Updated Results and Longer Follow-up from the AUGMENT-101 Phase 2 Study of Revumenib in All Patients with Relapsed or Refractory (R/R) KMT2Ar Acute Leukemia

Background: Rearrangements of the lysine methyltransferase 2A (KMT2Ar) gene occur in ≤10% of acute leukemias (ALs) and are associated with a poor prognosis. In patients (pts) with KMT2Ar AL, the menin-KMT2A fusion protein interaction is a key driver of leukemogenesis. Revumenib, an oral, potent, and selective menin inhibitor, demonstrated a high rate of complete remission (CR) or CR with partial hematologic recovery (CR+CRh; 23%) and overall response rate (ORR; 63%) with a tolerable safety profile in pts with R/R KMT2Ar AL in the phase 2 interim analysis of AUGMENT-101 (NCT04065399). The KMT2Ar cohorts met prespecified stopping rules for efficacy, and the data from this analysis (n=57) were the basis for a New Drug Application to the FDA. Here we report longer follow-up and a larger data set, including safety and efficacy results for all pts with KMT2Ar enrolled in the phase 2 study (N=116), representing the largest evaluation of menin inhibition in pts with R/R KMT2Ar AL to date.

Methods: Pts aged ≥30 d with R/R KMT2Ar AL were enrolled and received revumenib 163 mg (95 mg/m² if body weight <40 kg) every 12 h (q12h) with a strong CYP3A4 inhibitor azole in 28-d continuous cycles. Treatment continued until lack of at least morphological leukemia-free state (MLFS) after 4 cycles, disease progression, or unacceptable adverse events (AEs). Primary objectives were safety and tolerability and rate of CR+CRh. Key secondary endpoints included rate of composite CR (CRc [CR+CRh+CR with incomplete platelet recovery+CR with incomplete count recovery), ORR (CRc+MLFS+partial remission), and duration of response (DoR). The efficacy population included pts with centrally confirmed KMT2Ar and ≥5% baseline bone marrow blasts. Measurable residual disease (MRD) was assessed locally by flow cytometry or PCR at the discretion of investigators.

Results: At the time of the interim analysis (data cutoff [DCO]: July 24, 2023), 13 pts achieved CR+CRh (23%), 6 of whom remained in follow-up with no relapse or death at that time. In this current analysis, with 7 additional mo of follow-up (DCO: February 29, 2024), the updated median duration of CR+CRh in these 13 responders was 13.0 mo (95% CI, 3.4 mo-not reached [NR]); 5 remained in follow-up with no relapse or death, while 1 more pt had relapsed.

A total of 116 pts with R/R KMT2Ar AL received ≥1 dose of revumenib and were included in the safety population. Median age was 35.5 y (range, 0.6-75.0); 28 (24%) pts were <18 y, and 14 (12%) were ≥65 y. A total of 95 (82%) pts had AML, and 21 (18%) had ALL or MPAL; 67 (58%) were female, and 18 (16%) were non-White. Pts were heavily pretreated (median of 2 prior therapies [range, 1-11]), with 51 (44%) receiving ≥3 prior lines, 73 (63%) receiving prior venetoclax, and 59 (51%) underwent prior hematopoietic stem cell transplant (HSCT).

In the efficacy population (n=97), 22 pts (23% [95% CI, 15%-32%]) achieved CR+CRh with a median DoR of 6.4 mo (95% CI, 1.9 mo-NR). CRc rate was 42% (95% CI, 32%-53%); ORR was 64% (95% CI, 54%-73%). Of 18 CR+CRh responders with MRD results available, 11 (61%) achieved MRD negativity; 21/36 (58%) MRD-evaluable CRc responders achieved MRD negativity. Of 62 pts who achieved ORR, 21 (34%) proceeded to HSCT. Nine pts resumed revumenib post HSCT.

