On Sunday 10 December 2017 during an oral abstract session at the 59th Annual meeting American Society of Hematology (ASH), Jennifer Woyach of The Ohio State University Comprehensive Cancer Center in Columbus, Ohio, on behalf of her colleagues, presented results from the phase Ib/II ACE-CL-003 study. This early-stage clinical trial evaluated the activity and tolerability of acalabrutinib in combination with obinutuzumab in relapsed/refractory (R/R) and symptomatic, treatment-naïve (TN) patients with chronic lymphocytic leukemia (CLL).
This abstract (#432), “Acalabrutinib with Obinutuzumab in Relapsed/Refractory and Treatment-Naïve Patients with Chronic Lymphocytic Leukemia: The Phase 1b/2 ACE-CL-003 Study,” was presented during Oral Session: 642. “CLL: Therapy, excluding Transplantation: Targeting MRD Negative CLL Through Combinations of Novel Agents and Antibody”; this summary provides data presented during the session and may supersede data in the pre-published ASH abstract.
- High overall response rates in both R/R (92%) and symptomatic, TN (95%) patients
- Most patients remained on treatment at median follow-up of 24.7 months
- TN cohort-eligible patients were:
- previously untreated and ≥65 years of age, or
- <65 years of age and chemo-immunotherapy ineligible
- R/R cohort-eligible patients had ≥1 prior treatment
- Previous treatment with ibrutinib or another BTK inhibitor was permitted if the patient discontinued for a reason other than on-treatment disease progression
- Acalabrutinib administered 28-day cycles, orally at 100 mg BID or 200 mg QD, until progressive disease (PD)
- Obinutuzumab administered intravenously (IV), days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg) of cycle 2; day 1 (1000 mg) of cycles 3 to 7
- Primary endpoints: overall response rate (ORR), defined as partial response + complete response (CR), and safety
- Secondary endpoints: duration of response (DOR), time to response (TTR), progression-free survival (PFS) and pharmacodynamics (PD)
- ORR: TN, 95%; R/R, 92%
- CR: TN, 16%; R/R, 8%
- TTR: TN, 2.8 months; R/R, 2.8 months
- Median DOR was not reached in TN or R/R patients
- 18-month DOR rate was 86% (TN) and 94% (R/R)
- Median PFS (Figure) was not reached in either cohort
- Most patients remained on treatment at the time of cut off; TN (89%), R/R (92%)
- Study treatment discontinued, 2/19 TN patients; 1 metastatic squamous cell carcinoma which pre-existed trial therapy, 1 Richter transformation [RT] at 15.8 months in a patient with del(17p)
- Study treatment discontinued, 2/26 R/R patients; both due to RT at 18.4 and 24.0 months, respectively
- Most common AEs (≥40%), any grade: upper respiratory tract infection (69%), diarrhea (65%), nausea (62%), maculopapular rash (58%), increased weight (54%), cough, headache, and infusion-related reaction (50% each), contusion, vomiting, and constipation (42% each)
- Grade 3/4 AEs (≥5% of all patients): decreased neutrophil count (24%), decreased platelet count (9%), increased weight, and syncope (7% each)
The combination of acalabrutinib and obinutuzumab proved well-tolerated and yielded high response rates that deepened over time in both R/R and TN patients. What’s also encouraging was that most patients (41/45 [91%]), remained on treatment, with a median follow-up of 21 months.
This emerging combination of promising treatments will be interesting to watch, most certainly should it bear similar results in larger, randomized advanced-stage clinical trials. Of particular interest is ACE-CL-007, a phase III clinical trial investigating chlorambucil, acalabrutinib plus obinutuzumab, and acalabrutinib monotherapy in TN CLL patients (NCT02475681).