The latest data on the treatment of R/R CLL/SLL with Bcl-2 inhibitors by Ascent Pharmaceuticals: ORR reaches 80%

On June 7th, ASCO announced the oral report of the Bcl-2 inhibitor lisaftoclax (APG-2575) at the 57th American Society of Clinical Oncology (ASCO) annual meeting in the relapse/refractory (R/R) ) The latest data from the first human trials of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other hematological malignancies, and the application of MDM2-p53 inhibitor Alrizomadlin (APG-115) in combination with pembrolizumab The latest data of Phase II clinical studies in patients with unresectable/metastatic melanoma or advanced solid tumors who have failed immuno-oncology drug therapy
.

The latest clinical data of APG-2575 initially showed good effectiveness and safety
.

Its objective response rate (ORR) for the treatment of R/R CLL/SLL patients reached 80.

Dr.
Asher Chanan-Khan, professor of medicine at the Mayo Clinic in the United States and the global principal investigator of the clinical study, said: "APG-2575 is a potent and selective Bcl-2 inhibitor that can induce cellular Apoptosis and inhibit cell growth
.

In the first human studies in the United States and Australia, APG-2575 has initially shown good safety and potential anti-tumor activity for patients with R/R CLL/SLL, and has great potential for anti-tumor activity.

"APG-2575 initially showed an objective remission rate of 80% in patients with R/R CLL/SLL, and good safety.
Even if the daily dose is increased, no tumor lysis syndrome has been observed
.

Overview of the clinical research presented by ASCO at the 2021 ASCO annual meeting:

Two core points of clinical research presented orally at this ASCO annual meeting:

Abstract: 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)

The first human trial of a new Bcl-2 inhibitor APG-2575 in the treatment of patients with R/R CLL and other HMs

Abstract number: #7502

Abstract number: #7502

This first global phase I clinical study conducted in humans evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and maximum efficacy of APG-2575 in patients with R/R CLL and other HMs.
Tolerable dose (MTD)/Recommended dose for phase II study (RP2D)
.

APG-2575 is taken orally once a day for a cycle of 28 days

As of April 15, 2021, 36 patients were enrolled in the study and received APG-2575 20-1200mg treatment.
Their previous median number of treatment lines (range) was 2 (1-13), and they were diagnosed as R/R CLL /SLL (n=15), multiple myeloma (MM) (n=6), follicular lymphoma (FL) (n=5), Waldenstrom's macroglobulinemia (WM) (n=5), And acute myeloid leukemia (AML), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome (MDS) or hairy cell leukemia (HCL; n=1 respectively)
.

These patients received a median (range) 6 (1-24) cycles of APG-2575 treatment

APG-2575 is well tolerated and adverse events are controllable
.

No dose limiting toxicity (DLT) was observed at the highest dose of 1200 mg, MTD was not reached, and no clinical or laboratory TLS reports were reported

Among the 15 evaluable R/R CLL/SLL patients, 7 (46.
7%) were classified as stage III-IV of Rai disease, and 7 (46.
7%) were high-risk-very high-risk on the International Prognostic Index (IPI)
.

The median (range) treatment was 9 (5-24) cycles, 12 patients achieved partial remission (PR), ORR was 80.

The median (range) number of previous treatment lines of 21 R/R non-CLL/SLL patients was 3 (1-13), of which 20 patients could be evaluated
.

One MM patient with t(11;14) mutation achieved mild remission (MR) after 2 cycles of treatment

Preliminary PK results showed that the exposure of APG-2575 gradually increased from 20mg to 1200mg (average half-life: 4-5 hours)
.

On the BH3 expression profile, APG-2575 quickly triggers changes in the BCL-2 complex in CLL/SLL patient samples, which is consistent with the clinically rapid decrease in the absolute lymphocyte count (ALC)

Conclusion: The efficacy and safety data indicate that the Bcl-2 inhibitor APG-2575 provides a potential alternative treatment plan for R/R CLL/SLL patients and other HMs patients, and its daily dose escalation program is effective for patients More friendly
.

Abstract: Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanomaor advanced solid tumors that have failed immuno-oncologic (IO) drugs

Preliminary results of a phase II clinical study of APG-115 combined with pembrolizumab in patients with unresectable/metastatic melanoma or advanced solid tumors who have failed immuno-oncology drug therapy

Abstract number: #2506

Abstract number: #2506

This is an open, multi-center Phase II study conducted in the United States to evaluate the safety, tolerability, PK, PD and anti-tumor activity of APG-115 combined with pembrolizumab in patients with advanced solid tumors
.

As of April 15, 2021, a total of 102 patients have been included in the Phase II study
.
APG-115 is taken orally once every other day at a dose of 150 mg of RP2D and combined with pembrolizumab
.
There are 6 research cohorts in this study, namely: PD-1 / PD-L1 inhibitor-resistant melanoma, non-small cell lung cancer (NSCLC), urothelial carcinoma; malignant peripheral nerve tenoswanomas that have failed conventional treatment ( MPNST), liposarcoma and ATM mutant solid tumors
.

Observation of curative effect shows:

1) PD-1/PD-L1 inhibitor-resistant melanoma cohort (n=29): 1 out of 7 patients with uveal (ocular) melanoma was confirmed as PR; 2 out of 5 patients with mucosal melanoma There were 1 case of PR (1 case confirmed + 1 case not confirmed); 15 cases of skin melanoma patients had 1 case of CR (confirmed) and 3 cases of PR (2 cases confirmed + 1 case not confirmed)
.
The ORR of the melanoma cohort reached 24.
1% (7/29), and the disease control rate (DCR) was 55.
2% (16/29)
.

2) MPNST cohort (n=6): 1 case of PR (not confirmed)
.

3) Liposarcoma cohort (n=16): 1 case of PR (not confirmed) and 12 cases of SD, the DCR was 81.
2% (13/16)
.

4) In the PD-1/PD-L1 inhibitor-resistant NSCLC (n=15) and urothelial carcinoma (n=8) cohorts, 1 case of PR was confirmed respectively
.

Among the observed treatment-related adverse events (TRAEs) of any grade, those with an incidence greater than 10% were nausea, thrombocytopenia, vomiting, fatigue, decreased appetite, diarrhea, neutropenia, and anemia
.

Conclusion: APG-115 combined with pembrolizumab is well tolerated without superimposed toxicity
.
This preliminary research result provides a clinical basis for APG-115 combined with pembrolizumab to treat relapsed/refractory metastatic melanoma (including uveal, mucosal and skin melanoma) after tumor immunotherapy
.
At the same time, the combination therapy also has good anti-tumor activity in MPNST and liposarcoma patients with no approved indications for Pembrolizumab
.

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