In the safety population (N=116), 106 (91%) pts experienced a grade ≥3 treatment-emergent AE (TEAE) and 63 (54%) experienced a grade ≥3 treatment-related AE (TRAE). The most common (≥10%) grade ≥3 TEAEs were febrile neutropenia (45 [39%]), anemia (23 [20%]), platelet count decreased (19 [16%]), differentiation syndrome (17 [15%]; only 1 grade 4, no grade 5), neutrophil count decreased (17 [15%]), white blood cell count decreased (17 [15%]), sepsis (16 [14%]), and QTc prolongation (15 [13%]; all grade 3). Sixteen pts (14%) discontinued treatment due to a TEAE, and 6 (5%) discontinued due to a TRAE. Nineteen (16%) and 4 (3%) pts experienced a TEAE or TRAE leading to death, respectively.

Conclusions: Revumenib monotherapy provides clinically meaningful responses in heavily pretreated pts with R/R KMT2Ar acute leukemias, including high rates of MRD negativity and ability to proceed to HSCT. Continued treatment and follow-up of pts after the interim analysis demonstrate the durability of ongoing response. The safety profile of revumenib with this longer follow-up is consistent with prior reports. This trial represents the largest evaluation of a targeted therapy for pts with R/R KMT2Ar acute leukemias to date.

