Articles

Pembrolizumab or placebo with chemoradiotherapy

followed by pembrolizumab or placebo for newly diagnosed,
high-risk, locally advanced cervical cancer (ENGOT-cx11/
GOG-3047/KEYNOTE-A18): overall survival results from a
randomised, double-blind, placebo-controlled, phase 3 trial
Domenica Lorusso, Yang Xiang, Kosei Hasegawa, Giovanni Scambia, Manuel Leiva, Pier Ramos-Elias, Alejandro Acevedo, Jakub Cvek,
Leslie Randall, Andrea Juliana Pereira de Santana Gomes, Fernando Contreras Mejía, Limor Helpman, Hüseyin Akıllı, Jung-Yun Lee,
Valeriya Saevets, Flora Zagouri, Lucy Gilbert, Jalid Sehouli, Ekkasit Tharavichitkul, Kristina Lindemann, Nicoletta Colombo, Chih-Long Chang,
Marketa Bednarikova, Hong Zhu, Ana Oaknin, Melissa Christiaens, Edgar Petru, Tomoka Usami, Peng Liu, Karin Yamada, Sarper Toker,
Stephen M Keefe, Sandro Pignata*, Linda R Duska*, on behalf of the ENGOT-cx11/GOG-3047/KEYNOTE-A18 investigators†

Summary
Background At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of Published Online
pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in September 14, 2024
https://doi.org/10.1016/
progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from S0140-6736(24)01808-7
the second interim analysis of this study.
See Online/Comment
https://doi.org/10.1016/
Methods Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2–IIB with node-positive disease or S0140-6736(24)01918-4
stage III–IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, *Contributed equally
adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of †A complete list of principal
pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of investigators who participated in
pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered the ENGOT-cx11/GOG-3047/
KEYNOTE-A18 study is provided
intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity- in the appendix (pp 2–6)
modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical Gynaecology Oncology Unit,
cancer stage at screening (FIGO 2014 stage IB2–IIB node positive vs III–IVA), and planned total radiotherapy Fondazione Policlinico
(external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints Universitario A Gemelli IRCCS,
were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected Rome, Italy
(Prof D Lorusso MD PhD);
disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety Gynaecology Oncology Unit,
was a secondary endpoint. Humanitas San Pio X, Milan,
Italy (Prof D Lorusso);
Findings Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Department of Obstetrics and
Gynecology, Peking Union
Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the Medical College Hospital,
pembrolizumab–chemoradiotherapy group and 531 patients in the placebo–chemoradiotherapy group. At the protocol- National Clinical Research
specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3–34·3). Center for Obstetric &
Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4–86·1) in Gynecologic Diseases, Beijing,
China (Prof Y Xiang MD);
the pembrolizumab–chemoradiotherapy group and 74·8% (70·1–78·8) in the placebo–chemoradiotherapy group. The Department of Obstetrics and
hazard ratio for death was 0·67 (95% CI 0·50–0·90; p=0·0040), meeting the protocol-specified primary objective. Gynecology, Saitama Medical
413 (78%) of 528 patients in the pembrolizumab–chemoradiotherapy group and 371 (70%) of 530 in the placebo– University International
chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and Medical Center, Hidaka,
Saitama, Japan
neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events (Prof K Hasegawa MD PhD);
occurred in 206 (39%) of 528 patients in the pembrolizumab–chemoradiotherapy group and 90 (17%) of 530 patients in Scientific Directorate,
the placebo–chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. Fondazione Policlinico
Universitario Agostino Gemelli
IRCCS and Catholic University
Interpretation Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally of the Sacred Heart, Rome, Italy
advanced cervical cancer These data, together with results from the first interim analysis, support this immuno- (Prof G Scambia MD); Oncología
chemoradiotherapy strategy as a new standard of care for this population. Médica, Instituto Peruano de
Oncología y Radioterapia,
Lima, Perú (M Leiva MD MSc);
Funding Merck Sharp & Dohme, a subsidiary of Merck & Co. Oncología Médica, Integra
Cancer Institute, Edificio
Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, Integra Medical Center,
Guatemala City, Guatemala
and similar technologies.

www.thelancet.com Published online September 14, 2024 https://doi.org/10.1016/S0140-6736(24)01808-7 1

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(P Ramos-Elias MD);
Oncocentro, Valparaiso, Chile Research in context
(A Acevedo MD); Department of
Oncology, University of Evidence before this study Added value of this study
Ostrava, North Moravia, Czech Novel treatment advances for high-risk locally advanced At the second protocol-specified interim analysis of the ENGOT-
Republic (J Cvek MD PhD MBA); cervical cancer have been limited for more than two decades, cx11/GOG-3047/KEYNOTE-A18 study, we determined that
Gynecologic Oncology, Virginia
Commonwealth University,
with improvement in local control with modern radiotherapy pembrolizumab, when administered in combination with and
Massey Comprehensive Cancer techniques. We searched PubMed for phase 3 clinical trials after chemoradiotherapy, provides an overall survival benefit as
Center, Richmond, VA, USA published in English between Jan 1, 2013, and Jan 1, 2023, with compared with chemoradiotherapy alone for the treatment of
(Prof L Randall MD); Oncologia the terms “locally advanced cervical cancer” and newly diagnosed, high-risk, locally advanced cervical cancer. On
Clínica, Liga Norte
Riograndense Contra o Cancer,
“immunotherapy” and found that no positive study results the basis of these results, the trial met its second protocol-
Natal, Rio Grande do Norte, were reported. Subsequent to the previous disappointing specified primary objective. Adverse events were consistent
Brazil (A J Pereira de Santana results with chemoradiotherapy-based combination regimens with the prior interim analysis and the known safety profiles of
Gomes MD); Oncología Clínica,
in patients with locally advanced cervical cancer, results from each regimen.
Instituto Nacional de
Cancerologia, the first protocol-specified interim analysis of the global,
Implications of all the available evidence
Bogota, Colombia randomised, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18
To our knowledge, this is the first phase 3 study to report a
(F Contreras Mejía MD); Meir study showed that the addition of pembrolizumab to
Medical Center, Sackler School statistically significant and clinically meaningful improvement
chemoradiotherapy provided a statistically significant and
of Medicine, Tel Aviv in overall survival with the combination of a PD-1 inhibitor with
University, Kfar Saba, Israel clinically meaningful improvement in progression-free survival
modern, high-quality chemoradiotherapy in newly diagnosed,
(L Helpman MD MSc MPH); as compared with chemoradiotherapy alone in patients with
high-risk, locally advanced cervical cancer. These data support
Turkish Society of Gynecologic high-risk locally advanced cervical cancer.
Oncology, Başkent University, this strategy as a new standard of care for this population.
Ankara, Turkiye (H Akıllı MD);
Yonsei Cancer Center and
Severance Hospital, Yonsei
University College of Medicine, Introduction of disease progression as assessed by investigator review
Seoul, South Korea Cervical cancer is the fourth most common neoplasm in or death by 30% in the intention-to-treat population
(J-Y Lee MD PhD);
Gynaecological Oncology,
women worldwide, with approximately 660 000 new (hazard ratio 0·70, 95% CI 0·55–0·89; p=0·0020), with a
Chelyabinsk Regional Clinical cases and 350 000 deaths in 2022.1 Standard of care for higher 2-year progression-free survival in the
Center for Oncology and locally advanced disease is external beam radiotherapy pembrolizumab–chemoradiotherapy group (68%,
Nuclear Medicine, Chelyabinsk, with concurrent chemotherapy followed by 95% CI 62–73) as compared with the placebo–
Russia (V Saevets MD PhD);
Clinical Therapeutics,
brachytherapy,2–4 with few new therapeutic advances for chemoradiotherapy group (57%, 51–63). In this Article,
Alexandra Hospital, Athens, more than two decades beyond modern, image-guided we report the primary overall survival results from the
Greece (Prof F Zagouri MD PhD); radiotherapy and brachytherapy, which translated to protocol-specified second interim analysis of this study.
Division of Gynecologic improved long-term local control and reduced toxicity.5
Oncology, McGill University
Health Centre, Research
Patients with high-risk, locally advanced cervical cancer Methods
Institute-McGill University often have poor outcomes despite treatment with curative Study design and population
Health Centre, Gerald intent. 5-year progression-free survival and overall ENGOT-cx11/GOG-3047/KEYNOTE-A18 is an ongoing
Bronfman Department of survival range from 47% to 80%,5–7 which worsen in randomised, double-blind, placebo-controlled,
Oncology McGill University,
Montreal, QC, Canada
patients with advanced stage disease8,9 or nodal phase 3 trial being conducted at 176 sites in 30 countries
(Prof L Gilbert MD MSc); involvement.10 These data highlight a need for additional across Asia, Australia, Europe, North America, and South
Department of Gynecology, treatment options beyond the current standard of care to America; a full list of participating sites is provided in the
Charite Universitaetsmedizin,
improve prognosis. appendix (p 2). The complete methodology for this study
Berlin, Germany
(Prof J Sehouli MD PhD); North- The anti-PD-1 monoclonal antibody pembrolizumab was previously described,15 and the trial protocol is
Eastern German Society of has shown efficacy in patients with cervical cancer as available in the appendix. The patient eligibility criteria
Gynecological Oncology, Berlin, monotherapy and combined with chemotherapy with or included age of 18 years or older, newly diagnosed, high-
Germany (Prof J Sehouli);
without bevacizumab.11–14 We conducted the global, risk (FIGO 2014 stage IB2–IIB with node-positive disease
Division of Radiation Oncology,
Department of Radiology, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial to or stage III–IVA regardless of nodal status), locally
Faculty of Medicine, Chiang evaluate whether pembrolizumab, when administered in advanced, histologically confirmed squamous cell
Mai University, combination with and after chemoradiotherapy, would carcinoma, adenocarcinoma, or adenosquamous
Chiang Mai, Thailand
improve outcomes compared with chemoradiotherapy carcinoma of the cervix; an Eastern Cooperative Oncology
(Prof E Tharavichitkul MD);
Department of Gynecological alone in patients with newly diagnosed, high-risk, locally Group performance status score of 0 or 1;16 evaluable
Oncology, Oslo University advanced cervical cancer. At the first protocol-specified disease per Response Evaluation Criteria in Solid
Hospital and the Institute of interim analysis, the addition of pembrolizumab to Tumours (RECIST) version 1.1;17 provision of a tumour
Clinical Medicine, University of
chemoradiotherapy provided a statistically significant tissue sample collected from a core, incisional, or
Oslo, Oslo, Norway
(Prof K Lindemann MD PhD); and clinically meaningful improvement in progression- excisional biopsy; and adequate organ function. Key
Nordic Society of free survival.15 After a median study follow-up of exclusion criteria included other histological cervical
Gynaecological Oncology 17·9 months (IQR 11·3–22·3), the addition of cancer subtypes; FIGO 2014 stage IVB disease; previous
Clinical Trial Unit,
pembrolizumab to chemoradiotherapy reduced the risk hysterectomy; and previous systemic therapy,

