Ibrutinib Plus Palbociclib Has Efficacy in Mantle Cell Lymphoma

Published OnlineFirst February 8, 2019; DOI: 10.1158/2159-8290.CD-RW2019-016

RESEARCH WATCH

Clinical Trials

Major finding: The BTK inhibitor ibrutinib Clinical relevance: Responses to ibru- Impact: Ibrutinib plus palbociclib war- plus the CDK4 inhibitor palbociclib achieves tinib plus palbociclib were higher than rants further investigation for previ- responses in 67% of patients with MCL. in studies of single-agent ibrutinib. ously treated patients with MCL.

IBRUTINIB PLUS PALBOCICLIB HAS EFFICACY IN MANTLE CELL LYMPHOMA Inhibition of Bruton tyrosine kinase (BTK) by ibrutinib 2-year progression free survival (PFS) and overall survival represents a promising advance in therapy for mantle cell (OS) were 59.4% and 60.6%, respectively. Grade 3 rash was lymphoma (MCL) with an overall response rate (RR) of 68%. the dose limiting toxicity, and the most common serious However, most patients with MCL develop resistance within adverse events were neutropenia and thrombocytopenia. 10 to 14 months and have a poor survival rate after failure The results of this phase I trial suggested that the combina- of treatment. MCL exhibits abnormal cell cycle regulation tion of ibrutinib and palbociclib is feasible and active with due to cyclin D1 overexpression caused by chromosomal more complete responses and longer duration of response translocation. Preclinical studies have shown that treatment relative to single-agent ibrutinib. However, the overall RR of MCL cells with the CDK4 inhibitor, palbociclib, results in of this combination trial was similar to the RRs previously prolonged early G1 cell cycle arrest, and that combination reported for single-agent ibrutinib and other ibrutinib com- of ibrutinib and palbociclib showed synergistic killing of binations in previously treated MCL. Future trials will need ibrutinib-resistant MCL cells. Thus, Martin and colleagues to address how much improvement BTK-inhibitor-based evaluated the safety and effi cacy of ibrutinib plus palboci- combinations provide beyond single-agent ibrutinib and clib in in a phase I trial in 27 patients with previously treated which combinations are most appropriate for different MCL. The primary endpoint of the study was the identifi ca- patient populations. n tion of recommended phase II dose, and secondary end- points included determination of the toxicity and activity Martin P, Bartlett NL, Blum KA, Park S, Maddocks K, Ruan J, profi les. Of the 27 evaluated patients, 18 (67%) responded to et al. A phase I trial of ibrutinib plus palbociclib in previously treated treatment, and 10 (37%) had complete responses (CR). The mantle cell lymphoma. Blood 2019 Jan 28 [Epub ahead of print].

Gliomas

Major finding: ctDNA analysis of CSF Approach: ctDNA profiling was per- Impact: The ability to perform liquid recapitulates the genomic evolution formed on CSF samples from patients biopsy using CSF may enhance the of brain tumors. with low- and high-grade gliomas. diagnosis and treatment of gliomas. ctDNA PROFILING OF CEREBROSPINAL FLUID CHARACTERIZES GLIOMA EVOLUTION The detection of tumor-associated genomic in the tumor biopsies whereas no ctDNA was alterations in circulating tumor DNA (ctDNA) is found in plasma. This suggests that CSF-derived a highly sensitive and specifi c alternative to tradi- ctDNA exhibited alterations associated with early tional tissue biopsy for the diagnosis, longitudinal gliomagenesis, such as chromosome 1p/19q co- monitoring, and precision medicine–guided treat- deletion and mutations in IDH1/2 in low-grade ment of cancer. Given the diffi culty of perform- gliomas, and clonal mutations. Further, ctDNA ing ctDNA analysis on blood samples in patients from CSF samples obtained from lumbar punc- with brain tumors, Miller, Shah, Pentsova, and col- tures was highly concordant with ctDNA from leagues obtained post-treatment cerebrospinal ﬂ uid (CSF) via CSF obtained contemporaneously from ventricular shunts lumbar punctures from 85 patients with WHO grade IV glio- and gliomas resected within 3 weeks of lumbar puncture– blastoma, WHO grade III glioma, or WHO grade II glioma. derived CSF collection; moreover, CSF collected near the time The presence of ctDNA was detected by targeted sequencing of tumor resection more fully recapitulated glioma evolution in CSF from 42 of the 85 patients, which was agnostic of genomically. Taken together, these results characterize the WHO grade, disease duration, or prior therapy and was asso- high genomic concordance between CSF-derived ctDNA and ciated with radiographic tumor progression, tumor burden, glioma and may be helpful to monitor the evolution of the and intracranial tumor spread toward the ventricular system glioma genome during therapy. n and subarachnoid space. Targeted sequencing of matching tumor biopsies and plasma from 36 and 19, respectively, Miller AM, Shah RH, Pentsova EI, Pourmaleki M, Briggs S, of the 42 patients with ctDNA+ CSF showed that CSF- Distefano N, et al. Tracking tumor evolution in glioma through liquid derived ctDNA mirrored the genomic landscapes observed biopsies of cerebrospinal ﬂ uid. Nature 2019;565:654–8.

318 | CANCER DISCOVERY MARCH 2019 www.aacrjournals.org

Ibrutinib plus Palbociclib Has Efficacy in Mantle Cell Lymphoma

Cancer Discov 2019;9:318. Published OnlineFirst February 8, 2019.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2019-016

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