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Cervical cancer (CC) is the fourth most common neoplasia in women worldwide. Although early-stage CC is often curable, 40 to 50% of patients are diagnosed at a locally advanced stage. Metastatic disease accounts for the principal cause of death. Lymph node (LN) status is a major factor impacting treatment options and prognosis. Historically, CC was staged based only on clinical findings. However, in 2018, imaging modalities and/or pathological findings were included in the International Federation of Gynecology and Obstetrics (FIGO) staging classification. In the last decades, LN status assessment has evolved considerably. Full pelvic lymphadenectomy used to be the only way to determine LN status. Currently, several options exist: surgery with full lymphadenectomy, sentinel lymph node (SLN) biopsy or imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET). Regarding surgery, the SLN biopsy technique has become a standard procedure in cases of CC, with indocyanine green (ICG) being the preferred dye. Pelvic MRI is a valuable imaging technique modality for the evaluation of pelvic LNs. In locally advanced or in early-stage disease with suspicious LNs on CT scans or MRI, PET/CT is recommended for assessment of nodal and distant status. The best strategy for LN assessment remains a highly controversial topic in the literature. In this article, we aim to review and compare the advantages and limitations of each modality, i.e. imaging or surgical (lymphadenectomy or SLN biopsy) approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dheur, Kakkos, Danthine, Delbecque, Goffin, Gonne, Lovinfosse, Pleyers, Thille, Kridelka and Gennigens.)

Aims: Dostarlimab-gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein-1 (PD-1) receptor and blocks its ligands. RUBY (NCT03981796) is a two-part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure-efficacy/safety (ER) relationships., Methods: A PopPK model developed using GARNET (NCT02715284) study data for dostarlimab monotherapy was externally validated with RUBY Part 1 study data. Subsequently, the model was updated with data across the two studies. Exposure-safety analyses for adverse events related to dostarlimab alone or in combination with standard of care (SOC) were modelled using logistic regression. Exposure-efficacy analysis included Cox proportional hazards analysis of the primary efficacy endpoint of progression-free survival (PFS)., Results: For the model update, 7957 pharmacokinetics observations from 868 patients pooled from both RUBY and GARNET studies were available. The model was consistent with the previous model. Dostarlimab clearance was estimated to be 7.79% lower when dostarlimab was given as SOC combination therapy. However, no significant covariates were clinically relevant. Hepatic or renal impairment did not affect pharmacokinetics. Among the safety endpoints, only rash showed a small yet statistically significant effect (P < .05) in all subjects; however, this was not not deemed clinically relevant. There were no other clinically significant exposure-safety or exposure-PFS relationships., Conclusions: The addition of chemotherapy to dostarlimab had limited effect on dostarlimab PopPK, with no clinically significant covariates or clinically relevant exposure-safety or exposure-PFS relationships., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Competing Interests: I took part in an advisory board and in a health economics interview regarding the progression-free survival data from the ENGOT-cx11/GOG-3047/KEYNOTE-A18 study previously published,(7) but was not involved in the current Article.(3) I report grants from AstraZeneca, Deciphera, and GSK; consulting fees from GSK, Ipsen, and MSD; speakers fees from AstraZeneca, BMS, GSK, Ipsen, MSD, Pfizer, and Pharmamar; support for meetings or travel from AstraZeneca, GSK, Ipsen, MSD, Pfizer, and Pharmamar; and participation on data safety monitoring board or advisory boards for AstraZeneca, BMS, Eisai, GSK, Ipsen, and MSD.

