Mirvetuximab Soravtansine

1 INDICATIONS AND USAGE ELAHERE ® is indicated for the treatment of adult patients with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Select patients for therapy based on an FDA-approved test [see Dosage and Administration ( 2.1 )]. ELAHERE is a folate receptor alpha (FRα)-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Select patients for therapy based on an FDA-approved test. ( 1 , 2.1 )

2 DOSAGE AND ADMINISTRATION Administer ELAHERE as an intravenous infusion only after dilution in 5% Dextrose Injection, USP. ELAHERE is incompatible with normal saline. ( 2.5 ) The recommended dose of ELAHERE is 6 mg/kg adjusted ideal body weight administered as an intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. ( 2.2 ) Premedicate with a corticosteroid, antihistamine, and antipyretic. ( 2.3 ) Premedicate with an antiemetic, ophthalmic topical steroids, and lubricating eye drops. ( 2.3 , 5.1 ) See full Prescribing Information for preparation and administration instructions and dose modifications for adverse reactions. ( 2 ) 2.1 Patient Selection Select patients for the treatment of platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer with ELAHERE based on the presence of FRα tumor expression [see Indications & Usage ( 1 ) and Clinical Studies ( 14 )] using an FDA-approved test. Information on FDA-approved tests for the measurement of FRα tumor expression is available at http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Dosage The recommended dosage of ELAHERE is 6 mg/kg adjusted ideal body weight (AIBW) administered once every 3 weeks (21-day cycle) as an intravenous infusion until disease progression or unacceptable toxicity [see Dosage and Administration ( 2.5 )]. Dosing based on AIBW reduces exposure variability for patients who are either under or overweight. The total dose of ELAHERE is calculated based on each patient’s AIBW using the following formula: AIBW = Ideal Body Weight (IBW [kg]) + 0.4*(Actual weight [kg] – IBW) Female IBW [kg] = 0.9*height[cm] – 92 2.3 Premedication and Required Eye Care Premedica tion Administer the premedications in Table 1 prior to each infusion of ELAHERE to reduce the incidence and severity of infusion related reactions (IRRs), nausea, and vomiting. Table 1: Premedication Prior to Each ELAHERE Infusion Premedication Route of Administration Examples (or equivalent) Administration Time Prior to ELAHERE Infusion Corticosteroid intravenous dexamethasone 10 mg Antihistamine oral or intravenous diphenhydramine 25 mg to 50 mg At least 30 minutes prior Antipyretic oral or intravenous acetaminophen 325 mg to 650 mg Antiemetic oral or intravenous 5-HT 3 serotonin receptor antagonist or appropriate alternatives Before each dose and thereafter as needed Consider additional premedications including corticosteroids the day prior to ELAHERE administration for patients who experienced IRRs. Ophthalmic Exams and Premedication Ophthalmic E xam : Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first 8 cycles, and as clinically indicated. Ophthalmic Topical Steroids: The use of ophthalmic topical steroids is recommended. The initial prescription and renewals of any corticosteroid medication should be made only after examination with a slit lamp. Administer one drop of ophthalmic topical steroids in each eye 6 times daily starting the day prior to each infusion until day 4; then administer one drop in each eye 4 times daily for days 5-8 of each cycle of ELAHERE [see Warnings and Precautions ( 5.1 )]. Lubricating Eye Drops : The use of lubricating eye drops at least four times daily and as needed is recommended during treatment with ELAHERE. Instruct patients to use lubricating eye drops and advise to wait at least 10 minutes after ophthalmic topical steroid administration before instilling lubricating eye drops [see Warnings and Precautions ( 5.1 )] . 