Participants must have at least one EGFR sensitive mutation recorded: G719X, exon 19 deletion, S768I, L858R, and/or L861Q.
Conditions
Interventions
Dato-DXd monotherapy:Dato-DXd monotherapy
Dato-DXd + osimertinib combination therapy:Dato-DXd + osimertinib combination therapy
Platinum-based doublet chemotherapy (SoC):Platinum-based doublet chemotherapy (SoC)
Sponsors
Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: 1.Participant must be >= 18 years of age at the time of signing the ICF. 2.Histologically or cytologically confirmed non-squamous NSCLC. NSCLC of mixed histology is allowed, as long as not predominantly squamous histology. No small cell or large cell neuroendocrine components allowed. 3.Must have evidence of documented pre-existing EGFRm information (EGFRm known to be associated with EGFR TKI sensitivity [Ex19del, L858R, G719X, S768I, or L861Q], either alone or in combination with other EGFR mutations, which may include T790M) taken from medical records. 4.Documented extra-cranial radiologic progression on prior osimertinib monotherapy (as most recent line of treatment) in the adjuvant, locally advanced (clinical stage IIIB/IIIC not amenable to curative therapy), or metastatic (clinical stage IVA or IVB) setting, per Version 9 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology. (a) Participants ongoing on adjuvant osimertinib treatment that recur with locally advanced (not amenable to curative therapy) or metastatic disease are eligible. (b) Participants that completed neoadjuvant/adjuvant treatment of any type (including osimertinib) are eligible if they recurred with locally advanced (not amenable to curative therapy) or metastatic disease, were treated with osimertinib in the locally advanced/metastatic setting and then subsequently had disease progression while on osimertinib. (c) Participants with metastatic disease that progressed on first-line osimertinib are eligible.(d) Participants with metastatic disease that were treated with first- or second-generation EGFR TKI in the first-line setting followed by progression on osimertinib in the second-line setting are eligible. 5.= 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 (see Appendix F). If only 1 measurable lesion exists, it is acceptable to be used (as a TL) as long as it has not been previously irradiated and as long as it has not been biopsied within 14 days prior to the baseline tumor assessment scans. 8.WHO/ECOG performance status of 0 or 1. 9.Minimum life expectancy of > 12 weeks at time of screening. 10.Mandatory biopsy of tumor for retrospective evaluation of exploratory biomarkers (eg, TROP2), which fulfills the following requirements: (a) Biopsy following progression on prior osimertinib therapy must be attempted, and preferably from a site of progression. (b) Specimen to meet the requirements defined in the Central Laboratory Manual. 11.Adequate bone marrow reserve and organ function within 7 days before randomization defined as: (b) Hemoglobin >= 90 g/L (red blood cell/plasma transfusion is not allowed within 2 weeks prior to screening assessment). (c) Absolute neutrophil count >= 1.5 × 109 /L (granulocyte colony stimulating factor administration is not allowed with
Exclusion criteria
Exclusion criteria: 1.As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases and significant cardiac or psychological conditions), 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 jeopardize compliance with the protocol. 2.Inaccessible veins and/or inability to get a port to receive study intervention via IV infusion. 3.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. 4.Contraindication to brain MRI with contrast, including but not limited to, allergy to IV contrast, claustrophobia, pacemakers, metal implants, intracranial surgical clips, and metal foreign bodies. 5.History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected nonmelanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin), and curatively treated in situ disease. 6.Persistent toxicities caused by previous anti-cancer therapy, excluding alopecia, not yet improved to Grade Grade 2 for at least 3 months prior to the first dose of study intervention and managed with SoC treatment) which the investigator deems related to previous anti-cancer therapy, including (but not limited to): (a) Chemotherapy-induced neuropathy. (b) Fatigue. (c) Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies, which may include but are not limited to hypothyroidism/hyperthyroidism, Type I diabetes, hyperglycemia, adrenal insufficiency, or adrenalitis; and skin hypopigmentation (vitiligo). (d) Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss). 7.Unstable spinal cord compression and/or unstable brain metastases. Participants with spinal cord compression and/or brain metastases that have been stabilized after completion of local therapy (ie, radiation and/or surgery) and have a stable neurological status for at least 2 weeks after completion of the local therapy (confirmed by brain MRI) can be enrolled. Participants must be off steroids prior to start of study intervention. Participants with asymptomatic brain metastases (including leptomeningeal involvement) can be eligible for inclusion if, in the opinion of the investigator, immediate definitive treatment is not indicated. 8.Has significant third-space fluid retention (eg, ascites or pleural effusion) as judged by the investigator and is not amenable for required repeated drainage. 9.Clinically significant corneal disease. 10.Has active or uncontrolled hepatitis B or C virus infection. Participants with HBV are eligible if they: (a) Have demonstrated absence of HCV co-infection or history of HCV co-infection.(b) Have demonstrated absence of co-infection with HDV (HDV-positive infection is indicated by the p
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To demonstrate the superiority of Dato-DXd monotherapy compared to chemotherapy in terms of PFS.;To demonstrate the superiority of Dato-DXd combined with osimertinib compared to chemotherapy in terms of PFS.; | — |
Secondary
| Measure | Time frame |
|---|---|
| To assess the superiority of Dato-DXd with or without osimertinib compared to chemotherapy in terms of OS.;To assess the superiority of Dato-DXd with or without osimertinib compared to chemotherapy in terms of BICR-assessed CNS PFS.;Biomarker data; | — |
Countries
China
Contacts
Public Contactzhouqing
Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)
Outcome results
None listed