Lugano, Switzerland, 18 September 2021 – The addition of immunotherapy to standard first-line treatment extends survival by eight months for patients with recurrent, persistent or metastatic cervical cancer, according to late breaking results from the KEYNOTE-826 study presented at the ESMO Congress 2021. (1) 

Prof. Nicoletta Colombo

Credit: ESMO

Lugano, Switzerland, 18 September 2021 – The addition of immunotherapy to standard first-line treatment extends survival by eight months for patients with recurrent, persistent or metastatic cervical cancer, according to late breaking results from the KEYNOTE-826 study presented at the ESMO Congress 2021. (1) 

Cervical cancer is a global problem, with more than 600,000 new cases and approximately 340,000 deaths in 2020. (2) In women aged 15 to 44 years, it is the second most frequent cancer and the second cause of cancer death. 

Commenting on today’s results, Dr. Antonio González-Martín, Cancer Centre Director, Clínica Universidad de Navarra, Madrid, Spain said: “Patients with persistent, recurrent or metastatic cervical cancer have suffered historically from a dismal prognosis with an overall survival no longer than 12 months. The KEYNOTE-826 study is a new milestone, demonstrating a very relevant increment in the overall survival of patients with this condition and, for the first time, showing that incorporating immunotherapy into front line treatment can change the natural history of the disease.” 

The trial randomly allocated 617 women to immunotherapy (pembrolizumab) or placebo. Both groups also received chemotherapy (paclitaxel plus the doctor’s choice of cisplatin or carboplatin) and they could be given bevacizumab at the discretion of their doctor. Adding pembrolizumab reduced the risk of death by 33% and lowered the likelihood of disease progression or death by 35%. The most common side-effects were anaemia (30.3% in the pembrolizumab group versus 26.9% in the placebo group) and low concentration of white blood cells (12.4% versus 9.7%, respectively). 

Study author Prof. Nicoletta Colombo, Director of the Gynaecology Programme, European Institute of Oncology, Milan, Italy said: “Previous studies showed that adding anti-angiogenesis therapy with bevacizumab to chemotherapy prolonged survival by 3.7 months over chemotherapy alone. KEYNOTE-826 was the first study to explore the addition of PD-1 inhibition to chemotherapy with or without bevacizumab, and benefits in survival and disease progression were observed regardless of expression of PD-L1, a protein related to immunomodulation. Side-effects with the new combination therapy were manageable and the observed adverse events were as expected based on previous data on the individual drugs.”

Colombo noted that the benefit of the novel combination therapy was seen in those who received bevacizumab and in those who did not receive bevacizumab. But she added: “The study was not designed to statistically compare outcomes between these subgroups since bevacizumab treatment was not randomised but was left to the physician’s discretion. Some common complications of recurrent/persistent or metastatic cervical cancer are contraindications for the use of this drug. In this study, 63% of patients received bevacizumab. The trial indicates that bevacizumab should be used with pembrolizumab when it is safe. For patients who cannot use bevacizumab, adding pembrolizumab to chemotherapy alone still has clinically meaningful benefit.” 

“This is a practice-changing study,” highlighted González-Martín. “The data are so solid in terms of increment in overall survival that this combination should be considered the new standard of care for women with persistent, recurrent or metastatic cervical cancer. The backbone systemic therapy used with the immunotherapy (paclitaxel with cisplatin or carboplatin, with or without bevacizumab) reflects the standard treatment options in the real world, making the results easy adaptable. One potential limitation will be how to adopt this innovation in resource-limited healthcare systems.” 

While the findings could help many patients, González-Martín pointed out that: “One of the greatest challenges is to select the correct population for a new therapy, or at least the patients likely to obtain the most benefit. PD-L1 may be a potential biomarker, but other biomarkers are needed.” 

Colombo and González-Martín agreed that the next step for researchers is to evaluate the impact of immunotherapy in patients with earlier stages of cervical cancer. Ongoing trials adding immunotherapy to standard chemoradiotherapy in women with locally advanced cervical cancer include the CALLA study and the KEYNOTE-A18/ENGOT-cx11/GOG-3047 study. 

-END- 

Notes to Editors 
Please make sure to use the official name of the meeting in your reports: ESMO Congress 2021 
Official Congress Hashtag:  #ESMO21 

Disclaimer 
This press release contains information provided by the author of the highlighted abstract and reflects the content of this abstract. It does not necessarily reflect the views or opinions of ESMO who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct. 

