Ibrutinib/Obinutuzumab Combo Elicits Durable Responses in Relapsed/Refractory CLL

Christine Ryan, MD

Findings from a phase 1b trial (NCT02537613) showed that the addition of obinutuzumab (Gazyva) to ibrutinib (Imbruvica) produced a complete response (CR) rate that compared favorably with what has historically been observed with ibrutinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).¹

At a median follow-up of 41.5 months (range, 2.3-73.3), the doublet elicited a CR rate of 40% per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria among 52 evaluable patients. Moreover, 56% of patients achieved a partial response rate with the combination, and 2% had stable disease. One patient (2%) experienced disease progression.

Notably, responses proved to be durable. The 4-year progression-free survival (PFS) rate with the doublet was 74%, and the 4-year overall survival (OS) rate was 93%. Data from the phase 3 RESONATE trial (NCT01722487) showed that the 5-year PFS rate achieved with ibrutinib alone was just 40%.

“Further exploration of this regimen is warranted in relapsed/refractory CLL, including in patients who progress on venetoclax [Venclexta],” lead study author, Christine Ryan, MD, a hematology/oncology fellow in the Department of Medical Oncology at Dana-Farber Cancer Institute, and colleagues, wrote in a poster of the data shared during the 2022 EHA Congress.

The early-phase trial enrolled patients with a confirmed diagnosis of CLL or small lymphocytic lymphoma (SLL) that is relapsed or refractory to at least 1 therapy who are indicated for treatment per iwCLL 2008 criteria.

To be eligible, patients needed to be at least 18 years of age, an absolute neutrophil count of at least 500 cells/mm³, and a platelet count of at least 25 cells/mm³. They also needed to have an ECOG performance status of 0 to 2, as well as acceptable renal and hepatic function.

Patients could not have previously received ibrutinib or obinutuzumab, have a known bleeding disorder, require warfarin, nor could they have known central nervous system involvement of CLL or SLL or Richter syndrome.

Those who previously received allogeneic hematopoietic stem cell transplant were not excluded from the trial if it was done longer than 6 months before trial entry.

Study participants was randomized 1:1:1 to 1 of 3 arms: those in arm A received obinutuzumab for 1 cycle followed by obinutuzumab plus ibrutinib for 6 cycles (n = 10), those in arm B received ibrutinib for 1 cycle followed by obinutuzumab plus ibrutinib for 6 cycles (n = 21), and those in arm C received obinutuzumab plus ibrutinib for 6 cycles (n = 21).

Ibrutinib was given at a daily dose of 420 mg until disease progression or intolerable toxicity. Obinutuzumab was administered at 100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and 15, and then 1000 mg monthly for 5 months.

Patients were stratified based on age (≥ 65 years vs < 65 years) and del(17p) status (yes vs no).

Each treatment arm accrued a total of 10 patients, and then a safety analysis was subsequently conducted. Arms in which less than 3 dose-limiting toxicities or other significant safety events occurred were then expanded with 11 more patients enrolled to each. Investigators also performed safety and minimal residual disease (MRD) assessments.

Among the 52 evaluable patients, the median age at the time enrollment was 67 years (range, 33-84), and 77% were male. In 53% of patients, IGHV was unmutated; 14% of patients had del(17p), 28% had del(11q), and 14% had complex karyotype. Moreover, 34% of patients had TP53-aberrant disease.

The median number of prior therapies received was 1 (range 1-5), and 3 patients had progressed on venetoclax. Twenty-seven percent of patients had bulky lymphadenopathy at study entry.

Additional data showed that the best lymph node reduction of a radiographic CR was achieved in 60%, 52%, and 57% of patients in arms A, B, and C, respectively.

Moreover, the best MRD status achieved in the peripheral blood, was negative in 29% of patients and positive in 48% of patients; data were not available for 23% of patients. In the bone marrow, the best MRD status achieved was negative in 19% and positive in 71%, with data not available in 10% of patients.

When comparing levels before treatment with 1 week after treatment, patients who achieved MRD negativity in the peripheral blood and bone marrow experienced a significantly larger reduction in circulating CXCL13 and CCL4 levels, respectively.

The most common hematologic adverse effects (AEs) experienced with the doublet were thrombocytopenia (88%), anemia (73%), neutropenia (71%), and febrile neutropenia (8%). Additional AEs of interest included fatigue (85%), bruising (58%), hypertension (46%), arthralgia (38%), diarrhea (37%), upper respiratory infection (29%), myalgia (27%), atrial fibrillation (21%), and bleeding (21%).

A notable serious AEs (SAEs) was grade 3 bacterial pneumonia, which was reported in 2 patients. Additionally, grade 3 fungal pneumonia, cryptococcal meningitis, and pneumatosis intestinalis was reported in 1 patient who recently finished frontline FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]), grade 3 acute coronary syndrome occurred in 1 patient who was on their first cycle of ibrutinib, sudden cardiac death occurred in a patient who was on ibrutinib for 11 months, and grade 3 hemorrhage was reported in 2 patients. Other notable SAEs included grade 4 hematoma in 1 patient, grade 4 myelodysplastic syndrome in 1 patient, and grade 3 tumor lysis syndrome in 1 patient who was enrolled to arm C.

Obinutuzumab infusion reactions occurred in 60% of patients in arm A (grade 1/2, n = 5; grade 3, n = 1), 5% of those in arm B (grade 1/2, n = 1), and 19% of those in arm C (grade 1/2, n = 4).

“The rate of obinutuzumab infusion reactions was higher with obinutuzumab starting prior to ibrutinib compared to starting ibrutinib prior to obinutuzumab or starting both drugs simultaneously, supporting the currently approved regimen,” the study authors concluded.

Reference

Ryan CE, Brander DM, Barr PM, et al. Updated results of a phase 1b study of ibrutinib plus obinutuzumab in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 2022 EHA Congress; June 9-12, 2022. Abstract P674.