臨床研究等提出・公開システム

Phase II study of Trastuzumab Deruxtecan (DS-8201a) in subjects with non-small cell lung cancer (NSCLC)

DESTINY-Lung01

181

The median age was 63 years in cohort 1, 62 years in cohort 1a, and 60 years in cohort 2. The proportion of females was 19 (38.8%) in cohort 1, 19 (46.3%) in cohort 1a, and 60 (65.9%) in cohort 2. The proportion of Asians was 13 (26.5%) in cohort 1, 4 (9.8%) in cohort 1a, and 31 (34.1%) in cohort 2. The proportion of non-smokers was 16 (32.7%) in cohort 1, 9 (22.0%) in cohort 1a, and 52 (57.1%) in cohort 2. HER2 IHC status (central testing) was IHC 3+ in 10 (20.4%) and IHC 2+ in 39 (79.6%) in cohort 1, and IHC 3+ in 17 (41.5%) and IHC 2+ in 24(58.5%) in cohort 1a. HER2 mutation type (local testing) was kinase domain in 85 (93.4%) and extracellular domain in 6(6.6%).

181 enrolled/181 treated at least 1 dose of study drug 90 HER2-overexpressing patients (49 patients in Cohorts 1 and 41 patients in Cohort 1a) and 91 HER2-mutant patients in Cohort 2

All patients have experienced treatment-emergent adverse events (TEAE) in all cohorts. [HER2 Overexpression Cohort] T-DXd 5.4 mg/kg (Cohort 1a) The incidence of study drug-related serious TEAE was observed in 4 patients (9.8%), with pneumonitis in 2 patients (4.9%), and vomiting and fatigue in 1 patient (2.4%) each. Treatment discontinuation due to drug-related TEAE was occurred in 3 patients (7.3%). The ILD Independent Adjudication Committee adjudicated 3 events (7.3%) as treatment-related ILD. One event (2.4%) was Grade 1, One event (2.4%) was Grade 4, and one event (2.4%) was Grade 5. T-DXd 6.4 mg/kg (Cohort 1) The incidence of study drug-related serious TEAE was observed in 10 events (20.4%), with pneumonitis in 4 patients (8.2%), nausea in 2 patients (4.1%), and vomiting, diarrhea, acute kidney injury, asthenia, enterocolitis infectious, haemorrhoids, and partial seizures in 1 patient (2.0%) each. Treatment discontinuation due to drug-related TEAE was occurred in 8 patients (16.3%). The ILD Independent Adjudication Committee adjudicated 10 events (20.4%) as treatment-related ILD. 7 events (14.3%) were Grade 1 or 2, and 3 events (6.1%) was Grade 5. [HER2 Gene Mutation Cohort] T-DXd 6.4 mg/kg (Cohort 2) The incidence of study drug-related serious TEAE was observed in 7 patients (7.7%), drug-related interstitial lung disease in 3 patients (3.3%), vomiting in 2 patients (2.2%), with nausea, diarrhea, ileus, hypoxemia, presyncope, staphylococcal bacteraemia, thrombocytopenia, and troponin I increased in 1 patient (1.1%) each. Treatment discontinuation due to drug-related TEAE was occurred in 24 patients (26.4%). The ILD Independent Adjudication Committee adjudicated 25 events (27.5%) as treatment-related ILD. 19 events (20.9%) were Grade 1 or 2, and 4 events (4.4%) were Grade 3, and 2 events (2.2%) were Grade 5.

[HER2-overexpression] T-DXd 5.4 mg/kg (Cohort 1a) In the 41 patients on T-DXd demonstrated clinically meaningful antitumor activity (confirmed ORR based on ICR: 34.1% [95% confidence interval (CI): 20.1, 50.6]), with 2 responders having a confirmed complete response (CR) and 12 responders having a confirmed partial response (PR). T-DXd 6.4 mg/kg (Cohort 1) In the 49 patients on T-DXd 6.4 mg/kg, T DXd demonstrated clinically meaningful antitumor activity (confirmed ORR based on ICR: 26.5% [95% CI: 15.0, 41.1]), with all 13 responders having a confirmed PR. [HER2-mutation] T-DXd 6.4 mg/kg (Cohort 2): In the 91 patients on with T-DXd 6.4 mg/kg, T-DXd demonstrated clinically meaningful antitumor activity (confirmed ORR based on ICR: 54.9% [95% CI: 44.2, 65.4]).

