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ESMO Gynecological Cancers Congress

The addition of dostarlimab-gxly (Jemperli) to chemotherapy, followed by dostarlimab monotherapy, demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) vs placebo plus chemotherapy in patients with primary advanced or recurrent endometrial cancer, with benefits observed across molecular subgroups and irrespective of mismatch repair (MMR) status, according to updated findings from part 1 of the phase 3 RUBY trial (NCT03981796) presented at the 

At a median follow-up of 37.2 months for the overall population, patients treated with dostarlimab plus chemotherapy followed by dostarlimab (n = 245) achieved a median OS of 44.6 months (95% CI, 32.6–not evaluable [NE]) compared with 28.2 months (95% CI, 22.1-35.6) in those treated with placebo plus chemotherapy (n = 249; HR, 0.69; 95% CI, 0.54-0.89; 

 = .002). Notably, 38.2% of patients in the placebo arm received subsequent immunotherapy.

In the mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) population, the median OS was NE (95% CI, NE-NE) in the dostarlimab arm (n = 53) vs 31.4 months (95% CI, 20.3-NE) in the placebo arm (n = 65; HR, 0.32; 95% CI, 0.17-0.63; nominal 

 = .0002) at a median follow-up of 36.6 months. In the placebo arm, 41.5% of patients in the dMMR/MSI-H population received subsequent immunotherapy. 

There was also a clinically meaningful OS difference in the mismatch repair–proficient (pMMR)/microsatellite stable (MSS) population at a median follow-up of 37.5 months. The median OS was 34.0 months (95% CI, 28.6-NE) in the dostarlimab group (n = 192) vs 27.0 months (95% CI, 21.5-35.6) in the placebo group (n = 184; HR, 0.79; 95% CI, 0.60-1.04; nominal 

 = .0493). Notably, 37.0% of patients in the placebo arm in this subgroup received subsequent immunotherapy.

"These data confirm dostarlimab plus chemotherapy as a new standard of care for patients with primary advanced or recurrent endometrial cancer, regardless of MMR status,” presenting author Robert L. Coleman, MD, FACOG, FACS, of Sarah Cannon Research Institute in Nashville, Tennessee, said in a presentation of the data.

In July 2023, prior data from RUBY supported 

the FDA approval of dostarlimab in combination with carboplatin and paclitaxel

, followed by dostarlimab monotherapy, for adult patients with primary advanced or recurrent endometrial cancer that is dMMR or MSI-H.

The updated analysis included data for OS, time to second progression (PFS2), and safety. Coleman and colleagues also conducted an exploratory analysis on OS outcomes by molecular classification.

During RUBY, 494 patients with primary advanced or recurrent endometrial cancer were randomly assigned to either dostarlimab plus carboplatin and paclitaxel, followed by dostarlimab monotherapy; or placebo plus carboplatin and paclitaxel, followed by placebo monotherapy.

At the September 22, 2023, data cutoff, 130 patients in the dostarlimab arm discontinued treatment due to death from any cause (n = 96), consent withdrawal (n = 26), loss of follow-up (n = 5), or other reasons (n = 3). Eighty-eight patients remained in follow-up, and 27 patients were still receiving dostarlimab. In the placebo arm, 160 patients discontinued study treatment due to death from any cause (n = 133), consent withdrawal (n = 20), loss of follow-up (n = 5), or other reasons (n = 2). Sixty-seven patients were in follow-up, and 22 remained on placebo.

Enrolled patients presented with either dMMR/MSI-H (dostarlimab arm, 21.6%; placebo arm, 26.1%) or pMMR/MSS disease (78.4%; 73.9%), and were White (77.1%; 76.7%), Black (11.4%; 12.4%), or Asian (2.9%; 3.2%). Patients in the dostarlimab had a median age of 64 years (range, 41-81) vs 65 years (range, 28-85) in the placebo arm. Notably, 48.2% and 54.2% of patients, respectively, were at least 65 years of age.

Moreover, some patients received prior external pelvic radiation (dostarlimab arm, 16.7%; placebo arm, 18.1%). Disease status included primary stage II (18.4%; 18.9%), primary stage IV (33.9%; 33.3%), or recurrent (47.8%; 47.8%). The majority of patients had an ECOG performance status of 0 (60.2%; 65.0%).

Additionally, patients had a median BMI of 30.8 (range, 17.6-60.6) and 32.8 (range, 17.7-68.0) in the dostarlimab and placebo arms, respectively, and 86.5% and 88.0% of patients had measurable disease at baseline in these respective groups. A minority of patients received prior anticancer treatment (dostarlimab arm, 19.6%; placebo arm, 20.9%), including carboplatin-paclitaxel (14.7%; 15.7%). Histology types included carcinoma (10.2%; 7.6%), endometrioid (54.7%; 54.6%), serous adenocarcinoma (20.4%; 20.9%), or other (14.7%; 16.9%).

Molecular classification was performed for all patients with whole-exome DNA sequencing (WES) results (n = 400/494), and an exploratory analysis examined OS difference in patients with dMMR/MSI-H disease who underwent WES (HR for dostarlimab vs placebo, 0.40; 95% CI, 0.19-0.83), those harboring 

 mutations (HR, 0.59; 95% CI, 0.33-1.03), and patients with no specific molecular profile (HR, 0.89; 95% CI, 0.61-1.29). Notably, HR for patients with 

 mutations was not applicable, since all patients in the dostarlimab arm (n = 2) and placebo arm (n = 3) were alive at data cutoff. Coleman noted that the findings from molecular subgroup analysis were consistent with findings from the first interim analysis.

Additional data from the overall population showed that 49.0% of patients on the dostarlimab arm received any follow-up anticancer therapy vs 69.5% of patients in the placebo arm. Subsequent therapies included immunotherapy (dostarlimab arm, 35.0%; placebo arm, 54.9%) with either pembrolizumab (Keytruda; 10.8%; 23.7%), pembrolizumab plus lenvatinib (Lenvima; 20.8%; 26.0%), dostarlimab (0%; 1.7%), or other (4.2%; 6.9%).

Furthermore, a clinically meaningful PFS2 benefit was observed for the dostarlimab regimen in the overall population (HR, 0.66, 95% CI, 0.52-0.84). The median PFS2 was 32.3 months (95% CI, 24.6-NE) in the dostarlimab group vs 18.4 months (95% CI, 14.9-22.0) in the placebo group.

In the dMMR/MSI-H population, the median PFS2 was NE (95% CI, NE-NE) for the dostarlimab arm and 21.6 months (95% CI, 13.4-39.1) for the placebo arm (HR, 0.33; 95% CI, 0.18-0.63). In the pMMR/MSS population, the median PFS2 was 24.6 months (95% CI, 20.1-32.6) for the dostarlimab arm vs 15.9 months (95% CI, 13.6-22.0) for the placebo arm (HR, 0.74; 95% CI, 0.57-0.97).

Regarding safety, all patients in the dostarlimab arm (n = 241) and placebo arm (n = 246) experienced any treatment-emergent adverse effect (TEAE); 72.2% and 60.2% experienced grade 3 or higher TEAEs; 39.8% and 28.0% experienced serious TEAEs; and 40.7% and 60.3% had any treatment-related immune-related AE.

TEAEs that led to discontinuation of dostarlimab or placebo in 19.1% and 8.1% of patients, respectively. Additionally, 8.3% and 6.1% of patients had any TEAE that led to discontinuation of carboplatin in the dostarlimab and placebo arms, respectively; 10.8% and 10.2% had any TEAE leading to discontinuation of paclitaxel; 2.1% and 0% had any TEAE leading to death. Notably, 0.8% of patients in the experimental arm experienced any TEAE related to dostarlimab that led to death. Notably, the median duration of overall treatment was 43.0 weeks (range, 3.0-192.6) for the dostarlimab arm vs 36.0 weeks (range, 2.1-193.1) for the placebo arm.

