Lisaftoclax Plus Pd Yields High ORRs and Shows Encouraging Safety Profile in RRMM

The addition of lisaftoclax (APG-2575) to pomalidomide (Pomalyst) and dexamethasone (Pd) resulted in high overall response rates (ORRs) and was safe in patients with relapsed/refractory multiple myeloma (RRMM), according to data from a phase 1/2 trial (NCT04942067) presented at the 2024 ASH Annual Meeting.1

Across all patients who received lisaftoclax/Pd at multiple dose levels (n = 36), the ORR was 63.9%. Investigators also observed a potential to accelerate hematologic response with lisaftoclax in patients with relapsed/refractory immunoglobulin light-chain (AL) amyloidosis.

“Lisaftoclax/Pd has demonstrated impressive safety profile, even at a relatively high dose that has not been achieved with other BCL-2 inhibitors previously, especially in this Pd combination, which has allowed this all-oral regimen to have a longer treatment duration,” Sikander Ailawadhi, MD, of Mayo Clinic in Jacksonville, Florida, said in his presentation of the data.

This open-label, multicenter trial is exploring lisaftoclax, a novel BCL-2 inhibitor, in 2 combinations due to its ability to inhibit cell proliferation and induce apoptosis in MM cell lines. Ailawadhi said that lisaftoclax has a more transient binding to BCL-2 than venetoclax (Venclexta), which could preserve non-target cells and have fewer off-target effects.

Upon enrollment, patients with RRMM were assigned to arm A (n = 41) with lisaftoclax plus Pd, or arm B (n = 7) with lisaftoclax plus daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (DRd). Patients with AL amyloidosis were assigned to arm C (n = 10) with lisaftoclax plus Pd.

All 3 groups, each with 3 to 6 patients per dose level, will eventually receive 4 dose levels of lisaftoclax for the dose escalation portion of the trial: 600 mg, 800 mg, 1000 mg, and 1200 mg. Once that is completed, the dose expansion phase will begin at the recommended dose.

At the current cut-off date of November 5, 2024, arm A has completed the dose escalation phase and moved on the dose expansion phase of the trial at 800 mg or 1000 mg with 12 patients per dose level. Arm B is currently at 600 mg of lisaftoclax plus DRd, and arm C is at 1000 mg of lisaftoclax plus Pd.

The primary end points are safety and tolerability, including dose-limiting toxicities, maximum tolerated dose, and recommended phase 2/3 dosing of lisaftoclax/Pd and lisaftoclax/DRd. Secondary end points were efficacy of lisaftoclax/Pd and lisaftoclax/DRd in RRMM, such as ORR, complete response (CR), progression-free survival (PFS), overall survival, DOR, and time to response; efficacy of lisaftoclax/Pd in AL amyloidosis, such as hematologic and organ responses; and the pharmacokinetic profile all 3 arms.

All patients in arm A received a prior proteasome inhibitor, 95.1% had received a prior immunomodulatory agent, and 85.4% had received a prior anti-CD38 antibody.

In these patients with RRMM receiving lisaftoclax/Pd, there was an ORR of 33.3% with 400 mg (n = 3), 75.0% with 600 mg (n = 4), 57.1% with 800 mg (n = 14), 88.9% with 1000 mg (n = 9), and 50.0% with 1200 mg (n = 6). For the total group, the rate of very good partial response (VGPR) or better was 30.6%, with 3 CRs and 8 VGPRs.

Patients with translocation 11;14 (t[11;14]) RRMM were allowed on the trial, and Ailawadhi said that “out of these evaluable 36 patients, only 4 had t(11;14), out of which 3 had a PR or better, and 1 had stable disease.” He also pointed out that they are continuing to enroll more patients with t(11;14) on the trial to assess if the response and toxicity profile will be different.

Additionally, the investigators looked at the response rates for the 32 patients with RRMM pretreated with an anti-CD38 monoclonal antibody and saw an ORR of 62.5%. The median PFS in this group was 9.7 months.

With a median follow-up of 9.2 months, the median PFS in arm A across the dose levels was not evaluable, 6.5 months, 7.4 months, 11.1 months, 7.0 months, and 9.7 months in the 400 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, and total groups, respectively.

In all 41 patients with RRMM assessed in the lisaftoclax/Pd group, the most common hematologic grade 3 or higher treatment-emergent adverse events (TEAEs) were neutropenia at 44%, white blood cell count decreased at 22%, and anemia at 17%. Common nonhematologic TEAEs of grade 3 or higher were pneumonia at 15% and dyspnea at 7%. Serious AEs included pneumonia at 10% and hypomagnesemia, dyspnea, and dizziness all at 2%.

The primary reason for treatment discontinuation was disease progression in 51.2% of patients, withdrawal in 17.1%, and unacceptable AEs in 4.8%.

Patients with AL amyloidosis receiving lisaftoclax plus Pd had an ORR of 0% with 400 mg (n = 1), 100% with 600 mg (n = 4), 100% with 800 mg (n = 2), 100% with 1000 mg (n = 2), with an 88.9% ORR in the total group (n = 9). The median time to response was 0.9 months overall.

Grade 3 or higher TEAEs in arm C included insomnia, anemia, neutropenia, and hypotension all at 10%, and the only serious AE was hypotension at 10%.

In response to a follow-up question at the presentation, Ailawadhi noted that “the No. 1 enticing factor for the patients has been an all-oral regimen,” and that enrollment for the trial has been robust since all-oral regimens are uncommon in this setting.

“Enrollment is ongoing currently to confirm this efficacy and safety in a larger number of patients, hopefully to further explore the optimal dose, which seems to be in this 800- to 1000-mg range,” Ailawadhi concluded.

Reference

Ailawadhi S, Chanan-Khan A, Khouri J, et al. Lisaftoclax (APG-2575) combined with novel therapeutic regimens in patients (pts) with relapsed or refractory multiple myeloma (R/R MM) or immunoglobulin light-chain (AL) amyloidosis. Blood. 2024;144(suppl 1):1022. doi:10.1182/blood-2024-202713