2.4 Dosage Modifications Table 2 provides dose reduction levels and Table 3 provides dosage modifications for ELAHERE due to adverse reactions. Table 2: Dosage Reduction Schedule ELAHERE Dose Levels First Dose Reduction 5 mg/kg AIBW once every 3 weeks (21-day cycle) Second Dose Reduction 4 mg/kg AIBW once every 3 weeks (21-day cycle) * * Permanently discontinue in patients who cannot tolerate 4 mg/kg AIBW. Table 3: Dosage Modifications for Adverse Reactions Adverse Reaction Severity of Adverse Reaction * Dosage Modification Nonconfluent superficial keratitis Monitor. Keratitis/Keratopathy [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] Confluent superficial keratitis, a cornea epithelial defect, or 3-line or more loss in best corrected visual acuity Withhold until improved or resolved, then maintain at same dose level or consider dose reduction. Corneal ulcer or stromal opacity or best corrected distance visual acuity 20/200 or worse Withhold until improved or resolved, then reduce by one dose level. Corneal perforation Permanently discontinue. Grade 1/ Rare cell in anterior chamber Monitor. Uveitis [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] Grade 2/ 1-2+ Cell or Flare in anterior chamber Withhold until Grade 1 or less, then maintain dose at same dose level. Grade 3/ 3+ Cell or Flare in anterior chamber Withhold until Grade 1 or less, then reduce dose by one dose level. Grade 4/ Hypopyon Permanently discontinue. Grade 1 Monitor. Pneumonitis [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] Grade 2 Withhold until Grade 1 or less, then maintain at same dose level or consider dose reduction. Grade 3 or 4 Permanently discontinue. Peripheral Neuropathy [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )] Grade 2 Withhold until Grade 1 or less, then reduce by one dose level. Grade 3 or 4 Permanently discontinue. Grade 1 Maintain infusion rate. Infusion-Related Reactions/Hypersensitivity [see Adverse Reactions ( 6.1 )] Grade 2 Interrupt infusion and administer supportive treatment. After recovery from symptoms, resume the infusion at 50% of the previous rate, and if no further symptoms appear, increase rate as appropriate until infusion is completed [see Dosage and Administration ( 2.5 )]. Administer additional premedication for future cycles [see Dosage and Administration ( 2.3 )]. Grade 3 or 4 Immediately stop infusion and administer supportive treatment. Advise patient to seek emergency treatment and immediately notify their healthcare provider if the infusion-related symptoms recur. Permanently discontinue. Hematological [see Adverse Reactions ( 6.1 )] Grade 3 or 4 Withhold until Grade 1 or less, then resume at one lower dose level. Other Adverse Reactions Grade 3 Withhold until Grade 1 or less, then resume at one lower dose level. [see Adverse Reactions ( 6.1 )] Grade 4 Permanently discontinue. * Unless otherwise specified, National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. 2.5 Instructions for Preparation and Administration Preparation ELAHERE is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Calculate the dose (mg) (based on the patient’s AIBW), total volume (mL) of solution required, and the number of vials of ELAHERE needed [see Recommended Dosage ( 2.2 ) and Dose Modifications ( 2.4 )] . More than one vial will be needed for a full dose. Remove the vials of ELAHERE from the refrigerator and allow to warm to room temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ELAHERE is a clear to slightly opalescent, colorless solution. Gently swirl and inspect each vial prior to withdrawing the calculated dose volume of ELAHERE. Do not shake the vial. Using aseptic technique, withdraw the calculated dose volume of ELAHERE for subsequent dilution. ELAHERE contains no preservatives and is intended for single-dose only. Discard any unused drug remaining in the vial. Dilution ELAHERE must be diluted prior to administration with 5% Dextrose Injection, USP to a final concentration of 1 mg/mL to 2 mg/mL. ELAHERE is incompatible with 0.9% Sodium