Clinical trial NCT06350097: 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
Official title: A Phase III, Open-label, Randomised Study of Osimertinib With or Without Datopotamab Deruxtecan (Dato-DXd), as First-line Treatment in Participants With Epidermal Growth Factor Receptor (EGFR) Mutation-positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Keywords: Non-small Cell Lung Cancer, NSCLC, Epidermal Growth Factor Receptor (EGFR) Mutation-positive, Osimertinib, Dato-DXd, Datopotamab Deruxtecan, Tagrisso
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo
First posted: 2024-04-05
Enrollment: 582
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Age

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

   Type of Participant and Disease Characteristics
2. Histologically or cytologically documented nonsquamous NSCLC.
3. 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.
4. Participants must not have received prior EGFR TKIs or other systemic therapy for Stage IIIB, IIIC or IV NSCLC.
5. 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.
6. 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.
7. WHO performance status of 0 or 1.
8. 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.
9. Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention .

   Sex and Contraceptive/Barrier Requirements
10. 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.

    Other Inclusion Criteria
11. All races, gender and ethnic groups are eligible for this study.

Exclusion Criteria:

Medical Conditions

1. 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.
2. 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.
3. History of another primary malignancy.
4. Spinal cord compression and unstable brain metastases.
5. Clinically significant corneal disease.
6. Has active or uncontrolled hepatitis B or C virus infection.
7. Known HIV infection that is not well controlled.
8. 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).
9. Resting ECG with clinically abnormal findings.
10. Uncontrolled or significant cardiac disease.
11. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
12. Has severe pulmonary function compromise.

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

    Prior/Concurrent Clinical Study Experience
14. 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.

Primary outcomes:
measure: To demonstrate the superiority of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS by BICR in all randomised participants.
timeFrame: It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
Secondary outcomes:
measure: To demonstrate the superiority of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of OS in all randomised participants.
timeFrame: It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.
measure: 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
timeFrame: It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS by investigator in all randomised participants.
timeFrame: It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
measure: 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.
timeFrame: It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
measure: 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.
timeFrame: It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib on the prevention of CNS metastases
timeFrame: It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS2 in all randomised participants
timeFrame: It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.
measure: To assess the PK of osimertinib and Datopotamab Deruxtecan
timeFrame: It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.
measure: To investigate the immunogenicity of Datopotamab Deruxtecan
timeFrame: It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.
measure: 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
timeFrame: It is anticipated that it will be performed approximately 3 years after the first participant is randomised.
measure: 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
timeFrame: It is anticipated that it will be performed approximately 7 years after the first participant has been randomised.
Other outcomes:
Locations:
city: Fountain Valley
country: United States
facility: Research Site
state: California
city: Los Alamitos
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facility: Research Site
state: California
city: Los Angeles
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state: California
city: Los Angeles
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city: Wuhan
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city: Xi'an
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city: Xuzhou
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city: Yangzhou
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city: Zhengzhou City
country: China
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city: Zhengzhou
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city: Berlin
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city: Erfurt
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city: Goettingen
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city: Immenhausen
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city: München
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city: Hong Kong
country: Hong Kong
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city: Jordan
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city: Lai Chi Kok
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city: Mysuru
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city: Nashik
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city: New Delhi
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city: Vadodara
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city: Varanasi
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city: Milano
country: Italy
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city: Monza
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city: Orbassano
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city: Padova
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city: Parma
country: Italy
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city: Chuo-ku
country: Japan
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city: Fukuoka-shi
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Niigata-shi
country: Japan
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city: Osaka-shi
country: Japan
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city: Osakasayama-shi
country: Japan
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city: Sendai-shi
country: Japan
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city: Wakayama-shi
country: Japan
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city: Yokohama-shi
country: Japan
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city: Erie
country: Korea, Republic of
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city: Goyang-si
country: Korea, Republic of
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city: Namdong-gu
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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country: Thailand
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country: Turkey
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city: Ankara
country: Turkey
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city: Goztepe Istanbul
country: Turkey
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city: Izmir
country: Turkey
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city: Küçükçekmece
country: Turkey
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city: Seyhan
country: Turkey
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city: Ha noi
country: Vietnam
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city: Hanoi
country: Vietnam
facility: Research Site
city: Ho Chi Minh City
country: Vietnam
facility: Research Site
city: Ho Chi Minh
country: Vietnam
facility: Research Site
city: Ho Chi Minh
country: Vietnam
facility: Research Site
city: Vinh
country: Vietnam
facility: Research Site
Study officials:
References: