DATROWAY® Demonstrated Statistically Significant and Clinically Meaningful Improvement in Overall Survival as First-Line Therapy for Patients with Metastatic Triple Negative Breast Cancer for Whom Immunotherapy Was Not an Option in TROPION-Breast02
DATROWAY® Demonstrated Statistically Significant and Clinically Meaningful Improvement in Overall Survival as First-Line Therapy for Patients with Metastatic Triple Negative Breast Cancer for Whom Immunotherapy Was Not an Option in TROPION-Breast02
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Daiichi Sankyo and AstraZeneca’s DATROWAY is the first and only therapy to significantly improve overall survival versus chemotherapy in this patient population
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DATROWAY also demonstrated a highly statistically significant and clinically meaningful improvement in the dual primary endpoint of progression-free survival
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Plans for global regulatory submissions are underway
TOKYO & BASKING RIDGE, N.J.–(BUSINESS WIRE)–Positive topline results from the TROPION-Breast02 phase 3 trial showed DATROWAY® (datopotamab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement for the dual primary endpoints of overall survival (OS) and progression-free survival (PFS) compared to investigator’s choice of chemotherapy as first-line treatment for patients with locally recurrent inoperable or metastatic triple negative breast cancer (TNBC) for whom immunotherapy was not an option.
DATROWAY is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).
Approximately 70% of patients with metastatic TNBC are not candidates for immunotherapy, including all patients whose tumors do not express PD-L1 as well as patients with PD-L1 expressing tumors who cannot receive immunotherapy due to other factors.1 Chemotherapy remains the first-line standard of care for these patients.2
“DATROWAY is the first antibody drug conjugate and the only therapy to significantly improve overall survival compared to chemotherapy in patients with metastatic triple negative breast cancer for whom immunotherapy is not an option,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “These landmark results from TROPION-Breast02 strengthen our confidence in our ongoing clinical development program for DATROWAY in triple negative breast cancer and other tumor types. We look forward to discussing these data with global regulatory authorities and to bringing DATROWAY to patients with triple negative breast cancer as soon as possible.”
“TROPION-Breast02 is the only trial ever to show an overall survival benefit in the first-line treatment of patients with metastatic triple negative breast cancer for whom immunotherapy is not an option,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D, AstraZeneca. “We expect today’s results will mark an inflection point in the treatment of these patients who have the poorest prognosis of any type of breast cancer and urgently need better options.”
The safety profile of DATROWAY was consistent with previous clinical trials of DATROWAY in breast cancer. These data from TROPION-Breast02 will be presented at an upcoming medical meeting and shared with regulatory authorities.
Daiichi Sankyo and AstraZeneca are evaluating DATROWAY across stages and treatment settings of TNBC in three additional phase 3 trials. TROPION-Breast03 is evaluating DATROWAY as adjuvant therapy with or without AstraZeneca’s anti-PD-L1 therapy durvalumab versus investigator’s choice of therapy in patients with stage I-III TNBC with residual invasive disease after neoadjuvant systemic therapy. TROPION-Breast04 is evaluating neoadjuvant DATROWAY plus durvalumab versus neoadjuvant pembrolizumab plus chemotherapy in patients with stage II-III triple negative or hormone receptor (HR) low, HER2 low or negative breast cancer. TROPION-Breast05 is evaluating first-line DATROWAY with or without durvalumab versus investigator’s choice of therapy in patients with metastatic TNBC whose tumors express PD-L1.
About TROPION-Breast02
TROPION-Breast02 is a global, multicenter, randomized, open-label phase 3 trial evaluating the efficacy and safety of DATROWAY versus investigator’s choice of chemotherapy (paclitaxel, nab-paclitaxel, capecitabine, carboplatin or eribulin) in patients with previously untreated locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option. This included patients whose tumors did not express PD-L1 as well as patients with PD-L1 expressing tumors who could not receive immunotherapy due to prior exposure in early-stage disease, comorbidities or immunotherapy not being accessible in their geography. Enrollment included patients with de novo or recurrent disease, regardless of disease-free interval, and those with poor prognostic factors such as brain metastases.
The dual primary endpoints of TROPION-Breast02 are PFS assessed by blinded independent central review and OS. Key secondary endpoints include PFS as assessed by investigator, objective response rate, duration of response, disease control rate, pharmacokinetics and safety.
TROPION-Breast02 enrolled 644 patients at sites in Africa, Asia, Europe, North America and South America. For more information visit ClinicalTrials.gov.
