Abstract
Objective: The objective of this meta-analysis was to conduct a comprehensive assessment of the therapeutic effectiveness and safety profile of the combination of immune checkpoint inhibitors (ICIs) with either chemotherapy or tyrosine kinase inhibitors (TKIs) in the treatment of advanced-stage endometrial cancer (EC). Methods: This meta-analysis conducted a thorough literature search across PubMed, Cochrane Library, Embase, and Web of Science databases from their earliest records up to November 18, 2023, identifying qualified randomized controlled trials (RCTs), cohort studies, and single-arm trials for inclusion in the analysis. The meta-analysis were performed to quantify and analyzed the evidence from the existing literature, focusing on outcomes including the objective response rate (ORR), disease control rate (DCR), duration of response, overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Results: A total of 13 studies were included. In terms of ICI combined with chemotherapy, the single-arm trials showed that ICI combined with chemotherapy was effective in improving the ORR, but the overall rate of AE was higher. The results based on RCT suggested that ICI combined with chemotherapy resulted in a longer PFS of 12–24 months and OS of 18 months compared to the control group in advanced EC. In terms of ICI combined with TKI, the pooled ORR was 39.0%, the pooled DCR was 79.9%, the pooled OS rate was 50.4%, and the pooled overall AE rate was 95.8%, the pooled grade ≥3 AE rate was 73.8%, the pooled median progression-free survival was 6.126 months, and pooled OS was 15.099 months in advanced EC. Conclusions: The integrative therapeutic approach combining ICIs with chemotherapy or TKIs demonstrates notable clinical efficacy in advanced EC, which can prolong the survival and help disease control. Nevertheless, it is imperative for clinicians to be vigilant regarding the potential for adverse reactions to emerge. In addition, more RCTs are needed to solidify this study’s efficacy and safety further.
Journal Section:
Systematic Review
References
1.
Siegel
RL
, Miller
KD
, Wagle
NS
, Jemal
A
. Cancer statistics, 2023
. CA Cancer J Clin
. 2023
;73
(1
):17
–48
. 2.
Sung
H
, Ferlay
J
, Siegel
RL
, Laversanne
M
, Soerjomataram
I
, Jemal
A
, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
. CA Cancer J Clin
. 2021
;71
(3
):209
–49
. 3.
Gu
B
, Shang
X
, Yan
M
, Li
X
, Wang
W
, Wang
Q
, et al. 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
. 4.
Lu
KH
, Broaddus
RR
. Endometrial cancer
. N Engl J Med
. 2020
;383
(21
):2053
–64
. 5.
Ning
MS
, Ahobila
V
, Jhingran
A
, Stecklein
SR
, Frumovitz
M
, Schmeler
KM
, et al. Outcomes and patterns of relapse after definitive radiation therapy for oligometastatic cervical cancer
. Gynecol Oncol
. 2018
;148
(1
):132
–8
. 6.
Eskander
RN
, Sill
MW
, Beffa
L
, Moore
RG
, Hope
JM
, Musa
FB
, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer
. N Engl J Med
. 2023
;388
(23
):2159
–70
. 7.
Gao
FF
, Zhang
XL
, Chen
JL
, Zhang
TT
, Sui
XC
, Tang
YD
, et al. Tislelizumab combined with carboplatin-paclitaxel for treatment of metastatic or recurrent endometrial cancer: a retrospective clinical study
. Clin Lab
. 2022
;68
(11/2022
). 8.
Mirza
MR
, Chase
DM
, Slomovitz
BM
, dePont Christensen
R
, Novák
Z
, Black
D
, et al. Dostarlimab for primary advanced or recurrent endometrial cancer
. N Engl J Med
. 2023
;388
(23
):2145
–58
. 9.
Gotwals
P
, Cameron
S
, Cipolletta
D
, Cremasco
V
, Crystal
A
, Hewes
B
, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy
. Nat Rev Cancer
. 2017
;17
(5
):286
–301
. 10.