Disclosures: Dr Coleman reported receiving grants or contracts from AstraZeneca, Clovis, Genelux, Genmab, Immunogen, Merck, and Roche/Genentech; consulting fees from AbbVie, Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, Novocure, Merck, OncoQuest, Onxerna, Regeneron, and Roche/Genentech; honoraria from AstraZeneca, Clovis, Merck, and Roche/Genentech; and participation on a data safety monitoring board or advisory board with Eisai/BMS and VBL Therapeutics.

Powell MA, Auranen A, Willmott L, et al. Dostarlimab plus chemotherapy in primary advanced or recurrent endometrial cancer in the RUBY trial: overall survival by MMR status and molecular subgroups. Presented at: 2024 ESMO Gynecological Cancers Congress; June 20-22, 2024; Florence, Italy. Abstract 37MO.

Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed July 2, 2024. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/

The addition of dostarlimab-gxly to chemotherapy, followed by dostarlimab monotherapy, significantly improves overall survival in patients with primary advanced or recurrent endometrial cancer, regardless of mismatch repair status. The phase 3 RUBY trial demonstrated a median overall survival of 44.6 months for the dostarlimab group compared to 28.2 months for the placebo group. The trial included 494 patients and showed consistent benefits across molecular subgroups. Safety profiles indicated higher rates of treatment-emergent adverse effects in the dostarlimab group.

Dostarlimab plus chemotherapy demonstrated a meaningful overall survival improvement in primary endometrial cancer, regardless of mismatch repair status.


Dostarlimab/Chemo Shows OS Benefit Regardless of MMR Status in Endometrial Cancer

Dostarlimab-gxly (Jemperli) plus carboplatin and paclitaxel, followed by dostarlimab plus niraparib (Zejula) maintenance therapy, elicited a statistically significant progression-free survival (PFS) benefit vs placebo plus chemotherapy in patients with primary advanced or recurrent endometrial cancer regardless of mismatch repair (MMR) status, histological subgroup, or molecular subgroup, according to findings from the first interim analysis of part 2 of the ENGOT-EN6-NSGO/GOG-3031/RUBY trial (NCT03981796). Findings were presented at the 

In the overall population, at a median follow-up of 21.7 months, and a maturity rate of 56.4%, the median PFS with dostarlimab/chemotherapy/niraparib was 14.5 months (95% CI, 11.8-17.4) vs 8.3 months (95% CI, 7.6-9.8) with placebo plus chemotherapy (HR, 0.60; 95% CI, 0.43-0.82; 

= .0007). The 12-month PFS rates were 57.0% in the dostarlimab arm vs 33.7% in the placebo arm.

Furthermore, in the MMR-proficient (pMMR)/microsatellite-stable (MSS) population, at a median follow-up of 21.8 months, and a maturity rate of 61.1%, the median PFS with dostarlimab/chemotherapy/niraparib was 14.3 months (95% CI, 9.7-16.9) vs 8.3 months (95% CI, 7.6-9.8) with placebo plus chemotherapy (HR, 0.63; 95% CI, 0.44-0.91; 

= .0060). The 12-month PFS rates were 54.7% in the dostarlimab arm vs 31.1% in the placebo arm.

In the MMR-deficient (dMMR)/microsatellite instability–high (MSI-H) population, at a median follow-up of 21.2 months, and a maturity rate of 42.7%, the median PFS with dostarlimab/chemotherapy/niraparib was not evaluable (NE; 95% CI, 11.8-NE) vs 7.9 months (95% CI, 5.4-NE) with placebo plus chemotherapy (HR, 0.48; 95% CI, 0.24-0.96; 

= .0174). The 12-month PFS rates were 64.4% in the dostarlimab arm vs 40.8% in the placebo arm.

“These outcomes demonstrate a potential role for PARP inhibitor maintenance in patients receiving dostarlimab plus chemotherapy, in particular in the pMMR population,” lead study author Mansoor Raza Mirza, MD, said in a presentation of the data. Dr Mirza is the chief oncologist in the Department of Oncology at Rigshospitalet, Copenhagen University Hospital, in Denmark. 

In part 1 of RUBY, the dual primary end points of PFS and overall survival (OS) were met with dostarlimab plus chemotherapy, demonstrating a clinical benefit with the dostarlimab regimen regardless of patients’ MMR status. In the overall population, the 24-month PFS rate was 36.1% (95% CI, 29.3%-42.9%) with dostarlimab vs 18.1% (95% CI, 13.0%-23.9%) with placebo (HR, 0.64; 95% CI, 0.51-0.80; 

< .001).2 Furthermore, patients with dMMR/MSI-H disease achieved substantial benefit with the dostarlimab regimen, with an estimated 24-month PFS rate of 61.4% (95% CI, 46.3%-73.4%) vs 15.7% (95% CI, 7.2%-27.0%) with placebo.

“When we planned RUBY part 2, we kept the inclusion/exclusion criteria…completely similar to what we [used] in part 1,” Mirza noted. “We kept the stratification factors similar; we kept the trial design similar.”

Part 2 of the RUBY trial enrolled patients with stage III/IV or first recurrent endometrial cancer of all histologies except sarcoma.

Eligible patients were naive to systemic anticancer therapies or had disease recurrence or progressive disease at least 6 months after completing systemic anticancer therapy. Patients also needed to be naive to PARP inhibitors.

Patients were stratified by MMR/MSI status (dMMR/MSI-H, 25%; pMMR/MSS, 75%), receipt of prior external pelvic radiotherapy, and disease status. A total of 291 patients were randomly assigned 2:1 to the dostarlimab (n = 192) or placebo (n = 99) arms. Patients in the investigational arm received intravenous (IV) dostarlimab at 500 mg plus chemotherapy every 3 weeks for 6 cycles, followed by IV dostarlimab at 1000 mg every 6 weeks plus niraparib at 200 mg or 300 mg daily for up to 3 years. Patients in the placebo arm received IV placebo plus chemotherapy every 3 weeks for 6 cycles followed by IV placebo every 6 weeks plus oral and IV placebo daily for up to 3 years.

The primary end point of RUBY part 2 is investigator-assessed PFS per RECIST v1.1 in both the overall and pMMR/MSS patient populations. Secondary end points include OS, PFS by blinded independent central review, overall response rate, duration of response, disease control rate, time to second progression, health-related quality of life/patient-reported outcomes, pharmacokinetics, and safety.

At a data cutoff of November 1, 2023, 77 patients randomly assigned to the dostarlimab arm discontinued the study because of death from any cause (n = 52), withdrawal of consent (n = 21), loss to follow-up (n = 2), and other reasons (n = 2). Seventy-one patients were in follow-up, and 44 remained on treatment. Among patients randomly assigned to the placebo arm, 36 discontinued the study because of death from any cause (n = 25), withdrawal of consent (n = 8), loss to follow-up (n = 2), and other reasons (n = 1). Forty-three patients were in follow-up, and 20 remained on treatment.

“The baseline characteristics were very well balanced,” Mirza said.

Notably, in the overall population, 63.1% and 69.7% of patients in the dostarlimab and placebo arms, respectively, had endometrioid carcinoma. These respective values were 54.2% and 62.2% in the pMMR/MSS population.

Among patients in the overall population in the dostarlimab arm, 1.6%, 19.3%, 20.3%, and 39.1% had 

 mutations, and no specific molecular profile (NSMP), respectively; 19.8% of patients were NE for molecular subgroup. Furthermore, 64.1% and 33.3% of patients had PD-L1–positive and –negative disease, respectively; 2.6% were NE for PD-L1 status. 

-positive and -negative disease was reported in 3.1% and 77.1% of patients, respectively, and 19.8% of patients were NE for 

 mutation status. Additionally, 10.4% and 69.8% of patients had homologous recombination repair (HRR)–positive and –negative disease; 19.8% of patients were NE. Regarding histologic subgroup, 59.4% and 39.6% of patients had endometrioid carcinoma and other histologies, respectively.

