Mesa Shares Insight on Fedratinib Benefit in Myelofibrosis Subgroup

Ruben Mesa, MD

Treatment with fedratinib (Inrebic) led to similar reductions in spleen volume and symptom response rate in patients with myelofibrosis (MF) who had platelet counts <100 × 10⁹/L as those with platelet counts >100 x 10⁹/L, according to a pooled analysis from the JAKARTA and JAKARTA2 studies.¹

Fedratinib, a JAK2 inhibitor, was approved by the FDA in August 2019, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary MF, including post-polycythemia vera (PV) or post-essential thrombocytopenia (ET) MF.

The approval was based on data from the phase III JAKARTA and phase II JAKARTA2 studies, which demonstrated improvements in spleen response, spleen symptoms, and safety for patients with MF.² In the pooled analysis, which was presented at the 2019 ASH Annual Meeting, data demonstrated benefit with fedratinib in patients with platelet counts between 50 to <100 × 10⁹/L.

Investigators pooled data from patients with a baseline platelet count 50 to <100 × 10⁹/L to evaluate whether this subgroup of patients with myeloproliferative neoplasms (MPNs) could receive the full dose of fedratinib. Patients who met this criterion in JAKARTA who received either the full dose of fedratinib at 400 mg once daily or placebo and those in JAKARTA2 who were ruxolitinib relapsed/refractory or intolerant were included in the analysis.

"The therapy prior to fedratinib that had been approved, ruxolitinib (Jakafi), was available to these patients but typically at a reduced dose," said study investigator Ruben Mesa, MD. "We wanted to see if fedratinib could be given at the full dose in those patients and what the outcome was both in terms of efficacy and safety."

In the JAKARTA study, 15% of patients in the fedratinib arm and 19% in the placebo arm had baseline platelet counts below 100 X 10⁹/L. The overall spleen volume response rate (SVRR) was 36% in these patients in the fedratinib arm versus 0% in the placebo group. The median exposure to fedratinib in this group was 24 weeks, with a median relative dose intensity greater than 99%. Following cycle 6, 5% of patients in the fedratinib arm and 6% in the placebo group had grade 3/4 thrombocytopenia. One percent of patients had to have a dose modification in the fedratinib arm due to thrombocytopenia, and 2% of patients discontinued treatment because of adverse events (AEs).

Among patients with platelet counts below 100 X 10⁹/L in the JAKARTA2 study (n = 33), the SVRR was 36% with fedratinib, and the symptom response rate was 39%. The median exposure to fedratinib in these patients was 27 weeks (range, 1-79), and 97% of patients with platelet counts below 100 X 10⁹/L received the intended dose of fedratinib, compared with 80% of patients with platelet counts of 100 X 10⁹/L or greater. There was a higher frequency of thrombocytopenia in this subgroup of patients compared with other AEs, whereas the rate of grade 3/4 thrombocytopenia was noted in 49% versus 8% in those with platelet counts of 100 X 10⁹/L or greater. Four patients had a dose modification and 2 discontinued treatment due to thrombocytopenia.

In an interview with OncLive, Mesa, director of the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center, discussed the findings from the pooled analysis of fedratinib at full dose in patients with MF who had baseline platelet counts below 100 X 109/L. He also highlighted other agents and therapies that appear promising for the treatment of patients with MPNs.

OncLive: What was the rationale for conducting this analysis?

Mesa: Fedratinib is a JAK2 inhibitor that had been previously shown to be active in patients with MF. Two different studies were performed that led to its approval. The first was the JAKARTA study, which was a randomized phase III study in patients who were JAK inhibitor naïve. The second study was the JAKARTA2 study which was evaluating the use of fedratinib in the second-line in patients who had previously failed ruxolitinib. What we chose to do for the 2019 ASH Annual Meeting was to look at those patients with a baseline platelet count between 50 to <100 × 10⁹/L. The therapy prior to fedratinib that had been approved, ruxolitinib, was available to these patients but typically at a reduced dose for patients with a platelet count of 50 to <100 × 10⁹/L. We wanted to see if fedratinib could be given at the full dose in those patients and what the outcome was both in terms of efficacy and safety.

What were the findings from this analysis?

This was a pooled analysis between both of those studies, looking at the patients treated with fedratinib at 400 mg a day with a platelet count of 50 to 100 × 10⁹/L. We identified in both studies that the SVRR, as well as the improvement in symptoms, were both equivalent in patients with a platelet count between 50 to 100 × 10⁹/L and those above 100 × 10⁹/L.

