Ibrutinib, rituximab appear safe, effective for treatment-naive follicular lymphoma

Issue: January 25, 2016

ORLANDO, Fla. — Combined treatment with ibrutinib and rituximab demonstrated robust clinical activity and produced a high overall response rate in treatment-naive patients with follicular lymphoma, according to phase 2 study results presented at the ASH Annual Meeting and Exposition.

Perspective from John P. Leonard, MD

“While traditional cytotoxic regimes have improved outcomes, follicular lymphoma remains an incurable disease in most patients,” Nathan Fowler, MD, associate professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “Novel combinations targeting key cellular pathways and the immune microenvironment hold the potential to not only improve outcomes, but decrease the toxicity typically associated with treatment.”

Ibrutinib (Imbruvica; Janssen, Pharmacyclics) — an oral Bruton’s tyrosine kinase inhibitor — exhibited activity in a phase 1 trial of patients with follicular lymphoma. Thus, Fowler and colleagues conducted an open-label phase 2 trial to investigate the safety and efficacy of ibrutinib in combination with rituximab (Rituxan; Genentech, Biogen Idec) in 60 patients (median age, 58 years; range, 32-84) with treatment-naive follicular lymphoma. Eighty percent of patients had stage III or stage IV disease at baseline.

The researchers assigned patients to daily oral ibrutinib (560 mg) until progressive disease or unacceptable toxicity, along with four doses of weekly IV rituximab (375 mg/m²) for the first 4 weeks of the study.

ORR served as the primary endpoint. Secondary endpoints included duration of response, PFS, OS and safety.

The mean duration of ibrutinib treatment was 12.55 months. After a median follow-up of 13.8 months (range, 5.8-19.3), the researchers observed an ORR of 82% (95% CI, 70.1-89.4).

All treated patients had a complete response rate of 30% and a partial response rate of 52%, with a median time to best response of 2.7 months (range, 1.1-8.3).

Due to the small rates of progressive disease (n = 5) or death (n = 1), median PFS, OS and duration of response have not been reached, according to the researchers. However, Fowler reported a 12-month PFS rate of 86% (95% CI, 72.8-93.1) and OS rate of 98% (95% CI, 88.6-99.8).

Any-grade adverse events included fatigue (63%), diarrhea (50%), nausea (42%), constipation (28%), headache (27%), maculopapular rash (27%), myalgia (23%), vomiting (23%), cough (22%), infusion-related reaction (22%) and dry eye (20%).

Grade 3 or worse adverse events occurred in 48% of patients and included fatigue (5%), maculopapular rash (5%), neutropenia (3%), hypertension (3%) and arthritis (3%).

One patients died of Hodgkin’s lymphoma following study discontinuation.

Serious adverse events occurred in 17% of patients, with any-grade bleeding events occurring in 32% of patients.

One patient experienced grade 3 or worse atrial fibrillation.

The researchers observed secondary malignancies in four patients, including one case each of Hodgkin’s lymphoma, fallopian tube cancer, melanocytic nevus and basal cell carcinoma.

Sixty-five percent of patients remained on treatment at time of analysis, with 35% discontinuing treatment due to adverse events (15%), progressive disease (10%), patient choice (7%) or investigator decision (3%).

“Novel combinations targeting key cellular pathways and the immune microenvironment hold the potential to not only improve outcomes, but decrease the toxicity typically associated with treatment,” Fowler said. “Future studies comparing ibrutinib and rituximab to standard therapy are being planned.” – by Cameron Kelsall

Reference:

Fowler N, et al. Abstract 470. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

For more information:

Nathan Fowler, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: nfowler@mdanderson.org.

Disclosure: Fowler reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

John P. Leonard, MD

There is a lot of interest in ibrutinib (Imbruvica; Janssen, Pharmacyclics) for the treatment of lymphoma. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is approved for chronic lymphocytic leukemia and mantle cell lymphoma. There are a number of studies looking at it in a variety of venues in follicular lymphoma. This analysis included about 60 patients with untreated follicular lymphoma who received ibrutinib plus rituximab (Rituxan; Genentech, Biogen Idec). It is hard to interpret a single-arm study like this, but results showed a high response rate of about 80%. The regimen appeared well tolerated, with the occurrence of toxicities relating to what you would expect with ibrutinib and rituximab.
We have other combinations of biologic or non-chemotherapy agents being studied in the upfront setting that include lenalidomide (Revlimid, Celgene) or rituximab. There was another study presented at the ASH Annual Meeting that was led by Chaitra Ujjani, MD, of Georgetown and evaluated a triplet, rather than a doublet, of ibrutinib, lenalidomide and rituximab.
The questions really come down to: Do two drugs add to one drug? Do three drugs add to two drugs? How much toxicity are we seeing? What is the efficacy?
Because many of these are chronic treatment regimens for a period of time, the toxicity a patient goes through is particularly important.

These are interesting approaches that patients are interested in, but we really need comparative trials to sort out the contributions of various components. This is one interesting study to look at, and I look forward to seeing more data on this and longer follow-up.

Reference:

Ujjani C, et al. Abstract 471.

John P. Leonard, MD

Weill Cornell Medicine

NewYork-Presbyterian Hospital

Disclosures: Leonard reports no relevant financial disclosures.