Abstract
The BTK inhibitor ibrutinib plus the CDK4 inhibitor palbociclib achieves responses in 67% of MCL patients.
Major finding: The BTK inhibitor ibrutinib plus the CDK4 inhibitor palbociclib achieves responses in 67% of MCL patients.
Clinical relevance: Responses to ibrutinib plus palbociclib were higher than in studies of single-agent ibrutinib.
Impact: Ibrutinib plus palbociclib warrants further investigation for previously treated patients with MCL.
Inhibition of Bruton tyrosine kinase (BTK) by ibrutinib represents a promising advance in therapy for mantle cell lymphoma (MCL) with an overall response rate (RR) of 68%. However, most patients with MCL develop resistance within 10 to 14 months and have a poor survival rate after failure of treatment. MCL exhibits abnormal cell cycle regulation due to cyclin D1 overexpression caused by chromosomal translocation. Preclinical studies have shown that treatment of MCL cells with the CDK4 inhibitor, palbociclib, results in prolonged early G1 cell cycle arrest, and that combination of ibrutinib and palbociclib showed synergistic killing of ibrutinib-resistant MCL cells. Thus, Martin and colleagues evaluated the safety and efficacy of ibrutinib plus palbociclib in in a phase I trial in 27 patients with previously treated MCL. The primary endpoint of the study was the identification of recommended phase II dose, and secondary endpoints included determination of the toxicity and activity profiles. Of the 27 evaluated patients, 18 (67%) responded to treatment, and 10 (37%) had complete responses (CR). The 2-year progression free survival (PFS) and overall survival (OS) were 59.4% and 60.6%, respectively. Grade 3 rash was the dose limiting toxicity, and the most common serious adverse events were neutropenia and thrombocytopenia. The results of this phase I trial suggested that the combination of ibrutinib and palbociclib is feasible and active with more complete responses and longer duration of response relative to single-agent ibrutinib. However, the overall RR of this combination trial was similar to the RRs previously reported for single-agent ibrutinib and other ibrutinib combinations in previously treated MCL. Future trials will need to address how much improvement BTK-inhibitor-based combinations provide beyond single-agent ibrutinib and which combinations are most appropriate for different patient populations.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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