BTK Inhibitors Mushroom in Blood Cancer Field

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.

Ibrutinib

CLL Update

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.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.

GVHD Findings

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.”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.

Emerging Combination

Preclinical laboratory studies suggested that ibrutinib might also inhibit immune cells involved in cGVHD. Supported by earlier findings, ibrutinib was granted a breakthrough therapy designation by the FDA for cGVHD after failure of 1 or more lines of systemic therapy.Combination induction therapy with ibrutinib and obinutuzumab (Gazyva) after bendamustine debulking induced a 100% response rate in patients with CLL, according to findings from the phase II CLL2-BIG trial (Abstract 640). The minimal residual disease negativity rate in the peripheral blood at final restaging was 47.5%.

“The BIG regimen showed very promising efficacy in a heterogeneous CLL population,” lead study author Julia von Tresckow, MD, of the Department of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University of Cologne, Germany, said when presenting the data at 2016 ASH.

The data reported at ASH were for 61 of 66 patients recruited to the trial; 5 patients were excluded because they completed fewer than 2 cycles of induction therapy (1 death, 2 due to AEs, and 2 patient self-withdrawals).

Acalabrutinib

Second-line CLL

The overall response rate (ORR) with bendamustine debulking was 65.9%, including an unconfirmed CR rate of 9.1% (n = 4), an unconfirmed CR rate with incomplete recovery of the bone marrow (CRi) of 6.8% (n = 3), and a partial remission (PR) rate of 50% (n = 22). The stable disease rate was 25% (n = 11) and the progressive disease rate was 4.5% (n = 2).The investigational next-generation BTK inhibitor acalabrutinib has shown promise as a treatment for patients with CLL. In previously reported findings, monotherapy with acalabrutinib at 100 mg twice daily resulted in an ORR of 95% for patients with relapsed/refractory CLL/SLL. In findings from the frontline CLL setting that were presented at the 2016 ASCO Annual Meeting, the ORR was 97% with acalabrutinib.

Acalabrutinib is currently being compared with ibrutinib in a phase III study for high-risk patients with relapsed CLL (NCT02477696). Additionally, the agent is being explored alone or in combination with obinutuzumab versus chlorambucil and obinutuzumab (NCT02475681).

In the ACE-CL-001 study, only one-third of patients who were ibrutinib-intolerant and subsequently treated with acalabrutinib had a recurrent adverse event, reported Farrukah T. Awan, MD, associate professor, division of hematology, department of internal medicine, Ohio State University (Abstract 638). In addition, acalabrutinib generated a 79% ORR in ibrutinib-intolerant patients.

The study included 33 patients with confirmed CLL and intolerance to ibrutinib. They were treated with acalabrutinib, 100 mg twice daily (n = 30) or 200 mg daily (n = 3), until disease progression or discontinuation.

“Acalabrutinib was fairly well tolerated. There were very few grade-3 or higher adverse events, and those were primarily hypertension, fevers, and myalgia,” said Awan. “The majority of the events were grade 1, and those were most commonly diarrhea and headache.”

Richter Transformation

Two grade 5 events that occurred while patients were on acalabrutinib, stroke and disseminated systemic fungal infection, were both deemed unrelated to study drug.Acalabrutinib produced an ORR of 38.1% as a monotherapy for patents with Richter transformation (RT), according to the phase I/II ACE-CL-001 study presented at the 2016 ASH (Abstract 60). In the ongoing trial, the median PFS with acalabrutinib was 2.1 months.

“Acalabrutinib induced complete response and partial responses in a heavily pretreated group of patients with Richter transformation, which is a poor-prognostic group of patients,” said lead investigator Peter Hillmen, MD, PhD, Department of Haematology, Churchill Hospital Cancer Centre, Oxford, United Kingdom. “Initial data of acalabrutinib monotherapy in Richter transformation suggest that further investigation in combination with chemoimmunotherapy or other targeted therapies is warranted.”

The phase I/II study enrolled 29 patients with RT, with primary histologies of diffuse large B-cell lymphoma (DLBCL) with underlying CLL (n = 25), CLL transformed to prolymphocytic leukemia (PLL; n = 3), and follicular lymphoma to DLBCL (n = 1). During the study, acalabrutinib was administered at 200 mg twice daily, which is double the standard dose used in other studies. This higher dose was used to counter the aggressiveness of RT, Hillmen explained.

BGB-3111

The CR rate was 9.5% and the PR rate was 28.6%. An additional 23.8% of patients had stable disease. In patients with CLL-related DLBCL, the ORR was 32%. Both CRs were in patients with DLBCL, 1 of which received a stem cell transplant. A second patient with a PR also received a stem cell transplant.A relative newcomer to the BTK inhibitor scene, BGB-3111 is under exploration in 3 phase I clinical trials focused on establishing its safety and efficacy for patients with B-cell lymphoid malignancies as a single agent and in combinations. The agent is being combined with obinutuzumab (NCT02569476) and BGB-A317, an early-stage PD-1 inhibitor (NCT02795182).

In phase I research presented at 2016 ASH, BGB-3111 demonstrated a 96% ORR among patients with CLL and SLL, consisting entirely of PRs (67%) and PRs with lymphocytosis (28%) (Abstract 642). In those with high-risk molecular characteristics (del17p and/or del11q; n = 17), the ORR was 100%. Additionally, treatment with the agent was well tolerated, despite higher selectivity of targets such as TEC thought to induce greater AEs.

In all, 66 patients with CLL/SLL received BGB-3111 at escalating doses starting at 40 mg daily to 160 mg twice daily. The analysis included 46 patients with at least 12 week of follow-up. The median duration of follow-up in the study was 8.6 months.

“No patients had progressive disease or Richter transformation to date. With limited follow-up, efficacy appears independent of molecular risk features,” said lead investigator Constantine S. Tam, MBBS, Peter MacCallum Cancer Centre, Melbourne, Australia. “Late-stage clinical trials will reveal whether BGB-3111’s excellent tolerability and high target occupancy will translate into improvements in disease control, rates of drug resistance, and rates of treatment-limiting adverse events.”

BGB-3111 has similar BTK selectivity as ibrutinib; however, the agent is more selective for EGFR, ITK, JAK3, HER2, and TEC. In plasma studies conducted on peripheral blood and lymph nodes, the optimal dose, based on BTK occupancy, was defined 160 mg twice daily (P = .002).

For complete abstracts, visit https://ash.confex.com/ash/2016/webprogram/start.html.