Lisaftoclax With or Without Rituximab or Acalabrutinib Elicits Favorable Responses and Safety in CLL/SLL

Lisaftoclax (APG-2575) alone or in combination with acalabrutinib (Calquence) or rituximab (Rituxan) was active across a range of doses and displayed a tolerable safety profile in patients with relapsed/refractory and treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to findings from a phase 1/2 trial (NCT04215809) that were presented at the 2022 ASH Annual Meeting.

At a data cutoff of December 5, 2022, lisaftoclax demonstrated overall response rates (ORRs) of 67.4% (n = 29/43), 79.4% (n = 27/34), and 98% (n = 56/57) in patients with relapsed/refractory disease who received the agent alone or in combination with rituximab or acalabrutinib, respectively. In addition, treatment with lisaftoclax plus acalabrutinib resulted in a 100% ORR (n = 16/16) in patients with previously untreated CLL or SLL.

Lisaftoclax is a BCL-2 inhibitor that has shown rapid induction of mitochondrial apoptosis in CLL cells ex vivo and has also shown activity in patients with CLL and SLL with TP53 mutations and in those who have progressed on BTK inhibitors. Preclinical models have supported the activity of lisaftoclax plus rituximab or acalabrutinib.

“From an efficacy perspective, we saw very good initial signals. We didn't have data yet on rates of complete remission or minimal residual disease [MRD], so that will be important to [better] understand the depth of response of [lisaftoclax],” lead study author Matthew Davids, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, said in an interview with OncLive^®.

Eligible patients included those with confirmed CLL or SLL requiring treatment per 2018 International Workshop on CLL (iwCLL) criteria who had an ECOG performance score (PS) of 2 or less, adequate bone marrow function, and adequate renal and hepatic function. Patients were excluded if they had significant cardiovascular disease, had a QTc interval over 480 ms, or used warfarin or an equivalent vitamin K antagonist, although other anticoagulants were allowed. Patients who were relapsed or refractory to a BCL-2 inhibitor were permitted to enroll to the acalabrutinib plus lisaftoclax cohorts.

This study was conducted at 28 sites across the United States, Australia, and Europe and enrolled 164 patients with relapsed/refractory (n = 148) or treatment-naïve CLL or SLL (n = 16). Patients had a median age of 60.5 years (range, 41-80), 64 years (range, 34-75), and 64 years (range, 18-80) in the lisaftoclax monotherapy, rituximab, and acalabrutinib cohorts, respectively. Additionally, 85% (n = 39), 92% (n = 36), and 91% (n = 72) of patients in the monotherapy, rituximab, and acalabrutinib cohorts, respectively, had an ECOG PS of 0 to 1.

In the monotherapy, rituximab, and acalabrutinib cohorts, patients had a median of 2 (range, 1-14), 2 (range, 1-15), and 1 (range, 0-6) prior lines of therapy. In addition, 15% (n = 7), 18% (n = 7), and 23% (n = 18) of patients in the monotherapy, rituximab, and acalabrutinib cohorts, respectively, had 17p deletions and/or TP53 mutations. Tumor lysis syndrome (TLS) risk was medium in 35% (n = 16), 49% (n = 19), and 48% (n = 38) and high in 41% (n = 19), 33% (n = 13), and 30% (n = 24) of patients in the monotherapy, rituximab, and acalabrutinib cohorts, respectively.

Part 1 of this trial included a 3+3 dose escalation design with 46 patients who received lisaftoclax monotherapy at 400 mg (n = 18), 600 mg (n = 16), and 800 mg (n = 12). Part 2 included 3+3 dose-escalation cohorts of 18 patients total who received lisaftoclax in combination with rituximab (n = 9) or acalabrutinib (n = 9). Lisaftoclax was administered at 400 mg, 600 mg, and 800 mg to 3 patients each in each cohort. Patients received rituximab at 375 mg/m² intravenously (IV) on day 8 of cycle 1 and at 500 mg/m² on day 1 of cycles 2 through 6 or continuous oral acalabrutinib at 100 mg twice daily.

In the dose-expansion cohorts (n = 100), 30 patients received rituximab plus lisaftoclax at 400 mg (n = 10), 600 mg (n = 12), and 800 mg (n = 8), and 70 patients received acalabrutinib plus lisaftoclax at 400 mg (n = 13), 600 mg (n = 42), and 800 mg (n = 15).

The daily ramp-up scheme of lisaftoclax monotherapy for patients who had no TLS was 20 mg, 50 mg, 100 mg, 200 mg, and 400 mg on days 1, 2, 3, 4, and 5, respectively, followed by the target dose, which was continued thereafter. TLS labs were drawn at baseline, 6 to 8 hours, and 24 hours after each dose of lisaftoclax.

Patients in the combination cohorts began treatment with the same daily ramp-up of lisaftoclax and began the combination regimens 2 weeks after reaching the target dose of lisaftoclax.

"One of the objectives of this study was to see if it might be safe to ramp this drug up faster than traditional [treatment] with venetoclax [Venclexta], which is approved in this space," Davids said. "With venetoclax, it's a 5-week ramp-up that requires careful monitoring each week for a couple days in row, so it might be challenging for patients to do that. With [lisaftoclax], given its pharmacokinetic properties, we examined a daily dose ramp-up over 5 days instead of 5 weeks. This was done in an inpatient setting with careful monitoring."