Among patients in the overall population in the placebo arm, 2.0%, 17.2%, 10.1%, and 46.5% had 

 mutations, and NSMP, respectively; 24.2% of patients were NE for molecular subgroup. Furthermore, 62.6% and 31.3% of patients had PD-L1–positive and –negative disease, respectively, and 6.1% were NE for PD-L1 status. 

-positive and -negative disease was reported in 4.0% and 71.7% of patients, respectively; 24.2% of patients were NE for 

 mutation status. Additionally, 14.1% and 61.6% of patients had HRR-positive and -negative disease, and 24.2% of patients were NE. Regarding histologic subgroup, 67.7% and 32.3% of patients had endometrioid carcinoma and other histologies, respectively.

Among patients with pMMR/MSS disease in the dostarlimab arm (n = 142), 62.0% and 37.3% of patients had PD-L1–positive and –negative disease, respectively, and 0.7% were NE for PD-L1 status. Moreover, 2.8% and 79.6% of patients had 

-positive and -negative disease, and 17.6% of patients were NE for 

 mutation status. Additionally, 7.0% and 75.4% of patients had HRR-positive and -negative disease, and 17.6% of patients were NE.

Among patients with pMMR/MSS disease in the placebo arm (n = 74), 59.5% and 35.1% of patients had PD-L1–positive and –negative disease, respectively, and 5.4% were NE for PD-L1 status. Moreover, 4.1% and 74.3% of patients had 

-positive and -negative disease, and 21.6% of patients were NE for 

 mutation status. Additionally, 14.9% and 63.5% of patients had HRR-positive and -negative disease, and 21.6% of patients were NE.

Further analysis of PFS in the overall population according to patient subgroups demonstrated benefit with dostarlimab among all patients regardless of molecular or histology subgroup (HR, 0.59; 95% CI, 0.43-0.81). Patients with 

-mutated disease benefitted the most from treatment with dostarlimab/chemotherapy/niraparib (HR, 0.29; 95% CI, 0.13-0.63).

In the overall population, findings from exploratory PFS analyses also favored the dostarlimab arm regardless of PD-L1, 

 mutation, or HRR mutation status (HR, 0.59; 95% CI, 0.43-0.81). Similarly, in the pMMR/MSS population, exploratory analysis results favored the dostarlimab arm across these patient subgroups (HR, 0.62; 95% CI, 0.44-0.88).

Regarding safety in the overall population, among evaluable patients in the dostarlimab arm (n = 191), 99.5% experienced any treatment-emergent adverse effects (TEAEs), and 96.3% reported any treatment-related TEAEs. TEAEs of grade 3 or higher were observed in 84.8% of patients, and any treatment-related TEAEs of grade 3 or higher were observed in 70.7% of patients. Forty-four percent of patients reported any serious TEAEs, and 23.6% of patients experienced any treatment-related serious TEAEs. Any dostarlimab-related immune-related AEs were seen in 36.6% of patients. TEAEs led to treatment discontinuation and death in 36.6% and 2.1% of patients, respectively; however, no treatment-related TEAEs led to death. The median duration of overall treatment was 45.0 weeks (range, 0.9-136.3).

All evaluable patients in the placebo arm (n = 96) experienced any TEAEs, 97.9% of which were treatment-related TEAEs. Any TEAEs of grade 3 or higher were observed in 49.0% of patients, and any treatment-related TEAEs of grade 3 or higher were observed in 36.5% of patients. In total, 19.8% of patients had any serious TEAEs, and 9.4% of patients had any treatment-related serious TEAEs. Any dostarlimab-related immune-related AEs were seen in 6.3% of patients. TEAEs led to treatment discontinuation in 13.5% of patients. No deaths were observed in this arm.

“For the OS [outcomes]…we still have events, so we are following that…” Mirza concluded, adding that, “The safety profile observed [with the dostarlimab regimen] was generally consistent with the known safety profiles of the individual agents.”

Dr Mirza reports receiving consulting fees from AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, and Zailab; receiving speakers’ bureau fees from AstraZeneca and GSK; receiving institutional research funding from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and having personal financial interest in the form of stocks/shares or membership on the board of directors with Karyopharm.

Mirza MR, Ghamande S, Hanker LC, et al. Progression-free survival (PFS) in primary advanced or recurrent endometrial cancer (pA/rEC) in the overall and mismatch repair proficient (MMR/MSS) populations and in histological and molecular subgroups: results from part 2 of the RUBY trial. 

. 2024;9(suppl_5):1-8. doi:10.1016/esmoop/esmoop103499

Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. 

. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334

The combination of dostarlimab-gxly with carboplatin and paclitaxel, followed by maintenance therapy with dostarlimab and niraparib, significantly improved progression-free survival (PFS) in patients with primary advanced or recurrent endometrial cancer, regardless of mismatch repair status, histological, or molecular subgroups. The RUBY trial's interim analysis showed a median PFS of 14.5 months for the dostarlimab regimen versus 8.3 months for the placebo. The safety profile was consistent with known profiles of the individual agents, and the study continues to monitor overall survival outcomes.

Dostarlimab/chemotherapy/niraparib elicited favorable PFS outcomes across several subgroups in primary advanced or recurrent endometrial cancer.

Dostarlimab/Chemo/Niraparib Generates PFS Benefit in Primary/Recurrent Endometrial Cancer

Rebecca Kristeleit, BSc, MBChB, MRCP, PhD

Patients with newly diagnosed advanced ovarian cancer who responded to first-line chemotherapy and were then treated with rucaparib (Rubraca) maintenance therapy experienced a sustained and significant improvement in progression-free survival (PFS) irrespective of their risk of progression and exploratory subgroups, according to updated findings from the phase 3 ATHENA-MONO study (NCT03522246) presented at the 

In the intention-to-treat (ITT) population, treatment with rucaparib elicited a median PFS of 20.2 months (95% CI, 15.6-24.7) vs 9.2 months (95% CI, 8.5-12.2) with placebo (HR, 0.53; 95% CI, 0.41-0.68). Among patients with a homologous recombination deficiency (HRD), the median PFS was 31.4 months (95% CI, 23.0-46.0) in the rucaparib arm and 12.0 months (95% CI, 9.1-22.1) in the placebo arm (HR, 0.49; 95% CI, 0.33-0.73). The median follow-up for PFS was 4.0 years in the rucaparib arm and 3.5 years in the placebo arm.

Further analysis of PFS according to patient subgroups demonstrated benefit with rucaparib among all patients regardless of whether they harbored

mutations, had a high loss of heterozygosity (LOH), or were at a high risk for disease progression. A similar PFS advantage with rucaparib was seen in patients who had a complete response (CR) at baseline. In this population, the median PFS was 15.6 months (95% CI, 10.2-23.0) in the rucaparib arm compared with 6.4 months (95% CI, 2.7-23.0) in the placebo arm (HR, 0.49; 95% CI, 0.24-1.00).

“These data were not shown, but 35% of patients [treated] with rucaparib reached the 2-year treatment cap, with only 17% [of patients] reaching the full 2 years with placebo,” presenting author Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, a consultant medical oncologist and clinical senior lecturer in the Department of Oncology at the University College-London Cancer Institute in England, stated in the presentation. “[Additionally,] after 4 years of follow-up, 29% of rucaparib-treated patients had maintained a CR, compared with 12% of placebo-treated patients,” Kristeleit added.

