Prospective registration

A Phase III, Open-label, Sponsor-blind, Randomized Study of Dato-DXd With or Without Osimertinib Versus Platinum-based Doublet Chemotherapy for Participants With EGFR-mutated Locally Advanced or Metastatic Non-small Cell Lung Cancer Whose Disease Has Progressed on Prior Osimertinib Treatment (TROPION-Lung15)

A Phase III, Open-label, Sponsor-blind, Randomized Study of Dato-DXd With or Without Osimertinib Versus Platinum-based Doublet Chemotherapy for Participants With EGFR-mutated Locally Advanced or Metastatic Non-small Cell Lung Cancer Whose Disease Has Progressed on Prior Osimertinib Treatment (TROPION-Lung15)

zhouqing 

zhouqing 

No. 106 Zhongshan 2nd Road, Yuexiu District, Guangzhou City, Guangdong Province

No.106 Zhongshan Er Road, Guangzhou, China

Guangdong Provincial People's Hospital

Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)

Yes

Ethics Review Committee of Guangdong Provincial People's Hospital

Bai Sheng

No.106 Zhongshan Er Road, Guangzhou, China

Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)

No.106 Zhongshan Er Road, Guangzhou, China

AstraZeneca AB

Participants must have at least one EGFR sensitive mutation recorded: G719X, exon 19 deletion, S768I, L858R, and/or L861Q.

Interventional study

3

Parallel 

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.

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.<=2 prior lines of EGFR TKIs (osimertinib is the only permitted prior third generation EGFR TKI). 6.If a participant discontinues osimertinib prior to C1D1, they must have no more than 28 days off osimertinib prior to randomization. Post-progression osimertinib monotherapy is recommended to continue uninterrupted during the screening period up until C1D1 of study intervention. 7.At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 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 (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 within 1 week prior to screening assessment). (d) Platelet count >= 100 × 109 /L (platelet transfusion is not allowed within 10 days prior to screening assessment). (e) Serum albumin >= 2.5 g/dL. (f) TBL <=1.5 × ULN or <=3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia).(g) Except in the setting of HBV, ALT and AST <= 2.5 × ULN; for participants with hepatic metastases, ALT and AST <=5 × ULN. See Exclusion Criterion 10 for requirements in the setting of HBV. (h) Calculated CrCL will be determined by Cockcroft Gault (using actual body weight) or measured by 24-hour urine collection per local guidelines: i) CrCL >= 45 mL/min for all participants except for the following: o CrCL >= 60 mL/min for participants planned to receive cisplatin. 12.Male and/or female. Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; see Appendix G for further details. (a) Male participants: i) Use of a condom plus an additional contraceptive method or avoid intercourse from enrollment and throughout study for at least 6 months after the last dose of Dato-DXd with or without osimertinib, in addition to the female partner using a highly effective contraceptive method. ii) Starting at randomization/the first dose of study intervention, male participants must not freeze or donate sperm at any time during this study and for at least 6 months after the last dose of Dato-DXd with or without osimertinib. Preservation of sperm should be considered prior to randomization/the first dose of study intervention. iii) Due to the possibility of platinum-based chemotherapy and pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment. (b) Female participants: i) Females not of child-bearing potential, see Appendix G for definition. ii) Females receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for FOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued toallow confirmation of post-menopausal status prior to study enrollment; see Appendix G for further details. iii) Female participants of child-bearing potential must use one highly effective form of contraception or avoid intercourse from enrollment throughout study and for at least 7 months after the last dose of Dato-DXd with or without osimertinib; see Appendix G for further details. All FOCBP must have a negative serum pregnancy test documented during screening. iv) Starting at the time of randomization/the first dose of study intervention, female participants must not donate, or retrieve for their own use, ova at any time during this study and for at least 7 months after the last dose of Dato-DXd with or without osimertinib. Preservation of ova should be considered prior to randomization/the first dose of study intervention. 13.Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this CSP. 14.Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional Genomics Initiative research that supports the Genomic Initiative (see Appendix D); 15.All races, gender and ethnic groups are eligible for this study. 16.Willingness and ability to comply with study and follow-up procedures.

