Datopotamab Deruxtecan

DATROWAY is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of: adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who have received prior EGFR-directed therapy and platinum-based chemotherapy. ( 1.1 ) This indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14.1) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. adult patients with unresectable or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 inhibitor therapy [see Clinical Studies (14.2) ] . ( 1.2 ) adult patients with unresectable or metastatic, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. ( 1.3 )

1.1 Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC) DATROWAY is indicated for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who have received prior EGFR-directed therapy and platinum-based chemotherapy. This indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14.1) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

1.2 Unresectable or Metastatic Triple-Negative Breast Cancer (TNBC) DATROWAY is indicated for the treatment of adult patients with unresectable or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 inhibitor therapy [see Clinical Studies (14.2) ].

1.3 Unresectable or Metastatic, HR-Positive, HER2-Negative Breast Cancer DATROWAY is indicated for the treatment of adult patients with unresectable or metastatic, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.

For injection: 100 mg of datopotamab deruxtecan-dlnk as a white to yellowish white, lyophilized powder in a single-dose vial for reconstitution and further dilution. For injection: 100 mg lyophilized powder in a single-dose vial. ( 3 )

None. None. ( 4 )

Interstitial Lung Disease (ILD) and Pneumonitis: DATROWAY can cause severe and fatal cases of ILD/pneumonitis. Monitor for new or worsening signs and symptoms of ILD/pneumonitis. If ILD/pneumonitis is suspected, withhold DATROWAY and initiate corticosteroids. Permanently discontinue DATROWAY in patients with confirmed Grade 2 or higher ILD/pneumonitis. ( 5.1 ) Ocular Adverse Reactions: DATROWAY can cause ocular adverse reactions including dry eye, keratitis, blepharitis, meibomian gland dysfunction, increased lacrimation, conjunctivitis, and blurred vision. Monitor patients for ocular adverse reactions during treatment with DATROWAY. Advise patients to use preservative-free lubricating eye drops and to avoid using contact lenses during treatment with DATROWAY. Withhold, reduce the dose, or permanently discontinue DATROWAY based on the severity of ocular adverse reactions. Refer patients to an eye care professional for any new or worsening ocular signs and symptoms. ( 2.3 , 2.4 , 5.2 ) Stomatitis/Oral Mucositis: DATROWAY can cause stomatitis, including mouth ulcers and oral mucositis. Advise patients to use a steroid-containing mouthwash when starting treatment and to hold ice chips or ice water in mouth during the infusion of DATROWAY. Withhold, reduce the dose, or permanently discontinue DATROWAY based on severity. ( 2.3 , 2.4 , 5.3 ) Embryo-Fetal Toxicity : DATROWAY can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 )

5.1 Interstitial Lung Disease/Pneumonitis DATROWAY can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis. Locally Advanced or Metastatic NSCLC In the pooled safety population of 484 patients with NSCLC from TROPION-Lung01, TROPION-Lung05, and TROPION-PanTumor01 [see Adverse Reactions (6.1) ], ILD/pneumonitis occurred in 7% of patients treated with DATROWAY, including 0.6% of patients with Grade 3 and 0.4% with Grade 4. There were 8 (1.7%) fatal cases. The median time to first onset for ILD was 1.4 months (range: 0.2 months to 9 months). Eleven patients (2.3%) had DATROWAY withheld and 20 patients (4.1%) permanently discontinued DATROWAY due to ILD/pneumonitis. Systemic corticosteroids were required in 79% (26/33) of patients with ILD/pneumonitis. ILD/pneumonitis resolved in 45% of patients. Unresectable or Metastatic Breast Cancer In the pooled safety population of 841 patients with breast cancer from TROPION-Breast01, TROPION-Breast02, TROPION-PanTumor01 and TROPION-PanTumor02 [see Adverse Reactions (6.1) ], ILD/pneumonitis occurred in 3.0% of patients treated with DATROWAY, including 0.4% of patients with Grade 3. There were two fatal cases (0.2%). The median time to first onset for ILD was 5.3 months (range: 1.1 months to 19.3 months) and with a median duration of 1.2 months (range: 0.3 to 5.2). Eight patients (1.0%) had DATROWAY withheld and 10 patients (1.2%) permanently discontinued DATROWAY due to ILD/pneumonitis. Systemic corticosteroids were required in 64% (16/25) of patients with ILD/pneumonitis. ILD/pneumonitis resolved in 40% of patients. Patients were excluded from clinical studies for a history of ILD/pneumonitis requiring treatment with steroids or for ongoing ILD/pneumonitis. Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever) during treatment with DATROWAY. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), promptly initiate systemic corticosteroid treatment (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. Withhold DATROWAY in patients with suspected ILD/pneumonitis and permanently discontinue DATROWAY if ≥Grade 2 ILD/pneumonitis is confirmed [see Dosage and Administration (2.4) ].

