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

Official Summary

The purpose of this study is to evaluate efficacy and safety of osimertinib (tablet) in combination with Dato-DXd (i.v. infusion) compared with osimertinib (tablet) monotherapyas 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 8 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 Dato-DXd 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 or IP discontinuation. Participants who are receiving osimertinib + Dato-DXd are still required to attend visit to perform assessment every 3 weeks (q3w) per SoA.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 582 participants

Study Arms

• Arm 1: Osimertinib in combination with Datopotamab Deruxtecan (EXPERIMENTAL)
  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.
• Arm 2: Osimertinib monotherapy (ACTIVE_COMPARATOR)
  Participants in this group will receive osimertinib 80 mg QD as oral tablet.

Interventions

• DRUG: Osimertinib — Osimertinib 80 mg administered orally once daily (QD).
• DRUG: Datopotamab Deruxtecan — Datopotamab Deruxtecan 6 mg/kg administered as an intravenous (i.v.) infusion every 3 weeks (q3w).

Primary Outcomes

• To demonstrate the superiority of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of Progression Free Survival (PFS) by BICR in all randomised participants. (It is anticipated that it will be performed approximately 3 years after the first participant is randomised.)

Secondary Outcomes

• To demonstrate the superiority of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of Overall Survival (OS) in all randomised participants. (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 Central nervous system (CNS) metastases in participants with 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 PFS by investigator in all randomised participants. (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 Overall Response Rate (ORR) in all randomised participants with measurable disease 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 Duration of Response (DoR) in all randomised participants with measurable disease at baseline. (It is anticipated that it will be performed approximately 3 years after the first participant is randomised.)

Eligibility Criteria

Inclusion Criteria:

Age

1. Participant must be ≥ 18 years.

   Type of Participant and Disease Characteristics
2. Histologically or cytologically documented nonsquamous NSCLC. NSCLC of mixed histology is allowed if adenocarcinoma is the predominant histology. Mixed small-cell lung cancer and NSCLC histology, and sarcomatoid variant of NSCLC is ineligible.
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 at least 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 genomic alterations, which may include EGFR T790M, assessed by a CLIA-certified (US sites) or an accredited (outside of the US) local laboratory or by central prospective tissue testing.
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 before the first dose of study intervention.

Exclusion Criteria:

1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases, history of allogenic organ transplant 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/or unstable brain metastases, as defined by Protocol.
5. Clinically significant corneal disease.
6. Has active or uncontrolled hepatitis B or C virus infection, as defined by Protocol.
7. Past medical history of ILD/penumonitis, including radiation pneumonitis (apart from radiation pneumonitis that did not require steroids), or drug-induced ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
8. Pulmonary embolism within 3 months of the study enrolment or has severe pulmonary function compromise.
9. Has clinically severe pulmonary function compromise resulting from intercurrent pulmonary illnesses.

Trial Locations

• Research Site, Fountain Valley, California, United States
• Research Site, Los Alamitos, California, United States
• Research Site, Los Angeles, California, United States
• Research Site, Los Angeles, California, United States
• Research Site, Orange, California, United States
• Research Site, San Diego, California, United States
• Research Site, Santa Monica, California, United States
• Research Site, Walnut Creek, California, United States
• Research Site, New Haven, Connecticut, United States
• Research Site, Washington D.C., District of Columbia, United States
• ...and 10 more locations

Contact Information

• AstraZeneca Clinical Study Information Center — CONTACT
  Phone: 1-877-240-9479
  Email: information.center@astrazeneca.com

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