analyses

Central testing for MSI and PD-L1 expression status wasdone in patients with adequate samples at a College ofAmerican Pathology and Clinical Laboratory Improvement Amendments-certified lab (Shanghai OrigiMed
Co., Ltd), which was sponsored by Jiangsu Hengrui

Page 3 of 11

Pharmaceuticals Co., Ltd. Testing for MMR status wasdone at the Department of Pathology, Fudan University
Shanghai Cancer Center. Any previously available data
on MSI/MMR and PD-L1 expression status were alsocollected.
Immunohistochemical (IHC) assay

PD-L1 expression was determined with PD-L1 IHC
22C3 pharmDx assay (Dako, Carpinteria, CA, USA). The
combined positive score was calculated as the numberof PD-L1 staining cells (tumor cells, macrophages, andlymphocytes) divided by the total number of tumor cells
multiplied by 100. MMR status was determined by IHC
analysis using the primary antibodies against four MMR
proteins, MLH1, PMS2, MSH2, and MSH6. The dMMR
was defined as the lack of expression of any of the four
MMR proteins. The pMMR was defined as the expressions of all four MMR proteins.
Next‑generation sequencing (NGS)

Targeted NGS was performed using a custom hybridization capture panel, the Qirui Onco + assay (Shanghai OrigiMed Co., Ltd). DNA was extracted from FFPE
tumor samples using the QIAamp DNA FFPE Tissue
Kit (Qiagen). After quality control and concentration
quantification, the extracted DNA was used for library
construction using the KAPA Hyper Prep Kit (Kapa Biosystems). Hybridization capture was performed with the
Qirui Onco + panel (~ 4.5 Mb human genome) containing
most exons of 671 cancer-related genes and frequently
rearranged introns in cancer. Post-capture libraries weresequenced on the Illumina NovaSeq 6000 instruments(Illumina Inc., San Diego, CA). Sequence reads were thenpre-processed and checked for data quality inspection
and control, followed by processing with a customized
bioinformatics pipeline for variant calls (single nucleotide
variant, short insertion and deletion, copy number variation, and gene rearrangement). The variants were examined against an in-house annotation database for clinicalcuration.
MSI status

MSI was calculated as the number of unstable loci outof the 2174 screened microsatellite loci in the Qirui
Onco + assay. MSI-high was defined as 15 or more unstable loci, while MSS was defined as fewer than 15 unstableloci.
Statistical analysis

Simon’s two-stage minimax design was adopted witha one-sided α of 0.025 and a power of 80%. The null
hypothesis of an ORR of 15% [23, 24] was tested against
the desired alternative hypothesis of an ORR of 35%.

Tian et al. BMC Medicine(2024) 22:344

Twenty-one patients were planned to be enrolled in thefirst stage. If at least four responses were observed, an
additional 13 patients would be accrued during the second stage. The treatment would be considered promising if 10 or more responses were observed among the 34
patients.
The ORR and DCR were calculated, and the corresponding 95% confidence intervals (CIs) were estimatedwith the Clopper-Pearson method. The PFS, OS, andDoR were analyzed using the Kaplan–Meier method,
and the corresponding 95% CIs were estimated with the
Brookmeyer-Crowley method. The TTR and TTF wereexpressed as median and 95% CIs. Safety outcomes wereanalyzed descriptively. Post hoc sensitivity analyses of
ORR were done in the overall population based on baseline patient characteristics (including age, ECOG performance status, body mass index [BMI], prior treatment
line, FIGO stage, histologic feature, prior radiotherapy,
prior antiangiogenic therapy, and PD-L1 expression status). All statistical analyses were performed with SAS
version 9.4 (SAS® Institute Inc., Cary, NC).

Page 4 of 11

Table 1 Baseline characteristics
Variables

Patients (n = 36)

Median age (range), years

60 (29, 76)≥ 65 years, n (%)

13 (36.1)

ECOG performance status, n (%)
0

19 (52.8)

1

17 (47.2)

Mean body mass index (range), kg/m2

26.5 (19.6, 34.0)

Histologic features, n (%)
Endometrioid adenocarcinoma

28 (77.8)

FIGO grade 1

4 (11.1)

FIGO grade 2

12 (33.3)

FIGO grade 3

11 (30.6)

Missing

1 (2.8)Serous carcinoma

6 (16.7)

Mixed

1 (2.8)Endometrial clear cell carcinoma

1 (2.8)FIGO stage at initial diagnosis, n (%)
I–II

14 (38.9)

III–IV

22 (61.1)

Prior treatment lines, n (%)

Results

1

21 (58.3)

Patient characteristics

2

7 (19.4)