Until recently, patients diagnosed with locally advanced and metastatic endometrial cancer faced significant challenges in their treatment due to limited options and poor prognostic outcomes. The sequencing of tumors has been a major advancement in its management. It has led to The Cancer Genome Atlas classification currently used in clinical practice and the initiation of several clinical trials for innovative treatments targeting principally signaling pathways, immune checkpoints, DNA integrity, growth factors, hormonal signaling, and metabolism. Numerous clinical trials are investigating a combinatorial approach of these targeted therapies to counter tumoral resistance, cellular compensatory mechanisms, and tumor polyclonality. This review provides a comprehensive overview of historical, current, and promising therapies in advanced and metastatic endometrial cancer. It particularly highlights clinical research on targeted and hormonal therapies, but also immunotherapy, reflecting the evolving landscape of treatment modalities for this disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christine Gennigens = All support for the present manuscrit: no disclosures. Grant/contracts: Astra-Zeneca, GSK, Deciphera. Consulting fees: Ipsen, GSK, MSD. Honoraria for lectures: MSD, BMS, Ipsen, Pfizer, Pharmamar, Astra-Zeneca, GSK. Support for meetings and/or travel: Ipsen, Pharmamar, Pfizer, MSD, GSK, Astra-Zeneca. Participation on a data safety monitoring board or advisory board: MSD, BMS, Ipsen, Astra-Zeneca. GSK, Eisai. Others authors – No conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy., Methods: We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival., Results: A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P = 0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects., Conclusions: In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: Retifanlimab is a humanized immunoglobulin G4 monoclonal antibody against programmed death 1 being investigated in several solid tumor types. We report final results from patients with recurrent microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) endometrial cancer treated with retifanlimab in a POD1UM-101 expansion cohort., Methods: Eligible patients (≥18 years; histologically proven/unresectable/recurrent, MSI-H/dMMR endometrial cancer; checkpoint inhibitor naive) received retifanlimab 500 mg intravenously every 4 weeks for ≤2 years. Primary endpoint was safety/tolerability., Results: At data cutoff (May 17, 2023), 76 patients had received at least one retifanlimab dose. Median (range) age was 67 (49-88) years; 88.2% of patients had recurrent metastatic disease and 80.3% had visceral metastases. Seventy-five patients (98.7%) had received at least one prior systemic therapy. Median retifanlimab exposure was 10.0 (0.03-25.9) months; 23 patients completed treatment. 38 patients (50.0%) had grade ≥3 treatment-emergent adverse events (TEAEs), most commonly anemia (n = 10 [13.2%]). 63 patients (82.9%) had treatment-related AEs (TRAEs; grade ≥3, n = 14 [18.4%]); most common was fatigue (n = 14 [18.4%]). Two patients had TEAEs that led to death; no TRAEs were fatal. 39 patients had objective responses (51.3%; 95% CI, 39.6-63.0%); 19 patients (25.0%) had complete response and 20 (26.3%) had partial response. Median progression-free survival was 12.2 months; 30 patients (76.9%) had duration of response (DOR) ≥12 months. Median DOR was not reached after median follow-up time of 26.0 months., Conclusions: Retifanlimab was generally well tolerated and demonstrated encouraging anti-tumor activity in patients with pre-treated recurrent MSI-H/dMMR endometrial cancer., Competing Interests: Declaration of competing interest Patricia Pautier received travel funding from Amgen, AstraZeneca, GlaxoSmithKline, MSD, Novartis, PharmaMar, and Tesaro; had an advisory role with AstraZeneca, Genmab, MSD, Onxeo, PharmaMar, and Roche; and received honoraria from AstraZeneca, Eisai, MSD, and PharmaMar. Domenica Lorusso had consultancy roles with Novartis and PharmaMar; had advisory and invited speaker roles with AstraZeneca, Clovis Oncology, Genmab, GlaxoSmithKline, ImmunoGen, MSD, and Seagen; received institutional support from Clovis Oncology, Corcept, Genmab, ImmunoGen, and MSD; and received grants for academic trials from Clovis Oncology, GlaxoSmithKline, and MSD. Christine Gennigens received a grant from AstraZeneca, GlaxoSmithKline; received consulting fees from Ispen, GlaxoSmithKline, and MSD; received honoraria for lectures from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, MSD, Pfizer, and PharmaMar; received support for meetings and/or travel from GlaxoSmithKline, Ipsen, MSD, Pfizer, and PharmaMar; and participated in a data safety monitoring board/advisory board for AstraZeneca, Bristol Myers Squibb, Eisai, GlaxoSmithKline, Ipsen, and MSD. Laurence Gladieff participated in an advisory board for AstraZeneca, Clovis Oncology, GlaxoSmithKline, and MSD; received honoraria from AstraZeneca, GlaxoSmithKline, MSD, PharmaMar, and Roche; and received congress funding from GlaxoSmithKline, PharmaMar, Roche, and Viatris. Jill Bowman, Chuan Tian, and Mark Cornfeld have employment and stock ownership at Incyte Corporation. Toon Van Gorp received consulting fees from AstraZeneca, BionTech, Eisai, GlaxoSmithKline, ImmunoGen, Incyte, Karyopharm, MSD, OncXerna, Seagen, Tubulis, and Zentalis; had corporate-sponsored research from Amgen, AstraZeneca, and Roche; and received honoraria for lectures from GlaxoSmithKline, ImmunoGen, and MSD. All payments were via the institution. Dominique Berton and Anna Kryzhanivska have no conflict of interest related to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC)., Methods: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR)., Results: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E)., Conclusion: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

