Adjuvant Pembrolizumab/Chemotherapy Misses DFS End Point in High-Risk Endometrial Cancer, but Benefits dMMR Subgroup

The combination of adjuvant pembrolizumab (Keytruda) and chemotherapy with or without radiation did not improve disease-free survival (DFS) compared with chemotherapy with or without radiation alone in newly diagnosed patients with high-risk endometrial cancer. However, data suggest that the regimen did have a clinically meaningful benefit in those whose tumors were mismatch repair deficient (dMMR), according to interim results of the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 trial (NCT04634877) that were presented during the ESMO Congress 2024.^1,2

At a median follow-up of 23.9 months (95% CI, 0.2-37.3) in the intent-to-treat (ITT) population, findings of the protocol-specified third interim analysis showed that the median DFS was not reached (NR) in either arm (HR, 1.02; 95% CI, 0.79-1.32; P = .570). The 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo arms, respectively.

However, the median DFS was NR (95% CI, NR-NR) with pembrolizumab compared with NR (95% CI, 29.5-NR) with placebo (HR, 0.31; 95% CI, 0.14-0.69) in patients with dMMR tumors (n = 281); the 2-year DFS rates were 92% and 80%, respectively.

In those whose tumors were mismatch repair proficient (pMMR), the median DFS was NR in either arm (HR, 1.20; 95% CI, 0.91-1.57). These 2-year DFS rates were 69% and 75%, respectively.

“The subgroup analysis by MMR status suggests a clinically meaningful benefit in DFS for the dMMR subgroup—which is about 25% of the population—a biomarker population well established to have a high [tumor mutational burden] and an inflamed phenotype with elevated PD-L1 expression,” lead study author Toon Van Gorp, MD, a gynecologist oncologist in the Department of Gynecology and Obstetrics at UZ Leuven, in Leuven, Belgium, said in an oral presentation during the meeting.

Pembrolizumab plus chemotherapy is approved as a frontline treatment for patients with advanced or recurrent endometrial cancer, irrespective of mismatch repair (MMR) status.³ The decision was based on data showing that the combination reduced the risk of disease progression or death in patients with endometrial cancer regardless of MMR status (pMMR: HR, 0.54; 95% CI, 0.41-0.71) and (dMMR: HR, 0.30; 95% CI, 0.19-0.48).⁴

Currently in the curative intent, adjuvant setting, systemic chemotherapy with or without radiation is the standard treatment for patients with high-risk endometrial cancer, with 5-year DFS rates between 58% and 65% with chemotherapy or chemoradiation.^5,6

In stage 1 of the phase 3ENGOT-en11/GOG-3053/KEYNOTE-B21 trial of newly diagnosed patients with high-risk endometrial cancer following surgery with curative intent, investigators randomized 1095 patients 1:1 to receive adjuvant pembrolizumab at 200 mg (n = 545) or placebo (n = 550), both every 3 weeks for 6 cycles plus carboplatin at area under the curve 5 or 6 plus paclitaxel at 175 mg/m² every 3 weeks for 4 or 6 cycles.

In stage 2 of the trial, this was followed by pembrolizumab at 400 mg or placebo every 6 weeks for 6 cycles. Radiation therapy and/or cisplatin was administered following chemotherapy completion at the investigator’s discretion.

To be eligible for enrollment, patients had to be at least 18 years old with newly diagnosed, histologically confirmed high-risk endometrial cancer or carcinosarcoma post-surgery with curative intent and no postoperative evidence of disease. The criteria for high-risk disease were FIGO (2009) surgical stage I/II of non-endometrioid histology with myometrial invasion, FIGO (2009) surgical stage I/II of any histology with p53/TP53 abnormalities with myometrial invasion, or FIGO (2009) stage III/IVA of any histology.

Those who received prior radiation or systemic therapy were excluded from enrollment.

Stratification factors included MMR status (pMMR vs dMMR), as well as planned radiation (chemo-external beam radiation therapy [EBRT] vs EBRT vs no EBRT), histology (endometrioid vs non-endometrioid), and FIGO (2009) surgical stage (I/II vs III/IVA), all within the pMMR subgroup.

