DATROWAY - Daiichi Sankyo Inc.

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.

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)].

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.

Select patients with locally advanced or metastatic NSCLC for treatment with DATROWAY based on the presence of epidermal growth factor receptor (EGFR) mutations in tumor or plasma specimens [see Clinical Studies (14.1)]. Testing may be performed at any time from initial diagnosis and does not need to be repeated once EGFR mutation status has been established.

The recommended dosage of DATROWAY is 6 mg/kg (up to a maximum of 540 mg for patients ≥90 kg) administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses.

Conduct an ophthalmic exam including visual acuity testing, slit lamp examination (with fluorescein staining), intraocular pressure, and fundoscopy at initiation of DATROWAY, at end of treatment, and as clinically indicated. While on treatment, conduct visual acuity testing and slit lamp examination every 3 cycles.

Administer DATROWAY with the premedication and concomitant medications described in Table 1.

Monitor patients for infusion-related reactions in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 1 hour for the first 2 cycles of DATROWAY infusions. If there are no infusion-related reactions observed, monitor patients for at least 30 minutes for all subsequent cycles of infusions.

Dosage Modifications for Adverse Reactions

The recommended dose reduction levels for adverse reactions are described in Table 2.

Do not re-escalate the DATROWAY dose after a dose reduction. Permanently discontinue DATROWAY in patients who are unable to tolerate 3 mg/kg intravenously once every 3 weeks.

The recommended dosage modifications and management of adverse reactions for DATROWAY are described in Table 3.

Reconstitute and further dilute DATROWAY prior to intravenous infusion. Use appropriate aseptic technique.

DATROWAY (datopotamab deruxtecan-dlnk) is a hazardous drug. Follow applicable special handling and disposal procedures.¹

Reconstitution

• Reconstitute immediately before dilution.
• More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of reconstituted DATROWAY solution required, and the number of vial(s) of DATROWAY needed [see Dosage and Administration (2.2)].
• Reconstitute each 100 mg vial using a sterile syringe to slowly inject 5 mL of Sterile Water for Injection into each vial to obtain a final concentration of 20 mg/mL.
• Swirl the vial gently until completely dissolved. Do not shake.
• If not used immediately, refrigerate the reconstituted DATROWAY solution in the original vial at 2°C to 8°C (36°F to 46°F) for up to 48 hours from the time of reconstitution. Protect the vial from light. Do not freeze.
• The product does not contain a preservative. Discard unused reconstituted DATROWAY after 48 hours of refrigeration.

Dilution

• Withdraw the calculated amount from the vial(s) using a sterile syringe. Inspect for particulate matter and discoloration prior to administration. The reconstituted solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.
• Dilute the calculated volume of reconstituted DATROWAY in an infusion bag containing 100 mL of 5% Dextrose Injection. DO NOT use Sodium Chloride Injection. DATROWAY is compatible with an infusion bag made of polyvinylchloride or polyolefin (polypropylene or copolymer of ethylene and propylene).
• Gently invert the infusion bag to thoroughly mix the solution. Do not shake.
• Cover the infusion bag to protect from light.
• If not used immediately, store at room temperature at up to 25°C (77°F) for up to 4 hours including preparation or in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours. Do not freeze.
• Discard any unused portion left in the vial.

Administration

• The maximum time from reconstitution of the vial through the end of administration should not exceed 48 hours. Discard if storage time exceeds these limits.
• If the prepared infusion solution was stored refrigerated at 2°C to 8°C (36°F to 46°F), allow the solution to reach room temperature prior to administration, protected from light.
• Inspect for particulate matter and discoloration prior to administration.
• Administer DATROWAY as an intravenous infusion only with an infusion line and tubing set made of polyvinyl chloride, polybutadiene or low-density polyethylene.
• Administer DATROWAY with a 0.2-micron in-line polytetrafluoroethylene, polyethersulfone or nylon 66 filter.
• Do NOT administer as an intravenous push or bolus.
• Cover the infusion bag to protect from light during administration.
• Do not mix DATROWAY with other drugs or administer other drugs through the same intravenous line.
• Instruct the patient to hold ice chips or ice water in the mouth throughout the infusion of DATROWAY.
• First infusion: Administer infusion over 90 minutes. Observe patients during the infusion and for at least 1 hour following the initial dose for signs or symptoms of infusion-related reactions.
• Second Infusion: If first infusion was tolerated, administer second infusion over 30 minutes. Observe patients during the infusion and for at least 1 hour after infusion.
• Subsequent Infusions: Administer infusion over 30 minutes if prior infusions were tolerated. Observe patients during the infusion and for at least 30 min after infusion.