References  
1LBA2_PR ‘Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: randomized, double-blind, phase 3 KEYNOTE-826 study‘ will be presented by Nicoletta Colombo during Presidential Symposium 1 on Saturday, 18 September, 15:05 to 16:35 (CEST) on Channel 1. Annals of Oncology, Volume 32, 2021 Supplement 5 
2 Globocan 2020. 

About the European Society for Medical Oncology (ESMO) 
ESMO is the leading professional organisation for medical oncology. With more than 25,000 members representing oncology professionals from over 160 countries worldwide, ESMO is the society of reference for oncology education and information. Driven by a shared determination to secure the best possible outcomes for patients, ESMO is committed to standing by those who care about cancer through addressing the diverse needs of #ONEoncologycommunity, offering #educationforLIFE, and advocating for #accessiblecancerCARE. www.esmo.org   

LBA2_PR – Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: Randomized, double-blind, phase 3 KEYNOTE-826 study 

N. Colombo1, C. Dubot2, D. Lorusso3, V. Cáceres4, K. Hasegawa5, R. Shapira-Frommer6, K.S. Tewari7, P. Salman8, E. Hoyos9, E. Yañez10, M. Gumus11, M. Olivera Hurtado de Mendoza12, V. Samouëlian13, V. Castonguay14, A. Arkhipov15, S. Toker16, K. Li16, S.M. Keefe16, B.J. Monk17  

1Gynecologic Oncology, European Institute of Oncology IRCCS and Università degli Studi di Milano Bicocca, Milan, Italy, 2Oncologie Médicale, Institut Curie Saint Cloud, and GINECO, Paris, France, 3Gynaecology Oncology Unit, Fondazione Policlinico Universitario A Gemelli IRCCS and Catholic University of Sacred Heart, Rome, Italy, 4Medical Oncology, Instituto de Oncologia Angel H. Roffo, Buenos Aires, Argentina, 5Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan, 6Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan, Israel, 7Obstetrics & Gynecology, University of California, Irvine, Orange, United States of America, 8Medical Oncology, Oncovida Cancer Center, Providencia, Santiago, Chile, 9Medical Oncology, IMAT Oncomedica S.A., Monteria, Colombia, 10Medical Oncology, Universidad de la Frontera, Temuco, Chile, 11Medical Oncology, Istanbul Medeniyet University Hospital, Istanbul, Turkey, 12Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru, 13OB-GYN, Centre Hospitalier de l’Université de Montréal (CHUM), Centre de Recherche de l’Université de Montréal (CRCHUM), Université de Montréal, Montreal, Canada, 14Medical Oncology, Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, Canada, 15Oncology and chemical therapy, Medical Rehabilitation Center under the Ministry of Health of Russian Federation, Moscow, Russian Federation, 16Oncology, Merck & Co., Inc., Kenilworth, United States of America, 17Gynecologic Oncology, Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine, Phoenix, United States of America 

Background: Pembrolizumab (pembro) shows efficacy in patients (pts) with previously treated, PD-L1–positive advanced cervical cancer. In KEYNOTE-826 (NCT03635567), we evaluated the efficacy and safety of pembro + chemotherapy (chemo) ± bevacizumab (bev) for recurrent, persistent, or metastatic cervical cancer. 

Methods: Eligible adults with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemo (prior radiosensitizing chemo allowed) and not amenable to curative treatment were randomized 1:1 to pembro 200 mg or placebo Q3W for ≤35 cycles added to chemo (paclitaxel + cisplatin or carboplatin) ± bev. Pts were stratified by metastatic status at diagnosis, planned bev use, and PD-L1 combined positive score (CPS). Dual primary end points were PFS per RECIST v1.1 assessed by investigator review and OS, each tested sequentially in the PD-L1 CPS ≥1, all-comer, and CPS ≥10 populations. All data are from the protocol-specified first interim analysis (May 3, 2021 data cutoff). 

Results: From Nov 2018 to Jan 2020, 617 pts were randomized to pembro + chemo (N = 308; 63.6% with bev) or placebo + chemo (N = 309; 62.5% with bev); 548 (88.8%) pts had PD-L1 CPS ≥1 and 317 (51.4%) had CPS ≥10. Pembro + chemo significantly improved PFS and OS in the CPS ≥1, all-comer, and CPS ≥10 populations (Table). The pembro + chemo benefit was seen regardless of bev use. Grade ≥3 AE incidence was 81.8% in the pembro + chemo arm and 75.1% in the placebo + chemo arm. The most common grade ≥3 AEs were anemia (30.3% vs 26.9%) and neutropenia (12.4% vs 9.7%).  

