NCCN Adds Olverembatinib in Newest Guidelines on CML Management

Red blood cells: © vipman4 - stock.adobe.com

The National Comprehensive Cancer Network (NCCN) has added olverembatinib (HQP1351),a third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), to their latest guidelines for the treatment of patients with chronic myeloid leukemia (CML).¹

Findings from 2 Chinese clinical trials of olverembatinib in patients with chronic phase CML and accelerated phase CML were published in version 2.2024 of the NCCN Clinical Practice Guidelines in Oncology in CML and support the NCCN decision. These data, which were released on December 5, 2023, included in a table titled “Results from Selected Published Clinical Trials Evaluating Novel Treatment Options,” and reported topline findings from the studies which examined BCR-ABL inhibitors.²

In the phase 1 and 2 trials (NCT03883087; NCT03883100), experts reported major cytogenetic response (MCyR) rates of 79% and 47%, complete cytogenetic response (CCyR) rates of 69% and 47%, and major molecular response (MMR) rates of 56% and 45%, among patients with chronic phase CML (CML-CP) and accelerated phase CML (CML-AP) who were treated with olverembatinib, respectively.¹

"Inclusion in the prestigious NCCN guidelines marks another major milestone for olverembatinib. This event signals important recognition of our drug candidate by the oncology community,” said Dajun Yang, PhD, chairman and chief executive officer of Ascentage Pharma, the manufacturer of olverembatinib, in a press release. “We are most encouraged that our cutting-edge, patient-centric innovation, which has culminated in a safe and effective treatment even in relapsed, refractory, and/or difficult-to-treat cases of CML, will bring meaningful improvement to patients’ lives.”

In November 2021, olverembatinib was granted an approval in China for the treatment of adult patients with TKI-resistant CML-CP and T315I-mutated CML-AP. The TKI was then approved for the treatment of adult patients with CML-CP resistant to and/or intolerant of first- and second-generation TKIs in November 2023.^1,3

The first study was a phase 2, pivotal, single-arm study which enrolled patients with CML-CP. Patients included in the study were treated with olverembatinib. Among those who did not experience a MCyR at baseline (n = 121), a MCyR rate of 79.3% and a CCyR rate of 69.4% at a median follow-up of 3 months (range, 3-36) and 3 months (range, 3-37) were seen.

Among the 126 evaluable patients, the MMR rate was 55.6%, the molecular response (MR)4.0 rate was 44.4%, and an MR4.5 rate was 38.9%. At 3 years, the overall survival and progression-free survival probabilities were 92.0% and 94.0%, respectively.⁴

The second trial was a phase 2 study which enrolled patients with CML-AP. At a median of 3 months (range, 1-9) and 4 months (range, 1-15), respectively, patients who did not have a baseline MCyr (n = 38) reached an MCyr rate of 47.4% and a CCyR rate of 47.4%. Among the 37 patients who did not have a major hematologic response (MaHR) at baseline, at a median follow-up of 3 months (range, 1-7), the MaHR rate was 78.4%. At a median follow-up of 3 months (range, 1-14), the complete hematologic response (CHR) rate was 73.0%. Further, rates of MMR, MR4.0, and MR4.5 were 44.7%, 36.8%, and 34.2%, respectively.

Among a combined population from the phase 2 studies which included 165 patients, all patients had an any-grade treatment-related adverse effect (TRAE). A total of 79.4% were grade 3/4 in severity. The most commonly reported any-grade TRAEs were skin pigmentation (84.2%), thrombocytopenia (76.4%), hypertriglyceridemia (57.6%), anemia (54.5%), proteinuria (50.9%), and hyperbilirubinemia (41.8%), and the most common grade 3/4 TRAEs were thrombocytopenia (51.5%), anemia (23%), and leukopenia (20.6%).⁴

“Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will continue to investigate olverembatinib and accelerate our clinical development programs to benefit more patients," added Yang in the press release.¹

Updated findings from a Chinese phase 2 study (NCT04126681) which evaluated patients with CML-CP resistance and/or intolerance to first- and second-generation TKIs were also recently reported at the 2023 American Society of Hematology (ASH) Annual Meeting.⁵ Patients were randomized in a 2:1 fashion with 96 receiving olverembatinib and 48 receiving best available therapy.

At the data cutoff date of April 30, 2023, the median event-free survival (EFS), the primary end point of the study, was 21.22 months (95% CI, 10.15-not reached) vs 2.86 months (95% CI, 2.53-4.73) in the olverembatinib vs best available therapy arms, respectively (HR, 0.352; 95% CI, 0.228-0.545; P <.001). At 6, 12, and 24 months, patients in the olverembatinib had EFS rates of 73% (95% CI, 62.5%-81.0%), 58.7% (95% CI, 47.5%-68.2%), and 46.9% (95% CI, 35.9%-57.2%), vs 32.6% (95% CI, 19.7%-46.2%), 26.1% (95% CI, 14.5%-39.3%), and 16.9% (95% CI, 7.7%-29.2%) in the control arm.

Among those enrolled in the intent-to-treat population who were treated with olverembatinib, 85% (n = 51/60) had a CHR, 47.7% (n = 42/88) had an MCyR, 36.4% (n = 32/88) had a CCyR, and 27.3% (n = 24/88) had an MMR compared with, 34.8% (n = 8/23) who experienced a complete response, 29.7% (n = 11/37) who had a MCyR, 16.2% (n = 6/37) who had a CCyR, and 8.1% (n = 3/37) who had a MMR in the best available therapy arm.

"This recognition of olverembatinib as a potential CML treatment by the NCCN largely validates the impressive results on this drug candidate reported to date, including selection for oral presentation at the 2023 ASH Annual Meeting for the sixth consecutive year,” said Yifan Zhai, chief medical officer of Ascentage Pharma, MD, PhD, in a press release.¹ “Moving forward, we will expedite our clinical development programs to bring more safe and effective therapies to patients in need. These initiatives include our ongoing pivotal registrational phase 3 trials of olverembatinib, including a study in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia."

REFERENCES:

1. Olverembatinib included in newest guidelines on chronic myeloid leukemia (CML) management from the National Comprehensive Cancer Network (NCCN). News release. Ascentage Pharma. January 16, 2024. Accessed January 25, 2024. http://tinyurl.com/bdhyjuut

2. NCCN. Clinical Practice Guidelines in Oncology. Chronic myeloid leukemia, version 2.2024. Accessed January 25, 2024. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

3. Ascentage Pharma hosts ceremony marking the launch of olverembatinib in newly approved indication and the dispatch of first batch for the new indication. News release. Ascentage Pharma. November 24, 2023. Accessed January 25, 2024. http://tinyurl.com/4ar6t5nc

4. Jiang Q, Li Z, Qin Y, et al. Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial. J Hematol Oncol. 2022;15(1):113. doi:10.1186/s13045-022-01334-z

5. Jiang Q, Li Z, Zhang G, et al. Olverembatinib (HQP1351) demonstrates efficacy vs. best available therapy (BAT) in patients (pts) with tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia chronic-phase (CML-CP) in a registrational randomized phase 2 study. Blood. 2023;142(suppl 1):869. doi:10.1182/blood-2023-187740