Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody-drug ...conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623).
Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity.
Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% 95% confidence interval (CI): 13%-37%. Median duration of response (DOR) was 4.2 months (range: 1.0
-9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%-43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%-35%), median DOR of 6.0 months (range: 1.0
-9.7), and 6-month PFS rate of 40% (95% CI: 24%-55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed.
Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.
Molecular algorithms may estimate the risk of recurrence and death for patients with endometrial cancer (EC) and may impact treatment decisions. To detect microsatellite instabilities (MSI) and p53 ...mutations, immunohistochemistry (IHC) and molecular techniques are used. To select the most appropriate method, and to have an accurate interpretation of their results, knowledge of the performance characteristics of these respective methods is essential. The objective of this study was to assess the diagnostic performance of IHC versus molecular techniques (gold standard). One hundred and thirty-two unselected EC patients were enrolled in this study. Agreement between the two diagnostic methods was assessed using Cohen's kappa coefficient. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the IHC were calculated. For MSI status, the sensitivity, specificity, PPV and NPV were 89.3%, 87.3%, 78.1% and 94.1%, respectively. Cohen's kappa coefficient was 0.74. For p53 status, the sensitivity, specificity, PPV, and NPV were 92.3%, 77.1%, 60.0% and 96.4%, respectively. Cohen's kappa coefficient was 0.59. For MSI status, IHC presented a substantial agreement with the polymerase chain reaction (PCR) approach. For the p53 status, the moderate agreement observed between IHC and next generation sequencing (NGS) methods implies that they cannot be used interchangeably.
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_HISDE_PET_FBN64 and Shape_maxDiameter2D3_PET_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
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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.
Etirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This ...randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma.
A total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m(2) every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS).
The overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days.
Both schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m(2) once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.
Background
Hemoglobin (Hb), white blood cell (WBC), and polymorphonuclear neutrophil (PMN) blood counts may be correlated with outcomes in patients with locally advanced cervical cancer.
Methods
Hb, ...WBC, and PMN counts were measured at diagnosis and during concomitant cisplatin‐based chemoradiotherapy (CCRT) in a retrospective sample of 103 patients between 2010 and 2017. Red blood cell (RBC) transfusions were also recorded. The associations between hematological variables and patient overall survival (OS) and recurrence‐free survival (RFS) were assessed by Cox regression models.
Results
The 3‐year OS and RFS rates were 81.4% and 76.8%, respectively. In addition to tumor size and smoking, OS and RFS were found to be significantly associated with changes in WBC and PMN counts from the first to the last cisplatin cycle. Hb count throughout the treatment and RBC transfusions were not predictive of outcome.
Conclusions
This study found no association between Hb count or RBC transfusions and outcome. The daily practice of maintaining the Hb count above 12 g/dL during CCRT should be weighed against the potential risks of transfusions. Drops in WBC and PMN counts during treatment positively impacted OS and RFS and could, therefore, serve as biomarkers during CCRT to adapt the follow‐up and consider the need for adjuvant systemic treatments.