Additionally, we saw that it was safe to use fedratinib at 400 mg a day in that group. There was a very small number of patients that needed any dose modification, and only a handful of patients had grade 3/4 thrombocytopenia. Grade 2 thrombocytopenia is down to a platelet count of 50, so if patients went from a platelet count of 52 to 47, they would go from a grade 2 to a grade 3.

Overall, we saw this was safe and effective, which is impactful for our patients because now we know fedratinib can be prescribed at full dose for patients with a platelet count of 50 to 100 × 10⁹/L.

What are the next steps for fedratinib?

Now with the approval of fedratinib, it is clearly available in both the frontline and second-line settings. The outcome of our study might suggest a niche for its frontline consideration. I think it will be used in a larger degree based on the patient and physician’s comfort level with ruxolitinib at this point. It will begin first in the second-line setting, and it is already being used in that regard.

What new drugs are coming down the pike now?

A lot of exciting additional JAK inhibitors are in the pipeline, including 2 mature drugs that are close to approval. The first is momelotinib, which I helped to lead along with colleagues in a global phase III study that just launched called the MOMENTUM study for momelotinib in patients that have anemia and symptoms. That JAK1/JAK2 inhibitor can help to improve spleen symptoms and anemia. If successful, that experience with momelotinib may lead to approval.

Similarly, the JAK2 inhibitor pacritinib has had successful phase III studies, of which I got to lead the PERSIST-1 study. The new study that has been launched is the PACIFICA study which we hope will provide additional complementaryinformation to lead to an approval for the use of that drug particularly in patients with marked thrombocytopenia. Pacritinib is the only JAK inhibitor that has been used in patients with a platelet count below 50 × 109/L, so that provides a bit of a unique niche for that drug.

We are seeing an increased number of therapies for MF that are very impactful. There is a robust pipeline of JAK inhibitors and other drugs in development that will likely be important as well. They recently approved luspatercept (Reblozyl) in other indications, the bromodomain and extra-terminal domain (BET) inhibitor, and LSD1 inhibitors, amongst others. It is a very hopeful time right now for MF.

Were there any other exciting abstracts presented at the 2019 ASH Annual Meeting for the treatment of patient with MPNs?

Another key abstract from the meeting for MF is the BET inhibitor, CPI-0610. The drug was both used alone or in combination with ruxolitinib. It improved spleen, symptoms, anemia, and some degree of fibrosis. It is a multi-arm initial study that will now be pivoting to a phase III study where it perhaps might be used in the frontline setting in combination with ruxolitinib.

Another drug with an interesting mechanism of action is the LSD1 inhibitor. This is in its early days, but it is showing activity in spleen, symptoms, and anemia, as well as a bit in fibrosis.

Finally, we saw data on luspatercept in combination with ruxolitinib. It helps to improve anemia, and that is a clear unmet need for patients with MF. The approval now of luspatercept in patients with hemoglobinopathy and recently with myelodysplastic syndrome (MDS) will likely make this an important therapeutic consideration.

What are your final thoughts on the current state of MPNs?

It’s an exciting time in MPNs without a doubt. I would break it down into 2 advances. The first is in patients with ET and PV. At this meeting, there continues to be further updates on the important role of long-acting interferons. They are having a big impact and are probably superior to hydroxyurea in both the first- and second-line. At this meeting, we are seeing data on both thrombosis-free survival rates as well as the molecular impact in terms of its use.

In MF, I think we see a very robust set of therapies developing, including a robust group of JAK inhibitors that will complement each other in terms of their activity. Novel combinations are looking at different mechanisms of action, such as BET inhibition, TGF-beta inhibition, LSD1 inhibition, etc., as well as new drugs in development for use even as single-agents.

This is an exciting time with a lot of things in development. I think the parallel of events we are seeing in MDS with the oral hypomethylating agents and other agents will likely have benefit for patients with advanced MPNs as well.

References

1. Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib induces spleen responses and reduces symptom burden in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) and low platelet counts, who were either ruxolitinib-naïve or were previously treated with ruxolitinib. Blood. 2019;134(suppl_1; abstr 668). doi: 10.1182/blood-2019-129288.
2. FDA approves treatment for patients with rare bone marrow disorder. FDA website. Posted August 16, 2019. https://bit.ly/2ZawBtI. Accessed January 16, 2020.