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)].

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)].

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)].

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 [see Description (11)], is genotoxic and affects actively dividing cells [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].

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 [see Use in Specific Populations (8.1, 8.3)].

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.

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.

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.

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.

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.

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.

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.

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.

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)].

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

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.

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.

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.

Datopotamab deruxtecan-dlnk time course of pharmacodynamic response is unknown.

Exposure-Response Relationships

A relationship between datopotamab deruxtecan-dlnk exposure and efficacy has not been fully characterized in breast cancer or EGFR-mutated NSCLC.

In the pooled population of NSCLC (including EGFR-mutated NSCLC) and breast cancer patients, higher datopotamab deruxtecan-dlnk systemic exposure is associated with a higher incidence rate of serious adverse reactions, dosage interruptions, dose reductions, stomatitis/oral mucositis, ocular adverse reactions, and Grade ≥3 adverse reactions.

Cardiac Electrophysiology

At datopotamab deruxtecan-dlnk doses up to 10 mg/kg (1.7 times the recommended dose), mean increase in the QTc interval >20 ms was not observed.

Datopotamab deruxtecan-dlnk and DXd exposure after the first dose of the approved recommended dosage of cycle 1 are provided in Table 10. Datopotamab deruxtecan-dlnk and released DXd maximum concentration (C_max) and area under the time-concentration curve (AUC) increases proportionally over a dose range of 4 mg/kg to 10 mg/kg (approximately 0.7 to 1.7 times the approved recommended dosage). No clinically significant datopotamab deruxtecan-dlnk accumulation occurs between cycles 1 and 3.

Distribution

Datopotamab deruxtecan-dlnk mean steady state volume of distribution is 3.5 (23%) L.

DXd plasma protein binding is approximately 98% and the blood-to-plasma concentration ratio is 0.6 in vitro.

Elimination

The datopotamab deruxtecan-dlnk median elimination half-life (t_1/2) is 4.8 days (1.0, 8.2) and the released DXd median apparent t_1/2 is approximately 5.5 days (3.2, 8.8). The estimated datopotamab deruxtecan-dlnk clearance is 0.6 (31.5%) L/day.

Metabolism

Datopotamab deruxtecan-dlnk undergoes intracellular cleavage by lysosomal enzymes to release DXd.

The humanized Trop-2 IgG1 monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

In vitro, DXd is primarily metabolized by CYP3A4.

Specific Populations

The mean volume of distribution and clearance of datopotamab deruxtecan-dlnk and DXd increase with increasing body weight (36 kg to 156 kg).

No clinically significant differences in the pharmacokinetics of datopotamab deruxtecan-dlnk or DXd were observed based on age (26 to 86 years), race (Asian, White, or Black), sex, mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST), or CLcr 30 to <90 mL/min.

The pharmacokinetics of datopotamab deruxtecan-dlnk in patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST) was comparable to patients with normal hepatic function (total bilirubin and AST ≤ULN). The steady state average DXd AUC was 2.5-fold higher in patients with moderate hepatic impairment compared to patients with normal hepatic function. The effect of severe hepatic impairment (total bilirubin >3 times ULN and any AST) or CLcr <30 mL/min on datopotamab deruxtecan-dlnk or DXd pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

No clinically significant differences in DXd pharmacokinetics were predicted when used concomitantly with itraconazole (strong CYP3A inhibitor) or ritonavir (dual OATP1B and CYP3A inhibitor).

In Vitro Studies

CYP450 Enzymes: DXd does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A and does not induce CYP1A2, CYP2B6, or CYP3A.

UDP-Glucuronosyltransferase (UGT): DXd does not undergo significant metabolism by UGT enzymes.

Transporters Systems: DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP. DXd does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters.

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of DATROWAY or of other datopotamab deruxtecan products.

During the median 5.8-month treatment period across 6 clinical studies in patients with NSCLC or breast cancer who received DATROWAY 6 mg/kg once every 3 weeks, 17% (223 out of 1333) of patients developed anti-datopotamab deruxtecan-dlnk antibodies with 17% (37 out of 223) of these patients developing neutralizing antibodies against datopotamab deruxtecan-dlnk. Trough concentrations of datopotamab deruxtecan-dlnk during early treatment cycles were 45% to 61% lower in patients with anti-datopotamab deruxtecan-dlnk antibodies compared to those without. No apparent effect of ADAs on the effectiveness or safety of datopotamab deruxtecan-dlnk was observed.

Carcinogenicity studies have not been conducted with datopotamab deruxtecan-dlnk.

The topoisomerase inhibitor component of datopotamab deruxtecan-dlnk, DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.

