Clinical Trial

. 2023 Jun 8;388(23):2159-2170.

doi: 10.1056/NEJMoa2302312. Epub 2023 Mar 27.

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer

Ramez N Eskander¹, Michael W Sill¹, Lindsey Beffa¹, Richard G Moore¹, Joanie M Hope¹, Fernanda B Musa¹, Robert Mannel¹, Mark S Shahin¹, Guilherme H Cantuaria¹, Eugenia Girda¹, Cara Mathews¹, Juraj Kavecansky¹, Charles A Leath 3rd¹, Lilian T Gien¹, Emily M Hinchcliff¹, Shashikant B Lele¹, Lisa M Landrum¹, Floor Backes¹, Roisin E O'Cearbhaill¹, Tareq Al Baghdadi¹, Emily K Hill¹, Premal H Thaker¹, Veena S John¹, Stephen Welch¹, Amanda N Fader¹, Matthew A Powell¹, Carol Aghajanian¹

Affiliations

Affiliation

¹ From the Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, Rebecca and John Moores Cancer Center, La Jolla (R.N.E.), and the Kaiser Permanente National Cancer Institute Community Oncology Research Program (NCORP), Antioch Medical Center, Antioch (J.K.) - both in California; the Clinical Trial Development Division, Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo (M.W.S., S.B.L.), the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester (R.G.M.), the Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, and the Department of Medicine, Weill Cornell Medical College, New York (R.E.O., C.A.), and the Northwell Health Cancer Institute, New Hyde Park (V.S.J.) - all in New York; the Case Comprehensive Cancer Center, Cleveland Clinic Foundation, Cleveland (L.B.), and Ohio State University Wexner Medical Center and James Cancer Hospital, Columbus (F.B.); the Pacific Cancer Research Consortium, NCORP, Alaska Women's Cancer Care, and Providence Alaska Cancer Center, Anchorage (J.M.H.); the Pacific Cancer Research Consortium, NCORP, Swedish Medical Center-First Hill, Seattle (F.B.M.); the University of Oklahoma Health Sciences Center, Oklahoma City (R.M.); Jefferson Abington Hospital, Asplundh Cancer Pavilion of Sidney Kimmel Cancer Center, Jefferson Health, Willow Grove, PA (M.S.S.); Georgia NCORP, Atlanta (G.H.C.); Rutgers Cancer Institute of New Jersey, New Brunswick (E.G.); Women and Infants Hospital, Legoretta Cancer Center, Alpert Medical School, Brown University, Providence, RI (C.M.); the University of Alabama at Birmingham-Deep South Research Consortium, O'Neal Comprehensive Cancer Center, University of Alabama Hospital, Birmingham (C.A.L.); Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto (L.T.G.), and the London Regional Cancer Program, London, ON (S.W.) - both in Canada; Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (E.M.H.); the Indiana University Health Simon Cancer Center, Indianapolis (L.M.L.); the Michigan Cancer Research Consortium, NCORP, Trinity Health IHA Medical Group, Ypsilanti (T.A.B.); the University of Iowa Hospitals and Clinics, Iowa City (E.K.H.); the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis (P.H.T., M.A.P.); and the Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore (A.N.F.).

PMID: 36972022
PMCID: PMC10351614
DOI: 10.1056/NEJMoa2302312

Clinical Trial

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer

Ramez N Eskander et al. N Engl J Med. 2023.

. 2023 Jun 8;388(23):2159-2170.

doi: 10.1056/NEJMoa2302312. Epub 2023 Mar 27.

