Olverembatinib Sustain Benefit in BCR-ABL1 T315I-Mutant, TKI-Resistant CML

Three-year follow-up results from 2 a phase 2 trials, olverembatinib (HQP1351) upheld clinical benefit and continued to have an acceptable safety profile in patients with BCR-ABL1 T315I-mutant chronic myeloid leukemia (CML)-chronic phase (CP) or -acute phase (AP) that is resistant to TKIs, according a presentation during the 2022 ASH Annual Meeting.¹

Updated results for cumulative incidence of response showed that, in patients with T315I-mutant CML-CP, the major cytogenetic response (MCyR) at 3 years was 80% (95% CI, 64%-90%), the complete cytogenetic response (CCyR) was 71% (95% CI, 54%-83%), and the major molecular response (MMR) was 59% (95% CI, 42%-72%). The molecular response (MR) 4.0 and the MR 4.5 were both 51% (95% CI, 35%-66%).

In those with T315I-mutant CML-AP, the MCyR was 52% (95% CI, 30%-71%), the CCyR was 52% (95% CI, 29%-71%), and the MMR was 48% (95% CI, 25%-68%). The MR 4.0 and the MR 4.5 were both 35% (95% CI, 16%-55%).

“Olverembatinib is efficacious and well tolerated in TKI-resistant CML-CP and CML-AP patients with a BCR-ABL1 T315I mutation,” said Yifan Zhai, of Ascentage Pharma Group, the developer of the third-generation BCR-ABL inhibitor, in a presentation during the meeting. “The responses and safety profile of these studies are consistent with the T315I mutation subgroup in a phase 1 study.”

In November 2021, olverembatinib was granted conditional approval for the treatment of patients with CML-CP and CML-AP with a T315I mutation by the National Medical Products Administration in China.

In the single-arm, open-label, multicenter, registrational phase 2 HQP1351CC201 (NCT03883087) and HQp1351CC202 (NCT03883100) trials, patients with TKI-resistant CML-CP and CML-AP, respectively, who had T315I-mutant disease, were treated with oral olverembatinib at 40 mg every other day in 28-day cycles.²

To be eligible for enrollment, patients had to be at least 18 years old, have T315I-mutant CML in either CP or AP via MD Anderson Cancer Center criteria, an ECOG performance status of 0 to 2, and adequate organ function.

Those who received prior ponatinib (Iclusig), olverembatinib, or similar agents were excluded from enrollment, as well as those with uncontrolled cardiovascular diseases, pulmonary arterial pressure greater than 50 millimeters of mercury, and those who have CP disease with CCyR and AP disease with major hematologic response (MaHR).

In HQP1351CC201, MCyR ( ≥40% vs 15%) was the primary end point; this was MaHR (≥40% vs 10%) in the HQP1351CC202 trial.

Regarding baseline characteristics between the HQP1351CC201 and HQP1351CC202 studies, the median age was 47 years (range, 22-70) and 41 years (range, 21-74), respectively. Moreover, the time from diagnosis to starting olverembatinib was 5.3 years (range, 0.6-23.2) and 5.0 years (range, 0.4-10.2), respectively. In HQP1351CC201, patients had received 1 (22%), 2 (61%), or 3 (17%) prior lines of therapy; these rates were 17%, 61%, and 22%, respectively, in the HQP1351CC202 trial.

The data cutoff date was September 30, 2022, for both studies. The median duration of treatment was 38 months (range, 3-41) in HQP1351CC201 and 20 months (range, 1-41) in HQP1351CC202. Sixty-six percent and 44% of patients, respectively, continued treatment.

In HQP1351CC201 and HQP1351CC202, 34% and 57% of patients, respectively, discontinued treatment due to disease progression (5% and 22%), treatment failure (7% and 9%), intolerant adverse effects (AEs; 10% and 17%), withdrawn consent (7% and 0%), death (0% and 4%), or other unspecified reasons (5% and 4%).

Regarding duration of response, additional findings in HQP1351CC201 showed that at 36 months, the MCyR in patients with CML-CP was 80% (95% CI, 61%-91%), the CCyR was 81% (95% CI, 60%-92%), and the MMR was 85% (95% CI, 61%-95%). In the CML-AP population, the MCyR was 81% (95% CI, 44%-95%), the CCyR was 66% (95% CI, 32%-86%), and the MMR was 22% (95% CI, 4%-50%).

Progression-free survival (PFS) and (OS) at 3 years were also assessed. In the CML-CP population, the 3-year PFS and OS rates were 92% (95% CI, 77%-97%) and 95% (95% CI, 82%-99%), respectively. In the CML-AP population, these rates were 62% (95% CI, 38%-79%) and 70% (95% CI, 47%-84%), respectively.

When stratified by mutational status, investigators noted that response rates were similar regardless of whether patients harbored T315I single mutation or T315l and additional mutations, which included F317L, M244V, E459k, F359V, Y253H, E255V, E450A, and E459Q.

In an analysis of BCR-ABL1 mutation dynamic changes, it was found that while some patients did not have any changes or lost their T315I mutation with no response or loss of response to olverembatinib, 1 patient gained G250E and E255K mutations at 3 months and 8 months after treatment.

The study also included a multivariate analysis of responses pertaining to number of prior TKIs and interruption within 3 months, both of which were associated with lower response rates. Prior TKI use impacted olverembatinib response as it related to CCyR (HR, 0.5; 95% CI, 0.3-0.9; P = .015), MMR (HR, 0.4; 95% CI, 0.2-0.6; P = .001), and MR4.5 (HR, 0.6; 95% CI, 0.3-1.2; P = .122).

Regarding interruption within 3 months, the HR for CCyR was 0.4 (95% CI, 0.2-0.7; P = .002), 0.3 for MMR (95% CI, 0.2-0.6; P = .001), and 0.4 for MR4.5 (95% CI, 0.2-0.9; P = .024). Sixty-nine percent of patients experienced treatment interruption due to grade 3/4 thrombocytopenia, which occurred at 1.2 years (range, 1.0-1.4) from diagnosis to starting olverembatinib treatment (P = .015).

Zhai noted that the prevalence of treatment-related AEs decreased over time, with skin pigmentation being the main AE that remains. She noted that any-grade and grade 3 or higher arterial occlusive events and venous thrombotic events occurred in 3% and less than 2% of patients, respectively.

_References:

_{1. Jiang Q, Chen Zi, Niu Q, 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, Shi D, Li z, et al. Updated results of pivotal phase 2 trials of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)-resistant BCR-ABL1 T315I-mutated chronic- and accelerated-phase chronic myeloid leukemia (CML-CP and CML-AP). Blood. 2021;138(1):3598. doi:10.1182/blood-2021-153937}