Add-on parsaclisib demonstrates improvement in symptoms and SV in MV patients having a suboptimal response to ruxolitinib

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Published: 19 Dec 2022
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Dr Abdulraheem Yacoub - University of Kansas Cancer Center, Kansas City, USA

Dr Abdulraheem Yacoub speaks to ecancer about the final results from the Phase 2 trial evaluating the efficacy and safety of add-on parsaclisib to ruxolitinib for patients with myelofibrosis who had a suboptimal response to ruxolitinib resulted in additional spleen volume reduction and improvement in symptom burden with add-on parsaclisib.

Eligible patients in this trial were randomised to receive add-on parsaclisib alongside  their stable RUX dose. Primary efficacy endpoint was change in spleen volume (SV) from baseline to wk 12 by MRI/CT scan.

Key secondary endpoints included change in SV to wk 24, change in total symptom score and safety. Dr Yacoub explains that the final results demonstrates a suboptimal response to ruxolitinib. All daily dosing regimens are more efficacious than daily/weekly dosing.

With regard to the future of this study, phase 3 studies using 5 mg QD parsaclisib together with ruxolitinib in naive MF patients and ruxolitinib-experienced patients are in progress.
 

Myelofibrosis is a chronic malignancy that continues to have suboptimal control with the current available therapies.  The approved agent, ruxolitinib, has been in use for clinical use with patients for over ten years and we’ve seen some patients who have great benefit with it but some patients continue to have a suboptimal response. So our study was designed to attempt at improving the depth of response and the quality of response in patients on ruxolitinib so hopefully they will have a more sustainable and more effective control of their cancer.

What was the design of the study?

The study design was for patients who continue to be on ruxolitinib with an optimised dose who have been on a stable dose for many months, at least six months, but continue to have suboptimal responses defined by an enlarged spleen, more than 10cm, or enlarged spleen and persistent symptoms. For those patients the intervention was to add on a variable dose of parsaclisib at different dosing schedules and different doses and a maintenance schedule in order to identify the best dosing schedule for parsaclisib as well as to characterise the activity of this agent. We proposed this design so that for patients on a stable dose of ruxolitinib any additional benefit would be attributable to parsaclisib, the intervention, and this way we can characterise its activity.

What were the key findings?

The key finding is that this combination is very safe and at the dose level that is selected to move forward there were very few grade 3 or higher adverse events, there were very few, if any, treatment adverse events of special interest to PI3K inhibitors, there was a very low discontinuation rate due to side effects and most patients continued their baseline dose of ruxolitinib without dose reduction and continued the interventional drug, parsaclisib, at the planned dose without interruption. So the combination was very safe: many patients continue on study therapy on an extended protocol as we speak.

In terms of efficacy we have observed that the addition of parsaclisib for patients who are already on an optimised dose of ruxolitinib resulted in further splenic volume reduction and further symptom improvement that was consistent in all patient cohorts. Some dose responses were quite deep and we are very excited about these responses, especially that it was produced at different dose levels and different dose schedules. Based on that, this has generated two randomised prospective studies examining this combination in patients with myelofibrosis.

What do you think will be the clinical impact of these results?

That is a wonderful question. We have always been trying to improve the outcomes of our patients and the way we optimise the use of ruxolitinib. Hopefully once the studies are completed and the results are made available the combination agents with ruxolitinib, especially parsaclisib, can result in changing the standard of care in which patients with myelofibrosis are either offered a combination up front in order to achieve a deeper, higher quality response up front that would likely last longer, or this combination can be added on for patients already on ruxolitinib who continue to have disease-related manifestations.

Hopefully this combination can be the way of the future in which patients with myelofibrosis are receiving more targeted, more effective combinations that can result in better clinical outcomes.

I would definitely like to advocate for enrolling patients in clinical trials. This is the ideal way for which we can advance the field and help more patients and their caregivers. We strongly encourage considering clinical trials for patients with myelofibrosis in order to advance the field.