In the monotherapy, rituximab, and acalabrutinib cohorts, 65% (n = 30), 13% (n = 5), and 14% (n = 11) of patients, respectively, discontinued therapy. Reasons for treatment discontinuation included disease progression in 39% (n = 18), 5% (n = 2), and 3% (n = 2) of patients and death from COVID-19 in 0%, 2% (n = 1), and 5% (n = 4) in the monotherapy, rituximab, and acalabrutinib cohorts, respectively. Additionally, 1 patient each in the rituximab and acalabrutinib cohorts was lost because of the war in Ukraine.

The primary end points of this trial were the determination of a recommended phase 2 dose and safety. The primary efficacy end point was ORR per 2018 iwCLL criteria with computed tomography scans. Secondary efficacy end points included complete response (CR)/CR with incomplete count recovery, partial response, duration of response (DOR), progression-free survival, overall survival, and MRD in peripheral blood and bone marrow by central flow cytometry. Other secondary end points included the pharmacokinetics of all study treatment regimens, and the association between the clinical efficacy of lisaftoclax monotherapy and lisaftoclax plus rituximab or acalabrutinib and CLL prognostic markers, including cytogenetics, TP53, and IGHV mutational status.

Additional results showed that the median treatment duration in the relapsed/refractory population were 16.5 months (range, 1-36), 11 months (range, 1-21), and 12 months (range, 1-24) in the monotherapy, rituximab, and acalabrutinib cohorts, respectively. In those with relapsed/refractory disease in the rituximab cohort, 83% (n = 5/6) and 100% (n = 5/5) with TP53 mutations and/or 17p deletions and complex karyotypes, respectively, responded to the study treatment. In the relapsed/refractory acalabrutinib cohort, 92% (n = 11/12), 94% (n = 15/16), 92% (n = 23/25), and 100% (n = 13/13) of patients with TP53 mutations and/or 17p deletions, complex karyotypes, unmutated IGHV, and mutated IGHV responded to the study treatment. Of the patients with relapsed/refractory disease who were resistant or intolerant to BTK inhibitors, 67% (n = 4/6), 0% (n = 0/4), and 88% (n = 7/8) in the monotherapy, rituximab, and acalabrutinib cohorts, respectively, responded to the study treatment.

In the treatment-naïve, acalabrutinib-treated population, the median treatment duration was 7 months (range, 5-11). Additionally, 100% of patients with TP53 mutations and/or 17p deletions (n = 4), complex karyotypes (n = 7), unmutated IGHV (n = 9), and mutated IGHV (n = 3) responded to treatment.

Data on CR and MRD rates are not yet available.

Decreases in both the sum of the product of the lymph node diameters and absolute lymphocyte counts occurred in many patients in the monotherapy, rituximab, and acalabrutinib cohorts across various dose levels.

Regarding safety, the most common grade 3/4 adverse effects (AEs) in the monotherapy cohort were neutropenia (30.3%), COVID-19 infection (28%), pneumonia (6.5%), febrile neutropenia (4%), multiorgan failure (2%), and clinical TLS (2%). The most common grade 3/4 AEs in the rituximab cohort were neutropenia (21%) and clinical TLS (2.7%). The most common grade 3/4 AEs in the acalabrutinib cohort were neutropenia (23%), COVID-19 infection (11.5%), atrial fibrillation (3.8%), and abscesses (3%).

Across cohorts, many patients had neutropenia, thrombocytopenia, and anemia at screening. However, as patients received the combination therapies, their cytopenia rates decreased, particularly from cycle 3 onward. A total of 13.5% of patients (n = 22) received granulocyte colony-stimulating factor for neutropenia.

In total, 18 patients required lisaftoclax dose interruptions, 9 from neutropenia in the monotherapy cohort and 9 in the acalabrutinib cohort. Neutropenia caused lisaftoclax dose reductions in 1 patient each in the monotherapy and rituximab cohorts. One patient in the acalabrutinib cohort discontinued treatment because of non-infectious AEs.

Patients in this trial received no debulking strategies, and 79% had a medium-to-high risk of TLS at baseline. Four patients met Howard criteria for TLS. Two of these patients had laboratory TLS, which was transient and manageable with IV fluids. Additionally, 2 patients had clinical TLS. Both cases of clinical TLS were fully resolved, and these patients continued to receive 600 mg of lisaftoclax without additional clinical sequelae.

"[Reported instances of TLS] do speak to the need for careful monitoring of these patients, but a daily ramp-up does seem to be feasible as long as these patients are carefully monitored and TLS is managed if it occurs," Davids said.

Planning for a registrational phase 3 trial with lisaftoclax plus acalabrutinib in relapsed/refractory CLL has begun.

“For patients, it's always good to have options. If [lisaftoclax] is a BCL-2 inhibitor that can be developed with a more convenient ramp-up that's done daily instead of weekly—even if it's an otherwise similar drug to venetoclax—there may be some advantages there in terms of convenience for patients. Certainly based on the data we've seen so far, it looks like an active and well-tolerated drug,” Davids concluded.

Reference

Davids MS, Chanan-Khan A, Mudenda B, et al. Lisaftoclax (APG-2575) safety and activity as monotherapy or combined with acalabrutinib or rituximab in patients (pts) with treatment-naïve, relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL): initial data from a phase 2 global study. Blood. 2022;140(suppl 1):2326-2328. doi:10.1182/blood-2022-160386