Olverembatinib Delivers Durable Responses in T315I-Mutant, TKI-Resistant CML, Ph+ ALL

Olverembatinib (HQP1351) demonstrated sustained efficacy and reduced toxicity with longer follow-up in patients with TKI-resistant, T315I-mutant chronic myeloid leukemia in chronic phase (CML-CP) and accelerated phase (CML-AP), according to updated findings from 2 pivotal phase 2 trials (NCT03883087 and NCT03883100) that were presented at the 2022 ASH Annual Meeting.¹

In the CML-CP cohort, the 3-year rates of major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR) were 80% (95% CI, 64%-90%), 71% (95% CI, 54%-83%), and 59% (95% CI, 42%-72%), respectively. The rate of both MR4.0 and MR4.5 was 51% (95% CI, 35%-66%). The 3-year progression-free survival (PFS) and overall survival (OS) rates were 92% (95% CI, 77%-97%) and 95% (95% CI, 82%-99%), respectively.

In the CML-AP cohort, the 3-year rates of MCyR, CCyR, and MMR were 52% (95% CI, 30%-71%), 52% (95% CI, 29%-71%), and 48% (95% CI, 25%-68%), respectively. The rate of both MR4.0 and MR4.5 was 35% (95% CI, 16%-55%). The 3-year PFS and OS rates were 62% (95% CI, 38%-79%) and 70% (95% CI, 47%-84%), respectively.

Olverembatinib is a novel, potent, oral third-generation TKI with activity against BCR:ABL1 mediated resistance, including T315I and other mutations.

The drug was evaluated in 2 single-arm, open-label, multicenter, registrational phase 2 studies. The drug was administered once daily at 40 mg in 28-day cycles.

To be eligible for enrollment, patients had to be at least 18 years of age and have TKI-resistant CML-CP or CML-AP in addition to T315I mutations, an ECOG performance status of 2 or less, and adequate organ function.

Notably, patients who had received prior treatment with ponatinib (Iclusig), olverembatinib, or treatments with similar composition were excluded from enrollment.

Baseline characteristics illustrated a median patient age of 47 years (range, 22-70) in the CML-CP cohort and 41 years (range, 21-74) in the CML-AP cohort. The median interval from diagnosis to starting treatment with olverembatinib was 5.3 years (range, 0.6-23.2) and 5.0 years (range, 0.4-10.2), respectively. Most patients had received either 2 or 3 or more prior TKIs in the CML-CP (61% and 17%) and CML-AP (61% and 22%) cohorts, respectively.

At the cutoff date of September 30, 2022, the median treatment duration was 38 months (range, 3-41) in the CML-CP cohort and 20 months (range, 1-41) in the CML-AP cohort, and 66% (n = 27) and 44% (n = 10) of patients were continuing treatment, respectively.

Multivariate analysis of response illustrated that prior exposure to TKIs and treatment interruption within 3 months were associated with lower CCyR (HR, 0.5, P = .015; HR, 0.4, P = .002), MMR (HR, 0.4, P = .001; HR, 0.3, P = .001), and MR4.5 (HR, 0.6, P = .122; HR, 0.4, P = .024), respectively. The primary reason for treatment interruption was due to grade 3/4 thrombocytopenia (69%).

However, regarding safety, the incidence of grade 3/4 hematologic adverse effects (AEs) including thrombocytopenia, anemia, neutropenia, and leukopenia decreased from years 1 (n = 64) and 2 (n = 61) to years 3 (n = 56) and 4 (n = 39).

In multivariate analysis of the incidence of grade 3/4 thrombocytopenia, the hazard ratio for the interval from diagnosis to starting treatment was 1.2 (95% CI, 1.0-1.4; P = .015).

“The responses and safety profile of these studies are consistent with the T315I mutation subgroup in the phase 1 study,” the authors wrote in the presentation.

In a parallel phase 1 study (HQP1351-SJ0002) of patients with TKI-resistant CML-CP treated with at least 30 mg of olverembatinib in China, 5-year findings showed that the 4-year rates of MCyR, CCyR, and MMR were 80% (95% CI, 69%-87%), 71% (95% CI, 60%-80%), and 55% (95% CI, 44%-65%), respectively.² The rates of MR4.0 and MR4.5 were 45% (95% CI, 34%-55%) and 39% (95% CI, 28%-49%), respectively.

In the CML-AP cohort, the 4-year rates of MCyR, CCyR, MMR, MR4.0 and MR4.5 were all 40% (95% CI, 15%-64%).

“Olverembatinib treatment responses increased over time and correlated with favorable outcomes in patients with TKI-resistant CML-CP and CML-AP,” the study authors wrote.

