Revumenib

Based on findings in animals and its mechanism of action, revumenib can cause fetal harm when administered to a pregnant woman. There are no available data on revumenib use in pregnant women to evaluate for a drug-associated risk.

In an animal reproduction study, oral administration of revumenib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, malformations, and altered fetal growth at maternal exposures approximately 0.5 times the human exposure (AUC) at the recommended dose. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

There are no data on the presence of revumenib or its metabolites in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with revumenib and for 1 week after the last dose.

Carcinogenicity studies have not been conducted with revumenib. In a repeat dose toxicity study in rats treated with revumenib for 13 weeks, lymphoma was observed in multiple organs in one animal.

Revumenib was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, or an in vivo rat peripheral blood reticulocyte micronucleus assay.

Fertility studies in animals have not been conducted with revumenib.

In a repeat dose toxicity study in dogs treated with revumenib at 12.5, 25 or 40 mg/kg/day for 13 weeks, microscopic findings in the testes and epididymis consisted of depletion of germ cells and decreased sperm at ≥12.5 mg/kg/day. In females, microscopic changes of atrophy in the mammary glands, uterus, and vagina and decreased number of corpora lutea in the ovaries were observed at ≥12.5 mg/kg/day. At the end of the 13-week recovery period, the findings in the female reproductive organs were reversed at all doses, and the testicular and epididymal effects were reversed at 12.5 mg/kg/day. At the dose of 12.5 mg/kg/day in dogs, exposures (AUC) were approximately 1.3 times the human exposure (AUC) at the recommended dose.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of revumenib reflects exposure in 241 patients (207 adult and 34 pediatric patients) with relapsed or refractory (R/R) acute leukemia with a KMT2A translocation or an NPM1 mutation treated with revumenib at a dose approximately equivalent to 160 mg in adults orally twice daily with a strong CYP3A4 inhibitor. The median duration of exposure to revumenib was 2.5 months (range <1 to 40 months), and 10% of patients were exposed for more than 6 months.

Fatal adverse reactions occurred in 9 (4%) patients who received revumenib, including 4 with sudden death, 2 with differentiation syndrome, 2 with hemorrhage, and 1 with cardiac arrest. Serious adverse reactions were reported in 184 (76%) patients. The most frequent serious adverse reactions (≥10%) were infection (29%), febrile neutropenia (20%), bacterial infection (15%), differentiation syndrome (13%), and hemorrhage (11%).

Adverse reactions leading to dose interruption occurred in 49% of patients. The most common adverse reactions (≥5%) leading to dose interruption were electrocardiogram QT prolonged, infection, febrile neutropenia, differentiation syndrome, nausea, and hypokalemia. Adverse reactions leading to dose reduction occurred in 12% of patients who received revumenib. Adverse reactions leading to a dose reduction (≥5%) included electrocardiogram QT prolonged. Adverse reactions leading to permanent discontinuation occurred in 20% of patients. Adverse reactions resulting in permanent discontinuation (>1%) included infection.

The most common (≥20%) adverse reactions were phosphate increased, hemorrhage, nausea, infection without identified pathogen, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine increased, musculoskeletal pain, febrile neutropenia, electrocardiogram QT prolonged, potassium decreased, parathyroid hormone intact increased, alkaline phosphatase increased, diarrhea, bacterial infection, triglycerides increased, differentiation syndrome, fatigue, edema, viral infection, phosphate decreased, decreased appetite, and constipation.

The common adverse reactions are summarised in Table 1.

Table 1. Adverse Reactions Reported in ≥20% (Any Grade) or ≥5% (Grade 3 or 4) in Patients with R/R Acute Leukemia:

^# Includes the following fatal adverse reactions: DS (n=2); hemorrhage (n=2)
^a – Includes nausea and vomiting
^b – includes diarrhea, colitis, and neutropenic colitis
^c – includes epistaxis, contusion, petechiae, gingival bleeding, hematoma, hemoptysis, hemorrhoidal hemorrhage, mouth hemorrhage, hematuria, ecchymosis, hemorrhage intracranial, subdural hematoma, upper gastrointestinal hemorrhage, gastrointestinal hemorrhage, vaginal hemorrhage, post-procedural hemorrhage, rectal hemorrhage, subarachnoid hemorrhage, vitreous hemorrhage, catheter site hemorrhage, conjunctival hemorrhage, hematochezia, melaena, retinal hemorrhage, anal hemorrhage, brain stem hemorrhage, cystitis hemorrhagic, eye hematoma, genital contusion, injection site hematoma, lower gastrointestinal hemorrhage, mucosal hemorrhage, oral blood blister, oral contusion, oral purpura, pulmonary hemorrhage, shock hemorrhagic, spinal subdural hematoma
^d – includes disseminated intravascular coagulation, pulmonary embolism, cerebrovascular accident, superficial vein thrombosis, deep vein thrombosis, acute myocardial infarction, cerebral infarction, embolism, hemorrhoids thrombosed, medical device site thrombosis, myocardial infarction, renal infarction, splenic infarction, thrombosis, and transient ischaemic attack
^e – includes pneumonia, sepsis, urinary tract infection, septic shock, sinusitis, skin infection, upper respiratory tract infection, osteomyelitis, device related infection, enterocolitis infectious, conjunctivitis, hordeolum, rhinitis, acute sinusitis, diverticulitis, endocarditis, perirectal abscess, rectal abscess, tooth abscess, abscess limb, appendicitis, bronchitis, epididymitis, eye infection, gastroenteritis, infection, mucosal infection, neutropenic sepsis, rash pustular, retinitis, shock, sialadenitis, soft tissue infection, tooth infection, vascular device infection
^f – includes bacteraemia, clostridium difficile infection, cellulitis, escherichia bacteremia, paronychia, staphylococcal bacteremia, streptococcal bacteremia, alpha hemolytic streptococcal infection, clostridium difficile colitis, clostridium test positive, enterobacter infection, enterobacter sepsis, enterococcal bacteremia, escherichia urinary tract infection, pseudomonal bacteremia, pseudomonas infection, skin bacterial infection, bacteriuria, cellulitis staphylococcal, cornyebacterium bacteremia, enterobacter bacteremia, enterococcal infection, folliculitis, klebsiella infection, klebsiella sepsis, lactobacillus bacteremia, meningitis bacterial, stenotrophomonas infection
^g – includes COVID-19, rhinovirus infection, herpes simplex reactivation, herpes simplex, herpes zoster, oral herpes, respiratory syncytial virus infection, enterovirus infection, adenovirus infection, coronavirus infection, cytomegalovirus infection, cytomegalovirus infection reactivation, cytomegalovirus viremia, COVID-19 pneumonia, cytomegalovirus test positive, enterovirus test positive, Epstein-Barr virus infection, herpes simplex pharyngitis, herpes virus infection, influenza, norovirus infection, parainfluenzae virus infection, pneumonia cytomegaloviral viremia
^h – includes arthralgia, back pain, pain in extremity, neck pain, myalgia, musculoskeletal chest pain, myositis, flank pain, musculoskeletal discomfort, and musculoskeletal pain
ⁱ – includes fatigue, asthenia, malaise
^j – includes edema peripheral, generalised edema, edema, localized edema, peripheral swelling

Clinically relevant adverse reactions in less than 20% of patients who received revumenib include:

Cardiac disorders: Premature ventricular complex, cardiac failure, pericardial effusion, ventricular tachycardia, cardiac arrest

Endocrine disorders: Hyperparathyroidism

Eye disorders: Cataract

Gastrointestinal disorders: Abdominal pain

General disorders and administration site conditions: Sudden death

Immune system disorders: Drug hypersensitivity

Metabolism and nutrition disorders: Hyponatremia, hyperkalemia

Nervous system disorders: Taste disorder, syncope, headache, paresthesia

Renal disorders: Renal impairment

Skin and subcutaneous disorders: Rash

Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory acute leukemia are shown in Table 2.

Table 2. Selected New or Worsening Laboratory Abnormalities in Patients with R/R Acute Leukemia:

^* The denominator used to calculate the rate varied from 139 to 240 based on the number of patients with a baseline value and at least one post baseline value.