2 www.thelancet.com Published online September 14, 2024 https://doi.org/10.1016/S0140-6736(24)01808-7

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immunotherapy, definitive surgery, or radiation. The 6 weeks. Pembrolizumab or placebo was started on day 1 Rigshospitalet, Copenhagen
complete inclusion and exclusion criteria are available in of cycle 1 of concurrent chemoradiation. Pembrolizumab University Hospital,
Copenhagen, Denmark
the study protocol (appendix p 276). During screening or placebo and cisplatin were administered intravenously. (Prof K Lindemann);
and when permitted by law, patients self-reported their The chemoradiotherapy regimen included five cycles Department of Obstetrics and
sex as female, male, undifferentiated, or unknown, their (with an optional sixth dose per the investigator’s Gynecology, University of
race as one or more of American Indian or Alaska discretion) of cisplatin (40 mg/m²) once weekly plus Milan-Bicocca and European
Institute of Oncology IRCCS, –
Native, Asian, Black or African American, external beam radiotherapy followed by brachytherapy. Milan, Italy (N Colombo MD);
Native Hawaiian or Other Pacific Islander, or White, and Radiotherapy quality was evaluated by a central vendor Department of Obstetrics and
their ethnicity as Hispanic or Latino, Not Hispanic or before study initiation and for each patient treatment Gynecology, MacKay Memorial
Latino, or Unknown. plan throughout the study. Hospital, Taipei, Taiwan
(Prof C-L Chang MD PhD);
This trial was conducted in accordance with the Study treatment was continued until the planned Department of Internal
standards of Good Clinical Practice and the Declaration number of cycles for each treatment component, Medicine, Hematology and
of Helsinki. The trial protocol and all protocol radiographic progression, disease recurrence, Oncology, University Hospital
amendments were approved by the appropriate ethics unacceptable toxicity, confirmed positive pregnancy test, Brno and Faculty of Medicine,
Masaryk University, Brno,
committee at each participating institution. Clinically investigator decision, or patient withdrawal of consent Czech Republic
important deviations from protocol-directed require­ and could be interrupted or discontinued to manage (M Bednarikova MD PhD);
ments are listed in the appendix (p 8). An external, toxicity at the investigator’s discretion. Complete details Department of Oncology,
regarding treatment decisions and adverse event Xiangya Hospital, Central
independent data monitoring committee oversaw the
South University, Hunan, China
trial, periodically assessed safety, and assessed efficacy at management are included in the study protocol (Prof H Zhu MD); Medical
prespecified interim analyses. All patients provided (appendix p 241). Oncology Service, Vall
written informed consent before enrolment. Tumour imaging was scheduled at week 12 after the d’Hebron Institute of
Oncology, Vall d’Hebron
completion of chemoradiotherapy, every 12 weeks in
Barcelona Hospital Campus,
Randomisation and masking years 1 and 2, every 24 weeks in year 3, and once yearly Barcelona, Spain
Patients were randomly assigned, in a 1:1 ratio, to thereafter. PD-L1 expression was assessed during (Prof A Oaknin MD PhD);
pembrolizumab plus chemoradiotherapy followed by screening at an independent central laboratory using Department of Radiation
Oncology, University Hospitals
pembrolizumab (the pembrolizumab–chemo­ radio­ PD-L1 IHC 22C3 pharmDx (Agilent Technologies;
Leuven, Leuven, Belgium
therapy group) or placebo plus chemoradiotherapy Carpinteria, CA, USA) and measured according to the (M Christiaens MD);
followed by placebo (the placebo–chemoradiotherapy combined positive score, defined as number of PD-L1- Department of Obstetrics and
group). Patients were stratified before randomisation staining cells (tumour cells, lymphocytes, and Gynecology, Medical University
of Graz, Graz, Austria
according to planned external beam radiotherapy type macrophages) divided by the total number of viable
(Prof E Petru MD); AGO-Austria,
(intensity-modulated radiotherapy [IMRT] or volumetric- tumour cells, multiplied by 100. Specimens with a Innsbruck, Austria
modulated arc therapy [VMAT] vs non-IMRT or non- combined positive score of 1 or greater were considered (Prof E Petru); Department of
VMAT), cervical cancer stage at screening (FIGO 2014 PD-L1-positive. Patients were eligible for the study Obstetrics and Gynecology,
Ehime University Hospital,
stage IB2–IIB node positive vs III–IVA), and planned regardless of PD-L1 status.
Toon, Ehime, Japan
total radiotherapy (external beam radiotherapy plus Adverse events and laboratory abnormalities were (T Usami MD PhD); Merck & Co,
brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose monitored throughout the study and for 30 days after Rahway, NJ, USA (P Liu PhD,
of 2 Gy]). Randomisation was performed centrally using treatment discontinuation (90 days for serious adverse K Yamada MD MSc,
S Toker MD MBA,
an integrated interactive voice-response and Web- events). They were graded according to the National S M Keefe MD MSCE);
response system. The randomisation block size was 4. Cancer Institute Common Terminology Criteria for Department of Urology and
This was a double-blind study for pembrolizumab; Adverse Events, version 5.0. Immune-mediated adverse Gynecology, Istituto Nazionale
thus, the patients, investigators, other study site staff events were programmatically determined from a Tumori IRCCS Fondazione G.
Pascale, Napoli, Italy
(except the unmasked pharmacist), and sponsor predefined list of Medical Dictionary for Regulatory (S Pignata MD PhD); Gynelogic
personnel or delegates were masked to pembrolizumab Activities (MedDRA) terms and are reported regardless Oncology, University of
versus saline placebo administration. The unmasked of investigator attribution to treatment to provide the Virginia School of Medicine,
pharmacist provided the masked study site staff with most conservative estimates of risk. Charlottesville, VA, USA
(Prof L R Duska MD MPH)
ready-to-use identically packaged pembrolizumab and
Correspondence to:
saline infusion solutions for administration at scheduled Outcomes Prof Domenica Lorusso,
infusion visits. The two primary study endpoints were progression-free Gynaecology Oncology Unit,
survival assessed per RECIST version 1.1 by investigator Humanitas San Pio X,
Procedures review or by histopathological confirmation of suspected 20159 Milan, Italy
domenica.lorusso@hunimed.
The patients in the pembrolizumab–chemoradiotherapy progression and overall survival defined as the time from eu
group received five cycles of pembrolizumab 200 mg randomisation to death due to any cause. Key secondary
See Online for appendix
every 3 weeks plus chemoradiotherapy followed by endpoints include progression-free survival assessed per
15 cycles of pembrolizumab 400 mg every 6 weeks. The RECIST version 1.1 by blinded independent central review,
patients in the placebo–chemoradiotherapy group the percentage of patients alive and progression-free at
received five cycles of placebo every 3 weeks plus 24 months, the percentage of patients alive at 36 months,
chemoradiotherapy followed by 15 cycles of placebo every progression-free survival and overall survival by PD-L1

