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Adjuvant Pembrolizumab Plus Chemotherapy Improves DFS in Patients with Newly-Diagnosed, High-Risk dMMR Endometrial Cancer, but Not in All-Comer Population

Findings from the ENGOT-en11/GOG-3053/KEYNOTE-B21 study
01 Oct 2024
Immunotherapy;  Cytotoxic Therapy
Endometrial Cancer

Adding pembrolizumab to adjuvant chemotherapy did not improve disease-free survival (DFS) compared with the addition of placebo to adjuvant chemotherapy in the all-comer patient population with newly diagnosed, high-risk endometrial cancer after surgery with curative intent in a phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study.

However, the results of pre-planned subgroup analyses based on the study’s stratification factors suggest that adjuvant treatment with pembrolizumab plus chemotherapy provides clinically meaningful improvement in DFS for patients with mismatch repair-deficient (dMMR) tumours in the curative intent setting. Findings were presented at the ESMO Congress 2024 along with a simultaneous publication by Prof. Toon Van Gorp of the UZ Leuven in Leuven, Belgium, and colleagues on 14 September 2024 in the Annals of Oncology.

Adjuvant therapy that is initiated after surgery with curative intent in patients with endometrial cancer is tailored according to risk of disease recurrence. An unmet need exists for treatments that can prevent or delay recurrence and improve survival for patients with high-risk endometrial cancer. In the first-line setting, the addition of PD1 and PD-L1 inhibitors to standard-of-care chemotherapy has demonstrated benefit in patients with advanced or recurrent endometrial cancer. Benefit was seen in both dMMR and mismatch repair-proficient (pMMR) cohorts, although the benefit was numerically greater in the dMMR cohort.

The authors explained in the background that previous analyses showed significantly higher neoantigen load, CD3-positive and CD8-positive tumour-infiltrating lymphocytes, and overexpression of PD1 and PD-L1 in dMMR compared with pMMR endometrial cancers. These features of dMMR tumours may explain the greater treatment effect of anti−PD1 or anti–PD-L1 monoclonal antibodies in this population when administered as monotherapy or combination therapy.

The lack of these features may explain why pMMR tumours appear to require a combination therapy approach to augment the effects of anti−PD1 or anti–PD-L1 inhibition. Cytotoxic chemotherapy, for example, has demonstrated immunomodulatory activity that may enhance the effect of immunotherapy within pMMR tumours.

A phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study compared the addition of pembrolizumab versus placebo to adjuvant carboplatin-paclitaxel chemotherapy, with or without radiotherapy, in patients with newly diagnosed, high-risk (FIGO stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology) endometrial cancer who have no evidence of residual macroscopic disease following curative-intent surgery and with no prior radiotherapy or systemic therapy.

Patients were randomised to pembrolizumab 200 mg or placebo Q3W for 6 cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo Q6W for 6 cycles per treatment assignment. Radiotherapy was at the investigator’s discretion. Primary endpoints were investigator-assessed DFS and overall survival (OS) in the intention-to-treat (ITT) population.

A total of 1095 patients were randomised, 545 in the pembrolizumab and 550 in the placebo group. At the interim analysis with data cut-off on 4 March2024, median duration of follow-up was 23.7 months (range, 0.2 to 36.1) in the pembrolizumab group and 24.1 months (range, 2.4 to 37.3) in the placebo group; 119 DFS events (22%) occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group (hazard ratio 1.02, 95% confidence interval [CI] 0.79‒1.32; p = 0.570). Kaplan–Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. HR for DFS was 0.31 (95% CI 0.14‒0.69) in the dMMR population of 281 patients and 1.20 (95% CI 0.91‒1.57) in the pMMR population of 814 patients.

Too few patients had died at the time of this analysis (10%) to allow for OS assessment.

The safety profile of combination therapy was manageable. Grade ≥3 adverse events occurred in 386 of 543 patients (71%) and 348 of 549 patients (63%) in the pembrolizumab and placebo groups. No treatment-related grade 5 adverse events occurred.

Analysis of QLQ-C30 global health status/quality-of-life scores demonstrated least-squares mean changes from baseline to week 45 of −1.57 (95% CI −3.17 to 0.03) in the pembrolizumab group and −0.35 (95% CI −1.91 to 1.20) in the placebo group. The difference between the treatment groups was −1.21 (95% CI −3.23 to 0.80).

The authors commented that although an improvement in outcomes was not observed in the ITT population, they identified a clinically meaningful improvement in DFS with pembrolizumab in the dMMR subgroup of patients. These results with adjuvant pembrolizumab plus chemotherapy in patients with dMMR tumours suggest that earlier combination treatment may be the optimal approach for this population and may provide the best opportunity for a cure.

The ongoing phase III NRG-GY020 study is conducted exclusively in the early-stage, newly diagnosed, intermediate- to high-risk dMMR setting and will provide important additional information on the role of single-agent pembrolizumab in these patients. The study is evaluating the addition of pembrolizumab to vaginal brachytherapy after surgery, with results anticipated in the near future. Another ongoing phase III study in the dMMR population, the ENGOT-en14/RAINBO MMRd-GREEN study is evaluating the addition of the anti−PD-L1 monoclonal antibody durvalumab to adjuvant radiotherapy in patients with high-risk endometrial cancer, with results expected in 2030.

The ENGOT-en11/GOG-3053/KEYNOTE-B21 study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD).

References

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