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Phase III, Open-label Study of First-line Osimertinib With or Without Datopotamab Deruxtecan for EGFRm Locally Advanced or Metastatic Non-small Cell Lung Cancer

PHASE3RECRUITING

The purpose of this study is to evaluate efficacy and safety of osimertinib (tablet) in combination with Datopotamab Deruxtecan (i. v. infusion) compared with osimertinib (tablet) monotherapy as a first-line therapy in participants with locally advanced or metastatic EGFRm (Ex19del and/or L858R) NSCLC.

Study details include: 1. The study duration will be event-driven, with an estimated duration of approximately 9 years. 2.

Participants may receive study treatment until disease progression, unacceptable toxicity, or other specific discontinuation criteria are met. 3. The visit frequency will be every 3 weeks during the treatment period.

Note: Participants on osimertinib treatment (osimertinib only arm or who have discontinued Datopotamab Deruxtecan while are still receiving osimertinib) are required to attend visits to perform assessments every 6 weeks from Cycle 7 until Cycle 17 and then visits every 12 weeks until disease progression, IP discontinuation or primary PFS DCO. Participants who are receiving osimertinib + Datopotamab Deruxtecan are still required to attend visit to perform assessment every 3 weeks (q3w) per SoA.

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Study details:

This is a global Phase III, open-label, randomised, multicentre study assessing the efficacy and safety of osimertinib in combination with Datopotamab Deruxtecan compared with osimertinib in participants with locally advanced or metastatic EGFRm (Ex19del and/or L858R) NSCLC who have not received any prior therapy for advanced disease.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Participant must be ≥ 18 years; Participant from Japan must be ≥ 20 years, at the time of signing the ICF.

Histologically or cytologically documented nonsquamous NSCLC.

Stage IIIB or IIIC or Stage IV metastatic NSCLC or recurrent NSCLC (based on the American Joint Committee on Cancer Edition 8) not amenable to curative surgery or definitive chemoradiation at the time of randomisation.

Participants must not have received prior EGFR TKIs or other systemic therapy for Stage IIIB, IIIC or IV NSCLC.

The tumour harbors 1 of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations.

For participants enrolled in randomisation period, mandatory provision of an unstained, archival tumour tissue sample in a quantity sufficient to allow for central confirmation of the EGFR mutation status.

WHO performance status of 0 or 1.

At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with CT or MRI and is suitable for accurate repeated measurements.

Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention.

Male and female Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

All races, gender and ethnic groups are eligible for this study.

Exclusion criteria

As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases, psychiatric illness/social situations), history of allogenic organ transplant, and/or substance abuse which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.

Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of osimertinib.

History of another primary malignancy.

Spinal cord compression and unstable brain metastases.

Clinically significant corneal disease.

Has active or uncontrolled hepatitis B or C virus infection.

Known HIV infection that is not well controlled.

Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible).

Resting ECG with clinically abnormal findings.

Uncontrolled or significant cardiac disease.

Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.

Has severe pulmonary function compromise.

Prior exposure to any agent including an ADC containing a chemotherapeutic agent targeting topoisomerase I, TROP2-targeted therapy.

Participants with a known history of severe hypersensitivity reactions to either Dato-DXd and osimertinib or any excipients of Dato DXd and osimertinib or drugs with a similar chemical structure or class to DXd and osimertinib.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-04-29

Primary completion: 2028-03-21

Study completion finish: 2032-05-25

Study type

TREATMENT

Phase

PHASE3

Trial ID

NCT06350097

Intervention or treatment

DRUG: Osimertinib

DRUG: Datopotamab Deruxtecan

Conditions

• Non-small Cell Lung Cancer

Image related to Non-small Cell Lung Cancer

Condition: Non-small Cell Lung Cancer
DRUG: Osimertinib and other drugs
Clayton, Not Specified, Australia and more
Sponsor: AstraZeneca

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Find a site

Closest Location:

Research Site

Research sites nearby

Select from list below to view details:

Research Site
Clayton, Not Specified, Australia
Research Site
Kogarah, Not Specified, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm 1: Osimertinib in combination with Datopotamab Deruxtecan Participants in this group will receive osimertinib 80 mg QD as oral tablet with Datopotamab Deruxtecan 6mg/kg as i.v. infusion q3w of Day 1 of every 21-day cycle.	DRUG: Osimertinib Arm 1: Osimertinib 80 mg QD as oral tablet with Datopotamab Deruxtecan 6mg/kg as i.v. infusion. Arm 2: Osimertinib 80 mg QD as oral tablet .
ACTIVE_COMPARATOR: Arm 2: Osimertinib monotherapy Participants in this group will receive osimertinib 80 mg QD as oral tablet.	DRUG: Osimertinib Arm 1: Osimertinib 80 mg QD as oral tablet with Datopotamab Deruxtecan 6mg/kg as i.v. infusion. Arm 2: Osimertinib 80 mg QD as oral tablet .

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
To demonstrate the superiority of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS by BICR in all randomised participants.	PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause (in the absence of progression).	It is anticipated that it will be performed approximately 3 years after the first participant is randomised.

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
To demonstrate the superiority of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of OS in all randomised participants.	OS defined as the time from randomisation until the date of death due to any cause.	It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.
To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS on CNS metastases in participants with CNS metastases at baseline	Central nervous system progression-free survival (CNS PFS) is defined as the time from randomisation until the date of objective CNS progression assessed by CNS BICR or death (by any cause in absence of CNS progression).	It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS by investigator in all randomised participants.	PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by investigator, or death due to any cause (in the absence of progression).	It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of ORR in all randomised participants with measurable disease at baseline.	ORR is defined as the proportion of participants who have a confirmed CR or confirmed PR, as determined by BICR (and investigator) per RECIST 1.1.	It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of DoR in all randomised participants with measurable disease at baseline.	DoR is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1, as assessed by BICR (and investigator) assessment or death due to any cause. The measure of interest is the median of DoR.	It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib on the prevention of CNS metastases	Neuro-radiologist assessments according to CNS RECIST 1.1 to determine the presence/absence of CNS lesions at progression in participants without CNS metastases at baseline.	It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS2 in all randomised participants	PFS2 will be defined as the time from randomisation to the earliest of the progression event (following the initial progression) subsequent to first subsequent anti-cancer therapy, or death.	It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.
To assess the PK of osimertinib and Datopotamab Deruxtecan	Concentration of osimertinib and its metabolite AZ5104, Datopotamab Deruxtecan, total anti-TROP2 antibody and DXd in plasma.	It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.
To investigate the immunogenicity of Datopotamab Deruxtecan	Presence of ADAs for Datopotamab Deruxtecan (confirmatory results: positive or negative, titres, and neutralizing antibodies).	It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.
To compare the local EGFR mutation test result used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results from baseline tumour samples	Concordance of EGFR mutation status between the local EGFR mutation test and the central cobas® EGFR Mutation Test v2 results from tumour samples with evaluable results.	It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan vs. osimertinib monotherapy based on the cobas® EGFR Mutation Test v2 plasma screening test result for Ex19del or L858R EGFR mutations	PFS by Investigator by plasma EGFR mutation status PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by investigator, or death due to any cause (in the absence of progression).	It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.

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References

Clinical Trials Gov: Phase III, Open-label Study of First-line Osimertinib With or Without Datopotamab Deruxtecan for EGFRm Locally Advanced or Metastatic Non-small Cell Lung Cancer