San Diego, California—Treatment-naïve patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL) tolerated and responded well to triplet therapy with ibrutinib plus rituximab and lenalidomide in a recent phase 2 clinical trial, the findings of which were presented at the 2018 ASH Annual Meeting.

“Given the relapsing nature of indolent non-Hodgkin lymphomas (iNHL), the prolonged natural history suggests many patients will undergo multiple lines of therapy over the course of their disease,” explained lead investigator Loretta J. Nastoupil, MD, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, and colleagues.

“Combination approaches with rational selection of synergistic mechanisms of action are desirable to improve outcomes and minimize overlapping toxicity,” they added.

With existing phase 2 and 3 study data demonstrating the efficacy and manageable toxicity of rituximab and lenalidomide in treatment-naïve patients with untreated iNHL, and literature supporting the ability of ibrutinib to build on the therapeutic activity of rituximab plus lenalidomide, Dr Nastoupil and colleagues hypothesized that combining all 3 drugs would enhance treatment efficacy.

Because previous data from a phase 1 trial suggested a potential risk for excess grade 3 rash with the triplet therapy, Dr Nastoupil and colleagues altered the first cycle dosage of lenalidomide that was used in the phase 1 study and conducted their own study to evaluate the safety and efficacy of the 3-drug combination in treatment-naïve patients with FL and MZL.

The primary end point of the study was progression-free survival (PFS) at 2 years, and secondary end points included complete response (CR), partial response (PR), overall response rate (ORR), duration of response, and overall survival (OS).

In the open-label, single-center study of 48 adults (median age, 60 years) with untreated stage II, III, or IV FL (n = 38) or MZL (n = 10), patients were given an initial 28-day cycle of lenalidomide 15 mg daily on days 1 through 21, ibrutinib 560 mg daily, and rituximab 375 mg/m24 times weekly. During cycles 2 through 12, the patients received lenalidomide 20 mg daily on days 1 through 21, ibrutinib 560 mg daily, and rituximab 375 mg/m2on the first day of each cycle.

Approximately 70% of patients had stage IV disease, whereas 6% and 25% had stage II and III diseases, respectively.

The estimated 2-year PFS rate at a median follow up of 19 months was 76% (95% confidence interval, 60-96%). The ORR among patients with FL and MZL was 97% (CR, 78%) and 80% (CR, 60%), respectively.

The most common adverse events of grade 3 or higher reported in these patients were rash (46%), neutropenia (15%), and diarrhea (13%); the most common grade 2 adverse events included fatigue (23%), diarrhea (15%), myalgias (17%), rash (10%), and edema (10%).

Therapy had to be discontinued in 7 (15%) patients because of treatment-related adverse events, including recurrent grade 3 rash, grade 2 and 3 pneumonitis, grade 3 pneumonia, and grade 4 ventricular arrhythmia. To date, no deaths have been reported in the study.

“Ibrutinib in combination with rituximab and lenalidomide for untreated FL and MZL was associated with promising efficacy…Modification of lenalidomide dose did not significantly impact the incidence of grade 3 or higher rash,” Dr Nastoupil and colleagues concluded.

“Biomarkers are underway to identify patients most likely to benefit from triplet therapy,” they added.—Hina Khaliq

Nastoupil LJ,  Lee HJ, Hagemeister FB, et al. Safety and Efficacy of Ibrutinib in Combination with Rituximab and Lenalidomide in Previously Untreated Subjects with Follicular and Marginal Zone Lymphoma: An Open Label, Phase II Study. Presented at: the 60th ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 447.