Dr Mascarenhas on the Rationale for the KRT-232-109 Study in Secondary Myelofibrosis

John Mascarenhas, MD, professor, 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 the rationale for adding the first-in-class MDM2 inhibitor navtemadlin to ruxolitinib (Jakafi) in patients receiving treatment for primary or secondary myelofibrosis who have previously had suboptimal responses with ruxolitinib.

Notably, oncologists investigated this treatment approach in the phase 1b/2 KRT-232-109 study (NCT04485260) and presented updated data from the trial at the 2023 EHA Congress. The phase 1/2 trial evaluated the effects of navtemadlin in combination with ruxolitinib on spleen volume reduction in patients with primary or secondary TP53 wild-type myelofibrosis who have previously experienced suboptimal responses with ruxolitinib alone.

Myelofibrosis is predominantly a p53 wild-type disease, Mascarenhas begins, adding that MDM2 negatively regulates p53. p53 pathways are important for regulating cells and balancing pro-survival and pro-death signals in cells, he adds. In myelofibrosis, the overexpression of MDM2 in CD34 cells negatively regulates p53 activities; it is an alternative mechanism for cancer cells to increase their apoptosis induction threshold, Mascarenhas explains.

Because of this unmet need in patients with secondary myelofibrosis, oncologists investigated treatment with navtemadlin and ruxolitinib. Navtemadlin interrupts the interaction between MDM2 and wild-type p53, thereby activating p53 and inducing apoptosis, he expands. Mascarenhas shares his excitement that the phase 1b/2 study is adding navtemadlin to ruxolitinib for patients with a suboptimal response to ruxolitinib because ruxolitinib works synergistically with navtemadlin by introducing a protein called p21, which is a checkpoint inhibitor.

p21 further lowers the cancer cells’ apoptotic threshold to induce apoptosis in the setting of navtemadlin, Mascarenhas continues. Together, navtemadlin and p21 induce apoptosis in CD34-positive myelofibrosis cells, Mascarenhas says. Preclinical data justify this concept and provide the rationale for the clinical testing of navtemadlin plus ruxolitinib, Mascarenhas concludes.