www.thelancet.com Published online September 14, 2024 https://doi.org/10.1016/S0140-6736(24)01808-7 3

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when approximately 182 deaths were expected to have

1562 patients screened occurred. The efficacy analyses were conducted in the
intention-to-treat population, which included all randomly
502 excluded because they did not
assigned patients, and the safety analyses were conducted
meet eligibility criteria in the as-treated population, which included all patients
who received at least one dose of study treatment. The
non-parametric Kaplan–Meier method was used to
1060 randomly assigned
estimate the survival curves. The stratified log-rank test
was used to assess between-group differences, with the
stratified Cox model with Efron’s method of tie handling
529 assigned to pembrolizumab* 531 assigned to placebo* and with a single treatment covariate applied to assess the
(intention-to-treat) (intention-to-treat) magnitude of the difference. The hazard ratio and
associated 95% CI were derived using the stratified Cox
1 patient excluded due to 1 patient excluded model. The randomisation stratification factors were
physician decision due to protocol violation applied to all stratified analyses. The statistical analyses
were performed with SAS (version 9.4). The consistency of
the treatment effect in protocol-specified subgroups with
528 received treatment as assigned 530 received treatment as assigned
(as-treated population) (as-treated population) the overall population was assessed descriptively by means
of hazard ratios and associated 95% CIs using the non-
stratified Cox proportional hazards model. The
223 discontinued treatment 236 discontinued treatment
64 adverse event 24 adverse event
proportional hazard assumption was assessed by
4 clinical progression 9 clinical progression examining scaled Schoenfeld residuals.
6 protocol 1 protocol The graphical method of Maurer and Bretz18 was used to
non-compliance non-compliance
8 physician decision 7 physician decision control the family-wise type I error rate at a one-sided
2 progressive disease† 8 progressive disease† α of 0·025, with all alpha initially allocated to test
1 lost to follow-up‡ 1 lost to follow-up‡
108 radiographic 158 radiographic
progression-free survival superiority and overall survival
progression progression tested hierarchically following the successful outcome of
30 patient decision 28 patient decision progression-free survival. The prespecified statistical
analysis plan allows α from successful hypothesis to be
passed to the other hypothesis. Because there was a
219 completed 86 remained on 209 completed 85 remained on
statistically significant improvement in progression-free
treatment treatment treatment treatment survival in the pembrolizumab–chemoradiotherapy group
compared with the placebo–chemoradiotherapy group at
Figure 1: Trial profile the first interim analysis, all the α was passed to overall
*The treatment regimen in both groups included chemoradiotherapy. †Defined as histopathological progression survival, which was therefore tested by α of 0·025 at the
without radiographic progression. Histopathological confirmation of suspected disease progression in the absence second interim analysis. Statistical boundaries at each
of radiographic disease progression per RECIST 1.1 was allowed, but not required. ‡One patient in each treatment
group discontinued study medication due to loss to follow-up, whereas two of 91 patients in the pembrolizumab– interim analysis were updated using a Lan-DeMets
chemoradiotherapy group vs three of 119 patients in the placebo–chemoradiotherapy group discontinued from O’Brien-Fleming spending function based on the
the trial due to loss to follow-up. information fraction and α-level of the endpoint at each
interim analysis. The planned total enrolment of
status, the time from randomisation to subsequent approximately 980 patients was increased by
disease progression after initiation of new anticancer approximately 10% in June, 2022, to mitigate the risk of
therapy or death from any cause (termed progression-free potential dropout associated with the COVID-19 pandemic
survival 2), the objective response rate, the percentage of and the Russia–Ukraine war. The full statistical analysis
patients with confirmed complete response at 12 weeks, plan is available in the protocol.
patient-reported quality of life (reported previously15), and This study is registered with ClinicalTrials.gov,
safety. The original protocol, final protocol, and a summary NCT04221945.
of protocol changes are available in the appendix.
Role of the funding source
Statistical analysis The funder of the study participated in study design, data
The statistical analysis plan prespecified two interim collection, data analysis, data interpretation, and writing
analyses and a final analysis; the statistical plan and the of the report.
primary progression-free survival endpoint results were
previously reported.15 The results herein are from the Results
protocol-specified second interim analysis (data cutoff date From June 9, 2020, to Dec 15, 2022, 1060 patients
Jan 8, 2024), planned to occur approximately 34 months were randomly assigned to the pembrolizumab–
after the first patient had been randomly assigned and chemoradiotherapy group (n=529) or the

4 www.thelancet.com Published online September 14, 2024 https://doi.org/10.1016/S0140-6736(24)01808-7

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Pembrolizumab– Placebo– A
chemoradiotherapy chemoradiotherapy
100
(N=529) (N=531)
90
Age 80

Overall survival (%)

70
Median (IQR), years 49 (40–57) 50 (41–59) 60
≥65 years 56 (11%) 77 (15%) 50
40
Race Hazard ratio 0·67 (95% CI 0·50–0·90; one-sided p=0·0040)
30
White 254 (48%) 264 (50%) 20 Pembrolizumab–chemoradiotherapy group
Asian 156 (29%) 148 (28%) 10 Placebo–chemoradiotherapy group
0
Multiple 78 (15%) 86 (16%) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
American Indian or 24 (5%) 22 (4%) Time since randomisation (months)
Number at risk
Alaska Native (number censored)
Black or African American 14 (3%) 8 (2%) Pembrolizumab–chemoradiotherapy 529 527 522 509 500 463 412 374 326 273 210 136 63 11 1
group (0) (2) (3) (3) (3) (32) (68) (100) (141) (188) (246) (319) (391) (443) (453)
Native Hawaiian or other 2 (<1%) 1 (<1%) Placebo–chemoradiotherapy 531 527 518 508 493 455 405 366 316 259 194 125 58 12 0
Pacific Islander group (0) (0) (1) (2) (3) (30) (64) (92) (129) (177) (233) (298) (365) (410) (422)
Missing 1 (<1%) 2 (<1%)
Eastern Cooperative Oncology Group status score*
B
Events/patients Hazard ratio
0 380 (72%) 398 (75%) (95% CI)
1 149 (28%) 133 (25%)
Age, years
FIGO 2014 stage at screening
<65 162/927 0·61 (0·44–0·83)
IB2 to IIB 233 (44%) 226 (43%) ≥65 22/133 1·35 (0·58–3·11)
III to IVA 296 (56%) 305 (57%) Race
Lymph node involvement† White 96/518 0·92 (0·61–1·37)
Positive pelvic only 327 (62%) 324 (61%) All others 88/539 0·48 (0·31–0·74)
Positive para-aortic only 14 (3%) 10 (2%) Eastern Cooperative Oncology Group performance status score
Positive pelvic and para- 104 (20%) 104 (20%) 0 134/778 0·67 (0·47–0·94)
aortic 1 50/282 0·68 (0·39–1·20)
No positive pelvic or para- 84 (16%) 93 (18%) Planned external beam radiation therapy
aortic IMRT/VMAT 164/939 0·67 (0·49–0·92)
Histology non-IMRT/-VMAT 20/121 0·69 (0·28–1·69)
Non-squamous‡ 95 (18%) 80 (15%) FIGO 2014 stage