Between January 20, 2020, and October 14, 2022, a totalof 36 patients were enrolled and treated. All 36 patientswere included in the efficacy and safety analyses. As ofthe data cutoff on June 30, 2023, one patient was still on
study treatment. The primary reason for treatment discontinuation was disease progression (66.7%) (Additional
file 1: Fig. S1).
Median age of the patients was 60 (range: 29–76) years,
with 36.1% (13/36) aged 65 years or older. Almost half
(17/36) of the patients had an ECOG performance statusscore of 1. Mean BMI was 26.5 (range: 19.6, 34.0) kg/m2.
Most (77.8%) patients had a histological type of endometrioid adenocarcinoma (FIGO grade I–II: 57.1%; grade
III: 39.3%). Fifteen (41.7%) patients had received two or
more lines of prior systemic therapy. All patients hadreceived prior platinum plus taxane chemotherapy, 19(52.8%) had received prior radiotherapy, and 10 (27.8%)
had received prior antiangiogenic therapy. The baseline
demographic and clinical characteristics of the patientsare summarized in Table 1.
Of the 36 patients, 31 (86.1%) were tested for MSI/
MMR status, only two (5.6%) were MSI-H/dMMR; 24(66.7%) were tested for PD-L1 expression, seven (19.4%)
were PD-L1 positive.

≥3

8 (22.2)

Prior radiotherapy, n (%)

19 (52.8)

Prior antiangiogenic therapy, n (%)

10 (27.8)

Efficacy

Of the 21 patients enrolled in the first stage, 10 (47.6%)
achieved the confirmed CR or PR, exceeding the prespecified threshold of 4, and thus the trial proceeded to

Microsatellite status, n (%)
MSI-H/dMMR

2 (5.6)

MSS/pMMR

29 (80.6)

Unknown

5 (13.9)

PD-L1 status, n (%)
Positive (CPS ≥ 1)

7 (19.4)

Negative (CPS < 1)

17 (47.2)

Unknown

12 (33.3)

ECOG Eastern Cooperative Oncology Group, FIGO International Federation of
Gynecology and Obstetrics, PD-L1 Programmed death protein ligand 1, CPS
Combined positive score, MSI-H Microsatellite instability-high, dMMR Mismatch
repair deficient, MSS Microsatellite stability, pMMR Mismatch repair proficient

the second stage. Among the 36 patients finally enrolled,
16 achieved the confirmed CR (n = 3) or PR (n = 13), and17 had SD, resulting in an ORR of 44.4% (95% CI: 27.9,
61.9) and a DCR of 91.7% (95% CI: 77.5, 98.2) (Table 2).
Twenty-seven (75%) patients had tumor shrinkage(Fig. 1a). The median TTR was 1.9 (95% CI: 1.8, 2.5)
months. Thirteen (36.1%) patients showed objective
responses at the first radiographical assessment (Fig. 1b).
The median DoR was 9.3 (95% CI: 4.3, not reached)months, with 11 (30.6%) patients responding for at least
6 months (Fig. 1c). The median TTF was 6.1 (95% CI: 4.0,
10.4) months.

Tian et al. BMC Medicine(2024) 22:344

Page 5 of 11

Table 2 Tumor responses
Patients (n = 36)
Confirmed best overall response, n (%)
Complete response

3 (8.3)

Partial response

13 (36.1)

Stable disease17 (47.2)

Progressive disease

3 (8.3)

Confirmed objective response rate (95% CI)

44.4 (27.9, 61.9)

Confirmed disease control rate (95% CI)

91.7 (77.5, 98.2)

Median duration of response (95% CI), months

9.3 (4.3, not reached)≥ 6 months, n (%)

11 (30.6)≥ 12 months, n (%)

5 (13.9)

Median time to response (95% CI), months

1.9 (1.8, 2.5)

At the data cutoff (June 30, 2023), the median followup was 14.2 (interquartile range: 10.3, 27.6) months. A
total of 28 (77.8%) patients had disease progression or
had died. The median PFS was 6.2 (95% CI: 5.3, 11.1)
months (Fig. 2a). The median OS was 21.0 (95% CI: 13.4,
not reached) months, with a 12-month OS rate of 74.1%(95% CI: 56.0, 85.7) (Fig. 2b).
Among the 29 patients with MSS/pMMR tumors, 16(55.2%, 95% CI: 35.7, 73.6) achieved objective responses,
and the corresponding median PFS was 8.1 (95% CI: 5.6,
13.0) months. Two patients with MSI-H/dMMR tumors
did not respond to camrelizumab plus apatinib. The
ORR was 57.1% (95% CI: 18.4, 90.1) for patients with PDL1-positive tumors and 52.9% (95% CI: 27.8, 77.0) for
patients with PD-L1-negative tumors (Additional file 1:
Fig. S2). Details regarding PFS and OS stratified by PD-L1
expression are illustrated in Additional file 1: Fig. S3. The
ORRs were generally consistent across other subgroups(age, ECOG performance status, BMI, prior treatment
line, FIGO stage, histologic feature, prior radiotherapy),
except for prior antiangiogenic therapy (Additional file 1:
Fig. S2).
Exposure and safety

