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LETTERS TO THE EDITOR
Clinical activity of abemaciclib in patients with relapsed or refractory mantle cell lymphoma – a phase II study
Mantle cell lymphoma (MCL) accounts for ~6% of all non-Hodgkin lymphomas (NHL) with an aggressive clin- ical course in patients, especially after early relapse.1 Lack of cure for relapsed/refractory (R/R) MCL with conven- tional therapy1 has resulted in a search for targeted ther- apies. CDK4 and CDK6 inhibitors have emerged as ther- apeutic options for R/R MCL because MCL cell lines and patient-derived samples that express high levels of cyclin D1 are highly sensitive to CDK4 and CDK6 inhibitors.2 Oral abemaciclib is a potent and selective CDK4 and CDK6 inhibitor that reduced tumor growth in human xenograft models with MCL.3 In a phase I study of patients with MCL, palbociclib, another CDK4 and CDK6 inhibitor, was shown to overcome resistance to ibrutinib, a first-in-class bruton tyrosine kinase (BTK) inhibitor.4 Here, we evaluated the efficacy, safety, and pharmacokinetic profile of abemaciclib in patients with R/R MCL in a phase II trial.
In this multi-center, open-label, single arm trial, patients ≥18 years of age with R/R MCL received 200 mg oral abemaciclib Q12H (every 12 hours) each day of a 28- day cycle (Online Supplementary Appendix). The study enrolled 28 patients in eight centers in France and Germany from March 2013 to September 2015 (Online Supplementary Figure S1). Most patients were male (60.7%) and white (96.4%) with a median age of 70 years (range, 53-83) (Online Supplementary Table S1). The medi- an number of prior therapies was three (range, 1-6) and the majority of the patients (67.8%) had received ≤3 prior lines of therapies. Seven patients had received prior stem cell transplant and median time to treatment from stem cell transplant was 46 months (range, 18-87 months). During the study, patients completed a median of six cycles (range, 1-32).
Fluorescence in-situ hybridization (FISH)/cytogenetics showed that all evaluable samples (n=5) from patients had the t(11;14)(q13;q32) translocation, which is a genet- ic hallmark of MCL and four (14.3%) among them over- expressed cyclin D1 (Figure 1A). In addition, cyclin D1 was overexpressed in 16 more patients (57.1%) as evi- denced by immunohistochemistry although the
t(11;14)(q13;q32) translocation could not be verified in these patients due to lack of evaluable samples.
Primary objective was disease control rate (DCR) based on the Response Criteria for NHL (including bone mar- row evaluation).5 Key secondary objectives included the objective response rate (ORR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Single-agent abemaciclib demonstrated a DCR of 71.4% (95% Confidence interval [CI]: 51.3-86.8). ORR was 35.7% (95% CI: 18.6, 55.9) including two complete response (CR) (7.1%) (CR, n=1; CR unconfirmed [CRu], n=1) and eight partial response (PR) (28.6%) (Table 1; Figure 1A). Median time to best response was 110.5 days. At the end of cycle 2, 22 patients were evaluated; one patient had CRu, four had PR, 15 had stable disease (SD) and two had progressive disease (PD). At a median fol- low-up time of 13.8 months, median DoR was 12.39 months (95% CI: 3.19, not reached [NR]), median PFS was 8.18 months (95% CI: 4.34-16.03) and median OS was 16.03 months (95% CI: 6.77, NR; Online Supplementary Figure S2). A correlation could not be made between efficacy, and gene translocation and cyclin D1 expression due to the small number of samples and lack of sufficient information on the biomarkers.
In the subgroup of patients who had received ≤3 prior therapies DCR was higher (84.2%; n=16; 95%CI: 60.4- 96.6) than those who received >3 prior therapies (44.4%; n=4; 95% CI: 13.7-78.8). A similar trend was observed for ORR (47.4%; 95% CI: 24.5-71.1 vs. 11.1%; 95% CI: 0.3-48.3), DoR (12.39 months vs. 6.67 months), PFS (12.85 months vs. 5.09 months) and OS (NR vs. 8.18 months; Online Supplementary Table S2). Thus, abemaci- clib was more clinically active in patients who had received ≤3 prior therapies than those who received high- er numbers of prior therapies. In patients who received temsirolimus, an mTOR inhibitor, as prior therapy (n=14), ORR was 14.3% (95% CI: 1.8-42.8) vs. 57.1% (95% CI: 28.9-82.3) in those who did not receive tem- sirolimus.
Dose reductions and dose omissions were reported for 78.6% and 75% of the patients, respectively. The median relative dose intensity was 71.5%. The median time to dose reduction was 28 days (range, 15–117) for those who had received ≤3 prior therapies and 15 days (range, 15–43) for patients who had received >3 prior therapies.
Safety was assessed per Common Terminology Criteria
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Table 1. Summary of overall best response. Best overall response
Disease control rate (CR+CRu+PR+SD)
Overall response rate (CR+CRu+PR) Complete response (CR)
Complete response unconfirmed (CRu) Partial response (PR)
Stable disease (SD)
Progressive disease, n (%) (95% CI) Not assessed,a n (%)
Time to events
Median progression-free survival, months (95% CI)
Median overall survival, months (95% CI)
Abemaciclib (N=28), n (%) (95% CI)
20 (71.4) (51.3, 86.8)
10 (35.7) (18.6, 55.9)
1 (3.6) (0.1, 18.3)
1 (3.6) (0.1, 18.3)
8 (28.6) (13.2, 48.7)
10 (35.7) (18.6, 55.9)
2.0 (11.8) (0.9, 23.5)
6.0 (21.4)
Abemaciclib (N=28), n (%) (95% CI)
8.2 (4.34, 16.03)b
16.0 (6.77, NR)c
aPatients without post-baseline tumor assessment values at the time of data base lock. bNumber of PFS events were 19. cNumber of OS events were 17. CI: confidence interval.