Syndax Pharmaceuticals reported Monday that a Phase I/II study of its revumenib cancer therapy met a key goal in certain patients with acute leukaemia. An independent data monitoring committee has recommended that the AUGMENT-101 trial be stopped early, with Syndax saying it plans to file for FDA approval of the oral menin inhibitor, which is also known as SNDX 5613, by year-end."This pivotal dataset of revumenib monotherapy…is very compelling in that it demonstrates significant clinical benefit that includes deep molecular remissions and is well tolerated," remarked principal investigator Ibrahim Aldoss. "A high proportion of patients [proceeded] to potentially curative transplant and re-starting revumenib therapy," he added, noting "this is especially impressive given that these patients would generally not have an option for transplant with the current treatment options."AUGMENT-101 enrolled heavily pretreated adult and paediatric patients with relapsed/refractory KMT2A-rearranged (KMT2Ar) acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL). The current analysis looked at 57 patients, the majority of whom had relapsed after salvage therapy, including nearly half having undergone prior stem cell transplant, while 72% had previously been treated with AbbVie's Venclexta (venetoclax).Stock still slipsSyndax said the trial achieved its primary endpoint with a complete remission (CR) or a CR with partial haematological recovery (CRh) rate of 23% at the interim analysis of pooled KMT2Ar AML and ALL cohorts. Another 14% proceeded to transplant without achieving CR/CRh. In addition, the rate of CR/CRh was 24.5% among the subset of 49 patients with KMT2Ar AML, while the overall response rate was 65% in this cohort. The company noted that CR/CRh responses in both the overall population and the AML subset were durable with a 6.4-month median duration as of the July 24 cut-off, with six of 13 patients remaining in response. Syndax said the results suggest revumenib has the "potential to change the treatment paradigm" for post-transplant maintenance in late-stage KMT2Ar.However, investors signalled their disappointment, pulling down company shares by about 8.5% on Monday following the readout. Syndax may have set expectations high when it reported data last December from the Phase I portion of the trial, showing a 27% CR/CRh rate in both mNPM1 and KMT2Ar acute leukaemia patients treated at the recommended Phase II dose. The median duration of CR/CRh response was 9.1 months in the efficacy evaluable population as of data cut-off at that time. More recently, Barclay's analysts suggested that a CR/CRh rate of between 25% and 30% would be positive to Syndax's stock, along with a median duration of response pointing to roughly 9+ months, which would be consistent with the Phase I data. The analysts, who estimated that revumenib could generate peak sales of $225 million by 2027, also indicated that clinical data from Kura Oncology has helped to validate the menin class and points to a "potential advantage" for revumenib in KMT2Ar acute leukaemia. In February, Kura announced that its menin inhibitor ziftomenib had shown a 30% CR rate among NPM1-mutant AML patients in a Phase I trial.Differentiation syndromeMeanwhile, the safety analysis for AUGMENT-101 looked at 94 participants, with revumenib demonstrating a profile "consistent with previously reported data," according to Syndax. However, in the Phase I portion of the trial, while differentiation syndrome occurred in 16% of patients, all cases were Grade 2.At the latest readout, the company said 15% of patients in the safety analysis experienced treatment-related differentiation syndrome that was considered to be at least Grade 3 or worse, including one case that was Grade 4. Further, QT prolongation of ≥Grade 3 occurred in 14% of patients, with no Grade 4 or 5 events. Still, Syndax indicated that "only 6% of patients discontinued due to treatment-related adverse events," and none as a result of either differentiation syndrome or QT prolongation. Other common Grade 3 or more side effects included febrile neutropenia, anaemia, as well as decreased platelet and neutrophil counts.The company plans to present additional AUGMENT-101 data in KMT2Ar acute leukaemia patients at an upcoming medical meeting.
