Riding the Wave of Chemoimmunotherapy: A New Era in Endometrial Cancer Management
According to Brian Slomovitz, MD, “immunotherapy has activity and [provides] a benefit in all women with endometrial cancer.” Slomovitz, division director of gynecologic oncology at Mount Sinai Medical Center, professor of obstetrics and gynecology at Florida International University, and clinical trial lead for uterine cancers at the GOG Foundation, told Targeted Therapies in Oncology that especially for patients with deficient mismatch repair (dMMR) endometrial tumors, immunotherapy has resulted in up to a 70% decrease in the risk of recurrence or death compared with chemotherapy alone, which is greater even than the improvements seen with PARP inhibitors for women with BRCA-mutant ovarian cancer.
Even as platinum and taxane–based chemotherapy has been the backbone of treatment for patients with endometrial cancer for many years—providing modest survival rates—these promising results have established immunotherapy as a key component of endometrial cancer treatment, including in the first-line setting.1-4
Emerging trial results presented at major gynecologic meetings over the past year have led to shifts in the standard of care for women with endometrial cancer to suggest the use of early chemoimmunotherapy over chemotherapy alone or single-agent immune checkpoint inhibition.2,5
NRG-GY018 Trial: Pembrolizumab Hits the Right Notes
The combination of the PD-1 inhibitor pembrolizumab (Keytruda) and chemotherapy was explored in patients with advanced or recurrent endometrial cancer in the phase 3 NRG-GY018 trial (KEYNOTE-868; NCT03914612), which was presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.6
A total of 816 patients, stratified by MMR status, were enrolled in the double-blind, placebo- controlled, randomized study and randomly assigned to receive either pembrolizumab or placebo in combination with paclitaxel plus carboplatin. After 6 cycles, patients received pembrolizumab or placebo monotherapy maintenance for up to 14 cycles. Progression-free survival (PFS) in both cohorts was the primary end point.6,7
According to Bradley J. Monk, MD, vice president of GOG Foundation, codirector of GOG Partners, and medical director of late-phase clinical research at Florida Cancer Specialists, NRG-GY018 was a “transformational study,” showing such a significant reduction in the risk of disease progression or death in both cohorts of patients with the addition of pembrolizumab.
In the dMMR cohort (n = 225), the 12-month PFS rate was 74% with added pembrolizumab compared with 38% without, resulting in an HR of 0.30 (95% CI, 0.19-0.48; P < .001). Among proficient MMR (pMMR) patients (n = 591), the median PFS was 13.1 months in the pembrolizumab regimen arm and 8.7 months in the placebo arm.
In terms of adverse events (AEs), grade 3 or higher AEs were reported in more than 50% of patients in the pembrolizumab arm of both cohorts, with the most common events being anemia, neutropenia, and thrombocytopenia.
Following the preliminary results of the trial, the FDA granted a priority review to the supplemental biologics license application for pembrolizumab plus paclitaxel and carboplatin chemotherapy followed by pembrolizumab monotherapy for patients with primary advanced or recurrent endometrial cancer.8 The Prescription Drug User Fee Act target action date has been set as June 21, 2024. However, the National Comprehensive Cancer Network has already accepted the regimen with a category 1 preferred regimen recommendation for systemic therapy in patients with stage III or IV tumors.5
An update at the 2024 SGO Annual Meeting for the NRG-GY018 study showed a positive overall survival (OS) trend, despite the OS still being immature.9 In the pMMR cohort, the median OS was 27.96 months in the pembrolizumab combination arm compared with 27.37 months in the chemotherapy-alone arm (HR, 0.79; 95% CI, 0.53-1.17; P = .1157). The median OS was not reached (NR) in either arm in the dMMR cohort (HR, 0.55; 95% CI, 0.25-1.19; P = .0617).
The median PFS with pembrolizumab had still not been reached in the dMMR cohort as of the 2024 SGO Annual Meeting.
RUBY Trial: Dostarlimab Dazzles in Both dMMR and pMMR Cohorts
Also presented at the 2023 SGO Annual Meeting, findings from the 2-part, phase 3 global RUBY trial (ENGOT-EN6-NSGO/ GOG-3031; NCT03981796) similarly showed a great benefit from the addition of immunotherapy with the PD-1 inhibitor dostarlimab (Jemperli) to chemotherapy.10
In the RUBY study, 494 patients with primary advanced or first recurrent endometrial cancer were randomly assigned to receive either dostarlimab or placebo plus carboplatin and paclitaxel chemotherapy followed by dostarlimab or placebo monotherapy for up to 3 years. The primary end points were PFS in the dMMR/microsatellite instability–high (MSI-H) population and in the overall population, as well as OS in all patients.4,10
Among patients with dMMR/MSI-H tumors, the 24-month PFS rate was 61.4% in the dostarlimab arm and 15.7% in the placebo arm (HR, 0.28; 95% CI, 0.16-0.50; P < .001). Slomovitz said these results were unprecedented.