In this study, patients received oral olverembatinib once every other day in 28-day cycles in doses ranging from 1 mg to 60 mg. At data cutoff, 73% (n = 63) with CML-CP and 53% (n = 8) with CML-AP were continuing treatment.

Baseline demographics indicated that the interval from diagnosis to starting olverembatinib was 6 years (range, 0.6-15) in the CML-CP cohort and 7 years (range, 0.3-15) in the CML-AP cohort. Similarly, most patients in the CML-CP (50% and 33%) and CML-AP (54% and 33%) cohorts had received 2 or 3 or more prior TKIs, respectively.

Additional results showed a 4-year PFS rate of 88.6% (95% CI, 79.2%-93.9%) in the CML-CP cohort and 50.0% (95% CI, 22.9%-72.2%) in the CML-AP cohort.

Multivariate analysis of response demonstrated that absence of BCR:ABL1 mutation at baseline, longer interval from CML diagnosis to start of treatment, increasing age, and treatment interruption within 3 months were associated with lower CCyR (P = .178; P = .012; P <.001; P < .001), MMR (P = .008; P = .011; P = .01; P < .001), and MR4.5 (P < .001; P = .098; P = .519; P = .003), respectively. The primary reason for treatment interruption was due to grade 3/4 thrombocytopenia (88%), which was associated with lack of BCR:ABL1 mutation at baseline (P = .006) and longer interval from CML diagnosis to starting treatment (P = .021) in multivariate analysis.

The authors noted that the incidence of most treatment-emergent AEs decreased over time and that the safety profiles in the 5-year follow-up were comparable to those reported in prior analyses.

Further evidence of the agent’s activity was reflected in a phase 1 trial (NCT04260022) also presented at the 2022 ASH Annual Meeting.³ The study enrolled patients with CML in chronic phase, accelerated phase, or blast phase, or Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) with resistance or intolerance to at least 2 BCR:ABL1 inhibitors.

Patients were randomly assigned 3:3:2 to 30 mg (n = 21), 40 mg (n = 18), or 50 mg (n = 10) of olverembatinib once daily every 28 days. Notably, most patients were in their second (27.5%; n = 14) or third or later (49.0%; n = 25) salvage, and more than half of patients had prior ponatinib exposure (54.9%; n = 28).

Among patients with resistant CML-CP, the CCyR and MMR rates were 77.8% (n = 14/18) and 43.5% (n = 10/23), respectively. Those who failed prior ponatinib had CCyR and MMR rates of 83.3% (n = 10/12) and 42.9% (n = 6/14), respectively. The CCyR and MMR rates in the T315I-mutant population were 87.5% (n = 7/8) and 55.6% (n = 5/9), respectively.

In the 7 patients with Ph-positive ALL, the MCyR, CCyR, and MMR rates were 42.9% (n = 3), 28.6% (n = 2), and 28.6% (n = 2), respectively. Among the 6 evaluable patients with resistance to ponatinib, the combined CCyR and MMR rate was 33.3% (n = 2).

Regarding safety, the most common hematologic toxicities were thrombocytopenia (grade 3/4, 18.9%), neutropenia (grade 3/4, 16.2%), and leukopenia (grade 3/4, 13.5%). Treatment discontinuation occurred in 29.7% of patients (n = 11), owing to thrombocytopenia and leukopenia (2.7%; n = 1), worsening vascular issues (2.7%; n = 1), disease progression (8.1%; n = 3), or other reason (16.2%; n = 6).

The authors concluded “olverembatinib is efficacious in patients with refractory CML-CP, advanced Ph-positive leukemia, and/or T315I mutations. We saw strong efficacy in CML salvage patients with resistance or intolerance to ponatinib and was safe and well tolerated up to 50 mg once daily.”

References

1. Jiang Q, Li Z, Hou Y, et al. Updated results of pivotal phase 2 trials of olverembatinib (HQP1351) in patients (Pts) with tyrosine kinase inhibitor (TKI)-resistant chronic- and accelerated-phase chronic myeloid leukemia (CML-CP and CML-AP) with T315I mutation. Blood. 2022;140(suppl 1):203-204. doi:10.1182/blood-2022-170698
2. Jiang Q, Li Z, Qin YZ, et al. A five-year follow-up on safety and efficacy of olverembatinib (HQP1351), a novel third-generation BCR-ABL tyrosine kinase inhibitor (TKI), in patients with TKI-resistant chronic myeloid leukemia (CML) in China. Blood. 2022;140(suppl 1):198-199. doi:10.1182/blood-2022-170868
3. Jabbour E, Koller PB, Oehler VG, et al. Olverembatinib (HQP1351) overcomes ponatinib resistance in patients with heavily pretreated/refractory chronic myeloid leukemia (CML) and philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2022;140(suppl 1):200-202. doi:10.1182/blood-2022-162387