Objective: Recurrent platinum-resistant ovarian cancer has a poor prognosis with limited therapeutic options. Sub-therapeutic intra-tumoral drug concentrations may add to therapy resistance. CPC634 (docetaxel entrapped in CriPec nanoparticles) was designed to enhance tumor accumulation of drug with localized drug release at the target site to increase therapeutic efficacy. This study investigated the therapeutic effect of CPC634 in patients with platinum-resistant ovarian cancer., Methods: According to a Simon 2-stage design trial, the first stage included 13 patients, and 12 patients were enrolled in the second stage. Eligible patients had measurable disease and had progressed ≤6 months after the last platinum-based therapy. Platinum-refractory disease was excluded. In stage 1, the number of previous treatment lines was unlimited; in the second stage, a maximum of two prior lines altogether were allowed. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumor (RECIST) V1.1. Secondary endpoints included safety, progression-free survival at 6 months, cancer antigen 125 (CA125) response, and disease control rate., Results: The patients' median age was 66 years (range 22-77) and most were International Federation of Gynecology and Obstetrics (FIGO) stage III (56%). The median number of previous treatment lines was 3 (range 3-5) in stage I and 2 (range 1-4) in stage II of the study. None of the patients had an objective response, one patient had a CA125 response (5%), and seven patients had stable disease at first evaluation (35%). Median progression-free survival was 1.4 months in stage 1 and 3.0 months in stage 2. Adverse events (all grades) were mainly gastrointestinal in 24 patients (96%), fatigue in 11 (44%), dyspnea in 10 (40%), and infections in 10 (40%) of patients. Grade 3 or higher adverse events occurred in 14 patients (36%), including gastrointestinal in 4 (16%), anemia in 3 (12%), and febrile neutropenia, fatigue, chronic kidney disease, dehydration, and hypertension each in 1 (4%) patient. The trial was stopped prematurely due to futility., Conclusions: Treatment with CPC634 was feasible, but without apparent clinical activity in patients with recurrent platinum-resistant ovarian cancer. Side effects were mainly gastrointestinal in 24 (96%) patients, including nausea, vomiting, and decreased appetite, fatigue, anemia, and dyspnea., Competing Interests: Competing interests: CJFR was employee and is meanwhile paid consultant for Cristal Therapeutics, while RH was employed till August 2021 by Cristal Therapeutics., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To develop machine learning models to predict para-aortic lymph node (PALN) involvement in patients with locally advanced cervical cancer (LACC) before chemoradiotherapy (CRT) using 18 F-FDG PET/CT and MRI radiomics combined with clinical parameters., Methods: We retrospectively collected 178 patients (60% for training and 40% for testing) in 2 centers and 61 patients corresponding to 2 further external testing cohorts with LACC between 2010 to 2022 and who had undergone pretreatment analog or digital 18 F-FDG PET/CT, pelvic MRI and surgical PALN staging. Only primary tumor volumes were delineated. Radiomics features were extracted using the Radiomics toolbox®. The ComBat harmonization method was applied to reduce the batch effect between centers. Different prediction models were trained using a neural network approach with either clinical, radiomics or combined models. They were then evaluated on the testing and external validation sets and compared., Results: In the training set (n = 102), the clinical model achieved a good prediction of the risk of PALN involvement with a C-statistic of 0.80 (95% CI 0.71, 0.87). However, it performed in the testing (n = 76) and external testing sets (n = 30 and n = 31) with C-statistics of only 0.57 to 0.67 (95% CI 0.36, 0.83). The ComBat-radiomic (GLDZM&#95;HISDE&#95;PET&#95;FBN64 and Shape&#95;maxDiameter2D3&#95;PET&#95;FBW0.25) and ComBat-combined (FIGO 2018 and same radiomics features) models achieved very high predictive ability in the training set and both models kept the same performance in the testing sets, with C-statistics from 0.88 to 0.96 (95% CI 0.76, 1.00) and 0.85 to 0.92 (95% CI 0.75, 0.99), respectively., Conclusions: Radiomic features extracted from pre-CRT analog and digital 18 F-FDG PET/CT outperform clinical parameters in the decision to perform a para-aortic node staging or an extended field irradiation to PALN. Prospective validation of our models should now be carried out., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)