Chloride Injection. ELAHERE must not be mixed with any other drugs or intravenous fluids. Determine the volume of 5% Dextrose Injection, USP required to achieve the final diluted drug concentration. Either remove excess 5% Dextrose Injection, USP from a prefilled intravenous bag or add the calculated volume of 5% Dextrose Injection, USP to a sterile empty intravenous bag. Then add the calculated dose volume of ELAHERE to the intravenous bag. Gently mix the diluted drug solution by slowly inverting the bag several times to assure uniform mixing. Do not shake or agitate. • If the diluted infusion solution is not used immediately, store solution either at ambient temperature [(18°C to 25°C (64.4°F to 77°F)] for no more than 8 hours (including infusion time), or under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours. If refrigerated, allow the infusion bag to reach room temperature prior to administration. After refrigeration, administer diluted infusion solutions within 8 hours (including infusion time). Do not freeze prepared infusion solution. Administration Inspect the ELAHERE intravenous infusion bag visually for particulate matter and discoloration prior to administration. Administer pre-medications prior to ELAHERE administration [see Premedication and Prophylactic Regimen ( 2.3 )] . Administer ELAHERE as an intravenous infusion only, using a 0.2 or 0.22 µm polyethersulfone (PES) in-line filter. Do not substitute other membrane materials. Administer the initial dose as an intravenous infusion at the rate of 1 mg/min. If well tolerated after 30 minutes at 1 mg/min, the infusion rate can be increased to 3 mg/min. If well tolerated after 30 minutes at 3 mg/min, the infusion rate can be increased to 5 mg/min. If no infusion-related reactions occur with the previous dose, subsequent infusions should be started at the maximally tolerated rate and may be increased up to a maximum infusion rate of 5 mg/min, as tolerated. Following the infusion, flush the intravenous line with 5% Dextrose Injection, USP to ensure delivery of the full dose. Do not use any other intravenous fluids for flushing.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Ocular Disorders [see Warnings and Precautions ( 5.1 )] . Pneumonitis [see Warnings and Precautions ( 5.2 )] . Peripheral Neuropathy [see Warnings and Precautions ( 5.3 )] . The most common (≥20 %) adverse reactions, including lab abnormalities, were increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, blurred vision, nausea, increased alkaline phosphatase, diarrhea, abdominal pain, keratopathy, peripheral neuropathy, musculoskeletal pain, decreased lymphocytes, decreased platelets, decreased magnesium, decreased hemoglobin, dry eye, constipation, decreased leukocytes, vomiting, decreased albumin, decreased appetite, and decreased neutrophils. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 described in Warnings and Precautions reflect exposure to ELAHERE in 682 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 0416, Study 0417, Study 0403 (NCT02631876), and Study 0401 (NCT01609556). The median duration of treatment was 4.4 months (range: 1.0 to 30.0). In the pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, blurred vision, nausea, increased alkaline phosphatase, diarrhea, abdominal pain, keratopathy, peripheral neuropathy, musculoskeletal pain, decreased lymphocytes, decreased platelets, decreased magnesium, decreased hemoglobin, dry eye, constipation, decreased leukocytes, vomiting, decreased albumin, decreased appetite, and decreased neutrophils. Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Study 0416 The safety of ELAHERE was evaluated in Study 0416, a multicenter, open-label, active-controlled, randomized, two-arm, study in patients (n=453) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer [see Clinical Studies ( 14 )] . Patients received ELAHERE 6 mg/kg AIBW once every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 5 months (range: 0.69 to 27.4). Serious adverse reactions occurred in 24% of patients treated with ELAHERE. The most common (≥2%) serious adverse reactions were intestinal obstruction (5%), abdominal pain (3%), and pleural effusion (3%). Fatal adverse reactions occurred in 3% of patients, including intestinal obstruction, dyspnea in the setting of subileus, neutropenic sepsis, cardiopulmonary failure, respiratory failure, ischemic stroke, and pulmonary embolus. Permanent discontinuation of ELAHERE due to adverse reactions occurred in 9% of patients. The most common (≥1%) adverse reactions leading to permanent discontinuation were pneumonitis (2%), blurred vision (1%), and peripheral neuropathy (1%). Dosage delays of ELAHERE due to an adverse reaction occurred in 54% of patients treated with ELAHERE. Adverse reactions which required dosage delays in ≥3% of patients included blurred vision (22%), keratopathy (19%), dry eye (7%), neutropenia (6%), pneumonitis (6%), photophobia (5%), cataract (4%), and peripheral neuropathy (4%). Dose reductions of ELAHERE due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dose reductions in ≥3% of patients included blurred vision (14%), keratopathy (10%), peripheral neuropathy (6%), and dry eye (5%). Tables 4 and 5 summarize adverse reactions and laboratory abnormalities, respectively, occurring in ≥10% of patients who received ELAHERE in Study 0416. Table 4: Adverse Reactions Occurring in ≥10% of Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ELAHERE in Study 0416 Adverse Reaction ELAHERE (n=218) Chemotherapy ¥ (n=207) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal disorders Abdominal pain* 34 3 23 2 Diarrhea 29 1 17 0.5 Constipation 27 0 19 1 Nausea 27 2 29 2 Vomiting 18 3 18 1 Eye disorders Blurred vision ※ 45 9 3 0 Keratopathy † 37 11 0 0 Dry eye ‡ 29 3 5 0 Photophobia 18 0.5 0.5 0 Cataract ˄ 16 3 0.5 0 General disorders and administration site conditions Fatigue ⸙ 47 3 41 7 Nervous system disorders Peripheral neuropathy ¶ 37 4 23 4 Headache 14 0 10 0 Musculoskel e tal and connective tissue disorders Musculoskeletal pain ♦ 31 1 21 2 Metabolism and nutrition disorders Decreased appetite 18 1 14 1 Respiratory, thoracic, and mediastinal disorders Pneumonitis ± 10 0.5 0.5 0 ¥ Chemotherapy: paclitaxel, pegylated liposomal doxorubicin (PLD), topotecan. ※ Blurred vision includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, accommodation disorder, and visual impairment. † Keratopathy includes corneal disorder, corneal epithelial microcysts, keratitis, keratopathy, corneal deposits, punctate keratitis, and corneal opacity. ‡ Dry eye includes dry eye and lacrimation increased. ˄ Cataract includes cataract and cataract nuclear. ⸙ Fatigue includes fatigue and asthenia. * Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. ¶ Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, neurotoxicity, and peripheral sensorimotor neuropathy. ♦ Musculoskeletal pain includes back pain, myalgia, neck pain, arthralgia, musculoskeletal pain, non-cardiac chest pain, bone pain, pain in extremity, musculoskeletal stiffness, musculoskeletal chest pain, and musculoskeletal discomfort. ± Pneumonitis includes pneumonitis, interstitial lung disease, respiratory failure, and organizing pneumonia. Clinically relevant adverse reactions occurring in <10% of patients who received ELAHERE in Study 0416 included infusion related reactions/hypersensitivity (8%). Table 5: Select Laboratory Abnormalities ≥10% for All Grades, in Patients Who Received ELAHERE in Study 0416 Laboratory Abnormality ELAHERE (n=218) Chemotherapy (n=207) All Grades % Grades 3-4 % All Grades % Grades 3-4 % Liver Function Tests Increased aspartate aminotransferase 57 0 14 0 Increased alanine aminotransferase 38 1 15 1 Increased alkaline phosphatase 30 1 13 1 Chemistry Decreased albumin 21 1 27 2 Decreased magnesium 21 1 29 2 Decreased sodium 16 0 18 0 Decreased potassium 15 1 11 1 Increased calcium 12 0 