WELCOME TO THE INTERACTIVE PROGRAM OF THE IGCS 2023 MEETING

Introduction

Molecular characterization is important to inform treatment decisions for patients with endometrial cancer (EC). Wild type TP53 (TP53wt) is found in ~50% of advanced/recurrent EC and of those, ~70% are microsatellite stable (MSS/pMMR).

Methods

ENGOT-EN5/GOG-3055/SIENDO (NCT03555422) is a randomized double-blind, phase 3 trial evaluating selinexor vs placebo as a maintenance treatment for advanced/recurrent EC following response to prior systemic therapy. Here we report the updated efficacy and safety of a prespecified exploratory subgroup analysis of patients with TP53wt EC.

Results

113 patients with TP53wt EC received selinexor (n=77) or placebo (n=36) as maintenance therapy. As of March 2023, the median follow-up was 25.3 months, and 26 patients remain on treatment. Median PFS (mPFS) was 27.4 months with selinexor vs 5.2 months with placebo (HR 0.42; 95% CI [0.25-0.70], nominal one-sided p=0.0003). PFS improvement was observed regardless of microsatellite instability status; in the TP53wt/MSS(pMMR) subgroup, the mPFS was not reached with selinexor vs 4.9 months with placebo.

In patients with TP53wt, the most common adverse events (AEs) were nausea, vomiting, and diarrhea; most common grade ≥3 AEs were neutropenia, thrombocytopenia, and nausea; 16% of patients discontinued selinexor due to AEs. No grade 5 AEs occurred. No immune-related AEs were observed.

Conclusion/Implications

TP53wt status may represent a robust predictive biomarker for selinexor efficacy in EC. Additionally, a strong PFS signal was observed in the TP53wt/MSS(pMMR) subgroup, a patient population with high unmet need. Both additional data and updated data will be presented at the conference.

Introduction

Trastuzumab deruxtecan (T-DXd) has demonstrated significant survival benefit for patients with HER2-expressing breast and gastric cancers. In DESTINY-PanTumor02, T-DXd demonstrated clinically meaningful response rates, progression-free survival (PFS), and overall survival (OS) in HER2-expressing tumors.

Methods

This open-label, Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in patients across seven cohorts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local [with retrospective central testing] or central testing) locally advanced/metastatic disease after ≥1 systemic treatment, or without alternative treatment. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response, PFS, OS, and safety. Exploratory endpoints included pharmacodynamic biomarkers.

Results

At data cutoff (June 2023), 120 patients in the endometrial, cervical, and ovarian cancer cohorts had received treatment (median follow-up [range]: 19.94 [0.8–31.1], 12.60 [0.9–31.0], and 13.13 [0.7–30.6] months, respectively). Overall, 80.8% received ≥2 prior lines of therapy. Table 1 shows efficacy outcomes by HER2 expression levels by cohort. Table 2 shows ORR by HER2 in situ hybridization (ISH) amplification and plasma HER2 amplification by cohort. Grade (G)≥3 drug-related adverse events occurred in 54/120 (45.0%) patients; adjudicated treatment-related interstitial lung disease/pneumonitis occurred in 13/120 (10.8%) patients (n=12 G≤2; n=1 G5).

Conclusion/Implications

T-DXd demonstrated clinically meaningful benefit, including responses across HER2 expression levels and in ISH+ or plasma ERBB2 amplified subgroups, and encouraging survival outcomes in patients with gynecological tumors. Safety was consistent with the known profile. These data support T-DXd as a potential treatment for patients with gynecological HER2-expressing tumors who progressed on prior therapy.

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Background: Standard first-line chemotherapy for endometrial cancer is paclitaxel and carboplatin (PC). The benefit of adding pembrolizumab to chemotherapy remains unclear.

Methods: In this blinded, placebo-controlled, randomized phase 3 trial, 816 patients with measurable stage III/IVA, IVB, or recurrent EC (225 dMMR and 591 pMMR) were randomized 1:1 to pembrolizumab or placebo plus PC (planned six 3-weekly cycles), followed by up to 14 q6-week maintenance cycles of pembrolizumab or placebo. Prior adjuvant chemotherapy was permitted if completed ≥12 months prior. The primary endpoint was progression-free survival among two cohorts, patients with dMMR and with pMMR endometrial cancer based on central MMR immunohistochemistry. Interim analyses were triggered at ≥84 (dMMR cohort) and ≥196 (pMMR cohort) progression-free survival events.

Results: At time of analysis of the dMMR cohort (12/16/2022), and with median follow-up of 12 months, the risk of disease progression or death was 70% lower with pembrolizumab than with placebo (Kaplan–Meier estimate of the rate of freedom from disease progression and from death at 12 months, 74% vs. 38%, respectively; HR 0.30; 95% CI: 0.19-0.48. P<0.00001). In the pMMR cohort (analyzed 12/6/2022), with median follow up of 7.9 months, median progression-free survival was 13.1 months with pembrolizumab versus 8.7 months with placebo (HR, 0.54; 95% CI: 0.41-0.71 P<0.00001). Adverse events were as expected for PC and pembrolizumab.

