臨床研究等提出・公開システム

Phase 2 study of DS-8201a in subjects with breast cancer

DESTINY-Breast01

253

The median age at informed consent was 55.8 years (range: 28-96). In the overall 5.4 mg/kg dose cohort, the median age was 56.0 years (range, 28 to 96). In the 6.4 mg/kg dose cohort, the median age was 55.8 years (range, 29 to 79). In the 7.4 mg/kg dose cohort, the median age was 54.4 years (range, 32 to 69). All subjects were female. Most subjects were either white (132 [52.2 %] subjects) or Asian (104 [41.1 %] subjects).

253 enrolled/253 treated (184 subjects at 5.4 mg/kg dose[180 subjects at primary efficacy analysis], 48 subjects at 6.4 mg/kg dose, 21 subjects at 7.4 mg/kg dose)

(Data cut-off: 06 May 2024) In the overall 5.4 mg/kg dose cohort, 183 (99.5%) subjects experienced at least 1 treatment-emergent adverse event (TEAE), with the most common events being gastrointestinal (GI) or hematologic in nature, which is expected for this class of drugs. 117 (63.6%) subjects had at least 1 treatment-related Grade >=3 TEAE. The single most common Grade >=3 TEAE irrespective of causality was neutrophil count decrease (42 [22.8%] subjects). In comparison to the overall 5.4 mg/kg dose cohort, the frequency of Grade >=3 events was higher in the 6.4 mg/kg and 7.4 mg/kg dose cohorts, with neutrophil count decrease as the most commonly reported Grade >=3 TEAE irrespective of causality. [Dose Reduction] In the overall 5.4 mg/kg dose cohort, 52 (28.3%) subjects had TEAEs associated with dose reduction, which were considered to be drug related by the investigator in 47 (25.5%) subjects. The most common TEAEs associated with dose reductions were fatigue (9 [4.9%] subjects); nausea (7 [3.8%] subjects); neutrophil count decreased and blood bilirubin increased (5 [2.7%] subjects each); neutropenia (4 [2.2%] subjects); vomiting, anemia, and ILD (3 [1.6%] subjects each); pneumonitis, platelet count decreased, weight decreased, white blood cell count decreased, and decreased appetite (2 [1.1%] subjects each). TEAEs associated with dose reduction were Grade 1 in 3 (1.6%) subjects, Grade 2 in 16 (8.7%) subjects and Grade 3 in 33 (17.9%). Dose reductions due to TEAEs was reported in 25 (52.1%) subjects in the 6.4 mg/kg dose cohort: 1 (2.1%) subject with a Grade 1 event; 5 (10.4%) subjects with Grade 2 events; 15 (31.3%) subjects with Grade 3 events; and 4 (8.3%) subjects with a Grade 4 event. Dose reductions due to TEAEs was reported in 12 (57.1%) subjects in the 7.4 mg/kg dose cohort: 1 (4.8%) subject with Grade 1 events; 2 (9.5%) subjects with Grade 2 events; 7 (33.3%) subjects with a Grade 3 event; and 2 (9.5%) subjects with a Grade 4 event. [Dose Interruption] In the overall 5.4 mg/kg dose cohort, 80 (43.5%) subjects had dose interruptions due to TEAEs, which were considered to be drug related by the investigator in 62 (33.7%) subjects. The most common TEAEs associated with dose interruption were neutrophil count decreased (18 [9.8%] subjects); neutropenia (15 [8.2%] subjects); anemia (8 [4.3%] subjects); COVID-19 (7 [3.8%] subjects); fatigue (6 [3.3%] subjects); white blood cell (WBC) count decreased (8 [4.3%] subjects); platelet count decreased and upper respiratory tract infection (4 [2.2%] subjects each); interstitial lung disease (ILD), pneumonitis, nausea, pneumonia, lower respiratory tract infection, thrombocytopenia, hypokalemia, diarrhea, blood bilirubin increased, and ejection fraction decreased (3 [1.6%] subjects each); and cellulitis, dyspnea, vomiting, asthenia, alanine aminotransferase increased, and electrocardiogram QT prolonged (2 [1.1%] subjects