BGB-3111 Plus Obinutuzumab Effective in CLL and Follicular Lymphoma

Constantine S. Tam, MBBS

Combining the novel BTK inhibitor BGB-3111 with the CD-20 antibody obinutuzumab (Gazyva) demonstrated clinical activity and was well tolerated in patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) or follicular lymphoma (FL).

The findings were presented at the 2017 International Conference on Malignant Lymphoma (ICML) biennial meeting in Lugano, Switzerland.

“Notably, the response rate in FL demonstrated in this study was higher than the expected rates achieved with either BTK inhibitors or anti-CD20 therapy alone,” said Constantine S. Tam MD, Director of Hematology at St. Vincent’s Hospital in East Melbourne, Australia.

Overall response rates (ORR) were defined as complete response (CR) plus partial response, plus partial response with lymphocytosis. Treatment-naïve patients with CLL/SLL demonstrated an ORR of 88.9%, patients with relapsed/recurrent (R/R) CLL/SLL had an ORR of 92.0%, and the ORR was 73.3% in patients with R/R FL. The median follow-up for the 3 cohorts was 7.0 months, 8 months, and 6.2 months, respectively.

CR was reported for 4 (22.2%) patients in the treatment-naïve cohort, 4 (16.0%) patients in the R/R CLL/SLL cohort, and 5 (33.3%) patients in the R/R FL cohort. PR was achieved by 66.7%, 76.0%, and 40.0% of patients, respectively, and stable disease was achieved by 11.1%, 4.0%, and 13.3% (n = 2) of patients, in the respective cohorts. No patients in the treatment-naïve CLL/SLL groups experienced disease progression, which occurred in 1 (4.0%) R/R CLL/SLL patient and 2 (13.3%) FL patients.

The 1-year progression-free survival rate was 91.7% in all patients with CLL/SLL and 80% in FL patients.

“Both the frequency and depth of response, including overall and complete response rates in FL, compare favorably to reported data with either BTK inhibitors or anti-CD20 antibodies alone,” said Tam.

Tam reported interim safety and efficacy results for the CLL/SLL and FL cohorts of an ongoing, open-label, multicenter, phase Ib study of the combination of BGB-3111 and obinutuzumab in patients with B-cell malignancies with indication-specific expansion cohorts.

As of December 15, 2016, 20 treatment-naïve patients, and 25 R/R patients with CLL/SLL and 17 patients with FL were enrolled; the patients’ median age was 68 years (range, 38-82) and 58 years (range, 41-86), respectively.

In this study, complete (100%) BTK occupancy was observed in peripheral blood monocytic cells and the median trough occupancy of BTK was 100% at 160 mg twice daily versus 94% at 320 mg of once daily BGB-311 (P = .002).

The combination treatment was well tolerated: No fatal adverse events (AEs) occurred and treatment was discontinued in only one patient due to an AE of squamous cell carcinoma progression in a patient who had prior squamous cell carcinoma.

The most common AE was petechiae/purpura/ contusion (bruising) in both groups. In the CLL/SLL cohort, 19 (42.2%) patients had at least 1 grade ≥3 AE and 11 (24.4 %) had at least one serious AE (SAE). In the FL cohort, 4 (23.5% ) patients had at least 1 grade ≥3 AE and (23.5 %) had at least 1 SAE.

One obinutuzumab-related SAE of infusion-related reaction and one SAE of pneumonia occurred that was related to BGB-3111.

No atrial fibrillation event occurred in in either patient cohort.

Late stage trials of combined BGB-3111 and obinutuzumab in follicular lymphoma are being planned, according to Tam.

Obinutuzumab is a second-generation anti-CD20 humanized monoclonal antibody and BGB-3111 as a potent and irreversible BTK inhibitor that was specifically designed to minimize off-target inhibition of other TEC- and EGFR-family kinases, with the aim of decreasing the side-effects seen with other BTK inhibitors, such as ibrutinib (Imbruvica). BGB-3111 has minimal inhibitory effects against ITK and does not inhibit ITK-mediated rituximab-induced antibody-dependent cell-mediated cytotoxicity.

Tam CS, Quach H, Nicol A, et al. Safety and activity of the highly specific btk inhibitor, BGB-3111 plus obinutuzumab in patients (PTS) with follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Presented at: 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. Abstract 103. doi:10.1002/hon.2437_102.