5 0 Decreased bicarbonate 11 0 11 0 Increased creatinine 10 0 11 0 Hematology* Decreased lymphocytes 27 3 42 11 Decreased leukocytes 23 1 53 10 Decreased neutrophils 22 1 45 17 Decreased hemoglobin 18 1 63 8 Decreased platelets 17 1 20 5 * The denominator used to calculate the rate varied from 63 to 214 (ELAHERE); 63 to 194 (IC Chemo) based on the number of patients with a baseline value and at least one post-treatment value. Study 0417 The safety of ELAHERE 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 [see Clinical Studies ( 14 )] . Patients received ELAHERE 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 treated with ELAHERE. 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 ELAHERE 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 ELAHERE due to visual impairment (unilateral decrease to BCVA ≤ 20/200 that resolved to baseline after discontinuation). Dosage delays of ELAHERE due to an adverse reaction occurred in 39% of patients treated with ELAHERE. Adverse reactions which required dosage delays in ≥3% of patients included blurred vision (15%), keratopathy (11%), neutropenia (6%), dry eye (5%), cataracts (3%), and increased gamma-glutamyltransferase (3%). Dose reductions of ELAHERE due to an adverse reaction occurred in 20% of patients. Adverse reactions which required dose reductions in ≥3% of patients included blurred vision (9%) and keratopathy (7%). Table 6 summarizes the adverse reactions (≥10%) in patients treated with ELAHERE in Study 0417. Table 6: Adverse Reactions (≥10%) in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ELAHERE in Study 0417 Adverse Reaction All Grades N=106 (%) Grade 3-4 N=106 (%) Eye disorders Blurred Vision ※ 50 7 Keratopathy † 37 9 Dry eye ‡ 27 2 Cataract 18 3 Photophobia 17 0 Eye pain § 10 0 General disorders Fatigue 49 3 Gastrointestinal disorders Nausea 40 0 Abdominal pain * 36 7 Diarrhea 31 3 Constipation 30 1 Vomiting 19 0 Abdominal distension 11 0 Nervous system disorders Peripheral neuropathy ¶ 33 2 Metabolism and nutrition disorders Decreased appetite 18 1 Musculoskeletal and connective tissue disorders Arthralgia 17 0 Myalgia 10 0 Respiratory, thoracic, and mediastinal disorders Dyspnea^ 12 0 ※ Blurred vision 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. ⸙ Fatigue includes fatigue and asthenia. * Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. ¶ Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, and neurotoxicity. ^ Dyspnea includes dyspnea and exertional dyspnea. Clinically relevant adverse reactions occurring in <10% of patients who received ELAHERE in Study 0417 included infusion related reactions/hypersensitivity (9%), pneumonitis (8%), and uveitis (1%). Table 7 summarizes the laboratory abnormalities in Study 0417. Table 7: Select Laboratory Abnormalities ≥10% for All Grades, or ≥2% for Grades 3-4 in Patients Who Received ELAHERE Laboratory Abnormality ELAHERE* All Grades (%) Grade 3-4 (%) Liver Function Tests Increased aspartate aminotransferase 50 2 Increased alanine aminotransferase 39 2 Increased alkaline phosphatase 30 1 Hematology* Decreased lymphocytes 35 7 Decreased leukocytes 26 1 Decreased neutrophils 26 3 Decreased hemoglobin 25 3 Decreased platelets 18 2 Chemistry Decreased albumin 31 1 Decreased magnesium 27 2 Increased creatinine 16 0 Decreased potassium 15 4 * 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: Anti-Drug Antibody-Associated Adverse Reactions In studies 0416, 0417, 0401, and 0403 in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer who received ELAHERE at 6 mg/kg AIBW administered intravenously once every 3 weeks, 9% (57/626) developed anti-drug antibodies. Infusion reactions (including bronchospasm, erythema, eyelid erythema, flushing, hypersensitivity, periorbital edema, rash, allergic rhinitis, face edema) occurred in 26% (15/57) of patients with anti-drug antibodies and in 7% (41/569) who did not develop anti-drug antibodies [see Clinical Pharmacology ( 12.6 )] .

