As reported in The Lancet Oncology by Dean A. Fennell, FRCP, and colleagues, a phase II trial (MiST2) showed the activity of abemaciclib in previously treated patients with p16ink4A-deficient malignant mesothelioma.
As stated by the investigators, “Genetically stratified therapy for malignant mesothelioma is unavailable. Mesotheliomas frequently harbor 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 CDK4 and CDK6. Genetic restoration of p16ink4A suppresses mesothelioma in preclinical models, underpinning the rationale for targeting CDK4 and CDK6 in p16ink4A-negative mesothelioma.”
Dean A. Fennell, FRCP
In the study, 26 evaluable patients who had received at least one course of platinum-based chemotherapy were enrolled from two UK centers between September 2019 and March 2020. Treatment consisted of abemaciclib at 200 mg twice daily administered continuously in 28-day cycles for 24 weeks. The primary endpoint was the disease control rate (complete or partial response or stable disease) at 12 weeks. The null hypothesis was rejected if 11 patients or more had disease control.
Median follow-up was 18.4 weeks (interquartile range [IQR] = 6.7–23.9 weeks). Disease control was achieved at 12 weeks in 14 (54%, 95% confidence interval [CI] = 36%–71%) of 26 patients, with partial response in 3 (12%, 95% CI = 3%–27%) and stable disease in 11 (42%, 95% CI = 26%–60%). An additional patient exhibited partial response by week 24. In post hoc analysis, median progression-free survival was 128 days (95% CI = 105–252 days).
In post hoc analysis, loss of MTAP expression was identified in 11 (44%) of 25 evaluable patients. No patients with progressive disease as best response had MTAP loss. Median change in tumor volume after treatment was –18% (IQR= –17% to –26%) for MTAP-negative tumors vs 0% (IQR = –3% to 0%) for MTAP-positive tumors (P = .02).
The most common adverse events of any grade were fatigue (62%), diarrhea (50%), nausea (35%), anemia (31%), and decreased appetite (31%). Grade ≥ 3 adverse events occurred in 27% of patients; the most common was chest infection/suspected chest infection, observed in two patients (8%). Serious adverse events occurred 23%. A fatal adverse event (neutropenic sepsis) occurred in one patient (4%).
The investigators concluded, “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 randomized study as a targeted stratified therapy.”
Dr. Fennell, of Leicester Cancer Research Centre, University of Leicester, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by University of Leicester, Asthma UK and British Lung Foundation Partnership, and Victor Dahdaleh Foundation. For full disclosures of the study authors, visit thelancet.com.