After positive results from the phase 1/2 KRT-232-109 study, the phase 3 BOREAS-2 study will further evaluate the combination of navtemadlin and ruxolitinib in patients with myelofibrosis.
Clinically meaningful improvements in spleen volume reduction (SVR) were observed with ruxolitinib (Jakafi) plus navtemadlin in patients with primary or secondary TP53 wild-type myelofibrosis who experienced suboptimal response to ruxolitinib alone, according to findings from the phase 1/2 KRT-232-109 study (NCT04485260).1
Data presented at the 2023 EHA Congress showed that among evaluable patients at week 24 (n = 19) the addition of the MDM2 inhibitor elicited an SVR of at least 25% in 8 patients (42%) and an SVR of at least 35% in 6 patients (32%). Total symptom score improvement of at least 50% (TSS) was reported in 32% of patients.1
“Myelofibrosis is a clonal hematologic malignancy that arises from the level of the hematopoietic stem cell, driven by JAK/STAT signaling and ruxolitinib is a fantastic drug to afford symptom and spleen benefit but does not do that in many patients leaving them suboptimal and in need of further therapy,” John O. Mascarenhas, MD, said. Mascarenhas is professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of Tisch Cancer Institute in New York, New York.
Navtemadlin, formerly KRT-232, a first-in-class MDM2 inhibitor, demonstrated clinical activity as a single agent in patients with relapsed or refractory myelofibrosis.2 For patients with poor response to JAK inhibitors, investigators hypothesized that the mechanisms of action of JAK and MDM2 inhibitors would suppress survival signaling in the BCL2 proteins.1
“MDM2 is a negative regulator of wild-type TP53, [which] is the master regulator of sulfate induces p21 and cell cycle arrest, but most importantly induces mediators of apoptosis, added Mascarenhas who is also director of the Adult Leukemia Program at Mount Sinai. “What we’re trying to do [with navtemadlin is] induce apoptosis or programmed cell death selectively in the malignant CD34 cells by changing the balance between prosurvival and antisurvival mediators.
MPN CD34 cells overexpress MDM2, Mascarenhas explained, adding that this provides a therapeutic window to selectively target CD34 cells with navtemadlin. The rationale for combining this agent with ruxolitinib is supported by preclinical data demonstrating that in p51 is reduced with the dual agent regimen, therefore reducing the threshold for apoptosis, Mascarenhas said.
Further, at the data cutoff of May 2, 2023, the median time on treatment was 6 months or greater. The median decrease in CD34+ cell from C1D1 prior to treatment with navtemadlin to the combination at week 12 was –85% (n = 7). At week 24, the median decrease was –95% (n = 5). The mean decreases were –80% and –86%, respectively.1
For patients in this population the individual SVR changes from baseline to week 24 were reported and included baseline ruxolitinib dose administered orally once daily, baseline spleen volume, and prior ruxolitinib duration in years. These assessments were conducted by central review using MRI/CT imaging.1
The greatest reduction (SVR, –63%) was reported in a patient with a baseline spleen volume of 1967 cm3, who received a baseline ruxolitinib dose of 10 mg, and whose prior exposure to ruxolitinib was 1.3 years. The highest TSS reduction was –79% from baseline 20.1. TSS was evaluated using the myelofibrosis symptom assessment form version 4.0, this patient was receiving 5 mg of ruxolitinib at baseline and at week 24 with a prior exposure to ruxolitinib of 1.4 years.
