Positive Data With Parsaclisib/Ruxolitinib Pave the Way for Phase 3 Studies in Myelofibrosis

Abdulraheem Yacoub, MD

Daily treatment with parsaclisib, a PI3Kδ inhibitor, plus standard ruxolitinib (Jakafi) elicited clinically meaningful efficacy and minimal toxicity in patients with myelofibrosis who had a suboptimal response to ruxolitinib in a phase 2 study (NCT02718300), said Abdulraheem Yacoub, MD, who added that these data served as the basis for ongoing phase 3 studies evaluating the regimen in the first- (LIMBER-313; NCT04551066) and second-line settings (LIMBER-304; NCT04551053).

During week 1 of the 2021 AACR Annual Meeting, findings from the phase 2 trial were presented as a virtual poster. At 24 weeks, the all-daily regimen of parsaclisib plus ruxolitinib led to a median percentage change of –25.4% in spleen volume from baseline. The median percentage change in the Myelofibrosis Symptom Assessment Form-Total Symptom Score was –39.6% at 12 weeks.

Notably, the addition of parsaclisib to ruxolitinib did not yield significant toxicity and treatment-emergent adverse effects (AEs) common to the PI3K inhibitor class were infrequently observed.

“We are excited about the practice-changing [potential] of these data for ruxolitinib, which has changed the course of myelofibrosis,” said Yacoub, the lead study author. “The drug has helped so many patients and saved so many lives. However, we can do better. With encouraging clinical trials and combinations with novel drugs that do not add toxicity, we can further improve patient experiences, outcomes, and quality of life [QOL].”

In an interview with OncLive®, Yacoub, an associate professor of medicine at the University of Kansas School of Medicine, discussed the rationale for combining PI3K inhibitors with ruxolitinib in myelofibrosis, the results of the phase 2 study with parsaclisib, and ongoing phase 3 trials evaluating this novel combination.

OncLive^®: What was the clinical rationale to combine a PI3K inhibitor with ruxolitinib in patients with myelofibrosis?

Yacoub: Ruxolitinib is a very active drug for patients with myelofibrosis and it has resulted in splenic and clinical responses. Unfortunately, it is rare that the responses [from ruxolitinib] are complete, and they are almost never durable. The median time to loss of response is around 3 years.

Some of the incomplete responses or escape effects of ruxolitinib are probably due to the PI3Kδ pathway, which allows cancer cells to escape inhibition by JAK2 inhibitors.

The rationale [for the phase 2 study] was that combining a JAK inhibitor with a PI3K inhibitor could provide a double hit to that pathway and result in deeper, more durable responses. Basically, we would add an additional therapy without additional toxicity that could result in deeper and more effective benefits.

Have similar regimens been evaluated in myelofibrosis or other myeloproliferative neoplasms? What made parsaclisib a good first step in adding in PI3K inhibitors to the myelofibrosis paradigm?

This is actually a novel combination. The PI3K inhibitors, including parsaclisib, are well utilized and approved in other cancers and hematologic disorders. [Parsaclisib] has been investigated thoroughly in patients with lymphomas, chronic lymphoid leukemias, and Hodgkin lymphoma.

The pathway is very well known and investigated in oncology, with many successful attempts [at targeting it]. However, to my knowledge, this is the most advanced, if not the only, combination of a PI3K inhibitor and a JAK inhibitor that has been investigated.

The uniqueness of [parsaclisib] is how well tolerated it is. It has not shown any of the toxicities of interest [based on] other PI3K inhibitors. It has been neutral to anemia, [meaning] it has not potentiated anemia, which is a common toxicity of myelofibrosis therapy. The lack of additional toxicity in combination with JAK inhibitors could potentially benefit [patients].

Our understanding of the limited benefits from JAK inhibitors and the positive nature of [ruxolitinib] has resulted in many other attempts at very rationally designed combinations with JAK inhibitors plus agents that have different mechanisms of action to try to improve the responses [seen with ruxolitinib alone].

Although our approach is with the novel agent [parsaclisib], the combination strategy is not too uncommon in this disease. There have been many other examples of add-on agents to JAK inhibitors. Hopefully, this approach will soon challenge or change our standards of care and provide better therapy for our patients.

How was the study designed?

We designed this study in patients who are on a stable and maximized dose of ruxolitinib. Most of our patients were on therapy for over a year, and the average duration was 1.5 years. The methodology we adopted was to add on [parsaclisib] at 2 different dosing schedules to try to tease out which combination was effective and which we could carry forward to larger clinical trials.

We also combine this with extensive molecular testing and productive science testing in order to find predictors of response and on-target activity. In our study, we had 2 cohorts; we concluded that the one cohort was more effective and tolerable [compared with the other]. That was a key conclusion in our study, which we are carrying forward in a clinical trial.

What were the key findings observed from the phase 2 study regarding efficacy and safety?

Pleasantly, we have proven that the combination [of ruxolitinib and parsaclisib] is feasible, safe, and effective. Our patients who had been on a maximized and optimized therapy with JAK inhibitors had additional splenic volume reduction with the addition of [parsaclisib]. They also had very rapid and durable improvement in their QOL, patient outcomes, and symptom scores, on top of an already optimized therapy. Those were very encouraging findings.

Also, the safety [profile of the combination] was very impressive with this agent. There were very few non-hematologic toxicities or dose-limiting toxicities. Hemoglobin was also not affected [by the combination]. The only toxicity that was dose limiting was thrombocytopenia, which was mild and reversible in nearly all patients.

Among the 2 dosing schedules, patients who received daily parsaclisib induction therapy followed by daily maintenance seemed to have had the optimum response. These patients continue to have ongoing responses, even after 24 weeks, which was very encouraging. We also have noticed some molecular responses, but these are too early to discuss at this time.

What next steps are planned with this combination?

We have designed 2 international clinical trials investigating [parsaclisib] further. [The LIMBER-313] study is going to randomize patients with previously untreated myelofibrosis to ruxolitinib with [parsaclisib] vs ruxolitinib plus placebo. The goal of this study is to challenge the current standard of care to see if we can provide this combination therapy up front and [whether] that would be more efficacious for our patients long term. The study is ongoing and has accrual sites internationally; some patients have received protocol therapy already. We have also presented [initial results of these data] at the 2021 AACR Annual Meeting.

The second clinical trial, [the LIMBER-304 study] is similar to [the phase 2] trial in that it is [evaluating] an add-on strategy. [Eligible] patients have [received] ruxolitinib in a stable dose but achieved a suboptimal response. This international study [will] evaluate whether the addition of parsaclisib vs placebo to [ruxolitinib] will improve outcomes. The study is also active and enrolling patients globally. We’re very excited to hear the outcomes of those studies in the next 2 or 3 years.

Reference

1. Yacoub A, Wang ES, Rampal RK, et al. Addition of parsaclisib (INCB050465), a PI3Kδ inhibitor, in patients with suboptimal response to ruxolitinib: a phase 2 study in patients with myelofibrosis. Presented: 2021 AACR Annual Meeting; April 9-14, 2021; week 1; virtual. Abstract: CT162.