 

PD-L1 CPS ≥1  

All-Comer  

PD-L1 CPS ≥10  

Pembro + Chemo 
(N = 273)  

Placebo + Chemo 
(N = 275)  

Pembro + Chemo 
(N = 308)  

Placebo + Chemo 
(N = 309)  

Pembro + Chemo 
(N = 158)  

Placebo + Chemo 
(N = 159)  

PFS per RECIST v1.1 by investigator review  

Median, mo  

10.4  

8.2  

10.4  

8.2  

10.4  

8.1  

12-mo rate, %  

45.5  

34.1  

44.7  

33.5  

44.6  

33.5  

HR (95% CI)  

0.62 (0.50-0.77); 
P < 0.001  

0.65 (0.53-0.79); 
P < 0.001  

0.58 (0.44-0.77); 
P < 0.001  

OS  

Median, mo  

NR  

16.3  

24.4  

16.5  

NR  

16.4  

24-mo rate, %  

53.0  

41.7  

50.4  

40.4  

54.4  

44.6  

HR (95% CI)  

0.64 (0.50-0.81); 
P < 0.001  

0.67 (0.54-0.84); 
P < 0.001  

0.61 (0.44-0.84); 
P = 0.001  

 
Conclusions: Pembro + chemo provided statistically significant, clinically meaningful PFS and OS improvements in pts with persistent, recurrent, or metastatic cervical cancer, regardless of PD-L1 expression and concomitant bev use. Along with a manageable safety profile, these data suggest pembro + chemo ± bev may be a new standard of care for this population. 

Clinical trial identification: NCT03635567. 
Editorial acknowledgement: Medical writing and/or editorial assistance was provided by Melanie Leiby of Merck & Co., Inc., Kenilworth, NJ, USA. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. 
Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. 
Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. 

Disclosure:  