In patients with locally advanced cervical cancer. Daily practice of maintaining the Hb count above 12 g/dL during CCRT should be weighed against potential risks of transfusions. Drops in WBC and PMN counts during treatment positively impacted OS and RFS
BackgroundManagement of patients with recurrent endometrial cancer after failure on platinum-based therapy remains a clinical challenge. Retifanlimab (INCMGA00012) is an investigational humanized ...immunoglobulin G4 monoclonal antibody against programmed cell death 1 (PD-1). We previously reported encouraging results from a preplanned interim analysis in patients with microsatellite instability-high (MSI-H) recurrent endometrial cancer treated with retifanlimab in POD1UM-101 1. Here, we provide top-line results from the full cohort of patients in the POD1UM-101 study.MethodsEligible patients have histologically proven, unresectable recurrent MSI-H or deficient mismatch repair (dMMR) endometrial cancer (per local testing), ECOG PS ≤1, disease progression during or following 1 to ≤5 prior systemic treatments, measurable disease (per RECIST v1.1), and are naïve to prior immune checkpoint inhibitors. MSI-H and dMMR status were centrally confirmed using PCR and IHC, respectively. Patients receive retifanlimab 500 mg every 4 weeks for up to 2 years. The primary study endpoint is safety. Confirmed best overall response and duration of response (DOR) were evaluated by independent central review (ICR) using RECIST v1.1.ResultsAs of July 6, 2021, 76 patients with centrally confirmed MSI-H (65 85.5%) or dMMR (11 14.5%) endometrial cancer had received ≥1 dose of retifanlimab; median age was 67.0 (49–88) years, 70 (92.1%) had endometrioid histology, 67 (88.2%) had metastatic disease, and 61 (80.3%) had visceral metastases. Sixty-eight (89.5%) patients had prior surgery or procedure, 54 (71.1%) patients were treated with radiotherapy, and 75 (98.7%) patients had received prior systemic therapy for advanced disease (33 43.4% received ≥2 prior systemic therapies for advanced disease). Median retifanlimab exposure was 7.4 (0.03–23.0) months. At data cutoff, 2 (2.6%) patients completed treatment and 30 (39.5%) were on treatment. Grade ≥3 treatment emergent AEs (TEAEs) occurred in 33 (43.4%) patients, including 10 (13.2%) with anemia and 7 (9.2%) with an immune-related AE (nephritis, n=2; autoimmune hepatitis, hepatitis, myositis, rash, and pneumonitis, n=1 each). There were no treatment-related AEs with fatal outcome. Centrally confirmed objective responses were observed in 33 (43.4%) patients (95% CI, 32.1–55.3), with 11 (14.5%) complete and 22 (28.9%) partial responses. Of the 33 patients with objective response, 25 (75.8%) had DOR for ≥6 months; median DOR was not reached. Median follow-up time for response was 8.4 (range, 1.9–28.3) months.ConclusionsRetifanlimab was well tolerated and demonstrated encouraging antitumor activity in patients with pretreated recurrent MSI-H or dMMR endometrial cancer, consistent with that achieved with other PD-1 therapies.AcknowledgementsThis study is sponsored by Incyte Corporation (Wilmington, DE).Trial RegistrationClinicaltrialsgov NCT03059823, EudraCT 2017-000865-63ReferenceBerton-Rigaud D, et al. J ImmunoTher Cancer 2020;8(Suppl 3):A164–A165 Abstract 268.Ethics ApprovalThis study was approved by institutional review boards or independent ethics committees in Belgium (Aan de Commissie Medische Ethiek University Hospitals Leuven CEC: S62335; Ethics Committee of Hospital-Faculty University of Liège LEC: 2019/48); Bulgaria (Ethics Committee for Clinical Trials, Sofia RA: IAL-24443/08.06.2017; CEC: КИ-80/08.06.2017); Finland (HUS Tutkimuseettiset toimikunnat Biomedicum Helsinki RA: KLnro 124/2019); France (CPP Île-de-France X Hôpital, Aulnay-sous-Bois cedex RA: MED MSA NAT-2019-08-00080; CEC: CN-RIPH 19.02.17.56415/CPP 27-2019); Germany (Ethik-Kommission der Albert-Ludwigs-Universität Freiburg, Freiburg RA: 3102/012; EC: 506/18; Ethics Committee at the Technical University of Dresden, Dresden RA: 3102/012; EC: EK 4854 AB; Ethics Committee of the State of Berlin, Berlin RA: 3102/012; EC: 17/0411 EK 12/15); Italy (Comitato Etico del Policlinico Gemelli Fondazione Policlinico Universitario ”Agostino Gemelli”, Roma (RM) no approval number issued by RA or EC; Comitato Etico IRCCS di Candiolo, Candiolo-TO no approval number issued by RA or EC); Latvia (Ethics Committee for Clinical Research at Development Society of Pauls Stradins Clinical University Hospital, Riga no approval number issued by RA or EC); Lithuania (Lithuanian Bioethics Committee, Vilnius no approval number issued by RA or EC); Poland (Komisja Bioetyczna przy Uniwersytecie Medycznym, Pozna RA: UR.DBL.474.0350.2017; CEC: 622/17); Spain (Comité de Ética de Investigación con Medicamentos, Madrid Centro Actividades Ambulatoria RA: 17-073 (Locator: 2VK42NE57D); CEC: 17/211); Ukraine (Ethical Committee at Prykarpatsky Regional Clinical Oncology Center of Ivano-Frankivsk Regional Rada, Ivano-Frankivsk no approval number issued by RA or EC); United States (IntegReview IRB, Austin, TX no approval number issued by IRB; The University of Texas MD Anderson Cancer Center Institutional Review Board, Houston, TX no approval number issued by IRB).
