Ibrutinib: A Step Change in the Treatment of Mantle Cell Lymphoma

Becky McCall

June 21, 2013

STOCKHOLM — The latest data from 2 studies on the novel investigational agent ibrutinib, which is the first Bruton's tyrosine kinase inhibitor for lymphomas and leukemia, have generated excitement.

The clinical trial data on mantle cell lymphoma (MCL) were published online in the New England Journal of Medicine to coincide with their presentation here at the 18th Congress of the European Hematology Association (EHA).

"The results with ibrutinib are a further advance in the ever-changing management of hematological cancers, which is shifting from a chemotherapy-based approach to treatments aimed at the underlying biological mechanisms of disease occurrence and progression," write Robin Foà, MD, and Anna Guarini, PhD, both from the Department of Hematology at Sapienza University, Rome, Italy, in an accompanying editorial.

In the phase 2 trial of patients with relapsed or refractory mantle cell lymphoma, the 70% response rate to ibrutinib was both durable and tolerable.

Ibrutinib was recognized as a step change in the treatment of MCL when the US Food and Drug Administration (FDA) granted it breakthrough status earlier this year, said study author Simon Rule, MD, professor of hematology and consultant at Derriford Hospital, Plymouth, United Kingdom, who presented the data.

It will change the landscape for this disease. Dr. Simon Rule

"It will change the landscape for this disease," he predicted. "In the United States, it looks like a license will be received relatively rapidly."

Ibrutinib "is the most important breakthrough to date in the treatment of mantle cell lymphoma," said his colleague Michael Wang, MD, associate professor in the Departments of Lymphoma and Myeloma and Stem Cell Transplantation and Cellular Therapy at the University of Texas M.D. Anderson Cancer Center in Houston.

"It is an oral drug taken once a day and its side effects are not severe, yet it can achieve more than previous combination chemotherapy approaches. Our results constitute excellent news for our patients and patients around the world," Dr. Wang said in a statement.

ibrutinib has had an extremely rapid clinical development timeline, and was one of the first drugs ever granted FDA breakthrough status, explained Wyndham Wilson, MD, a lymphoma specialist from the National Cancer Institute, Bethesda, Maryland. The FDA considered ibrutinib "so promising that there was a need to get it into the public domain quickly," he told Medscape Medical News.

"Its activity in chronic lymphocytic leukemia and MCL is so good that there is a push to get this approved early," said Dr. Wilson, who presented the clinical trial data on chronic lymphocytic leukemia at the meeting.

Response Twice That Seen With Other Agents

According to the 15-month results of the MCL trial that Dr. Rule presented, 68% of heavily pretreated patients responded to ibrutinib. "This is twice the response level seen with any other drug used in this disease. Other drugs have a response rate of up to 40%, at most," Dr. Rule told Medscape Medical News.

"Ibrutinib is durable and tolerable, and its side effects are modest. None of my patients have side effects. It's almost too good to be true," he noted.

Importantly, the longer patients stayed on the drug, the better the response. "This is important for clinicians to know because, unlike conventional chemotherapy, with ibrutinib you need to stick with it because the patients feel better with time," he said.

At 2 months, overall response was 52.3%; at 15 months, it was 68.0%.

"When you assess the disease, it might not change much unless the patient stays on the drug," he noted. In the study, it took up to 9 months to see a response in some patients, Dr. Rule reported.

Study Design

In the study cohort of 111 patients with MCL, average age was 68 years, most were male, and 55% had been treated with at least 3 previous regimens (65 patients were bortezomib-naïve).

Most patients had been treated with doxorubicin, vincristine, and dexamethasone (Hyper-CVAD), 10% had undergone stem cell transplantation, and 25% had received lenalidomide. Some patients were refractory to every treatment attempted.

Patients took once-daily oral ibrutinib 560 mg until disease progression or unacceptable toxicity. Tumor response was assessed every two 28-day cycles with CT scans.

Estimated median duration of response was 17.5 months. "This is actually very long in this setting," Dr. Rule remarked. "If patients experienced a complete remission, then the median duration hasn't been reached yet."

Median progression-free survival for the overall population (including nonresponders) was 13.9 months. "This is very good because other drugs in this situation would do well to achieve 3 or 4 months," he noted.

"It is key to note that median overall survival for the whole group has not been reached yet, but we know that 58% have survived to 18 months," he reported.

Rates of complete response were 3.6% at 2 months, 9.0% at 4 months, 13.5% at 6 months, and 20.7% at 15 months. The rate of partial response at 15 months was 47.3%.

Minor adverse effects, such as diarrhea, were transient, Dr. Rule reported. Grade 3/4 toxicity was insignificant. Only 8 of 111 patients discontinued treatment because of adverse events.

The rate of hematologic toxicity, including neutropenia, was 7%, which is not unexpected in "a new hematologic drug in cancer. This means that this drug can be added to chemotherapy," so it might find a role in combination therapy, Dr. Rule noted.

Activity in Subtype of DLBCL

Dr. Wilson presented results from a multicenter phase 2 study of single-agent ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL).

AlthoughDLBCL can be cured in some people, there is a large unmet medical need in many patients, he explained.

He and his colleagues identified abnormalities in the B-cell receptor signaling pathway that are critical for the survival of many B-cell lymphomas, particularly the activated B-cell-like (ABC) subtype of DLBCL, which comprises 40% of all DLBCL and has the lowest cure rate with current therapy.

The researchers found that patients with the ABC subtype of DLBCL are the most sensitive to ibrutinib. In contrast, patients with germinal center (GCB) subtype DLBCL, which does not rely on the B-cell receptor signaling cascade, had very little response to the drug.

A clear difference was seen in activity between the 2 subtypes, Dr. Wilson explained. "Activity in the ABC subtype was 41%, but in the GCB subtype only 1 of 20 patients responded."

Effectively, by blocking the B-cell receptor signaling pathway in the ABC subtype, the tumor cells could be killed; this did not happen in the GCB subtype.

"The trial was in small numbers, but it worked out that the response rates we found more or less fit our hypothesis," said Dr. Wilson.

In the context of personalized medicine, ibrutinib would only be used in patients with the ABC subtype of DLBCL. "But theoretically, our findings take this down to an even finer level. We are interested in patients who might have no mutations; then we wouldn't use the drug at all," Dr. Wilson said.

These very exciting data help to demonstrate the future of clinical research in lymphoma, said Jonathan W. Friedberg, MD, MMSc, chief of hematology/oncology and director of hematologic malignancies clinical research at the University of Rochester in New York.

"We have known for years that diffuse large B-cell lymphoma is a heterogeneous disease. These data suggest that we can use information from gene-expression profiling and cell of origin to predict response to a rational targeted agent. If confirmed in future studies, this could lead to registration for this specific subtype of DLBCL," Dr. Friedberg said.

The trial was sponsored by Pharmacyclics, the company developing ibrutinib. Dr. Rule, Dr. Wilson, and Dr. Friedberg have disclosed no relevant financial relationships.

N Engl J Med. Published online June 19, 2013. Abstract, Editorial

18th Congress of the European Hematology Association (EHA): Abstracts S1178 and S1180. Presented June 16, 2013.

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