Aldoss:Jazz Pharmaceuticals: Other: consulting fees; Takeda Pharmaceuticals: Other: consulting fees; Sobi: Other: consulting fees; AbbVie: Other: research support; Kite Pharma: Other: consulting fees; Pfizer: Honoraria, Other: consulting fees; Syndax Pharmaceuticals, Inc.: Other: consulting fees; Amgen: Honoraria, Other: consulting fees. Issa:Astex: Research Funding; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Merck: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees. Blachly:Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees. Thirman:Merck: Other: institutional funding; Nurix: Other: institutional funding; AbbVie: Honoraria, Other: institutional funding; Syndax Pharmaceuticals, Inc.: Other: institutional funding. Mannis:Gilead: Research Funding; Glycomimetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Jazz: Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Aptose: Research Funding; Syndax Pharmaceuticals, Inc.: Research Funding; Immunogen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Research Funding; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arellano:Syndax Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board meeting 5/31/24, Syndax pharmaceuticals, role of menin inhibition in treatment of acute leukemias. DiPersio:MacroGenics: Other: grant; Wugen: Other: grant, Patents & Royalties: royalties/licenses ; BioLineRx: Consultancy, Other: grant, consulting fees; Incyte: Other: grant; Magenta Therapeutics: Patents & Royalties: royalties/licenses ; RiverVest: Consultancy, Other: consulting fees; Vertex Pharmaceuticals: Consultancy, Other: consulting fees. Traer:Servier Laboratories: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Rigel Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Schrödinger: Research Funding; Incyte Corporation: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zwaan:Incyte Corporation: Consultancy, Other: consulting fees; Daiichi Sankyo, Inc.: Other: institutional grant; Kura Oncology: Consultancy, Other: institutional grant, consulting fees; Bristol Myers Squibb: Consultancy, Other: consulting fees; Gilead Sciences, Inc.: Consultancy, Other: consulting fees; Astra Zeneca: Consultancy, Other: consulting fees; Beigene: Consultancy, Other: consulting fees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: institutional fees, consulting fees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: institutional fees; Innovative Therapies for Children with Cancer in Europe (ITCC) Hematologic Malignancies Committee: Other: leadership role; Chair of the Medical Research Ethics Committee (MREC) Utrecht: Other: leadership role; Jazz Pharmaceuticals: Other: institutional grant; Takeda Pharmaceuticals: Other: institutional grant; Pfizer: Other: institutional grant; AbbVie: Other: institutional grant. Shukla:Syndax Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Cuglievan:LLS: Research Funding; Octapharma: Other: travel, accommodations, research; Syndax Pharmaceuticals, Inc.: Other: travel, accommodations, Research Funding; Kura Oncology: Research Funding. Grove:Otsuka Australia Pharmaceutical: Other: institutional consultancy payment; Astellas Pharma: Other: institutional consultancy payment; institutional payment for educational event; AbbVie: Other: institutional consultancy payment. Greenwood:Servier Laboratories: Honoraria, Other: receipt of trial related materials ; Amgen: Honoraria, Other: receipt of trial related materials ; Jazz Pharmaceuticals: Honoraria. McMahon:Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals, Inc.: Research Funding; Syros Pharmaceuticals: Research Funding. Perl:ImmunoGen: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees, Research Funding; Syndax Pharmaceuticals, Inc.: Other: grant, Research Funding; Foghorn: Consultancy; Rigel Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; BeatAML, LLC: Other: DSMC member; Aptose Biosciences: Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; Schrödinger,: Membership on an entity's Board of Directors or advisory committees. Stone:Aptevo Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees; AROG Pharmaceuticals: Consultancy, Other: consulting fees; AvenCell: Consultancy, Other: consulting fees; BerGenBio: Consultancy, Other: consulting fees; Bristol Myers Squibb: Consultancy, Other: consulting fees; Boston Scientific: Consultancy, Other: consulting fees; Celularity: Consultancy, Other: consulting fees; CTI BioPharma: Consultancy, Other: consulting fees; DAVA Oncology: Consultancy, Other: consulting fees; GSK: Consultancy, Other: consulting fees; Hemavant Sciences: Consultancy, Other: consulting fees; Janssen: Consultancy, Other: consulting fees; Jazz Pharmaceuticals: Consultancy, Other: consulting fees; Kura Oncology: Consultancy, Other: consulting fees; LAVA Therapeutics: Consultancy, Other: consulting fees; Ligand Pharmaceuticals: Consultancy, Other: consulting fees; Novartis: Consultancy, Other: consulting fees; Rigel Therapeutics, Inc.: Consultancy, Other: consulting fees; Syros Pharmaceuticals: Consultancy, Other: consulting fees; Syntrix Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees; Amgen: Consultancy, Other: consulting fees; Actinium Pharmaceuticals, Inc.,: Consultancy, Other: consulting fees; AbbVie: Consultancy, Other: consulting fees; Epizyme Inc: Consultancy, Other: consulting fees; Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees. Papayannidis:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Menarini/Stemline: Honoraria; Servier: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Delbert Laboratories: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Dickens:Tempus: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; YmAbs: Consultancy; American Academy of Pediatrics: Other: unpaid advocacy role; American Society of Pediatric Hematology Oncology: Other: unpaid advocacy role; Iowa Cancer Consortium: Other: unpaid advocacy role. Žučenka:Novartis: Consultancy, Honoraria, Other: travel expenses; Pfizer: Consultancy; Astellas: Consultancy, Honoraria; Johnson & Johnson: Consultancy, Honoraria, Other: travel expenses; Takeda: Other: travel expenses; AbbVie: Consultancy, Honoraria, Other: travel expenses. Montesinos:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Daiichi Sankyo, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Jazzpharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Kura Oncology: Consultancy; Syndax: Consultancy; Glycomimetics: Consultancy. Kovacsovics:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Servier Laboratories: Honoraria; Rigel Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals, Inc.: Other: institutional research support; GlycoMimetics, Inc.: Other: institutional research support; Gilead Sciences, Inc.: Other: institutional research support; Amgen: Other: institutional research support; AbbVie: Other: institutional research support; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; NeoGenomics Laboratories: Membership on an entity's Board of Directors or advisory committees. Shami:RJH BioSciences: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abcuro, Inc.: Other: grant; Amgen: Other: grant; Chimerix, Inc.: Other: grant; JSK Therapeutics: Other: Chief Medical Officer and serves on the Board of Directors ; National Cancer Network: Other: leadership role; US Patents: Patents & Royalties: holds US Patents (8,404,665; 9,005,656). Yu:Syndax Pharmaceuticals, Inc.: Current Employment, Other: stocks/stock options. Bagley:Syndax Pharmaceuticals, Inc.: Current Employment, Other: stocks/stock options. McNeer:Syndax Pharmaceuticals, Inc.: Current Employment, Other: stock/stock options. Stein:Jazz Pharmaceuticals: Consultancy, Other: consulting fees; Agios Pharmaceuticals: Consultancy, Other: consulting fees; Abbvie: Consultancy, Other: consulting fees; Servier: Consultancy, Other: consulting fees; Gilead: Consultancy, Other: consulting fees; Genentech: Consultancy, Other: consulting fees; AstraZeneca: Consultancy, Other: consulting fees; Celgene: Consultancy, Other: consulting fees; Astellas Pharmaceuticals: Consultancy, Other: consulting fees; Daiichi Sankyo, Inc.: Consultancy, Other: consulting fees.