Myelofibrosis Paradigm Slated to Expand With Investigative Therapies Showing Potential | OncLive

Myelofibrosis Paradigm Slated to Expand With Investigative Therapies Showing Potential

September 25, 2020

The myelofibrosis paradigm is bursting with novel agents and combinations that have been developed with the ultimate goal of helping patients live longer.

The myelofibrosis paradigm is bursting with novel agents and combinations that have been developed with the ultimate goal of helping patients live longer, said Srdan Verstovsek, MD, PhD, who added that several phase 3 trial are underway to bring more options into the clinic.

The National Comprehensive Cancer Network guidelines for the treatment of patients with myelofibrosis are based on risk of death, as well as symptoms and signs, said Verstovsek. Patients who are determined to be higher risk should be referred to transplant. For those who are not candidates for transplant, ruxolitinib (Jakafi), fedratinib (Inrebic), or a clinical trial is recommended. Patients who are lower risk and asymptomatic should undergo observation or consider a clinical trial, while those who are lower risk and symptomatic should consider a clinical trial, ruxolitinib, ropeginterferon a-2α, or hydroxyurea.

“These drugs do not fulfill all the needs [that exist in this disease]—far from that; that’s why we have clinical trials listed almost everywhere,” said Verstovsek. “A huge number of new medications are being tested that target different parts of the disease biology; it’s not just about the inhibition of the JAK/STAT pathway alone [anymore]. Many other drugs are in development and most of them are being tested in the second-line setting, after JAK inhibitors.”

In a virtual presentation during the 2020 SOHO Annual Meeting, Verstovsek highlighted the different phase 3 efforts that are being made and which agents are generating excitement in the field of myelofibrosis.1

JAK Inhibitors Under Investigation

To date, 2 JAK inhibitors have received approval for use in patients with myelofibrosis: ruxolitinib and fedratinib. Now, fedratinib is under exploration in the second-line setting, and several other agents have emerged.

In the phase 3 PACIFICA trial (NCT03165734), investigators are examining pacritinib compared with physician’s choice in patients with myelofibrosis and severe thrombocytopenia with a platelet count of less than 50,000 mL.2 “This JAK inhibitor is not myelosuppressive; it can improve the signs and symptoms of the disease, even in patients with platelets below 50,000 mL.”

Additionally, momelotinib is under examination in the second-line setting in the phase 3 MOMENTUM trial. In this trial, 180 patients who received previous treatment with a JAK inhibitor and who have a total symptom score of 10 or greater and are anemic are undergoing a 2:1 randomization between momelotinib at 200 mg daily versus danazol at 600 mg daily followed by momelotinib at 200 mg daily.3

“Momelotinib appears to improve anemia,” said Verstovsek. “Therefore, this is a study for patients who do not feel well and have anemia; this is a different way of thinking when it comes to JAK inhibitors.”

Luspatercept

Luspatercept-aamt (Reblozyl), which received FDA approval in April 2020 for myelodysplastic syndromes–associated anemia, is now under exploration in patients with myelofibrosis-associated anemia in a phase 2 trial.4 “This is a huge area of unmet need; we don’t have any drug approved for anemia, and here we have a study underway,” said Verstovsek.

A total of 74 patients were enrolled; 41 did not receive concomitant ruxolitinib at study entry. Results indicated that the cohorts who received a stable dose of ruxolitinib (cohort 3A and cohort 3B) experienced better responses.

These data led to the launch of a double-blind, randomized phase 3 trial examining the safety of luspatercept compared with placebo in patients with myeloproliferative neoplasm–associated myelofibrosis who are on concomitant JAK2 inhibitor therapy and require red blood cell transfusions.

CPI-0610

Another agent that has emerged in recent years is the BET inhibitor CPI-0610; this is a potent and selective small molecule that was developed to encourage antitumor activity by inhibiting a function of BET proteins to reduce the expression of abnormally expressed genes in cancer.5

In the phase 2 MANIFEST trial (NCT02158858), investigators are examining CPI-0610 in combination with ruxolitinib in patients with myelofibrosis who had not received prior treatment with JAK inhibitors (Arm 3). These patients had a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-2 or higher and a platelet count of ≥100 x 109/L. In Arms 1 and 2 of the trial, CPI-0610 is being examined as a monotherapy and as an add-on to ruxolitinib, respectively, in patients who had received prior JAK inhibitors.

Results showed that at the April 17, 2020 data cutoff, 63% (n = 19/30) of patients experienced a ≥35% spleen volume reduction (SVR35) with a median percentage change of 53%. Moreover, 59% (n = 17/29) of patients achieved a ≥50% total symptom score improvement (TSS50) with a median percentage change of 64%.6 These data have led to the launch of a global phase 3 trial, which will examine CPI-0610 plus ruxolitinib versus placebo plus ruxolitinib in patients with primary myelofibrosis or post-essential thrombocytopenia/polycythemia vera who have not received JAK inhibitors, noted Verstovsek.

Navitoclax

Another agent, navitoclax, is a novel small molecule that binds with high affinity to BCL-XL, BCL-2, and BCL-W, leading to cell death and apoptosis.7 Because BCL-XL inhibition possesses the potential to thwart fibrosis growth in the bone marrow, and the combination of JAK inhibitors and BCL-XL/BCL-2 has been shown to have a synergistic effect in eliminating JAK-mutated cells, investigators set out to examine navitoclax in combination with ruxolitinib. The hypothesis was that the combination would overcome resistance to JAK2 inhibition, explained noted Verstovsek.

