Welcome to The Five Under 5, your go-to roundup of the top 5 videos of the week.
These short videos are designed for busy oncologists to view on the go, and feature expert insights on breaking news, regulatory updates, practice-changing data shared at medical meetings, and other key topics in the realm of oncology.
Here’s what you may have missed:
FDA Approval of Ropeginterferon Alfa-2b for Essential Thrombocythemia: Ruben A. Mesa, MD, FACP
Ruben A. Mesa, MD, FACP, of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, examined the FDA approval of ropeginterferon alfa-2b-njft (Besremi) for adult patients with essential thrombocythemia (ET), regardless of genotype or disease status. ET affected an estimated 150,000 to 200,000 people in the United States, many of whom were younger patients, and treatment options had historically been limited to anagrelide (Agrylin) and off-label hydroxyurea, Mesa noted. He explained that hydroxyurea lowered platelet counts without meaningfully altering the underlying biology of ET and carried risks such as skin toxicity and secondary skin cancers. The approval was supported by the phase 3 SURPASS-ET trial (NCT04285086), in which the durable modified European LeukemiaNet response rate at months 9 and 12 was 37.4% (95% CI, 27.4%-48.1%) with ropeginterferon alfa-2b (n = 91) vs 3.6% (95% CI, 0.8%-10.2%) with anagrelide (n = 83). Mesa expressed enthusiasm about the data, noting the agent may address the underlying disease biology rather than platelet counts alone.
Long-Term Data for Dose-Optimized Ponatinib in CML: Hagop M. Kantarjian, MD
Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center, reviewed 5-year follow-up data from the phase 2 OPTIC trial (NCT02467270) evaluating a response-based dose-optimization strategy for ponatinib (Iclusig) in chronic-phase chronic myeloid leukemia. Patients with a BCR::ABL1 T315I mutation or resistance to at least 2 prior TKIs began ponatinib at 45 mg, 30 mg, or 15 mg daily, with doses reduced to 15 mg once BCR::ABL1 transcript levels fell below 1%, Kantarjian explained. The dose-adjusted schedule lowered rates of arterial and venous occlusive adverse effects, hypertension, and skin rash compared with continuous 45-mg dosing, he said. Among patients with a baseline T315I mutation, the 5-year overall survival rate was 86.3% (95% CI, 63.2%-95.4%) for those starting at 45 mg, versus 61.7% (95% CI, 37.7%-78.7%) and 31% (95% CI, 44.1%-85%) for the 30-mg and 15-mg starting doses, respectively. Kantarjian concluded that optimizing the ponatinib dose schedule preserved potency while substantially improving tolerability.
The Mechanism of Action of INCB161734 in KRAS G12D–Mutated Metastatic Pancreatic Cancer: Brandon Huffman, MD
Brandon Huffman, MD, of Dana-Farber Cancer Institute, detailed the mechanism of action of the KRAS G12D inhibitor INCB161734 and the design of the phase 3 DAWN-303 trial (NCT07522073) evaluating the agent in previously untreated, KRAS G12D–mutated metastatic pancreatic ductal adenocarcinoma (PDAC). INCB161734 was a selective, noncovalent inhibitor that bound the switch II pocket of mutant KRAS with picomolar affinity and demonstrated greater than 80-fold selectivity over wild-type KRAS, functioning as a dual ON/OFF inhibitor that Huffman said distinguished it from molecular glue degraders and PROTAC-based agents. In the phase 1 INCB161734-101 trial (NCT06179160), single-agent INCB161734 produced an overall response rate of 37% and a disease control rate of 78% in heavily pretreated patients with PDAC at the recommended phase 2 dose of 1200 mg once daily (n = 41). Huffman explained that patients enrolled in DAWN-303 received a chemotherapy backbone of mFOLFIRINOX or gemcitabine plus nab-paclitaxel (Abraxane) before being randomly assigned to that regimen combined with either INCB161734 or placebo, with overall survival, progression-free survival, and overall response rate by blinded independent central review serving as primary end points. He noted that preliminary data showed the combination was well tolerated without added toxicity beyond what would be expected from either agent alone.
How to Approach JAK Inhibitor Selection in Myelofibrosis: Aaron Gerds, MD, MS
Aaron Gerds, MD, MS, of Cleveland Clinic, outlined his approach to selecting among the 4 FDA-approved JAK inhibitors—ruxolitinib (Jakafi), fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara)—for patients with myelofibrosis. Ruxolitinib remained the reflexive first choice in clinic as the first JAK inhibitor approved in this setting, and clinicians typically considered it before weighing the other agents, Gerds said. For patients with proliferative myelofibrosis, defined as a good platelet count without significant anemia, ruxolitinib was the right choice, while momelotinib was preferred for those with myelofibrosis-associated anemia who needed spleen and symptom control, he noted. Pacritinib was reserved for patients with platelet counts below 50 × 10⁹/L or those at risk of falling to that level, reflecting enrollment in the phase 3 PERSIST-2 trial (NCT02055781), which included patients with platelet counts as high as 100 × 10⁹/L. Gerds concluded that fedratinib was his choice for patients previously treated with ruxolitinib, citing high rates of spleen volume and symptom response with the agent in the phase 2 JAKARTA2 trial (NCT01523171).
The Rationale for Exploring Mavorixafor in Chronic Neutropenia: David Sykes, MD, PhD
David Sykes, MD, PhD, of Massachusetts General Hospital, explored the rationale for evaluating the oral CXCR4 antagonist mavorixafor (Xolremdi) in patients with chronic neutropenia. In adults, chronic neutropenia is likely immune-mediated in most cases, presenting as autoimmune neutropenia of uncertain B-cell, T-cell, or natural killer-cell origin, and granulocyte colony-stimulating factor (G-CSF) remained the mainstay of treatment despite working only by prompting the bone marrow to produce more neutrophils, Sykes said. Mavorixafor, already approved for patients 12 years and older with WHIM syndrome, instead releases immature neutrophil progenitors and band cells into circulation rather than mature cells, offering the theoretical advantage that these cells might evade an immune response typically directed at fully mature neutrophils. In an open-label phase 1b/2 trial (NCT04154488), monotherapy produced durable mean increases in absolute neutrophil count (ANC), with patients who had severe disease achieving nearly 3-fold increases out to 6 months, while all patients with congenital neutropenia on G-CSF reduced their dose and maintained a normal mean ANC. Sykes noted that the agent was being evaluated further in the pivotal phase 3 4WARD trial (NCT06056297).
