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Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma.

ABSTRACT: This multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. In C1, 25 patients were enrolled, and CBR was 20% (95% CI: 9-39) with median clinical benefit duration of 5.3 months. The ORR was 4% (95% CI: 0-20). In C2, 22 patients were enrolled, and the CBR was 31.8% (95% CI: 16-53) with median clinical benefit duration of 6.8 months. The ORR was 14% (95% CI: 3-35). No new safety signals were detected. No significant association was detected between clinical benefit and IHC markers (PTEN, p53, MMR, PD-L1), or molecular profiling (PTEN, TP53, homologous recombination repair genes). In conclusion, niraparib monotherapy did not meet the efficacy threshold. Niraparib in combination with dostarlimab showed modest activity.

SUBMITTER: Madariaga A

PROVIDER: S-EPMC10017680 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma.

Madariaga Ainhoa A Garg Swati S Tchrakian Nairi N Dhani Neesha C NC Jimenez Waldo W Welch Stephen S MacKay Helen H Ethier Josee-Lyne JL Gilbert Lucy L Li Xuan X Rodriguez Angela A Chan Lucy L Bowering Valerie V Clarke Blaise B Zhang Tong T King Ian I Downs Gregory G Stockley Tracy T Wang Lisa L Udagani Smitha S Oza Amit M AM Lheureux Stephanie S

Nature communications 20230315 1

This multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an ...[more]

PMID: 36922497

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Project description:ObjectiveIn the double-blind, phase III, placebo-controlled RUBY randomized clinical trial, dostarlimab plus carboplatin-paclitaxel significantly increased survival among patients with primary advanced or recurrent endometrial cancer (EC). We conducted a cost-effectiveness analysis of dostarlimab in combination with chemotherapy in these patients stratified by mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) subgroups from the perspective of a United States payer.Materials and methodsA Markov model with three states was employed to simulate patients who were administered either dostarlimab in combination with chemotherapy or chemotherapy based on the RUBY trial. Quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER) were calculated with a willingness-to-pay (WTP) threshold of $150,000 per QALY. Both univariate and probabilistic sensitivity analyses were carried out to explore the robustness of the model.ResultsIn dMMR EC, the combination of dostarlimab and chemotherapy achieved an additional 5.48 QALYs at an incremental cost of $330,747 compared to chemotherapy alone, resulting in an ICER of $60,349.30 per QALY. In pMMR EC, there were 1.51 additional QALYs gained at an extra cost of $265,148, yielding an ICER of $175,788.47 per QALY. With a 15.2% discount on dostarlimab, the ICER decreased to $150,000 per QALY in the pMMR EC. The univariate sensitivity analysis revealed that the cost of dostarlimab, utility of progression-free survival (PFS), and progressive disease (PD) had the most significant impacts on the outcomes. Probabilistic sensitivity analysis revealed that dostarlimab had a 100% likelihood of being considered cost-effective for patients at a WTP threshold of $150,000 per QALY for dMMR EC, whereas this likelihood was only 0.5% for pMMR EC.ConclusionDostarlimab in combination with chemotherapy was cost-effective for primary advanced or recurrent dMMR EC from the perspective of a United States payer at a WTP threshold of $150,000 per QALY, but not for pMMR EC. Lowering the prices of dostarlimab could potentially enhance the cost-effectiveness of treatment for pMMR EC.

Project description:ObjectiveThere is an increase in patient-reported outcome assessments to gain information on new drug candidates from the patient's perspective. A data gap remains in patient-reported outcome measurements for anti-programmed death 1 (anti-PD-1) therapies in endometrial cancer. We present patient-reported outcome measures collected from patients with mismatch repair-deficient/microsatellite instability-high advanced or recurrent endometrial cancer treated with dostarlimab, an anti-PD-1 monoclonal antibody, in an expansion cohort of the GARNET trial.MethodsGARNET (NCT02715284) is a phase I single-arm study of dostarlimab monotherapy in multiple tumor types. Patients with advanced or recurrent mismatch repair-deficient/microsatellite instability-high endometrial cancer were treated with 500 mg of intravenous dostarlimab once every 3 weeks for four cycles, then 1000 mg of intravenous dostarlimab every 6 weeks. Patient-reported outcome assessments were an exploratory endpoint, measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).ResultsAt data cut-off, 88 patients with mismatch repair-deficient endometrial cancer were included in the analysis. Patient-reported outcome assessment completion was >95.5% throughout cycle 7 of the trial, with no individual domain completion <90.9%. Quality of life, emotional functioning, and social functioning showed improvement compared with baseline. All symptom scores showed either improvement or stability from baseline through cycle 7. Categorical change in response across all symptom scales and single-item response scores showed stability or improvement for most patients. For patients who saw a worsening of their categorical change in response, ≤7.4% experienced a 2-category worsening and ≤2.5% experienced a 3-category worsening.ConclusionsMost patients remained stable or had improved quality of life while receiving dostarlimab for the treatment of recurrent or advanced mismatch repair-deficient endometrial cancer.Trial registration numberNCT02715284.

