Atezolizumab with chemotherapy for advanced or recurrent endometrial cancer: does targeting PD-1 or PD-L1 matter in this clinical situation?

Introduction

Endometrial cancer is the most common gynecologic malignancy among women in the United States (1) and the second most common gynecologic malignancy worldwide (2). Recent large database studies have demonstrated that endometrial cancer incidence and mortality has been increasing. This trend is recent, as prior to 1997 the incidence and mortality of endometrial cancer had been decreasing. Reportedly, mortality of uterine cancer has increased 1.94% annually from 2008 till 2018 (3). The American Cancer Society estimates there will be 67,880 new diagnoses of uterine cancer in 2024, and that approximately 13,250 patients will die of endometrial cancer (4). Endometrial cancer is often diagnosed in early stage, with high cure rates, but this increase in mortality is reflective of later stage presentation and increased recurrences of endometrial cancer. Unfortunately, in the United States, the incidence and mortality of advanced endometrial cancer is especially concerning and increasing in Black and/or Hispanic women (3). There has been an unmet need for effective and well-tolerated systemic therapy. Prior to 2023, the most recent advancements in systemic therapy for endometrial cancer had occurred in the second line or greater setting, with the introduction of immunotherapy. Then, in March of 2023, two groundbreaking trials were presented at the Society of Gynecologic Oncology’s Annual meeting; NRG-GYO18 and the RUBY trial, which had promising results for checkpoint inhibitors pembrolizumab and dostarlimab in the front-line setting for advanced or recurrent endometrial cancer (5,6). Later in 2023, results from the AtTEnd trial would be presented, again with promising results for another checkpoint inhibitor, atezolizumab (7,8). The purpose of this paper is to examine how the AtTEnd trial, in comparison to NRG-GY018 and RUBY have changed the treatment landscape for endometrial cancer.

Background

Checkpoint inhibitors are medications that target immunosuppressive pathways that tumors utilize to evade the immune system. The last 5 years have seen important advancements in the use of checkpoint inhibitors targeting the programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway for endometrial cancer. PD-L1 is a transmembrane protein that is expressed on various different tissues and PD-1 is protein expressed on immune cells like T-cells. During normal physiologic function, when PD-1 binds to PD-L1 receptors, it results in downregulation of the immune response to protect host tissue from immunopathology. However, tumor cells that express PD-L1 utilize this pathway to evade the host immune response. Medications which inhibit PD-L1 or PD-1 disrupt this mechanism, and allows the immune system to recognize and target tumor cells (9). In 2021, the first of these checkpoint inhibitors to be approved for use in endometrial cancer was pembrolizumab (a PD-1 inhibitor) concurrently with lenvatinib in recurrent microsatellite stable (MSS) endometrial cancer (10). Dostarlimab (also a PD-1 inhibitor) was approved as a single agent in recurrent microsatellite instability-high (MSI-H) or dMMR endometrial cancer in 2021 (11), followed by pembrolizumab for the same indication in 2022 (12). In March 2023, the results of the RUBY trial and the NRG-GY018 trial were presented at the Society of Gynecologic Oncology national meeting, reporting efficacy of dostarlimab and pembrolizumab, respectively, in combination with carboplatin and paclitaxel to treat advanced or recurrent endometrial cancer. The results were published immediately following (5,6), and Food and Drug Administration (FDA) approval for dostarlimab with chemotherapy for recurrent or advanced mismatch repair deficient (dMMR) endometrial cancer was granted in July of 2023 (13). The National Comprehensive Cancer Network (NCCN) lists carboplatin/paclitaxel and pembrolizumab for stage III/IV endometrial tumors and recurrent disease except for carcinosarcoma and carboplatin/paclitaxel and dostarlimab for all stage III/IV endometrial tumors and recurrent disease, both as category 1 listing (14). The landscape has opened up for the role of checkpoint inhibitors in endometrial cancer and thus far the two approved medications (pembrolizumab and dostarlimab) are both PD-1 inhibitors.