Randall
ME
, Filiaci
VL
, Muss
H
, Spirtos
NM
, Mannel
RS
, Fowler
J
, et al. 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
. 11.
Garon
EB
, Hellmann
MD
, Rizvi
NA
, Carcereny
E
, Leighl
NB
, Ahn
MJ
, et al. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study
. J Clin Oncol
. 2019
;37
(28
):2518
–27
. 12.
Gandhi
L
, Rodríguez-Abreu
D
, Gadgeel
S
, Esteban
E
, Felip
E
, De Angelis
F
, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer
. N Engl J Med
. 2018
;378
(22
):2078
–92
. 13.
Mo
Z
, Liu
J
, Zhang
Q
, Chen
Z
, Mei
J
, Liu
L
, et al. Expression of PD-1, PD-L1 and PD-L2 is associated with differentiation status and histological type of endometrial cancer
. Oncol Lett
. 2016
;12
(2
):944
–50
. 14.
Chaft
JE
, Oezkan
F
, Kris
MG
, Bunn
PA
, Wistuba
II
, Kwiatkowski
DJ
, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial
. Nat Med
. 2022
;28
(10
):2155
–61
. 15.
Hurwitz
H
, Fehrenbacher
L
, Novotny
W
, Cartwright
T
, Hainsworth
J
, Heim
W
, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer
. N Engl J Med
. 2004
;350
(23
):2335
–42
. 16.
Hantschel
O
. Unexpected off-targets and paradoxical pathway activation by kinase inhibitors
. ACS Chem Biol
. 2015
;10
(1
):234
–45
. 17.
Lamore
SD
, Kohnken
RA
, Peters
MF
, Kolaja
KL
. Cardiovascular toxicity induced by kinase inhibitors: mechanisms and preclinical approaches
. Chem Res Toxicol
. 2020
;33
(1
):125
–36
. 18.
Vergote
I
, Teneriello
M
, Powell
MA
, Miller
DS
, Garcia
AA
, Mikheeva
ON
, et al. A phase II trial of lenvatinib in patients with advanced or recurrent endometrial cancer: angiopoietin-2 as a predictive marker for clinical outcomes
. J Clin Oncol
. 2013
;31
(15_Suppl l
):5520
. 19.
Aghajanian
C
, Sill
MW
, Darcy
KM
, Greer
B
, McMeekin
DS
, Rose
PG
, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study
. J Clin Oncol
. 2011
;29
(16
):2259
–65
. 20.
McMeekin
S
, Dizon
D
, Barter
J
, Scambia
G
, Manzyuk
L
, Lisyanskaya
A
, 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
. 21.
Makker
V
, Colombo
N
, Casado Herráez
A
, Santin
AD
, Colomba
E
, Miller
DS
, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer
. N Engl J Med
. 2022
;386
(5
):437
–48
. 22.
Makker
V
, Rasco
D
, Vogelzang
NJ
, Brose
MS
, Cohn
AL
, Mier
J
, 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
. 23.
Slim
K
, Nini
E
, Forestier
D
, Kwiatkowski
F
, Panis
Y
, Chipponi
J
. Methodological index for non-randomized studies (minors): development and validation of a new instrument
. ANZ J Surg
. 2003
;73
(9
):712
–6
. 24.
Stang
A
. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses
. Eur J Epidemiol
. 2010
;25
(9
):603
–5
. 25.
Jadad
AR
, Moore
RA
, Carroll
D
, Jenkinson
C
, Reynolds
DJ
, Gavaghan
DJ
, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary
. Control Clin Trials
. 1996
;17
(1
):1
–12
. 26.
Barber
EL
, Chen
S
, Pineda
MJ
, Robertson
SE
, Hill
EK
, Teoh
D
, et al. Clinical and biological activity of chemoimmunotherapy in advanced endometrial adenocarcinoma: a phase II trial of the big ten cancer research consortium
. Cancer Res Commun
. 2022
;2
(10
):1293
–303
. 27.
