Ibrutinib Expert Ponders Prospects for Novel Combinations in CLL

Jennifer A. Woyach, MD

Assistant Professor, Internal Medicine

Division of Hematology

The Ohio State University James Comprehensive Cancer Center

Columbus, OH

The development of ibrutinib (Imbruvica) has progressed rapidly since the orally administered agent became the first Bruton tyrosine kinase (BTK) inhibitor to gain the FDA’s approval in November 2013. It is now approved in two indications in chronic lymphocytic leukemia (CLL) as well as in mantle cell lymphoma and Waldenström macroglobulinemia.

As monotherapy, ibrutinib has demonstrated response rates ranging from approximately 43% to nearly 66% in clinical trials in the malignancies in which it is indicated,¹ yet some researchers believe its greatest potential may lie in combination therapies. More than 30 clinical trials evaluating ibrutinib in combination with a range of therapeutic strategies are under way.

Notably, researchers reported at the 2015 ASCO Annual Meeting that adding ibrutinib to the standard bendamustine and rituximab (BR) regimen reduced the risk of disease progression by 80% compared with BR plus placebo in patients with relapsed/refractory CLL or small lymphocytic leukemia previously treated with at least one line of systemic therapy.² The results of the phase III HELIOS study have been hailed as practice-changing.

Another phase III study of ibrutinib is evaluating the novel agent as monotherapy and in combination with either BR or rituximab alone in previously untreated patients aged 65 years and older with CLL.³ The three-arm trial, which the National Cancer Institute launched in December 2013, aims to recruit 523 patients with intermediate- or high-risk disease and good performance scores.

Jennifer A. Woyach, MD, an assistant professor at The Ohio State University James Comprehensive Cancer Center, is the principal investigator for this study. In addition to studying the role of BTK in the development and progression of CLL, Woyach and colleagues are examining the role of BTK inhibition in CLL using murine and cellular models and mechanisms of resistance to BTK inhibitor therapy. In an interview with OncLive, Woyach discussed key issues in the practical application and ongoing research into this novel therapy.

Q: How has BTK-targeted therapy changed the treatment landscape?

BTK-targeted therapy has dramatically changed treatment for patients with relapsed CLL, shifting the paradigm from combination chemoimmunotherapy or single-agent antibody therapy to oral therapy. In addition, with the introduction of these agents we have moved from a fixed treatment duration to one of indefinite duration, at least at this time. More importantly, relapsed patients, including those with traditionally poor prognostic markers, are remaining in remission for long periods of time and for the most part are tolerating therapy well.

Q: What are the main limitations of ibrutinib monotherapy and how important is combination therapy likely to be?

Certainly for patients with high-risk features such as complex karyotype, combination therapy is appealing as a strategy to induce longer remissions. However, with a 30-month progression-free survival of 69%, it is hard to argue that all patients are in need of combination therapy. If we found that a combination could clear disease enough that patients were either cured or could interrupt therapy for long periods of time, this would make combinations more appealing for standard-risk patients.

Q: What are the most promising combinations tested to date?

Besides the results of the HELIOS trial presented at ASCO, promising results have been presented with ibrutinib in combination with rituximab or ofatumumab, but it is not clear that the results are better than single-agent therapy. I think that current trials investigating BTK inhibition in combination with PI3K inhibition, BCL2 inhibition, or antibodies such as obinutuzumab are more interesting, but results are not yet available from these combinations.

Q: How is combination therapy most likely to be used?

I think that combination therapy is most likely to be beneficial to prevent resistance in high-risk patients (ie, complex karyotype) or to induce deeper remissions that could allow for therapy discontinuation.

Q: What mechanisms of resistance to BTK targeted therapy have been uncovered?

We have shown that mutations in BTK at the binding site of ibrutinib, C481, are so far the most common mechanism of resistance. These mutations decrease the binding affinity of ibrutinib for BTK and change ibrutinib from an irreversible inhibitor to a reversible inhibitor. As well, we have found that mutations in PLCG2, the kinase immediately downstream of BTK, can induce resistance by allowing activation downstream of BTK even when BTK remains inhibited. There have been a few patients presented to have relapsed without these mutations, so other mechanisms are likely to be discovered. Mutations in BTK and PLCG2, especially BTK, are the most common at this time.

References

1. Imbruvica [prescribing information]. Sunnyvale, CA, and Horsham, PA: Pharmacyclics, Inc, and Janssen Biotech, Inc; 2015.
2. Chanan-Khan AAA, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): first results from a randomized, double-blind, placebo-controlled, phase III study. J Clin Oncol. 2015;33 (suppl; abstr LBA7005).
3. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01886872.