each). TEAEs associated with dose interruption were Grade 1 in 10 (5.4%) subjects; Grade 2 in 18 (9.8%) subjects; Grade 3 in 49 (26.6%) subjects and Grade 4 in 2 (1.1%) subjects (hyperglycemia and neutropenia). A Grade 5 TEAE associated with dose interruption was reported for 1 (0.5%) subject with general physical health deterioration. Dose interruptions due to TEAEs were reported in the 6.4 mg/kg dose cohort in which 23 (47.9%) subjects had dose interruptions due to TEAEs, including 1 (2.1%) subject with a Grade 1 event, 7 (14.6%) subjects with Grade 2 events, 14 (29.2%) subjects with Grade 3 events, and 1 (2.1%) subject with a Grade 4 event (neutropenia). In the 7.4 mg/kg dose cohort, 12 (57.1%) subjects had dose interruptions due to TEAEs, which included 2 (9.5%) subjects with Grade 1 events, 3 (14.3%) subjects with Grade 2 events, 5 (23.8%) subjects with Grade 3 events, and 2 (9.5%) subjects with Grade 4 events (WBC count decreased and aspartate aminotransferase /transaminase (AST) increased and alanine aminotransferase /transaminase (ALT) increased). [Study Drug Discontinuation] In the overall 5.4 mg/kg dose cohort, 38 (20.7%) subjects had TEAEs associated with study drug discontinuation, which were considered to be drug related by the investigators in 35 (19.0%) subjects. The most common TEAE associated with study drug discontinuation was pneumonitis (15 [8.2%] subjects). Other TEAEs associated with study drug discontinuation included ILD (6 [3.3%] subjects) and dyspnea and platelet count decreased (2 [1.1%] subjects each). TEAEs associated with drug discontinuation were Grade 1 in 10 (5.4%) subjects, Grade 2 in 12 (6.5%) subjects, Grade 3 in 14 (7.6%) subjects, and Grade 5 in 2 (1.1%) subjects. Discontinuation of treatment due to TEAEs was reported in 13 (27.1%) subjects in the 6.4 mg/kg dose cohort: 4 (8.3%) subjects with a Grade 1 event; 4 (8.3%) subjects with Grade 2 (LV systolic dysfunction, ILD, asthenia, and thrombocytopenia) and Grade 3 events (pneumonitis, WBC count decreased, ILD, and 1 subject with both fatigue and asthenia); and 1 (2.1%) subject with a Grade 4 event (thrombocytopenia). Discontinuation of treatment due to TEAEs was reported in 9 (42.9%) subjects in the 7.4 mg/kg dose cohort: 4 (19.0%) subjects with Grade 1 events; 3 (14.3%) subjects with Grade 2 events; 1 (4.8%) subject with a Grade 3 event (lung infection); and 1 (4.8%) subject with a Grade 5 event (pneumonitis). [ILD/pneumonitis] In the overall 5.4 mg/kg dose cohort, adjudicated, drug-related ILD/pneumonitis was reported in 30/184 (16.3%) subjects; Grade 3 (2 [1.1%] subjects) and Grade 5 (5 [2.7%] subjects) events, and the majority of events reported as Grade 1 (6 [3.3%] subjects) or Grade 2 (17 [9.2%] subjects). In the 6.4 mg/kg dose cohort, adjudicated, drug-related ILD/pneumonitis was reported in 8/48 (16.7%) subjects, with no Grade 3 or Grade 5 events, and the majority of events reported as Grade 1 (3 [6.3%] subjects) or Grade 2 (5 [10.4%] subjects). In the 7.4 mg/kg dose cohort, adjudicated, drug-related ILD/pneumonitis was reported in 7/21 (33.3%) subjects, Grade 3 (1 [4.8%] subject), Grade 5 (1 [4.8%] subject) events, and the majority of events reported as Grade 1 (2 [9.5%]) or Grade 2 (3 [14.3%] subjects). [Left ventricular ejection fraction (LVEF)] Across all dose cohorts, 8 (3.2%) subjects had TEAEs of LV dysfunction: 6 (3.3%) subjects in the 5.4 mg/kg dose cohort and 2 (4.2%) subjects in the 6.4 mg/kg dose cohort, primarily Grade 1 or 2, with 1 Grade 3 ejection fraction decreased in the 5.4 mg/kg dose cohort. There were no Grade 4 or fatal events.

