Mirvetuximab Soravtansine

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 )

Injection: 100 mg/20 mL (5 mg/mL) clear to slightly opalescent, colorless solution in a single-dose vial. Injection: 100 mg/20 mL (5 mg/mL) in a single-dose vial. ( 3 )

None. None. ( 4 )

Pneumonitis: Withhold ELAHERE for persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue ELAHERE for Grade 3 or 4 pneumonitis. ( 2.4 , 5.2 ) Peripheral Neuropathy: Monitor patients for new or worsening peripheral neuropathy. Withhold dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of peripheral neuropathy. ( 2.4 , 5.3 ) Embryo-Fetal Toxicity: ELAHERE can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 )

5.1 Ocular Disorders ELAHERE can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis. Ocular adverse reactions occurred in 59% of patients with ovarian cancer treated with ELAHERE. Eleven percent (11%) of patients experienced Grade 3 ocular adverse reactions, including blurred vision, keratopathy (corneal disorders), dry eye, cataract, photophobia, and eye pain; two patients (0.3%) experienced Grade 4 events (keratopathy and cataract). The most common (≥5%) ocular adverse reactions were blurred vision (48%), keratopathy (36%), dry eye (27%), cataract (16%), photophobia (14%), and eye pain (10%). [see Adverse Reactions ( 6.1 )]. The median time to onset for first ocular adverse reaction was 5.1 weeks (range: 0.1 to 68.6). Of the patients who experienced ocular events, 53% had complete resolution; 38% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Ocular adverse reactions led to permanent discontinuation of ELAHERE in 1% of patients. Premedication and use of lubricating and ophthalmic topical steroid eye drops during treatment with ELAHERE are recommended [see Dosage and Administration ( 2.3 )]. Advise patients to avoid use of contact lenses during treatment with ELAHERE unless directed by a healthcare provider. Refer patients to an eye care professional for an ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation, every other cycle for the first 8 cycles, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms. Monitor for ocular toxicity and withhold, reduce, or permanently discontinue ELAHERE based on severity and persistence of ocular adverse reactions. [see Dosage and Administration ( 2.4 )].

5.2 Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ELAHERE. Pneumonitis occurred in 10% of patients treated with ELAHERE, including 1% with Grade 3 events and 1 patient (0.1%) with a Grade 4 event. One patient (0.1%) died due to respiratory failure in the setting of pneumonitis and lung metastases. One patient (0.1%) died due to respiratory failure of unknown etiology. Pneumonitis led to permanent discontinuation of ELAHERE in 3% of patients. Monitor patients for pulmonary signs and symptoms of pneumonitis, which may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations. Withhold ELAHERE for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤ Grade 1 and consider dose reduction. Permanently discontinue ELAHERE in all patients with Grade 3 or 4 pneumonitis [see Dosage and Administration ( 2.4 )] . Patients who are asymptomatic may continue dosing of ELAHERE with close monitoring.

5.3 Peripheral Neuropathy Peripheral neuropathy occurred in 36% of patients with ovarian cancer treated with ELAHERE across clinical trials; 3% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (9%), paraesthesia (6%), neurotoxicity (3%), hypoesthesia (1%), peripheral motor neuropathy (0.9%), polyneuropathy (0.3%), and peripheral sensorimotor neuropathy (0.1%). The median time to onset of peripheral neuropathy was 5.9 weeks (range 0.1 to 126.7). Of the patients who experienced peripheral neuropathy, 23% had complete resolution and 12% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Peripheral neuropathy led to discontinuation of ELAHERE in 0.7% of patients. Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, withhold dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of peripheral neuropathy [see Dosage and Administration ( 2.4 )].

5.4 Embryo-Fetal Toxicity Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for 7 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

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%). […]

Strong CYP3A4 Inhibitors: Closely monitor for ELAHERE adverse reactions. ( 7.1 )

7.1 Effects of Other Drugs on ELAHERE Strong CYP3A4 Inhibitors DM4 is a CYP3A4 substrate. Concomitant use of ELAHERE with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of ELAHERE adverse reactions [see Adverse Reactions ( 6 )] . Closely monitor patients for adverse reactions with ELAHERE when used concomitantly with strong CYP3A4 inhibitors [ see Warnings and Precautions ( 5 ) ] .

Lactation: Advise not to breastfeed. ( 8.2 ) Moderate or severe hepatic impairment: Avoid use. ( 8.7 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells [see Clinical Pharmacology ( 12.1 ), Nonclinical Toxicology ( 13.1 )] . Human immunoglobulin G (IgG) is known to cross the placental barrier; therefore, ELAHERE has the potential to be transmitted from the mother to the developing fetus. There are no available human data on ELAHERE use in pregnant women to inform a drug-associated risk. No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine-gynx. 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-gynx. The cytotoxic component of ELAHERE, DM4, disrupts microtubule function, is genotoxic, and can be toxic to actively dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.

8.2 Lactation Risk Summary There are no data on the presence of mirvetuximab soravtansine-gynx 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 ELAHERE and for 1 month after the last dose.

8.3 Females and Males of Reproductive Potential ELAHERE can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating ELAHERE. Contraception Females: Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for 7 months after the last dose.

8.4 Pediatric Use Safety and effectiveness of ELAHERE have not been established in pediatric patients.

8.5 Geriatric Use Of the 682 patients with epithelial ovarian cancer who were treated with ELAHERE across studies, 44% of patients were ≥65 years old. Grade ≥3 adverse reactions occurred in 51% of patients ≥65 years and in 45% <65 years. No clinically meaningful differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Age does not have a clinically meaningful effect on the pharmacokinetics of ELAHERE [see Clinical Pharmacology ( 12.3 )] .

8.6 Renal Impairment No dosage adjustment of ELAHERE is recommended for patients with mild to moderate renal impairment (CLcr 30 to 89 mL/min). The effect of severe renal impairment (CLcr 15 to < 30 mL/min) or end-stage renal disease on ELAHERE is unknown [see Clinical Pharmacology ( 12.3 )] .

8.7 Hepatic Impairment Avoid use of ELAHERE in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN). No dosage adjustment of ELAHERE is recommended for patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) [see Clinical Pharmacology ( 12.3 )] .

Mirvetuximab soravtansine-gynx is an antibody-drug conjugate (ADC). The antibody is a chimeric IgG1 directed against folate receptor alpha (FRα). The small molecule, DM4, is a microtubule inhibitor attached to the antibody via a cleavable linker. Upon binding to FRα, mirvetuximab soravtansine-gynx is internalized followed by intracellular release of DM4 via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, resulting in cell cycle arrest and apoptotic cell death.