Ascentage Pharma Group International announced that Prof. Xiaoyuan Gong of the Institute of Hematology and Blood Diseases Hospital, the Chinese Academy of Medical Sciences, has presented the preliminary results from a Phase II study of Ascentage Pharma's novel drug candidate, olverembatinib, combined with reduced-intensity chemotherapy in treatment-naïve patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), in an Oral Report at the 65thAmerican Society of Hematology (ASH) Annual Meeting, taking place in San Diego, CA, the United States. The ASH Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, multiple studies of Ascentage Pharma's key drug candidates (olverembatinib and lisaftoclax) have been selected for presentations at this year's ASH Annual Meeting, including two Oral Presentations on olverembatinib.

This is the sixth consecutive year in which the clinical results of olverembatinib have been selected for Oral Presentations at the ASH Annual Meeting. Following the introduction of tyrosine kinase inhibitors (TKIs), the combination of TKIs and intensive chemotherapy has become a widely adopted treatment for patients with Ph+ ALL because it can offer significantly improved prognosis. However, a large number of patients are ineligible for the treatment because of intolerance to intensive chemotherapy.

Clinical results featured in this Oral Presentation demonstrated encouraging clinical benefit and favorable tolerability of olverembatinib, a third-generation TKI, when combined with reduced-intensity chemotherapy in patients with Ph+ ALL, with data showing a complete remission/incomplete hematologic recovery (CR/CRi) rate of 100% in patients treated with the olverembatinib combination regimen; a complete molecular response (CMR) rate of 62.2% in patients who received three cycles of the treatment that was free of intensive chemotherapy or immunotherapy; and a favorable tolerability profile. Compared to the existing data on TKI plus intensive chemotherapy combinations, patients on this combination regimen have a lower need for transfusion and a reduced incidence of infections. Olverembatinib is a global best-in-class novel drug developed by Ascentage Pharma.

As the first and only approved third-generation BCR-ABL inhibitor in China, olverembatinib has been approved for the treatment of adult patients with TKI-resistant chronic-phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation and adult patients with CML-CP resistant and/or intolerant to first- and second-generation TKIs. Olverembatinib is being jointly commercialized in China by Ascentage Pharma and Innovent Biologics. Highlights: Background: The combination of olverembatinib (HQP1351), a novel third-generation TKI, with venetoclax generated high response rates in patients with relapsed/refractory (R/R) Ph+ ALL.

However, the efficacy and safety of these two agents-based regimens as frontline treatment remains unknown. Methods: This is a single-arm Phase II study (NCT05594784) that enrolled patients = 14 years (yrs) of age with newly diagnosed Ph+ ALL. In cycle 1, patients were treated with a combination of venetoclax (100 mg on day 1, 200 mg on day 2, 400 mg on day 3-28), olverembatinib (40 mg once every continuously other day [QOD], from day 1-28), vincristine (1.4 mg/m2 [maximum dose 2 mg] on day 1, 8, 15, 22), and prednisone (60 mg/m2 on day 1-14; 40 mg/m2 on day 15-28).

In cycle 2-3, oral treatment with venetoclax (400 mg × 7 days), olverembatinib once every other day continuously, and injectable prednisone (60 mg/m2 × 7 days) were administered. Cycles were repeated every 28 days. During cycle 1, the dose of olverembatinib for patients who reached CMR was reduced from 40 mg QOD to 30 mg QOD.

The primary endpoint of this study was the rate of CMR at 3 months. CMR was defined as undetectable BCR-ABL1 transcripts by using the RT-PCR method with a sensitivity of 0.001%. Major molecular response (MMR) was defined as more than 3-log reduction of BCR::ABL1 transcripts.

Patients: From August 2022 to July 2023, a total of 45 patients were enrolled. The median age was 42 years (range, 19-74) and males accounted for 48.9%. 31 patients (68.9%) expressed the p190 transcript, and 14 patients (31.1%) expressed the p210 transcript.

The median expression level of BCR::ABL1 was 90.3% (range, 25.9%-175.4%). Efficacy results: All patients have reached CR/CRi. At the end of cycle 1, 53.3% of patients achieved CMR and 28.9% MMR; at the end of cycle 2, 60.0% achieved CMR and 35.6% MMR; at the end of cycle 3, 62.2% achieved CMR and 31.1% MMR. As of October 30, 2023, 16 of the 45 patients received autologous hematopoietic stem cell transplantation (Auto-SCT, 1 death), 8 patients received allogeneic hematopoietic stem cell transplantation (Allo-SCT), 5 patients received olverembatinib combined with blinatumomab, and 16 received olverembatinib combined with chemotherapy.

88.9% (40) of patients achieved CMR during treatment. The median (range) duration of follow-up was 8 (3-14) months, and no patient relapsed during follow-up. Safety results: The combination regimen was well tolerated and safe.

Most adverse events were grade 1-2. The demand for transfusion and the incidence of infections significantly decreased compared to the existing data on intensive chemotherapy plus TKI combinations. No patient discontinued olverembatinib or venetoclax because of toxicity. Conclusions: The combination of olverembatinib and venetoclax with reduced-intensity chemotherapy is a safe and effective regimen in patients with newly diagnosed Ph+ ALL.

The regimen results in high rates of CMR in the absence of intensive chemotherapy or immunotherapy.