Background
Endometrial cancer is the fourth most common malignancy in women and the sixth most common cause of all cancer-related deaths.1 The majority of patients with endometrial cancer present with early-stage disease and have a five-year overall survival (OS) greater than 90%.2 Unfortunately, this number is significantly lower in patients with advanced or recurrent disease receiving first-line (1L) carboplatin and paclitaxel, with an OS of approximately 3 years.3
Importantly, there have been no major changes in 1L treatment options for advanced or recurrent endometrial cancer since GOG209, which established the role of the combination of carboplatin and paclitaxel in this patient population.3 However, the use of molecular classification within endometrial cancer has continued to evolve with the incorporation of biomarker-driven therapy based upon mismatch repair deficient (dMMR) or proficient (pMMR) status, microsatellite stability (MSS) or microsatellite instability-high (MSI-H) status, and presence or absence of other biomarkers.4 In fact, approximately 20% - 30% of endometrial cancers are caused by dMMR or MSI-H aberrations, leading to prognostic and treatment considerations for patients.4
The presentation of two recent clinical trials, RUBY trial5 and NRG GY018/Keynote-868 trial,6 at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting highlight an impending change in 1L treatment for this patient population, utilizing a combination of immune checkpoint inhibitors (ICI) and chemotherapy.
RUBY5
The RUBY trial was a phase 3, double-blind, randomized, placebo-controlled trial that enrolled patients with advanced stage III, stage IV, or first recurrent endometrial cancer. The trial evaluated dostarlimab, an ICI that targets the programmed death-1 (PD-1) receptor, at a dose of 500 mg or placebo in combination with carboplatin and paclitaxel every 21 days for 6 cycles followed by dostarlimab 1000 mg or placebo every 6 weeks for up to 3 years. Patients with carcinosarcoma, clear-cell, serous, or mixed histologies were allowed per protocol. Patients with first recurrence of disease with no prior treatment and patients who recurred greater than 6 months after prior treatment were allowed per protocol. Patients were randomized 1:1 and stratified by MMR and MSI status, previous external pelvic radiotherapy, and disease status. Primary endpoints included progression free survival (PFS) and OS in the dMMR-MSI-H population as well as the overall population.
From July 2019 to February 2021, 494 patients were randomized 1:1 to dostarlimab or placebo with chemotherapy. Patient demographics were represented by 18.6%, 33.6%, and 47.8% of patients with stage III, stage IV, and recurrent disease, respectively. Of the patients enrolled, 8.9% had carcinosarcoma. The majority of patients (82.7%) had not received external pelvic radiation. In the overall population, 23.9% patients were dMMR-MSI-H, reflective of patients with endometrial cancer.4
With a median duration of follow-up of about 25 months, the 24-month PFS for patients with dMMR-MSI-H endometrial cancer was 61.4% (95% CI, 46.5 to 73.4) in the dostarlimab group compared to 15.7% (95% CI, 7.2 to 27) in the placebo group. In the overall population, the 24-month PFS was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group compared to 18.1% (95% CI, 13 to 23.9) in the placebo group. For the first interim OS analysis in the overall population, OS was higher with dostarlimab versus placebo (HR for death, 0.64; 95% CI, 0.46 to 0.87; p=0.0021) but did not reach the level of significance established as the stopping rule (p=0.001777). For patients with dMMR-MSI-H tumors, OS at 24 months was 83.3% with dostarlimab and 58.7% with placebo (HR 0.3; 95% CI 0.13 to 0.7). For patients with pMMR-MSS tumors, PFS at 24 months was 28.4% with dostarlimab compared with 18.8% with placebo (HR 0.76; 95% CI, 0.59 to 0.98), and OS at 24 months was 67.7% with dostarlimab compared with 55.1% with placebo (HR 0.73; 95% CI 0.52 to 1.02).
No new signals for adverse events were found, and adverse events were consistent with the known adverse effects of the experimental agents. There was a higher incidence of rash and maculopapular rash with dostarlimab. The most common immune-related adverse events were hypothyroidism, rash, arthralgia, and transaminitis.
NRG GY018/Keynote-8686
The NRG GY018-Keynote-868 trial was a phase 3, double-blind, randomized, placebo-controlled trial that enrolled patients with advanced stage III, stage IV, or recurrent endometrial cancer. The trial evaluated pembrolizumab, an ICI that targets the PD-l receptor, at a dose of 200 mg or placebo in combination with carboplatin and paclitaxel every 21 days for 6 cycles followed by pembrolizumab 400 mg or placebo every 6 weeks for 14 cycles. Patients with carcinosarcoma were excluded per protocol. Patients with first recurrence of disease with no prior treatment as well as patients who recurred >12 months after prior treatment were allowed per protocol. Patients were stratified into two cohorts based on dMMR or pMMR status. Primary endpoints included PFS in the dMMR and pMMR cohorts.
From July 2019 to December 2022, 816 patients were enrolled with 225 patients in the dMMR cohort and 591 patients in the pMMR cohort, which is reflective of the patient population with endometrial cancer. Patient demographics were represented by approximately 41% and 58% of evaluable patients with stage III-IV and recurrent disease, respectively.
Median duration of follow-up was 12 months in the dMMR cohort and 7.9 months in the pMMR cohort. For the dMMR cohort, median PFS was not reached in the pembrolizumab group compared to 7.6 months in the placebo group (HR 0.3; 95% CI 0.19 to 0.48). For the pMMR cohort, median PFS was 13.1 months in the pembrolizumab group compared to 8.7 months in the placebo group (HR 0.54; 95% CI, 0.41 to 0.71).
No new signals for adverse events were found and adverse events were consistent with the known adverse effects of the agents. For the dMMR cohort, there was a higher incidence of adverse events for those patients treated with pembrolizumab, 63.3% compared to 47.2%, similarly reflected in the pMMR cohort.
Discussion
Both the RUBY and GY018 trials demonstrated efficacy of adding anti-PD-1 therapy to carboplatin and paclitaxel,5,6 but there are differences to recognize between the two trials. Duration of treatment, including maintenance therapy with dostarlimab, was 3 years for the RUBY trial5 while duration of treatment, including maintenance therapy with pembrolizumab, was a little less than 2 years in the GY018 trial.6 The GY018 trial excluded patients with carcinosarcoma, and time from prior treatment was 12 months6 compared with the RUBY trial that enrolled patients with carcinosarcoma and allowed a shorter time from prior treatment of 6 months.5 However, both trials had similar enrollment for stage III, stage IV, and recurrent endometrial cancer patients.5,6
Although benefit was seen with ICI therapy in both pMMR and dMMR patients in both trials, the benefit of adding ICI was more dramatic in the dMMR population, as expected.5,6 In the dostarlimab trial, the PFS for the pMMR population was a pre-specified subgroup analysis whereas it was a primary endpoint for GY018. Additionally, there was a signal for a more heterogeneous response to dostarlimab therapy in the subgroup of patients with primary stage III disease in the RUBY trial in both the dMMR-MSI-H and overall population.5 More remains to be seen with regards to OS benefit with longer follow-up, as the RUBY trial has had 2 years of follow-up so far, whereas only 1 year of follow-up has been reported with GY018.5,6
Sequencing of treatment will continue to be an ongoing discussion, as subsequent lines of therapy include ICI for both the dMMR/pMMR and MSI-H/MSS populations. In the overall population, 9.4% and 4.9% of patients who received dostarlimab with chemotherapy went on to receive pembrolizumab and lenvatinib or pembrolizumab alone.5 In the current state, subsequent-line therapies for advanced or recurrent endometrial cancer include pembrolizumab for patients with MSI-H and TMB-H endometrial cancer,7 pembrolizumab with lenvatinib for pMMR patients,8 and dostarlimab for dMMR/MSI-H tumors.9
Both trials were presented at SGO this year, providing potential new 1L treatment options for patients with advanced or recurrent endometrial cancer to include ICI therapy.5, 6 Both treatment options are listed in the NCCN Guideline Recommendations for 1L therapy for recurrent endometrial cancer regardless of MMR status.11 It remains to be seen what regulatory approval will be granted and how biomarker status will play a role in the approvals.
References
- Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023; 73: 317-48.
- Lu KH, Broaddus RR. Endometrial Cancer. N Engl J Med 2020; 383:2053-64.
- Miller DS, Filiaci VL, Mannel RS, et al. Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209). J Clin Oncol 2020; 38:3841-3850.
- Corr B, Cosgrove C, Spinosa D, et al. Endometrial cancer: molecular classification and future treatments. BM Med 2022; 1:e000152.
- Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med 2023 Mar 27. doi: 10.1056/NEJMoa2216334
- Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med 2023 Mar 27. doi: 10.1056/NEJMoa2302312
- O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in Patients With Microsatellite Instability–High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. J Clin Oncol 2022; 40: 752-61.
- Makker V, Colombo N, Herraez C, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med 2022; 386: 437-48.
- Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti–programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair–deficient endometrial cancer a nonrandomized phase 1 clinical trial. JAMA Oncol 2020; 6:1766-1772.
- Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 2020; 21:1353-1365.
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Uterine Neoplasms V.2.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed [June 9, 2023].
Get the full HOPA News Volume 20, Issue 2 here.
