In a first-in-human trial treatment using a new targeted anticancer drug, revumenib, resulted in remission in patients with a common form of leukemia. But therapy also induced the cancer cells to reveal one mechanism by which they can resist revumenib, investigators at Dana-Farber Cancer Institute and other research centers reported in two separate studies published in Nature. The teams say that their combined findings point to the promise of a targeted approach to acute leukemia treatment that is exemplified by revumenib, and also to the potential to extend its benefits using drugs that trip up the identified resistance mechanism.
One of the two newly released papers “The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia,” describes results from the ongoing Phase I/II clinical trial in which approximately 40% of patients with two subtypes of acute leukemia exhibited a complete response—a disappearance of all signs of cancer—to treatment with revumenib. In their paper, the investigators wrote, “We found an encouraging clinical benefit, with deep molecular remissions and minimal toxicities, in a heavily pretreated population of both children and adults with advanced acute leukaemia.” However, a proportion of patients developed resistance to the drug, and in a second published paper “MEN1 mutations mediate clinical resistance to menin inhibition” the researchers describe a molecular countermove by which the leukemia cells develop resistance by sidestepping the drug and so reassert their growth.
The prognosis for patients with acute leukaemias harbouring rearrangements of the gene lysine methyltransferase 2A (KMT2A)—previously known as mixed-lineage leukaemia (MLL) —is poor, with a five-year overall survival of less than 25%, the authors wrote in their paper describing the clinical trial. “KMT2A rearrangements (KMT2Ar) occur in 80% of infant acute lymphoblastic leukaemia (ALL) and in 5–15% of children and adults with acute leukaemia, whether myeloid, lymphoid or mixed phenotype.” Mutations in another gene, nucleophosmin 1 (NPM1) represent the most common genetic alteration in adult acute myeloid leukaemia (AML), and are present in up to 30% of patients. The Phase I/II trial was designed to investigate the effectiveness of revumenib in leukemia patients harboring either KMT2A gene rearrangements, or NPM1 mutations.
“The two genetic subtypes of acute leukemia involved in this research account for approximately 40% of all cases of acute myeloid leukemia (AML) in children and adults,” said Scott Armstrong, MD, PhD, president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and co-senior author of the paper on revumenib resistance. “They’re driven by a rearrangement of the MLL1 gene or a mutation in the NPM1 gene. Both types depend on a protein called menin to sustain their growth.”
The authors further explained in their paper on revumenib resistance, “Acute leukaemias driven by rearrangement of the mixed lineage leukemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukemogenic gene expression programs.” However, they continued, “Currently there are no targeted therapies specifically approved for acute leukaemia with KMT2Ar or mutated NPM1 … Despite notable progress in the treatment of childhood acute leukaemia, infant KMT2Ar acute leukaemias have remained a therapeutic challenge with high rates of resistance to multi-agent chemotherapy.”
Menin is a critical part of the cell’s epigenetic mechanism for switching gene activity on and off. It binds to chromatin – the braid of DNA and protein packaging within the nucleus – and summons large protein complexes to join it. The complexes tighten or loosen the coils of DNA, changing the activity level of the genes at that site. One of the key proteins within these complexes is MLL1. Revumenib contains a small molecule that inhibits the interaction of menin and MLL1,” Armstrong explained. The first-in-human Phase I/II AUGMENT-101 clinical trial evaluated revumenib therapy in 68 patients with acute leukemia that exhibited either KMT2A rearrangements or mutated NPM1, and whose disease wasn’t responding to other therapies.
The study population included 56 patients (82%) with relapsed or refractory AML, 11 (16%) with ALL and one with mixed-phenotype acute leukaemia (2%). Forty-six patients (68%) had KMT2Ar, 14 (21%) had mutated NPM1 and another eight (12%) had neither KMT2Ar nor NPM1 mutations. Sixty patients were adults (at least 18 years old) and eight were children or adolescents (under 18 years of age). The median adult age was 50.5 years, and the median pediatric age was 2.5 years, with the youngest patient being under one year old. “All patients who received at least one dose of revumenib were included in the safety analysis whereas only patients with KMT2Ar or mutated NPM1 were included in the efficacy analysis,” the trial investigators explained.