[Objective Response Rate (ORR) (Data cut-off: 21 Mar 2019 )] In the primary 5.4 mg/kg dose cohort, the confirmed ORR based on independent central review (ICR) was 60.6 % (95 % CI: 53.0, 67.8): 109/180 subjects had confirmed best overall responses (BORs) of complete response (CR) (8 [4.4 %] subjects) or partial response (PR) (101 [56.1 %] subjects). At the 6.4 mg/kg dose, the confirmed ORR based on ICR was 68.8 % (95 % CI: 53.8, 81.3), with 33/48 subjects having BORs of CR (2 [4.2 %] subjects) or PR (31 [64.6 %] subjects). At the 7.4 mg/kg dose, the confirmed ORR based on ICR was 81.0 % (95 % CI: 58.1, 94.6), with 17/21 subjects having BORs of CR (1 [4.8 %] subject) or PR (16 [76.2 %] subjects).

[Safety] Refer to the "Adverse events" section. [Pharmacokinetics (Data cut-off: 21 Mar 2019 )] Following administration of 5.4 mg/kg of DS-8201a, PK parameters were comparable for FL-DP2 and Lyo-DP, with ratios for maximum plasma/serum concentration (Cmax) and area under the serum concentration-time curve (AUC) close to 1 and 90 % CI for ratio of geometric means including 1. Pharmacokinetic parameters for DS-8201a and total anti-HER2 antibody were comparable. The ratio of DS-8201a and total anti-HER2 antibody for Cmax was approximately 1 and for AUC and trough concentrations was approximately 0.8. Serum concentrations of MAAA-1181a gradually increased and reached peak concentrations with longer median time to Cmax (Tmax) (approximately 7 hours) compared to those for DS-8201a (approximately 4 hours). On a molar basis, the DS-8201a Cmax and trough concentrations were approximately 54-fold and 74-fold higher than those for MAAA-1181a, demonstrating in vivo stability of the antibody drug conjugate (ADC). The rate of ADAs at baseline was low with 13/253 (5.1 %) subjects with positive antidrug antibody (ADA) samples. A total of 5 (2.0 %) subjects had positive post-baseline ADA samples: 1 subject had no detectable ADAs at baseline and was positive post-baseline; 1 subject was negative for ADAs at baseline and positive post-baseline; and 3 subjects were positive both at baseline and post-baseline. [Duration of Response (DoR) (Data cut-off: 21 Mar 2019 )] In the primary 5.4 mg/kg dose cohort, of the 109 subjects with BORs of CR or PR by ICR, 79 (72.5 %) subjects had ongoing responses without progressive disease (PD); 95 (87.2 %) subjects were censored for the DoR analysis. The median DoR for confirmed responses for the primary 5.4 mg /kg dose cohort was not estimable. Based on Kaplan-Meier (KM) estimate, 83.4 % (95 % CI: 71 .8, 90 .5) of responders in the primary 5.4 mg /kg dose cohort were progression-free and continuing to respond at 6 months. In the 6.4 mg /kg dose cohort, the median DoR by ICR was not estimable. In the 7.4 mg /kg dose cohort, the median DoR by ICR was 6.0 months. [Best Percent change in the sum of the longest diameters of measurable tumors (Data cut-off: 21 Mar 2019 )] In the primary 5.4 mg/kg dose cohort, the mean best percent change from baseline in sum of diameters of Target Lesions (TLs) during the study period (N = 166) was -50.5 %. In the 6.4 mg /kg dose cohort, the mean best percent change from baseline in sum of diameters of TLs during the study period (N = 43) was -59.5 %. In the 7.4 mg /kg dose cohort, the mean best percent change from baseline in sum of diameters of TLs during the study period (N = 21) was -65.3 %. [Disease Control Rate (DCR) / Clinical Benefit Rate (CBR) (Data cut-off: 21 Mar 2019 )] In the primary 5.4 mg/kg dose cohort, the confirmed DCR based on ICR was 97.2 % (95 % CI: 93.6, 99.1): in addition to the 109 subjects with confirmed CR or PR, 66 (36.7 %) subjects had confirmed Stable Disease (SD). The confirmed CBR (with SD lasting more than 6 months) for the primary 5.4 mg /kg dose cohort based on ICR was 70.6 % (95 % CI: 63.3, 77.1). In the 6.4 mg /kg dose cohort, the confirmed DCR by ICR was 97 .9 % (95 % CI: 88 .9, 99 .9), and the confirmed CBR by ICR was 85.4 % (95 % CI: 72.2, 93.9). In the 7.4 mg /kg dose cohort, the confirmed DCR by ICR was 100.0 % (95 % CI: 83.9, 100.0), and the confirmed CBR was 95.2 % (95 % CI: 76.2, 99.9). [Progression Free Survival (PFS) (Data cut-off: 21 Mar 2019 )] In the primary 5.4 mg /kg dose cohort, 40/180 (22.2 %) subjects had PFS events: 30 (16.7 %) subjects had progressed, and 10 (5.6 %) subjects had died. A total of 140 (77.8 %) subjects were censored for the PFS analysis: 135 (75.0 %) subjects had no events of PD or death; 4 (2.2 %) subjects received new anticancer therapy; and 1 (0.6 %) subject had no post-baseline tumor assessment. In the primary 5.4 mg/kg dose cohort, the median PFS based on ICR was not estimable. Based on a KM analysis, the proportion of subjects estimated to be progression-free at 6 months was 81 % (95 % CI: 73, 86) In the 6.4 mg/kg dose cohort, the median PFS was not estimable. In the 7.4 mg/kg cohort, the median PFS was 9.5 (95 % CI: 7.4, 13.2) months. [Overall Survival (OS) (Data cut-off: 06 May 2024)] The median OS by cohort was as follows: -Overall 5.4 mg/kg dose cohort: 29.3 months (95% CI: 24.6, 36.6) -Primary 5.4 mg/kg dose cohort: 29.3 months (95% CI: 24.8, 36.6) -6.4 mg/kg dose cohort: 32.3 months (95% CI: 21.8, 57.8) -7.4 mg/kg dose cohort: 23.6 months (95% CI: 8.5, 35.8) [ORR assessed by the investigator based on RECIST version 1.1 (Data cut-off: 21 Mar 2019 )] The confirmed ORR based on investigator assessment in the primary 5.4 mg /kg dose cohort was 64.4 % (95 % CI: 57.0, 71.4), with 116 /180 subjects having BORs of CR (4 [2.2 %] subjects) or PR (112 [62.2 %] subjects). The overall concordance rate between the ICR and investigators in the assessment of confirmed tumor responses in the overall subject population (N = 253) was 69.6 %: there was agreement on responses of CR, PR, SD, PD or NE for 176 /253 subjects. When CR and PR are treated as a single response category, the overall concordance rate was 75.9 %.

