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OBJECTIVE: Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL). METHODS: The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of disease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28). RESULTS: This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were -2.1 (95% confidence interval -2.4, -1.7) for FOSI, -4.6 (-5.6, -3.5) for the EQ-5D-5L index, and -7.9 (-9.6, -6.3) for EQ-VAS. CONCLUSIONS: Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL. ispartof: GYNECOLOGIC ONCOLOGY vol:166 issue:3 pages:494-502 ispartof: location:United States status: published

Background: Tumor biomarkers such as CD8 density and location (i.e., immune inflamed phenotype) and immune rich molecular subtype have been linked to immune checkpoint blockade (ICB) overall survival (OS) in different cancers. The IMagyn050 trial (NCT03038100), which evaluated the efficacy of Atezo vs placebo (Pla) with carboplatin, paclitaxel and bevacizumab (CPB) in front line ovarian cancer patient (pts), did not meet its co-primary endpoints of PFS in ITT or PD-L1+ (Moore et al. JCO 2021). In the current IMagyn050 substudy we assessed potential predictive tumor immune biomarkers for Atezo clinical benefit. Methods: FFPE tumors from the biomarker evaluable population were tested for PD-L1 IHC, CD8/PanCK IHC (total CD8 T cells and immune location phenotypes [inflamed, excluded, desert]) and RNA-seq (to derive molecular subtypes, biological pathways and cellular components [xCELL]) in tissue from baseline (n=860), on-treatment (OT, 9 weeks, n=233), intra- (n=8) and inter-lesion (n=12) matched samples. Hazard ratio (HR) interaction test from multivariate adjusted Cox-regression analysis for PFS and OS was performed to test predictive biomarkers. Results: While tumors with CD8 T cells, immunoreactive molecular subtypes or immune inflamed phenotype were enriched for PD-L1+, only pts with immune inflamed tumors showed improved OS Atezo benefit (HR 0.67). Improved Atezo PFS/OS benefit was also observed in pts with whose tumors had high oxidative phosphorylation (OXPHOS, HR: 0.72/0.65) and UV Response (UV, HR: 0.64/0.58) but not IFNγ response. Plasma B cells were linked to improved OS Atezo benefit vs Pla (HR 0.53). We leveraged OT samples from pts in the neoadjuvant cohort to assess treatment effect on the tumor microenvironment. Analyses showed that CPB reduced tumor proliferation and increased tumor immune inflammation (CD8 T cells, PD-L1 and IFNα/IFNγ response), further increased by Atezo. Immune inflammation is challenging in ovarian cancer due to extensive tumor heterogeneity. Prevalence of tumor biomarkers varied by anatomic locations: total CD8, CD8 localization and molecular subtypes. Inter- and intra-lesion biomarker status within the same pt showed PD-L1 and plasma B cells as most consistent. Molecular subtypes and immune phenotypes had moderate intra-lesion agreement but discordant between lesions. PD-L1 and OXPHOS were the only biomarkers linked to Atezo benefit regardless of anatomical location. Conclusion: This comprehensive exploratory study suggests that DNA damage, OXPHOS, plasma B cells and immune inflamed tumors, but not molecular subtypes or total CD8 T cells, may predict Atezo + CPB OS. This treatment promotes immune inflammation in OC tumors. Notably, we found that several biomarkers are highly heterogeneous. Our findings highlight the challenges of achieving durable clinical benefit from targeted immunotherapy in ovarian cancer pts. Citation Format: Venkatesh Krishnan, Ching-Wei Chang, Habib Hamidi, Michael A. Bookman, Charles Landen, Tashanna Myers, Hiroaki Kajiyama, Sakari Hietanen, Lyndsay Willmott, Premal Thaker, Cagatay Taskiran, Jalid Sehouli, Victor Khor, Yvonne Lin Liu, Sandro Pignata, Kathleen Moore, Luciana Molinero. Ovarian cancer tumor microenvironment and atezolizumab (atezo) clinical activity: IMagyn050 sub-study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5702.

TPS5623 Background: Carboplatin-paclitaxel chemotherapy (with trastuzumab for HER2+ uterine serous carcinoma) is the standard of care first-line systemic treatment for recurrent or metastatic endometrial carcinoma (EC), which has a 5-year relative survival rate of only 17%. Worse survival outcomes have been shown for the mismatch repair deficient (dMMR) subtype of EC. Pembrolizumab (pembro), an anti-PD-1 antibody, showed compelling antitumor activity in previously treated, advanced MSI-H/dMMR EC in the phase 2 KEYNOTE-158 study (ORR, 48%; median duration of response [DOR], not reached; O’Malley JCO 2022). KEYNOTE-C93/GOG-3064/ENGOT-en15 (NCT05173987) is a phase 3, randomized, open-label study evaluating first-line pembro versus carboplatin-paclitaxel chemotherapy in patients with dMMR advanced or recurrent EC. Methods: Patients aged ≥18 years with histologically confirmed stage III/IV recurrent EC including carcinosarcoma (mixed Mullerian tumor), radiographically evaluable disease (measurable or nonmeasurable per RECIST v1.1), no prior systemic therapy (prior radiation with or without radiosensitizing chemotherapy > 2 weeks before first dose or prior hormonal therapy ≥1 week before randomization is permitted), and an ECOG PS ≤1 are eligible. Patients must have central confirmation of dMMR status. Approximately 350 patients will be randomized 1:1 to receive pembro 400 mg IV Q6W for 18 cycles (̃2 years) or carboplatin AUC 5 or 6 mg/mL/min IV Q3W and paclitaxel 175 mg/m2 IV Q3W for 6 cycles (with option for > 6 cycles). Trastuzumab is permitted for patients in the chemotherapy arm with HER2+ serous EC. Randomization is stratified by disease status (newly diagnosed advanced EC vs recurrent EC) and histology (endometrioid vs nonendometrioid). Treatment will continue for the specified number of cycles or until PD or unacceptable toxicity. Patients in the chemotherapy arm have the option to receive pembro following confirmed PD by blinded independent central review (BICR). Tumor imaging will be performed Q9W from randomization to week 54 and Q12W thereafter. AEs will be assessed from randomization to 30 days (90 days for serious AEs) after treatment discontinuation and graded per NCI CTCAE version 5.0. Dual primary endpoints are PFS per RECIST v1.1 by BICR and OS. Secondary endpoints are ORR, disease control rate, and DOR per RECIST v1.1 by BICR; PFS per RECIST v1.1 by investigator review; PFS2 (ie, time from randomization to PD per investigator assessment or death from any cause after start of subsequent anticancer therapy); safety; and patient-reported outcomes. PFS and OS will be estimated by the Kaplan-Meier method, with treatment differences assessed by the stratified log-rank test and HRs with 95% CIs determined using a Cox proportional hazard model. Enrollment is ongoing. Clinical trial information: NCT05173987.