Move Over Ibrutinib? New Agent Shows Strong Results for CLL

Nancy A. Melville

June 23, 2014

MILAN — Response rates were robust in patients with refractory or relapsed chronic lymphocytic leukemia (CLL) who were treated with ABT-199/GDC-0199, an investigational selective inhibitor of B-cell lymphoma-2 proteins, in a phase 1 study. In addition, the safety profile was strong.

"We have seen remarkable efficacy in a patient population with multiple relapses or refractory disease, high overall response rates, and impressive complete remission rates even in a high-risk subset of patients with CLL," said lead investigator John Seymour, MD, associate professor and chair of the Department of Hematology and Medical Oncology at the Peter MacCallum Cancer Centre in East Melbourne, Australia.

CLL cells are known to overexpress the B-cell lymphoma-2 protein, which, along with other proteins, ordinarily regulate apoptosis.

The oral drug ABT-199/GDC-0199, being jointly developed by AbbVie and Genentech, was designed to mimic the BH3-binding element that the cells all share, and thereby restore the physiologic regulatory process that normally causes the cancer cells to self-destruct.

"The drug is a selective, potent, orally bioavailable BCL-2 inhibitor that induces the rapid apoptosis of CLL cells," Dr. Seymour explained.

Previous analyses of the agent have shown antitumor activity, including complete remissions.

Dr. Seymour and his colleagues conducted the first in-human, phase 1, open-label, dose-escalation study of ABT-199 monotherapy in refractory or relapsed CLL patients.

The study results were presented here at the 19th Congress of the European Hematology Association (EHA).

As of April, 105 patients were enrolled in the study. Of the 78 evaluable patients, the overall response rate was 77%, with 23% showing a complete response. Similar efficacy was seen in high-risk patients with the chromosomal abnormality 17p deletion and those with fludarabine-refractory disease.

Importantly, patients had been treated with a median of 4 previous therapies.

"Response rates are very high," said Stephan Stilgenbauer, MD, associate professor in the Department of Hematology, Oncology, Rheumatology, and Infectious Diseases at the University of Ulm in Germany, who was not involved in the study.

"Despite heavy previous therapy, the response rate was still 70% to 80%, and that's independent of 17p status, which is a very remarkable observation," he explained.

ABT-199 is part of a new class of paradigm-changing drugs that could finally unseat chemotherapy as a first-line treatment, Dr. Stilgenbauer said in an interview presented by the EHA.

"With these very exciting new agents targeting CLL biology, we really are entering an era where chemotherapy as the mainstay of treatment can be overcome," he said.

Compared with ibrutinib, it leads to much more rapid cell destruction.

"The striking thing about ABT-199 is that, compared with [the CLL drug] ibrutinib, it leads to much more rapid cell destruction, even in high-risk CLL patients," he said in the EHA interview.

ABT-199 is also in phase 2 and 3 studies of CLL in combination with anti-CD20 monoclonal antibodies and standard chemotherapy, the investigators report.

Progression-Free Survival Data and More Comments

The investigators conducted a preliminary analysis of minimal residual disease in 11 of 18 patients who had a complete response. They found no detectable residual disease in 6 patients and low levels of residual disease in 4. Three patients were refractory to fludarabine, 1 had the 17p deletion, and 1 was refractory to fludarabine and had the 17p deletion.

An actuarial progression-free survival rate of 59% was seen in patients treated with ABT-199 400 mg for 24 months

Previous research has shown an association between the drug's rapid tumor destruction and risk for tumor lysis syndrome (TLS). Dr. Seymour's team reduced this risk by using a carefully monitored dose-escalation regimen, consisting of daily dose increases from 20 mg in week 1 (down from the previous initial dose of 50 mg) to 400 mg in week 5.

As of April, 37 study patients had discontinued the drug — 22 had progressive disease, 12 experienced adverse events, 2 proceeded to allogeneic hematopoietic cell transplantation, and 1 required warfarin.

The most common adverse events were nausea, diarrhea, fatigue, and anemia. In terms of grade 3/4 adverse events, 35 (33%) patients developed neutropenia that lasted a median 7 days, but the condition was ameliorated in approximately two-thirds of patients who received transient growth factor.

Febrile neutropenia developed in 7 (7%) patients and TLS developed in 7 (7%) patients prior to the dose-escalation regimen. There have been no cases of TLS since the initiation of the new regimen.

"The drug shows an excellent long-term safety profile, with few patients stopping the drug due to toxicities beyond the first weeks of dosing," Dr. Seymour reported.

"Based on the preliminary safety and efficacy profile of ABT-199, 400 mg is currently being explored as the safety expansion dose," he noted.

These are indeed unique, exciting data.

"These are indeed unique, exciting data, achieved with a single, relatively nontoxic agent in a large series of high-risk CLL patients," said Anton Hagenbeek, MD, from the Department of Hematology at the Academic Medical Center, University of Amsterdam, who was not involved in the research.

"The study looks very straightforward and I don't see any caveats here," Dr. Hagenbeek told Medscape Medical News. "The future lies in combining these drugs with other smart molecules or antibodies to further improve the results."

Dr. Seymour is a consultant for and has received research funding from AbbVie and Roche/Genentech. Dr. Stilgenbauer has been a consultant for Roche. Dr. Hagenbeek has disclosed no relevant financial relationships.

19th Congress of the European Hematology Association (EHA): Abstract S702. Presented June 14, 2014.


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