STUDY OVERVIEW EFFICACYSTUDY OVERVIEW

DATROWAY was studied in a global, phase 3 trial for 2L+ HR+/HER2− mBC^1,2

Study overview
Baseline characteristics

TROPION-Breast01 was a randomized, open-label trial

Dual primary endpoints*: PFS (BICR), OS

SELECT SECONDARY ENDPOINTS: ORR, DCR, DoR, safety

ELIGIBILITY CRITERIA

Unresectable or metastatic HR+/HER2− breast cancer^† (IHC 0, IHC 1+ or IHC 2+/ISH−)
Previously treated with 1 or 2 lines of chemotherapy in unresectable/metastatic setting^‡

Progressed on and not suitable for further ET
ECOG PS 0 or 1

STRATIFICATION FACTORS

1 or 2 lines of chemotherapy in unresectable/metastatic setting

Previous CDK4/6 inhibitor use
Geography

732 patients were randomized 1:1 to receive either DATROWAY® or physician’s choice of chemotherapy

DATROWAY, 6 mg/kg IV Q3W (n=365)

Investigator’s choice of chemotherapy^§ (n=367)

[eribulin, capecitabine, vinorelbine, gemcitabine]

Trop-2 testing not required for DATROWAY.¹

During the study, ADCs were approved for use in HR+/HER2− mBC. After treatment discontinuation, some patients in both arms received subsequent ADC therapy^2-4

*The study was considered positive if either the PFS analysis results or the OS analysis results were statistically significant.^1,5

^†Per American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines.²

^‡No prior ADC use was permitted.²

^§Investigator's choice of chemotherapy (ICC) was administered as follows: eribulin 1.4 mg/m² IV on Days 1 and 8, Q3W; capecitabine, 1000 or 1250 mg/m² orally twice daily on Days 1 to 14, Q3W; vinorelbine, 25 mg/m² IV on Days 1 and 8, Q3W; or gemcitabine, 1000 mg/m² IV on Days 1 and 8, Q3W.²

TROPION-Breast01 was a global trial and included patients often seen in clinical practice^1,2,6,7

Baseline characteristics		DATROWAY (n=365)	Chemotherapy (n=367)
Age, median (range), years^¶		56 (29–86)	54 (28-86)
Sex, %	Female	99	99
Race, %	White	49	46
	Asian	40	41
	Black or African American	1	2
Ethnicity, %	Hispanic/Latino	11	12
Ethnicity, %	Not Hispanic or Latino	88	87
ECOG performance status, %	0	54	60
ECOG performance status, %	1	45	40
Sites of metastases at study entry, %	Visceral disease^#	96	98
	Liver metastases	75	68
	Stable brain metastases	10	6
Prior endocrine therapy, %^\|\|
Prior endocrine therapy, %^\|\|	Unresectable/metastatic setting	88	89
Prior lines of chemotherapy, %**	1	63	61
Prior lines of chemotherapy, %**	2	37	38
Prior taxanes or anthracyclines, %	Taxanes	81	81
Prior taxanes or anthracyclines, %	Anthracyclines	63	65
Prior CDK4/6 inhibitor, %	Yes	83	82
Prior CDK4/6 inhibitor, %	No	17	18

Baseline characteristics	DATROWAY (n=365)	Chemotherapy (n=365)
Age, median (range), years^¶	54 (28-86)	54 (26–86)
Sex, %
Female	99	99
Race, %
White	49	46
Asian	40	41
Black or African American	1	2
Ethnicity, %
Hispanic/Latino	11	12
Not Hispanic or Latino	88	87
ECOG performance status, %
0	54	60
1	45	40
Sites of metastases at study entry, %
Visceral disease^#	96	98
Liver metastases	75	68
Stable brain metastases	10	6
Prior endocrine therapy, %^\|\|
Unresectable/metastatic setting	88	89
Prior lines of chemotherapy, %**
1	63	61
2	37	38
Prior taxanes or anthracyclines, %
Taxanes	81	81
Anthracyclines	63	65
Prior CDK4/6 inhibitor, %
Yes	83	82
No	17	18

^¶Of patients treated with DATROWAY, 25% were ≥65 and 5% were ≥75 years of age.¹

^#Visceral metastases includes all sites except bone.⁶

^||95% of patients in the DATROWAY arm and 96% in the chemotherapy arm had received any prior hormonal therapy, including the adjuvant setting.²