In the pMMR/microsatellite stable (MSS) group, the PFS rate at 24 months was 28.4% with dostarlimab vs 18.8% without (HR, 0.76; 95% CI, 0.59-0.98). In the overall population, the 24-month PFS rate was 36.1% in the dostarlimab arm and 18.1% in the placebo arm (HR, 0.64; 95% CI, 0.51-0.80; P < .001).
The first interim analysis for OS showed a trend toward improved OS with dostarlimab in the overall population (HR, 0.64; 95% CI, 0.46-0.87; P = .0021) as well as in the dMMR/MSI-H (HR, 0.30; 95% CI, 0.13-0.70) and the pMMR/MSS populations (HR, 0.73; 95% CI, 0.52-1.02). Serious AEs were reported in 37.8% of patients treated with dostarlimab and chemotherapy compared with 27.6% in patients who received placebo.
Following these results, the FDA approved the use of dostarlimab plus carboplatin and paclitaxel chemotherapy followed by dostarlimab monotherapy for the treatment of patients with dMMR primary advanced or recurrent endometrial cancer.11 The role of immunotherapy in women with endometrial cancer has been firmly established, especially in patients with deficient mismatch repair endometrial tumors.
Additional data from the RUBY study presented at the 2023 European Society for Medical Oncology (ESMO) Annual Congress demonstrated improvements in quality of life with the dostarlimab regimen compared with placebo in patient-reported outcomes; improvements were specifically seen in global quality of life, emotional function, social function, and pain.12 Also, in addition to patients with dMMR/MSI-H tumors, those with TP53 mutations and those with no specific mutational profile all achieved a PFS benefit from the dostarlimab combination vs the placebo arm. Those with a POLε mutation, however, did not achieve a PFS benefit. Similar trends were also seen in terms of OS.13
A second interim analysis, presented at the 2024 SGO Annual Meeting, showed the median OS in the overall population was 44.6 months with dostarlimab/chemotherapy and 28.2 months with placebo/ chemotherapy (HR, 0.69; 95% CI, 0.54-0.89; P = .002). In the dMMR/MSI-H population, the median OS was not evaluable in the dostarlimab arm vs 31.4 months in the placebo arm (HR, 0.32; 95% CI, 0.17-0.63). Patients with pMMR/MSS tumors showed a median OS of 34.0 months with dostarlimab and 27.0 months with placebo (HR, 0.79; 95% CI, 0.60-1.04).14
Monk noted in an interview with Targeted Therapies in Oncology that “it’s pretty easy for me to [support] checkpoint [inhibition] in the pMMR [population],” based on the more mature results of the RUBY trial and the FDA approval.
RUBY Trial Part 2: Dostarlimab Further Dazzles
The second part of the RUBY trial, which was also presented at the 2024 SGO Annual Meeting, looked at the use of dostarlimab plus niraparib (Zejula) in the maintenance setting after dostarlimab and chemotherapy as compared with placebo after placebo plus chemotherapy in patients with primary advanced or recurrent endometrial cancer. The participants had never received PARP inhibition before. The primary end point was PFS in the overall population followed by PFS in the pMMR/MSS population.15
In the overall population, the median PFS was 14.5 months with dostarlimab and niraparib compared with 8.3 months with placebo (HR, 0.60; 95% CI, 0.43-0.82; P = .0007). At 12 months, the PFS rates were 57.0% and 33.7% in the dostarlimab/niraparib and placebo arms, respectively.
Among patients with pMMR/MSS tumors, the median PFS was 14.3 months with dostarlimab and niraparib vs 8.3 months with placebo (HR, 0.63; 95% CI, 0.44-0.91; P = .0060); the PFS rates at 1 year were 54.7% and 31.1%, respectively.
In patients with dMMR/MSI-H tumors, the median PFS was not evaluable in the dostarlimab/niraparib arm as compared with 7.9 months in the placebo arm (HR, 0.48; 95% CI, 0.24-0.96; nominal P = .0174). At 12 months, the PFS rates were 64.4% and 40.8% in the dostarlimab/niraparib and placebo arms, respectively.
