Sonrotoclax

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

In animal reproduction studies, oral administration of sonrotoclax to pregnant mice and rabbits during the period of organogenesis resulted in adverse developmental outcomes, including structural abnormalities and altered fetal growth, at maternal exposures approximately ≥2 times the human exposure (AUC) at the recommended dose of 320 mg daily. Advise patients of the potential risk to a fetus.

There are no data on the presence of sonrotoclax 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 sonrotoclax and for 1 week after the last dose.

Carcinogenesis

Carcinogenicity studies have not been conducted with sonrotoclax.

Mutagenesis

Sonrotoclax was not mutagenic in a bacterial mutagenicity (Ames) assay and not clastogenic in a chromosome aberration assay in mammalian cells or in an in vivo bone marrow micronucleus assay in mice.

Impairment of Fertility

Fertility studies in animals have not been conducted with sonrotoclax. In a repeat dose, 13-week toxicity study in mice treated with oral administration of sonrotoclax at 20, 100, or 300 mg/kg/day, changes were reported in female reproductive organs at all doses, including the development of ovarian cysts, vaginal mucification, and uterine atrophy. At the dose of 20 mg/kg/day in mice, exposures (AUC) were approximately the same as the human exposure at the recommended dose. In a repeat dose, 13-week toxicity study in dogs treated with oral administration of sonrotoclax at 10, 30, or 100 mg/kg/day, changes were reported in male reproductive organs at all doses, including atrophy, necrosis, and vacuolation of the epididymis with reduced sperm, and atrophy of the prostate and testis. At the dose of 10 mg/kg/day in dogs, exposures were approximately 2 times the human exposure at the recommended dose. Reversibility was noted in both species by the end of the recovery period.

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.

Mantle Cell Lymphoma

The safety of sonrotoclax was evaluated in 115 adult patients with previously treated MCL in a single-arm, multicenter clinical trial, BGB-11417-201 (NCT05471843). The trial required prior receipt of anti-CD20–based therapy and a BTK inhibitor. The trial excluded patients on moderate or strong CYP3A inhibitors or strong CYP3A inducers and required an absolute neutrophil count (ANC) ≥1000/mm³; platelets ≥75,000/mm³; creatinine clearance ≥50 mL/min; AST and ALT ≤3 × upper limit of normal (ULN); and serum total bilirubin ≤2 × ULN.

Patients received sonrotoclax 320 mg orally once daily following completion of a 4-week ramp-up dosing schedule. Of the 115 patients who received sonrotoclax, 52% were exposed for at least 6 months and 34% were exposed for at least 1 year.

Serious adverse reactions were reported in 37% of patients who received sonrotoclax, most frequently (≥2%) from pneumonia (10%). Fatal adverse reactions occurred in 4.3% of patients, including from pneumonia (2.6%) and sudden death (1.7%).

Adverse reactions led to dose interruption of sonrotoclax in 27% of patients, dose reduction in 0.9%, and permanent discontinuation in 8%. The most common reasons for dose interruption were infections (10%) and neutropenia (5%). The most common adverse reaction leading to treatment discontinuation was infection (1.7%).

Table 1 summarizes select adverse reactions in Study BGB-11417-201, excluding laboratory terms.

Table 1. Adverse Reactions (≥10%) in Patients with MCL Who Received Sonrotoclax in BGB-11417-201:

^* Additionally includes three fatal cases (2.6%) of pneumonia.
^a Includes pneumonia, COVID-19 pneumonia, pneumonia bacterial, and other related terms.
^b Includes upper respiratory tract infection, pharyngitis, sinusitis, and other related terms.
^c Includes fatigue and asthenia.
^d Includes edema peripheral, generalized edema, and other related terms.
^e Includes rash, dermatitis, drug eruption, and other related terms.
^f Includes musculoskeletal pain, back pain, bone pain, and other related terms.

Clinically relevant adverse reactions in <10% of patients who received sonrotoclax included: TLS, headache, nausea, vomiting, mucositis, peripheral sensory neuropathy, febrile neutropenia, pneumonitis, herpes zoster infection, and sepsis.

Table 2 summarizes new or worsening laboratory abnormalities throughout treatment. Grade 4 laboratory abnormalities in ≥2% of patients included decreases in neutrophils (6%) and platelet count (3.5%).

Table 2. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Previously Treated MCL Who Received Sonrotoclax:

^a The denominator used to calculate the rate varied from 103 to 115 based on the number of patients with a baseline value and at least one post-treatment value.