In a single-arm, multicenter, open-label phase 2 trial, investigators examined the combination in patients with myelofibrosis. Navitoclax was administered at a starting dose of 50 mg once daily and the dose was increased on a weekly basis, in a stepwise fashion, up until a maximum dose of 300 mg once daily based on patient tolerability and platelet count.

Results showed that 26.5% (n = 9/34) achieved a SVR35 at week 24 with the combination. Fifty-three percent (n = 18/34) of patients experienced resolved palpable splenomegaly during study treatment, and 29.4% (n = 10/34) showed reduction in bone marrow fibrosis of grade 1 or higher.8

“These are the best results that I have seen so far with an add-on approach,” said Verstovsek. “In the same setting, we see that quality of life also gets improved. This is a signal that needs to be explored.

Other phase 3 studies are planned to examine this agent further. In the TRANSFORM-1 trial, navitoclax plus ruxolitinib will be compared with ruxolitinib plus placebo in patients with myelofibrosis who had not received previous JAK-2 inhibitors. In the TRANSFORM-2 trial, investigators will compare navitoclax/ruxolitinib versus best available therapy in patients with myelofibrosis who have been treated and relapsed on or were refractory to JAK-2 inhibitor treatment.

Imetelstat

The first-in-class telomerase inhibitor imetelstat was evaluated at 2 doses, 9.4 mg/kg and 4.7 mg/kg given intravenously every 3 weeks, in patients with DIPSS intermediate-2 or high-risk myelofibrosis that was relapsed or refractory to previous JAK inhibition in a phase 2 trial.9

At 24 weeks, 10% (n = 6) of patients who received 9.4 mg/kg of the agent experienced SVR35, while 37% (n = 23) of patients who received that dose experienced a SVR of ≥10%. Additionally, at a median follow-up of 27.4 months, the median overall survival (OS) was 19.9 months (95% CI, 17.1–not evaluable [NE]) in those who received the 4.7 mg/kg dose versus 29.9 months (95% CI, 22.8-NE) in those who received the higher dose.

“In this setting, there was no extraordinary benefit with regard to the spleen or symptoms,” said Verstovsek. “What was interesting with this study was that there was possibility that imetelstat would provide survival benefit…The higher dose of the drug appeared to provide that survival benefit.”

Based on that survival benefit, a phase 3 trial is being planned. This trial will enroll patients with intermediate-2 and high-risk myelofibrosis with inadequate spleen or symptom response following 6 months or longer of treatment with a JAK inhibitor.

“This is an important development. We are talking about upping the bar,” said Verstovsek. “This is one of those moments in drug development where we’re going from anemia as an end point to, for the first time ever, examining survival as the primary end point.”

The primary end point of the trial is OS; key secondary end points include symptom response, spleen response, progression-free survival, complete response, partial response, clinical improvement, duration of responses, safety, pharmacokinetics, and patient-reported outcomes. In the trial, patients will receive 9.4 mg/kg of imetelstat every 3 weeks compared with best available therapy with the exclusion of JAK inhibitors. Open enrollment is planned for the first quarter of 2021.

“Why are we witnessing all these new developments? So many studies are happening, beyond the phase 3 trials shared. We need more therapies and we have the ability to identify new targets,” concluded Verstovsek. “It is not only about the JAK/STAT pathway anymore; there are many other abnormalities. We are focused on targeting these abnormalities in several clinical trials. Engage in clinical trials. We can enhance what we are able to do for our patients.”

References

  1. Verstovsek S. New therapies in development for myelofibrosis. Presented at: 2020 SOHO Annual Meeting; September 9-12, 2020; Virtual.
  2. Harrison CN, Gerds AT, Kiladjian J-J, et al. Pacifica: a randomized, controlled phase 3 study of pacritinib vs physician’s choice in patients with primary myelofibrosis, post polycythemia vera myelofibrosis, or post essential thrombocytopenia myelofibrosis with severe thrombocytopenia (platelet count <50,000 mL). Blood. 2019;134(suppl 1):4175. doi:10.1182/blood-2019-129245.
  3. Sierra Oncology launches the MOMENTUM phase 3 clinical trial for patients with myelofibrosis. News release. Sierra Oncology. November 20, 2019. Accessed September 24, 2020. https://bit.ly/2RWuLqS.
  4. Gerds AT, Vannucchi AM, Passamonti F, et al. A phase 2 study of luspatercept in patients with myelofibrosis-associated anemia. Blood. 2019;134(suppl 1):557. doi:10.1182/blood-2019-122546
  5. Pipeline. Constellation Pharmaceuticals. Accessed September 24, 2020. https://bit.ly/3056X8H.
  6. Mascarenhas J, Harrison C, Patriarca A, et al. CPI-0610, a bromodomain and extraterminal domain protein (BET) inhibitor, in combination with ruxolitinib, in JAK inhibitor treatment naïve myelofibrosis partients: update from MANIFEST phase 2 study. Presented at: European Hematology Association Annual Meeting; June 12, 2020. Abstract EP1084. https://bit.ly/368WSvh.
  7. Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421-3428. doi:10.1158/0008-5472.CAN-07-5836.
  8. Harrison C, Garcia JS, Mesa R, et al. Navitoclax in combination with ruxolitinib in patients With primary or secondary myelofibrosis: a phase 2 study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; virtual. Abstract EP1081.
  9. Mascarenhas J, Komrokji RS, Cavo M, et al. Imetelstat is effective treatment for patients with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to Janus Kinase inhibitor therapy: results of a phase 2 randomized study of two dose levels. Blood. 2018;132(suppl 1):685. doi:10.1182/blood-2018-99-115163

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