About Triple Negative Breast Cancer
TNBC accounts for approximately 15% of all breast cancer cases, with an estimated 345,000 diagnoses globally each year.3,4 TNBC is diagnosed more frequently in younger and premenopausal women, and is more prevalent in Black and Hispanic women.5,6,7 Metastatic TNBC is the most aggressive type of breast cancer and has the worst prognosis, with median overall survival of just 12 to 18 months and only about 14% of patients living five years following diagnosis.5,8,9
While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of HER2, TNBC tests negative for all three.5 Due to its aggressive nature and absence of common breast cancer receptors, TNBC is characteristically difficult to treat.5 For patients with metastatic disease with PD-L1 expressing tumors, the addition of immunotherapy to chemotherapy has improved outcomes in the first-line setting.10,11 However, for approximately 70% of patients with metastatic TNBC who are not candidates for immunotherapy, chemotherapy remains the first-line standard of care.1,2
TROP2 is a protein broadly expressed in several solid tumors, including TNBC.12 TROP2 is associated with increased tumor progression and poor survival in patients with breast cancer.13,14
About DATROWAY
DATROWAY (datopotamab deruxtecan; datopotamab deruxtecan-dlnk in the U.S. only) is a TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, DATROWAY is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. DATROWAY is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
DATROWAY (6 mg/kg) is approved in more than 35 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HR positive, 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 based on the results from the TROPION-Breast01 trial.
DATROWAY (6 mg/kg) is approved in Russia and the U.S. for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who have received prior EGFR-directed therapy and platinum-based chemotherapy, based on the results from TROPION-Lung05 and TROPION-Lung01 trials. Continued approval for this indication in the U.S. may be contingent upon verification and description of clinical benefit in a confirmatory trial.
About the DATROWAY Clinical Development Program
A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of DATROWAY across multiple cancers, including NSCLC, TNBC and urothelial cancer. The program includes eight phase 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating DATROWAY as a monotherapy and in combination with other cancer treatments in various settings.
About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU® in March 2019 and DATROWAY in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and DATROWAY.
About the ADC Portfolio of Daiichi Sankyo
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo.
The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and DATROWAY, a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.
The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.
Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
DATROWAY U.S. Important Safety Information
Indications
DATROWAY® is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of:
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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.
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.
Unresectable or Metastatic Breast Cancer
In the pooled safety population of 443 patients with breast cancer from TROPION-Breast01 and TROPION-PanTumor01, ILD/pneumonitis occurred in 3.6% of patients treated with DATROWAY, including 0.7% of patients with Grade 3. There was one fatal case (0.2%). The median time to onset for ILD was 2.8 months (range: 1.1 months to 10.8 months). Four patients (0.9%) had DATROWAY withheld and 7 patients (1.6%) permanently discontinued DATROWAY due to ILD/pneumonitis. Systemic corticosteroids were required in 60% (9/15) 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.
Ocular Adverse Reactions
DATROWAY can cause ocular adverse reactions including dry eye, keratitis, blepharitis, meibomian gland dysfunction, increased lacrimation, conjunctivitis, and blurred vision.
In the pooled safety population, 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.
In the pooled safety population, 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.
In patients who received DATROWAY in TROPION-Breast01, 39% 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.
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
The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to DATROWAY in 927 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, 297 patients with NSCLC in TROPION-Lung01, 360 patients with HR-positive, HER2-negative breast cancer in TROPION-Breast01, and 50 patients with NSCLC and 83 patients with breast cancer in TROPION-PanTumor01 (NCT03401385). Among 927 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 (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 (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.
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. 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 (59%), nausea (56%), fatigue (44%), decreased leukocytes (41%), decreased calcium (39%), alopecia (38%), decreased lymphocytes (36%), decreased hemoglobin (35%), constipation (34%), decreased neutrophils (30%), dry eye (27%), vomiting (24%), increased ALT (24%), keratitis (24%), increased AST (23%), and increased alkaline phosphatase (23%).
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.
Contacts
Global/US:
Jennifer Brennan
Daiichi Sankyo, Inc.
jennifer.brennan@daiichisankyo.com
+1 908 900 3183 (mobile)
Japan:
Daiichi Sankyo Co., Ltd.
DS-PR_jp@daiichisankyo.com
Investor Relations Contact:
DaiichiSankyoIR_jp@daiichisankyo.com
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