The ongoing KEYNOTE-B21 trial aims to determine whether pembrolizumab plus adjuvant chemotherapy with or without radiation therapy will improve disease-free survival and overall survival in patients with newly diagnosed endometrial cancer.
Researchers have begun evaluating the use of adjuvant pembrolizumab (Keytruda) plus chemotherapy or chemoradiotherapy in patients with newly diagnosed high-risk early endometrial cancer in the phase trial. 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 (NCT04634877). Details of the ongoing trial were presented in a poster by author Brian Slomovitz, MD, during 2022 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.1
Researchers in the ongoing study are evaluating pembrolizumab versus placebo given in combination with adjuvant chemotherapy – carboplatin plus paclitaxel – with or without radiation therapy in patients with newly diagnosed high-risk endometrial cancer after curative surgery. Slomovitz, who is director of gynecologic oncology at Mount Sinai Medical Center in Miami Beach, Florida, noted that the individual efficacy results for the 2 approaches led to the rationale for the trial.
Specifically, the authors noted that efficacy data from a phase 3 trial (NCT00942357) demonstrated that the estimated 5-year disease-free survival rate for patients with high-grade endometrial cancer risk is 58% (95% CI, 53% to 64%). and 59% (95% CI, 53% to 65%) after adjuvant chemotherapy alone (n=361) or chemotherapy plus radiotherapy (n=346), respectively.2
Previous studies have already proven the durable antitumor activity and manageable safety of pembrolizumab monotherapy for this patient population. For example, in the Phase 2 KEYNOTE 158 trial (NCT02628067), the agent achieved an overall response rate (ORR) of 57% (95% CI, 42% to 71%) – 16% being responses complete and 41% partial responses. responses – among 49 evaluable patients with advanced endometrial cancer with high microsatellite instability, with 93% of responses ongoing after at least 9 months of follow-up.3
Additionally, pembrolizumab in combination with lenvatinib (Lenvima) showed promising antitumor activity in the Phase 1b/2 KEYNOTE-146 trial (NCT02501096), in which 108 patients with previously advanced endometrial cancer treated achieved an ORR of 38% (95% CI, 28.8%-47.8%) at week 24. In addition, the median progression-free survival was 7.4 months (95% CI, 5 .3-8.7) and the median overall survival (OS) was 16.7 months (range: 15.0 – not estimable).4
ENGOT-en11/GOG-3053/KEYNOTE-B21, which started in 2020, has an estimated enrollment of 990 patients. Patients will be randomized 1:1 to receive either pembrolizumab 200 mg every 3 weeks for 6 infusions or placebo in combination with carboplatin, area under the curve 5 or 6, and 175 mg/m2 paclitaxel every 3 weeks. For patients planning to receive elective radiotherapy at the discretion of the investigator, paclitaxel should be administered for 4 cycles; all other individuals should receive 6 cycles of paclitaxel. If radiotherapy is continued, it should be started within 6 weeks of finishing carboplatin and paclitaxel. After completion of 6 treatment cycles, patients will transition to 6 cycles of pembrolizumab 400 mg with or without radiation therapy and with or without cisplatin.
To be eligible for enrollment, patients must be at least 18 years of age and have an ECOG performance status of 0 or 1 within 7 days of randomization. They must also have a histologically confirmed new diagnosis of carcinoma or carcinosarcoma of the endometrium (Muller’s mixed tumor) and have undergone curative surgery including hysterectomy and bilateral salpingo-oophorectomy and be at high risk of recurrence, as assessed by the International Federation of Gynecology and Obstetrics (FIGO) Staging Criteria.1
Additional inclusion criteria include: being disease-free with no evidence of locoregional disease or postoperative distant metastasis and on imaging, no prior radiotherapy or systemic therapy – including immunotherapy or hormone therapy – in any what background, submission of tumor tissue sample from current diagnosis of endometrial carcinoma or carcinosarcoma and adequate organ function.
With respect to exclusion criteria, key elements include the presence of a uterine mesenchymal tumor, FIGO (2009) surgical endometrial cancer I/II without known p53 aberrant expression or p53 mutation, a POLE mutation, or stage IVB FIGO disease of any histology, even if there was no evidence of disease after surgery. Patients are also ineligible if they have measurable or non-measurable residual tumor after surgery or a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 3 years. Patients are not permitted if they have previously received treatment with an anti-PD-L1 or anti-PD-L2 agent with an agent directed to another stimulatory or co-inhibitory T cell receptor or if they have received a live vaccine within 30 days of the first study dose.