**One patient in the DATROWAY arm had received three previous lines of chemotherapy and one patient in the chemotherapy arm had received four previous lines of chemotherapy.²

ADC, antibody-drug conjugate; ALT, alanine aminotransferase; ARs, adverse reactions; AST, aspartate aminotransferase; BICR, blinded independent central review; CDK, cyclin-dependent kinase; CI, confidence interval; ET, endocrine therapy; HER2−, human epidermal growth factor receptor 2-negative; HR, hazard ratio; HR+, hormone receptor-positive; IHC, immunohistochemistry; ISH, in situ hybridization; IV, intravenous; mBC, metastatic breast cancer; mPFS, median progression-free survival; OS, overall survival; PFS, progression-free survival; Q3W, once every three weeks; TRAEs, treatment-related adverse events; Trop-2, trophoblast cell-surface antigen 2.

2L+, second-line or later; ADC, antibody-drug conjugate; ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists; BICR, blinded independent central review; CDK, cyclin-dependent kinase; DCR, disease control rate; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; ICC, investigator's choice of chemotherapy; IHC, immunohistochemistry; ISH, in situ hybridization; IV, intravenous; mBC, metastatic breast cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; Q3W, once every three weeks; Trop-2, trophoblast cell-surface antigen 2.

BICR, blinded independent central review; CDK, cyclin-dependent kinase; Cl, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; HER2−, human epidermal growth factor receptor 2-negative; HR, hazard ratio; HR+, hormone receptor-positive; mBC, metastatic breast cancer; mOS, median overall survival; mPFS, median progression-free survival; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumours; SD, stable disease.

ADC, antibody-drug conjugate; ALT, alanine aminotransferase; ARs, adverse reactions; AST, aspartate aminotransferase; CLcr, creatinine clearance; G-CSF, granulocyte-colony stimulating factor; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; ILD, interstitial lung disease; mBC, metastatic breast cancer; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; Q3W, once every three weeks; TRAEs, treatment-related adverse events; Trop-2, trophoblast cell-surface antigen 2.

ADC, antibody-drug conjugate; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; IHC, immunohistochemistry; ISH, in situ hybridization; IV, intravenous; Q3W, once every three weeks; Trop-2, trophoblast cell-surface antigen 2.

5-HT3, 5-hydroxytryptamine type 3; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; ILD, interstitial lung disease; Trop-2, trophoblast cell-surface antigen 2.

DNA, deoxyribonucleic acid; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mAb, monoclonal antibody; Trop-2, trophoblast cell-surface antigen 2.

HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive.

INDICATION AND IMPORTANT SAFETY INFORMATION

WARNING: INTERSTITIAL LUNG DISEASE AND EMBRYO-FETAL TOXICITY

Severe and fatal cases of ILD/pneumonitis have been reported with DATROWAY. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
Exposure to DATROWAY during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

INDICATION

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.

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

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, 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 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.

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.

Ocular Adverse Reactions

DATROWAY can cause ocular adverse reactions including dry eye, keratitis, blepharitis, meibomian gland dysfunction, increased lacrimation, conjunctivitis, and blurred vision.

Locally Advanced or Metastatic NSCLC and Other Solid Tumors

In patients with locally advanced or metastatic NSCLC and other solid tumors, ocular adverse reactions occurred in 36% of patients treated with DATROWAY. Twenty patients (2.2%) experienced Grade 3 ocular adverse reactions, which included keratitis, dry eye, and blurred vision, and one patient experienced a Grade 4 ocular adverse reaction of conjunctival hemorrhage. The most common (≥5%) ocular adverse reactions were dry eye (17%), keratitis (14%), and increased lacrimation (7%). The median time to onset for ocular adverse reactions was 2.3 months (range: 0.03 months to 23.2 months). Of the patients who experienced ocular adverse reactions, 39% had complete resolution, and 10% 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 3.6% of patients, dosage reductions in 2.5% of patients, and permanent discontinuation of DATROWAY in 1% of patients.

Patients with clinically significant corneal disease were excluded from clinical studies.

Advise patients to use preservative-free lubricant eye drops several times daily for prophylaxis. Advise patients to avoid use of contact lenses unless directed by an eye care professional.

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, annually while on treatment, at end of treatment, and as clinically indicated.

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.

Stomatitis

DATROWAY can cause stomatitis, including mouth ulcers and oral mucositis.