Squamous 434 (82%) 451 (85%) IB2 to IIB 68/459 0·89 (0·55–1·44)
III to IVA 116/601 0·57 (0·39–0·83)
Planned type of external beam radiation therapy
Planned total radiotherapy dose
IMRT or VMAT 469 (89%) 470 (89%)
<70 gy 16/93 0·64 (0·23–1·75)
Non-IMRT and non-VMAT 60 (11%) 61 (11%)
≥70 gy 168/967 0·68 (0·50–0·92)
Planned total radiotherapy dose (Gy in equivalent dose in 2 Gy Overall 184/1060 0·67 (0·50–0·90)
fractions)
<70 Gy 47 (9%) 46 (9%) 0·25 0·50 1·00 2·00 4·00

≥70 Gy 482 (91%) 485 (91%) Favours Favours

PD-L1 combined positive score pembrolizumab–chemoradiotherapy placebo–chemoradiotherapy
<1 22 (4%) 28 (5%)
Figure 2: Overall survival
≥1 502 (95%) 498 (94%) (A) Kaplan-Meier estimates of overall survival in the intention-to-treat population. Tick marks indicate censoring
Missing 5 (1%) 5 (1%) of data. (B) Analysis of overall survival in protocol-specified subgroups of the intention-to-treat population.
IMRT=intensity-modulated radiation therapy. VMAT=volumetric modulated arc therapy.
Data are n (%), unless otherwise specified. *IMRT=intensity-modulated radiation
therapy. VMAT=volumetric modulated arc therapy. Scores range from 0 to 5,
with 0 indicating no symptoms and higher scores indicating greater disability. †Per definitive surgery, or radiation (figure 1). As previously
protocol, a positive lymph node is defined as ≥1·5 cm shortest dimension by MRI
or CT. ‡Includes adenocarcinoma and adenosquamous carcinoma.
reported,15 the baseline demographics and disease
characteristics were generally balanced between the two
Table 1: Baseline demographic and disease characteristics in the treatment groups (table 1). At screening, 601 (57%)
intention-to-treat population
of 1060 patients had FIGO 2014 stage III–IVA cervical
cancer; 651 (61%) had positive pelvic lymph nodes,
placebo–chemoradiotherapy group (n=531). 502 (32%) 24 (2%) had positive para-aortic lymph nodes, 208 (20%)
of the 1562 screened patients were not assigned, had positive pelvic and para-aortic lymph nodes, and
498 of whom because they did not meet the eligibility 177 (17%) had node negative disease; and 1000 (94%) had
criteria. 25 (5%) of the 498 patients who did not meet PD-L1-positive status.
the eligibility criteria were excluded because they had At the protocol-specified second interim analysis, the
received previous systemic therapy, immunotherapy, median time from randomisation to data cutoff was

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29·9 months (IQR 23·3–34·3). Of the 1060 patients 109 patients (21%) in the placebo–chemoradiotherapy
randomly assigned to treatment, all but two—one in each group had died (76·7% information fraction), with a
treatment group—started study treatment, 428 (40%) hazard ratio of 0·67 (95% CI 0·50–0·90; one-sided
completed study treatment, and 459 (43%) discontinued p=0·0040; figure 2A). According to the prespecified
study treatment, predominantly owing to radiographic statistical boundary of 0·01026 (one-sided) at the second
progression (n=266 [25%]) and adverse events (n=88 [8%]; interim analysis, there was a statistically significant
figure 1). At the time of this interim analysis, 171 patients improvement in overall survival in the pembrolizumab–
(16%) remained on study medication. chemoradiotherapy group as compared with the placebo–
At the Jan 8, 2024, data cutoff date, 75 patients (14%) in chemoradiotherapy group, making this the final,
the pembrolizumab–chemoradiotherapy group and formally-tested overall survival result. Median overall
survival was not reached in either treatment group. The
estimated overall survival at 36 months was
A
82·6% (95% CI 78·4–86·1) in the pembrolizumab–
100
90 chemoradiotherapy group and 74·8% (70·1–78·8) in the
Progression-free survival (%)

80 placebo–chemoradiotherapy group. The hazard ratio for

70
60
death was less than 1 in the protocol-specified subgroups,
50 except in the subgroup of patients aged 65 years and
40 older (figure 2B). The hazard ratio for death was
30 Hazard ratio 0·68 (95% CI 0·56–0·84)
20 Pembrolizumab–chemoradiotherapy group 0·66 (0·49–0·89) in the subgroup of patients with PD-L1-
10 Placebo–chemoradiotherapy group positive (CPS ≥1) tumours (n=1000) and
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 1·06 (0·26–4·29) in the small subgroup of patients with
Time since randomisation (months) PD-L1–negative (CPS <1) tumours (n=50; appendix p 9).
Number at risk
(number censored) The hazard ratio for disease-specific survival, defined as
Pembrolizumab–chemoradiotherapy 529 515 474 430 402 353 317 280 217 179 86 69 2 0 the time from randomisation to death due to cervical
group (0) (8) (13) (20) (24) (58) (86) (112) (169) (204) (293) (306) (372) (374)
Placebo–chemoradiotherapy 531 513 452 395 366 325 283 241 178 148 78 69 2 0 cancer specifically, was 0·64 (0·46–0·89), and the
group (0) (11) (16) (22) (26) (48) (74) (98) (152) (179) (244) (252) (319) (321) estimated disease-specific survival at 36 months
was 86·8% (95% CI 83·1–89·7) in the pembrolizumab–
B
Events/patients Hazard ratio
chemoradiotherapy group and 79·0% (74·6–82·8) in the
(95% CI) placebo–chemoradiotherapy group.
Because there was a statistically significant
Age, years
<65 318/927 0·69 (0·55–0·86)
improvement in progression-free survival in the
≥65 47/133 0·64 (0·35–1·16)
pembrolizumab–chemoradiotherapy group as compared
Race with the placebo–chemoradiotherapy group at the
White 202/518 0·74 (0·56–0·98) protocol-specified first interim analysis, no formal testing
All others 161/539 0·65 (0·47–0·88) of progression-free survival was performed at this
Eastern Cooperative Oncology Group performance status score analysis. At the present data cutoff, 155 patients (29%) in
0 266/778 0·72 (0·57–0·92) the pembrolizumab–chemoradiotherapy group and
1 99/282 0·59 (0·40–0·88) 210 patients (40%) in the placebo–chemoradiotherapy
Planned external beam radiation therapy group had a progression-free survival event and the
IMRT/VMAT 325/939 0·66 (0·53–0·82) hazard ratio was 0·68 (95% CI 0·56–0·84; figure 3A).
non-IMRT/-VMAT 40/121 0·90 (0·49–1·68)
Median progression-free survival was not reached in
FIGO 2014 stage
either group. The results of the analysis of progression-
IB2 to IIB 161/459 0·85 (0·62–1·16)
free survival assessed by blinded independent central
III to IVA 204/601 0·57 (0·43–0·76)
Planned total radiotherapy dose
review were generally consistent with those based on
<70 Gy* 32/93 0·67 (0·33–1·35)
investigator review (appendix p 10). The hazard ratio for
≥70 Gy 333/967 0·68 (0·55–0·85) disease progression or death was 0·69 (95% CI
Overall 365/1060 0·68 (0·56–0·84) 0·56–0·85) in the subgroup with PD-L1-positive (CPS ≥1)
tumours and 0·57 (0·19–1·71) in the subgroup with
0·25 0·50 1·00 2·00 4·00
PD-L1-negative (CPS <1) tumours (appendix p 11). At this
Favours Favours interim analysis, 66 patients had received immunotherapy
pembrolizumab–chemoradiotherapy placebo–chemoradiotherapy
as post-progression treatment, including 15 (11%) of
Figure 3: Progression-free survival at the second interim analysis. 138 patients in the pembrolizumab–chemoradiotherapy
(A) Kaplan-Meier estimates of progression-free survival in the intention-to-treat population. Tick marks indicate group and 51 (26%) of 193 patients in the placebo–
censoring of data. (B) Analysis of progression-free survival in protocol-specified subgroups of the intention-to- chemoradiotherapy group; of those, ten (7%) and
treat population. Progression-free survival was assessed per RECIST version 1.1 by investigator review.
IMRT=intensity-modulated radiation therapy. VMAT=volumetric modulated arc therapy. *The patients who
41 (21%), respectively, had received pembrolizumab.
received total radiotherapy dose <70 Gy in Japan per Japanese guidelines used the central shielding technique in 81 patients (15%) in the pembrolizumab–chemo­
the pelvic radiotherapy. radiotherapy group and 129 patients (24%) in the

