STUDY OVERVIEW STUDY OVERVIEW

DATROWAY was granted accelerated approval based on pooled data of patients with locally advanced or metastatic EGFRm NSCLC in two clinical studies^1,2,4-7

Study design
Baseline characteristics

Efficacy and safety were evaluated in the TROPION-Lung05 and TROPION-Lung01 studies

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TROPION-Lung05 (PHASE II STUDY)

Stage IIIB, IIIC, or IV NSCLC
Previously treated with ≥1 line of systemic therapy, including a targeted therapy and platinum-based chemotherapy in the advanced or metastatic setting
Presence of ≥1 actionable genomic alteration (eg, EGFR, ALK, ROS1, etc)
ECOG performance status of 0 or 1

TROPION-Lung01 (PHASE III STUDY)

Stage IIIB, IIIC, or IV NSCLC
Those with AGA had 1-2 prior targeted therapies and platinum-based chemotherapy in the advanced or metastatic setting
No prior docetaxel
ECOG performance status of 0 or 1

DATROWAY
6 mg/kg IV Q3W
(n=137)*^†

DATROWAY
6 mg/kg IV Q3W
(n=299)^†

Docetaxel
75 mg/m² IV Q3W
(n=305)^†

EGFRm Pool:
N=114

TROPION-Lung05
(n=77)

TROPION-Lung01
(n=37)

MAJOR EFFICACY OUTCOME:

ORR by BICR per RECIST v1.1

ADDITIONAL EFFICACY OUTCOME:

DOR by BICR

Treatment with DATROWAY was continued until disease progression or unacceptable toxicity.

Trop-2 testing was not required in these studies

SELECT EXCLUSION CRITERIA ACROSS BOTH STUDIES

History of ILD/pneumonitis requiring treatment with steroids, ongoing ILD/pneumonitis, or clinically significant corneal disease at screening
Brain metastases that were untreated and symptomatic^‡

*Patients in the total study population (n=137) included those with ≥1 actionable genomic alteration (EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET).⁴

^†Patients received tumor imaging every 6 weeks.^5,6

^‡Exclusion criteria included clinically active CNS metastases (untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control symptoms).^4,6

Appendix: Study Design
TROPION-Lung05⁴

TROPION-Lung05 is a global, phase II, single-arm, open-label study of DATROWAY in patients with advanced/metastatic NSCLC with actionable genomic alterations who progressed on or after targeted therapy and platinum-based chemotherapy.

Eligibility: adults with pathologically documented advanced/metastatic NSCLC (stage IIIB/C or IV) and any of the following actionable genomic alterations: EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET

Patients were required to have received prior treatment with 1-2 cytotoxic therapies (including 1 platinum-containing regimen) in the metastatic setting and 1-2 targeted therapies

Also required: documentation of radiographic disease progression during or after the previous regimen for advanced/metastatic NSCLC, measurable disease based on local imaging using RECIST v1.1, and ECOG performance status of 0 or 1

Exclusion criteria included prior treatment with topoisomerase I-targeted chemotherapeutic agent or Trop-2-directed therapy, clinically active CNS metastases (untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control symptoms), history of ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis

Patients with KRAS mutations were excluded as no targeted therapy was approved for this group at trial initiation
TROPION-Lung01⁶

TROPION-Lung01 is a randomized, open-label, global, phase III study comparing the safety and efficacy of DATROWAY versus docetaxel in patients with advanced/metastatic NSCLC.

Eligible patients had stage IIIB/C or IV NSCLC

Patients without actionable genomic alterations must have only received platinum-based chemotherapy and anti–PD-1/PD-L1 immunotherapy

Patients with eligible actionable genomic alterations (EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET) must have received 1-2 lines of targeted therapy and platinum-based chemotherapy, with or without anti–PD-1/PD-L1

Exclusion criteria: active or untreated, symptomatic CNS metastases; current or suspected diagnosis or history of ILD/pneumonitis requiring steroids

Patients were randomly assigned 1:1 (stratified by histology, actionable genomic alteration status, geographic region, and immediate previous therapy with anti–PD-1/PD-L1) to receive DATROWAY 6 mg/kg or docetaxel 75 mg/m² intravenously Q3W until disease progression, unacceptable toxicity, or other reasons

Crossover between study groups was not permitted

Most patients in the pooled analysis of the EGFRm subgroup were heavily pretreated^1,3

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Select EGFRm NSCLC baseline characteristics

DATROWAY
(n=114)

Age

Median (range), years

63 (36–81)

≥65 years of age, %

Female, %

Race, %

Asian

White

Hispanic/Latino

History of brain metastasis, %	53
Brain metastasis at baseline, %*	33

Liver metastasis at baseline, %

ECOG PS, %

Nonsquamous, %

Squamous, %

EGFR mutations, %

Exon 19 deletions	53
Exon 21 L858R	34
T790M	28
Exon 20 insertion	3
Other EGFR mutations	14

EGFR mutations in the efficacy population included exon 19, 20,^† and 21 mutations, among others

Prior lines of therapy, %

1	4
2	39
≥3	57

Patients with EGFRm mNSCLC in TROPION-Lung05 and TROPION-Lung01 were heavily pretreated, with most patients having received at least 3 prior regimens in the locally advanced/metastatic setting

Prior systemic therapy, %

EGFR-directed

100

Osimertinib

≥2 prior lines of EGFR-targeted therapies

Platinum-containing

Anti-PD-1/PD-L1

*Patients who had brain metastases that were untreated and symptomatic were excluded.^4,6

^†Inclusive of both T790M and exon 20 insertion mutations.¹

AGA, actionable genomic alteration; ALK, anaplastic lymphoma kinase; BICR, Blinded Independent Central Review; BRAF, proto-oncogene B-raf; CNS, central nervous system; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group performance status; EGFRm, epidermal growth factor receptor-mutated; ILD, interstitial lung disease; IV, intravenous; KRAS, Kirsten rat sarcoma virus; MET, mesenchymal-epithelial transition; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; ORR, objective response rate; PD-1/PD-L1, programmed cell death protein 1/programmed death-ligand 1; Q3W, once every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1; Trop-2, trophoblast cell surface antigen 2.

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 granted accelerated approval based on pooled data of patients with locally advanced or metastatic EGFRm NSCLC in two clinical studies1,2,4-7

Efficacy and safety were evaluated in the TROPION-Lung05 and TROPION-Lung01 studies

NOW APPROVED for locally advanced or metastatic EGFRm NSCLC

DATROWAY was granted accelerated approval based on pooled data of patients with locally advanced or metastatic EGFRm NSCLC in two clinical studies^1,2,4-7