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Letters to the Editor
Table 2. Treatment-emergent adverse events. Events occurring in
All Grades n (%)
21 (75.0)
14 (50.0)
Grade 1 n (%)
7 (25.0)
2 (7.1)
Grade 2 n (%)
10 (35.7)
1 (3.6)
Grade 3 n (%
4 (14.3)
6 (21.4)
Grade 4 n (%)
0
5 (17.9)
≥20% of patients (N=28) Diarrhea
Thrombocytopenia
Fatigue 12 (42.9) 4 (14.3) 7 (25.0) 1 (3.6) 0 Neutropenia 11 (39.3) 0 2 (7.1) 2 (7.1) 7 (25.0)
Anemia 10 (35.7) 2 (7.1) 6 (21.4) 1 (3.6) 2 (7.1) Nausea 9 (32.1) 6 (21.4) 1 (3.6) 2 (7.1) 0
Vomiting 8 (28.6) 6 (21.4) 2 (7.1) 0 0 Creatinine increased 7 (25.0) 3 (10.7) 3 (10.7) 1 (3.6) 0
Pharmacokinetic (PK) evaluations included assessing plasma concentrations of abemaciclib and its metabolites by liquid chromatography–mass spectrometry (LC-MS) method. The median abemaciclib tmax after a single dose was 5.7 hours (range, 3.9-8.0 hours) (Figure 1B). The mean (coefficient of variation) steady-state abemaciclib trough concentration was 364 ng/mL (85%), indicating a high degree of interindividual variability in exposure. After single and multiple doses of abemaciclib, the mean accumulation ratio based on Cmax was 2.14 for abemaci- clib and 3.91 to 5.17 for its metabolites, LSN2839567, LSN3106726, and LSN3106729 (Online Supplementary Table S3).
In this single arm phase II trial, abemaciclib monother- apy demonstrated clinical activity and a manageable safe- ty profile in patients with R/R MCL. The ORR of 35.7% achieved with abemaciclib was similar to the 33% ORR with bortezomib,6 28% with lenalidomide,7 and 47% with temsirolimus,8 which are approved agents for MCL treatment. This study did not investigate the effect of abemaciclib in patients who previously received BTK inhibitors or lenalidomide as these compounds were not approved at the time of enrollment; the results post tem- sirolimus, however, suggest a potential influence of prior pathway specific treatment. Compared to this, ORR was higher with BTK inhibitors; 81% with alacabrutinib9 and 68% with ibrutinib.10 However, de novo or acquired resist- ance to BTK inhibition11 followed by uncontrolled growth of resistant MCL cells have led to poor prognosis. Therefore, the current challenge in the treatment of R/R MCL is to overcome the resistance to BTK inhibitors by choosing combination therapies targeting non-overlap- ping pathways.
Simultaneous inhibition of BTK and BCL2 with ibruti- nib and venetoclax in a phase II trial, improved patient outcomes at 16 weeks (CR: 42%) compared to historical controls at the same time point (9%).12 A CR of 37% was demonstrated in a phase I trial of R/R MCL patients who were treated with a combination of ibrutinib and palbo- ciclib.4 Prolonging cell cycle arrest using a CDK4 and CDK6 inhibitor was reported to have reverted ibrutinib resistance.13 These data are promising and indicate that abemaciclib may have a potential role in the treatment of R/R MCL. It is important to explore the CDK4 and CDK6 inhibitors in combination with BTK inhibitors with potential synergistic effects.
Previous PK assessments performed in Colo-205 xenograft tumors showed that continuous inhibition of CDK4 and CDK6 and the resulting cell-cycle arrest were associated with an abemaciclib plasma concentration of approximately 200 ng/mL.14 In this study, although the mean steady state trough abemaciclib plasma concentra-
tions in patients were higher than the levels associated with durable cell cycle arrest in preclinical models, the range of the observed concentrations was consistent with patients with solid tumors.14 Similar to abemaciclib, its major metabolites, LSN2839567 and LSN3106726, also inhibit CDK4 and CDK6 with similar potencies in in vitro biochemical and cell-based assays and the metabo- lite exposure achieved in patients with MCL at a dosage of 200 mg twice daily exceeds the 50% inhibition con- centration (IC50) for CDK4/cyclin D1 and CDK6/cyclin D1.15 Thus, the exposure of abemaciclib and its active metabolites is consistent with what is expected to yield biological activity. However, the optimal abemaciclib dose in MCL based on the relationship between expo- sure, efficacy, and safety requires further elucidation.
In conclusion, this study demonstrated that single- agent abemaciclib dosed on a continuous schedule has clinical activity in patients with R/R MCL who received multiple prior systemic therapies. The safety profile of abemaciclib in this patient group is generally consistent with other abemaciclib studies on advanced breast cancer except for higher thrombocytopenia. Additional clinical trials of abemaciclib in combination with current pre- ferred therapies such as a BTK inhibitors are needed to determine the synergistic effects and positioning of CDK4 and CDK6 inhibitors in MCL.
Franck Morschhauser,1 Kamal Bouabdallah,2
Stephan Stilgenbauer,3 Catherine Thieblemont,4
Sophie de Guibert,5 Florian Zettl,6 Lawrence M. Gelbert,7
P. Kellie Turner,8 Siva Rama Prasad Kambhampati,8° Li Li,8 Lily Q. Li,8 Sean Buchanan,8 Susana Barriga,8
Melissa M. Bear,8 Martin Wilhelm9 and Georg Hess10
1Universitè de Lille, CHU Lille, ULR 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associees, Lille, France; 2Hôpital Haut-Lévêque, Centre Hospitalier Régional
3
Universitaire de Bordeaux, Pessac, France; Internal Medicine III, Ulm
University, Ulm, Germany; 4APHP, Hôpital Saint-Louis, Hemato- Oncology Department, Paris & Diderot University, Paris, France ; 5Hôpital de Pontchaillou, Rennes, France; 6Universitätsmedizin Göttingen, Göttingen, Germany; 7LMG PharmaTech, LLC., Indianapolis, IN, USA; 8Eli Lilly and Company, Indianapolis, IN, USA; 9Klinikum Nürnberg Nord, Nürnberg, Germany and 10Universitätsmedizin Mainz, Mainz, Germany
°Current address: Arkos Pharma Inc., Princeton, NJ, USA
Correspondence:
FRANCK MORSCHHAUSER - franck.morschhauser@chru-lille.fr
doi:10.3324/haematol.2019.224535
Disclosures: FM reports personal fees from Celgene, Roche, Gilead, Epizyme, Janssen, BMS and Bayer outside the submitted work. KB has nothing to disclose. SS has received grants from AbbVie, Amgen,
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