Previously reported data from the primary analysis of ATHENA-MONO proved the efficacy of rucaparib monotherapy as a first-line maintenance approach in patients with newly diagnosed ovarian cancer with or without HRD. Results showed a median PFS of 28.7 months (95% CI, 23.0-NR) with rucaparib vs 11.3 months (95% CI, 9.1-22.1) with placebo (HR, 0.47; 95% CI, 0.31-0.72; log-rank 

= .0004) in the HRD population. The median PFS outcomes in the ITT population were 20.2 (95% CI, 15.2-24.7) months and 9.2 months (95% CI, 8.3-12.2), respectively, (HR, 0.52; 95% CI, 0.40-0.68; log-rank 

The ATHENA trial enrolled patients with newly diagnosed stage III to IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Eligible patients must have completed frontline platinum-doublet chemotherapy and surgery, achieved either an investigator-assessed CR or partial response, and gone on to receive cytoreductive surgery. An ECOG performance status of 0 or 1 and no prior exposure to frontline maintenance therapy for ovarian cancer were also required.

Patients were randomly assigned 4:4:1:1 to receive 600 mg of oral rucaparib twice daily plus intravenous (IV) nivolumab (Opdivo) at 480 mg (arm A); IV placebo and rucaparib (arm B); oral placebo and nivolumab (arm C); or an IV and oral placebo regimen (arm D).1 Treatment was administered for 24 months or until radiographic progression, unacceptable toxicity, or other reasons for discontinuation. Key stratification factors for randomization included tumor HRD test status, disease status post-chemotherapy, and the timing of surgery.

Following randomization, the ATHENA study was divided into 2 separate analyses according to the treatment regimen administered. ATHENA-MONO comprised arms B (n ≈ 400) and D (n ≈ 100), and the ATHENA-COMBO study included arms A (n ≈ 400) and B (n ≈ 400).

The primary end point of the study was investigator-assessed PFS in the HRD and ITT populations. The data cutoff for the current analysis was March 1st, 2024.

-mutant group was NR with rucaparib vs 16.7 months with placebo (HR, 0.47; 95% CI, 0.26-0.84). For patients with 

 wild-type disease who were LOH high, low, or intermediate, the median PFS with rucaparib was 22.3 months, 12.1 months, and 17.5 months, respectively. Corresponding median PFS outcomes with placebo were 9.2 months (HR, 0.56; 95% CI, 0.33-0.92), 9.1 months (HR, 0.66; 95% CI 0.46-0.96) and 8.9 months (HR, 0.38; 95% CI, 0.19-0.76).

Patients at a high risk for disease progression were classified as FIGO stage IV or FIGO stage III ovarian cancer with residual disease after surgery or prior treatment with neoadjuvant chemotherapy. Patients at a low risk for disease progression were classified as having FIGO stage III ovarian cancer with no residual disease following resection. In the high-risk group, the median PFS was 14.8 months and 9.1 months with rucaparib vs placebo, respectively (HR, 0.47; 95% CI, 0.35-0.63). In the low-risk group, the median PFS in each arm was 31.4 months and 24.0 months (HR, 0.80; 95% CI, 0.49-1.31).

To conclude her presentation, Kristeleit noted that, “the final safety profile was consistent with that of the primary end point analysis, as presented by David M. O’Malley, [MD], of The Ohio State University College of Medicine [in Columbus], at the 2024 ASCO Annual Meeting.”

Disclosures: Dr Kristeleit discloses receiving institutional funding from Clovis Oncology/pharma; grant and research support for the current trial from Incyte; honoraria from AstraZeneca, Basilea, Celcuity, Clovis Oncology/pharma&, Duke Street Bio, Eisai, GSK, iTeos, Leucid, MSD, Prokarium, Seattle Genetics, Shattuck Labs, and Tubulis; and serving on speaker’s bureaus for AstraZeneca, Eisai, GSK, and MSD.

Kristeleit R, O’Malley D, Lim M, et al. Updated progression-free survival (PFS) in patients (pts) with newly diagnosed advanced ovarian cancer (OC) treated with rucaparib (RUC) in ATHENA-MONO. 

. 2024;9(suppl 5):1-19. doi:10.1016/esmoop/esmoop103501

Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). 

. 2022;40(34):3952-3964. doi:10.1200/JCO.22.01003

First-line rucaparib maintenance therapy maintained a PFS benefit vs placebo at 4 years of follow-up in newly diagnosed advanced ovarian cancer. 

Rucaparib Maintenance Elicits Continued PFS Benefit Across Newly Diagnosed Ovarian Cancer Subgroups

Although the first-line administration of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) did not demonstrate statistically superior survival outcomes compared with chemotherapy in patients with mismatch repair–proficient (pMMR) advanced or recurrent endometrial cancer, numerical increases in overall survival (OS) and progression-free survival (PFS), as well as notable antitumor activity across histologic subtypes, were observed among patients with prior neoadjuvant/adjuvant chemotherapy, according to data from an exploratory analysis of the phase 3 ENGOT-en9/LEAP-001 study (NCT03884101).

Findings from the randomized, open-label trial were presented at the 

, where an analysis of PFS and OS according to histology showed trends in favor of the lenvatinib/pembrolizumab combination vs chemotherapy in patients with endometroid histology vs non-endometroid histology. In the all-comers and pMMR populations who presented with endometroid histology, hazard ratios (HRs) for PFS were 0.78 (95% CI, 0.62-0.97) and 0.96 (95% CI, 0.75-1.24), respectively; corresponding HRs for OS were 0.80 (95% CI, 0.63-1.01) and 0.93 (95% CI, 0.71-1.22). Conversely, all-comers with non–endometroid histology had a PFS HR of 1.12 (95% CI 0.83-1.50) and OS HR of 1.14 (95% CI, 0.84-1.54). In those with pMMR disease and non–endometroid histology, the PFS HR was 1.06 (95% CI, 0.77-1.44) and the OS HR was 1.16 (95% CI, 0.85-1.58).

A numeric trend toward PFS and OS benefit was also observed among patients with prior exposure to neoadjuvant or adjuvant chemotherapy. In the all-comer population, the HR for PFS was 0.52 (95% CI, 0.33-0.82) and the HR for OS was 0.64 (95% CI, 0.40-1.03). In the pMMR population, HRs were 0.60 (95% CI, 0.37-0.97) and 0.67 (95% CI, 0.41-1.11) for PFS and OS, respectively.

The objective response rate (ORR) was 55.7% (95% CI, 50.8%-60.5%) with lenvatinib/pembrolizumab and 55.5% (95% CI, 50.6%-60.35) with chemotherapy in the all-comer population. Among the pMMR population, ORRs were 50.6% (95% CI, 45.0%-56.2%) and 54.7% (95% CI, 49.0%-60.2%), respectively. The median duration of response (DOR) was 23.2 months (range, 1.0+ to 49.0+) with the doublet and 10.9 months (range, 1.1+ to 46.9+) with chemotherapy in all comers; corresponding DORs were 16.1 months (range, 1.0+ to 48.7+) and 10.6 months (range, 1.1+ to 43.8+) in the pMMR population.

“Based on all these data, we can conclude that lenvatinib/pembrolizumab can be considered an option for patients who have received previous therapy, reinforcing the data from the [phase 3] KEYNOTE-775 study [NCT03517449],” presenting author Sandro Pignata, MD, PhD, the IRCCS National Cancer Institute “Fondazione G. Pascale” in Naples, Italy, stated in an oral presentation.

In July 2021, treatment with lenvatinib plus pembrolizumab was 

for patients with advanced endometrial cancer that is not microsatellite instability-high or mismatch repair deficient (dMMR), have disease progression following prior systemic therapy in any setting, and are not candidates for curative surgery or radiation. This approval was based on data from KEYNOTE-775, in which the regimen demonstrated a significant OS and PFS benefit vs investigator's choice of doxorubicin or paclitaxel.

 Subsequent analyses of this trial showed that treatment benefit was observed regardless of disease histology.

LEAP-001 accordingly compared the efficacy and safety of this chemotherapy-free doublet with paclitaxel and carboplatin in the first-line treatment of patients with stage III, IV or recurrent advanced endometrial cancer. Patients were required to have measurable or nonmeasurable radiographically apparent disease, no previous exposure to chemotherapy outside of the neoadjuvant or adjuvant setting, an ECOG performance status of 0 or 1, and available tumor tissue for mismatch repair testing. Patients were stratified according to whether they had pMMR or dMMR disease. Those with pMMR endometrial cancer were further stratified by their ECOG performance status, whether they had measurable disease, and if they received prior chemotherapy and/or chemoradiation.

A total of 842 patients were enrolled onto the study and randomly assigned 1:1 to receive 20 mg of oral lenvatinib once daily plus 200 mg of intravenous (IV) pembrolizumab every 3 weeks (n = 420) for up to 35 cycles vs 175 mg/m2 of IV paclitaxel plus carboplatin at an area under the curve of 6 every 3 weeks (n = 422) for up to 7 cycles.

The trial’s dual primary end points were PFS per RECIST criteria by blinded independent central review (BICR) and OS. Secondary end points included ORR, safety, and health-related quality of life (HRQOL). DOR was an exploratory end point. In the current exploratory analysis, PFS per RECIST criteria by BICR and OS were analyzed by tumor histology.

A total of 842 patients were enrolled onto the study, 420 of whom received lenvatinib/pembrolizumab and 422 who received chemotherapy. In these respective arms, 320 and 322 patients had pMMR disease; 100 patients with dMMR endometrial cancer were included in each arm.

Within the all-comer population, the median age in the combination arm was 63 years (range 22-93) vs 64 years (range, 32-88) in the chemotherapy arm. In these respective arms, 17.6% vs 16.1% of patients received prior chemotherapy and/or chemoradiotherapy; the majority of patients in both arms had an ECOG PS of 0 (59.5% with doublet; 56.9% with chemotherapy); and had measurable disease (99.5%; 98.6%).

The most common histology was non–high-grade endometroid cancer (combination arm, 33.6%; chemotherapy arm, 37.0%) followed by high-grade endometrioid cancer (33.1%; 30.1%). Patients also had serous carcinoma (18.3%; 19.0%), mixed histology (6.9%; 5.5%), clear cell carcinoma (2.9%; 4.5%), and other histologies (5.2%; 4.0%).

In the all-comer population, the median PFS was 12.5 months (95% CI, 10.3-15.1) with the combination vs 10.2 months (95% CI, 8.4-10.4) with chemotherapy (HR, 0.91; 95% CI, 0.76-1.09). The median OS was 37.7 months (95% CI, 32.2-43.6) vs 32.1 months (95% CI, 27.2-35.7) in each respective arm (HR, 0.93; 95% CI, 0.77-1.12).

For the pMMR population, the median PFS was 9.6 months (95% CI, 8.2-11.9) vs 10.2 months (95% CI, 8.4-10.5) in these respective arms (HR, 0.99; 95% CI, 0.82-1.21). The median OS was 30.9 months (95% CI, 25.4-37.7) in the lenvatinib/pembrolizumab arm vs 29.4 months (95% CI, 26.2-35.4) in the chemotherapy arm (HR, 1.02; 95% CI, 0.83-1.26; noninferiority 

Further breakdown of efficacy by histology in the pMMR population showed a numerical trend towards superior PFS with the combination over chemotherapy in patients with high-grade endometrioid carcinoma (HR, 0.84; 95% CI, 0.59-1.21), clear cell carcinoma (HR, 0.70; 95% CI, 0.25-1.96), and mixed histology (HR 0.86; 95% CI 0.36-2.07). This was not evident in patients with non–high-grade endometroid carcinoma (HR, 1.05; 95% CI, 0.74-1.51) or serous carcinoma (HR, 1.18; 95% CI, 0.81-1.74).

A similar trend was observed in the all-comer population, with a numerical trend in favor of the doublet for patients with high-grade endometrioid carcinoma (HR, 0.72; 95% CI, 0.52-0.98), non–high-grade endometroid carcinoma (HR, 0.82; 95% CI 0.60-1.12), clear cell carcinoma (HR, 0.60; 95% CI, 0.21-1.70), and mixed histology (HR 0.83; 95% CI 0.41-1.70). The HR for those with serous carcinoma was 1.29 (95% CI, 0.88-1.89).

In the assessment of OS by histology in the pMMR population, patients with high-grade endometroid cancer (HR, 0.72; 95% CI, 0.49-1.06) and mixed histology (HR, 0.55; 95% CI, 0.23-1.33) appeared to experience benefit with lenvatinib and pembrolizumab vs chemotherapy; HRs did not favor the doublet numerically in those with non–high-grade endometroid carcinoma (HR, 1.16; 95% CI, 0.76-1.73), clear cell carcinoma (HR, 1.87; 95% CI, 0.67-5.17), and serous carcinoma (HR, 1.15; 95% CI, 0.79-1.67).

Among all comers, HRs slightly favored the combination in high-grade endometroid carcinoma (HR, 0.64; 95% CI, 0.46-0.89), non–high-grade endometroid carcinoma (HR, 0.97; 95 % CI 0.69-1.37), and mixed histology (HR, 0.59; 95% CI, 0.26-1.32) numerically. HRs were 1.81 (95% CI, 0.58-4.46) and 1.18 (95% CI, 0.81-1.71) in patients with clear cell and serous carcinoma, respectively.

Assessment of response rates by histology showed that lenvatinib plus pembrolizumab was active and produced responses across all histologies in both the pMMR and all-comer populations. Signs of higher activity with the doublet were seen in the high-grade endometroid and clear cell carcinoma populations.

In the pMMR population, 51.0% (95% CI, 40.7%-61.3%) and 45.5% (95% CI, 16.7%-76.6%) of patients with high-grade endometrioid carcinoma and clear cell carcinoma, respectively, achieved an ORR with the doublet. Conversely, 56.7% (95% CI, 45.8%-67.1%) and 31.6% (95% CI, 12.6%- 56.6%) achieved an ORR with chemotherapy. The median DOR was 16.4 months (range, 2.1+ to 46.3+) and not reached (NR; 6.1+- 30.2+) with the combination in those with high-grade endometroid and clear cell carcinoma, respectively. The median DOR with chemotherapy was 10.9 months (range, 2.1+ to 38.3+) and 11.1 months (range, 4.2+ to 30.6+) for patients with these respective histologies. Similar results were observed in the all-comer populations.

Notable limitations for the ad-hoc exploratory analysis include a small sample size for certain histologic subtypes. Additionally, the study was not designed or powered to demonstrate improvement in survival within these subgroups.

Disclosures: Dr Pignata discloses financial and personal interests, as well as service on an advisory board for Roche, AstraZeneca, MSD, Clovis, GSK, and PharmaMar; he also discloses financial interests and receiving institutional funding from Roche, MSD, Pfizer, and AstraZeneca.

Pignata S, Marth C, Moore RG, et al. Phase III ENGOT-En9/LEAP-001 study: Lenvatinib + pembrolizumab (LEN/PEMBRO) vs chemotherapy (chemo) as first-line (1L) therapy for advanced or recurrent endometrial cancer. Presented at: 2024 ESMO Gynecological Cancers Congress; June 20-22, 2024; Florence, Italy. Abstract 39MO.

FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA. July 22, 2021. Accessed June 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-pembrolizumab-and-lenvatinib-advanced-endometrial-carcinoma

The combination of lenvatinib and pembrolizumab did not show statistically superior survival outcomes compared to chemotherapy in patients with mismatch repair–proficient advanced or recurrent endometrial cancer. However, numerical increases in overall survival and progression-free survival were observed, particularly in patients with prior neoadjuvant/adjuvant chemotherapy. The study highlighted notable antitumor activity across various histologic subtypes. The combination therapy showed a trend towards benefit in certain histologies, reinforcing its potential as a treatment option for patients with previous therapy, despite not achieving statistical superiority.

First-line lenvatinib plus pembrolizumab demonstrated antitumor activity across various histologic subtypes in advanced or recurrent endometrial cancer. 

Lenvatinib/Pembrolizumab Misses OS End Points, But Still Shows Activity, in Advanced Endometrial Cancer 

Frontline treatment with the combination of durvalumab (Imfinzi), carboplatin, and paclitaxel, followed by maintenance durvalumab with or without olaparib (Lynparza), led to improved objective response rates (ORR), durations of response (DOR), and time to treatment discontinuation (TDT) vs chemotherapy alone, followed by maintenance placebo, in patients with stage III/IV or recurrent endometrial cancer, according to updated findings from the phase 3 DUO-E trial (NCT04269200).

 also showed that the experimental regimen improved ORR, DOR, and TDT in patients with mismatch repair–deficient (dMMR) disease. DOR and TDT were improved in the population of patients with mismatch repair–proficient (pMMR) disease.

In the intention-to-treat (ITT) population, evaluable patients treated with durvalumab plus chemotherapy, followed by durvalumab alone as maintenance therapy (CP+D arm; n = 202), achieved an ORR of 61.9%, including complete response (CR) and partial response (PR) rates of 12.9% and 49.0%, respectively. Conversely, the ORR was 55.1% in patients treated with chemotherapy alone, followed by placebo maintenance (CP arm; n = 198; odds ratio [OR], 1.32; 95% CI, 0.89-1.98). Patients in the CP arm had CR and PR rates of 9.6% and 45.5%, respectively. Patients treated with durvalumab plus chemotherapy, followed by durvalumab plus olaparib as maintenance (CP+D+O arm; n = 184) experienced an ORR of 63.6% (OR vs the CP arm, 1.44; 95% CI, 0.95-2.18) with a CR rate of 16.3% and a PR rate of 47.3%.

The median time to response was 2.1 months (interquartile range [IQR], 2.0-2.3) in all 3 arms. The median DOR was 13.1 months (IQR, 6.0–not reached [NR]) in the CP+D arm, 21.3 months (IQR, 8.1-29.9) in the CP+D+O arm, and 7.7 months (IQR, 5.1-13.5) in the CP arm. The 18-month DOR rates were 46.6%, 55.7%, and 14.8%, respectively. The respective 24-month DOR rates were 38.0%, 47.1%, and 14.8%.

“DUO-E results support the addition of durvalumab to platinum-based chemotherapy as a new treatment option for patients with endometrial cancer, with the greatest benefit for dMMR disease. Adding [maintenance] olaparib has a further benefit for the pMMR subpopulation,” lead study author Els Van Nieuwenhuysen, MD, a gynecologist/oncologist at UZ Leuven in Belgium, said in a presentation of the data.

 of progression-free survival (PFS) in the ITT population for the CP+D arm vs the CP arm, as well as the CP+D+O arm vs the CP arm.

 The median PFS was 10.2 months (95% CI, 9.7-14.7) in the CP+D arm (n = 238) vs 9.6 months (95% CI, 9.0-9.9) in the CP arm (n = 241; HR, 0.71; 95% CI, 0.57-0.89; 

 = .003). The median PFS was 15.1 months (95% CI, 12.6-20.7) in the CP+D+O arm (n = 239; HR vs the CP arm, 0.55; 95% CI, 0.43-0.69; 

The randomized, placebo-controlled, double-blind study enrolled patients with newly diagnosed FIGO stage III/IV or recurrent endometrial cancer.

 Patients with newly diagnosed stage III disease needed to have measurable disease. All patients were required to have a known MMR status, be naive to first-line systemic treatment for advanced disease, and be naive to PARP inhibitors and immune-mediated therapy. Prior adjuvant chemotherapy was allowed if at least 12 months had passed since last treatment to relapse. The study included patients with all histologies other than sarcomas.

The study included 718 patients who were randomly assigned 1:1:1 to receive carboplatin at area under the curve of 5 or 6 mg/mL/min plus paclitaxel at 175 mg/m2 twice daily every 3 weeks followed by maintenance placebo (CP arm); the same chemotherapy regimen plus intravenous (IV) durvalumab at 1120 mg every 3 weeks, followed by maintenance durvalumab at 1500 mg every 4 weeks (CP+D arm); or chemotherapy plus IV durvalumab every 3 weeks, followed by maintenance durvalumab every 4 weeks plus oral olaparib at 300 mg twice daily (CP+D+O arm). The chemotherapy phase lasted for 6 cycles, and patients were only allowed to receive maintenance therapy if they were free from disease progression. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Stratification factors included MMR status (dMMR vs pMMR), disease status (recurrent vs newly diagnosed), and geographic region (Asia vs non-Asia).

Along with the primary end point of investigator-assessed PFS per RECIST 1.1 criteria, secondary end points included overall survival, ORR, DOR, TDT, and safety. Exploratory end points included a post-hoc analysis of ORR, DOR, and TDT based on MMR status.

The median age was 64 years (range, 31-85) in the CP arm, 64 years (range, 22-84) in the CP+D arm, and 63 years (range, 27-86) in the CP+D+O arm. The majority of patients in all 3 arms were White (CP, 59.3%; CP+D, 57.1%; CP+D+O, 55.6%), had an ECOG performance status of 0 (64.7%; 65.5%; 69.5%), had recurrent disease (52.3%; 52.5%; 52.3%), had endometroid histology (57.7%; 59.2%; 63.6%), had pMMR disease (79.7%; 80.7%; 79.9%), did not harbor homologous recombination repair mutations (54.8%; 58.0%; 59.0%), had positive PD-L1 expression (67.6%; 71.4%; 62.8%), did not receive prior chemotherapy (78.8%; 78.6%; 77.4%), and underwent prior surgery (83.8%; 86.1%; 86.6%).

Additional data from the ITT population showed that the median TDT was 9.9 months (95% CI, 8.8-11.2) in the CP+D arm (n = 238) vs 8.8 months (95% CI, 7.6-9.7) in the CP arm (n = 241; HR, 0.74; 95% CI, 0.60-0.91). The median TDT was 15.1 months (95% CI, 12.5-18.6) in the CP+D+O arm (n = 239; HR vs the CP arm, 0.51; 95% CI, 0.41-0.63).

The post-hoc analysis of patients with dMMR disease showed that those treated in the CP+D arm (n = 30) achieved an ORR of 71.4%, including a CR rate of 28.6% and a PR rate of 42.9%, vs an ORR of 40.5% in the CP arm (n = 42; OR, 3.68; 95% CI, 1.51-9.39). The respective CR and PR rates in the CP arm were 9.5% and 31.0%. The ORR was 73.0% in the CP+D+O arm (n = 37; OR vs the CP arm, 3.97; 95% CI, 1.57-10.65), including CR and PR rates of 18.9% and 54.1%, respectively. The median time to response was 2.1 months in each arm, and the median DOR was NR (IQR, 22.0-NR) in the CP+D arm (n = 30), 29.9 months (IQR, 9.7-29.9) in the CP+D+O arm (n = 27), and 10.5 months (IQR, 4.5-NR) in the CP arm (n = 17). The respective 18-month DOR rates were 75.2%, 73.6%, and 48.2%. The 24-month DOR rates were 60.2%, 73.6%, and 48.2%, respectively.

In the dMMR population, the median TDT was 21.2 months (95% CI, 9.3-NR) in the CP+D arm (n = 46) vs 6.7 months (95% CI, 5.1-7.9) in the CP arm (n = 49; HR, 0.47; 95% CI, 0.27-0.79). The median TDT was 20.6 months (95% CI, 13.4-NR) in the CP+D+O arm (n = 48; HR vs the CP arm, 0.36; 95% CI, 0.21-0.62).

In the pMMR population, the ORR was 59.4% in the CP+D arm (n = 160) vs 59.0% in the CP arm (n = 156; OR, 1.02; 95% CI, 0.65-1.59). The ORR was 61.2% in the CP+D+O arm (n = 147; OR vs the CP arm, 1.10; 95% CI, 0.69-1.74). The respective CR and PR rates were 8.8% and 50.6% for the CP+D arm, 15.6% and 45.6% for the CP+D+O arm, and 9.6% and 49.4% for the CP arm.