Project description:ObjectivesImmune checkpoint inhibitors have emerged as novel treatment options in patients with endometrial cancer. In this study we aimed to compare the survival outcomes of patients with recurrent or advanced endometrial cancer. These patients had received dostarlimab after platinum-based chemotherapy in the single-arm, Phase I GARNET trial. We compared them with a matched indirect real-world cohort.MethodsThe real-world cohort was established using National Cancer Registration and Analysis Service data, with five treatment-specific real-world sub-cohorts identified. To compare clinical outcomes between the GARNET trial and real-world cohorts, we performed matching-adjusted indirect comparisons. We used prognostic variables to create matching scenarios, including scenario 1 that incorporated grade, histology, and platinum-based chemotherapy number; scenario 2 that considered histology and platinum-based chemotherapy number; and scenario 3 that included race/ethnicity, stage at diagnosis, histology, and prior surgery. Overall survival was defined as the time between the first dostarlimab dose or second-line real-world treatment and death. Adjusted hazard ratios for matching-adjusted indirect comparisons were estimated via weighted Cox proportional-hazards models. Progression-free survival, using time-to-next treatment as a proxy for real-world cohorts, was summarized descriptively.ResultsDistribution of baseline characteristics that were matched was similar between the GARNET cohort (n=153) and the real-world cohort (n=999). The most common International Federation of Gynecology and Obstetrics (FIGO) stage in both cohorts was stage III/IV (n=88; 57.5% and n=778; 77.9%, respectively), with endometroid histology predominating in the GARNET cohort (n=121; 79.1%) and non-endometrioid the predominant form in the real-world cohort (n=575; 57.6%). The median overall survival for dostarlimab was longer (range 27.1-40.5 months [95% confidence interval (CI) 6.4-non-estimable and 19.4-non-estimable]) both before and after matching for all scenarios compared with the real-world cohort (10.3 months). Across all matching scenarios, patients in the GARNET cohort had a decreased risk of death, with a HR for overall survival of 0.32 (p<0.0001) before matching, as compared with the overall real-world cohort and most treatment-specific real-world cohorts. For all three scenarios, progression-free survival rates at 12 and 18 months were higher for patients on dostarlimab compared with the real-world cohort (0.48 and 0.43 respectively before matching in the GARNET cohort vs 0.28 and 0.16 respectively in the real-world cohort; using time to next treatment as proxy). The effective sample size for scenario 1 was low when compared with the other scenarios (scenario 1: n=18; scenario 2: n=62; scenario 3: n=67).ConclusionIn this adjusted indirect dataset, patients with recurrent/advanced mismatch repair deficient/microsatellite instability-high endometrial cancer post-platinum-based chemotherapy who received dostarlimab in the GARNET trial had significantly improved overall survival compared with patients receiving current second-line treatment in England.

Project description:Background: Patients with advanced or recurrent endometrial cancer (EC) have limited treatment options following platinum-based chemotherapy and poor prognosis. The single-arm, Phase I GARNET trial (NCT02715284) previously reported dostarlimab efficacy in mismatch repair-deficient/microsatellite instability-high advanced or recurrent EC. Objectives: The objective of this study was to compare overall survival (OS) and describe time to treatment discontinuation (TTD) for dostarlimab (GARNET Cohort A1 safety population) with an equivalent real-world external control arm receiving non-anti-programmed death (PD)-1/PD-ligand (L)1/2 treatments (constructed using data from a nationwide electronic health record-derived de-identified database and applied GARNET eligibility criteria). Methods: Propensity scores constructed from prognostic factors, identified by literature review and clinical experts, were used for inverse probability of treatment weighting (IPTW). Kaplan-Meier curves were constructed and OS/TTD was estimated (Cox regression model was used to estimate the OS-adjusted hazard ratio). Results: Dostarlimab was associated with a 52% lower risk of death vs real-world treatments (hazard ratio, 0.48; 95% confidence interval [CI], 0.35-0.66). IPTW-adjusted median OS for dostarlimab (N=143) was not estimable (95% CI, 19.4-not estimable) versus 13.1 months (95% CI, 8.3-15.9) for real-world treatments (N = 185). Median TTD was 11.7 months (95% CI, 6.0-38.7) for dostarlimab and 5.3 months (95% CI, 4.1-6.0) for the real-world cohort. Discussion: Consistent with previous analyses, patients treated with dostarlimab had significantly longer OS than patients in the US real-world cohort after adjusting for the lack of randomization using stabilized IPTW. Additionally, patients had a long TTD when treated with dostarlimab, suggesting a favorable tolerability profile. Conclusion: Patients with advanced or recurrent EC receiving dostarlimab in GARNET had significantly lower risk of death than those receiving real-world non-anti-PD-(L)1/2 treatments.

Dataset Information

Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma.

Publications

Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma.

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