The median duration of study treatment was 28.8 (range
9.3, 102.4) weeks; the median number of cycles of camrelizumab therapy was 7.1 (ranges: 2, 26); the median

duration of apatinib therapy was 27.5 (range: 8.0, 102.4)
weeks. The median relative dose intensity (the ratio of thedelivered dose intensity to the standard dose intensity)
was 83.3% (range: 50, 100) with camrelizumab and 79.8%(range: 42, 100) with apatinib.
TRAEs of any grade occurred in 35 (97.2%) patients,
and those of grade 3 or 4 occurred in 20 (55.6%) patients.
The most common grade 3 or 4 TRAEs were increased
γ-glutamyl transferase (27.8%), increased alanine aminotransferase (16.7%), increased aspartate aminotransferase (13.9%), and hypertension (11.1%) (Table 3).
TRAEs led to interruption of any study drugs in 25(69.4%) patients, dose reduction of apatinib in 19 (52.8%)
patients, and discontinuation of any study drugs in 2
(5.6%) patients. No patients discontinued study treatment due to adverse events. No treatment-related deathoccurred.
IrAEs of any grade occurred in 20 (55.6%) patients,
and those of grade 3 or 4 occurred in 12 (33.3%) patients(Table 3). Reactive cutaneous capillary endothelial proliferation (RCCEP) occurred in 7 (19.4%) patients, and all
were mild (grade 1 or 2).

Discussion
Camrelizumab plus apatinib has shown encouraging antitumor activity and manageable safety in various
types of solid tumors. The CAP 04 trial showed promising antitumor activity, with a well-tolerated safety profile,of camrelizumab plus apatinib in advanced or recurrent
endometrial cancer after failure of at least one prior systemic therapy. The positive results of the study support
further investigation of camrelizumab plus apatinib as
an alternative therapeutic option, especially for patientswith MSS/pMMR tumors.
The ORR was 44.4% (RECIST v1.1, 16/36) and the
median PFS was 6.2 months with camrelizumab plus
apatinib. These data were in line with the previous
studies of pembrolizumab plus lenvatinib in the KEYNOTE-146 (irRECIST ORR: 39.8% [43/108], median
PFS: 7.4 months) [12] and KEYNOTE-775 (RECIST
v1.1 ORR: 31.9% [131/411], median PFS: 7.2 months)[13], nivolumab plus cabozantinib (RECIST v1.1 ORR:
25% [9/36], median PFS: 5.3 months) [25], TQB2450
plus anlotinib (RECIST v1.1 ORR: 33.3% [10/30],(See figure on next page.)
Fig. 1 Antitumor activity of camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer who had failed prior systemic
therapy. a Waterfall plot showing the best percentage changes from baseline in the sum of diameters of measurable lesions (n = 35). One
patient who achieved a complete response had no target lesion; b Spider plot showing percentage change over time from baseline in the sumof diameters of measurable lesions (n = 35). One patient who achieved a complete response had no target lesion; c Swimmer plot showing
tumor response and treatment duration (n = 36). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; PD-L1,
programmed death ligand 1; MSI, microsatellite instability; MSI-H, MSI-high; dMMR, mismatch repair deficient; MSS, microsatellite stability; pMMR,
mismatch repair proficientTian et al. BMC Medicine(2024) 22:344

Fig. 1 (See legend on previous page.)

Page 6 of 11

Tian et al. BMC Medicine(2024) 22:344

Page 7 of 11

Fig. 2 Kaplan–Meier analyses of progression-free survival (a) and overall survival (b) in patients with advanced or recurrent endometrial cancer
receiving camrelizumab plus apatinib

Tian et al. BMC Medicine(2024) 22:344

Page 8 of 11

Table 3 Treatment-related adverse events (TRAEs) occurring in ≥ 10% of patients and immune-related adverse events (irAEs)
Patients (n = 36)
Any grade

Grade 1–2

Grade 3–4

Any TRAEs, n (%)

35 (97.2)

15 (41.7)

20 (55.6)

γ-glutamyl transferase increased

19 (52.8)

9 (25.0)

10 (27.8)

Alanine aminotransferase increased

19 (52.8)

13 (36.1)

6 (16.7)

Hypertension

16 (44.4)

12 (33.3)

4 (11.1)

Aspartate aminotransferase increased

15 (41.7)

10 (27.8)

5 (13.9)