5.2 Ocular Adverse Reactions DATROWAY can cause ocular adverse reactions including dry eye, keratitis, blepharitis, meibomian gland dysfunction, increased lacrimation, conjunctivitis, and blurred vision. In the pooled safety population [see Adverse Reactions (6.1) ] , ocular adverse reactions occurred in 38% of patients treated with DATROWAY. Forty-two patients (3.1%) experienced Grade 3 ocular adverse reactions, which included keratitis and dry eye, and four patients (0.3%) experienced a Grade 4 ocular adverse reaction of keratitis, corneal epithelium defect, corneal lesion, and conjunctival hemorrhage. The most common (≥5%) ocular adverse reactions were dry eye (18%), keratitis (16%), increased lacrimation (6%), and conjunctivitis (5%). The median time to first onset for ocular adverse reactions was 2.3 months (range: 0.03 months to 30 months) and with a median duration of 2.3 months (range: 0.03 to 19.5). Of the patients who experienced ocular adverse reactions, 39% had complete resolution, and 8% 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 dosage interruption in 4.3% of patients, dosage reductions in 2.8% of patients, and permanent discontinuation of DATROWAY in 0.9% of patients. Patients with clinically significant corneal disease were excluded from clinical studies. Advise patients to use preservative-free lubricant eye drops at least four times daily and as needed for prophylaxis. Advise patients to avoid use of contact lenses unless directed by an eye care professional [see Dosage and Administration (2.3) ] . Refer patients to an eye care professional for an ophthalmic exam including visual acuity testing, slit lamp examination (with fluorescein staining), intraocular pressure, and fundoscopy at treatment initiation, at end of treatment, and as clinically indicated. While on treatment, conduct visual acuity testing and slit lamp examination every 3 cycles. Promptly refer patients to an eye care professional for any new or worsening ocular adverse reactions. Monitor patients for ocular adverse reactions during treatment with DATROWAY, and if diagnosis is confirmed, withhold, reduce the dose, or permanently discontinue DATROWAY based on severity [see Dosage and Administration (2.4) ] .

5.3 Stomatitis DATROWAY can cause stomatitis, including mouth ulcers and oral mucositis. In the pooled safety population [see Adverse Reactions (6.1) ], stomatitis occurred in 63% of patients treated with DATROWAY, including 8% of patients with Grade 3 events and one patient with a Grade 4 reaction. The median time to first onset of stomatitis was 0.5 months (range: 0.03 months to 19.8 months) and with a median duration of 1.1 months (range: 0.03 to 33.2). Stomatitis led to dosage interruption in 5% of patients, dosage reductions in 11% of patients, and permanent discontinuation of DATROWAY in 0.4% of patients. In patients who received DATROWAY in TROPION-Breast01 and TROPION-Breast02, 39% and 51% respectively used a mouthwash containing corticosteroid for management or prophylaxis of stomatitis/oral mucositis at any time during the treatment. Advise patients to use a steroid-containing mouthwash for prophylaxis and treatment of stomatitis. Instruct the patient to hold ice chips or ice water in the mouth throughout the infusion of DATROWAY. Monitor patients for signs and symptoms of stomatitis. If stomatitis occurs, increase the frequency of mouthwash and administer other topical treatments as clinically indicated. Based on the severity of the adverse reaction, withhold, reduce the dose, or permanently discontinue DATROWAY [see Dosage and Administration (2.4) ]. […]

