Background
Kaposi sarcoma (KS), caused by KS herpesvirus (KSHV), is a multicentric angioproliferative tumor seen in people with and without HIV. Abemaciclib (Abema) is an oral cyclin-dependent kinase (CDK) inhibitor that targets CDK4 (cyclin D1) and CDK6 (cyclin D3) that is FDA-approved for breast cancer. In vitro studies of KSHV-infected cells have shown that CDK4/6 inhibitors enhance T-cell activation and host immune cell surface expression, hindering immune evasion. Here, we investigate the safety and activity of Abema in participants (pts) with KS.
Methods
This is a Phase 1/2 study of Abema in pts with KS. Phase 1 evaluated safety and tolerability of Abema using a 3+3 dose de-escalation design to identify a maximum tolerated dose (MTD). Pts were treated at dose level 1 of 200mg twice daily in 28-day cycles. Phase 2 assessed overall response rate of Abema of all pts and stratified by previously treated (Arm 1) or untreated KS (Arm 2). Eligibility criteria included adherence to antiretroviral therapy in people with HIV (PWH) for > 8 weeks prior to enrollment and no concomitant strong CYP3A4 inhibitors. Dose de-escalation was permitted for pts who experienced toxicities. KS response was evaluated using the modified AIDS Clinical Trials Group criteria.
Results
Twenty-five cisgender men (18 PWH), median age of 47 years are enrolled in this ongoing study. Twenty pts had stage T1 KS. In Phase 1, 6 pts were enrolled at 200mg BID with no dose-limiting toxicities. In Phase 2, 12 pts (10 PWH) were enrolled to Arm 1, and 7 pts (4 PWH) enrolled to Arm 2. The most common grade 1/2 adverse events were anemia and diarrhea. Twelve pts had dose reductions for grade 3/4 neutropenia. Among 23 evaluable pts receiving >2 cycles, 18 pts had a partial response (PR) (78% [95% confidence interval: 56-93%]), 4 pts had stable disease and 1 pt had progressive disease. All 7 pts in Arm 2 with previously untreated KS had a PR. The median HIV viral load among PWH was <20 copies/ml. Among PWH, the median CD4 T-cell count was 279 cells/µL (interquartile range: 176-435 cells/µl) without significant changes prior to cycle 3 (P=0.23) or at the end-of-treatment (P=0.39, Figure 1).
Conclusions
Abema is a novel therapeutic option in KS, with notable activity among pts with previously untreated KS. Adverse events were managed with dose reduction and supportive measures. Unlike chemotherapies for KS, there was no impact on CD4 T-cell counts among PWH.