Study of DS-1062a with or without Pembrolizumab in Advanced or Metastatic Non-small Cell Lung Cancer without Actionable Genomic Alterations

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Daiichi Sankyo Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Aug 2022 → ongoing

Decision date (initial)

2024-06-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Daiichi Sankyo Inc

External identifiers

EU CT number

2023-507933-12-00

EudraCT number

2021-002555-10

ClinicalTrials.gov

NCT05215340

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Safety, Efficacy, Pharmacokinetic, Pharmacogenetic

To compare the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone, as measured by progression-free survival (PFS) by blinded independent central review (BICR) in subjects with non-squamous histology.

To compare the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone, as measured by overall survival (OS), in subjects with non-squamous histology.

Secondary objectives 6

1. To compare the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone, as measured by PFS by BICR, across all randomized subjects.
2. To further evaluate the efficacy of Dato- DXd in combination with pembrolizumab versus pembrolizumab alone.
3. To evaluate the patient-reported outcomes (PROs) of Dato-DXd in combination with pembrolizumab and of pembrolizumab alone.
4. To further evaluate the safety of Dato- DXd in combination with pembrolizumab
5. To assess the immunogenicity of Dato-DXd in the investigational treatment arm.
6. To compare the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone, as measured by overall survival (OS), across all randomized subjects, including subjects with non-squamous and squamous histology.

Conditions and MedDRA coding

Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

De-identified individual participant data (IPD) 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/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Sign and date the Tissue Screening and Main ICFs, prior to the start of any study-specific qualification procedures.
2. Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time of informed consent. (Follow local regulatory requirements if the legal age of adult voluntary consent for study participation is >18 years old.
3. 3. Histologically documented non-squamous NSCLC that meets all of the following criteria (Note: Subjects with squamous histology were eligible prior to Protocol Version 5.0. After Protocol Version 5.0, subjects with squamous histology are not eligible. Subjects with mixed histology, including those with a squamous component, remain eligible for the study even after Protocol Version 5.0): a. Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition). Subjects with early-stage NSCLC who have relapsed should be restaged during screening to ensure their eligibility for the study. b. Documented negative test results for EGFR, ALK, and ROS1 AGAs based on analysis of tumor tissue. If test results for EGFR, ALK, and ROS1 are not available, subjects are required to undergo testing performed locally for these genomic alterations. c. No known AGAs in NTRK, BRAF, RET, MET, or other actionable driver kinases with locally approved therapies. (Testing for genomic alterations besides EGFR, ALK, and ROS1 is not required prior to randomization). Subjects whose tumors harbor KRAS mutations are eligible for the study.
4. Has provided a formalin-fixed tumor tissue sample. If a documented law or regulation prohibits (or does not approve) sample collection for exploratory biomarkers, then such sample will not be collected.
5. Tumor has high PD-L1 expression (TPS ≥50%) as determined by PDL1 IHC 22C3 pharmDx assay by central testing (minimum of 6 slides).
6. Has an adequate treatment washout period before Cycle 1 Day 1 as defined in protocol Section 5.1.
7. Measurable disease based on local imaging assessment using RECIST Version 1.1 (see Section 10.4 of the protocol).
8. Has left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days before randomization.
9. ECOG PS of 0 or 1 at screening.
10. Has a life expectancy of at least 3 months.
11. Adequate bone marrow function within 7 days before randomization as defined in protocol Section 5.1.
12. If the subject is a female of childbearing potential, she must not be pregnant, breastfeeding or intend to become pregnant during the study; she must also have a negative serum pregnancy test at screening and must be willing to use highly effective birth control (as detailed in protocol Section 10.3.4) or avoid heterosexual intercourse upon randomization, during the Treatment Period, for 7 months following the last dose of Dato-DXd, and for 4 months following the last dose of pembrolizumab, whichever occurs later. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
13. If male, the subject must be surgically sterile or must use a condom in addition to their partner using a highly effective birth control (Section 10.3.4 of the protocol) if their partner is of reproductive potential or avoid heterosexual intercourse upon enrollment, during the Treatment Period, and for 4 months following the last dose of Dato-DXd.
14. Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the last dose of Dato-DXd. Preservation of sperm should be considered prior to enrollment in this study.
15. Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the last dose of Dato-DXd, or for at least 4 months after the last dose of pembrolizumab, whichever occurs later. Preservation of ova should be considered prior to enrollment in this study.
16. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

