Abemaciclib in patients with p16ink4A-deficient mesothelioma (MiST2): a single-arm, open-label, phase 2 trial
Mené au Royaume-Uni sur 27 patients atteints d'un mésothéliome présentant une déficience de p16ink4A (durée médiane de suivi : 18,4 mois), cet essai de phase II évalue l'efficacité, du point de vue du taux de contrôle, et la toxicité de l'abémaciclib, après l'échec d'au moins une ligne de chimiothérapie à base de sels de platine
Background : Genetically stratified therapy for malignant mesothelioma is unavailable. Mesotheliomasfrequently harbour loss of the chromosome 9p21.3 locus (CDKN2A–MTAP), which is associated with shorter overall survival due to loss of the tumour suppressor p16ink4A, an endogenous suppressor of cyclin-dependent kinase (CDK)4 and CDK6. Geneticrestoration of p16ink4A suppresses mesothelioma in preclinical models, underpinningthe rationale for targeting CDK4 and CDK6 in p16ink4A-negative mesothelioma. We developeda multicentre, stratified, phase 2 trial to test this hypothesis. Methods : The MiST2 study was a single-arm, open-label, phase 2 clinical trial done two UK centres. Patients older than 18 years with any histologically confirmed subtype of mesothelioma(pleural or peritoneal) with radiological progression after at least one course of platinum-based chemotherapy were molecularly screened by immunohistochemistry for p16ink4A. Patients with p16ink4A-negative mesothelioma were eligible for inclusionin the study. Patients were required to have measurable disease by modified ResponseEvaluation Criteria in Solid Tumours version 1.1 for malignant mesothelioma, a predictedlife expectancy of at least 12 weeks, and an Eastern Cooperative Oncology Group performancestatus score of 0–1. Patients received oral abemaciclib 200 mg twice daily, administeredin 28-day cycles for 24 weeks. The primary endpoint was the disease control rate (patientswith complete responses, partial responses, or stable disease) at 12 weeks. The nullhypothesis could be rejected if at least 11 patients had disease control. The efficacyand safety populations were defined as all patients who received at least one doseof the study drug. The study is registered with ClinicalTrials.gov, NCT03654833, and is ongoing (but MiST2 is now closed). Findings : Between Sept 31, 2019, and March 2, 2020, 27 eligible patients consented to molecularscreening. The median follow-up was 18·4 weeks (IQR 6·7–23·9). One patient was excludedbefore treatment because of a serious adverse event before study drug allocation.26 (100%) of 26 treated patients were p16ink4A deficient and received at least onedose of abemaciclib. Disease control at 12 weeks was reported in 14 (54%) of 26 patients(95% CI 36–71). Grade 3 or worse treatment-related adverse events (of any cause) occurredin eight (27%) of 26 patients (diarrhoea, dyspnoea, thrombocytopenia, vomiting, urinarytract infection, increased alanine aminotransferase, ascites, chest infection or suspectedchest infection, neutropenic sepsis, alopecia, blood clot left calf, fall [brokenneck and collar bone], haemoptysis, lower respiratory tract infection, and pulmonaryembolism). Grade 3 or worse treatment-related adverse events occurred in three (12%)of 26 patients (diarrhoea, thrombocytopenia, vomiting, increased alanine aminotransferase,and pulmonary embolism). Serious adverse events occurred in six (23%) of 26 patients,leading to treatment discontinuation in one (4%) patient (diarrhoea, urinary tractinfection, chest infection, neutropenic sepsis, fall [broken neck and collar bone],haemoptysis, lower respiratory tract infection, and pulmonary embolism). One patienthad a serious adverse event related to abemaciclib (diarrhoea). One (4%) of 26 patientsdied from an adverse event (neutropenic sepsis). Interpretation : This study met its primary endpoint, showing promising clinical activity of abemaciclib in patients with p16ink4A-negative mesothelioma who were previously treated with chemotherapy,and warrants its further investigation in a randomised study as a targeted stratifiedtherapy.
The Lancet Oncology 2022