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Investigational selective PIM1 inhibitor, nuvisertib (TP-3654), was found to be well tolerated and displayed no dose-limiting toxicities (DLTs) and also demonstrated promising efficacy signals in patients with relapsed/refractory myelofibrosis, according to data from a phase 1/2 study (NCT04176198) presented at the
Results from the study showed that patients with relapsed or refractory myelofibrosis who are intolerant or ineligible for JAK inhibition (n = 77) were given 480-mg (n = 1) or 720-mg (n = 15) daily doses of nuvisertib or 360-mg (n = 11), 480-mg (n = 24), or 720-mg (n = 26) twice daily doses of nuvisertib. No patients across all dose levels experienced any DLTs.
Regarding adverse effects (AEs), the most common grade 1 treatment-emergent adverse effects (TEAEs) that occurred in at least 10% of patients were diarrhea (53.2%; n = 41), nausea (40.3%; n = 31), and vomiting (29.9%; n = 23). Common grade 2 TEAEs that occurred in patients were the similar, occurring at rates of 20.8% (n = 16), 16.9% (n = 13), 10.4% (n = 8), and 10.4% for nausea, diarrhea, vomiting, and fatigue, respectively. Finally, common grade 3 TEAEs experienced by patients were diarrhea, increased blood bilirubin levels, and asthenia which occurred at respective rates of 5.2% (n = 4), 3.9% (n = 3), and 2.6% (n = 2), respectively.
Common grade 3 hematologic TEAEs from the trial were decreased platelet counts and anemia, occurring at respective rates of 16.9% (n = 13) and 13% (n = 10).
“[These] emerging data support ongoing clinical development of nuvisertib in combination with ruxolitinib [Jakafi] and momelotinib [Ojjaara],” lead study author Lindsay A.M. Rein, MD, and coauthors wrote in a poster presentation of the data.
Rein is an associate professor of medicine, hematologic malignancies, and cellular therapy at Duke Cancer Institute in Durham, North Carolina.
JAK inhibitors occupy the current standard of care for myelofibrosis, leaving patients who are ineligible or intolerant to the treatment with limited options, underscoring the unmet need for therapies that have unique mechanisms of action and low myelosuppressive effects. Additionally, trial investigators wanted to see the effect of cytokine modulation caused by a PIM1 inhibitor such as nuvisertib.
Patients with confirmed pathological diagnoses of primary myelofibrosis, post-PV myelofibrosis, post-ET myelofibrosis and intermediate or high-risk primary or secondary myelofibrosis were enrolled in the trial.1,2 Patients also needed to have a platelet count higher than 25 x 109 L, no restriction on hemoglobin, and a spleen volume of at least 450 cm3.
Patients were treated with daily nuvisertib at 480 mg or 720 mg or twice daily at 360 mg, 480 mg, or 720 mg.1
Safety and tolerability were the primary end points of the trial. Spleen volume reduction (SVR), total symptom score (TSS) reduction, overall survival (OS), bone marrow fibrosis change, and pharmacokinetics were secondary end points.
Baseline characteristics revealed that patients were a median age of 71 years (range, 49-85) and were mostly male (53%; n = 41). Median spleen length and volumes for patients were 12 cm (range, 0-34) and 1988 cm3 (range, 270-7718), respectively. The median platelet count was 96 x 109/L (range, 24-816), and slightly more patients had a platelet count lower than 100 x 109/L (51%; n = 39). Additionally, median hemoglobin for patients in the trial was 9.7 g/dL (range, 5.6-17.2) and 39% of patients required transfusions (n = 30). Subtypes of myelofibrosis in patients were primary, post-PV, and post-ET, shown at respective rates of 48% (n = 37), 35% (n = 27), and 17% (n = 13). Ruxolitinib was the most common JAK inhibitor that patients had previous exposure to (92%; n = 71).
Regarding efficacy, the 1-year OS rate was 81%, with 18 patients remaining on treatment. Moreover, 20% of patients who were treated with a twice-daily 720-mg dose of nuvisertib (n = 20) demonstrated a SVR of at least 25%. Forty-five percent of patients at the same dose level also yielded a TSS reduction of at least 50% (TSS50). Patients with TSS50 responses had early and sustained symptom reduction, lasting for up to 100 weeks of treatment.
Bone marrow fibrosis improvements grade 1 or higher occurred in 38.2% of patients, and 8.8% instances of bone marrow fibrosis in patients worsened and 52.9% remained unchanged.
Trial investigators noted that cytokine modulation caused by PIM1 inhibition and nuviertib is associated with OS data, SVR, TSS50, and bone marrow fibrosis improvements.
