BTK Inhibitors Mushroom in Blood Cancer Field

Published: Thursday, Jan 19, 2017
Susan O'Brien, MD

Susan O'Brien, MD

It was little more than 3 years ago that ibrutinib (Imbruvica) became the first Bruton tyrosine kinase (BTK) inhibitor to gain the FDA’s approval with a second-line indication for patients with mantle cell lymphoma.

Today, ibrutinib is broadly approved in chronic lymphocytic leukemia (CLL) and Waldenström macroglobulinemia, and efforts continue to expand its uses in other hematologic malignancies.

Meanwhile, the drug development pipeline is stocked with several promising candidates that attack the same target.

Although a new generation is chasing ibrutinib, the original BTK inhibitor continues to demonstrate its paradigm-changing value in CLL and its potential to make an impact in other blood cancers. An application is pending with the FDA for an indication in marginal zone lymphoma.

The progress that has been made in targeting BTK was evident at the 2016 American Society of Hematology (ASH) Annual Meeting held in December, where the latest research into ibrutinib and several novel candidates was presented.

BTK is a downstream component of B-cell antigen receptor signaling; its inappropriate activation has been demonstrated to be involved in the maintenance of a wide variety of malignancies including CLL, acute lymphoblastic leukemia, chronic myeloid leukemia, and even in solid tumors such as colorectal carcinoma.

Ibrutinib

CLL Update

At 2016 ASH, findings from the longest follow- up to date evaluating up to 5 years of ibrutinib in patients with CLL and small lymphocytic lymphoma (SLL) show that the agent is safe and effective, with 89% of both treatment-naïve (TN) and relapsed patients experiencing a complete (CR) or partial response (PR) to the therapy (Abstract 233).

“These 5-year results suggest that both previously treated or untreated CLL/SLL patients may achieve robust and long-lasting responses with single-agent ibrutinib, with more patients developing a complete response over time,” said lead investigator Susan O’Brien, MD, associate director for clinical science at the Chao Family Comprehensive Cancer Center, University of California Irvine Health. “Our data suggest that starting treatment with ibrutinib as early as possible in CLL/SLL has promising clinical potential for long-term progression-free and overall survival.”

The data are from the phase Ib/ II PCYC-1102 trial, which evaluated single-agent ibrutinib in TN patients with CLL/SLL and relapsed/ refractory (R/R) patients. O’Brien reported long-term findings based on 132 patients with CLL/SLL: 31 were TN and 101 participants were R/R. Patients received either 420 mg or 840 mg once daily until disease progression or unacceptable toxicity.

Median duration of response had not been reached for TN patients and is 45 months for R/R patients. “Ninety-two percent of treatment-naïve patients are progression-free at 5 years,” O’Brien stated, adding that CR rates have increased over time to 29% for TN patients and to 10% in the R/R group. Median progression-free response (PFS) has not been reached in the TN group; for R/R patients, median PFS is 52 months.

A long-term extension study (PCYC-1103), collected data on grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation. “Ibrutinib is well-tolerated,” O’Brien said, “with onset of most new grade ≥3 AEs decreasing over time.”

GVHD Findings

In a separate study, ibrutinib demonstrated encouraging findings as a treatment for patients with chronic graft-versus-host-disease (cGVHD) that was not resolved by corticosteroids. Ibrutinib showed clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD (Abstract LBA3).



Of the 42 participants who experienced GVHD, 67% responded to ibrutinib, and 71% had sustained improvements over a 5-month period. According to the researchers, the results are encouraging for a subset of patients with limited treatment options beyond corticosteroids.

“Clinicians will find these data support the use of ibrutinib in patients with steroid-refractory chronic GHVD, who currently suffer a range of symptoms that can be chronic and debilitating,” said David Miklos, MD, PhD, associate professor of Blood and Marrow Transplantation at the Stanford University Medical Center.


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