Proteinuria

12 (33.3)

11 (30.6)

1 (2.8)

Palmar-plantar erythrodysesthesia syndrome

11 (30.6)

11 (30.6)

0Neutrophil count decreased

10 (27.8)

9 (25.0)

1 (2.8)White blood cell count decreased

9 (25.0)

8 (22.2)

1 (2.8)

Hypothyroidism

8 (22.2)

6 (16.7)

2 (5.6)

Platelet count decreased

8 (22.2)

8 (22.2)

0

RCCEP

7 (19.4)

7 (19.4)

0Blood bilirubin increased

7 (19.4)

5 (13.9)2 (5.6)Thyroid stimulating hormone increased

6 (16.7)

6 (16.7)

0

Fatigue

5 (13.9)

5 (13.9)

0

Activated partial thromboplastin time prolonged

5 (13.9)

5 (13.9)0Hyperglycemia

4 (11.1)

1 (2.8)3 (8.3)Lymphocyte count decreased

4 (11.1)

3 (8.3)1 (2.8)Rash

4 (11.1)

4 (11.1)

0Creatine phosphokinase increased

4 (11.1)

4 (11.1)

0

Any irAEs, n (%)

20 (55.6)

8 (22.2)

12 (33.3)

Alanine aminotransferase increased

9 (25.0)

4 (11.1)

5 (13.9)

Aspartate aminotransferase increased

9 (25.0)

4 (11.1)

5 (13.9)

Hypothyroidism

8 (22.2)

6 (16.7)

2 (5.6)RCCEP

7 (19.4)

7 (19.4)0γ-glutamyl transferase increased

5 (13.9)05 (13.9)

Creatine phosphokinase increased

4 (11.1)

4 (11.1)

0Hyperglycemia

3 (8.3)0

3 (8.3)

Blood bilirubin increased

3 (8.3)1 (2.8)2 (5.6)

Platelet count decreased

3 (8.3)3 (8.3)0

Cardiac troponin T increased

1 (2.8)1 (2.8)0Creatine kinase isoenzyme increased

1 (2.8)1 (2.8)0Hyperthyroidism

1 (2.8)0

1 (2.8)Thyroid stimulating hormone increased

1 (2.8)1 (2.8)0

Alkaline phosphatase increased

1 (2.8)1 (2.8)0

Direct bilirubin increased

1 (2.8)1 (2.8)0

RCCEP Reactive cutaneous capillary endothelial proliferation

median PFS: 6.6 months) [26], and avelumab plus axitinib (RECIST v1.1 ORR: 39.3% [11/28], median PFS:
7.3 months) [27], despite the different tumor response
criteria used. However, a previous study of sintilimab
plus anlotinib by Wei et al. reported a high ORR of
73.9% (irRECIST) in patients with previously treatedadvanced or recurrent endometrial cancer, and the
median PFS was not reached at the time of data analysis[28].

The introduction of molecular/genomic profilingand immunotherapy would help to tailor treatment inpatients with endometrial cancer [29]. MSI-H/dMMR isan agnostic biomarker that has been reported to occur
in approximately 30% of patients with primary endometrial cancer [30]. In the study of sintilimab plus anlotinib,
9 (39.1%) of the 23 patients with recurrent endometrial
cancer had MSI-H/dMMR tumors. This proportion was
substantially higher than that observed in our and otherTian et al. BMC Medicine(2024) 22:344