Dedicated fertility studies have not been conducted with datopotamab deruxtecan-dlnk. In a 3-month repeat-dose toxicity study, intravenous administration of datopotamab deruxtecan-dlnk once every 3 weeks in rats resulted in decreased weights in the testes and epididymides, degeneration of the germinal epithelium and atrophy of seminiferous tubules in testes, and cell debris, decreased number of sperm, and single-cell necrosis of the ductal epithelium in epididymides at 200 mg/kg (approximately 29 times the human recommended dose of 6 mg/kg based on AUC). Findings in female rats included increased atretic secondary follicles and decreased vesicular follicles in the ovary and single cell necrosis of mucosal epithelium in the vagina at 200 mg/kg. These findings, except for the lesions in the testis and epididymis, were not observed after a 2-month recovery period.

The efficacy of DATROWAY was evaluated in a pooled subgroup of patients with locally advanced or metastatic EGFR-mutated NSCLC who were enrolled across two clinical studies: TROPION-Lung05 and TROPION-Lung01.

TROPION-Lung05 (NCT04484142) was a global, multicenter, single-arm, open-label trial in patients with previously treated NSCLC with an actionable genomic alteration and TROPION-Lung01 (NCT04656652) was a global, multicenter, randomized, active-controlled, open-label trial in patients with previously treated NSCLC with or without an actionable genomic alteration. For both trials, eligible patients with EGFR-mutated NSCLC must have previously received an EGFR-directed therapy and platinum-based chemotherapy. Patients with a history of ILD/pneumonitis requiring treatment with steroids, ongoing ILD/pneumonitis, or clinically significant corneal disease at screening were ineligible. Patients who had brain metastases that were untreated and symptomatic were also ineligible. Patients received DATROWAY 6 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression.

For the pooled efficacy population, the major efficacy outcome measure was overall response rate (ORR) by BICR per RECIST v1.1. An additional efficacy outcome was duration of response (DOR) by BICR.

Efficacy was assessed in 114 patients with EGFR-mutated NSCLC. The median age was 63 years (range 36 to 81); 43% were ≥65 years of age; 63% were female; 70% were Asian and 22% were White; 1.8% were of Hispanic/Latino ethnicity; 68% had ECOG PS of 1 and 32% had ECOG PS of 0; and 33% had brain metastases at baseline. Fifty-three percent (53%) of patients had tumors with exon 19 deletions, 34% had exon 21 L858R mutations, 28% had T790M mutations, 2.6% had exon 20 insertion mutations and 14% had other EGFR mutations. Four percent (4.4%) of patients received one prior line of systemic therapy, 39% received two prior lines of systemic therapy, and 57% received three or more prior lines of systemic therapy in the locally advanced or metastatic setting. All patients received prior EGFR-directed therapy including 84% receiving prior osimertinib; 99% received prior platinum-based chemotherapy and 28% received prior anti-PD-1/ PD-L1 therapy.

Efficacy results are summarized in Table 11.

In the TROPION-Lung05 trial, a difference was noted between ORR by BICR and ORR assessed by investigator; investigator assessed ORR was 34% (95% CI: 23, 45). In the TROPION-Lung01 trial, ORR assessed by investigator was similar to ORR by BICR.

TROPION-Breast02

The efficacy of DATROWAY was evaluated in TROPION-Breast02 (NCT05374512), a multicenter, open-label, randomized trial of 644 patients with unresectable or metastatic triple-negative breast cancer (TNBC) who had not received prior chemotherapy or other systemic anti-cancer therapy for unresectable or metastatic breast cancer. Patients with either de novo metastatic or recurrent disease were enrolled. The study enrolled patients with PD-L1–negative tumors and patients with PD-L1–positive tumors who were ineligible for PD-1/PD-L1 inhibitor treatment due to one of the following: prior (neo)adjuvant PD-1/PD-L1 inhibitor treatment, a comorbidity precluding PD-1/PD-L1 inhibitor use, or unavailability of a PD-1/PD-L1 inhibitor in their country. Patients with known germline BRCA pathogenic variants were enrolled if they were ineligible for PARP inhibitor therapy. Patients with recurrent disease were expected to have been treated with (neo)adjuvant anthracycline and those with de novo metastatic disease were enrolled if treatment with anthracycline was contraindicated or not considered the best treatment option. Patients with stable brain metastases were included in the study.

Patients were excluded for a history of ILD/pneumonitis requiring treatment with steroids, ongoing ILD/pneumonitis, or clinically significant corneal disease at screening. Patients with ECOG performance status >1 were also excluded. Randomization was stratified by geographical region (United States, Canada and Europe or Rest of World), PD-L1 status (positive or negative) and disease-free interval (DFI) history (de novo or ≤12 months or >12 months).