Authors

Affiliation

¹ From the Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, Rebecca and John Moores Cancer Center, La Jolla (R.N.E.), and the Kaiser Permanente National Cancer Institute Community Oncology Research Program (NCORP), Antioch Medical Center, Antioch (J.K.) - both in California; the Clinical Trial Development Division, Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo (M.W.S., S.B.L.), the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester (R.G.M.), the Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, and the Department of Medicine, Weill Cornell Medical College, New York (R.E.O., C.A.), and the Northwell Health Cancer Institute, New Hyde Park (V.S.J.) - all in New York; the Case Comprehensive Cancer Center, Cleveland Clinic Foundation, Cleveland (L.B.), and Ohio State University Wexner Medical Center and James Cancer Hospital, Columbus (F.B.); the Pacific Cancer Research Consortium, NCORP, Alaska Women's Cancer Care, and Providence Alaska Cancer Center, Anchorage (J.M.H.); the Pacific Cancer Research Consortium, NCORP, Swedish Medical Center-First Hill, Seattle (F.B.M.); the University of Oklahoma Health Sciences Center, Oklahoma City (R.M.); Jefferson Abington Hospital, Asplundh Cancer Pavilion of Sidney Kimmel Cancer Center, Jefferson Health, Willow Grove, PA (M.S.S.); Georgia NCORP, Atlanta (G.H.C.); Rutgers Cancer Institute of New Jersey, New Brunswick (E.G.); Women and Infants Hospital, Legoretta Cancer Center, Alpert Medical School, Brown University, Providence, RI (C.M.); the University of Alabama at Birmingham-Deep South Research Consortium, O'Neal Comprehensive Cancer Center, University of Alabama Hospital, Birmingham (C.A.L.); Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto (L.T.G.), and the London Regional Cancer Program, London, ON (S.W.) - both in Canada; Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (E.M.H.); the Indiana University Health Simon Cancer Center, Indianapolis (L.M.L.); the Michigan Cancer Research Consortium, NCORP, Trinity Health IHA Medical Group, Ypsilanti (T.A.B.); the University of Iowa Hospitals and Clinics, Iowa City (E.K.H.); the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis (P.H.T., M.A.P.); and the Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore (A.N.F.).

PMID: 36972022
PMCID: PMC10351614
DOI: 10.1056/NEJMoa2302312

Abstract

Background: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear.

Methods: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort.

Results: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy.

Conclusions: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.).

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Figures

**Figure 1.. Enrollment and Outcomes.**
The patients were stratified into two cohorts according to whether they had mismatch repair–deficient (dMMR) or mismatch repair–proficient (pMMR) disease on immunohistochemical (IHC) assessment.

**Figure 2.. Progression-free Survival in the Two Cohorts.**
Shown are Kaplan–Meier estimates of progression-free survival in the population of patients with advanced or recurrent endometrial cancer with mismatch repair–deficient (dMMR) disease (Panel A) or mismatch repair–proficient (pMMR) disease (Panel B). Tick marks in both panels indicate censoring of data. Patients in both the pembrolizumab and the placebo groups received combination chemotherapy with paclitaxel and carboplatin. NR denotes not reached.

See this image and copyright information in PMC

Comment in

Adding immune-checkpoint inhibitors to chemotherapy extends survival in endometrial cancer.
Romero D. Romero D. Nat Rev Clin Oncol. 2023 Jun;20(6):353. doi: 10.1038/s41571-023-00763-0. Nat Rev Clin Oncol. 2023. PMID: 37024681 No abstract available.
PD-1 and PD-L1 Blockade plus Chemotherapy in Endometrial Cancer.
Polak P, Fu L, Foulkes WD. Polak P, et al. N Engl J Med. 2023 Aug 31;389(9):866. doi: 10.1056/NEJMc2308037. N Engl J Med. 2023. PMID: 37646693 No abstract available.
PD-1 and PD-L1 Blockade plus Chemotherapy in Endometrial Cancer.
Cetin B, Gumusay O. Cetin B, et al. N Engl J Med. 2023 Aug 31;389(9):866-867. doi: 10.1056/NEJMc2308037. N Engl J Med. 2023. PMID: 37646694 No abstract available.
PD-1 and PD-L1 Blockade plus Chemotherapy in Endometrial Cancer. Reply.
Mirza MR, Powell MA. Mirza MR, et al. N Engl J Med. 2023 Aug 31;389(9):867. doi: 10.1056/NEJMc2308037. N Engl J Med. 2023. PMID: 37646695 No abstract available.
PD-1 and PD-L1 Blockade plus Chemotherapy in Endometrial Cancer. Reply.
Eskander RN. Eskander RN. N Engl J Med. 2023 Aug 31;389(9):867-868. doi: 10.1056/NEJMc2308037. N Engl J Med. 2023. PMID: 37646696 No abstract available.
Adding immunotherapy to chemotherapy improves survival for endometrial cancer patients.
Fillon M. Fillon M. CA Cancer J Clin. 2023 Sep-Oct;73(5):445-447. doi: 10.3322/caac.21809. CA Cancer J Clin. 2023. PMID: 37665330 No abstract available.
Immune checkpoint inhibitors: here to stay.
Carvalho FM, Estevez Diz MDP, Carvalho JP. Carvalho FM, et al. Transl Cancer Res. 2023 Oct 31;12(10):2438-2441. doi: 10.21037/tcr-23-1343. Epub 2023 Oct 20. Transl Cancer Res. 2023. PMID: 37969375 Free PMC article. No abstract available.

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Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer

Affiliation

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer

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Abstract

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