studies (CAP 04: 5.6% [2/36]; nivolumab plus cabozantinib: 5.6% [2/36]; KEYNOTE-146: 10.2% [11/108];
KEYNOTE-775: 15.8% [65/411]). Patients with MSI-H/
dMMR tumors seem to benefit more from immunotherapy alone or in combination with antiangiogenic therapy
when compared with their MSS/pMMR counterparts(KEYNOTE-146: ORR 63.6% vs 37.2%, median PFS: 26.4
vs 7.4 months; KEYNOTE-775: ORR: 40.0% vs 30.3%,
median PFS: 10.7 vs 6.6 months) [12, 13]. Among the 29(80.6%) patients with MSS/pMMR diseases in our study,
16 achieved an objective response, resulting in a high
ORR of 55.2%. By contrast, only two (5.6%) patients had
MSI-H/dMMR tumors. The limited number of patientswith MSI-H/dMMR tumors precluded the possibilityof subgroup comparison regarding MSI/MMR status.
The prevalence of MSI/MMR status in Chinese patientswith recurrent endometrial cancer and its clinical significance still need further investigation. Nevertheless, theseresults establish the antitumor activity of camrelizumab
plus apatinib in patients with previously treated endometrial cancer, even in MSS/pMMR patients who have limited treatment options.
In addition to MSI/MMR status, the PD-L1 expression
status was not associated with the antitumor activity of
camrelizumab plus apatinib in patients with previously
treated endometrial cancer. These results were partiallyconsistent with the report from the previous studies,
which indicated the antitumor activity of pembrolizumab
plus lenvatinib and sintilimab plus anlotinib irrespectiveof PD-L1 expression status [15, 28]. BMI has been identified as a promising biomarker for predicting response
to immunotherapy in patients with recurrent gynecologic cancer, with overweight patients (BMI ≥ 25 kg/m2)
showing favorable outcomes [31]. In our study, the ORR
rate was generally consistent between the patients withBMI ≥ 25 kg/m2 and those with BMI < 25 kg/m2. However, due to the small sample size of patients enrolled foranalysis, future studies are required to clarify the prognostic values of these biomarkers. Besides, a small subsetof patients with histological types other than endometrial
adenocarcinoma were included, such as patients withserous carcinoma (n = 6, 16.7%), although camrelizumab
plus apatinib did show potential antitumor activity (ORR:
50% [3/6]) in this subgroup of the patients. Additionally,
patients who had received one and two or more priortreatment lines all responded to some extent, while those
who had received prior antiangiogenic therapy were lesslikely to respond. Future studies using a large sample size
are needed to clarify it further. By the way, other sustainable methods beyond molecular or genomic profiling,such as radiomics, have been assessed as alternative tools
to provide additional information on the treatment andprognosis of endometrial cancer. The integration of these

Page 9 of 11

methods may provide new insights into the characterization of endometrial cancer [32].
As for safety, the combination of camrelizumab andapatinib was generally manageable, with no new safety
signals. The most common TRAEs were increased
γ-glutamyl transferase, increased alanine aminotransferase, hypertension, and increased aspartate aminotransferase. The safety profile of camrelizumab plus
apatinib was generally similar to the known profiles ofeach agent and their combination [18, 33]. The incidence of RCCEP (19.4% [7/36]), a typical camrelizumab-related adverse event, was quite within the range(6 ~ 29%) reported for camrelizumab plus apatinib invarious solid tumors [17, 18, 20]. However, it was lower
than that reported (67 ~ 81%) for camrelizumab alone
or combined with chemotherapy [34–38]. The potential
mechanism may involve the inhibition of angiogenesis byanti-VEGFR inhibitors like apatinib, which may decrease
the development of RCCEP driven by camrelizumab
binding to vascular endothelial growth factor [39, 40].
Unlike most of the previous studies, the present data
feature an Asian cohort. However, this study is limitedby the single center, single-arm study design, and retrospective registration. Besides, molecular tests for PD-L1
expression, MSI/MMR, and tumor mutation burden(TMB) were done only in some of the patients due to theunavailability or poor quality of tissue samples. In addition to the central targeted NGS for TMB/MSI testing,a fair number of other miscellaneous methods were also
used for exploratory analyses (Additional file 2: Table S1).
The results of the TMB subgroup analysis are notreported herein, and subgroup analyses for PD-L1 andMSI/MMR status should be interpreted cautiously. Additionally, the follow-up in this study is not long enough tocapture the OS of the patients.

Conclusion
Camrelizumab plus apatinib showed promising antitumor activity with manageable toxicity in patients withadvanced or recurrent endometrial cancer after failure ofat least one prior systemic therapy. The findings of thisstudy support further investigation of the combination
therapy with camrelizumab and apatinib as an alternative therapeutic option, especially for patients with MSS/
pMMR tumors.
Abbreviations
PD-1	Programmed death 1
PD-L1	Programmed death ligand-1
ORR	Objective response rate
MSS	Microsatellite stability
MSI-H	Microsatellite instability-highpMMR	Mismatch repair proficientdMMR	Mismatch repair deficient
NMPA	National Medical Products Administration
VEGFR2	Vascular endothelial growth factor receptor 2

Tian et al. BMC Medicine(2024) 22:344

ECOG	Eastern Cooperative Oncology Group
RECIST v1.1	Response Evaluation Criteria In Solid Tumors version 1.1
FIGO	International Federation of Gynecology and Obstetrics
CR	Complete response
PR	Partial responseSD	Stable disease
DCR	Disease control rate
TTR​	Time to response
DoR	Duration of response
TTF	Time to treatment failure
PFS	Progression-free survival
OS	Overall survival
TRAEs	Treatment-related adverse events
irAEs	Immune-related adverse events
NGS	Next-generation sequencing
CIs	Confidence intervals
BMI	Body mass index
RCCEP	Reactive cutaneous capillary endothelial proliferation

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03564-z.
Additional file 1: Figures S1-S3. Fig. S1. Patient flowchart. Fig. S2. Subgroup
analyses of objective response rate regarding baseline patient characteristics. Fig. S3. Kaplan-Meier analyses of progression-free survivaland overall
survivalstratified by PD-L1 expression.