12.3 Pharmacokinetics The pharmacokinetics were characterized in patients who received mirvetuximab soravtansine-gynx 0.16 mg/kg to 8.7 mg/kg adjusted ideal body weight (AIBW) (0.03 times to 1.4 times the approved recommended dose of 6 mg/kg AIBW), unless otherwise noted. Table 8 summarizes the exposure parameters of mirvetuximab soravtansine-gynx, unconjugated DM4, and its metabolite S-methyl-DM4 following administration after the first cycle (3-weeks). Peak mirvetuximab soravtansine-gynx concentrations were observed near the end of intravenous infusion, while peak unconjugated DM4 concentrations were observed on the second day after administration and the peak S-methyl-DM4 concentrations were observed approximately 3 days after administration. Steady state concentrations of mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 were reached after one 3-week cycle. Accumulation of the mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 was minimal following multiple cycles. Table 8: Exposure Parameters of Mirvetuximab Soravtansine-gynx, Unconjugated DM4, and S-methyl DM4 After First Cycle at a Dosage of 6 mg/kg Mirvetuximab Soravtansine-gynx Mean (±SD) Unconjugated DM4 Mean (±SD) S-methyl-DM4 Mean (±SD) C max 137.3 (±62.3) µg/mL 4.1 (±2.3) ng/mL 7.0 (±6.8) ng/mL AUC tau 20.6 (±6.8) h*mg/mL 530 (±245) h*ng/mL 1848 (±1585) h*ng/mL C max = maximum concentration, AUC tau = area under the concentration vs. time curve over the dosing interval (21 days). Distribution The mean (±SD) steady state volume of distribution of mirvetuximab soravtansine-gynx was 2.6 (±2.9) L. Human plasma protein binding of DM4 and S-methyl DM4 was >99%, in vitro. Elimination For mirvetuximab soravtansine-gynx, total plasma clearance (mean [CV%]) of was 19 mL/hour (52%) and the mean terminal phase half-life after the first dose was 4.8 days leading to a steady state at approximately 24 days. For the unconjugated DM4, the total plasma clearance (mean [CV%]) was 14 L/hour (31%) and the mean terminal phase half-life was 2.8 days. For S-methyl-DM4, the total plasma clearance (mean [CV%]) was 4.3 L/hour (64%) and the mean terminal phase half-life was 5 days. Metabolism The monoclonal antibody portion of mirvetuximab soravtansine-gynx is expected to be metabolized into small peptides by catabolic pathways. Unconjugated DM4 and S-methyl-DM4 undergo metabolism by CYP3A4. In human plasma, DM4 and S-methyl DM4 were identified as the main circulating metabolites, accounting for approximately 0.4% and 1.4% of mirvetuximab soravtansine-gynx AUC, respectively. Excretion S-methyl DM4 and DM4-sulfo-SPDB-lysine were detected in urine within 24 hours of infusion as the main metabolites. Specific Populations No clinically significant differences in the pharmacokinetics of mirvetuximab soravtansine-gynx were observed based on age (32 to 89 years), race (White, Black, or Asian), body weight (36 to 136 kg), mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST), or mild to moderate renal impairment (CLcr 30 to 89 mL/min). The pharmacokinetics of mirvetuximab soravtansine-gynx in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST) or severe renal impairment (CLcr 15 to 30 mL/min) is unknown. Drug Interaction Studies Clinical S tudies and M odel I nformed A pproaches No clinical studies to evaluate the drug-drug interaction potential of mirvetuximab soravtansine-gynx were conducted. There were no differences in exposure between patients who received concomitant weak or moderate CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors and those who did not. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Unconjugated DM4 is a time-dependent inhibitor of CYP3A4. Unconjugated DM4 and S-methyl DM4 are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. DM4 and S-methyl DM4 are not inducers of CYP1A2, CYP2B6, or CYP3A4. Transporter Systems: Unconjugated DM4 and S-methyl DM4 are substrates of P-gp but are not inhibitors of P-gp.