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The durable antitumor activity of pembrolizumab and the clinically beneficial outcomes demonstrated with both adjuvant chemotherapy and adjuvant chemoradiotherapy have provided investigators with the foundation to assess the 2 approaches in combination in a phase 3 study.
The durable antitumor activity of pembrolizumab (Keytruda) and the clinically beneficial outcomes demonstrated with both adjuvant chemotherapy and adjuvant chemoradiotherapy have provided investigators with the foundation to assess the 2 approaches in combination in a phase 3 study. Details of the trial in progress—ENGOT-en11/GOG-3053/KEYNOTE-B21 trial (NCT04634877) —were presented in a poster by author Brian Slomovitz, MD, during the Society of Gynecologic Oncology 2022 Annual Meeting on Women’s Cancer.1
Investigators of the ongoing ENGOT-en11/GOG-3053/KEYNOTE-B21 trial are evaluating pembrolizumab vs placebo administered in combination with adjuvant chemotherapy—carboplatin plus paclitaxel—with or without radiation therapy in patients with newly diagnosed high-risk endometrial cancer after surgery with curative intent. 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 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 chemotherapy 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 partial responses—among 49 evaluable patients with previously treated microsatellite instability high advanced endometrial cancer, with 93% of responses ongoing after at least 9 months of follow-up.3
Also, pembrolizumab in combination with lenvatinib 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 enrollement of 990 patients. Patients will be randomly assigned 1:1 to receive either pembrolizumab at 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 who plan to receive optional radiotherapy per investigator decision, paclitaxel should be administred for 4 cycles; all other individuals should receive 6 cycles of paclitaxel. If radiotherapy is purused it should be started within 6 weeks of completion of carboplatin and paclitaxel. Following completion of 6 cycles of treatment 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 endometrial carcinoma or carcinosarcoma (mixed Mullerian tumor) and have undergone curative intent surgery that included hysterectomy and bilateral salpingo-oophorectomy and are at high risk of recurrence as assessed by the International Federation of Gynecology and Obstetrics (FIGO) staging criteria.1,5
Additional inclusion criteria include: disease free with no evidence of locoregional disease or distant metastasis postoperatively and on imaging, no prior radiation or systemic therapy—including immunotherapy or hormonal therapy—in any setting, submission 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 residual tumor after surgery or a history of a second malignancy, unless potentially curative treatment had been completed, with no evidence 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 stimulatory 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 chromic 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 systemic treatment in the past 2 years, history of noninfectious pneumonitis or active pneumonitis, history of HIV infection or hepatitis B, history of or active hepatitis C, allogenic tissue 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 (endometrioid 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 (BICR), 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 randomization), 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 analysis will be carried out for all patients who complete at least 1 PRO assessment and received at least 1 dose of study treatment.
Patient-reported outcomes (PROs) will be assessed every cycle where pembrolizumab or placebo is administered, until treatment completion or discontinuation, and will continue to be collected in posttreatment follow-up until disease recurrence.
The exploratory end points for the study include evaluating changes in the visual analog 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 the European Quality of Life 5-Dimensions 5-Level questionnaire 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.