Cui
Q
, Mao
Y
, Hu
Y
, Ma
D
, Liu
H
. Anlotinib in recurrent or metastatic endometrial cancer
. Int J Gynecol Cancer
. 2022
;32
(9
):1147
–52
. 28.
How
JA
, Patel
S
, Fellman
B
, Lu
KH
, Hwu
P
, Ramondetta
LM
, et al. Toxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer
. Gynecol Oncol
. 2021
;162
(1
):24
–31
. 29.
Kim
J
, Noh
JJ
, Lee
TK
, Kim
SI
, Lee
JY
, Lee
JW
, et al. Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: a multicenter study in Korea
. Gynecol Oncol
. 2022
;165
(2
):369
–75
. 30.
Makker
V
, Aghajanian
C
, Cohn
AL
, Romeo
M
, Bratos
R
, Brose
MS
, 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
. 31.
Pignata
S
, Scambia
G
, Schettino
C
, Arenare
L
, Pisano
C
, Lombardi
D
, et al. Carboplatin and paclitaxel plus avelumab compared with carboplatin and paclitaxel in advanced or recurrent endometrial cancer (MITO END-3): a multicentre, open-label, randomised, controlled, phase 2 trial
. Lancet Oncol
. 2023
;24
(3
):286
–96
. 32.
Wei
W
, Ban
X
, Yang
F
, Li
J
, Cheng
X
, Zhang
R
, 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
. 33.
Westin
SN
, Moore
K
, Chon
HS
, Lee
JY
, Thomes Pepin
J
, Sundborg
M
, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial
. J Clin Oncol
. 2024
;42
(3
):283
–99
. 34.
Zammarrelli
WA
3rd, Ma
W
, Espino
K
, Gordhandas
S
, Yeoshoua
E
, Ehmann
S
, et al. Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer
. Gynecol Oncol
. 2023
;178
:27
–35
. 35.
Makker
V
, Colombo
N
, Casado Herráez
A
, Monk
BJ
, Mackay
H
, Santin
AD
, et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: updated efficacy and safety from the randomized phase III study 309/KEYNOTE-775
. J Clin Oncol
. 2023
;41
(16
):2904
–10
. 36.
Mamat Yusof
MN
, Chew
KT
, Hafizz
A
, Abd Azman
SH
, Ab Razak
WS
, Hamizan
MR
, et al. Efficacy and safety of PD-1/PD-L1 inhibitor as single-agent immunotherapy in endometrial cancer: a systematic review and meta-analysis
. Cancers
. 2023
;15
(16
):4032
. 37.
Chen
L
, Mo
DC
, Hu
M
, He
W
, Yang
QW
, Tang
J
. Combination therapy with immune checkpoint inhibitors in recurrent or metastatic squamous cell carcinoma of the head and neck: a meta-analysis
. Int Immunopharmacol
. 2023
;119
:110270
. 38.
Cancer Genome Atlas Research Network
; Kandoth
C
, Schultz
N
, Cherniack
AD
, Akbani
R
, Liu
Y
, et al. Integrated genomic characterization of endometrial carcinoma
. Nature
. 2013
;497
(7447
):67
–73
. 39.
Ott
PA
, Bang
YJ
, Berton-Rigaud
D
, Elez
E
, Pishvaian
MJ
, Rugo
HS
, et al. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study
. J Clin Oncol
. 2017
;35
(22
):2535
–41
. 40.
van Halteren
HK
, Bennouna
J
, Brasiuniene
B
, Tomas
AJC
, Trinidad
AMG
, Indini
A
, et al. Twelve ESMO Congress 2022 breakthroughs: practicing oncologists’ perceptions and potential application on presented data
. ESMO Open
. 2023
;8
(1
):100773
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