N. Colombo: Financial Interests, , Invited Speaker: AstraZeneca, MSD/Merck, Novartis, Clovis, GSK; Financial Interests, , Advisory Board: Roche, Pharmamar, AstraZeneca, MSD/Merck, Clovis Oncology, Tesaro, GSK, Pfizer, Takeda, BIOCAD, Immunogen, Mersana, Eisai, Oncxerna; Financial Interests, , Funding: Roche, AstraZeneca. 
C. Dubot: Financial Interests, Institutional, Funding: MSD. 
D. Lorusso: Financial Interests, Personal and Institutional, Funding, funding/advisory role: MSD; Financial Interests, Personal and Institutional, Funding, funding/advisory role: Clovis Oncology; Financial Interests, Personal and Institutional, Funding, funding/advisory role: GSK; Financial Interests, Personal and Institutional, Funding, funding/advisory role: AstraZeneca; Financial Interests, Personal and Institutional, Funding, funding/advisory role: Pharmamar; Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Amgen. 
V. Cáceres: Financial Interests, Institutional, Funding: MSD. 
K. Hasegawa: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Role: MSD. 
R. Shapira-Frommer: Financial Interests, Institutional, Funding: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Clovis Oncology; Financial Interests, Personal, Advisory Board: VBL Therapeutics. 
K.S. Tewari: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Clovis; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Tesaro; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Tesaro; Financial Interests, Personal, Speaker’s Bureau: Clovis; Financial Interests, Personal, Speaker’s Bureau: Eisai. 
P. Salman: Financial Interests, Institutional, Principal Investigator: MSD. 
E. Hoyos: Financial Interests, Institutional, Funding: MSD. 
E. Yañez: Financial Interests, Institutional, Funding: MSD. 
M. Gumus: Financial Interests, Institutional, Funding: MSD. 
M. Olivera Hurtado de Mendoza: Financial Interests, Institutional, Funding: MSD; Financial Interests, Personal and Institutional, Principal Investigator: MSD. 
V. Samouëlian: Financial Interests, Institutional, Funding: MSD. 
V. Castonguay: Financial Interests, Personal, Advisory Board: MSD. 
A. Arkhipov: Financial Interests, Institutional, Funding: MSD; Financial Interests, Personal, Principal Investigator: MSD. 
S. Toker: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck Sharp & Dohme Corp.. 
K. Li: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.. 
S.M. Keefe: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck Sharp & Dohme Corp.. 
B.J. Monk: Financial Interests, Institutional, Funding: MSD; Financial Interests, Personal, Leadership Role: US Oncology; Financial Interests, Personal, Other, honoraria/consulting: AbbVie; Financial Interests, Personal and Institutional, Other, honoraria/consulting, funding: Advaxis; Financial Interests, Personal, Other, honoraria/consulting: Agenus; Financial Interests, Personal, Other, honoraria/consulting: Akeso Biopharma; Financial Interests, Personal and Institutional, Other, honoraria/consulting, funding: Amgen; Financial Interests, Personal, Other, honoraria/consulting: Aravive; Financial Interests, Personal and Institutional, Other, honoraria/consulting/speakers’ bureau, funding: AstraZeneca; Financial Interests, Personal, Other, honoraria/consulting: Asymmetric Therapeutics; Financial Interests, Personal, Other, honoraria/consulting: Boston Biomedical; Financial Interests, Personal, Other, honoraria/consulting: ChemoID; Financial Interests, Personal, Other, honoraria/consulting/speakers’ bureau: Clovis Oncology; Financial Interests, Personal, Other, honoraria/consulting: Deciphera Pharmaceuticals; Financial Interests, Personal, Other, honoraria/consulting/speakers’ bureau: Eisai; Financial Interests, Personal, Other, honoraria: Elevar Therapeutics; Financial Interests, Personal, Other, honoraria/consulting: Geistlich Pharma; Financial Interests, Personal, Advisory Role: ChemoCare; Financial Interests, Personal, Other, honoraria/consulting : Genmab/Seattle Genetics; Financial Interests, Personal, Other, honoraria/consulting: GOG Foundation; Financial Interests, Personal, Other, honoraria/consulting: Gradalis; Financial Interests, Personal and Institutional, Other, honoraria/consulting, funding: ImmunoGen; Financial Interests, Personal, Other, honoraria/consulting: Immunomedics; Financial Interests, Personal, Other, honoraria/consulting: Incyte; Financial Interests, Personal, Other, honoraria/consulting: Iovance Biotherapeutics; Financial Interests, Personal, Other, honoraria/consulting: Karyopharm Therapeutics; Financial Interests, Personal, Other, honoraria/consulting: Laekna Health Care; Financial Interests, Personal, Other, honoraria/consulting/speakers’ bureau: Merck; Financial Interests, Personal, Other, honoraria/consulting: Mersana; Financial Interests, Personal, Other, honoraria/consulting: Myriad Pharmaceuticals; Financial Interests, Personal, Other, honoraria/consulting : Novocure; Financial Interests, Personal and Institutional, Other, honoraria/consulting, funding: Nucana; Financial Interests, Personal, Other, honoraria/consulting: Oncomed; Financial Interests, Personal, Other, honoraria/consulting : Oncoquest; Financial Interests, Personal, Other, honoraria/consulting: Oncosec; Financial Interests, Personal, Other, honoraria/consulting: Perthera; Financial Interests, Personal and Institutional, Other, honoraria/consulting, funding: Pfizer; Financial Interests, Personal, Other, honoraria/consulting: Puma Biotechnology; Financial Interests, Personal and Institutional, Other, honoraria/consulting, funding: Regeneron; Financial Interests, Personal, Other, honoraria/consulting/speakers’ bureau: Roche/Genentech; Financial Interests, Personal, Other, honoraria/consulting: Senti Biosciences; Financial Interests, Personal, Other, honoraria: Starton Therapeutics; Financial Interests, Personal, Other, honoraria/consulting: Takeda; Financial Interests, Personal, Other, honoraria/consulting: Tarveda Therapeutics; Financial Interests, Personal, Other, honoraria/consulting/speakers’ bureau: Tesaro/GSK; Financial Interests, Personal, Other, honoraria/consulting: Vascular Biogenics; Financial Interests, Personal, Other, honoraria/consulting: Vavotar Life Sciences; Financial Interests, Personal, Other, honoraria/consulting: Vigeo Therapeutics; Financial Interests, Personal, Advisory Role: Sorrento Therapeutics; Financial Interests, Institutional, Funding: Array BioPharma; Financial Interests, Institutional, Funding: Genentech; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Lilly; Financial Interests, Institutional, Funding: Morphotek; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Tesaro. 


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