Page 10 of 11

Conference on Harmonization, and the local regulatory requirements. The
study protocol and any amendments were approved by the Institutional
Review Board (Ref. 1911210–9/-2109B). All patients provided written informed
consent before participation.
Consent for publication
Not applicable.
Competing interests
Zhiguo Hou, Ting Yang, and Wenqing Zhu are employees of the Jiangsu
Hengrui Pharmaceuticals Co., Ltd. All the other authors declare no competinginterests.
Author details
1
Department of Gynecologic Oncology, Fudan University Shanghai Cancer
Center, 270 Dong’an Road, Xuhui District, Shanghai 200032, China. 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. 3 Department of Radiology, Shanghai Medical College,
Fudan University, Shanghai 200032, China. 4 Department of Nuclear Medicine,
Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai 200127, China.
5
School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
6
Department of Medical Affairs, Jiangsu Hengrui Pharmaceuticals Co., Ltd,
Shanghai 201210, China. 7 Department of Nursing, Fudan University Shanghai
Cancer Center, Shanghai 200032, China.
Received: 8 March 2024 Accepted: 14 August 2024

Additional file 2: Table S1. Data on exploratory biomarker analyses.
Acknowledgements
We would like to thank the patients and their families for participating in thisstudy. We want to thank the staff of the nursing team, radiology team, andclinical trial pharmacy from Fudan University Shanghai Cancer Center. We also
want to thank Ni Guan, Zijin Zhang, and Jinyun Sun from Jiangsu Hengrui
Pharmaceuticals Co., Ltd. for their support in data collection, statistical analysis,
and medical writing assistance.
Authors’ contributions
HW contributed to the conception, design, and control of the study. WTcontributed to patient recruitment and management, data collection andanalysis, and manuscript writing. YR recruited patients and collected the data.
WZ and CJ contributed to patient management and data collection. JL, HL,
and TW evaluated the radiographic examination. BS, HY, and XC contributed
to the patient’s recommendation. YZ contributed to the patient’s care. ZH
and TY contributed to the literature search, data analysis, and interpretation.
QWZ contributed to the statistical analyses. All authors contributed to criticallyreviewing or revising the manuscript, had full access to all the data in the
study, and had final responsibility for the decision to submit for publication. All
authors read and approved the final manuscript.
Funding
This study was supported by grants from the National Natural Science
Foundation of China (No. 82002758) and Technological innovation projects ofmedicine founded by the Science and Technology Commission of Shanghai
Municipality (20Z11900703). The study drugs (camrelizumab and apatinib)
were provided by Jiangsu Hengrui Pharmaceuticals Co., Ltd. free of charge.
Availability of data and materials
The datasets generated and/or analyzed during the current study are notpublicly available due to privacy or ethical restrictions but are available fromthe corresponding author upon reasonable request.

Declarations
Ethics approval and consent to participate
This study was performed in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice Guidelines of the International

References
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray
F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence andMortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin.
2021;71(3):209–49.
2. Gu B, Shang X, Yan M, Li X, Wang W, Wang Q, Zhang C. Variations in incidence and mortality rates of endometrial cancer at the global, regional,
and national levels, 1990–2019. Gynecol Oncol. 2021;161(2):573–80.
3. Han B, Zheng R, Zeng H, Wang S, Sun K, Chen R, Li L, Wei W, He J. Cancer
incidence and mortality in China, 2022. Journal of the National Cancer
Center. 2024;4(1):47–53.
4. Brooks RA, Fleming GF, Lastra RR, Lee NK, Moroney JW, Son CH, Tatebe K,
Veneris JL. Current recommendations and recent progress in endometrial
cancer. CA Cancer J Clin. 2019;69(4):258–79.
5 National Cancer Institute. Surveillance Epidemiology and End Results(SEER) program. Cancer Stat Facts; 2023.
6. Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, Thigpen
JT, Benda JA. Randomized phase III trial of whole-abdominal irradiation
versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol.
2006;24(1):36–44.
7. Gordhandas S, Zammarrelli WA, Rios-Doria EV, Green AK, Makker V.
Current Evidence-Based Systemic Therapy for Advanced and Recurrent
Endometrial Cancer. J Natl Compr Canc Netw. 2023;21(2):217–26.
8. O’Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus
AA, Miller WH Jr, Safra T, Italiano A, Mileshkin L, et al. Pembrolizumabin Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. J Clin Oncol.
2022;40(7):752–61.
9. Oaknin A, Tinker AV, Gilbert L, Samouëlian V, Mathews C, Brown J,
Barretina-Ginesta MP, Moreno V, Gravina A, Abdeddaim C, et al. Clinical Activity and Safety of the Anti-Programmed Death 1 Monoclonal
Antibody Dostarlimab for Patients With Recurrent or Advanced Mismatch
Repair-Deficient Endometrial Cancer: A Nonrandomized Phase 1 Clinical
Trial. JAMA Oncol. 2020;6(11):1766–72.
10. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A,
Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, et al. Efficacy ofPembrolizumab in Patients With Noncolorectal High Microsatellite
Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II
KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1–10.

