Immunotherapy

Study 309/KEYNOTE-775 (NCT03517449) was a large, international, multicenter, randomized trial that compared the combination of pembrolizumab (200mg intravenously [IV] every 3 weeks for up to 35 cycles) and lenvatinib (20mg orally daily) with physician's choice of chemotherapy. The study enrolled women with advanced or recurrent endometrial cancer who had disease progression after a platinum-based regimen (measurable disease was required). All histologies except carcinosarcoma and sarcoma were permitted. Patients were stratified by mismatch repair (MMR) status. The two primary end points were PFS and OS.[30]

Study 309/KEYNOTE-775 (NCT03517449) was a large, international, multicenter, randomized trial that compared the combination of pembrolizumab (200mg intravenously [IV] every 3 weeks for up to 35 cycles) and lenvatinib (20mg orally daily) with physician's choice of chemotherapy. The study enrolled women with advanced or recurrent endometrial cancer who had disease progression after a platinum-based regimen (measurable disease was required). All histologies except carcinosarcoma and sarcoma were permitted. Patients were stratified by mismatch repair (MMR) status. The two primary end points were PFS and OS.[30]

After a median follow-up of approximately 12 months in both groups, survivals were statistically longer for patients in the pembrolizumab-lenvatinib group. The benefit persisted despite the patients' MMR statuses. Among all patients, the median PFS was 7.3 months for patients who received pembrolizumab and lenvatinib and 3.8 months for patients who received chemotherapy (HR, 0.56; 95% CI, 0.48–0.66; P < .001). The median OS was 18.7 months for patients who received pembrolizumab and lenvatinib and 11.9 months for patients who received chemotherapy (HR, 0.65; 95% CI, 0.55–0.77; P < .001).[30][Level of evidence A1]

Study 309/KEYNOTE-775 (NCT03517449) was a large, international, multicenter, randomized trial that compared the combination of pembrolizumab (200mg intravenously [IV] every 3 weeks for up to 35 cycles) and lenvatinib (20mg orally daily) with physician's choice of chemotherapy. The study enrolled women with advanced or recurrent endometrial cancer who had disease progression after a platinum-based regimen (measurable disease was required). All histologies except carcinosarcoma and sarcoma were permitted. Patients were stratified by mismatch repair (MMR) status. The two primary end points were PFS and OS.[30]

The most frequent serious side effect in the experimental group was hypertension.

The double-blind placebo-controlled KEYNOTE-868 study (NCT03914612) included 810 patients with advanced (stage III, stage IVA, or stage IVB) or recurrent endometrial cancer.[31] Patients were randomly assigned to receive six cycles of paclitaxel and carboplatin with either pembrolizumab or placebo. Afterwards, patients received up to 14 cycles of maintenance therapy with pembrolizumab or placebo. Patients were stratified according to MMR statuses (proficient [pMMR; n =588] or deficient [dMMR; n = 222]) to investigate if the checkpoint inhibitor, pembrolizumab, was efficacious in patients with dMMR tumors.

The double-blind placebo-controlled KEYNOTE-868 study (NCT03914612) included 810 patients with advanced (stage III, stage IVA, or stage IVB) or recurrent endometrial cancer.[31] Patients were randomly assigned to receive six cycles of paclitaxel and carboplatin with either pembrolizumab or placebo. Afterwards, patients received up to 14 cycles of maintenance therapy with pembrolizumab or placebo. Patients were stratified according to MMR statuses (proficient [pMMR; n =588] or deficient [dMMR; n = 222]) to investigate if the checkpoint inhibitor, pembrolizumab, was efficacious in patients with dMMR tumors.

After a median follow-up of 12.0 months, the 1-year PFS for patients with dMMR tumors was 74% in the pembrolizumab group and 38% in the placebo group (HR, 0.30; 95% CI, 0.19–0.48; P < .001).[31][Level of evidence B1]

The double-blind placebo-controlled KEYNOTE-868 study (NCT03914612) included 810 patients with advanced (stage III, stage IVA, or stage IVB) or recurrent endometrial cancer.[31] Patients were randomly assigned to receive six cycles of paclitaxel and carboplatin with either pembrolizumab or placebo. Afterwards, patients received up to 14 cycles of maintenance therapy with pembrolizumab or placebo. Patients were stratified according to MMR statuses (proficient [pMMR; n =588] or deficient [dMMR; n = 222]) to investigate if the checkpoint inhibitor, pembrolizumab, was efficacious in patients with dMMR tumors.

After a median follow-up of 7.9 months, the median PFS for patients with pMMR tumors was 13.1 months in the pembrolizumab group and 8.7 months in the placebo group (HR, 0.54; 95% CI, 0.41–0.71; P < .001).[31][Level of evidence B1]

The double-blind placebo-controlled KEYNOTE-868 study (NCT03914612) included 810 patients with advanced (stage III, stage IVA, or stage IVB) or recurrent endometrial cancer.[31] Patients were randomly assigned to receive six cycles of paclitaxel and carboplatin with either pembrolizumab or placebo. Afterwards, patients received up to 14 cycles of maintenance therapy with pembrolizumab or placebo. Patients were stratified according to MMR statuses (proficient [pMMR; n =588] or deficient [dMMR; n = 222]) to investigate if the checkpoint inhibitor, pembrolizumab, was efficacious in patients with dMMR tumors.

Regardless of MMR status, pembrolizumab showed significant PFS improvement in patients with advanced or recurrent endometrial cancer.