The median time to response was 2.1 months in all 3 arms. The median DOR was 10.6 months (IQR, 5.6-NR) in the CP+D arm, 18.7 months (IQR, 8.0-NR) in the CP+D+O arm, and 7.6 months (IQR, 5.1-13.1) in the CP arm. The respective 18-month DOR rates were 37.4%, 50.0%, and 12.1%. The 24-month DOR rates were 32.4%, 37.8%, and 12.1%, respectively.

Patients in the pMMR population treated in the CP+D arm (n = 192) achieved a median TDT of 9.6 months (95% CI, 8.1-10.6) compared with 9.3 months (95% CI, 8.0-9.9) in the CP arm (n = 192; HR, 0.81; 95% CI, 0.65-1.02). The median TDT was 13.4 months (95% CI, 10.6-15.6) in the CP+D+O arm (n = 191; HR vs the CP arm, 0.54; 95% CI, 0.43-0.69).

Safety data showed that the most common adverse effects (AEs) in the CP+D arm were alopecia, anemia, fatigue, and asthenia; the most common in the CP+D+O arm were anemia, nausea, fatigue, and asthenia. No cases of acute myeloid leukemia or myelodysplastic syndrome were reported in any arms. In the CP+D+O arm, 3 patients (1.6%) experienced pure red cell aplasia; no instances of this AE occurred in the CP or CP+D arms. Autoimmune hemolytic anemia was reported in 1 patient (<1%) in the CP+D arm and 2 patients (<1%) in the CP+D+O arm, compared with none in the CP arm. All instances of pure red cell aplasia and autoimmune hemolytic anemia were grade 3, and none were fatal.

The rates of immune-mediated AEs were 8.6% in the CP arm, 28.1% in the CP+D arm, and 23.5% in the CP+D+O arm. AEs led to discontinuation of any study treatment in 18.6%, 20.9%, and 24.4% of patients, respectively.

: Dr Van Nieuwenhuysen reported serving in a consulting or advisory role with Regeneron (institution), Oncoinvent (individual), and AstraZeneca (institution); receiving travel accommodations or expenses from Regeneron (institution); and receiving institutional research funding from AstraZeneca, Lilly, Merck, Seagen, Roche, Novartis, Regeneron, and Oncoinvent.

Van Nieuwenhuysen E, Chon HS, Pepin JT, et al. First-line durvalumab + carboplatin/paclitaxel followed by durvalumab ± olaparib for endometrial cancer (DUO-E): objective response rate, duration of response and time to treatment discontinuation or death by mismatch repair status. Presented at: 2024 ESMO Gynecological Cancers Congress; June 20-22, 2024; Florence, Italy. Abstract: 40MO.

The combination of durvalumab, carboplatin, and paclitaxel, followed by maintenance durvalumab with or without olaparib, significantly improved objective response rates, durations of response, and time to treatment discontinuation in patients with stage III/IV or recurrent endometrial cancer compared to chemotherapy alone. The greatest benefits were observed in patients with mismatch repair–deficient disease. The study also confirmed progression-free survival benefits and highlighted the safety profile of the treatment regimens, with manageable adverse effects and no cases of acute myeloid leukemia or myelodysplastic syndrome reported.

Durvalumab plus chemotherapy, followed by durvalumab maintenance with or without olaparib, improved responses in advanced endometrial cancer.

Frontline Durvalumab/Chemo, Then Maintenance Durvalumab ± Olaparib, Improves ORR in Endometrial Cancer

Mirvetuximab soravtansine-gynx (Elahere) generated clinically meaningful improvements in progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) vs investigator’s choice of chemotherapy in patients with folate receptor alpha (FRα)–positive, platinum-resistant ovarian cancer who required dose modifications during the phase 3 MIRASOL trial (NCT04209855), according to findings from post-hoc analyses of the study presented at 2024 ESMO Gynecological Cancers Congress.

Among patients in MIRASOL who received modified doses of mirvetuximab soravtansine (n = 124), the median PFS was 7.23 months (95% CI, 5.85-8.48) vs 5.59 months (95% CI, 4.34-6.47) in those who received modified doses of investigator’s choice of chemotherapy in the control arm (n = 114; HR, 0.58; 95% CI, 0.43-0.78; nominal 

“Dose modifications should be considered to maximize the potential of remaining on mirvetuximab soravtansine and also then having the opportunity to derive benefit,” Susana Banerjee, MBBS, MA, PhD, FRCP, a consultant medical oncologist and research lead of the Gynaecology Unit at The Royal Marsden NHS Foundation Trust in London, United Kingdom, said in the presentation.

MIRASOL was an open-label trial that enrolled 453 patients with platinum-resistant ovarian cancer that was FRα high and high-grade serous who had received 1 to 3 prior lines of therapy. Patients were allowed to have received prior bevacizumab (Avastin) and PARP inhibitors, and patients with 

 mutations were permitted to enroll. Patients with first platinum-refractory disease were excluded.

Patients were randomly assigned 1:1 to receive either mirvetuximab soravtansine at 6 mg/kg per adjusted ideal body weight every 3 weeks (n = 227) or investigator’s choice of chemotherapy (n = 226). Patients were stratified by the type of prior investigator’s choice chemotherapy they had received (paclitaxel vs pegylated liposomal doxorubicin [PLD] vs topotecan) and number of prior lines of therapy (1 vs 2 vs 3).

Investigator-assessed PFS served as the primary end point. Key secondary end points included ORR as assessed by the investigators, OS, and the primary patient-reported outcome analysis. Other secondary end points included safety and tolerability, duration of response, CA-125 response, and time to second progression.

In the MIRASOL trial, mirvetuximab soravtansine elicited significant and clinically meaningful survival improvements in PFS (HR, 0.65; 95% CI, 4.3-5.9; 

< .0001) and OS (HR, 0.67; 95% CI, 0.50-0.88; 

= .0046) vs investigator’s choice of chemotherapy.

 Based on these findings, in March 2024, mirvetuximab soravtansine was 

 for the treatment of adult patients with FRα-positive, platinum-resistant ovarian cancer who have received 1 to 3 prior systemic therapies.

In MIRASOL, 55% of patients who received mirvetuximab soravtansine and 50% of those who received chemotherapy had dose modifications, defined as dose delays, reductions, or interruptions from day 1 of cycle 1 onward.

 Therefore, investigators conducted post-hoc analyses to determine the effect of dose modifications on the safety and efficacy of mirvetuximab soravtansine and chemotherapy, as well as to provide data on the safety and efficacy of these agents in patients who had dose modifications in the MIRASOL trial.

Among the patients in the mirvetuximab soravtansine arm who had dose modifications, the median age was 63 years (range, 32-88), and 15% had 

 mutations. Furthermore, 36%, 55%, and 100% of patients had prior exposure to bevacizumab, PARP inhibitors, and taxanes, respectively. Most patients had a primary platinum-free interval of 12 months or less (63%) or a platinum-free interval of more than 3 months but less than or equal to 6 months (55%). In total, 12%, 40%, and 48% of patients had received 1, 2, and 3 prior lines of therapy, respectively. Forty-four percent, 35%, and 21% of patients had received prior paclitaxel, PLD, and topotecan, respectively.

Among the patients in the chemotherapy arm who had dose modifications, the median age was 64 years (range, 29-87), and 18% had 

 mutations. Furthermore, 45%, 59%, and 100% of patients had prior exposure to bevacizumab, PARP inhibitors, and taxanes, respectively. Most patients had a primary platinum-free interval of 12 months or less (56%), and 49% of patients had a platinum-free interval of 3 months or less. In total, 10%, 41%, and 49% of patients had received 1, 2, and 3 prior lines of therapy, respectively. Fifty-four percent, 23%, and 24% of patients had received prior paclitaxel, PLD, and topotecan, respectively.

