Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer

Author(s): Ramez N. Eskander, M.D., Michael W. Sill, Ph.D., Lindsey Beffa, M.D., Richard G. Moore, M.D., Joanie M. Hope, M.D., Fernanda B. Musa, M.D., Robert Mannel, M.D., Mark S. Shahin, M.D., Guilherme H. Cantuaria, M.D., Eugenia Girda, M.D., Cara Mathews, M.D., Juraj Kavecansky, M.D., Charles A. Leath III, M.D., M.S.P.H., Lilian T. Gien, M.D., Emily M. Hinchcliff, M.D., M.P.H., Shashikant B. Lele, M.D., Lisa M. Landrum, M.D., Floor Backes, M.D., Roisin E. O’Cearbhaill, M.D., Tareq Al Baghdadi, M.D., Emily K. Hill, M.D., Premal H. Thaker, M.D., Veena S. John, M.D., Stephen Welch, M.D., Amanda N. Fader, M.D., Matthew A. Powell, M.D., and Carol Aghajanian, M.D.

Source: DOI: 10.1056/NEJMoa2302312

Dr. Anjan Patel's Thoughts

Chemo + IO may become the SOC for 1L treatment of met-endometrial adenoCa. For pembro + chemo, there was a 70% lower risk of disease progression in dMMR and a 46% lower risk in pMMR compared to placebo + chemo. For pMMR patients, the impact on 2L therapy responses will need to be considered carefully, as lenvantinib + pembro has been found to be superior to either agent alone after chemo.

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. opens in new tab.)

Author Affiliations

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.).

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

Initial results from the DUO-E study in metastatic endometrial cancer. The preliminary report suggests that maintenance durvalumab and maintenance durvalumab + olaparib were superior to standard observation after systemic carbo/taxol. As the trial data matures, the question will be: is this in all patients or driven by those with dMMR or HDR mutations?

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer

This is another possibility for maintenance therapy. It will require further study.

Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer

An interesting study where the authors performed a post hoc analysis of randomized trials using molecular classification of endometrial cancers. There was good evidence to omit RT for those with POLE mutations and def-MMR. There seems to be a higher degree of benefit in those with a p53 mutation.