The study found that of 60 patients who could be evaluated, 53% responded to the drug and 30% had a complete response.The authors reported, “In this first-in-human clinical trial, we provide clinical evidence of the effectiveness of menin inhibition with an oral targeted therapy, which is the first epigenetic therapy that evicts protein complexes from chromatin, leading to remissions in patients with acute leukaemia. We found an encouraging clinical benefit, with deep molecular remissions and minimal toxicities, in a heavily pretreated population of both children and adults with advanced acute leukaemia.” Armstrong added, “For patients with acute leukemia who have undergone several previous treatments, this is a very encouraging result.”
However as Armstrong further noted, “… after the second cycle of treatment, some patients did develop resistance to revumenib.” And writing in their second paper detailing revumenib resistance, the team noted “Despite significant single-agent activity of revumenib in a heavily pretreated patient population with KMT2Ar and NPM1-mutant leukaemia, we identified patients who were treated on the AUGMENT-101 Phase 1 study and subsequently developed acquired resistance following an initial response.”
For this follow-up study, Armstrong colleagues sought to identify the source of revumenib resistance. When they analyzed bone marrow samples from some of the patients who became resistant to the treatment they found that many individuals had developed mutations in the menin protein gene, MEN1. “… we identified somatic mutations in MEN1 at the revumenib–menin interface in patients with acquired resistance to menin inhibition,” they wrote. The mutation leads to a deformed version of menin that doesn’t bind well to revumenib but does still attach firmly to MLL1. So, as menin and MLL1 are able to renew their interaction, leukemia cell growth restarts.
As the authors explained, “These mutants attenuate drug–target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin.” The finding provides “formal proof in patients that menin itself is a valid target for therapy in both genetic subtypes of AML,” Armstrong commented.
Revumenib in effect acted akin to a truth-telling serum. By placing leukemia cells under pressure, it prompts them to unveil one of their strategies for survival. “The fact that the cell has gone through so much trouble to mutate MEN1 in order to survive is a strong indication that we’re hitting a target the cell truly relies on,” Armstrong stated. And the ability of revumenib to stress leukemia cells to the point where they develop a mutation in order to remain alive is testament to the drug’s effectiveness, he continued. “This is the first time a drug targeting a chromatin-binding protein complex has been shown to put that degree of pressure on cancer in a human patient.” “To our knowledge, this is the first report of clinically occurring somatic mutations that mediate acquired resistance to small molecules targeting chromatin-binding protein complexes,” the authors stated. “These data support chromatin complexes and epigenetic mechanisms as critical therapeutic targets in cancer but also suggest that a common mechanism of resistance to therapies targeting these complexes may result from acquired mutagenesis of essential, non-driver epigenetic regulators.”
By tracking the development of mutations in MEN1 and other genes in patients with acute leukemia, doctors may be able to identify patients at high risk of relapsing, Armstrong suggested. These patients might then benefit from further treatment. The discovery of MEN1 mutation as a resistance mechanism suggests that new drugs that specifically target menin or other chromatin-associated proteins could prevent or delay revumenib resistance or treat patients who have become resistant to the drug. “Most importantly, the discovery of acquired mutations in menin validates the menin–MLL1 interaction as a key oncogenic driver in patients with AML harbouring KMT2Ar or NPM1 mutations and, as such, represents a promising therapeutic target,” the authors pointed out.
“Seeing Dr Armstrong’s work translated elegantly into the clinic where patients—including some at Dana-Farber, who had dramatic responses in dire situations—was highly gratifying personally and professionally,” said Dana-Farber’s Richard Stone, MD, a co-author of both the Nature studies. “We are now ready to magnify the impact of these results by conducting clinical trials combining revumenib with standard chemotherapy as well as with novel agents, also based on preclinical work done in great part by Armstrong.”