6 www.thelancet.com Published online September 14, 2024 https://doi.org/10.1016/S0140-6736(24)01808-7

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placebo–chemoradiotherapy group had a progression-

Pembrolizumab– Placebo–chemoradiotherapy
free survival 2 event (ie, disease progression after chemoradiotherapy (N=528) (N=530)
initiation of new anticancer therapy or death from any
Any grade Grade ≥3 Any grade Grade ≥3
cause) after next-line treatment and the hazard ratio was
Any adverse event* 528 (100%) 413 (78%) 526 (99%) 371 (70%)
0·60 (95% CI 0·46–0·80). The hazard ratio for disease
Anaemia 358 (68%) 122 (23%) 349 (66%) 117 (22%)
progression or death was <1 in all the protocol-specified
Nausea 320 (61%) 8 (2%) 338 (64%) 10 (2%)
subgroups (figure 3B).
456 (87%) of 521 patients in the pembrolizumab– Diarrhoea 301 (57%) 27 (5%) 298 (56%) 25 (5%)

chemoradiotherapy group and 437 (84%) of 522 in the White blood cell count decreased 175 (33%) 105 (20%) 186 (35%) 113 (21%)

placebo–chemoradiotherapy group had an objective Neutrophil count decreased 164 (31%) 83 (16%) 152 (29%) 81 (15%)
response per investigator review during the study; there Vomiting 160 (30%) 5 (1%) 177 (33%) 7 (1%)
were also fewer patients in the pembrolizumab– Hypomagnesaemia 130 (25%) 15 (3%) 124 (23%) 13 (3%)
chemoradiotherapy group who experienced disease Leukopenia 129 (24%) 69 (13%) 98 (9%) 59 (11%)
progression (appendix p 12). The median duration of Neutropenia 123 (23%) 61 (12%) 109 (21%) 57 (11%)
response was not reached in either group, and 312 (83%) Urinary tract infection 121 (23%) 21 (4%) 146 (28%) 18 (3%)
in the pembrolizumab–chemoradiotherapy group and Constipation 118 (22%) 1 (<1%) 124 (23%) 2 (<1%)
279 (78%) in the placebo–chemoradiotherapy group had a Hypothyroidism 118 (22%) 3 (1%) 36 (7%) 0
response duration of at least 12 months (appendix p 7). Platelet count decreased 118 (22%) 25 (5%) 113 (21%) 15 (3%)
Treatment exposure is summarised in the appendix (p 13). Hypokalaemia 116 (22%) 30 (6%) 92 (17%) 20 (4%)
The median treatment duration was 19 months (IQR 9–23) Alanine aminotransferase increased 115 (22%) 13 (3%) 87 (16%) 7 (1%)
in the pembrolizumab–chemoradiotherapy group and Aspartate aminotransferase 106 (20%) 11 (2%) 71 (13%) 3 (1%)
18 months (8–23) in the placebo–chemoradiotherapy increased
group. In the pembrolizumab–chemoradiotherapy group, Fatigue 102 (19%) 4 (1%) 113 (21%) 5 (1%)
patients received a median of 17 treatment cycles (9–20) of Decreased appetite 96 (18%) 3 (1%) 106 (20%) 2 (<1%)
pembrolizumab and five treatment cycles (5–5) of cisplatin. Treatment-related adverse event† 512 (97%) 365 (69%) 513 (97%) 325 (61%)
In the placebo–chemoradiotherapy group, patients Anaemia 317 (60%) 101 (19%) 296 (56%) 85 (16%)
received a median of 16 treatment cycles (8–20) of placebo Nausea 304 (58%) 7 (1%) 317 (60%) 10 (2%)
and five treatment cycles (5–5) of cisplatin. For exposure to Diarrhoea 268 (51%) 24 (5%) 271 (51%) 22 (4%)
radiation therapy, the treatment time and dosing for both White blood cell count decreased 173 (33%) 104 (20%) 183 (35%) 111 (21%)
treatment groups were similar and within the intended Neutrophil count decreased 156 (30%) 79 (15%) 148 (28%) 78 (15%)
parameters. The median overall treatment time was Vomiting 135 (26%) 3 (<1%) 150 (28%) 7 (1%)
52 days (IQR 49–57) in both groups, and 787 Leukopenia 125 (24%) 67 (13%) 92 (17%) 57 (11%)
(74%) of 1058 patients received radiation therapy within Platelet count decreased 116 (22%) 25 (5%) 109 (21%) 13 (2%)
the predefined threshold of 56 days. In both groups, the Neutropenia 114 (22%) 56 (11%) 94 (18%) 52 (10%)
median total cervix physical dose was 76 Gy (IQR 73–79), Hypothyroidism 112 (21%) 3 (<1%) 30 (6%) 0
and the median total cervix equivalent dose of 2 Gy dose Immune-mediated adverse event‡ 206 (39%) 25 (5%) 90 (17%) 7 (1%)
was 87 Gy (83–92). Hypothyroidism 119 (23%) 3 (<1%) 36 (7%) 0
Treatment-emergent adverse events occurred in all Hyperthyroidism 64 (12%) 2 (<1%) 15 (3%) 0
528 patients (100%) in the pembrolizumab– Gastritis 22 (4%) 2 (<1%) 20 (4%) 0
chemoradiotherapy group and in 526 (99%) of 530 patients Colitis 16 (3%) 4 (<1%) 11 (2%) 4 (<1%)
in the placebo–chemoradiotherapy group, including
413 (78%) of 528 and 371 (70%) of 530 patients who had *Please see the appendix (p 14) for a full table of graded adverse events.†Listed are adverse events that occurred during
the treatment period or within 30 days after the treatment period (within 90 days for serious events). The as-treated
grade 3 or higher events (appendix p 14). The risk difference population included all the patients who had undergone randomisation and received at least one trial treatment. The
for any adverse event was 0·2 (95% CI –2·0 to 2·4). The severity of adverse events was graded according to the Common Terminology Criteria for Adverse Events, version 5.0,
adverse events for which there was a 5% or more higher of the National Cancer Institute. †Treatment-related adverse events were events that were attributed to a trial
treatment by the investigators. Treatment-related adverse events that occurred in at least 20% of the patients in either
risk in the pembrolizumab–chemoradiotherapy group treatment group are reported. The events are listed in descending order of frequency in the pembrolizumab–
were hypo­thyroidism (118 [22%] of 528 vs 36 [7%] of 530; chemoradiotherapy group. Patients may have had more than one event. Grade 5 treatment-related adverse events
risk difference 15·6, 95% CI 11·4 to 19·8), hyperthyroidism were immune-mediated gastritis (n=1) and large intestine perforation (n=1) in the pembrolizumab–
(63 [12%] vs 15 [3%]; risk difference 9·1, 6·1 to 12·4), chemoradiotherapy group, and bone marrow failure (n=1) and neutropenic colitis (n=1) in the placebo–
chemoradiotherapy. ‡Immune-mediated adverse events were determined according to a list of terms specified by the
leukopenia (129 [24%] vs 98 [18%]; risk difference 5·9, sponsor, regardless of attribution to any trial treatment by the investigators. Adverse events of interest that occurred
1·0 to 10·9), increased alanine aminotransferase (115 [22%] in at least 15 patients in either treatment group are reported.
vs 87 [16%]; risk difference 5·4, 0·6 to 10·1), and increased
Table 2: Adverse events that occurred in at least 20% of the patients in the as-treated population
aspartate aminotransferase (106 [20%] vs 71 [13%];
risk difference 6·7, 2·2–11·2); no grade 3 or higher
adverse events had a 5% or more higher risk in the treatment by the study investigator occurred in
pembrolizumab–chemoradiotherapy group. Grade 3 or 365 (69%) of 528 patients in the pembrolizumab–
higher adverse events that were considered related to study chemoradiotherapy group and 325 (61%) of 530 patients in

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the placebo–chemoradiotherapy group (table 2). Serious generally consistent with that observed in the intention-
treatment-related adverse events occurred in 102 (19%) of to-treat population, with hazard ratios for death of less
528 patients in the pembrolizumab–chemoradiotherapy than 1 in most patient subgroups, except for those
group and 71 (13%) of 530 patients in the placebo– defined by age ≥65 years and by PD-L1–negative
chemoradiotherapy group, with anaemia (15 [3%] vs expression status. However, these results should be
7 [1%]), diarrhoea (9 [2%] vs 4 [1%]), and pyrexia (9 [2%] vs interpreted with caution owing to the small sample sizes
5 [1%]) being the most common events. Treatment-related and few events in these subgroups. As expected, patients
adverse events led to discontinuation of any treatment with FIGO stage III-IVA disease derived a greater
component in 99 (19%) of 528 and 69 (13%) of 530 patients, treatment benefit than those with FIGO stage IB2 to IIB
with anaemia (9 [2%] vs 6 [1%]), neutropenia (9 [2%] vs disease (hazard ratios for death were 0·57 and 0·89,
6 [1%]), neutrophil count decreased (8 [2%] vs 4 [1%]), respectively); however, there was a meaningful
leukopenia (7 [1%] vs 5 [1%]), diarrhoea (6 [1%] vs 3 [<1%]), improvement in overall survival in the subgroup of
and thrombocytopenia (6 [1%] vs 3 [<1%]) being the most patients with earlier stage disease relative to the results
common events, and of all treatment in 0 and one (<1%), from first interim analysis when the hazard ratio
respectively. Treatment-related adverse events led to death was 1·62. Still, these analyses are event-driven and,
in two patients (<1%) in each group (immune-mediated with only 15% of events reported in patients with FIGO
gastritis and large intestine perforation in the stage IB2 to IIB disease, there is potential for further
pembrolizumab–chemoradiotherapy group and bone improvement with additional events and longer follow-
marrow failure and neutropenic colitis in the placebo– up is needed to draw more definitive conclusions. The
chemoradiotherapy group). results of the disease-specific survival analysis were
Potentially immune-mediated adverse events occurred generally consistent with those of the overall survival
in 206 (39%) of 528 patients in the pembrolizumab– analysis, demonstrating a favourable benefit of
chemoradiotherapy group and 90 (17%) of 530 patients in pembrolizumab–chemoradiotherapy as compared with
the placebo–chemoradiotherapy group, including 25 (5%) placebo–chemoradiotherapy on cervical cancer deaths
and seven (1%) who had grade 3 or higher events (table 2). specifically.
Serious immune-mediated adverse events occurred in Consistent with the results from the first interim
20 (4%) of 528 patients in the pembrolizumab– analysis,15 pembrolizumab–chemoradiotherapy provided
chemoradiotherapy group and six (1%) of 530 patients in a clinically meaningful improvement in progression-free
the placebo–chemoradiotherapy group. One patient (<1%) survival as compared with chemoradiotherapy alone. In
in the pembrolizumab–chemoradiotherapy group died the present analysis, the addition of pembrolizumab to
from an immune-mediated adverse event (immune- chemoradiotherapy reduced the risk of disease
mediated gastritis). Infusion-related reactions occurred in progression as assessed by investigator review or death
nine (2%) of 528 patients in the pembrolizumab– by 32% in the intention-to-treat population. The updated
chemoradiotherapy group and nine (2%) of 530 patients progression-free survival results in the patient subgroups
in the placebo–chemoradiotherapy group; events were of are in line with those previously reported, with all hazard
grade 3 or higher in one patient (<1%) in both groups. ratios below 1, including in the subgroups defined by age
Quality-of-life outcomes were previously reported,15 ≥65 years and PD-L1-negative tumours. In the subgroups
and remained similar at the time of this second interim defined by disease stage, the hazard ratios for disease
analysis (data not shown). progression or death in patients with FIGO
stage IB2 to IIB disease and FIGO stage III-IVA disease
Discussion signalled a trend towards further improvement in
At the protocol-specified second interim analysis of this progression-free survival with additional events relative
phase 3 study, pembrolizumab combined with to the first interim analysis when the hazard ratios were
chemoradiotherapy provided a statistically significant 0·91 and 0·58, respectively.15 As with the earlier results, a
and clinically meaningful improvement in overall higher percentage of patients with an objective response
survival as compared with chemoradiotherapy alone in and a longer duration of response were noted in the
patients with newly diagnosed, high-risk, locally pembrolizumab–chemoradiotherapy group than in the
advanced cervical cancer. The addition of pembrolizumab placebo–chemoradiotherapy group. These rates have
to chemoradiotherapy reduced the risk of death in the improved since the first interim analyses, supporting the
intention-to-treat population, with a higher 3-year overall resolution of the treatment effect over time.
survival in the pembrolizumab–chemoradiotherapy Although previous efforts to improve chemoradio­
group than in the placebo–chemoradiotherapy group. therapy-based combination regimens for locally advanced
The overall survival curves separated in favour of cervical cancer have been generally unsuccessful,19,20 the
pembrolizumab–chemoradiotherapy after approximately incorporation of immunotherapy has since shifted the
10·5 months and remained apart over the subsequent treatment paradigm. Several phase 3 clinical trials of
follow-up. The benefit of pembrolizumab–chemoradio­ immunotherapy alone or combined with chemotherapy,
therapy in the protocol-specified patient subgroups was with or without bevacizumab, for the first-line or second-

8 www.thelancet.com Published online September 14, 2024 https://doi.org/10.1016/S0140-6736(24)01808-7

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line treatment of recurrent disease provided evidence of pembrolizumab–chemoradiotherapy as compared with

an efficacy benefit.13,14,21,22 In KEYNOTE-826, the addition placebo–chemoradiotherapy;15 updated results are
of pembrolizumab to platinum-based chemotherapy, planned for future reporting. Furthermore, the incidence
with or without bevacizumab, significantly improved of immune-mediated colitis was low in both treatment
progression-free survival and overall survival in patients groups. Given the manageable safety profile of this
with chemotherapy-naive, persistent, recurrent, or regimen, the survival benefit is particularly notable,
metastatic cervical cancer.13,14 Our present findings in especially in this potentially curable setting.
patients with locally advanced disease before recurrence To our knowledge, this is the first phase 3 study to
support the use of pembrolizumab earlier in treatment report a statistically significant improvement in overall
in a potentially curative setting. However, data from survival with the combination of a PD-1 inhibitor and
studies of other immune checkpoint inhibitors targeting chemoradiotherapy in newly diagnosed, high-risk, locally
PD-1 or PD-L1 combined with chemoradiotherapy in this advanced cervical cancer. The study strengths include the
setting are limited. Results from the phase 3 CALLA prospective and masked study design, the large sample
study showed that the addition of the anti-PD-L1 antibody size and power to assess overall survival, the diverse
durvalumab to chemoradiotherapy did not provide a population of patients representing 30 countries, and the
statistically significant improvement in progression-free high-quality radiotherapy delivery. One study limitation
survival compared with chemoradiotherapy alone in is the use of FIGO 2014 (vs the current 2018) staging,
patients with locally advanced cervical cancer.23 In the because the earlier criteria were still used globally during
interim analysis of overall survival in CALLA, no study conduct. Although this is not expected to limit the
difference was observed between the treatment groups generalisability of these findings, it could affect the
(not formally tested).23 Although the precise reasons for immediate identification of the patients eligible for this
the discordant results between CALLA and our study are treatment regimen. Additionally, the subgroup analyses
uncertain, contributing factors could include differences should be interpreted with caution due to multiple
in the specific drug effects, inhibition pathways (PD-1 vs comparisons and inadequate power, in addition to the
PD-L1), or study populations (eligibility criteria, such as small sample sizes in several subgroups. Furthermore,
the definitions of positive lymph nodes, and population the study was not designed to distinguish the relative
risk). In the phase 3 INTERLACE study, statistically contributions towards toxicity coming from the
significant improvements in progression-free survival concurrent versus the monotherapy treatment phases;
and overall survival were seen with induction however, the potential overlapping toxicities between
chemotherapy followed by chemoradiotherapy versus pembrolizumab and chemoradiation (such as
chemoradiation alone in patients with locally advanced myelotoxicity and gastrointestinal toxicities) were similar
cervical cancer;24 however, differences in design and between the two treatment groups. Although translational
conduct, population risk, the countries that participated, data are currently unavailable, analyses of molecular
and radiotherapy delivery between INTERLACE and biomarkers that might predict a clinical response to the
ENGOT-cx11/GOG-3047/KEYNOTE-A18 preclude cross- addition of pembrolizumab to chemoradiotherapy are
study comparisons. Other early phase clinical trials of ongoing.
immunotherapy combined with chemoradiotherapy are In conclusion, the results of ENGOT-cx11/GOG-3047/
ongoing,25–29 with encouraging early results reported for KEYNOTE-A18 show that pembrolizumab administered
nivolumab.28,29 in combination with chemoradiotherapy and continued
After additional follow-up, the safety profile of after chemoradiotherapy provides statistically significant
pembrolizumab plus chemoradiotherapy remained and clinically meaningful improvements in overall
consistent with the previous analysis15 and the known survival compared with chemoradiotherapy alone in
toxicities of the individual therapies.11–14,30,31 The most patients with newly diagnosed, previously untreated,
common treatment-related adverse events occurred at a high-risk, locally advanced cervical cancer. The safety
similar rate in both treatment groups. The addition of profile was consistent with known profiles of the
pembrolizumab did not limit exposure to cisplatin or individual therapies, with no new safety signals
delay radiotherapy delivery. In addition, the percentage of identified. These findings, together with results from the
patients who discontinued treatment due to treatment- first interim analysis, support the role of pembrolizumab
related adverse events was similar between the two in addition to chemoradiotherapy as a new standard of
treatment groups. As anticipated with the addition of care for patients with locally advanced cervical cancer.
immunotherapy, a higher incidence of immune- This regimen should be incorporated into the control
mediated adverse events was observed in the group of future clinical trials in this setting.
pembrolizumab–chemoradiotherapy group, which was Contributors
primarily driven by hypothyroidism and hyperthyroidism. All authors substantially contributed to the conception, design, or
Nevertheless, the previously reported quality-of-life planning of the study; or the acquisition or analysis of the data or
interpretation of the results; and substantially contributed to the drafting
analyses from this study showed no clinically meaningful of the manuscript or critically reviewing or revising it for important
differences between patients treated with intellectual content; and reviewed the final version of the manuscript to

www.thelancet.com Published online September 14, 2024 https://doi.org/10.1016/S0140-6736(24)01808-7 9