Tian et al. BMC Medicine(2024) 22:344

11. Cortes-Ciriano I, Lee S, Park WY, Kim TM, Park PJ. A molecular portraitof microsatellite instability across multiple cancers. Nat Commun.
2017;8:15180.
12. Makker V, Aghajanian C, Cohn AL, Romeo M, Bratos R, Brose MS, Messing
M, Dutta L, Dutcus CE, Huang J, et al. A Phase Ib/II Study of Lenvatinib
and Pembrolizumab in Advanced Endometrial Carcinoma (Study 111/
KEYNOTE-146): Long-Term Efficacy and Safety Update. J Clin Oncol.
2023;41(5):974–9.
13. Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller
DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, et al. Lenvatinib
plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med.
2022;386(5):437–48.
14. Makker V, Taylor MH, Aghajanian C, Oaknin A, Mier J, Cohn AL, Romeo
M, Bratos R, Brose MS, DiSimone C, et al. Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. J Clin Oncol.
2020;38(26):2981–92.
15. Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, Di Simone
C, Hyman DM, Stepan DE, Dutcus CE, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis
of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol.
2019;20(5):711–8.
16. Zhao S, Ren S, Jiang T, Zhu B, Li X, Zhao C, Jia Y, Shi J, Zhang L, Liu X, et al.
Low-Dose Apatinib Optimizes Tumor Microenvironment and Potentiates Antitumor Effect of PD-1/PD-L1 Blockade in Lung Cancer. Cancer
Immunol Res. 2019;7(4):630–43.
17. Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, Chen Z, Jia W, Jin Y, Guo Y, et al.
Camrelizumab plus rivoceranib versus sorafenib as first-line therapy forunresectable hepatocellular carcinoma (CARES-310): a randomised, openlabel, international phase 3 study. Lancet. 2023;402(10408):1133–46.
18. Lan C, Shen J, Wang Y, Li J, Liu Z, He M, Cao X, Ling J, Huang J, Zheng M,
et al. Camrelizumab Plus Apatinib in Patients With Advanced Cervical
Cancer (CLAP): A Multicenter, Open-Label, Single-Arm. Phase II Trial J
Clin Oncol. 2020;38(34):4095–106.
19. Cheng H, Zong L, Kong Y, Wang X, Gu Y, Cang W, Zhao J, Wan X, Yang J,
Xiang Y. Camrelizumab plus apatinib in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia (CAP 01): asingle-arm, open-label, phase 2 trial. Lancet Oncol. 2021;22(11):1609–17.
20. Meng X, Wu T, Hong Y, Fan Q, Ren Z, Guo Y, Yang X, Shi P, Yang J, Yin X,
et al. Camrelizumab plus apatinib as second-line treatment for advanced
oesophageal squamous cell carcinoma (CAP 02): a single-arm, openlabel, phase 2 trial. Lancet Gastroenterol Hepatol. 2022;7(3):245–53.
21. Mao L, Lian B, Li C, Bai X, Zhou L, Cui C, Chi Z, Sheng X, Wang X, Tang B,
et al. Camrelizumab Plus Apatinib and Temozolomide as First-Line Treatment in Patients With Advanced Acral Melanoma: The CAP 03 Phase 2
Nonrandomized Clinical Trial. JAMA Oncol. 2023;9(8):1099–107.
22. Ding X, Zhang WJ, You R, Zou X, Wang ZQ, Ouyang YF, Peng L, Liu YP,
Duan CY, Yang Q, et al. Camrelizumab Plus Apatinib in Patients With
Recurrent or Metastatic Nasopharyngeal Carcinoma: An Open-Label,
Single-Arm. Phase II Study J Clin Oncol. 2023;41(14):2571–82.
23. Aghajanian C, Sill MW, Darcy KM, Greer B, McMeekin DS, Rose PG, Rotmensch J, Barnes MN, Hanjani P, Leslie KK. Phase II trial of bevacizumab
in recurrent or persistent endometrial cancer: a Gynecologic Oncology
Group study. J Clin Oncol. 2011;29(16):2259–65.
24. McMeekin S, Dizon D, Barter J, Scambia G, Manzyuk L, Lisyanskaya A,
Oaknin A, Ringuette S, Mukhopadhyay P, Rosenberg J, et al. Phase III
randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer. Gynecol Oncol.
2015;138(1):18–23.
25. Lheureux S, Matei DE, Konstantinopoulos PA, Wang BX, Gadalla R, BlockMS, Jewell A, Gaillard SL, McHale M, McCourt C, et al. Translationalrandomized phase II trial of cabozantinib in combination with nivolumab
in advanced, recurrent, or metastatic endometrial cancer. J Immunother
Cancer. 2022;10(3):e004233.
26. Wu X, Liang S, Chen X, Hou J, Wang K, Wang D, An R, Zang A, Li X, Zhang
B, et al. 555P TQB2450 injection combined with anlotinib hydrochloride
capsule in the treatment of advanced, recurrent or metastatic endometrial cancer: A multicohort, open label, multicenter phase II clinical trial- The TQB2450-II-08 trial. Ann Oncol. 2022;33:S802.
27. Lee EK, Xiong N, Cheng S, Polak M, Krasner CN, Campos SM, WrightAA, Liu JF, Shea M, Yeku OO, et al. A phase 2, two-stage study ofavelumab and axitinib in patients with mismatch repair–proficient