Atezoliumab and the AtTEnd trial

Atezolizumab is a PD-L1 inhibitor whose efficacy in treatment endometrial cancer is being evaluated by the AtTEnd study. Preliminary results from that study were presented at the European Society for Medical Oncology (ESMO) National Meeting in October of 2023 by Dr. Nicoletta Colombo. The AtTEnd study was designed for patients with advanced stage (III–IV) or recurrent endometrial cancer who received 0-1 prior lines of platinum-based chemotherapy at least 6 or more months prior. This study did not include patients from the United States. Carcinosarcoma histology was permitted. Patients had to have a performance status of 0–2 on the Eastern Cooperative Oncology Group (ECOG) scale. There were 549 patients randomized to two groups: one group to receive atezolizumab, carboplatin, paclitaxel followed by atezolizumab maintenance, until progression (N=360 patients), and the other to receive a placebo, carboplatin, paclitaxel, and the placebo during maintenance period. Roughly 23% in each group had dMMR endometrial cancer. Primary endpoints were progression-free survival (PFS) and overall survival (OS) in the all-comer population as well as PFS in the dMMR population. When looking at PFS, the hazard ratio (HR) for dMMR patients was 0.36 [95% confidence interval (CI): 0.23–0.57] and for allcomers was 0.74 (95% CI: 0.61–0.91). OS data had reached 43% maturity at the time of presentation and the HR for OS was 0.41 (95% CI: 0.22–0.76) for dMMR patients and 0.82 (95% CI: 0.63–1.07) for all-comers (7,8).

The AtTEnd study results are positive and in line with the efficacy that RUBY and GY-018 showed for checkpoint inhibitors in endometrial cancer. The three trials have many similarities and some key differences, summarized below and in Table 1.

Exploration of the differences between AtTEnd, NRG-GY018, and RUBY trials

Trial design

All three trials involved the same backbone of chemotherapy—carboplatin (AUC5) and paclitaxel 175 mg/m² dosed every 3 weeks for six cycles. All three involved concurrent administration of immunotherapy with the chemotherapy. All three trials involved a maintenance component of immunotherapy, though the duration and frequency of administration differed. NRG-GY018 allowed for q6 week maintenance therapy with the study drug or placebo up to 20 cycles total, RUBY also dosed maintenance therapy at q6 weeks but for up to 3 years and AtTEnd dosed maintenance therapy at q3 weeks until progression. Randomization for NRG-GY018 and RUBY occurred in a 1:1 fashion for treatment vs placebo, while AtTEnd randomized in a 2:1 fashion. NRG-GY018 is the only of the three trials to pre-specify the mismatch repair proficient (pMMR) cohort for analysis, whereas RUBY and AtTEnd evaluated that group in secondary analysis. The primary endpoint for NRG-GY018 was PFS, while for RUBY and AtTEnd there were two: PFS and OS. Inclusion criteria varied between the three studies. All three trials included measurable or evaluable stage III and IV endometrial cancer, as well as recurrent disease. NRG-GYO18 allowed for non-measurable stage IVB or recurrent disease, while AtTEnd did not allow for any non-measurable disease. RUBY inclusion criteria included non-measurable disease only if stage IIIC1 with carcinosarcoma, clear-cell, serous, or mixed histology disease, or primary stage IIIC2 or IV disease. Information regarding the percentage of patients with non-measurable disease was not available for all three trials. NRG-GY018, RUBY and AtTEnd all allowed prior platinum doublet chemotherapy, but for NRG-GY018 the platinum free interval (PFI) had to be 12 months or greater, while for RUBY and AtTEnd the PFI had to be 6 months or greater. RUBY and AtTEnd allowed for carcinosarcoma histology, but NRG-GY018 did not. Both RUBY and AtTEnd accrued similar percentage of carcinosarcoma patients (10.9% in RUBY and 11.5% in AtTEnd), though RUBY trial design only allowed for a maximum of 10% patients with carcinosarcoma (5-8).