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 <=1 or baseline. Note: participants may be enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to > 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 presence of anti-HDV antibodies). (c) Have demonstrated absence of HIV infection. (d) Have been curatively treated for HCV infection as demonstrated clinically and by viral serologies. (e) Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis. (f) Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii of criterion (g) below: (g) Are HBsAg + with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below: i) HBV DNA viral load < 100 IU/mL. ii) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT < 3 × ULN, which are not attributable to HBV infection. iii) Receiving anti-viral prophylaxis for 2-4 weeks prior to study intervention and maintain anti-viral treatment during and post-study intervention as determined by their hepatologist. 11.Has known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: (a) Demonstrated absence of HBV/HCV co-infection (b) Undetectable viral RNA for 6 months (c) CD4+ count >= 350 cells/μL (d) No history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). (e) If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count per local SoC (eg, every 3 months) is recommended. Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/IEC. 12.Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, suspected infections (eg, prodromal symptoms), or inability to rule out infections (participants with localized fungal infections of skin or nails are eligible). 13.Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination, and radiographic findings, or tuberculosis testing in line with local practice). 14.Resting ECG with clinically abnormal findings, including: (a) Mean resting corrected QT interval (QTc) > 470 ms, obtained from 3 ECGs, using the screening clinic ECG machine derived QTcF value (b) Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, eg, complete left bundle branch block, third-degree heart block, second degree heart block (c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as electrolyte abnormalities including: i) Serum/plasma potassium < LLN* ii) Serum/plasma magnesium < LLN* iii) Serum/plasma calcium < LLN* iv) Heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause TdP (see Section 6.9.2 and Appendix I 4). *correction of electrolyte abnormalities to be within normal ranges can be performed during screening and must be corrected prior to C1D1. 15.Uncontrolled or significant cardiac disease including: (a) Myocardial infarction or uncontrolled/unstable angina within 6 months before the first dose of study intervention. (b) Congestive heart failure (New York Heart Association Class II to IV). (c) Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg). (d) Cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, and ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the investigator judgment with cardiologist consultation recommended. 16.History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids or drug-induced ILD, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. 17.Has severe pulmonary function compromise resulting from intercurrent pulmonary illnesses including, but not limited to any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, symptomatic pleural effusion, etc). 18.Use of chemotherapy, vascular endothelial growth factor inhibitor (eg, bevacizumab, ramucirumab), immunotherapy (ie, PD-1 inhibitor, PD-L1 inhibitor, cytotoxic T lymphocyte antigen 4 inhibitor) or any anti-cancer therapy in the metastatic setting. Platinum-based chemotherapy in non-metastatic setting within 12 months prior to randomization. Concurrent use of anti-resorptive/bone therapy (eg, bisphosphonates, RANKL inhibitors) for bone metastases is allowed. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, HRT) is allowed. 19.Prior treatment with a third generation EGFR TKI (aside from osimertinib). 20.Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period of > 14 days before the first dose of study intervention (see Appendix I 5). 21.Current use of (or unable to stop use prior to receiving the first dose of study intervention) medications or herbal supplements known to be strong inducers of CYP450, CYP3A4 (at least 3 weeks prior) (See Appendix I 2). All participants must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4. 22.Receipt of live, attenuated vaccine within 30 days prior to the first dose of study intervention. 23.Any surgical procedure (excluding placement of vascular access) or significant traumatic injury within <=3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study. 24.Received prior radiotherapy to metastatic or recurrent disease within 2 weeks prior to the first dose of study intervention. If radiotherapy field involves the lung, consider waiting at least 4 weeks to the first dose of study intervention if concern for radiation pneumonitis (consult with treating radiation oncologist). Definitive radiation (locally advanced curative setting, ie, conventional radiation ~60 Gy in 30 fractions) to lung cancer within the lung within 6 months prior to first dose of study intervention. Ongoing radiation toxicities should resolve to Grade 1 or baseline prior to first dose of study intervention. 25.Participation in another clinical study with a study intervention (with the exception of osimertinib monotherapy) or investigational medicinal device administered in the last 12 months prior to the first dose of study intervention, or concurrent enrollment in another clinical study (unless the study is observational [noninterventional], or the participant is in the follow-up period of an interventional study). 26.Participants with a known history of severe hypersensitivity reactions to either the drug or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd,osimertinib, or chemotherapy, or drugs with a similar chemical structure or class to Dato-DXd or osimertinib. 27.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 28.Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. 29.Previous randomization in the present study. 30.For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding or planning to become pregnant. 31.Female participants should refrain from breastfeeding from enrollment throughout the study and for at least 7 months after last dose of study intervention. 32.In addition, the following are considered criteria for exclusion from the exploratory Genomics Initiative research: (a) Prior allogeneic bone marrow transplant (b) Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection. 33.Participants with confirmed small cell histologic transformation following progression on prior osimertinib therapy. A biopsy following progression on prior osimertinib therapy must be attempted to exclude histologic transformation.

Randomization will be stratified by baseline brain metastases (yes versus no), prior osimertinib line of therapy (adjuvant versus first-line versus second-line), and race (Chinese Asian versus non-Chinese Asian versus non-Asian)

Open-label study

NA

Electronic Data Capture