Based on an overall benefit/risk assessment, the 5.4 mg/kg dose was chosen as the recommended dose of DS-8201a for HER2 positive metastatic BC. Analysis of the 180 subjects assigned to receive the 5.4 mg/kg dose of DS-8201a after failure of T-DM1 demonstrate clinical activity with clinically meaningful and durable responses. The DS-8201a safety profile was generally manageable, with the most common TEAEs being GI and hematologic in nature and mild to moderate in severity.

Dec. 11, 2019

https://www.nejm.org/doi/10.1056/NEJMoa1914510?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

Yes

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Information: - Study Protocol - Statistical Analysis Plan (SAP) - Informed Consent Form (ICF) Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

Inoguchi Akihiro

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial@daiichisankyo.co.jp

Contact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

dsclinicaltrial@daiichisankyo.co.jp

completed

Aug. 30, 2017

Interventional

Multicenter, open-label, phase 2 study

treatment purpose

2

1. Men or women the age of majority in their country
2. Has pathologically documented breast cancer that:
is unresectable or metastatic
has HER2 positive expression confirmed per protocol
3. Has an adequate tumor sample
4. Has at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
5. Has protocol-defined adequate cardiac, renal and hepatic function
6. Agrees to follow protocol-defined method(s) of contraception

1. Has a medical history of myocardial infarction, symptomatic CHF (NYHA classes II-IV), unstable angina or serious cardiac arrhythmia
2. Has a QTc prolongation to > 450 millisecond (ms) in males and > 470 ms in females
3. Has a medical history of clinically significant lung disease

Both

HER2 positive unresectable and/or metastatic breast cancer subjects who are resistant or refractory to T-DM1

investigational material(s)
Generic name etc : DS-8201a
INN of investigational material : trastuzumab deruxtecan
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : Intravenous

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

efficacy
Objective response rate (ORR)
assessment by independent central imaging facility
review based on RECIST version 1.1.

safety
efficacy
pharmacokinetics
Duration of response, best percent change in the sum of the longest diameters of measurable tumors, disease control rate, clinical benefit rate, progression free survival, overall survival, ORR assessed by the investigator based on RECIST version 1.1, Pharmacokinetics, safety

July. 11, 2017