Targeted Drug Shows Promise in Common Form of Lymphoma
Preliminary results from two early-phase clinical trials suggest that the investigational drug ibrutinib may benefit some patients with an aggressive type of non-Hodgkin lymphoma (NHL). In the trials, some patients with diffuse large B-cell lymphoma (DLBCL) who did not respond to standard therapies, or who had stopped responding to these treatments, experienced complete or substantial tumor shrinkage after treatment with ibrutinib. The treatment was well tolerated, with only minor side effects.
Dr. Louis Staudt of NCI’s Center for Cancer Research (CCR), who co-led both trials, presented the findings April 1 at the 2012 American Association for Cancer Research annual meeting in Chicago. The impetus for the trials was a series of discoveries made by Dr. Staudt and his colleagues in CCR’s Metabolism Branch.
One of the trials, a phase I pilot study of 10 patients, enrolled only patients with activated B-cell-like (ABC) DLBCL. The ABC subtype is one of three molecular subtypes of DLBCL identified several years ago by Dr. Staudt’s lab. Patients with the ABC subtype, which accounts for about 40 percent of DLBCL diagnoses, have the poorest survival, they found.
Dr. Staudt’s lab also identified a signaling pathway—a communication network within cells—that is controlled by the B-cell receptor (BCR) and that, when overactive, enables tumor cells in the ABC subtype to survive and multiply. The receptor mutations Dr. Staudt’s lab identified in some patients with this subtype suggested the importance of this pathway in DLBCL. Finally, the researchers found that blocking a component of the BCR signaling pathway, called Bruton’s tyrosine kinase (BTK), causes ABC DLBCL cells to die.
“We had both functional evidence and genetic evidence that the BCR pathway was important in the ABC subtype,” Dr. Staudt said. “And that’s why we were excited about ibrutinib, because it’s a potent BTK inhibitor.”
Both trials were conducted in conjunction with California-based Pharmacyclics, which developed ibrutinib.
Two patients in the phase I trial had a complete response, one had a partial response, and a fourth patient who had not responded to any prior treatment had substantial tumor regression and a major improvement in his symptoms.
One patient with a complete response continues to take the oral therapy daily and has shown no signs of disease for 16 months, Dr. Staudt stated. And the patient whose disease stabilized had enough tumor shrinkage to qualify for an allogeneic bone marrow transplant and is now in complete remission.
Complete and partial responses also have been seen in the second trial. The phase II trial, which had enrolled 47 patients as of March 1, is not limited to patients with the ABC subtype, and patients with non-ABC subtypes have also responded to treatment with ibrutinib. (The researchers will share more complete findings from the trial at a later date.)
This preliminary finding likely means that tumor growth in some patients with non-ABC subtypes of DLBCL is driven at least in part by overactive BCR signaling, Dr. Staudt added.
“It’s hard to overstate the significance of seeing tumor shrinkage in patients who have never responded to any previous treatment,” known as primary refractory disease, said the trial’s principal investigator, Dr. Wyndham Wilson, also of CCR’s Metabolism Branch.
Primary refractory disease is the worst of the worst, so to see responses in these patients is really impressive.
—Dr. Wyndham Wilson
—Dr. Wyndham Wilson
Initial treatments for DLBCL produce remissions in approximately 95 percent of patients. “Primary refractory disease is the worst of the worst,” Dr. Wilson said. “So to see responses in these patients is really impressive.”
The limited side effects of ibrutinib, most often mild nausea and fatigue, are another important finding from the studies.
“We have yet to have a case where we’ve stopped treatment or reduced the dose due to toxicity,” Dr. Wilson continued. “And that’s saying a lot, because many of these patients are fairly sick.”
Future research should include the development of tests to determine which patients have BCR-dependent lymphoma prior to treatment and whether the receptor is being affected during treatment, said Dr. Jonathan Licht of Northwestern University during the meeting’s opening plenary session.
Drs. Staudt and Wilson are continuing their work with ibrutinib. “We’re already discussing strategies for the next trials,” Dr. Wilson said. These are likely to include testing the drug in combination with chemotherapy in patients whose cancer has returned after remission or who did not respond to initial treatment, as well as testing the drug as a first-line treatment.