The following clinically significant adverse reactions are described elsewhere in the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1) ] Ocular Adverse Reactions [see Warnings and Precautions (5.2) ] Stomatitis [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥20%), including laboratory abnormalities, in patients with: EGFR-mutated NSCLC were stomatitis, nausea, alopecia, fatigue, decreased hemoglobin, decreased lymphocytes, constipation, increased calcium, increased AST, decreased white blood cell count, increased lactate dehydrogenase, musculoskeletal pain, decreased appetite, increased ALT, and rash. ( 6.1 ) TNBC were stomatitis, increased amylase, nausea, alopecia, decreased hemoglobin, decreased white blood cells, constipation, decreased calcium, decreased lymphocytes, fatigue, decreased neutrophils, increased ALT, increased AST, dry eye, keratitis, decreased albumin, vomiting, musculoskeletal pain, decreased sodium, and increased blood alkaline phosphatase. ( 6.1 ) HR-positive, HER2-negative breast cancer were stomatitis, nausea, fatigue, decreased leukocytes, decreased calcium, alopecia, decreased lymphocytes, decreased hemoglobin, constipation, decreased neutrophils, dry eye, vomiting, increased ALT, keratitis, increased AST, and increased alkaline phosphatase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 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 reflects exposure to DATROWAY in 1365 patients as a single agent at 6 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. This included 137 patients with NSCLC in TROPION-Lung05 [see Clinical Studies (14.1) ] , 297 patients with NSCLC in TROPION-Lung01 [see Clinical Studies (14.1) ] , 360 patients with HR-positive, HER2-negative breast cancer in TROPION-Breast01 [see Clinical Studies (14.3) ] , 319 patients with TNBC in TROPION-Breast02 [see Clinical Studies (14.2) ] , 50 patients with NSCLC and 83 patients with breast cancer in TROPION-PanTumor01 (NCT03401385), and 40 patients with NSCLC and 79 patients with breast cancer in TROPION-PanTumor02 (NCT05460273). Among the 1365 patients who received DATROWAY, 48% were exposed for greater than 6 months and 22% were exposed for greater than one year. In this pooled safety population, the most common (≥20%) adverse reactions were stomatitis (63%), nausea (51%), fatigue (42%), alopecia (38%), constipation (30%), vomiting (23%), decreased appetite (22%), and rash (20%). In this pooled safety population, the most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (8%), decreased hemoglobin (3.7%), decreased sodium (3.0%), and decreased blood potassium (2.3%). Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer TROPION-Lung05, TROPION-Lung01, TROPION-PanTumor01 The safety of DATROWAY was evaluated in 125 patients with EGFR-mutated NSCLC who received DATROWAY 6 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity in TROPION-Lung05 and TROPION-Lung01 [see Clinical Studies (14.1) ] as well as TROPION-PanTumor01 (NCT03401385). Among these patients, the median duration of treatment was 6.1 months (range 0.7 months to 41.7 months). The median age was 63 years (range: 36 to 81), 56% of patients were <65 years, 62% of patients were female; 66% were Asian, 26% were White, 0.8% were Black, 6% were other races; and 2.4% were of Hispanic ethnicity. Serious adverse reactions occurred in 26% of patients who received DATROWAY. Serious adverse reactions in >1% of patients who received DATROWAY were COVID-19 (4%), stomatitis (2.4%), and pneumonia (1.6%). Fatal adverse reactions occurred in 1.6% of patients who received DATROWAY, due to death not otherwise specified. Permanent discontinuation of DATROWAY due to an adverse reaction occurred in 8% of patients. Adverse reactions which resulted in permanent discontinuation of DATROWAY in >1% of patients included ILD/pneumonitis (2.4%) and abnormal hepatic function (1.6%). Dosage interruptions of DATROWAY due to an adverse reaction occurred in 43% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 (13%), stomatitis (7%), fatigue (6%), pneumonia (4%), anemia (2.4%), amylase increased (2.4%), keratitis (2.4%), ILD/pneumonitis (1.6%), decreased appetite (1.6%), dyspnea (1.6%), rash (1.6%), and infusion-related reaction (1.6%). Dose reductions of DATROWAY due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dose reduction in >1% of patients included stomatitis (14%), keratitis (1.6%), fatigue (1.6%), decreased weight (1.6%) and COVID-19 (1.6%). The most common (≥20%) adverse reactions, including laboratory abnormalities, were stomatitis, nausea, alopecia, fatigue, decreased hemoglobin, decreased lymphocytes, constipation, increased calcium, increased AST, decreased white blood cell count, increased lactate dehydrogenase, musculoskeletal pain, decreased appetite, increased ALT, and rash. Table 4: Adverse Reactions (≥10%) in Patients with Locally Advanced or Metastatic EGFR-Mutated NSCLC Who Received DATROWAY in TROPION-Lung05, TROPION-Lung01, and TROPION-PanTumor01 Adverse Reaction DATROWAY N=125 All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE v5.0. Gastrointestinal disorders Stomatitis Includes other related terms 71 9 Nausea 50 0 Constipation 31 0 Vomiting 16

0.8 Diarrhea 12 0 Skin and subcutaneous tissue disorders Alopecia 49 0 Rash 20

0.8 Pruritus 12 0 General disorders and administration site conditions Fatigue Includes fatigue, asthenia, and malaise 42 6 Musculoskeletal and connective tissue disorders Musculoskeletal pain 22

0.8 Metabolism and nutrition disorders Decreased appetite 20

1.6 Infections and Infestations COVID-19 19

2.4 Respiratory, Thoracic, and Mediastinal Disorders Cough 18 0 Dyspnea 11

2.4 Eye disorders Dry eye 13 0 Keratitis Includes corneal disorder, corneal erosion, keratitis, punctate keratitis, and ulcerative keratitis 12