Grade 3 or higher AEs were observed in 36% of patients in the dostarlimab arm and 36.6% of all AEs in the treatment arm were considered immune related.
DUO-E Trial: The Triple Threat
Findings from the phase 3 DUO-E/GOG3041/ENGOT-EN10 trial (NCT04269200) were presented at the 2023 ESMO Annual Congress.15 Monk said that this was an interesting trial because of the 3 comparative arms of the trial: durvalumab (Imfinzi) and carboplatin/paclitaxel followed by maintenance durvalumab plus olaparib (Lynparza); durvalumab and carboplatin/ paclitaxel followed by maintenance durvalumab and placebo; and placebo with carboplatin/paclitaxel followed by maintenance placebo. A total of 718 patients with newly diagnosed, advanced, or recurrent endometrial cancer were enrolled into the trial and randomly assigned equally between the 3 trial arms.
The primary end points were PFS in the durvalumab and olaparib arm vs the con18 months, the PFS rates were 46.3% in the durvalumab/olaparib arm, 37.8% in the durvalumab alone arm, and 21.7% in the control arm. An interim analysis of OS showed the median OS was NR in either investigational arm compared with 25.9 months in the control arm. The risk for death was reduced by 41% in the durvalumab/olaparib arm compared with the control arm (HR, 0.59; 95% CI, 0.42-0.83; P = .003) and by 23% in the durvalumab monotherapy arm vs the control arm (HR, 0.77; 95% CI, 0.561.07; P = .120).
Exploratory analysis showed that the dMMR population had a significant improvement with the use of durvalumab with or without olaparib compared with chemotherapy alone.
The median PFS in the durvalumab and olaparib arm was 31.8 months compared with 7.0 months in the control arm (HR, 0.41; 95% CI, 0.21-0.75). In the durvalumab arm, the median PFS was NR compared with the control arm (HR, 0.42; 95% CI, 0.22-0.80).
In the pMMR population, the median PFS was 15.0 months with durvalumab and olaparib compared with 9.7 months with placebo (HR, 0.57; 95% CI, 0.44-0.73). With durvalumab monotherapy, the median PFS was 9.9 months vs the control arm (HR, 0.77; 95% CI, 0.60-0.97).
Grade 3 or higher treatment-emergent AEs were reported in 67.2% of patients in the durvalumab and olaparib arm and in 41.1% with the maintenance phase, 54.9% in the durvalumab arm and 16.4% with maintenance, and 56.4% with chemotherapy and 16.6% with maintenance placebo.
AtTEnd Trial: PD-L1 Inhibitor Is Promising With Chemotherapy Doublet
Atezolizumab (Tecentriq), a PD-L1 inhibitor, added to chemotherapy was investigated in the phase 3 AtTEnd trial (NCT03603184), which was presented at the 2023 ESMO Annual Congress. Patients with advanced newly diagnosed or recurrent endometrial carcinoma/carcinosarcoma were randomly assigned in a 2:1 fashion to either carboplatin/paclitaxel chemotherapy and atezolizumab or chemotherapy and placebo. The primary end points were PFS in the dMMR patients followed by PFS and OS in all comers.18
The median PFS was not evaluable in the atezolizumab arm in the dMMR group compared with 6.9 months in the placebo arm (HR, 0.36; 95% CI, 0.23-0.57; P = .0005). At 2 years, the PFS rates were 50.4% with atezolizumab vs 16.0% without. Median OS was not evaluable with atezolizumab and was 25.7 months with placebo (HR, 0.41; 95% CI, 0.22-0.76); the OS rates at 2 years were 75.0% and 54.2%, respectively.
In the all-comer population, the median PFS was 10.1 months with atezolizumab compared with 8.9 months with placebo (HR, 0.74; 95% CI, 0.61-0.91; P = .0219). The PFS rates at 2 years were 28.1% and 17.0% in the atezolizumab and placebo arms, respectively. The median OS was 38.7 months in the atezolizumab arm vs 30.2 months in the placebo arm (HR, 0.82; 95% CI, 0.63-1.07; P = .024); at 2 years, the OS rates were 62.2% and 50.8%, respectively. Grade 3 or higher AEs were reported in 25.8% of patients in the atezolizumab arm compared with 14.1% in the chemotherapy-alone arm.
What Comes Next?
The excitement of the dostarlimab and chemotherapy approval, as well as the promising data from other chemoimmunotherapy trials, has propelled use of and interest in chemoimmunotherapy in earlier settings for patients with endometrial cancer. However, questions remain regarding the optimal use of such regimens.