Trial results

All three trials demonstrated significant improvement in the dMMR populations. For dMMR patient populations, the PFS HR in NRG-GY018 was 0.30 (95% CI: 0.19–0.48), in RUBY the PFS HR was 0.28 (95% CI: 0.16–0.50), and in AtTEnd, the PFS HR was 0.36 (95% CI: 0.23–0.57). Overall PFS HRs were 0.64 (95% CI: 0.51–0.80) in RUBY and 0.74 (95% CI: 0.61–0.91) in AtTEnd. NRG-GY018 pre-specified a pMMR subgroup and PFS HR for their pMMR subgroup was 0.54 (95% CI: 0.41–0.71). OS was not a primary outcome in NRG-GY018. In RUBY, the OS HR for dMMR patients was 0.30 (95% CI: 0.127–0.699) and in AtTEnd the OS HR for dMMR patients was 0.41 (95% CI: 0.22–0.76). For all-comers, the OS HR was 0.64 (95% CI: 0.46–0.87) for RUBY and 0.82 (95% CI: 0.63–1.07) in AtTEnd (5-8).

Adverse effects

Immunotherapy has been shown to be well-tolerated in the literature. In RUBY, the rate of any dostarlimab/placebo associated adverse event was 84.2% in the treatment group and 74.4% in the placebo group (33.2% and 19.5%, respectively for grade 3 or greater). In AtTEnd, atezolizumab/placebo related adverse events occurred in 75.6% of the treatment group and 63.8% of the placebo group (25.8% and 14.1%, respectively for grade 3 or greater). In NRG-GY018, adverse events were reported globally, and not separated into immunotherapy/placebo associated events. As well, they are described separately for pMMR and dMMR cohorts. The rate of grade 3 or greater adverse events in the dMMR group was 63.3% in the treatment group versus 47.2% in the placebo group. In pMMR patients, the rate was 55.1% in the treatment group and 45.3% in the placebo group. There is a separate chart for adverse events of interest described as having a possible immune-related etiology which describes grade 3 or greater adverse events in 4.9% of the treatment group and 3.4% of the placebo group (5-8).

Conclusions

There are some key findings from the AtTEnd trial that adds to the growing body of knowledge of immunotherapy treatment of endometrial cancer. For one, atezolizumab is a PD-L1 inhibitor, whereas pembrolizumab and dostarlimab are PD-1 inhibitors. AtTEnd demonstrates that interruption of the PD-1/PD-L1 pathway with either protein is efficacious. AtTEnd supports the inclusion of carcinosarcoma histology to clinical trials, as it is understudied, and treatment options are scarce for recurrent carcinosarcoma. This trial also includes a prolonged period of maintenance immunotherapy, for which final results will be of interest to the field. It remains uncertain if one PD-1 or PD-L1 inhibitor is more efficacious than another, and trials do not exist that compare them to one another. FDA approval for immunotherapy in recurrent/advanced disease is currently limited to dMMR patient populations, but as these trials come to maturity, it is possible FDA approval may expand to include pMMR or all-comer populations. Prior to 2023, PD-1/PD-L1 inhibitors had been limited to the second line or higher setting for recurrent endometrial cancer. Now that immunotherapy is recommended in the frontline setting for certain tumor types, it remains to be seen what options remain for those patients who progress or recur on frontline immunotherapy. No studies have yet been performed to evaluate the effectiveness of immunotherapy in the second line setting following front line treatment with chemotherapy and immunotherapy for endometrial cancer. Within the next 5 years, we may find ourselves tackling this very issue and working to find effective treatments for recurrences following the chemotherapy and immunotherapy regimen. It is important to note that the atezolizumab, pembrolizumab, and dostarlimab had been treatment options for other cancer types for years prior to these new findings for endometrial cancer. There are likely other medications like these, that have yet to be trialed for endometrial cancer. In the current era of targeted therapy and widespread availability of molecular testing, more options may emerge.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-9/prf

Funding: This work was supported by the UCLA Patient-Centered Outcomes Research Training in Urologic and Gynecologic Cancers (PCORT UroGynCan, National Institutes of Health Award Number 5T32CA251072, to C.E.S.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-9/coif). C.E.S. reported funding from the UCLA Patient-Centered Outcomes Research Training in Urologic and Gynecologic Cancers (PCORT UroGynCan, National Institutes of Health Award Number 5T32CA251072). The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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