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ASH 2022 | Phase I study of olverembatinib in patients with R/R CML & Ph+ ALL

Elias Jabbour, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, describes the findings of a Phase I study of olverembatinib in patients with relapsed/refractory (R/R) chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL; NCT04260022). Overall, olverembatinib showed high efficacy and good tolerability in heavily pre-treated patients, including those that had T315I mutations or who were resistant to ponatinib and asciminib. This interview took place at the 64th ASH Annual Meeting and Exposition congress in New Orleans, LA.

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Transcript (edited for clarity)

My name is Elias Jabbour. And I want to update you on my presentation at the ASH meeting. And the first one is olverembatinib in CML. It’s a presentation to be done on Saturday. We know this drug is a multi kinase inhibitors, [inaudible 00:00:16] activity in wild type and mutated BCR-ABL including T315I mutation. It does inhibit other TKIs as well. It’s a brand new study done in the USA to assess the PKs in Caucasian population, and of course efficacy and safety of this regimen...

My name is Elias Jabbour. And I want to update you on my presentation at the ASH meeting. And the first one is olverembatinib in CML. It’s a presentation to be done on Saturday. We know this drug is a multi kinase inhibitors, [inaudible 00:00:16] activity in wild type and mutated BCR-ABL including T315I mutation. It does inhibit other TKIs as well. It’s a brand new study done in the USA to assess the PKs in Caucasian population, and of course efficacy and safety of this regimen.

The study allowed patients who failed prior TKIs, at least two prior TKIs. A patient should not have a response, meaning nobody with a BCR above 1%. And this study will randomize patients to three arms, 30 milligrams every other day, 40 milligrams every other day, and 50 milligrams every other day. The ratio was 3:3:2, and again, the primary end point was PK studies. But these patients enrolled have what is called cardiovascular issues, be it in chronic phase or advanced stage disease, the bulk is chronic phase. I will say, 47% of the patients had cardiovascular comorbidities and made them tough candidates for other TKIs, including ponatinib.

In this study, we enrolled patient mainly in salvage [inaudible 00:01:12] 47% in chronic phase, which is a high number that tells you that these patients are really resistant to prior therapy, including ponatinib, where patients enrolled in chronic phase were resistant to ponatinib in 65%, overall, 72% of the cases. The PK data were equivalent independent on the dose given. And the PK profiling was similar to the Asian population. And therefore, the study met its endpoint. When it comes to efficacy, we’ve seen great efficacy overall. In chronic phase, 78% of the patients achieving a CCyR, 43% achieving MMR. And when we look at the patients who already failed ponatinib, the rate of CCyR was 83.3% and MMR was 43%. And among the group who is resistant, it’s 78%, which is the best responses seen so far in this group of patients. 

In T315I mutation, we’ve seen as well great responses where the rate of CCyR was 87.5%, MMR being 55.6%, which is great. These are chronic phase patients. Therefore, if in multiple-resistant patient, this drug is really performing so well, we know as well that responses are durable. The follow-up is around eight months plus, and yet, patients are achieving response within three months. And these responses are being durable. Time to response was 14 weeks for CCyR and for MMR, it was 24 weeks. Of note, there’s patients here who failed asciminib, one patient responded, achieved a CCyR and MMR. In advanced stage disease as well, we’ve seen responses. At different dose schedule, the rate of CCyR was 43% and MMR was around 29%. And we’ve seen activity across all subsets, mainly patients who failed ponatinib who are resistant. The rate of responses where eight patients who had enrolled with resistance to ponatinib, 33% of them responded, again in advanced stage disease. Yet, the follow-up is short, but patients do equally respond. Patients [inaudible 00:03:30] are still mainly on our study, a third of them had to stop the treatment, mainly to go to transplant or other options.

From adverse events, there’s nothing clinically significant. But we’ve seen a CK increase. Although it’s not clinically meaningful, we did not see significant rates of vascular events. So I will say in conclusion, olverembatinib has shown dose proportion increase in [inaudible 00:03:54] exposure, for 30-50 milligrams every other day. And that’s comparable to the Chinese population. We’re seeing extremely high efficacy in refractory population and in patient who failed prior therapies including ponatinib. And finally, it’s safe and tolerated up to 50 milligrams every other day. And the next step is to move to expansion and really have a Phase II study done, and hopefully get the drug available to our patients with CML.

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Disclosures

Takeda: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Pfizer: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding.