StemCell Therapy

Novel agents that disrupt protein-protein interactions in the MLL network may be the key to unlocking new therapeutic avenues for patients with acute leukemias, which are characterized by diverse genetic and epigenetic alterations that are challenging to target, according to investigators.1

Early clinical data have demonstrated an antitumor effect of small molecule inhibitors directed at interactions of menin, a tumor suppressor protein, and MLL fusion proteins in acute myeloid leukemia (AML).2 One such agent, KO-539, is being investigated in 2 genetic subsets of AML: patients with rearrangements in KMT2A (also known as MLL1 or MLL) or with NPM1 mutations, which both promote leukemogenesis.

KMT2A(MLL) translocations are found in approximately 5% to 10% of patients with acute leukemias, including lymphoid, myeloid, or biphenotypic subtypes2; the 5-year survival rate for this population is approximately 35%.1 Over 30% of patients with AML have NPM1 mutations that, when they occur along with FLT3-ITD mutations, result in an overall survival rate of less than 50%.1

Investigators believe that menin is involved with a variety of cellular processes including aiding in the structural modification of MLL that stabilizes the bond between MLL and lens epithelium derived growth factor, a transcriptional coactivator believed to play a role in cancer.2 By causing a genetic disruption of the menin-MLL fusion protein interaction, they hypothesize, a novel agent could block the development of acute leukemia (Figure).3

In preclinical research, KO-539 prolonged survival compared with quizartinib, a FLT3 inhibitor, in 2 patient-derived xenograft models of NPM1/DNMT3/FLT3-mutant AML. In a confirmatory study, animals that were NPM1- and FLT3-mutant/DNMT3A wild-type and were treated with quizartinib relapsed by approximately day 35; those treated with KO-539 had no evidence of disease progression after 56 days.4

Although translocations of KMT2A(MLL) occur in approximately 3% of patients with AML, the mutational burden of these patients is far less than that of other cancer types; as a result, the translocations alone may result in the generation of the leukemic phenotype. Further, gene expression profiling has demonstrated overexpression of both HOXA9 and MEIS1, 2 oncoproteins thought to be critical for enhanced self-renewal in AML. Specifically, transcription of the HOXA9 and MEIS1 genes are dependent on KMT2A(MLL)-fusion protein binding to menin.5

The menin-MLL interaction seems to trigger the upregulation of certain leukemogenic or leukemia-promoting proteins, such as HOXA9 and MEIS1, said Amir T. Fathi, MD, in an interview with OncLive. [Developing] drugs that inhibit the leukemogenic signals can, in theory, lead to promotion of differentiation and maturation and response. Fathi is an associate professor of medicine at Harvard Medical School and director of the Leukemia Program at Massachusetts General Hospital, both in Boston.

Although KMT2A(MLL) and NPM1 alterations currently are the frontrunners as targets for in-human studies, Fathi suggested that, in time, investigators may learn more about efficacy in other subpopulations of patients with AML whose disease may be affected by epigenetic dysregulation from the menin-MLL interaction. If so, such findings may emerge as points of interest.

Other mutations that are seen in AML and myeloid malignancies, such as NPM1, DNMT3, EZH2, and others, appear to have their impact upstream from the menin-MLL, interaction, Fathi said. These alterations, too, can theoretically affect the menin-KMT2A interaction and complex and promote epigenetic dysregulation and leukemogenesis.

Because of the potential for broad efficacy, KO-539 is undergoing testing in a varied patient population in the phase 1 portion of the KOMET-001 trial (NCT04067336). We are assessing patients across a wide range of molecular subtypes to further define who may benefit from this class of targeted drug, explained Fathi, one of the leading investigators. We suspect that some patients with an NPM1 mutation or those with MLL rearrangements may be susceptible to response based on what we know from preclinical science, and we should study these populations carefully, but we are also assessing more broadly initially across AML to better characterize the other patient populations that may benefit.

KOMET-001 is the first in-human study of the menin-MLL inhibitor, which is being developed by Kura Oncology. The study will evaluate the safety and tolerability of escalating doses of KO-539 monotherapy for patients with relapsed and/or refractory AML.

Up until now, initial studies have been done extensively in preclinical models, said Eunice S. Wang, MD. If we extrapolate from some of our clinical models, we think that a dose of approximately 600 milligrams once per day would be effective, but because this is a first-in human study, we [followed] the typical phase 1 study design where we increase the dose.

Wang serves as chief of Leukemia Service, medical director of Infusion Services, at Roswell Park Comprehensive Cancer Center, and an associate professor in the Department of Medicine at Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo. She is scheduled to present preliminary data from the study during the 2020 American Society of Hematology Annual Meeting, which is being held in a virtual format December 5 to 8.

In an interview in advance of her presentation, Wang noted that investigators used a novel study design and started the first dose of KO-539 at 50 mg. KO-539 was administered orally once daily to patients in 28-continuous-day cycles and, as of data cutoff of August 10, 2020, 6 patients had proceeded through to the 200-mg dose. Following this, an expansion cohort of 3 patients at a 200 mg dose was initiated to better characterize the pharmacokinetics and exposure of KO-539.6

Early data show that KO-539 demonstrated biologic activity in 3 patients in the first 3 dose cohorts of 50 mg, 100 mg, and 200 mg. Tumor lysis syndrome was reported for 2 patients in the 50- and 200-mg cohorts. The patients had a KMT2A(MLL)-rearrangement and a TP53 mutation with a PICALM-AF10 fusion, respectively. The third patient treated at the 100-mg dose level had SETD2 and RUNX1 comutations and achieved a complete remission with confirmed negative minimal residual disease after 2 cycles of therapy. The patient remains on treatment.6

Although the study sample data are too small to reach conclusions, activity of the agent is promising. The complete remission data was very exciting, for a pill taken once a day for a patient who had multiple relapses, said Fathi. The responding patient did not have an MLL-translocation nor an NPM1-mutation, but there were other alterations that may have ultimate effects on the menin-MLL interaction and whose disease may thus have been susceptible to menin inhibition. It leaves open the door for the possibility to identify other groups of patients across AML who may benefit.

In safety data for 3 evaluable patients, no dose-limiting or dose-interrupting toxicities have been reported.6 Wang plans to present updated safety and efficacy data at the meeting.

Expansion cohorts are planned to further assess the safety and activity of KO-539 in an NPM1-mutant cohort and a KMT2A(MLL)-rearranged cohort. Right now, the expansion cohorts are designed to target subsets of patients with AML that have those specific mutations, said Wang. However, if we see evidence [of efficacy] in the early dose-escalation trials, we may consider trying to expand out [to other mutational subtypes] as well to a pool of patients with leukemia that are what we call mutation agnostic.

Theres still a lot of ground to go and patients to enroll, but there is a lot of opportunity to probe that signal a little bit more, to learn more, and to hopefully help these patients, Fathi said.

Another drug that aims to disrupt menin-MLL interactions is SNDX-5613, an oral inhibitor being developed by Syndax Pharmaceuticals under an FDA orphan drug designation for adults and pediatric patients with AML.7 The phase 1/2 AUGMENT-101 trial (NCT04065399) is testing the agent in patients with relapsed/refractory leukemias.

The study, which seeks to recruit 186 pediatric and adult patients, will evaluate escalating doses of SNDX-5613 monotherapy in phase 1. After the recommended dose is established, patients will be enrolled in 1 of 3 cohorts: acute lymphoblastic leukemia or mixed phenotype acute leukemia; KMT2A(MLL)-rearranged AML; and NPM1-mutant AML.8

Read more:
MLL Fusion Proteins Emerge as a Promising Target in AML - OncLive

This entry was posted on December 4, 2020 at 12:03 am and is filed under Genetic medicine. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |