Biomarker-driven therapy in endometrial cancer

dMMR/MSI-H endometrial cancer is characterized by loss of DNA mismatch repair and high mutation rates. This subtype accounts for 25–30% of endometrial cancers and over 90% have endometrioid histology.3 dMMR/MSI-H endometrial cancer can be identified through microsatellite or immunohistochemistry testing for loss of expression of DNA mismatch repair proteins (MLH1, MSH2, MSH6, PMS2). The majority of dMMR/MSI-H endometrial cancers are sporadic; 75% of cases result from MLH1-promoter hypermethylation. In contrast, Lynch syndrome is caused by germline mutations in mismatch repair genes and accounts for approximately 10–20% of dMMR and 3% of all endometrial cancers.5 Current guidelines recommend screening for mismatch repair at initial diagnosis, but data presented at the Society of Gynecologic Oncology annual meeting 2022 suggest it may be appropriate to retest mismatch repair status on relapse.2 6 In a retrospective cohort study, 3/32 (9.4%) patients with initially MMR proficient (pMMR) endometrial cancer were found to have dMMR at recurrence.6 These findings need confirmation in a larger prospective cohort.

Conventional Therapy

Recent data suggest adjuvant radiation is effective in dMMR/MSI-H endometrial cancer. Molecular analysis of PORTEC-3, a randomized phase III trial of combined adjuvant chemotherapy and external beam radiotherapy versus radiotherapy alone, found no benefit with the addition of chemotherapy to adjuvant radiation in dMMR endometrial cancer. Five-year overall survival was 84% with radiotherapy alone and 79% with chemoradiation (p=0.445).7 A retrospective study of patients with advanced stage, MSI-H endometrial cancer found improved progression-free survival with the addition of radiation to chemotherapy versus chemotherapy alone in this group.8 Prospective studies are needed to confirm the role of adjuvant radiation and/or chemotherapy in dMMR/MSI-H endometrial cancer.

Immunotherapy

Hypermutated dMMR/MSI-H and ultra-mutated POLEmut endometrial cancers have immunogenic microenvironments.3 High mutational burden increases production of tumor-mutated antigens, leading to increased tumor infiltration by cytotoxic T-cells and upregulated T-cell mediated antitumor responses.9 Programmed cell death protein 1 (PD-1) on T-cells helps facilitate this immune response and is inhibited when bound to its ligands within the tumor microenvironment, programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2).9 High expression of immune checkpoint-associated proteins, including PD-L1, in dMMR/MSI-H tumors make them susceptible to immune checkpoint inhibitors.3 9

Pembrolizumab (anti-PD-1) was the first immune checkpoint inhibitor approved in endometrial cancer. Blocking the interaction between PD-1 and its ligands, pembrolizumab prevents tumor cells from escaping immune surveillance.9 Pembrolizumab received accelerated US Food and Drug Administration (FDA) approval for unresectable/metastatic MSI-H solid tumors, including endometrial cancer, in 2017 and for unresectable/metastatic tumor mutational burden-high solid tumors, including endometrial cancer, in 2020.10 In March and April 2022, respectively, the FDA fully approved and the European Medicines Agency adopted a positive opinion recommending pembrolizumab for previously treated dMMR/MSI-H endometrial cancer following the non-randomized, open-label, phase II KEYNOTE-158 study (objective response rate (ORR) 48% (95% CI 36.7% to 59.6%); progression-free survival 13.1 (95% CI 4.3 to 34.4) months; overall survival, not reached).10–12

Dostarlimab (anti-PD-1) received both accelerated approval by the FDA and conditional marketing authorization by the European Medicines Agency for advanced/recurrent dMMR endometrial cancer that has progressed on or after platinum-based therapy.13 In the single-arm, open-label, phase I GARNET trial, dostarlimab conferred an ORR of 43.5% (95% CI 34.0% to 53.4%) with a 12-month duration of response in 90.6% of patients with dMMR/MSI-H disease.14 Long-term GARNET data presented at the 2022 annual meeting of the American Society of Clinical Oncology showed that 83.7% of patients treated with dostarlimab remained in response at 24 months.15 Other drugs within this class include nivolumab (anti-PD-1) and atezolizumab, avelumab, and durvalumab (anti-PD-L1), with ORRs in phase II trials of 23%, 13%, 26.7%, and 47%, respectively (Table 1).5 Interestingly, in a small cohort, Bellone et al found improved ORR, progression-free survival, and overall survival in Lynch-associated (n=6) versus sporadic (n=18) dMMR endometrial cancer when treated with pembrolizumab.16 Moreover, results at the Society of Gynecologic Oncology annual meeting 2022 suggest a correlation between MLH1-hypermethylation and poor response to single-agent immunotherapy with pembrolizumab in recurrent endometrial cancer.17 However, data from the GARNET trial in the largest cohort evaluating this noted that MSI-H tumors regardless of mutation or presumed methylation had similar efficacy with single-agent immunotherapy with dostarlimab.14