Background
The spread of the COVID‐19 pandemic has led to a rapid reorganization in all human and hospital activities, with impact on cancer patients.
Aim
An analysis of cancer patients fears, and ...awareness of COVID‐19 has been done in this study.
Methods and results
We analyzed cancer patients' reactions to the pandemic and their perception of oncological care reorganization, through a 12‐item survey, proposed at the peak of pandemic and 3 months later. Overall, 237 patients were included in the study. During the peak of pandemic 34.6% of patients were more worried about COVID‐19 than cancer versus 26.4% in the post‐acute phase (p = .013). Although 49.8% of patients in the acute phase and 42.3% in the post‐acute phase considered their risk of death if infected ≥50%, and more than 70% of patients thought to be at higher risk of complications, the majority of them did not consider the possibility to stop or delay their treatment. Patients were more interested in following news about COVID‐19 than cancer and they complied with all preventive measures in more than 90% of the cases.
Conclusions
Although cancer patients worried about COVID‐19 and evaluated the risk of complication or death due to COVID‐19 as extremely high, they were still asking for the best oncological treatment.
Introduction: Locally advanced cervical cancer (LACC) (International Federation of Gynecology and Obstetrics (FIGO) 2009/2018 - stages IB2-IVA/IB3-IVA, respectively) is treated using a multimodal ...approach that includes chemoradiotherapy followed by brachytherapy.
Areas covered: This review provides an overview of the progress made over the past decade in the treatment of LACC. Prognostic factors, FIGO classification and the role of imaging staging will be discussed. Efficacy of external-beam radiotherapy, brachytherapy and chemotherapy will be detailed. Indications for para-aortic staging lymphadenectomy and adjuvant hysterectomy, as well as follow-up and special population, will be covered.
Expert opinion: The initial workup is one of the most crucial steps in the optimal care of patients, which should be realized by a multidisciplinary expert team. With the implementation of modern conformal radiotherapy techniques, the local control rate has been optimized. Nevertheless, 40% of patients experience recurrence with distant metastasis and a dismal prognosis. Currently, a clear benefit of neo- and adjuvant chemotherapy has not been established. The future likely involves (1) improved selection of patients for whom treatment intensification is justified, (2) a combination of new drugs with chemoradiation that are currently being tested in trials, and (3) the development of tailored treatment based on molecular characteristics.
Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue ...factor-directed antibody–drug conjugate, in this patient population.
This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396.
102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1–13·0). The confirmed objective response rate was 24% (95% CI 16–33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 38% of 101 patients), epistaxis (30 30%), nausea (27 27%), conjunctivitis (26 26%), fatigue (26 26%), and dry eye (23 23%). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three 3% patients), fatigue (two 2%), ulcerative keratitis (two 2%), and peripheral neuropathies (two 2% each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two 2% patients) and pyrexia (two 2%). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes.
Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer.
Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.
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.
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.
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.
Retifanlimab was generally well tolerated and demonstrated encouraging anti-tumor activity in patients with pre-treated recurrent MSI-H/dMMR endometrial cancer.
•We evaluated safety and anti-tumor activity of retifanlimab in patients with recurrent MSI-H/dMMR endometrial cancer.•Retifanlimab was generally well tolerated and demonstrated a safety profile typical of the PD-(L)1 inhibitor class.•Objective response rate of 51% (95% CI, 39.6–63.0%) was observed with retifanlimab; median DOR was not reached.•Retifanlimab represents a potential new treatment option for patients with recurrent MSI-H/dMMR endometrial cancer.
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