Exclusion criteria 9

1. Has received prior systemic treatment for advanced or metastatic NSCLC.
2. Has received prior treatment for NSCLC with any of the following, including in the adjuvant/neoadjuvant setting: a. Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I. b. TROP2-targeted therapy. c. Any anti-programmed death receptor-1 (PD-1), anti-PD-L1, or anti- PD-ligand 2 (L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137). d. Any other immune checkpoint inhibitors. Subjects who received adjuvant or neoadjuvant therapy OTHER than those listed above, are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the diagnosis of advanced/metastatic disease.
3. 3. Has spinal cord compression or active and untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases and who are asymptomatic may participate provided they are radiologically stable (ie, without evidence of progression) for at least 2 weeks by repeat imaging (note: repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 7 days before the first dose of study drug. Note: A computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the brain at baseline (MRI preferred) is required for all subjects. For those subjects in whom CNS metastases are first discovered at the time of screening, are asymptomatic, and who do not require radiotherapy,the treating investigator should consider delay of study treatment to document stability of CNS metastases with repeat imaging 4 weeks from the time of detection of asymptomatic brain metastases (in which case, repeat of all screening activity may be required).
4. 4. Has received prior radiotherapy ≤4 weeks of start of study intervention or more than 30 Gy to the lung within 6 months of Cycle 1 Day 1 or has ongoing radiation-related toxicities requiring corticosteroids. A 2-week washout is permitted for palliative radiation to the non-thoracic region.
5. History of another primary malignancy (beyond NSCLC) except for the following: - Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study treatment and of low potential risk for recurrence - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease - Subjects with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤T2cN0M0 without biochemical recurrence or progression and who in the opinion of the investigator are not deemed to require active intervention.
6. Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
7. Clinically severe pulmonary compromise, as judged by the investigator, resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli diagnosed within 3 months of Cycle 1 Day 1, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.), or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc), or prior complete pneumonectomy.
8. Uncontrolled or significant cardiovascular disease, including: a. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval >470 ms regardless of sex (based on the average of the 12-lead electrocardiogram determination at screening). b. Myocardial infarction within 6 months prior to randomization. c. Uncontrolled angina pectoris within 6 months prior to randomization. d. LVEF <50% by ECHO or MUGA scan within 28 days before randomization. e. New York Heart Association Class 2 to 4 congestive heart failure (CHF) at screening. Subjects with a history of Class 2 to 4 CHF prior to screening, must have returned to Class 1 CHF and have LVEF ≥50% (by either an ECHO or MUGA scan within 28 days before randomization) in order to be eligible. f. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) within 28 days before randomization.
9. Has clinically significant corneal disease. For full list of principal exclusion criteria please see Clinical Study Protocol Section 5.2.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first. Overall survival (OS) is defined as the time from randomization to death due to any cause.

Secondary endpoints 11

1. PFS is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first
2. PFS is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first.
3. PFS2 is defined as the time from date of randomization to the first documented disease progression on next-line therapy or death due to any cause, whichever occurs first.
4. ORR is defined as the proportion of subjects who achieved a BOR of confirmed CR or confirmed PR.
5. Duration of response (DoR) is defined as the time from the date of the first documentation of objective response (confirmed CR or confirmed PR) to the date of the first radiographic disease progression or death due to any cause, whichever occurs first.
6. Time to response (TTR) is defined as the time from randomization to the date of the first documentation of objective response (confirmed CR or confirmed PR) in responding subjects.
7. Disease control rate (DCR) is defined as the proportion of subjects who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD).
8. Time to deterioration (TTD) is defined as the time from randomization to first onset of a ≥10-point increase in cough, chest pain, or dyspnea, confirmed by a second adjacent ≥10- point increase from randomization in the same symptom, or confirmed by death within 21 days of a ≥10- point increase from randomization.
9. Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs), Eastern Cooperative Oncology Group performance status (ECOG PS), vital sign measurements, standard clinical laboratory parameters (hematology, clinical chemistry, and urinalysis), electrocardiogram parameters, echocardiogram (ECHO)/multigated acquisition (MUGA) scan findings, and ophthalmologic findings.
10. Anti-drug antibody (ADA) prevalence: the proportion of subjects who are ADA-positive at any point in time (at baseline or post-baseline) ADA incidence: the proportion of subjects having a treatment-emergent ADA Titer and neutralizing antibodies will be determined when the ADA is positive.
11. OS is defined as the time from randomization to death due to any cause.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Daiichi Sankyo Inc.

Sponsor organisation

Daiichi Sankyo Inc.

Address

211 Mount Airy Road

City

Basking Ridge

Postcode

07920-2311

Country

United States

Scientific contact point

Organisation

Daiichi Sankyo Inc.

Contact name

Clinical Trial Office

Public contact point

Organisation

Daiichi Sankyo Inc.

Contact name

Clinical Trial Office

Third parties 6

Locations

12 EU/EEA countries · 77 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 234 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

24 submissions — initial application plus substantial / non-substantial modifications