Additional exclusion criteria were: diagnosis of immunodeficiency or chronic treatment with systemic steroids (> 10 mg prednisone equivalent) or any immunosuppressive treatment within 7 days prior to the first study dose, severe hypersensitivity (grade ≥ 3) pembrolizumab and/or one of its excipients, active autoimmune disease requiring systemic treatment within the last 2 years, history of non-infectious pneumonitis or active pneumonitis, history of HIV infection or hepatitis B, history of active or active hepatitis C, allogeneic tissue or solid organ transplant, and inadequate recovery or complications from operation.
Patients were stratified by: mismatch repair status (MMR) [pMMR] vs MMR deficient) and in the pMMR stratum, planned radiotherapy (chemotherapy plus external radiotherapy [EBRT] vs EBRT vs no EBRT), histology (endometrioid vs non-endometrioid) and FIGO (2009) surgical stage (stage I/II vs stage III/IVA).
The primary endpoints are disease-free survival (DFS) as assessed by the investigator and OS.
Secondary endpoints are SSM as assessed by blinded independent central review (BICR), OS and SSM as assessed by the investigator by PD-L1 status, OS and SSM as assessed by the investigator based on tumor mutational load (TMB) status and safety. Additional endpoints are patient-reported quality of life (QOL) as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), score global and physical function subscale, as well as the endometrial cancer-specific QOL module of the EORTC (EORTC QLQ_EN24) symptom-specific scale.
With regard to assessments, tumor imaging of the thorax, abdomen and pelvis will be acquired by computed tomography during screening (after surgery but within 28 days before randomisation), then every 12 weeks until week 96, then every 24 weeks the third year, and annually thereafter. ECOG status will be assessed at screening and on day 1 of each cycle from stage 1 to cycle 2 day 1.
SSM will be assessed by X-ray or histopathological confirmation of suspected disease recurrence. Adverse events (AEs), including serious AEs, will be monitored throughout the study until the last follow-up or efficacy visit or until 30 days after the last dose of study treatment, depending on the first possibility. PD-L1 expression will be assessed using the PD-L1 IHC 22C3 pharDx assay, and TMB will be assessed from tumor samples.
Safety outcomes will be assessed in all patients who receive at least 1 dose of study treatment and analyzed by treatment received; and PRO analysis will be performed for all patients who completed at least 1 PRO assessment and received at least 1 dose of study treatment.
Patient-reported outcomes (PRO) will be assessed at each cycle that pembrolizumab or placebo is administered, until completion or discontinuation of treatment, and will continue to be collected at post-treatment follow-up until the recurrence of the disease.
Exploratory endpoints of the study include assessment of changes in visual analogue scale and characterization of health services using the European 5-Dimensional 5-Level Quality of Life Questionnaire (EQ-5D- 5L), as well as assessment of global symptom severity using Patient Global Impression of Severity (PGI-S) and global assessment of change using Patient Global Impression of Change (PGI -VS). The PRO questionnaires will be administered in the following order: EORTC QLQ-C30, EROTC QLQ-EN24, PGI-S, PGI-C and the European 5-Dimensional 5-Level Quality of Life Questionnaire EQ-5D-5L.
Researchers will also explore locoregional vs. distant metastatic recurrence as assessed by the investigator, in addition to identifying molecular biomarkers of response or resistance to treatments using blood and/or tumor tissue.
Enrollment began in December 2020 and the study plans to recruit at 21 global sites.
- Slomovitz B, Mirza MR, Lortholary A, et al. ENGOT-en11/GOG-3053/KEYNOTE-B21: A Phase 3 Study of Pembrolizumab or Placebo in Combination With Adjuvant Chemotherapy With or Without Radiation Therapy in Patients With Newly Diagnosed High-Risk Endometrial Cancer . Presented at: 2022 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. March 18-21, 2022. Phoenix, AZ. Poster 570.
- Matei D, Filiaci V, Randall M, et al. Adjuvant chemotherapy plus radiotherapy for locally advanced endometrial cancer. N English J med. 2019;380(24):2317-2326. doi:10.1056/NEJMoa1813181
- O’Malley D, Marabelle A, De Jesus-Acosta A, et al. Pembrolizumab in Patients with MSI-H Advanced Endometrial Cancer from the KEYNOTE-158 Study. Anne Oncol. 2019;30(5):v403-v434. doi:10.1093/announce/mdz250
- Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38(26):2981-2992. doi:10.1200/JCO.19.02627