Dr Mascarenhas on the Initial Efficacy of Navtemadlin Plus Ruxolitinib in Myelofibrosis

John Mascarenhas, MD, professor of medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, Mount Sinai, discusses initial clinical activity observed with the addition of the first-in-class MDM2 inhibitor navtemadlin to ruxolitinib (Jakafi) in primary or secondary myelofibrosis.

The phase 1/2 KRT-232-109 study (NCT04485260) evaluated the ability of navtemadlin plus ruxolitinib to reduce spleen volume in patients with primary or secondary TP53 wild-type myelofibrosis who had previously experienced suboptimal responses with ruxolitinib alone. Based on data from the phase 1 portion, the recommended phase 2 dose was identified as 240 mg of navtemadlin for one week during 28-day cycle in addition to the stable dose of ruxolitinib. Baseline doses of ruxolitinib at study entry were either 5 mg, 10 mg, 15 mg, or 20 to 25 mg. The primary objective of the ongoing phase 2 portion was to determine the combination's efficacy as measured by symptom improvement and spleen volume reduction at 24 weeks.

Findings showed that 42% of all patients (n = 28) experienced a clinically meaningful reduction in spleen volume of at least 25%, and 32% experienced a spleen volume reduction of at least 35% with the combination at 24 weeks, Mascarenhas reports. Moreover, 32% of patients experienced at least a 50% increase in total symptom score, he states. As many of these patients had substantial symptom burden at baseline, this further signals the drug's efficacy, Mascarenhas emphasizes.

Additionally, patients who received the lowest dose of ruxolitinib twice a day and had large spleens experienced meaningful and deep spleen volume and symptom reduction from baseline to week 24, Mascarenhas notes. There were no dose escalations or de-escalations at this dose level, suggesting that these higher responses were not driven by increasing dose of ruxolitinib, nor was toxicity a major factor, he says. Accordingly, the synergistic activity of this combination is in line with preclinical data showing that navtemadlin bolsters the reduction of p51, thereby selectively inducing TP53-mediated apoptosis alongside ruxolitinib, Mascarenhas concludes.

Disclosures: Mascarenhas reports consulting and research funding from Abbvie, Celgene/BMS, Imago, Incyte, CTI BioPharma Corp, Galecto, Geron, GSK, Kartos Therapeutics, Karyopharm, Novartis, Pfizer, and PharmaEssentia.