Revumenib (SYNDX-5613) demonstrated comparable security and efficacy in pediatric sufferers with KMT2A-rearranged acute leukemia to that noticed in grownup sufferers, based on information from the part 2 AUGMENT-101 research (NCT04065399) offered through the 2024 American Society of Pediatric Hematology/Oncology.1
In pediatric sufferers who comprised the interim evaluation efficacy inhabitants (n = 13), revumenib induced a whole remission (CR)+CR with partial hematologic restoration (CRh) fee of 23% (95% CI, 5.0%-53.8%) at a knowledge cutoff date of July 24, 2023. Within the combination inhabitants of adults and kids (n = 57), the CR+CRh fee was 22.8% (95% CI, 12.7%-35.8%; 1-sided P = .0036), which met the first finish level of the research.
Further information within the pediatric inhabitants revealed that the agent induced a composite CR (CRc) fee of 38.5% (95% CI, 13.9%-68.4%). Furthermore, the target response fee (ORR) achieved with the agent was 46% on this inhabitants. Greatest responses included CR (8%), CRh (15%), CR with incomplete hematologic restoration (8%), CR with incomplete platelet restoration (CRp; 8%), morphological leukemia-free state (MLFS; 8%), illness development (23%), or different (8%); 3 sufferers didn’t reply to remedy.
“AUGMENT-101 met its main efficacy finish level in an combination inhabitants of adults and kids with relapsed/refractory KMT2A-rearranged acute leukemia, validating part 1 outcomes,” C. Michel Zwaan, MD, PhD, a professor of pediatric oncology at Erasmus MC Rotterdam and the Princess Máxima Heart in Utrecht, Netherlands, mentioned in a plenary presentation through the assembly. “The vast majority of responding kids, 67%, had been capable of proceed to transplant, with 2 resuming revumenib upkeep submit transplant. The protection profile [of the agent] in kids was manageable and in keeping with [the] security profile [observed] in adults.”
Pediatric sufferers with KMT2A-rearranged acute leukemia expertise poor outcomes, and no focused brokers have been authorised for this illness. The interplay between menin and KMT2A drives leukemogenesis, however remedy with revumenib disrupts that interplay, based on Zwaan. “By treating the affected person with revumenib, the gene transcription sign is off, and this results in differentiation of leukemia in addition to apoptosis of leukemic cells,” he defined.
Knowledge from the part 1 portion of the trial confirmed that revumenib elicited responses in sufferers with relapsed or refractory KMT2A-rearranged and NPM1-mutated acute leukemia, and 67% of those that responded to remedy went on to bear transplant.2 The agent was additionally discovered to have acceptable security and tolerability. “Furthermore, on this trial, kids had been included, and preliminary antileukemic exercise was famous [in them],” Zwaan mentioned. As a result of revumenib is a substrate of CYP384, two dosages had been established – one with and one and not using a CYP384 inhibitor, he added.
The research enrolled sufferers with relapsed or refractory acute leukemia who had been at the least 30 days outdated and harbored KMT2A rearrangements or NMP1 mutations. Sufferers obtained revumenib on the really helpful part 2 dose (RP2D) plus a powerful CYP384 inhibitor in 28-day cycles. If their physique weight was beneath 40 kg, the RP2D was 95 mg/m2; if 40 kg or over, they obtained revumenib at a flat dose of 163 mg. The drug might be given as capsules or an oral resolution.
The first finish factors of the research had been CR+CRh fee and security. Necessary secondary finish factors included CRc and ORR.
A deliberate interim evaluation of sufferers with KMT2A-rearranged acute leukemia was carried out. The cohort of sufferers with NPM1-mutated acute myeloid leukemia (AML) remains to be enrolling, based on Zwaan.
Within the efficacy inhabitants (n = 13), the median affected person age was 5.0 years (vary, 1.3-17.0); 23% of sufferers had been beneath 2 years, 54% had been at the least 2 years however youthful than 12 years, and 23% had been at the least 12 years however youthful than 18 years. Forty-six p.c of sufferers had been feminine and 69% had been White. Concerning sort of leukemia, 85% had AML and 15% had acute lymphoblastic leukemia. At baseline, 38% of sufferers had main refractory illness, 38% had refractory relapsed illness, and 23% had early untreated relapsed illness.
Sufferers had obtained a median of 4 prior strains of remedy, with a spread of 1 to 11 strains. Notably, 54% of sufferers had obtained 3 or extra strains of prior remedy. Greater than half of sufferers had prior publicity to venetoclax (Venclexta; 62%) and 15% beforehand obtained CAR T-cell remedy. Forty-six p.c of sufferers beforehand underwent hematopoietic stem cell transplant (HSCT), with 15% of these sufferers having obtained greater than 1 prior transplant.
Further efficacy information confirmed that in those that had unfavorable minimal residual illness standing by circulation cytometry, 2 of three sufferers achieved a CR+CRh and three of 5 sufferers achieved a CRc. Furthermore, in all evaluable sufferers, the median general survival was 6.9 months (95% CI, 2.3-not reached).
The median time to CR+CRh was 2.27 months (vary, 1.0-3.9). Amongst responders (n = 6), 67% proceeded to HSCT, 50% proceeded to transplant in CR or CRh, and 50% proceeded to transplant in MLFS or CRp. Half of those sufferers restarted revumenib after HSCT.
Within the 23 sufferers who had been evaluable for security, the antagonistic results (AEs) of particular curiosity included grade 2 or larger differentiation syndrome and grade 2 or larger QTc prolongation, and so they occurred in 35% and 4% of sufferers, respectively. Remedy-related AEs that had been grade 3 or larger in severity and occurred in at the least 10% of sufferers included febrile neutropenia (13%) and decreased neutrophil rely (13%).
One affected person skilled an AE that led to discontinuation within the type of febrile neutropenia, and this was not decided to be related to revumenib.
“The impartial NPM1-mutated cohort continues to enroll in any respect websites,” Zwaan concluded.
In March 2024, the FDA granted precedence evaluation to a brand new drug utility (NDA) searching for the approval of revumenib within the remedy of grownup and pediatric sufferers with relapsed/refractory acute leukemia and KMT2A rearrangements.3 The NDA is supported by findings from AUGMENT-101, and has a goal motion date of September 26, 2024. Beforehand, in December 2022, the regulatory company granted revumenib a breakthrough remedy designation for a similar indication.4
References
- Zwaan CM, Shukla N, Karras N, et al. Pivotal part 2 outcomes of AUGMENT-101 for revumenib in KMT2Ar acute leukemia: pediatric expertise. Offered at: 2024 American Society of Pediatric Hematology/Oncology; April 3-6, 2024; Seattle, Washington. Summary 2002.
- Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023;615(7954):920-924. doi:10.1038/s41586-023-05812-3
- Syndax pronounces FDA precedence evaluation of NDA for revumenib for the remedy of relapsed/refractory KMT2Ar acute leukemia. Information launch. Syndax. March 26, 2024. Accessed April 4, 2024. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-fda-priority-review-nda-revumenib-treatme
- Syndax pronounces U.S. FDA breakthrough remedy designation granted for revumenib for the remedy of grownup and pediatric sufferers with relapsed or refractory KMT2A- rearranged (MLLr) acute leukemia. Information launch. Syndax Prescription drugs. December 5, 2022. Accessed April 4, 2024. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-us-fda-breakthrough-therapy-designation-granted