The patient with the smallest SVR (–2%), had a baseline spleen volume of 3549 cm3, a baseline ruxolitinib dose of 25 mg, and their prior ruxolitinib exposure was 9.1 years. TSS increased in 2 patients with baseline scores of 15.4 and 15.0 at rates of 16% and 7%, respectively.1
To be eligible for the study, patients were required to be symptomatic with splenomegaly, have an ECOG performance status of 0 to 2, platelet count of at least 100 × 109/L, and be receiving a stable dose of ruxolitinib of at least 5 mg orally once daily for 8 weeks or longer. Those who experienced spleen response or progression with ruxolitinib were not eligible for enrollment.1,3
Twenty-eight patients were enrolled to receive navtemadlin 240 mg plus stable ruxolitinib dose at the time of data cutoff. This dose was determined following outcomes from phase 1b of the study which evaluated navtemadlin at 120 mg (n = 4), 180 mg (n = 4), and 240 mg (n = 6) in addition to the dose of ruxolitinib patients were receiving at enrollment for at least 18 weeks.1
The most common myelofibrosis subtype was secondary (64%) and most had a dynamic international prognostic scoring system for myelofibrosis score of intermediate 1/2 (75%), with 25% having a score of high. The median duration of prior ruxolitinib was 21.6 months (range, 7-129). Median spleen volume was 2039 cm3 (range, 650-3549) and the median TSS was 15.0 (range, 3.2-49.1).1
Median platelet counts at baseline was 165 ´ 109/L (range, 100-636). Fourteen patients had hemoglobin level of less than 10 g/dL (50%) and 7 patients (25%) were transfusion dependent. The median prior lines of therapy was 1 (range, 1-5).1
Ruxolitinib dose at entry was as follows: 5 mg (14%), 10 mg (25%), 15 mg (18%), and 20 to 25 mg (39%). In discussing the SVR responses, which Mascarenhas noted are FDA supported primary end points, he said, “Importantly, I want to draw your attention to the dose of ruxolitinib at baseline and at week 24. At baseline you can see that even patients who are receiving 5 mg twice a day of ruxolitinib, even in the setting of big spleens had significant SVR with the addition of navtemadlin. If you look at the week 24 doses, you’ll notice 2 things. One is that there were no dose escalations—the patients who were having these responses were not driven by increasing dose of ruxolitinib. And 2, there were no dose de-escalation, therefore there was no toxicity driving that aspect either.”
Potential for disease modification was also reported using improvement of at least 1 grade for bone marrow fibrosis via central pathology review at week 24. Among 7 evaluable patients, 57% of patients had an improvement, with 2 patients having an improvement of at least 1 grade and 2 patients having an improvement of at least 2 grades. Additionally, 2 patients had stable fibrosis and 1 patient experienced worsened fibrosis.
Finally, a reduction of driver VAF of at least 20% via central review was 71% (n = 5 of 7).
In terms of safety, most treatment-emergent adverse effects (TEAEs) were grade 1/2. Any-grade TEAEs were reported in 96% of patients and grade 3/4 AEs were reported in 46% of patients. The most common any-grade TEAEs were nausea (68%), diarrhea (64%), thrombocytopenia (61%), constipation (43%), vomiting (39%), asthenia (32%), anemia (25%), and fatigue (25%). ALT increase, dysgeusia, and abdominal pain were each reported in 14% of patients. Headache, gastroesophageal reflux, decreased appetite, pyrexia, pruritis, and urinary tract infection were each reported in 11% of patients. Grade 3/4 TEAEs included thrombocytopenia (29%), anemia (18%), nausea (7%), diarrhea (4%), vomiting (4%), asthenia (4%).1
The randomized, double-blind, phase 3 BOREAS-2 study will further evaluate this combination vs placebo in patients with myelofibrosis with suboptimal response to ruxolitinib. The study is not yet recruiting.4
1. Mascarenhas J, Jain T, Otoukesh S, et al. An open-label, global, phase (Ph) 1b/2 study adding navtemadlin (NVTM) to ruxolitinib (RUX) in patients (Pts) with primary or secondary myelofibrosis (MF) who have a suboptimal response to RUX. HemaSphere. 2023;7(suppl 3):S210.
2. Vachani P, Lange A, Garcia Delgado R, et al. Potential disease-modifying activity of navtemadlin (KRT-232), a first-in-class MDM2 inhibitor, correlates with clinical benefits in relapsed/refractory myelofibrosis (MF). Blood. 2021;138(suppl1):3581. doi:10.1182/blood-2021-147543
3. An open-label, multicenter, phase 1b/2 study of the safety and efficacy of KRT-232 combined with ruxolitinib in patients with primary myelofibrosis (PMF), post-polycythemia vera MF (Post-PV-MF), or post-essential thrombocythemia MF (Post ET-MF) who have a suboptimal response to ruxolitinib. ClinicalTrials.gov. Updated May 9, 2022. Accessed June 10, 2023. https://clinicaltrials.gov/ct2/show/NCT04485260
4. Our clinical research. Kartos Therapeutics. Accessed June 10, 2023. https://kartosthera.com/research