Locally Advanced or Metastatic NSCLC and Other Solid Tumors

In patients with locally advanced or metastatic NSCLC and other solid tumors, 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 18.6 months). Stomatitis led to dosage interruption in 6% of patients, dosage reductions in 11% of patients, and permanent discontinuation of DATROWAY in 0.5% of patients.

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.

Embryo-Fetal Toxicity

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.

Advise patients of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose. 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.

ADVERSE REACTIONS

Locally Advanced or Metastatic NSCLC and Other Solid Tumors

The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to DATROWAY 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 in 927 patients in TROPION-Lung05, TROPION-Lung01, TROPION-PanTumor01, and other clinical trials. Among these patients who received DATROWAY, 45% were exposed for 6 months or longer and 19% were exposed for greater than one year. In this pooled safety population, the most common (≥ 20%) adverse reactions were stomatitis (63%), nausea (52%), fatigue (45%), alopecia (38%), constipation (28%), decreased appetite (23%), rash (23%), vomiting (22%), and musculoskeletal pain (20%). In this pooled safety population, the most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (9%) and decreased hemoglobin (3.5%).

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 as well as TROPION-PanTumor01. 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 (71%), nausea (50%), alopecia (49%), fatigue (42%), decreased hemoglobin (34%), decreased lymphocytes (32%), constipation (31%), increased calcium (31%), increased AST (28%), decreased white blood cell count (27%), increased lactate dehydrogenase (23%), musculoskeletal pain (22%), decreased appetite (20%), increased ALT (20%), and rash (20%).

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.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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. 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.
Lactation: 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.
Females and Males of Reproductive Potential: 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. 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.
Pediatric Use: Safety and effectiveness of DATROWAY have not been established in pediatric patients.
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.
Renal Impairment: A higher incidence of ILD/pneumonitis has been observed in patients with mild and moderate renal impairment (creatinine clearance [CLcr] 30 to <90 mL/min). Monitor patients with renal impairment for increased adverse reactions, including respiratory reactions. No dosage adjustment is recommended in patients with mild to moderate renal impairment. The effect of severe renal impairment (CLcr <30 mL/min) on the pharmacokinetics of datopotamab deruxtecan-dlnk or DXd is unknown.
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). Limited data are available in patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST). Monitor patients with moderate hepatic impairment for increased adverse reactions. The recommended dosage of DATROWAY has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please click here for full Prescribing Information, including WARNINGS AND PRECAUTIONS, and click here for Medication Guide.

2L+=second-line or later; ADC=antibody-drug conjugate; BICR=blinded independent central review; CDK=cyclin-dependent kinase; DCR=disease control rate; DoR=duration of response; ECOG=Eastern Cooperative Oncology Group; ET=endocrine therapy; HER2−=human epidermal growth factor receptor 2-negative; HR+=hormone receptor-positive; IHC=immunohistochemistry; ISH=in situ hybridization; IV=intravenous; mBC=metastatic breast cancer; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; PS=performance status; Q3W=once every three weeks; Trop-2=trophoblast cell-surface antigen 2.

ADC=antibody-drug conjugate; BICR=blinded independent central review; CDK=cyclin-dependent kinase; Cl=confidence interval; CR=complete response; DCR=disease control rate; DoR=duration of response; ECOG=Eastern Cooperative Oncology Group; ET=endocrine therapy; HER2−=human epidermal growth factor receptor 2-negative; HR=hazard ratio; HR+=hormone receptor-positive; mBC=metastatic breast cancer; mOS=median overall survival; mPFS=median progression-free survival; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumours; SD=stable disease.

ADC=antibody-drug conjugate; HER2−=human epidermal growth factor receptor 2-negative; HR+=hormone receptor-positive; IHC=immunohistochemistry; ISH=in situ hybridization; IV=intravenous; Q3W=once every three weeks; Trop-2=trophoblast cell-surface antigen 2.

DNA=deoxyribonucleic acid; HER2−=human epidermal growth factor receptor 2-negative; HR+=hormone receptor-positive; mAb=monoclonal antibody; Trop-2=trophoblast cell-surface antigen 2.

HER2−=human epidermal growth factor receptor 2-negative; HR+=hormone receptor-positive.

INDICATION

CONTRAINDICATIONS

None.

DATROWAY was studied in a global, phase 3 trial for 2L+ HR+/HER2− mBC1,2

TROPION-Breast01 was a randomized, open-label trial

NOW APPROVED for locally advanced or metastatic EGFRm NSCLC

DATROWAY was studied in a global, phase 3 trial for 2L+ HR+/HER2− mBC^1,2