In the mirvetuximab soravtansine and chemotherapy arms, the respective ORRs were 60% (95% CI, 50.5%-68.4%) and 26% (95% CI, 18.5%-35.4%), translating to an ORR difference of 33.4% (95% CI, 21.5%-45.2%; odds ratio, 4.14; 95% CI, 2.39-7.18; nominal 

< .0001). Best overall responses in the mirvetuximab soravtansine arm included complete response (8.1%), partial response (51.6%), stable disease (35.5%), progressive disease (4.0%), and not evaluable (NE; 0.8%). These respective rates in the chemotherapy arm were 0.0%, 26.3%, 53.5%, 15.8%, and 4.4%.

The median OS was 20.2 months (95% CI, 17.4-NE) with mirvetuximab soravtansine vs 13.1 months (95% CI, 11.4-16.7) with chemotherapy (HR, 0.45; 95% CI, 0.30-0.68; nominal 

Regarding safety, all patients in both arms had any treatment-emergent adverse effects (TEAEs). In the mirvetuximab soravtansine arm, 53% of patients had grade 3 or higher TEAEs, 24% of patients had serious AEs, and 1 patient died during treatment or within 30 days of their last dose of the study drug. Moreover, 59%, 85%, and 10% of patients had dose reductions, delays, and discontinuations, respectively, due to TEAEs. In the chemotherapy arm, 72% of patients had grade 3 or higher TEAEs, 39% of patients had serious AEs, and 2 patients died during treatment or within 30 days of their last dose of the study drug. Moreover, 42%, 82%, and 22% of patients had dose reductions, delays, and discontinuations, respectively, due to TEAEs.

The most common TEAEs in the mirvetuximab soravtansine arm were neutropenia (any-grade, 17%; grade ≥3, 2%), anemia (12%; 2%), thrombocytopenia (6%; 2%), peripheral neuropathy (24%; 2%), alopecia (2%; 0%), diarrhea (26%; 2%), nausea (26%; 2%), stomatitis (5%; 0%), blurred vision (56%; 12%), keratopathy (48%; 15%), and dry eye (40%; 6%). The most common TEAEs with control paclitaxel were neutropenia (any-grade, 44%; grade ≥3, 31%), anemia (44%; 15%), thrombocytopenia (5%; 0%), peripheral neuropathy (34%; 7%), alopecia (31%; 0%), diarrhea (34%; 2%), nausea (30%; 3%), stomatitis (11%; 0%), blurred vision (3%; 0%), and dry eye (5%; 0%). The most common TEAEs with control PLD were neutropenia (any-grade, 15%; grade ≥3, 4%), anemia (8%; 0%), peripheral neuropathy (15%; 0%), alopecia (8%; 0%), diarrhea (4%; 0%), nausea (35%; 0%), stomatitis (15%; 4%), blurred vision (4%; 0%), and dry eye (8%; 0%). The most common TEAEs with control topotecan were neutropenia (any-grade, 63%; grade ≥3, 48%), anemia (70%; 33%), thrombocytopenia (78%; 44%), alopecia (4%; 0%), diarrhea (%; 2%0), nausea (41%; 4%), stomatitis (11%; 0%), and blurred vision (4%; 0%).

“[Mirvetuximab soravtansine] is the new standard of care for patients with FRα-positive platinum-resistant ovarian cancer, and I very much hope that we will have access [to this agent] beyond the United States as soon as possible,” Banerjee concluded.

Mirvetuximab soravtansine is currently under investigation in patients with platinum-sensitive ovarian cancer, both as monotherapy and in combination with other agents.

Banerjee S, Van Gorp T, Konecny GE, et al. Safety and efficacy results in patients who received dose modifications in the phase III MIRASOL (GOG 3045/ENGOT-ov55) trial of mirvetuximab soravtansine vs investigator’s choice chemotherapy (ICC) in platinum-resistant ovarian cancer (PROC) with high folate receptor-alpha expression. Presented at: 2024 ESMO Gynecological Cancers Congress; June 20-22, 2024; Florence, Italy. Abstract 44O.

FDA approves mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. FDA. Accessed March 22, 2024. Accessed June 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant-epithelial-ovarian

Mirvetuximab soravtansine-gynx demonstrated significant improvements in progression-free survival, overall response rate, and overall survival compared to chemotherapy in patients with FRα-positive, platinum-resistant ovarian cancer in the phase 3 MIRASOL trial. Dose modifications were common and did not compromise efficacy. The trial led to full FDA approval of mirvetuximab soravtansine for this patient population. Safety profiles indicated manageable adverse effects, with dose modifications often necessary. The drug is now considered the new standard of care for this condition and is being further investigated in platinum-sensitive ovarian cancer.

Mirvetuximab soravtansine generated PFS, OS, and ORR improvements in patients with ovarian cancer who required dose modifications in the MIRASOL trial.

Mirvetuximab Soravtansine Elicits Benefits in Ovarian Cancer Regardless of Dose Modifications 

Treatment with durvalumab (Imfinzi) plus carboplatin, paclitaxel, and bevacizumab (Avastin), followed by maintenance therapy with olaparib (Lynparza) plus durvalumab and bevacizumab, continued to demonstrate improved progression-free survival (PFS) compared with chemotherapy plus bevacizumab, followed by maintenance bevacizumab, in patients with newly diagnosed advanced ovarian cancer that did not harbor 

 mutations, according to updated data from the phase 3 DUO-O trial (NCT03737643) presented at the 2024 ESMO Gynecological Cancers Congress.

Results from the final PFS analysis indicated that in patients with 

-unmutated, homologous recombination deficient (HRD)–positive disease, the median PFS was 45.1 months with durvalumab plus chemotherapy and bevacizumab, followed by maintenance olaparib, durvalumab, and bevacizumab (arm 3; n = 140) compared with 23.3 months for patients treated with chemotherapy plus bevacizumab, followed by maintenance bevacizumab (arm 1; n = 143; HR, 0.46; 95% CI, 0.33-0.65). Patients treated with durvalumab plus chemotherapy and bevacizumab, followed by maintenance durvalumab plus bevacizumab (arm 2; n = 148) achieved a median PFS of 25.1 months (HR vs arm 1, 0.89; 95% CI, 0.67-1.19).

-unmutated, intention-to-treat (ITT) population, the median PFS was 25.1 months for arm 3 (n = 578) vs 19.3 months for arm 1 (n = 378; HR, 0.61; 95% CI, 0.51-0.73). The median PFS for arm 2 (n = 374) was 20.6 months (HR vs arm 1, 0.87; 95% CI, 0.74-1.03; 

“DUO-O continues to demonstrate a clinically meaningful PFS benefit with first-line durvalumab, chemotherapy, and bevacizumab, followed by durvalumab, bevacizumab, and olaparib maintenance [in arm 3] vs the control [arm 1],” Fabian Trillsch, MD, of LMU Munich University Hospital in Germany stated during the presentation of data.

at a previously planned interim PFS analysis

, investigators shared that the investigational approach led to a statistically significant improvement in PFS compared with the control.

Updated data from the phase 3 DUO-O trial presented at the 2024 ESMO Gynecological Cancers Congress demonstrated that treatment with durvalumab plus chemotherapy and bevacizumab, followed by maintenance therapy with olaparib, durvalumab, and bevacizumab, significantly improved progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer without BRCA1/2 mutations. The study showed a median PFS of 45.1 months in the HRD-positive cohort for the investigational arm compared to 23.3 months for the control arm. Safety profiles were consistent with previous analyses.

Durvalumab/chemotherapy/bevacizumab, then durvalumab/bevacizumab/olaparib maintenance, sustained a PFS benefit in BRCA-unmutated advanced ovarian cancer.

ESMO Gynecological Cancers Congress | Conference

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