 Articles

be submitted. All authors had full access to all the data in the study, events, consulting fees, support for attending meetings or travel, and data
approved the decision to submit for publication, and vouch for the safety monitoring board and advisory board participation for
completeness and accuracy of the data presented. All authors agree to be AstraZeneca, Daiichi, Eli-Lilly, Merck, Novartis, MSD, Pfizer, Genesis-
accountable for all aspects of the work in ensuring that questions related Pharma, and Roche. LG reports institutional grants from IMV, Pfizer,
to the accuracy or integrity of any part of the work are appropriately Sutro Bio, Pharma, Merck Sharpe Dohme, Corcept Therapeutics,
investigated and resolved. ImmunoGen, Shattuck Labs, Roche, Tesaro, K-Group, Beta Inc., GOG
Foundation, GSK, AstraZeneca, OncoQuest Pharmaceuticals, Novocure,
Declaration of interests
Alkermes, Espersas, and Mersana; consulting fees from Merck and GSK;
DL, YX, KH, GS, ML, PR-E, AA, JC, LR, AJPdSG, FCM, LH, HA, J-YL,
payment or honoraria for lectures and presentations from Merck and
VS, FZ, LG, JS, ET, KL, NC, C-LC, MB, HZ, AO, MC, EP, TU, SP, and
GSK; support for attending meetings or travel from GSK, Merck,
LRD received funding to their institutions from Merck Sharp & Dohme,
EndomERA, and Zentalis; and participation on advisory board meetings
a subsidiary of Merck & Co, Rahway, NJ, USA (MSD) to support the
for GSK, Merck, Eisai, Novocure, Kora Health, Corcept, ImmunoGen,
study. DL reports grants or contracts from AstraZeneca, Clovis Oncology,
Canariabio, and Repare Therapeutics. JS reports grants or contracts from
Pharma&, Genmab, GSK, Immunogen, MSD, Pharmamar, Novartis,
Roche, MSD, GSK, Tesaro, AstraZeneca, Eisai, Merck, and Novocure;
Seagen, Alkermes, Incyte, Roche, and Corcept; consulting fees from
consulting fees from Immunogen, Incyte, GSK, AstraZeneca, Clovis,
AstraZeneca, Corcept, Clovis Oncology, Daiichi Sankyo, Genmab, GSK,
Novocure, MSD, Eisai, and Merck; payment or honoraria for lectures,
Immunogen, MSD, Novartis, Oncoinvest, Novocure, Seagen, and Sutro;
presentations, speakers bureaus, manuscript writing, or educational
speaker fees from AstraZeneca, Corcept, Genmab, GSK, Immunogen,
events from Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure,
MSD, and Seagen; travel grants from AstraZeneca, Menarini, GSK, and
BMS, Eisai, and Novartis; support for attending meetings or travel from
MSD; advisory board participation for AstraZeneca, Corcept, Clovis
GSK, Astra Zeneca, Roche, Novocure, Immunogen, Incyte, MSD, and
Oncology, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD,
Eisei; participation on a data safety monitoring board or advisory board
Oncoinvest, Novocure, Seagen, and Sutro; and leadership or fiduciary
for Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, Bristol
role in other board, society, committee, or advocacy group, paid or
Myers Squibb, MSD, Merck, Bayer, and PharmaMar; leadership or
unpaid, for GCIG, MITO, and ENGOT. YX reports study funding, paid to
fiduciary role in other board, society, committee or advocacy group, paid
the Peking Union Medical College Hospital, and support for attending
or unpaid, for ENGAGE, ESGO, ASCO, ESGO, GCIG, Deutsche Stiftung
meetings or travel from MSD. KH reports research contracts from
Eierstockkrebs, and AGO; and medical writing assistance from MSD.
Daiichi Sankyo, Eisai, MSD, and Takeda; advisory board fees from
ET reports honoraria for presentations and meeting travel support from
Chugai, Eisai, Takeda, MSD, Roche, Genmab, Sanofi, GSK, and
Elektra. KL reports study funding from MSD; grants or contracts from
Zymeworks; honoraria from Daiichi Sankyo, AstraZeneca, Chugai, Eisai,
GSK; lecture honoraria from Eisai and AstraZeneca; participation on a
Genmab, MSD, Takeda, Sanofi, Kyowa Kirin, Kaken, and GSK; and travel
data safety monitoring board for Karyopharm; participation on an
support from Regeneron and Seagen. GS reports consulting fees from
advisory board for Eisai, MSD, Nykode, AstraZeneca, and GSK; and
AstraZeneca, MSD, Coviden AG (a Medtronic company), Johnson &
serving as deputy medical director for the Nordic Society of Gynecological
Johnson, and TESARO Bio Italy; and payment or honoraria for lectures,
Oncology Clinical Trial Unit. NC reports institutional grants from
presentations, speakers bureaus, manuscript writing, or education events
AstraZeneca and Roche; payment or honoraria for lectures,
from Baxter Healthcare, Olympus Europa, Intuitive Surgical, GSK, and
presentations, speakers bureaus, manuscript writing, or educational
Clovis Oncology Italy. ML reports payment for expert testimony from
events from GSK and MSD; payment for participation on a data safety
MSD, support for attending meetings or travel from MSD and
monitoring board or advisory board for AstraZeneca, Clovis Oncology,
AstraZeneca; and other financial or non-financial interests from MSD,
Eisai, GSK, ImmunoGen, Mersana, MSD, Merck, Nuvation Bio,
AstraZeneca, and Roche. PR-E reports honoraria for educational events
Onxerna, Pfizer, PharmaMar, Pieris, Roche, and Novocure; and non-
from MSD, AstraZeneca, Novartis, Asofarma, Pfizer, and Roche; support
remunerated leadership role as Chair of the Alleanza Contro il Tumore
for attending ESMO and ASCO meetings from AstraZeneca, Pfizer, and
Ovarico Scientific Committee. MB reports honoraria for lectures and
Asofarma; and honoraria for advisory boards from MSD, Roche,
educational events from Roche, AstraZeneca, and GSK; and support for
AstraZeneca, Asofarma, BMS and Novartis. LR reports medical writing
attending meetings from Roche, AstraZeneca, and Viatris. AO reports
support from Merck, institutional grants from Merck, Zentalis,
consulting fees from Agenus, AstraZeneca, Clovis Oncology, Corcept
Karyopharn, GOG Foundation, Regeneron, ImmunoGen, Acrivon,
Therapeutics, Deciphera Pharmaceuticals, Daïichi Sankyo, Debiopharm
CanariaBio, Corcept Therapeutics, and Seagen; consulting fees from
International, Eisai, Exelisis, F. Hoffmann-La Roche, Genmab, GSK,
AstraZeneca, Merck, GSK, Genmab, Seagen, GOG Foundation, Zentalis,
ImmunoGen, Itheos, MSD, Mersana Therapeutics, Myriad Genetics,
ImmunoGen, Semline, Eisai, Caris, Nykode, and Clovis; payment or
Novocure, OncoXerna Therapeutics, PharmaMar, Regeneron,
honoraria for lectures, presentations, speakers bureaus, manuscript
Sattucklabs, Seagen–Pfizer, Sutro Biopharma, TORL Therapuetics,
writing, or educational events from Seagen and Genmab; and leadership
Zentalis, and Zymeworks; payment or honoraria for lectures,
or fiduciary role in other board, society, committee or advocacy group,
presentations, speakers bureaus, manuscript writing, or educational
paid or unpaid, from GOG Foundation. AJPdSG reports consulting fees
events from NSGO, Peerview, Peervoice, Medscape, Asociación
and payment for expert testimony from Bayer, Astellas, and Janssen;
Colombiada de Ginecológos Oncólogos, ESO, AstraZeneca, and GSK;
payment or honoraria for lectures, presentations, speakers bureaus,
support for attending meetings or travel from AstraZeneca, PharmaMar,
manuscript writing, or educational events for expert testimony from
and Roche; participation on a data safety monitoring board or advisory
Astellas, AstraZeneca, Bayer, and Janssen; and participation on a data
board from Agenus, AstraZeneca, Clovis Oncology, Corcept
safety monitoring board or advisory board for Astellas, Bayer, and
Therapeutics, Deciphera Pharmaceuticals, Daïichi Sankyo, Debiopharm
Janssen. FCM reports honoraria for presentations from MSD and BMS;
International, Eisai, Exelisis, F Hoffmann-La Roche, Genmab, GSK,
support for attending meetings or travel from AstraZeneca and MSD;
ImmunoGen, Itheos, MSD, Mersana Therapeutics, Myriad Genetics,
and advisory board participation from Janssen and MSD. J-YL reports
Novocure, OncoXerna Therapeutics, PharmaMar, Regeneron,
support for the present manuscript from MSD; grants or contracts from
Sattucklabs, Seagen–Pfizer, Sutro Biopharma, TORL Therapuetics,
Advenchen, Ascendis Pharma, Alkermes, AstraZeneca, Beigene,
Zentalis, and Zymeworks; leadership or fiduciary role in other board,
BergenBio, BMS, CanariaBio, Corcept, Cellid, CKD, Clovis Oncology,
society, committee or advocacy group, paid or unpaid, for Gynecologic
Eisai, Genmab, Genemedicine, GII, GSK, ImmunoGen, Janssen, Kelun,
Cancer Intergroup and European Society for Medical Oncology; and
Merck, Mersana, MSD, Novartis, Onconic Therapeutics, ONO,
other financial or non-financial interests in Gynecologic Cancer
Regeneron, Roche, Seagen, Sutro, Synthon, and Takeda; payment or
Intergroup, European Society for Medical Oncology, American Society of
honoraria for lectures, presentations, speakers bureaus, manuscript
Clinical Oncology, Spanish Society of Medical Oncology, and GOG
writing, or educational events from AstraZeneca, Janssen, MSD, Roche,
Foundation. EP reports provision of study material from MSD; honoraria
Takeda, and ONO; and leadership or fiduciary role in other board, society,
for lectures, presentations, and educational events from MSD, Roche,
committee or advocacy group, paid or unpaid, for AstraZeneca,
GSK, and AstraZeneca; and receipt of investigational drug for study
CanariaBio, Genmab, GII, ImmunoGen, Seagen, Merck, Sutro,
treatment from MSD. PL, KY, ST, and SMK are current or former full-
Regeneron, and MSD. FZ reports payment or honoraria for lectures,
time employees of MSD and hold stock or restricted stock units in the
presentations, speakers bureaus, manuscript writing, or educational

10 www.thelancet.com Published online September 14, 2024 https://doi.org/10.1016/S0140-6736(24)01808-7

 Articles

company. SP reports research funding from Roche, MSD, GSK, Pfizer, Ambreen Naqvi and Susan Galligan for study management,
and AstraZeneca; payment or honoraria for lectures, presentations, Stephanie Shapiro, Harneet Arora, Pranava Katkuri, Arpan Patel, and
speakers bureaus, manuscript writing, or educational events from Bhavika Patel for study support, Jing Zhao for statistical expertise and
AstraZeneca, MSD, Roche, Pfizer, Novartis, and GSK; and participation oversight, Christine McCrary Sisk for medical writing support,
on a Data Safety Monitoring Board or Advisory Board for GSK, MSD, and Michele McColgan for editorial assistance. This study was funded by
Eisai, Biontech, and AstraZeneca. LRD reports institutional grants from MSD.
Merck, Genentech, Roche, AbbVie, Acrivon, Advaxis, Aduro BioTech,
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12 www.thelancet.com Published online September 14, 2024 https://doi.org/10.1016/S0140-6736(24)01808-7