Endometrial Cancer: A Revolution That Is Only Just Beginning

In the last two years, first-line treatment of advanced, recurrent or metastatic endometrial cancer (EC) has been revolutionised. Previously, treatment consisted of chemotherapy and led to disappointing results, as most patients relapsed within the first year (1).

The addition of immune checkpoint inhibitors to carboplatin and paclitaxel enabled outcome improvements in the RUBY (dostarlimab), NRG-GY018 (pembrolizumab), AtTEnd (atezolizumab) and DUO-E (durvalumab plus olaparib) trials (2–5). Their results must be considered in relation to microsatellite stability (MSS) status. In mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H), chemoimmunotherapy led to remarkable and significant improvements in progression-free survival (PFS) compared to chemotherapy alone in all four studies, with hazard ratios (HR) of around 0.30 (2-5). The sustained effect was striking, as evidenced by a plateauing of the PFS curves after one year. In contrast, the mismatch repair deficiency (pMMR)/MSS group showed a significantly lower PFS benefit, although some patients benefited from the addition of dostarlimab (RUBY) or pembrolizumab (NRG-GY018). However, it is still not possible to prospectively identify these cohorts.

In the RUBY study, the mortality rate in the group with dMMR/MSI-H decreased significantly with dostarlimab plus chemotherapy (HR: 0.32; p = 0.0002), while there was only a trend in the pMMR cohort (HR: 0.79) (6). However, the substantial cross-over must be considered when assessing these data.

Adjuvant Pembrolizumab: KEYNOTE-B21

In the adjuvant setting, the guidelines recommend chemotherapy with or without radiotherapy for high-risk EC (7). According to a retrospective analysis of the PORTEC-3 trial, chemoradiotherapy prolonged recurrence-free survival compared to radiotherapy alone in p53-mutated disease, which is associated with a poor prognosis (8). In contrast, radiotherapy alone was sufficient in the POLE-mutated population due to the favourable prognosis of this group (8). There was no clear advantage to the combined approach in patients with intermediate prognosis (dMMR, non-specific molecular profile).

The randomized phase III KEYNOTE-B21 trial was therefore conducted to evaluate adjuvant pembrolizumab in high-risk EC (9). Pembrolizumab was used for up to six cycles in addition to carboplatin and paclitaxel, followed by a further six cycles of pembrolizumab with or without radiotherapy and cisplatin as decided by the investigators. The control arm received a placebo instead of pembrolizumab. Unfortunately, the KEYNOTE-B21 study failed to meet its primary endpoint of disease-free survival (DFS). (HR: 1.02; p = 0.570). Within the pre-specified subgroups, only the dMMR population benefited from the addition of pembrolizumab. Here, a clinically relevant DFS benefit of almost 70% was observed with 24-month rates of 92% vs. 80% (HR: 0.31).

Antibody-Drug Conjugates on the Horizon

The number of new antibody-drug conjugates (ADCs) has increased substantially worldwide in recent years. Targets of particular interest in EC include HER2, TROP2 and folate receptor alpha (FRα). In pre-treated patients with HER2-expressing EC, trastuzumab deruxtecan achieved overall response rates (ORR) of up to 84.6 % in the DESTINY PanTumor02 study (Fig. 1) and favourable PFS results depending on the extent of HER2 expression (10).

Figure 1. Response to T-DXd in HER2-expressing endometrial cancer (modified from F. Meric-Bernstam et. al) (11).

In the field of TROP2-targeted ADC, datopotamab deruxtecan (Dato-DXd) showed promising activity in the EC cohort of the phase II basket study TROPION-PanTumor03 (11). In this population with advanced/metastatic EC that had progressed after ≥ 1 line of platinum-based chemotherapy, Dato-DXd produced an ORR of 27.5% and a median duration of response of 16.4 months regardless of the level of TROP2 expression. Similarly, the TROP2-directed ADC sacituzumab-tirumotecan in the Phase II setting resulted in an ORR of 34.1 % in pretreated patients (12). Phase III trials are already underway or planned to confirm the efficacy of sacituzumab-tirumotecan after chemotherapy and immunotherapy (NCT06132958, NCT05382268).

The safety aspect must be considered when usingADCs, as the “payloads” are potent chemotherapies. We must learn to address the toxicity of these agents. In TROPION-PanTumor03, side effects of Dato-DXd therapy forced dose reductions in 25% of patients and treatment discontinuations in 35% (11). The most common side effects were stomatitis, nausea, loss of appetite, constipation, and alopecia.

Conclusion

Immunotherapy has fundamentally changed the first-line treatment of advanced EC. In early high-risk disease, the results of the KEYNOTE-B21 study indicate that pembrolizumab is a new standard option in the dMMR group in addition to adjuvant chemotherapy. The role of chemotherapy in this group will have to be discussed in the future.

HER2- and TROP2-targeted ADC achieved promising signals in advanced stages after pre-treatment. Phase III results are expected. There are still many unanswered questions, especially with regard to biomarkers, sequencing of different ADCs, and selection between products with similar targets and payloads. Nevertheless, these developments represent a steady improvement in the outcomes of our patients with EC.

Explore more about the latest gynecological cancers with Drs. Apostolos Sarivalasis, Ilaria Colombo, and Christina Fotopoulou.

References

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