The benefit of pembrolizumab compared with placebo in combination with adjuvant chemotherapy with or without radiation therapy in patients with newly diagnosed high-risk endometrial cancer after surgery with curative intent is under evaluation in the ENGOT-en11/GOG-3053/KEYNOTE-B21 trial.
The benefit of pembrolizumab (Keytruda) vs placebo in combination with adjuvant chemotherapy with or without radiation therapy in patients with newly diagnosed high-risk endometrial cancer after surgery with curative intent is under evaluation in the ENGOT-en11/GOG-3053/KEYNOTE-B21 trial (NCT04634877). The rationale for the trial is attributed to the antitumor activity of the immune checkpoint inhibitor and outcomes with both adjuvant chemotherapy and adjuvant chemoradiotherapy.
Details of the trial were presented in a poster by author Brian Slomovitz, MD, during the Society of Gynecologic Oncology 2022 Annual Meeting on Women’s Cancer.1 Slomovitz is director of gynecologic oncology at Mount Sinai Medical Center in Miami Beach, Florida.
Specifically, the authors of the poster noted that efficacy data from a phase 3 trial (NCT00942357) demonstrated that the estimated 5-year recurrence-free survival rate for patients with high-risk endometrial cancer is 58% (95% CI, 53%-64%) and 59% (95% CI, 53%-65%) following adjuvant chemoherapy alone (n = 361) or chemotherapy plus radiation therapy (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 elicited an overall response rate ORR) of 57% (95% CI, 42%-71%), with 16% being complete responses and 41% being par- tial responses, among 49 evaluable patients with previously treated microsatellite insta- bility–high advanced endometrial cancer, with 93% of responses ongoing after at least 9 months of follow-up.3
Also, 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 treated advanced endometrial cancer achieved an ORR of 38% (95% CI, 28.8%-47.8%) at week 24. Additionally, 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 commenced in 2020, has an estimated enrollment of 990 patients. Patients will be randomly assigned 1:1 to receive either pembrolizumab at 200 mg or placebo in combination with carboplatin area under the curve 5 or 6, and 175-mg/m2 paclitaxel every 3 weeks. For patients who plan to receive optional radiotherapy per investigator deci- sion, paclitaxel should be administered for 4 cycles; all other individuals should receive 6 cycles of paclitaxel. If radiotherapy is pursued it should be started within 6 weeks of completion of carboplatin and paclitaxel. Following completion of 6 cycles of treat- ment, patients will proceed to 6 cycles of pembrolizumab at 400 mg with or without radiotherapy 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 endo- metrial carcinoma or carcinosarcoma (mixed Mullerian tumor) and have undergone curative intent surgery that included 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 dis- ease free with no evidence of locoregional disease or distant metastasis postoperatively and on imaging, no prior radiation or sys- temic therapy—including immunotherapy or hormonal therapy—in any setting, submis- sion of a tumor tissue sample from current diagnosis of endometrial carcinoma or carcinosarcoma, and adequate organ function.
As for exclusion criteria, key items include presence of a uterine mesenchymal tumor, FIGO (2009) surgical I/II endometrial cancer without a known aberrant p53 expression or p53 mutation, a known POLE mutation, or FIGO stage IVB disease of any histology even if there was no evidence of disease after surgery. Patients are also ineligible if they have a measurable or nonmeasurable resid- ual tumor after surgery or a history of a sec- ond malignancy, unless potentially curative treatment had been completed, with no evi- dence of malignancy for 3 years. Patients are not permitted if they have received prior therapy with an anti–PD-L1 or anti–PD-L2 agent with an agent directed to another stim- ulatory or coinhibitory T-cell receptor or to have received a live vaccine within 30 days before the first study dose.
Additional exclusion criteria were diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (> 10 mg prednisone equivalent) or any immunosuppressive therapy within 7 days before the first study dose, severe hypersensitivity (grade ≥3) to pembrolizumab and/or any of its excipients, active autoimmune disease that required sys- temic treatment in the past 2 years, history of noninfectious pneumonitis or active pneumo- nitis, history of HIV infection or hepatitis B, history of or active hepatitis C, allogenic tis- sue or solid organ transplant, and inadequate recovery or complications from surgery.
Patients were stratified by mismatch repair (MMR) status (proficient MMR [pMMR] vs deficient MMR) and within pMMR stratum, planned radiation therapy (chemotherapy plus external beam radiation therapy [EBRT] vs EBRT vs no EBRT), histology (endometri- oid vs nonendometrioid), and FIGO (2009) surgical stage (stage I/II vs stage III/IVA).
The primary end points are disease-free survival (DFS) as assessed by the investigator and OS.
The secondary end points are DFS as assessed by blinded independent central review, OS and DFS as assessed by the investigator by PD-L1 status, OS and DFS as assessed by the investigator by tumor mutational burden (TMB) status, and safety. Additional end points are patient-reported quality of life (QOL) assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) global score and physical function subscale, along with EORTC endometrial cancer-specific QOL module (EORTC QLQ- EN24) symptom specific scale.
As for assessments, tumor imaging of the chest, abdomen, and pelvis will be acquired by computed tomography at screening (after surgery but within 28 days before random- ization), then every 12 weeks until week 96, then every 24 weeks in the third year, and annually thereafter. ECOG status will be assessed at screening and on day 1 of each cycle starting at stage 1 cycle 2 day 1.
DFS will be assessed radiographically or by histopathologic confirmation of suspected disease recurrence. Adverse events (AEs), including serious AEs, will be monitored throughout the study until the last efficacy follow-up or visit or until 30 days after the last dose of study treatment, whichever is earlier. PD-L1 expression will be evaluated using the PD-L1 IHC 22C3 pharDx assay, and TMB will be assessed from tumor samples.
Safety outcomes will be evaluated in all patients who receive at least 1 dose of study treatment and analyzed according to the treatment received and the PROs (patient-reported outcomes) analysis will be conducted for all patients who complete at least 1 PRO assessment and received at least 1 dose of study treatment.
PROs will be assessed every cycle where pembrolizumab or placebo is administered, until treatment completion or discontinuation, and will continue to be collected in post- treatment follow-up until disease recurrence.
The exploratory end points for the study include evaluating changes in the visual ana- log scale and characterizing health utilities using the European Quality of Life 5-Dimensions 5-Level questionnaire (EQ-5D-5L), along with assessing global severity of symptoms using Patient Global Impression of Severity (PGI-S) and global rating of change using the Patient Global Impression of Change (PGI-C). PRO questionnaires will be administered in the following order: EORTC QLQ-C30, EROTC QLQ-EN24, PGI-S, PGI-C, and EQ-5D-5L.
Investigators 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 is planned to recruit across 21 global sites.
1. 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 radiotherapy in patients with newly diagnosed high-risk endometrial cancer. Pre- sented at: Society of Gynecologic Oncology 2022 Annual Meeting on Women’s Cancer; March 18-21, 2022; Phoenix, AZ. Poster 570.
2. Matei D, Filiaci V, Randall M, et al. Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. N Engl J Med. 2019;380(24):2317-2326. doi:10.1056/NEJMoa1813181
3. O’Malley D, Marabelle A, De Jesus-Acosta A, et al. Pembrolizumab in patients with MSI-H advanced endometrial cancer from the KEY- NOTE-158 study. Ann Oncol. 2019;30(5):v403-v434. doi:10.1093/ annonc/mdz250
4. Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembroli- zumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38(26):2981-2992. doi:10.1200/JCO.19.02627