2.4 Injury, poisoning and procedural complications Infusion-related reaction 13 0 Nervous system disorders Headache 13 0 Clinically relevant adverse reactions occurring in <10% of patients who received DATROWAY included dry skin, blurred vision, abdominal pain, conjunctivitis, dry mouth, ILD/pneumonitis, skin hyperpigmentation, increased lacrimation, and visual impairment. Table 5: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Locally Advanced or Metastatic EGFR-Mutated NSCLC Who Received DATROWAY in TROPION-Lung05, TROPION-Lung01, and TROPION-PanTumor01 Laboratory Abnormality Frequencies were based on NCI CTCAE v5.0 grade-derived laboratory abnormalities. DATROWAY The denominator used to calculate the rate varied from 115 to 124 based on the number of patients with a baseline value and at least one post-treatment value. All Grades % Grades 3 or 4 % Hematology Decreased hemoglobin 34

4.8 Decreased lymphocytes 32 11 Decreased white blood cell count 27

1.6 Chemistry Increased calcium 31 0 Increased AST 28

2.4 Increased lactate dehydrogenase 23 0 Increased ALT 20

2.4 Unresectable or Metastatic Triple-Negative Breast Cancer (TNBC) TROPION-Breast02 The safety of DATROWAY was evaluated in 319 patients with triple-negative breast cancer who received at least one dose of DATROWAY 6 mg/kg in TROPION-Breast02 [see Clinical Studies (14.2) ]. […]

Lactation: Advise not to breastfeed. ( 8.2 ) Infertility: May impair fertility in males and females. ( 8.3 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, DATROWAY can cause embryo-fetal harm when administered to a pregnant woman because the topoisomerase inhibitor component of DATROWAY, DXd, is genotoxic and affects actively dividing cells [see Clinical Pharmacology (12.1) , Nonclinical Toxicology (13.1) ] . There are no available data on the use of DATROWAY in pregnant women to inform a drug-associated risk. Advise patients of the potential risks 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 There were no animal reproductive or developmental toxicity studies conducted with datopotamab deruxtecan-dlnk.

8.2 Lactation Risk Summary There are no data regarding the presence of datopotamab deruxtecan-dlnk or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with DATROWAY and for 1 month after the last dose.

8.3 Females and Males of Reproductive Potential DATROWAY can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiation of DATROWAY. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose. Males Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with DATROWAY and for 4 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Based on findings in animal toxicity studies, DATROWAY may impair male and female reproductive function and fertility. The effects on reproductive organs in animals were irreversible [see Nonclinical Toxicology (13.1) ] .

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

8.5 Geriatric Use Of the 125 patients with EGFR-mutated NSCLC in TROPION-Lung05, TROPION-Lung01, TROPION-PanTumor01 treated with DATROWAY 6 mg/kg, 44% were ≥65 years of age and 10% were ≥75 years of age. No clinically meaningful differences in efficacy and safety were observed between patients ≥65 years of age versus younger patients. Of the 841 patients with breast cancer in TROPION-Breast01, TROPION-Breast02, TROPION-PanTumor01, and TROPION-PanTumor02 treated with DATROWAY 6 mg/kg, 23% were ≥65 years of age and 4.5% were ≥75 years of age. Grade ≥3 and serious adverse reactions were more common in patients ≥65 years (45% and 22%, respectively) compared to patients <65 years (38% and 16%, respectively). No other meaningful differences in safety or efficacy were observed between patients ≥65 years of age versus younger patients.

8.6 Renal Impairment Monitor patients with renal impairment for increased adverse reactions, including respiratory reactions. A higher incidence of ILD/pneumonitis has been observed in patients with creatinine clearance (CLcr) 30 to <90 mL/min (estimated by Cockcroft Gault) [see Warnings and Precautions (5.1) ]. No dosage adjustment is recommended in patients with CLcr 30 to <90 mL/min [see Clinical Pharmacology (12.3) ] . The pharmacokinetics of datopotamab deruxtecan-dlnk or DXd in patients with CLcr <30 mL/min is unknown.

8.7 Hepatic Impairment Monitor patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST) for increased adverse reactions [see Dosage and Administration (2.4) ] . Limited data are available in patients with moderate hepatic impairment. No dosage adjustment is recommended in patients with mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST). The recommended dosage of DATROWAY has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) [see Clinical Pharmacology (12.3) ].

Datopotamab deruxtecan-dlnk, is a Trop-2-directed antibody-drug conjugate. The antibody is a humanized anti-Trop2 IgG1. The small molecule, DXd, is a topoisomerase I inhibitor attached to the antibody by a cleavable linker. Following binding to Trop-2 on cells, including tumor cells, datopotamab deruxtecan-dlnk undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death. Datopotamab deruxtecan-dlnk had anti-tumor activity in mouse models of lung cancer including EGFR-mutated and breast cancer.