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A Phase 2, Multicenter, Randomized, Study of Trastuzumab Deruxtecan in Subjects with HER2-overexpressing Locally Advanced, Unresectable or Metastatic Colorectal Cancer (DESTINY-CRC02)

Trastuzumab deruxtecan for subjects with HER2-overexpressing advanced or metastatic CRC (DESTINY-CRC02)

122

The median age overall was 60.2 (range 26 to 84) years. There were 64 (52.5%) male subjects and 58 (47.5%) female subjects. The majority of the subjects were White (50 [41.0%]) or Asian (66 [54.1%]). Demographics were generally similar between the 2 treatment groups, with the exception of the following notable difference (5.4 mg/kg treatment group versus 6.4 mg/kg treatment group): A lower proportion of Japanese subjects (30.5% versus 45.0%)

Screened: 135 subjects Randomized: 122 subjects enrolled and treated Discontinued: At the time of DCO for the primary analysis (01 Nov 2022), 108 subjects had discontinued treatment (74 in the 5.4 mg/kg treatment group and 34 in the 6.4 mg/kg treatment group); and 14 subjects were still receiving T-DXd (9 in the 5.4 mg/kg treatment group and 5 in the 6.4 mg/kg treatment group)

(Data Base Lock: 04 Dec 2024, with an LSLV date of 08 Oct 2024) In the 5.4 mg/kg dose group, 82/83 (98.8%) subjects experienced at least 1 TEAE. All subjects in the 6.4 mg/kg dose group experienced at least 1 TEAE. TEAEs affecting >=30% of subjects in either dose group were the following: Nausea (49/83 [59.0%] subjects in the 5.4 mg/kg dose group and 22/39 [56.4%] subjects in the 6.4 mg/kg dose group) Anemia (22/83 [26.5%] subjects in the 5.4 mg/kg dose group and 16/39 [41.0%] subjects in the 6.4 mg/kg dose group) Neutrophil count decreased (18/83 [21.7%] subjects in the 5.4 mg/kg dose group and 16/39 [41.0] subjects in the 6.4 mg/kg dose group) Platelet count decreased (18/83 [21.7%] subjects in the 5.4 mg/kg dose group and 12/39 [30.8%] subjects in the 6.4 mg/kg dose group) Decreased appetite (25/83 [30.1%] subjects in the 5.4 mg/kg dose group and 6/39 [15.4%] subjects in the 6.4 mg/kg dose group)

(Data cut-off: 01 Nov 2022) Clinically meaningful antitumor activity was observed at both doses of T-DXd evaluated in this study. Evaluation of the efficacy results was primarily based on the FAS. In the FAS, confirmed ORR by BICR was 37.8% (95% confidence interval [CI] = 27.3, 49.2) in the 5.4 mg/kg treatment and 27.5% (95% CI = 14.6, 43.9) in the 6.4 mg/kg treatment. A numerically higher confirmed ORR by BICR was observed in the T-DXd 5.4 mg/kg treatment group. Other efficacy endpoints show clinically meaningful results: The median DoR in months based on BICR was 5.5 (95% CI = 4.2, 8.1) and 5.5 (95% CI = 3.7, not evaluable [NE]), at 5.4 and 6.4 mg/kg treatment groups, respectively. DCR (FAS) based on BICR was similar for both treatment groups. CBR (FAS) based on BICR was 45.1% (95% CI = 34.1, 56.5) and 32.5% (95% CI = 18.6, 49.1) in the T-DXd 5.4 mg/kg and T-DXd 6.4 mg/kg treatment groups, respectively. The median PFS based on BICR in months was 5.8 (95% CI = 4.6, 7.0) and 5.5 (95% CI = 4.2, 7.0) at 5.4 and 6.4 mg/kg, respectively. Median OS data are considered as immature at the DCO date for primary analysis. It is important to note that Stage 1 subjects (who had longer duration of follow-up at primary analysis compared to subjects enrolled in Stage 2) at 5.4 mg/kg report a longer DoR (8.1 months [95% CI = 4.2, NE], and 4.6 [95% CI = 4.1, 7]), for Stage 1 and 2, respectively) and median PFS (7.0 months [95% CI = 5.4 to 9.8], and 5.5 months [95% CI = 2.9, 6.9] for Stage 1 and 2, respectively). Antitumor activity was consistent across subgroups, regardless of ECOG status, prior use of anti-HER2 therapy, prior treatment with egorafenib/trifluridine/tipiracil, tumor location (left/right), or RAS mutational status. Greater antitumor activity was observed in subjects with HER2 status IHC3+.