Conclusions: In patients with advanced or recurrent endometrial cancer, addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone (NRG Oncology NRG-GY018, ClinicalTrials.gov number: NCT03914612).

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Background
The standard therapy for advanced/recurrent endometrial cancer includes carboplatin and paclitaxel (CP).Robust biological rationale suggested a synergy between immunotherapy and chemotherapy in this setting.
Methods
AtTEnd is an international academic study in endometrial carcinoma/carcinosarcoma patients (pts) withadvanced newly diagnosed or recurrent disease with no prior systemic chemotherapy for recurrence. Pts wererandomized (2:1 ratio) to receive either CP chemotherapy and atezolizumab (atezo) or placebo, followed byatezo or placebo until disease progression. The mismatch repair (MMR) status was evaluated centrally.Coprimary endpoints with a hierarchical approach were: progression free survival (PFS) in the deficient MMR(dMMR) population, PFS and overall survival (OS) in all comers.
Results
Five hundred and fifty-one pts were enrolled from Oct 2018 to Jan 2022 in 89 sites across 10 countries (medianfollow-up 28.3 months). Of the 549 pts included in the intention to treat population, 125 (22.8%) had dMMRtumours and 352 (64.1%) had endometrioid carcinoma; 369 (67.2%) had recurrent disease and 148 (82.2%) ofnewly diagnosed cases had primary stage IV. In the dMMR population, the addition of atezo showed asignificant improved PFS (HR 0.36 95% CI:0.23-0.57; p=0.0005; median PFS: not reached vs. 6.9 months foratezo vs placebo). The superiority in PFS was confirmed in all comers (HR 0.74 95%CI:0.61-0.91; p=0.0219;median PFS: 10.1 months vs 8.9 months for atezo vs placebo). Interim analysis of OS in all comers indicated atrend in favor for atezo, despite 45 (24.3%) placebo patients received immunotherapy as subsequent therapy. Second PFS and duration of response in the dMMR population confirmed the efficacy of atezo. Grade≥3adverse events occurred in 66.9% and 63.8% of pts in atezo vs placebo arm. Safety profile for CP + atezo wasmanageable and consistent with expected toxicities.
Conclusions
The addition of atezo to standard CP chemotherapy demonstrated a statistically significant improvement inPFS for pts with advanced/recurrent endometrial carcinomas with a substantial benefit in pts with dMMRcarcinomas.
Clinical trial identification
EudraCT 2018-001072-37; NCT03603184;

Introduction

DUO-E (NCT04269200) evaluated the addition of durvalumab to standard first-line chemotherapy followed by maintenance durvalumab±olaparib in endometrial cancer (EC).

Patients with newly diagnosed FIGO Stage III/IV or recurrent EC and naïve to first-line systemic treatment were randomised 1:1:1 to CP (carboplatin/
paclitaxel+durvalumab placebo [six cycles] followed by maintenance durvalumab placebo+olaparib placebo), CP+durvalumab (carboplatin/paclitaxel+durvalumab [1120 mg IV q3w] [six cycles] followed by maintenance durvalumab [1500 mg IV q4w]+olaparib placebo), or CP+durvalumab+olaparib (carboplatin/paclitaxel+durvalumab [six cycles] followed by maintenance durvalumab+olaparib [300 mg tablets bid]). Dual primary endpoints were investigator‑assessed progression-free survival (PFS; RECIST v1.1) in the intent-to-treat population for CP+durvalumab versus CP and CP+durvalumab+olaparib versus CP. Overall survival (OS) was a secondary endpoint. A multiple testing procedure with gatekeeping strategy was applied to PFS and OS. PFS by mismatch repair (MMR) status (deficient [dMMR] or proficient [pMMR]) was a prespecified subgroup analysis.

CP+durvalumab and CP+durvalumab+olaparib demonstrated clinically meaningful and statistically significant PFS improvements versus CP in the intent-to-treat population (Table). Interim OS data were immature (27.7%; CP+durvalumab vs CP: HR [95% CI] 0.77 [0.56–1.07]; P=0.120; CP+durvalumab+olaparib vs CP:
0.59 [0.42–0.83]; P=0.003). PFS subgroup analysis showed benefit for both arms versus CP in dMMR/pMMR patients. In pMMR patients, maintenance olaparib further enhanced PFS benefit (Table). Safety profiles of the treatment arms were generally consistent with the individual components.

DUO-E met both primary endpoints, showing statistically significant and clinically meaningful PFS improvement with the addition of durvalumab to CP followed by maintenance durvalumab±olaparib versus CP. Maintenance olaparib further improved PFS in pMMR patients.