Efficacy results: [HER2-overexpression] T-DXd 5.4 mg/kg (Cohort 1a) - Median DoR was 6.2 months (95% CI: 4.2, 9.8), the median PFS was 6.7 months (95% CI: 4.2, 8.4) and the median OS was 11.2 months (95% CI: 8.4, not evaluable [NE]). - Efficacy results in the immunohistochemistry (IHC) 3+ subgroup were consistent with the overall efficacy results in patients with HER2-overexpression, with the exception of ORR, which was higher in the IHC 3+ subgroup. The confirmed ORR was 52.9% (9 of 17 patients; 95% CI: 27.8, 77.0), though these results should be considered with caution due to the low number of patients included in this analysis. T-DXd 6.4 mg/kg (Cohort 1) - Median DoR of 5.8 months (95% CI: 4.3, NE), the median PFS was 5.7 months (95% CI: 2.8, 7.2) and the median OS was 12.4 months (95% CI: 7.8, 17.2). - Efficacy results in the IHC 3+ subgroup were consistent with the overall efficacy results in patients with HER2-overexpression on T-DXd 6.4 mg/kg. The confirmed ORR was 20.0% (2/10 patients; 95% CI: 2.5, 55.6), though these results should be considered with caution due to the low number of patients in this analysis. [HER2-mutation] T-DXd 6.4 mg/kg (Cohort 2): - Median DoR of 10.6 months (95% CI: 5.8, 17.7), and the median PFS was 8.2 months (95% CI: 6.0, 11.9) and the median OS was 18.6 months (95% CI: 13.8, 25.8). Safety Results: The safety profile of T-DXd in patients with HER2-overexpression and HER2-mutation was acceptable and generally manageable. For more details, please refer to the "Adverse events".

With respect to HER2-overexpressing NSCLC, efficacy results continued to show clinically meaningful activity in heavily pretreated NSCLC, both at 5.4 and 6.4 mg/kg, with consistent activity regardless of T-DXd dose. Additionally, in HER2-mutatnt-positive NSCLC patients T-DXd 6.4 mg/kg has demonstrated linically meaningful responses. Overall, the observed safety profile of T-DXd in this study was acceptable, generally manageable and was consistent with the previously reported safety profile.

Jan. 20, 2022

https://pubmed.ncbi.nlm.nih.gov/38547891/

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_jp@daiichisankyo.com

Contact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

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

+81-3-6225-1111

dsclinicaltrial_jp@daiichisankyo.com

completed

May. 21, 2018

Interventional

Multicenter, open-label, 2-cohort, phase II trial

treatment purpose

2

1. Age >= 20 years old.
2. Pathologically documented unresectable and/or metastatic non-squamous NSCLC.
3. Has relapsed from or is refractory to standard treatment or for which no standard treatment is available.
4. For Cohort 1 and Cohort 1a only: HER2-overexpression (IHC 2+ or 3+) status must be assessed and confirmed from an archival tumor tissue sample.
5. For Cohort 2 only: Documented any known activating HER2 mutation from an archival tumor tissue sample.
6. Presence of at least 1 measurable lesion assessed by the investigator based on RECIST ver. 1.1.
7. Is willing and able to provide an adequate archival tumor tissue sample.
8. Is willing to undergo a tissue biopsy, after the completion of the most recent treatment regimen.

1. Was previously treated with HER2-targeted therapies, except for pan-HER class tyrosine kinase inhibitors.
2. For Cohort 1 and Cohort 1a only: Has known HER2 mutation.
3. Has an uncontrolled or significant cardiovascular disease
4. Has a medical history of clinically significant lung disease.

Both

HER2-over-expressing or HER2-mutated unresectable and/or metastatic non-squamous NSCLC

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)
ORR assessed by independent central imaging facility review based on RECIST ver. 1.1.

efficacy
pharmacokinetics
safety
Duration of response, disease control rate, progression free survival, overall survival, safety, pharmacokinetics

April. 24, 2018