2021 ASCO Prospects | The first human study of the new BCL-2 inhibitor lisaftoclax in the treatment of R/R CLL and other hematological malignancies

Lisaftoclax (APG-2575) is a new type of selective BCL-2 inhibitor with anti-tumor activity against hematological malignancies.

Professor Sikander Ailawadhi and others in the United States conducted the world’s first phase I dose study to evaluate the safety and pharmacokinetics of lisaftoclax in the treatment of patients with relapsed and refractory chronic lymphocytic leukemia (R/R CLL) and other hematological malignancies (PK), pharmacodynamics (PD), efficacy and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D).

The study was selected as an oral report at the 2021 American Society of Clinical Oncology (ASCO) annual meeting.
Yimaitong organizes its main contents as follows for the reference of readers.

Study method: Patients take Lisaftoclax orally every day for a period of 28 days.

Patients with CLL or high-risk tumor lysis syndrome (TLS) increase the starting dose daily until the start of the study.

Results of the study until January 7, 2021, 35 patients received lisaftoclax (dose range 20-1200mg) treatment, the median number of previous treatment was 2 (range: 1-13), and the diagnosis was R/R CLL Or small lymphocytic lymphoma (SLL; n=15), multiple myeloma (MM; n=6), follicular lymphoma (FL; n=5), Waldenstrom's macroglobulinemia (WM; n= 4) and acute myeloid leukemia (AML), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome (MDS) or hairy cell leukemia (HCL) (each n=1 ).

Although 1200 mg is regarded as the highest dose for treatment, no dose limiting toxicity (DLT) was observed.

MTD has not been reached, and laboratory or clinical TLS has not been reported.

All grades of treatment-related adverse events (TRAE) with an incidence >10% include neutropenia (22.
9%), anemia (17.
1%), fatigue (28.
6%), diarrhea (17.
1%), and nausea (11.
4%) .

>Level 3 TRAE includes neutropenia (14.
3%) and thrombocytopenia, leukopenia, lymphopenia, fatigue and nausea (2.
9% each).

In CLL/SLL patients, grade 3-4 TRAEs including neutropenia (13.
3%) and thrombocytopenia (6.
7%) did not cause treatment-related discontinuation.

Among all 35 patients, 12 (34.
3%) had serious adverse events (SAE) not related to treatment, and only 2 patients had >1 SAE.

After a median of 7 (range: 3-20) cycles of treatment, of the 14 evaluable R/R CLL/SLL patients, 12 achieved partial remission (PR), and the overall remission rate (ORR) was 85.
7%.
The median time to remission was 3 (range: 2-7) cycles.

When the dose of Lisaftoclax is as low as 20 mg/day, the absolute lymphocyte count (ALC) decreases.

The preliminary PK profile indicated that as the dose of lisaftoclax increased, the exposure increased from 20 mg to 1200 mg (average half-life: 4-5 hours).

In the BH3 analysis, lisaftoclax quickly triggered changes in the BCL-2 complex in CLL/SLL patient samples, which was consistent with the rapid clinical decrease in peripheral blood ALC.

The study concluded that the tolerance of Lisaftoclax is as high as 1200 mg per day.

Even if the dose was increased daily, TLS was not observed.

There are no obvious, new or uncontrollable safety issues, and the ORR in R/R CLL/SLL patients is as high as 85.
7%.

Even at dose levels of 800 mg and above, grade 3-4 TRAE is not common.

The BCL-2 inhibitor lisaftoclax provides a treatment option for patients with R/R CLL/SLL and other hematological malignancies.

Reference: Sikander Ailawadhi, et al.
First-in-human study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor (BCL-2i), in patients (pts) with relapsed/refractory (R/R) CLL and other hematologic malignancies (HMs).
2021 ASCO Annual Meeting.
Abstract 7502.
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