Page 11 of 11

28.

29.
30.
31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

(MMR-P) recurrent or persistent endometrial cancer (EC). J Clin Oncol.
2023;41(16_suppl):TPS5628–TPS5628.
Wei W, Ban X, Yang F, Li J, Cheng X, Zhang R, Huang X, Huang Y, Li Q, Qiu
Y, et al. Phase II trial of efficacy, safety and biomarker analysis of sintilimab
plus anlotinib for patients with recurrent or advanced endometrial cancer. J Immunother Cancer. 2022;10(5):e004338.
Di Donato V, Giannini A, Bogani G. Recent Advances in Endometrial
Cancer Management. J Clin Med. 2023;12(6):2241.
Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson
AG, Pashtan I, Shen R, Benz CC, et al. Integrated genomic characterizationof endometrial carcinoma. Nature. 2013;497(7447):67–73.
Bartl T, Onoprienko A, Hofstetter G, Müllauer L, Poetsch N, FuerederT, Kofler P, Polterauer S, Grimm C. Overweight as a Favorable Clinical
Biomarker for Checkpoint Inhibitor Therapy Response in Recurrent
Gynecologic Cancer Patients. Biomol. 2021;11(11):1700.
Bogani G, Chiappa V, Lopez S, Salvatore C, Interlenghi M, D’Oria O, Giannini A, Leone Roberti Maggiore U, Chiarello G, Palladino S, et al. Radiomics
and Molecular Classification in Endometrial Cancer (The ROME Study):
A Step Forward to a Simplified Precision Medicine. Healthcare (Basel).
2022;10(12):2464.
Ren Y, Wang T, Cheng X, Ke G, Huang Y, Yang H, Huang X, Tian W, Wang H.
Efficacy and safety of apatinib in patients with recurrent uterine malignancy: a prospective, single-center, single-arm, phase 2 study. Ann Transl
Med. 2023;11(2):106.
Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J, Bai Y, Yang L, Zhu H, Fang
W, et al. Camrelizumab in patients with previously treated advanced
hepatocellular carcinoma: a multicentre, open-label, parallel-group,
randomised, phase 2 trial. Lancet Oncol. 2020;21(4):571–80.
Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao
S, et al. Effect of Camrelizumab vs Placebo Added to Chemotherapy
on Survival and Progression-Free Survival in Patients With Advanced
or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st
Randomized Clinical Trial. JAMA. 2021;326(10):916–25.
Huang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, Chen J, Zhang H, Niu
Z, Fan Q, et al. Camrelizumab versus investigator’s choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal
squamous cell carcinoma (ESCORT): a multicentre, randomised, openlabel, phase 3 study. Lancet Oncol. 2020;21(6):832–42.
Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y,
et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced nonsquamous non-small-cell lung cancer (CameL): a randomised, open-label,multicentre, phase 3 trial. Lancet Respir Med. 2021;9(3):305–14.
Ren S, Chen J, Xu X, Jiang T, Cheng Y, Chen G, Pan Y, Fang Y, Wang Q,
Huang Y, et al. Camrelizumab Plus Carboplatin and Paclitaxel as First-Line
Treatment for Advanced Squamous NSCLC (CameL-Sq): A Phase 3 Trial. J
Thorac Oncol. 2022;17(4):544–57.
Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS,
Walsh K. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest.
2005;115(8):2108–18.
Song G, Zhang FF, Cheng HD. Thalidomide for prevention of camrelizumab-induced reactive cutaneous capillary endothelial proliferation.
Australas J Dermatol. 2022;63(2):217–21.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.