Modest Benefit Found With Addition of Durvalumab to Ibrutinib in R/R FL and DLBCL

Alex Herrera, MD

The combination of ibrutinib (Imbruvica) and durvalumab (Imfinzi) demonstrated a modest clinical benefit for patients with relapsed or refractory follicular lymphoma (FL) and germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL), according to the results of a phase I/II trial. Although a slight benefit was also seen in a subgroup of patients with non-GCB DLBCL, the benefit failed to exceed the activity historically seen with single-agent ibrutinib, the investigators noted.

Alex Herrera, MD, discussed the takeaways from the trial during a presentation at the 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland.

A phase I/II study was conducted to evaluate the safety and efficacy of the combination of the Bruton tyrosine kinase inhibitor in combination with an anti—PD-L1 therapy in patients with relapsed/refractory lymphomas (NCT02401048). Patients with WHO grade 1-3a relapsed/refractory disease were eligible for the trial.

The phase Ib portion of the study utilized a 6+3 de-escalation design to determine the recommended phase II dosing for the ibrutinib/durvalumab combination. As no dose-limiting toxicities were observed, the highest dose was selected for the phase II portion of the trial.

Phase II focused on the objective response rate (ORR) with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Sixty-one patients were treated with 560 mg once daily ibrutinib plus 10 mg/kg ibrutinib on days 1 and 15 of each 28-day cycle for up to 12 cycles, including 27 in the FL group and 34 patients in the DLBCL group, split 1:1 between patients with GCB DLBCL and non-GCB DLBCL.

In the FL population, the median age was 57 (range, 31-79) and 66 (range, 22-82) in the DLBCL population. Across the study, more than 50% of patients were male in each subgroup and almost 40% had bulky disease. Twenty-six percent of patients with B symptoms were observed at baseline. These symptoms were noted more often in the FL group than in the DLBCL group (33% vs 21%).

Almost half of the patients (48%) were heavily pretreated with ≥3 prior treatment regimens and more than half (52%) were refractory to their most recent regimen, with 38% having relapsed after achieving a complete response. The median time from diagnosis to the first dose was 49.9 months in the FL population and 14.7 months in the DLBCL group, for a total median time of 26.1 months.

All patients had discontinued treatment by the time of data cutoff, mostly due to progressive disease, with a median duration of treatment of 3.8 months (range, 0.1-23.2). Sixty-six percent discontinued ibrutinib and 56% discontinued durvalumab due to progressive disease. Adverse events (AEs) led to discontinuation from ibrutinib in 5% and durvalumab in 6%.

The overall ORR was 25% (95% CI, 15%-37%). In the FL group, the ORR was 26% comprising a 4% complete response (CR) rate, and 52% of patients achieved stable disease (SD), “suggesting that the majority of patients did derive some clinical benefit from the combination,” commented Herrera, an assistant professor in the Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center in Duarte, California.

Among patients with GCB DLBCL, the ORR was 13% with a 6% CR rate and SD observed in an additional 19%. Patients with non-GCB DLBCL had an ORR of 38% from the combination with 31% achieving a CR.

“This is basically what you would expect with single-agent ibrutinib, which works particularly well in [patients with] non-GCB DLBCL as compared with [patients with] GCB DLBCL,” Herrera said. He also noted that not enough patients in the study had a high PD-L1 expression to analyze for an association with clinical response.

The overall median DOR was 11.3 months (95% CI, 5.5-nonestimable [NE]) and was the same in the FL group and not estimable in the DLBCL group. “But you can see that there’s a number of patients who had a [DOR] of about a year or more,” he added.

The median PFS was 4.6 months (95% CI, 2.6-7.8) for all patients. In the FL population, the median PFS was 10.2 months with a PFS rate of 39% at 1 year. In the DLBCL population, the median PFS was 2.6 months with a 1-year PFS rate of 18%. The PFS was longer in the patients with non-GCB DLBCL with a median PFS of 4.1 months and a 1-year PFS rate of 27%.

The median OS in the overall population was 18.1 months (95% CI, 7.8-NE). The median OS was not reached in the FL population, but the 1-year OS rate was 89%. In the DLBCL population, the median OS was 5.1 months with an OS rate of 33% at 1 year, and patients with non-GCB DLBCL had a median OS of 7.3 months and a 1-year OS rate of 40%.

“Similar to what we observed with progression-free survival, the overall survival was longer in patients with FL than patients with DLBCL,” he commented.

The most common treatment-emergent AEs (TEAEs) were diarrhea, fatigue, nausea, cough, and anorexia, most of which were grade 1/2, and Herrera noted that these were pretty common with ibrutinib treatment. Grade 3/4 events occurred more frequently in the DLBCL population, but no grade 5 TEAEs were observed in either population.

Common grade 3/4 TEAEs across the study included neutropenia (FL, 15%; DLBCL, 26%) dermatitis/rash (FL, 15%; DLBCL, 9%), dyspnea (FL, 7%; DLBCL, 12%), fatigue (FL, 4%; DLBCL, 12%), atrial fibrillation (FL, 4%; DLBCL, 9%), and peripheral edema (FL, 4%; DLBCL, 9%).

Immune-related TEAEs were observed in 19% of patients in the FL population and in 21% of the DLBCL population, which were grade 3/4 in 15% in the FL group and in 9% of the DLBCL group. The most common immune-related TEAEs were rash/dermatitis in 6 patients, pneumonitis in 3, and dyspnea in 2.

“Unfortunately a clinical benefit of the combination over single-agent ibrutinib really was not observed. Perhaps increasing understanding of tumor biology might identify an effective setting for this particular combination,” Herrera concluded.

Reference:

Herrera A, Goy A, Mehta A, et al. Activity and safety of ibrutinib and durvalumab in patients with relapsed or refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). Presented at: 2018 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 13-16, 2018; Dublin, Ireland. Abstract 7.