A total of 644 patients were randomized 1:1 to receive either DATROWAY 6 mg/kg (N=323) by intravenous infusion every 3 weeks or investigator's choice of chemotherapy (N=321), until unacceptable toxicity or disease progression. The choice of chemotherapy was based on the patient's prior use of taxane and DFI history. Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: paclitaxel (28%), nab-paclitaxel (54%), capecitabine (2.2%), eribulin (11%) or carboplatin (4.7%).

The major efficacy outcomes were progression-free survival (PFS) as assessed by BICR based on RECIST v.1.1 and overall survival (OS). Additional efficacy outcomes included ORR.

The median age was 56 years (range: 23-85), 25% were ≥65 years and 99.7% were female; 44% were White, 4.2% were Black or African American, 44% were Asian, and 15% were of Hispanic/Latino ethnicity, 83% were not of Hispanic/Latino ethnicity and 2% had ethnicity not reported. At the time of randomization, 59% had ECOG PS 0 and 41% had ECOG PS of 1; 75% had visceral disease, 30% had liver metastases, and 10% had stable brain metastases.

Ninety percent (90%) of patients had PD-L1 negative disease and 10% of patients had PD-L1 positive disease. Thirty four percent (34%) of patients had de novo metastatic disease. DFI was ≤12 months in 21% of patients and >12 months in 45% of patients. DFI was ≤6 months in 15% of patients. Fifty-six percent (56%) of patients had received anthracyclines in prior lines of therapy.

The study demonstrated a statistically significant improvement in PFS and OS in patients randomized to DATROWAY compared to chemotherapy.

Efficacy results are shown in Table 12 and Figures 1 and 2.

Figure 1: Kaplan-Meier Plot of PFS in TROPION-Breast02

Figure 2: Kaplan-Meier Plot of OS in TROPION-Breast02

TROPION-Breast01

The efficacy of DATROWAY was evaluated in TROPION-Breast01 (NCT05104866), a multicenter, open-label, randomized trial of 732 patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer. Eligible patients must have progressed on and deemed not suitable for further endocrine therapy. Patients were required to have received 1 or 2 lines of prior chemotherapy in the unresectable or metastatic disease setting. Patients were excluded for a history of ILD/pneumonitis requiring treatment with steroids, ongoing ILD/pneumonitis, clinically active brain metastases, or clinically significant corneal disease at screening. Patients were also excluded for ECOG performance status >1. Randomization was stratified by previous lines of chemotherapy (one or two), prior treatment with a CDK4/6 inhibitor (yes or no), and geographical region.

A total of 732 patients were randomized 1:1 to receive either DATROWAY 6 mg/kg (N=365) by intravenous infusion every 3 weeks or investigator's choice of chemotherapy (N=367) until unacceptable toxicity or disease progression. Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (60%), capecitabine (21%), vinorelbine (10%), or gemcitabine (9%).

The major efficacy outcomes were progression-free survival (PFS) as assessed by blinded independent central review (BICR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 and overall survival (OS). Additional efficacy outcomes included confirmed objective response rate (ORR) and duration of response (DOR) by BICR.

The median age was 55 years (range 28-86); 22% were ≥65 years; 99% were female; 48% were White, 41% were Asian, 1.5% were Black or African American, and 11% were of Hispanic/Latino ethnicity; 57% had ECOG PS of 0 and 42% had ECOG PS of 1; 97% had visceral disease, 72% had liver metastases, and 8% had stable brain metastases.

Sixty percent (60%) of patients received prior endocrine therapy in the (neo)adjuvant setting, and 89% received prior endocrine therapy in the unresectable or metastatic setting. Eighty-three percent (83%) of patients had prior treatment with a CDK4/6 inhibitor. All patients received prior chemotherapy regimens in the unresectable or metastatic setting (81% received prior taxanes; 64% received prior anthracyclines). Sixty-two percent (62%) of patients had 1 prior chemotherapy regimen and 38% of patients had 2 prior chemotherapy regimens for treatment of unresectable or metastatic disease.

The study demonstrated a statistically significant improvement in PFS in patients randomized to DATROWAY compared to chemotherapy.

Efficacy results are shown in Table 13 and Figure 3.

Figure 3: Kaplan-Meier Plot of PFS by BICR in TROPION-Breast01

Storage and Handling

Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of reconstitution. Do not freeze. Do not shake the reconstituted or diluted solution [see Dosage and Administration (2.5)].

DATROWAY (datopotamab deruxtecan-dlnk) is a hazardous drug. Follow applicable special handling and disposal procedures.¹