Slomovitz suggested that patients with particular molecular profiles may not require the use of immunotherapy with chemotherapy going forward, and that single-agent checkpoint inhibition may provide sufficient benefit. He highlighted 2 trials looking to answer this question: the KEYNOTE-C93 trial (GOG-3064/ENGOT-en15; NCT05173987), looking at first-line pembrolizumab vs platinum-doublet chemotherapy in patients with dMMR advanced or recurrent endometrial cancer; and the DOMENICA trial (GINECO- EN105b/ENGOT-en13; NCT05201547), looking at first-line dostarlimab vs chemotherapy alone in patients with dMMR advanced or metastatic disease.
Monk questioned what treatment would be best for a patient after progressing on immunotherapy and noted that there was little evidence that immunotherapy after prior immunotherapy has any benefit, whether using the same agent or switching to a different product or target. Other treatments are also being investigated for efficacy in the recurrent setting and in later lines of therapy.
“We need to come up with not only good first- and second-line therapies, but also, if needed, third- and fourth-line therapies to help make this more of a chronic disease,” Slomovitz said. Answering these questions and others will require innovative clinical trials and further research to continue to advance care for women with endometrial cancer.
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8. FDA grants priority review to Merck’s application for Keytruda (pembrolizumab) plus chemotherapy as treatment for primary advanced or recurrent endometrial carcinoma. News release. Merck. February 20, 2024. Accessed April 2, 2024. https://tinyurl.com/yc2v3n3r
9. Eskander RN, Sill M, Miller A, et al. Overall survival, progression-free survival by PD-L1 status, and blinded independent central review results with pembrolizumab plus carboplatin/paclitaxel (CP) versus placebo plus CP in patients with endometrial cancer: results from the NRG GY018 trial. Presented at: Society of Gynecologic Oncology 2024 Annual Meeting for Womens Cancer; March 15-18, 2024; San Diego, CA. Accessed April 17, 2024.
10. Mirza M, Chase D, Slomovitz, et al. Dostarlimab in combination with chemotherapy for the treatment of primary advanced or recurrent endometrial cancer: a placebo-controlled randomized phase 3 trial (ENGOT-EN6-NSGO/GOG3031/RUBY). Presented at: 2023 SGO Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL.
11. FDA approves dostarlimab-gxly with chemotherapy for endometrial cancer. FDA. July 31, 2023. Accessed April 2, 2024. https://tinyurl.com/4s5y87ba
12. Valabrega G, Powell MA, Hietanen S, et al. Patient- reported outcomes (PROs) in patients (pts) with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer (pA/rEC) in the ENGOT-EN6-NSGO/GOG3031/RUBY trial. Ann Oncol. 2023;34(suppl 2):749P. doi:10.1016/j. annonc.2023.09.1928
13. Mirza MR, Sharma S, Herrstedt J, et al. Dostarlimab + chemotherapy for the treatment of primary advanced or recurrent endometrial cancer (pA/rEC): analysis of progression free survival (PFS) and overall survival (OS) outcomes by molecular classification in the ENGOT-EN6-NSGO/ GOG-3031/RUBY trial. Ann Oncol. 2023;34(suppl 2):740MO. doi:10.1016/j.annonc.2023.09.1919
14. Powell MA, Auranen A, Willmott LJ, et al. Overall survival among patients with primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy in the ENGOT-EN6-NSGO/GOG-3031/RUBY trial. Presented at: Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.
15. Positive RUBY phase III data show potential for Jemperli (dostarlimab) combinations in more patients with primary advanced or recurrent endometrial cancer. News release. GSK. March 16, 2024. Accessed April 7, 2024. https://tinyurl.com/y4zwbhzs
16. Westin SN, Moore KN, Chon HS, et al. Durvalumab (durva) plus carboplatin/paclitaxel (CP) followed by maintenance (mtx) durva ± olaparib (ola) as a first-line (1L) treatment for newly diagnosed advanced or recurrent endometrial cancer (EC): results from the phase III DUO-E/GOG-3041/ ENGOT-EN10 trial. Ann Oncol. 2023;34(suppl 2):LBA41. doi:10.1016/S0923-7534(23)04149-2
17. Westin SN, Moore K, Chon HS, et al; DUO-E Investigators. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol. 2023;42(3):283-299. doi:10.1200/ JCO.23.02132
18. Colombo N, Harano K, Hudson E, et al. Phase III double-blind randomized placebo controlled trial of atezolizumab in combination with carboplatin and paclitaxel in women with advanced/recurrent endometrial carcinoma. Ann Onc. 2023;34(S2):S1277. doi:10.1016/j.annonc.2023.10.034
