Mirvetuximab soravtansine

DM4 is a CYP3A4 substrate. Concomitant use of mirvetuximab-soravtansine with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure, which may increase the risk of mirvetuximab-soravtansine adverse reactions. Closely monitor patients for adverse reactions with mirvetuximab-soravtansine when used concomitantly with strong CYP3A4 inhibitors.

The effect of severe renal impairment (CLcr 15 to <30 mL/min) or end-stage renal disease on mirvetuximab soravtansine is unknown.

Avoid use of mirvetuximab soravtansine in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN).

Risk Summary

Based on its mechanism of action, mirvetuximab soravtansine can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells. Human immunoglobulin G (IgG) is known to cross the placental barrier; therefore, mirvetuximab soravtansine has the potential to be transmitted from the mother to the developing fetus. There are no available human data on mirvetuximab soravtansine use in pregnant women to inform a drug-associated risk. No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine. Advise patients of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

Data

Animal Data

No reproductive or developmental animal toxicity studies have been conducted with mirvetuximab soravtansine. The cytotoxic component of mirvetuximab soravtansine, DM4, disrupts microtubule function, is genotoxic, and can be toxic to actively dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.

There are no data on the presence of mirvetuximab soravtansine 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 mirvetuximab soravtansine and for 1 month after the last dose.

Carcinogenicity studies have not been conducted with mirvetuximab soravtansine or DM4.

DM4 and the metabolite, S-methyl DM4, were clastogenic in the in vivo rat bone marrow micronucleus study. DM4 and S-methyl DM4 were not mutagenic in the bacterial reverse mutation (Ames) assay.

Fertility studies have not been conducted with mirvetuximab soravtansine or DM4.

• Ocular Disorders.
• Pneumonitis.
• Peripheral Neuropathy.

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population reflect exposure to mirvetuximab soravtansine in 464 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer at 6 mg/kg AIBW administered intravenously once every 3 weeks until disease progression or unacceptable toxicity in Study 0417; Study 0403 (NCT02631876), and Study 0401 (NCT01609556). The median duration of treatment was 4.3 months (range: 0.7 to 30.4).

Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study 0417

The safety of mirvetuximab soravtansine was evaluated in Study 0417, a single-arm, open-label study in patients (n=106) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients received mirvetuximab soravtansine 6 mg/kg AIBW once every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 4.2 months (range: 0.7 to 13.3).

Serious adverse reactions occurred in 31% of patients. The most common (≥2%) serious adverse reactions were intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Fatal adverse reactions occurred in 2% of patients, including small intestinal obstruction (1%) and pneumonitis (1%).

Permanent discontinuation of mirvetuximab soravtansine due to adverse reactions occurred in 11% of patients. The most common (≥2%) adverse reactions leading to permanent discontinuation were intestinal obstruction (2%) and thrombocytopenia (2%). One patient (0.9%) permanently discontinued mirvetuximab soravtansine due to visual impairment (unilateral decrease to BCVA ≤ 20/200 that resolved to baseline after discontinuation).

Dosage delays of mirvetuximab soravtansine due to an adverse reaction occurred in 39% of patients treated with mirvetuximab soravtansine. Adverse reactions which required dosage delays in ≥3% of patients included visual impairment (15%), keratopathy (11%), neutropenia (6%), dry eye (5%), cataracts (3%), and increased gamma-glutamyltransferase (3%).

Dose reductions of mirvetuximab soravtansine due to an adverse reaction occurred in 20% of patients. Adverse reactions which required dose reductions in ≥3% of patients included visual impairment (9%) and keratopathy (7%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, were vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin.

Table 1 summarizes the adverse reactions (≥10%) in patients treated with mirvetuximab soravtansine in Study 0417.

Table 1. Adverse Reactions (≥10%) in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received Mirvetuximab soravtansine in Study 0417:

Fatigue includes fatigue and asthenia.
^* Visual Impairment includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, presbyopia, accommodation disorder, visual impairment, and refraction disorder.
^† Keratopathy includes corneal disorder, corneal epithelial microcysts, corneal epithelial defect, keratitis, keratopathy, corneal deposits, and punctate keratitis.
^‡ Dry eye includes dry eye and lacrimation increased.
^§ Eye pain includes eye pain and ocular discomfort.
^¶ Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort.
^# Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, and neurotoxicity.
^Þ Dyspnea includes dyspnea and exertional dyspnea.

Clinically relevant adverse reactions occurring in <10% of patients who received mirvetuximab soravtansine in Study 0417 included infusion related reactions/hypersensitivity (9%), pneumonitis (8%), thrombocytopenia (5%), and uveitis (1%).

Table 2 summarizes the laboratory abnormalities in Study 0417.

Table 2. Select Laboratory Abnormalities ≥10% for All Grades, or ≥2% for Grades 3-4 in Patients Who Received Mirvetuximab soravtansine:

^* The denominator used to calculate the rate varied from 98 to 101 based on the number of patients with a baseline value and at least one post-treatment value.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation against mirvetuximab soravtansine-gynx is highly dependent on the sensitivity and specificity of the assay. The observed incidence of anti-drug antibodies (including neutralizing antibody) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies to mirvetuximab soravtansine-gynx in other studies.

With a median duration of treatment of 4.3 months in Studies 0417, 0401, and 0403, a total of 55/423 (13%) ovarian cancer patients treated with mirvetuximab soravtansine-gynx at 6 mg/kg AIBW had at least 1 post-baseline positive sample for anti-mirvetuximab soravtansine-gynx antibodies. Of those patients, 28/423 patients (7%) had developed treatment-emergent ADA and 3/423 patients (0.7%) had treatment-enhanced ADA. Neutralizing antibodies were detected in 24/423 (6%) of patients.

Because of the low occurrence of anti-mirvetuximab soravtansine-gynx antibodies, the effect of these antibodies on the pharmacokinetics, efficacy, and/or safety of mirvetuximab soravtansine-gynx is unknown.