Olverembatinib Added to NCCN Guidelines for CML

The National Comprehensive Cancer Network (NCCN) has included the third-generation BCR-ABL1 TKI olverembatinib in their latest guidelines for the treatment of patients with chronic myeloid leukemia (CML).¹

Olverembatinib was approved in China in November 2021 for the treatment of adult patients with TKI-resistant chronic phase CML and T315I-mutated accelerated phase CML and again in November 2023 for the treatment of adult patients with chronic phase CML resistant to and/or intolerant of first- and second-generation TKIs^.1,2

"Inclusion in the prestigious NCCN guidelines marks another major milestone for olverembatinib,” Dajun Yang, PhD, chairman and CEO of Ascentage Pharma, the manufacturer of olverembatinib, said in a press release. “This event signals important recognition of our drug candidate by the oncology community. 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. 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."¹

In version 2.2024 of the NCCN Clinical Practice Guidelines in Oncology in CML, which were released on December 5, 2023, the NCCN reported findings from 2 Chinese clinical trials evaluating olverembatinib in patients with chronic phase CML and accelerated phase CML. The findings were included in a table titled “Results from Selected Published Clinical Trials Evaluating Novel Treatment Options,” which reported topline findings from clinical trials examining BCR-ABL inhibitors.³

In a pivotal, single-arm, phase 2 study (NCT03883087), patients with chronic phase CML who received olverembatinib and did not experience a major cytogenetic response (MCyR) at baseline (n = 121) achieved an MCyR rate of 79.3% and a complete cytogenetic response (CCyR) rate of 69.4% at a median follow-up of 3 months (range, 3-36) and 3 months (range, 337), respectively. Additionally, evaluable patients (n = 126) achieved a major molecular response (MMR) rate of 55.6%, a molecular response (MR)4.0 rate of 44.4%, and an MR4.5 rate of 38.9%. The 3-year overall survival and progression-free survival probabilities were 92.0% and 94.0%, respectively.⁴

In another phase 2 trial (NCT03883100), patients with accelerated phase CML who did not have a baseline MCyr (n = 38) achieved an MCyr rate of 47.4% and a CCyR rate of 47.4% at a median of 3 months (range, 1-9) and 4 months (range, 1-15), respectively. Moreover, among patients without a major hematologic response (MaHR) at baseline (n = 37), the MaHR rate was 78.4% at a median follow-up of 3 months (range, 1-7) and the complete hematologic response (CHR) rate was 73.0% at a median follow-up of 3 months (range, 1-14). The MMR, MR4.0, and MR4.5 rates were 44.7%, 36.8%, and 34.2%, respectively.⁴

In terms of safety, in a combined population from the phase 2 studies (n = 165) all patients experienced an any-grade treatment-related adverse effect (TRAE), of which 79.4% were grade 3 or 4 in severity. Common any-grade TRAEs included skin pigmentation (84.2%), thrombocytopenia (76.4%), hypertriglyceridemia (57.6%), anemia (54.5%), proteinuria (50.9%), and hyperbilirubinemia (41.8%). Common grade 3 or 4 TREAs included thrombocytopenia (51.5%), anemia (23%), and leukopenia (20.6%).⁴

During the 2023 ASH Annual Meeting, investigators presented updated findings from a Chinese phase 2 study (NCT04126681) of patients with chronic phase CML who are resistant and/or intolerant to first- and second-generation TKIs. The study randomly assigned patients 2:1 to receive olverembatinib (n = 96) or best available therapy (n = 48). The primary end point was event-free survival (EFS).⁵

At the April 30, 2023, data cutoff, the median EFS in the olverembatinib and best available therapy arm was 21.22 months (95% CI, 10.15-not reached) vs 2.86 months (95% CI, 2.53-4.73), respectively (HR, 0.352; 95% CI, 0.228-0.545; P < .001). The estimated 6-, 12-, and 24-month EFS rates were 73% (95% CI, 62.5%-81.0%), 58.7% (95% CI, 47.5%-68.2%), and 46.9% (95% CI, 35.9%-57.2%), in the investigational arm, compared with 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%), respectively, in the control arm.⁵

In the intent-to-treat population who received olverembatinib, 85% (n = 51/60) achieved a CHR, 47.7% (n = 42/88) achieved an MCyR, 36.4% (n = 32/88) experienced a CCyR, and 27.3% (n = 24/88) had an MMR. In the best available therapy arm, 34.8% (n = 8/23) experienced a complete response, 29.7% (n = 11/37) had a MCyR, 16.2% (n = 6/37) had a CCyR, and 8.1% (n = 3/37) had a MMR.⁵

"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,” Yifan Zhai, chief medical officer of Ascentage Pharma, MD, PhD, said in the press release. “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 [NCT06051409]."¹

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 19, 2024. https://www.prnewswire.com/news-releases/olverembatinib-included-in-newest-guidelines-on-chronic-myeloid-leukemia-cml-management-from-the-national-comprehensive-cancer-network-nccn-302036514.html
2. 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 19, 2024. https://www.biospace.com/article/releases/ascentage-pharma-hosts-ceremony-marking-the-launch-of-olverembatinib-in-newly-approved-indication-and-the-dispatch-of-first-batch-for-the-new-indication/#:~:text=In%20November%202021%2C%20olverembatinib%20was,AP)%20harboring%20the%20T315I%20mutation.
3. NCCN. Clinical Practice Guidelines in Oncology. Chronic myeloid leukemia, version 2.2024. Accessed January 19, 2024. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
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