The phase III randomized KEYNOTE-B21 trial (NCT04634877) included 1,095 patients with newly diagnosed high-risk stage I to stage IVA endometrial cancer (including carcinosarcoma) without evidence of disease postsurgery. All patients received either six cycles of chemotherapy with optional EBRT or four cycles of chemotherapy followed by chemoradiation therapy. Vaginal brachytherapy was allowed in both groups. Patients were randomly assigned to receive either adjuvant pembrolizumab or placebo every 3 weeks for six cycles, then every 6 weeks for six cycles. A total of 66% of patients had stage III or stage IVA disease, 26% had dMMR tumors, and 67% were treated with radiation therapy.[32,33]This study evaluated giving pembrolizumab to patients with positive lymph nodes after surgery who had no other visible evidence of disease. It also evaluated combining radiation therapy and pembrolizumab. Results were significant because they expanded the population of patients who can receive pembrolizumab.

The phase III randomized KEYNOTE-B21 trial (NCT04634877) included 1,095 patients with newly diagnosed high-risk stage I to stage IVA endometrial cancer (including carcinosarcoma) without evidence of disease postsurgery. All patients received either six cycles of chemotherapy with optional EBRT or four cycles of chemotherapy followed by chemoradiation therapy. Vaginal brachytherapy was allowed in both groups. Patients were randomly assigned to receive either adjuvant pembrolizumab or placebo every 3 weeks for six cycles, then every 6 weeks for six cycles. A total of 66% of patients had stage III or stage IVA disease, 26% had dMMR tumors, and 67% were treated with radiation therapy.[32,33]This study evaluated giving pembrolizumab to patients with positive lymph nodes after surgery who had no other visible evidence of disease. It also evaluated combining radiation therapy and pembrolizumab. Results were significant because they expanded the population of patients who can receive pembrolizumab.

After a median follow-up of 24 months, the 2-year disease-free survival (DFS) rate was 75% in the pembrolizumab group and 76% in the placebo group (HR, 1.02; 95% CI, 0.79–1.32; P = .57).[33][Level of evidence B1]

The phase III randomized KEYNOTE-B21 trial (NCT04634877) included 1,095 patients with newly diagnosed high-risk stage I to stage IVA endometrial cancer (including carcinosarcoma) without evidence of disease postsurgery. All patients received either six cycles of chemotherapy with optional EBRT or four cycles of chemotherapy followed by chemoradiation therapy. Vaginal brachytherapy was allowed in both groups. Patients were randomly assigned to receive either adjuvant pembrolizumab or placebo every 3 weeks for six cycles, then every 6 weeks for six cycles. A total of 66% of patients had stage III or stage IVA disease, 26% had dMMR tumors, and 67% were treated with radiation therapy.[32,33]This study evaluated giving pembrolizumab to patients with positive lymph nodes after surgery who had no other visible evidence of disease. It also evaluated combining radiation therapy and pembrolizumab. Results were significant because they expanded the population of patients who can receive pembrolizumab.

In the dMMR cohort, the 2-year DFS rate was 92.4% in the pembrolizumab group and 80.2% in the placebo group (HR, 0.31; 95% CI, 0.14–0.69).

The phase III randomized KEYNOTE-B21 trial (NCT04634877) included 1,095 patients with newly diagnosed high-risk stage I to stage IVA endometrial cancer (including carcinosarcoma) without evidence of disease postsurgery. All patients received either six cycles of chemotherapy with optional EBRT or four cycles of chemotherapy followed by chemoradiation therapy. Vaginal brachytherapy was allowed in both groups. Patients were randomly assigned to receive either adjuvant pembrolizumab or placebo every 3 weeks for six cycles, then every 6 weeks for six cycles. A total of 66% of patients had stage III or stage IVA disease, 26% had dMMR tumors, and 67% were treated with radiation therapy.[32,33]This study evaluated giving pembrolizumab to patients with positive lymph nodes after surgery who had no other visible evidence of disease. It also evaluated combining radiation therapy and pembrolizumab. Results were significant because they expanded the population of patients who can receive pembrolizumab.

No other predetermined subgroup benefitted from adding pembrolizumab.

The RUBY trial (NCT03981796) was a large multicenter trial in women with Fédération Internationale de Gynécologie et d’Obstétrique stage III, IV, or recurrent endometrial cancer of all histologies not amenable to curative therapy. Unlike the Study 309/KEYNOTE-775 trial, some patients without measurable disease qualified for inclusion. Women were randomly assigned to receive TC with or without dostarlimab (500 mg IV) every 3 weeks for six cycles followed by maintenance dostarlimab (1,000 mg IV every 6 weeks) for up to 3 years. Patients were stratified by MMR status. The primary end point was PFS.[34]

The RUBY trial (NCT03981796) was a large multicenter trial in women with Fédération Internationale de Gynécologie et d’Obstétrique stage III, IV, or recurrent endometrial cancer of all histologies not amenable to curative therapy. Unlike the Study 309/KEYNOTE-775 trial, some patients without measurable disease qualified for inclusion. Women were randomly assigned to receive TC with or without dostarlimab (500 mg IV) every 3 weeks for six cycles followed by maintenance dostarlimab (1,000 mg IV every 6 weeks) for up to 3 years. Patients were stratified by MMR status. The primary end point was PFS.[34]

After a median follow-up of approximately 2 years, the dostarlimab group from the overall population had a 36% lower risk of progression or death (HR, 0.64; 95% CI, 0.51–0.80; P < .001). The dostarlimab group from the dMMR population had a 72% lower risk of progression or death (HR, 0.28; 95% CI, 0.16–0.50; P < .001). Similar benefit was seen in OS (HR, 0.64; 95% CI, 0.46–0.87, P = .0021 for the overall population; HR, 0.30; 95% CI, 0.13–0.70 for the dMMR population).[34][Level of evidence B1]