Antitumor activity was observed in subjects with HER2-overexpressing mCRC at both the 5.4 mg/kg and 6.4 mg/kg doses of T-DXd. Overall safety was consistent with the known safety profile of T-DXd. The most common treatment-emergent adverse events (including >=Grade 3 TEAEs) were GI or hematologic. Adverse events were manageable by dose modification and routine clinical practice in the majority of subjects.

No

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/

https://jrct.mhlw.go.jp/latest-detail/jRCT2051200124

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

Complete

Feb. 15, 2021

Interventional

randomized controlled trial

double blind

dose comparison control

parallel assignment

treatment purpose

1. Adults aged >=20 years in Japan, Taiwan, and Korea, or those aged >=18
years in other countries, at the time the Informed Consent Forms (ICFs)
are signed.
2. Pathologically-documented, unresectable, recurrent, or metastatic
colorectal adenocarcinoma. Participants must have BRAF wild-type
cancer and RAS status identified in primary or metastatic site.
3. The following therapies should be included in prior lines of therapy:
a. Fluoropyrimidine, oxaliplatin, and irinotecan, unlesscontraindicated
b. Anti-EGFR treatment, if RAS wild-type and if clinically indicated
c. Anti-VEGF treatment, if clinically indicated
d. Anti-PD-(L)-1 therapy, if tumor is MSI-high/deficient mismatch repair (dMMR), or tumor mutational burden (TMB)-high, if clinically indicated
4. Confirmed HER2-overexpressing status assessed by central laboratory
and defined as IHC 3+ or IHC 2+/ISH+.
5. Presence of at least one measurable lesion assessed by the Investigator
per RECIST version 1.1.
6. ECOG PS of 0 or 1.
7. Has LVEF >=50% within 28 days before randomization/registration.

1. Medical history of myocardial infarction (MI) within 6 months before randomization/registration, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Participants with troponin levels above ULN at Screening (as defined by the manufacturer), and without any MI-related symptoms, should have a cardiologic consultation before randomization/registration to rule out MI.
2. Has a corrected QT interval (QTcF) prolongation to >470 msec (female participants) or >450 msec (male participants) based on the average of the Screening triplicate 12-lead ECGs.
3. Has a history of (non-infectious) ILD/pneumonitis that required steroids,
has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
4. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the randomization/registration, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.).
5. Any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjogren syndrome, sarcoidosis, etc.) where there is documented, or a suspicion of, pulmonary involvement at the time of Screening.
6. Prior pneumonectomy.
7. Has spinal cord compression or clinically active central nervous system
metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole-brain radiotherapy and randomization/registration.
8. Participants with leptomeningeal carcinomatosis.
9. Has known human immunodeficiency virus (HIV) infection.
10. Active hepatitis B and/or hepatitis C infection, such as those with
serologic evidence of viral infection within 28 days before study randomization/registration. Participants with past or resolved hepatitis B
virus (HBV) infection are eligible if hepatitis B surface antigen (HBsAg) negative (-) and antibody to hepatitis B core antigen (anti-HBc) positive (+).
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
11. Previous treatment with a DXd-containing ADC.

Both

Subjects with HER2-overexpressing locally advanced, unresectable, or metastatic colorectal cancer.

- T-DXd 5.4 mg/kg Q3W
Participants will be randomized to receive intravenous T-DXd administered at a dose of 5.4 mg/kg Q3W.

- T-DXd 6.4 mg/kg Q3W
Participants will be randomized to receive intravenous T-DXd administered at a dose of 5.4 mg/kg Q3W.

To assess the efficacy of trastuzumab deruxtecan (T-DXd), as measured by the confirmed ORR by BICR in HER2-overexpressing (defined as IHC 3+ or IHC2+/ISH+) mCRC subjects treated at the 5.4 mg/kg and 6.4 mg/kg doses

- To evaluate the clinical efficacy of T-DXd by confirmed ORR by Investigator assessment
- To evaluate the clinical efficacy of T-DXd by DoR
- To further evaluate the clinical efficacy of T-DXd by DCR, CBR, PFS, and OS
- To further evaluate the safety and tolerability of T-DXd
- To evaluate HEOR endpoints including patient-reported HRQoL, symptoms, and physical functioning
- To evaluate healthcare resource utilization for both treatment arms
- To evaluate PK of T-DXd
- To evaluate immunogenicity of T-DXd

+81-6-6942-1331

Jan. 19, 2021

Australia/Belgium/France/Italy/SK/ Spain/Taiwan/United Kingdom/United States