1 INDICATIONS AND USAGE 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.

6 ADVERSE REACTIONS 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) ].

DATROWAY was administered by intravenous infusion once every three weeks.

The median duration of treatment was 8.5 months (range: 0.7 months to 38.0 months) for patients who received DATROWAY.

Serious adverse reactions occurred in 17% of patients who received DATROWAY.

Serious adverse reactions in >1% of patients who received DATROWAY were pneumonia (2.2%), vomiting (1.9%), COVID-19 (1.6%), and anemia (1.3%).

Fatal adverse reactions occurred in one patient (0.3%) who received DATROWAY and was due to ILD/pneumonitis.

Permanent discontinuation of DATROWAY due to an adverse reaction occurred in 4.7% of patients.

Adverse reactions which resulted in permanent discontinuation of DATROWAY in >0.5% of patients included ILD/pneumonitis (0.9%) and keratitis (0.9%).

Dosage interruptions of DATROWAY due to an adverse reaction occurred in 35% of patients.

Adverse reactions which required dosage interruption in >1% of patients included stomatitis (5%), increased amylase (4.1%), keratitis (3.4%), neutropenia (3.1%), COVID-19 (2.8%), pneumonia (2.2%), dry eye (1.9%), upper respiratory tract infection (1.6%), anemia (1.3%), leukopenia (1.3%), IRR (1.3%), and ILD/pneumonitis (1.3%).

Dose reductions of DATROWAY due to an adverse reaction occurred in 28% of patients.

Adverse reactions which required dose reduction in >1% of patients included stomatitis (11%), keratitis (4.1%), fatigue (3.8%), increased amylase (2.8%), and pneumonia (1.3%).

The most common (≥20%) adverse reactions, including laboratory abnormalities in patients receiving DATROWAY, 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.

Table 6: Adverse Reactions (≥10%) in Patients Who Received DATROWAY in TROPION-Breast02 Adverse Reactions DATROWAY N=319 Chemotherapy N=309 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE v5.0.

Gastrointestinal Disorders Stomatitis Includes other related terms 63 8 14 0.3 Nausea 48 0.6 22 0.6 Constipation 40 0.3 17 0 Vomiting 23 1.6 11 0.6 Skin and Subcutaneous Tissue Disorders Alopecia 43 0 35 0.3 Rash Includes rash, erythematous rash, maculo-papular rash, pruritic rash 16 0.6 10 0.3 Skin hyperpigmentation Includes pigmentation disorder, skin discoloration, skin hyperpigmentation 10 0 0.3 0 General Disorders Fatigue 36 2.8 32 2.9 Eye Disorders Keratitis Includes corneal disorder, corneal epithelium defect, corneal erosion, corneal exfoliation, corneal lesion, corneal toxicity, injury corneal, keratitis, keratopathy, punctate keratitis, ulcerative keratitis 26 6 2.8 0.3 Dry eye 26 1.3 4.9 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 22 0.6 22 1.3 Respiratory, Thoracic, and Mediastinal Disorders Cough 19 0 14 0 Metabolism and Nutrition Disorders Decreased appetite 19 0.6 8 0.3 Clinically relevant adverse reactions occurring in <10% of patients who received DATROWAY included infusion-related reactions including anaphylactic reaction, diarrhea, conjunctivitis, lacrimation increased, dry mouth, dry skin, pruritus, rhinorrhea, blepharitis, meibomian gland dysfunction, blurred vision, ILD/pneumonitis, visual impairment, photophobia, and madarosis.

Table 7: Select Laboratory Abnormalities (≥20%) in Patients Who Received DATROWAY in TROPION-Breast02 Laboratory Abnormality DATROWAY The denominator used to calculate the rate varied from 235 to 317 based on the number of patients with a baseline value and at least one post-treatment value.

Chemotherapy All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Frequencies were based on NCI CTCAE v5.0 grade-derived laboratory abnormalities.

Hematology Decreased hemoglobin 43 3.8 63 6 Decreased white blood cells 41 0.9 58 10 Decreased lymphocytes 36 6 46 7 Decreased neutrophils 35 3.5 48 14 Chemistry Increased amylase 54 38 8 0 Decreased calcium 39 1.9 44 1.0 Increased ALT 28 1.6 26 1.3 Increased AST 27 1.6 26 1.3 Decreased albumin 25 1.0 20 0.3 Decreased sodium 21 3.5 18 2.7 Increased blood alkaline phosphatase 20 0.3 15 0 Unresectable or Metastatic, HR-Positive, HER2-Negative Breast Cancer TROPION-Breast01 The safety of DATROWAY was evaluated in 360 patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who received at least one dose of DATROWAY 6 mg/kg in TROPION-Breast01 [see Clinical Studies (14.3) ] .

DATROWAY was administered by intravenous infusion once every three weeks.

The median duration of treatment was 6.7 months (range: 0.7 months to 16.1 months) for patients who received DATROWAY.

Serious adverse reactions occurred in 15% of patients who received DATROWAY.

Serious adverse reactions in >0.5% of patients who received DATROWAY were urinary tract infection (1.9%), COVID-19 infection (1.7%), ILD/pneumonitis (1.1%), acute kidney injury, pulmonary embolism, vomiting, diarrhea, hemiparesis, and anemia (0.6% each).

Fatal adverse reactions occurred in 0.3% of patients who received DATROWAY and were due to ILD/pneumonitis.

Permanent discontinuation of DATROWAY due to an adverse reaction occurred in 3.1% of patients.

Adverse reactions which resulted in permanent discontinuation of DATROWAY in >0.5% of patients included ILD/pneumonitis (1.7%) and fatigue (0.6%).

Dosage interruptions of DATROWAY due to an adverse reaction occurred in 22% of patients.

Adverse reactions which required dosage interruption in >1% of patients included COVID-19 (3.3%), infusion-related reaction (1.4%), ILD/pneumonitis (1.9%), stomatitis (1.9%), fatigue (1.7%), keratitis (1.4%), acute kidney injury (1.1%), and pneumonia (1.1%).

Dose reductions of DATROWAY due to an adverse reaction occurred in 23% of patients.

Adverse reactions which required dose reduction in >1% of patients included stomatitis (13%), fatigue (3.1%), nausea (2.5%), and weight decrease (1.9%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, 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.

Table 8: Adverse Reactions (≥10%) in Patients Who Received DATROWAY in TROPION-Breast01 Adverse Reactions DATROWAY N=360 Chemotherapy N=351 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE v5.0.

Gastrointestinal Disorders Stomatitis Includes other related terms.

59 7 17 2.6 Nausea 56 1.4 27 0.6 Constipation 34 0.3 17 0 Vomiting 24 1.1 12 1.1 Diarrhea 11 0.6 19 1.4 Abdominal pain 11 0.6 15 1.4 General Disorders and Administration Site Conditions Fatigue Includes fatigue, asthenia, lethargy, malaise 44 4.2 40 3.7 Skin and Subcutaneous Tissue Disorders Alopecia 38 0 22 0 Rash 19 0 17 2.3 Eye Disorders Dry eye 27 0.8 13 0 Keratitis Includes corneal disorder, corneal erosion, corneal infiltrates, corneal lesion, corneal toxicity, injury corneal, keratitis, keratopathy, punctate keratitis, and ulcerative keratitis 24 1.1 10 0 Metabolism and Nutrition Disorders Decreased appetite 16 1.4 16 0.9 Infections and Infestations COVID-19 16 1.4 13 0.9 Respiratory, Thoracic, and Mediastinal Disorders Cough 15 0 10 0 Clinically relevant adverse reactions occurring in <10% of patients who received DATROWAY included infusion-related reactions (including bronchospasm), ILD/pneumonitis, headache, pruritus, dry skin, dry mouth, conjunctivitis, blepharitis, meibomian gland dysfunction, blurred vision, increased lacrimation, photophobia, visual impairment, skin hyperpigmentation, and madarosis.

Table 9: Select Laboratory Abnormalities (≥20%) in Patients Who Received DATROWAY in TROPION-Breast01 Laboratory Abnormality DATROWAY The denominator used to calculate the rate varied from 264 to 359 based on the number of patients with a baseline value and at least one post-treatment value.

Chemotherapy All Grades % Grades 3-4 % All Grades % Grades 3-4 % Frequencies were based on NCI CTCAE v5.0 grade-derived laboratory abnormalities.

Hematology Decreased leukocytes 41 1.1 63 18 Decreased lymphocytes 36 9 42 11 Decreased hemoglobin 35 2.8 51 4.4 Decreased neutrophils 30 1.6 61 35 Chemistry Decreased calcium 39 1.4 43 1.2 Increased AST 23 1.9 28 0.9 Increased ALT 24 1.7 31 0.6 Increased alkaline phosphatase 23 0.6 20 0.6