Dr Christopher Arendt on OPTIC Findings for Dose Optimization of Ponatinib in Patients With CP-CML

Christopher Arendt, PhD, head, Oncology Therapeutic Area Unit, Takeda, speaks on efficacy and safety findings of the OPTIC study examining dose optimization of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to second-generation tyrosine kinase inhibitor therapy.

Findings of the OPTIC study examining dose-optimization of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) indicated that the highest dose of 45 mg achieved optimal results, which were maintained after lowering the dosage, said Christopher Arendt, PhD, head, Oncology Therapeutic Area Unit, Takeda.


Transcript

Can you discuss the general rationale for the phase 2 OPTIC study, and why patients taking third-generation TKIs are at risk for events such as thrombocytopenia?

So, this is a study that involved Iclusig [ponatinib]. Iclusig is an oral tyrosine kinase inhibitor [TKI] that targets a specific genetic fusion. It's a fusion of BCR and ABL1 that's associated with some subtypes of CML, and also Philadelphia chromosome–positive acute lymphoblastic leukemia, or ALL.

This is a medicine that was developed by computational- and structure-based drug design. And so what's interesting is that it's able to inhibit this lesion, but it's also uniquely able to inhibit, in addition, a resistance mutation that develops in response to targeted therapies against BCR-ABL1, and that mutation is known as T315I that identifies one specific amino acid change that renders these tumors ultimately resistant to the initial classes of targeted therapies against BCR-ABL.

So, Iclusig is called a third-generation inhibitor. And again, it has this added virtue that it's able to address that so-called gatekeeper mutation, or resistance mutation. So, there's a bit of a misconception when it comes to chronic phase CML that this is a good cancer to have, but in reality, there's certainly very resistant forms of disease, as well as intolerant forms of disease that develop, and these are associated with extremely poor outcomes.


Balancing its clinical efficacy with a safety profile is all about sort of threading that needle and threading that needle at the level of the dosing schedule. You want that dosing schedule to be just high enough to address the tumor growth, but not so high that there are unwanted side effects. So, you really want to minimize those. And so, Iclusig was already an approved medicine in chronic phase CML, but it was kind of relegated to the last line of therapy, which we felt was not optimal for patients who could benefit earlier and have that protection against the resistance mutation.

So, what OPTIC sought to do was to really optimize, essentially, the dose and schedule, and so it evaluated a number of different doses. What was found is that a starting dose of 45 mg was optimal in the study. The patients were monitored for a clinical response by a blood test, and when that genetic lesion fell to a nearly undetectable levelso less than 1% in bloodthat was when the dose schedule was reduced to a third of that dose, 15 mg daily.

With this, the safety and efficacy profile was really optimized within the OPTIC study. The trial met its primary end point, and actually toward the end of last year, the FDA approved the sNDA [supplemental new drug application] for adult patients with CP-CML who received 2 prior TKIs. So, this allowed the medicine to really move up to an earlier stage of treatment, and we believe that's going to be very beneficial, ultimately, for patients. Again, keeping in mind that resistance ultimately is a hallmark of the first- and second-generation TKIs in this particular treatment setting.

So, you also asked about thrombocytopenia as one of the potential side effects in this class. The mechanistic basis for this is not fully clear, but it's thought to be potentially due to inhibiting some of the signal transduction pathways that Iclusig hits that are important in megakaryosites, which is sort of in the same kind of myeloid lineage that ultimately we're targeting in this particular disease setting.

How do the results being presented at ASCO contribute to precision medicine in the treatment of CML?

So, precision medicine is all about matching the right medicine to a patient who has an identifiable, if you will, kind of biomarker or genetic signature in that disease setting. And so what's exciting around the OPTIC study data is that we now have the ability to really tailor the treatment with this medicine to patients who can benefit, because either they have that driver mutation that can be specifically identified to have become resistant to the other classes in this space. And again, that's the T315I mutation.

So, that's a wonderful example of precision medicine being allowed for that very agile treatment with the appropriate medicine, instead of having to wait and sort of test and allow for a cancer to progress when it could benefit from really having the right tailored therapy from the start. So, that's a wonderful example.

Clearly, also the fact that Iclusig moves up in the treatment schedule paradigm also allows, we hope, to prevent the development of that particular lesion. So, to be able to still have that precision, genetic connection between the BCR-ABL1 lesion and offering a patient Iclusig, and then following that patient with the expectation that that T315I mutation is going to be under a very strong selective pressure from this particular medicine. And the hope would be that it doesn't develop and the hope would be that patients then can benefit for a longer duration of response ultimately.

What subgroup results are noteworthy?

So, in the OPTIC study, as mentioned, what we looked at, different therapeutic doses, it was all about, again, being able to thread that needle in the best possible way for patient benefit: maximizing responses, but ultimately minimizing any of the adverse events or side effects with the medicine.

So, the most interesting subgroup is the one that, again, received the highest dose that was tested in that study, initially; that's the 45-mg cohort. These patients had the best initial response and then sustained responses. They were dropped down to that 15-mg dose, maintained, and followed over the course of the study.

Reference

Cortes JE, Apperley J, Lomaia E, et al. OPTIC primary analysis: A dose-optimization study of 3 starting doses of ponatinib (PON). J Clin Oncol. 2021;(suppl 15; abstr 7000). doi:10.1200/JCO.2021.39.15_suppl.7000