iwAL 2022 Session III: novel targets, combinations and treatment strategies in AML
Nov 16, 2022
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Experts Richard Stone and David Sallman discuss novel targets, combinations, and treatment strategies in AML. They explore the potential of drugs Eptenoprop and Magrolumab for TP53-mutated AML, and the importance of mature data sets and specific population focus in phase three trials. The use of complete remission rate as a primary endpoint for TP53 mutant patients is questioned, and CD47 inhibition as a potential therapy is explored.
P53 refolding agents like Eptenoprop and Magrolumab show promise in treating AML, with response rates of around 70% and overall survival at 12 months in phase two studies, but future efficacy remains uncertain due to negative phase three trials in MDS.
Combination studies with Magrolumab and other agents like Venetoclax have demonstrated promising response rates in TP53 AML patients, highlighting their potential as an interesting option to target TP53 mutated patients.
Deep dives
Development of P53 refolding agents in AML
Experts discuss the potential of P53 refolding agents in treating AML, particularly focusing on drugs like Eptenoprop and Magrolumab. Phase two studies showed promising results with response rates of around 70% and overall survival at 12 months. Some patients even achieved deep CR before transplantation. However, phase three trials in MDS were negative, raising questions about the future of these drugs. Combination studies with other agents like Venetoclax showed promising response rates in TP53 AML patients, making them a potential interesting option to target TP53 mutated patients.
Challenges and insights from the Eplenetapot phase three trial
The Eplenetapot phase three trial failed to show significant improvement, leading to discussions about potential reasons. Concerns were raised about study design, including the open-label nature and potential differences in patient treatment and drug handling between arms. It was also noted that the control arm exhibited better outcomes than expected. Experts suggest focusing on overall survival (OS) as the primary endpoint for TP53 studies, rather than complete remission (CR), given the lack of durability and depth in remissions. Ongoing phase three studies for Magrolumab with a larger patient population and double-blind placebo control are expected to provide additional insights.
The potential of Magrolumab in P53 mutant patients
Magrolumab, an anti-CD47 antibody, shows promise as a favored option for P53 mutant patients. By inhibiting CD47, which helps cancer cells avoid the immune system, Magrolumab enables antibody-dependent cellular phagocytosis and enhances the activity of agents like Aesocidating. Preclinical models demonstrated activity, but monotherapy showed limited complete remission. Combining Magrolumab with agents that induce pro-phagocytic signals, such as Aesocidating, led to synergy. However, the full mechanism of action and the significance of molecular clearance and LSC eradication require further study. Phase three trials will provide more conclusive evidence on the efficacy of Magrolumab in P53 mutant patients.
The 4th International Workshop on Acute Leukemias (iwAL) 2022 took place in Nice, France, and brought together leading experts in the field as they discussed several topics. In this podcast series, you will hear the latest updates in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and gain an insight into the sessions that took place at this year’s meeting.
In this podcast, Richard Stone, MD, Dana-Farber Cancer Institute, Boston, MA, David Sallman, MD, H. Lee Moffitt Cancer Center, Tampa, FL, and Thomas Cluzeau, MD, PhD, Central University Hospital of Nice, Nice, France, discuss novel targets and combinations in AML, treatment approaches for patients with TP53-mutated disease, and more.