Table 1

Treatment options in dMMR/MSI-H endometrial cancer: Approved and in trial

The benefit of immune checkpoint inhibitors is evident in patients with advanced/recurrent dMMR/MSI-H endometrial cancer following first-line therapy. However, it has yet to be determined if patients with dMMR/MSI-H endometrial cancer could benefit from immunotherapy in other settings, such as adjuvant use in high-risk patients or combined use with first-line chemotherapy or other targeted therapies. Currently, NRG-GY020, the first molecularly selected adjuvant therapy trial in endometrial cancer, is evaluating the addition of pembrolizumab to radiation in newly diagnosed early-stage dMMR endometrioid endometrial cancer and has completed accrual (NCT0421406). Following GY020, ENGOT-en11/GOG-3053/KEYNOTE-B21 is a phase III study of pembrolizumab or placebo in combination with adjuvant chemotherapy with or without radiotherapy, which has also completed accrual (NCT04634877). Results of several clinical trials assessing the efficacy of immune checkpoint inhibitors in combination with first-line chemotherapy in advanced/recurrent endometrial cancer are pending: ENGOT-EN6/NSGO-RUBY using dostarlimab, AtTEnd/ENGOT-en7 using atezolizumab, and NRG-GY018 using pembrolizumab (NCT03981796, NCT03603184, NCT03914612). Chemotherapy may increase immune stimulation and induce PD-L1 expression on cancer cells, making the combination of immune checkpoint inhibitors and chemotherapy promising.9 Further, there is evidence for first-line treatment with immune checkpoint inhibitors in dMMR solid tumors outside of endometrial cancer. In locally advanced dMMR rectal cancer, first-line dostarlimab induced complete response in 100% of patients at 6 months of follow-up.18 Two studies are evaluating first-line immune checkpoint inhibitor versus carboplatin-paclitaxel in advanced/recurrent dMMR endometrial cancer: KEYNOTE-C93/GOG-3064/ENGOT-en15 using pembrolizumab, and GINECO-EN105b/ENGOT-en13 using dostarlimab (NCT05173987, NCT05201547).

Within the dMMR/MSI-H subtype, combination therapies for patients who failed or progressed through single-agent immunotherapy include inhibiting cytotoxic T-lymphocyte antigen-4, which decreases T-cell function when bound to co-stimulatory molecules on antigen presenting cells.9 NRG-GY025 is assessing nivolumab (anti-PD1) plus ipilimumab (anti-cytotoxic T-lymphocyte antigen-4) versus single-agent nivolumab in recurrent dMMR endometrial cancer (NCT05112601). Poly (ADP-ribose) polymerase (PARP) inhibitors are also being investigated in combination with immunotherapy. PARP inhibition causes accumulation of DNA damage, which may alter immune checkpoint receptor expression and increase immune checkpoint inhibitor activity. However, in the single-arm phase II DOMEC trial, the combination of durvalumab (anti-PD-L1) and olaparib (PARP inhibitor) did not meet the pre-specified 50% 6-month progression-free survival in the overall population (median progression-free survival 3.4 months, 95% CI 2.8 to 6.2 months) nor in the dMMR cohort (median progression-free survival 5.7 months, 95% CI 2.8 to NR).19 Two trials, RUBY part 2 and DUO-E, are investigating the combination of platinum-based chemotherapy, immune checkpoint inhibitors, and PARP inhibitors in first-line treatment of advanced endometrial cancer (NCT03981796, NCT04269200). Additionally, avelumab, in combination with either talazoparib (PARP inhibitor) or axitinib (tyrosine kinase inhibitor), is being studied in patients with endometrial cancer based on mismatch repair status (NCT02912572). Finally, one arm of an ongoing multicohort biomarker directed study of targeted agents with atezolizumab (AFT-50/ENDOMAP) is evaluating the combination of atezolizumab with tiragolumab (anti-TIGIT) in MSI-H endometrial cancer which has progressed following single-agent immunotherapy (NCT04486352).

Agents on the Horizon

Lymphocyte activation gene-3 participates in the immune escape of tumor cells and is thus a target for immunotherapy. In March 2022, based on longer progression-free survival from RELATIVITY-047, the first lymphocyte activation gene-3 inhibitor, relatlimab, received FDA approval in combination with nivolumab for melanoma.20 In endometrial cancer, lymphocyte activation gene-3 expression is found in over 30% of patients, with greater prevalence in the dMMR/MSI-H (66.3%) and POLEmut (34.4%) subtypes.21

Another possible target for future therapy is T-cell immunoglobulin-3, an immune checkpoint molecule similar to PD-1. T-cell immunoglobulin-3 is found in multiple solid tumors, including endometrial cancer.22 Stronger expression was observed in dMMR endometrial cancer than pMMR, especially for MLH1-hypermethylated and MSH6-loss cases.23 Research targeting T-cell immunoglobulin-3 is ongoing. PODIUM 204 is a phase II study of retifanlimab (anti-PD-1) in advanced or metastatic endometrial cancer as monotherapy or in combination with other targeted agents, including one targeting lymphocyte activation gene-3 and one targeting T-cell immunoglobulin-3 (NCT04463771).

Bispecific antibodies, which target two different epitopes, are a novel approach in endometrial cancer. A phase II trial in advanced gynecologic cancers is evaluating an immunoglobulin G1 bispecific antibody against PD-1 and vascular endothelial growth factor (VEGF) and plans to assess differences by dMMR status in endometrial cancer (NCT04870177). A second phase II trial in advanced gynecologic cancers, including endometrial, is evaluating a bispecific monoclonal antibody that targets PD-1 and cytotoxic T-lymphocyte antigen-4 (NCT05032040). Additionally, next generation cytotoxic T-lymphocyte antigen-4 inhibitors have shown promise in multiple solid tumors, including endometrial cancer. AGEN1181, a fragment crystallizable-enhanced anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody, demonstrated clinical activity as a monotherapy and in combination with balstilimab (anti-PD-1) in heavily pretreated advanced solid tumors. In three patients with microsatellite stable endometrial cancer who received monotherapy or combination dosing, the disease control rate was 100% with one complete response and two partial responses.22

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