The coprimary end points were investigator-assessed DFS and overall survival (OS) in the ITT population.

Baseline characteristics were generally balanced between the 2 arms. Overall, the median age was 62 years (range, 27-95), 75.5% of patients had an ECOG performance status of 0, and 62% were White. Ninety percent of patients had lymph nodes dissected, and 43% had lymph node involvement. Most patients had pMMR tumors (74.5%), with the remaining having dMMR tumors. A total 26.5% of patients had FIGO 2009 stage IA/B (26.5%), II (7%), IIIA (18.5%), IIIB (3.5%), IIIC1 (28.5%), IIIC2 (14.5%), and IVA/B (~1%). Forty-six percent of patients had EBRT without cisplatin and 54% had endometrioid histology.

At the data cutoff date of March 4, 2024, there were 111 (27%) and 96 (23%) DFS events in the pembrolizumab and placebo arms in the pMMR subgroup compared with 8 (6%) and 25 (18%) in the dMMR subgroup, respectively. OS data were immature at the time of the interim analysis.

Regarding safety, any-grade adverse effects (AEs) occurred in all patients in both arms; grade 3 or higher AEs occurred in 71% of patients on the pembrolizumab arm compared with 63% of those on the placebo arm. There were no treatment-related deaths.

Treatment discontinuation rates occurred in 24% and 16% of patients on the pembrolizumab and placebo arms; treatment discontinuations led to death in 3% and 1% of patients, respectively. There were similar rates between arms of the different chemotherapy and radiation discontinuations, Van Gorp noted. Immune-related AEs and infusion reactions occurred in 42% of pembrolizumab-treated patients; these were grade 3 to 5 in 10% of patients, led to treatment discontinuation in 6%, and led to death in 1 patient. In the placebo arm, these rates were 24%, 4%, and 4%; no patients died because of immune-related AEs or infusion reactions.

In the safety population, AEs occurring in at least 25% of patients in the pembrolizumab and placebo arms comprised alopecia (63%; 65%), anemia (52%; 52%), nausea (44%; 48%), diarrhea (40%; 38%), decreased neutrophil count (35%; 32%), constipation (33%; 30%), peripheral neuropathy (29%; 34%); decreased white blood cell count (34%; 28%), arthralgia (29%; 30%), and fatigue (28%; 30%).

Immune-mediated AEs and infusion reactions occurring in at least 1% of patients in either treatment arm were consistent with the known safety profiles of checkpoint inhibitors, Van Gorp explained. These included hypothyroidism, hyperthyroidism, infusion reactions, severe skin reactions, pneumonitis, thyroiditis, colitis, adrenal insufficiency, and gastritis.

Disclosures: Dr Van Gorp reported consulting or advisory roles with AbbVie, BioNTech, Eisai, GSK, ImmunoGen, Incyte, Karyopharm, Merck Sharp & Dohme LLC, OncXerna, Seagen, Tubulis, and Zentalis; honoraria from AstraZeneca, Eisai, GSK, ImmunoGen, and MSD; research funding from Amgen, AstraZeneca, and Roche; and travel, accommodations, and expenses from AstraZeneca, ImmunoGen, MSD, and PharmaMar. Funding for this research was provided by MSD.

References

1. Van Gorp T, Rob L, Lv W, 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. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain. Abstract LBA28.
2. Van Gorp T, Cibula D, Lv W, et al. ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase 3 study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. Ann Oncol. Published online September 14, 2024. doi:10.1016/j.annonc.2024.08.2242
3. FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma. FDA. June 17, 2024. Accessed June 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma
4. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab pluschemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312
5. De Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;20(9):1273-1285. doi:10.1016/S1470-2045(19)30395-X
6. Matei D, Filiaci V, Randall ME, et al. Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. N Eng J Med. 2019;380(24):2317-2326. doi:10.1056/NEJMoa1813181