Cosibelimab

Risk Summary

Based on its mechanism of action, cosibelimab can cause fetal harm when administered to a pregnant woman. There are no available data on the use of cosibelimab in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death (see Data). Human IgG1 immunoglobulins (IgG1) are known to cross the placental barrier; therefore, cosibelimab has the potential to be transmitted from the mother to the developing fetus. Advise 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% to 4% and 15% to 20%, respectively.

Data

Animal Data

Animal reproduction studies have not been conducted with cosibelimab to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering cosibelimab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to cosibelimab may increase the risk of developing immune-mediated disorders or altering the normal immune response.

There is no information regarding the presence of cosibelimab in human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment and for 4 months after the last dose of cosibelimab.

No studies have been performed to assess the potential of cosibelimab for carcinogenicity or genotoxicity.

Fertility studies have not been conducted with cosibelimab in animals. In 1- and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs up to the highest dose tested of 100 mg/kg/dose; however, many animals in these studies were not sexually mature.

Clinical Trials Experience

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

The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to cosibelimab as a single agent in 223 patients in two open-label, single-arm, multicohort studies, including 141 patients with advanced CSCC and 82 patients with other solid tumors and hematologic malignancies. cosibelimab was administered intravenously at doses of 800 mg every 2 weeks (n=174), 1,200 mg every 3 weeks (n=35), or other doses (n=14). Among the 223 patients, 54% were exposed for ≥24 weeks and 17% were exposed for ≥72 weeks.

The safety of cosibelimab was evaluated in Study CK-301-101 in 141 patients with metastatic or locally advanced disease CSCC. Patients received cosibelimab 800 mg every 2 weeks (n=115) or 1,200 mg every 3 weeks (n=26) as an intravenous infusion until disease progression or unacceptable toxicity. The median duration of exposure was 36 weeks (2 weeks to 3.7 years).

Serious adverse reactions occurred in 31% of advanced patients with CSCC who received cosibelimab. The most frequent serious adverse reactions (≥2% of patients) were sepsis (2.8%), pneumonia (2.8%) and pyrexia (2.1%).

Permanent discontinuation of cosibelimab due to an adverse reaction occurred in 8% of patients. Adverse reactions resulting in permanent discontinuation of cosibelimab were COVID-19, COVID-19 pneumonia, sepsis, ulcerative keratitis, tumor thrombosis, axillary pain, paresthesia, cholestasis, hepatic cytolysis, wound hemorrhage, neck pain, pemphigoid, and eye pain (1 patient each).

Dosage interruptions due to an adverse reaction occurred in 36% of patients who received cosibelimab. The adverse reaction that required dosage interruption in ≥2% of patients who received cosibelimab was COVID-19 (2%).

The most common (≥10%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation, nausea, headache, pruritus, edema, localized infection, and urinary tract infection.

Table 1 and Table 2 summarize adverse reactions and laboratory abnormalities, respectively in CK-301-101.

Table 1. Adverse Reactions in ≥10% of Patients with Metastatic or Locally Advanced CSCC Receiving Cosibelimab in Study CK-301-101:

Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 (or later version)
^* Represents a composite of multiple related terms

Table 2. Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥1% of Patients with Metastatic or Locally Advanced CSCC Receiving Cosibelimab in Study CK-301-101:

Toxicity graded per NCI CTCAE v5
^* The denominator used to calculate the rate varied from 122-140 based on the number of patients with a baseline value and at least one post-treatment value.