TROPION-Lung14 study protocol: a phase III study of osimertinib in combination with datopotamab deruxtecan versus osimertinib alone as first-line treatment for patients with EGFR -mutated locally advanced or metastatic non-small cell lung cancer

Abstract

Background:

Osimertinib is a first-line (1L) treatment option for patients with locally advanced/metastatic epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Resistance to 1L osimertinib often develops and treatment options after disease progression are limited. The clinical benefit of 1L osimertinib in combination with agents which have broad antitumor activity has been demonstrated in phase III trials. Datopotamab deruxtecan (Dato-DXd), an antibody–drug conjugate composed of a humanized anti-trophoblast cell-surface antigen 2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor, has demonstrated efficacy as monotherapy and in combination with osimertinib in NSCLC, including patients with EGFR-mutated advanced NSCLC.

Objectives:

TROPION-Lung14 (NCT06350097), an ongoing phase III, open-label, sponsor-blind, multicenter, randomized study, is evaluating the efficacy and safety of osimertinib + Dato-DXd, versus osimertinib, as 1L therapy in patients with EGFR-mutated LA/M NSCLC.

Methods and design:

The study is enrolling adults with histologically/cytologically confirmed stage IIIB/IIIC or intravenously (IV) non-squamous, EGFR-mutated (exon 19 deletion (Ex19del) or L858R) NSCLC, and no prior EGFR-TKI or other systemic therapy for stage IIIB/IIIC or IV disease. Prior to the randomized study period, ~20 patients will receive osimertinib + Dato-DXd in a safety run-in. Following safety run-in, ~562 patients will be randomized 1:1 to osimertinib (80 mg orally once daily (PO QD)) + Dato-DXd (6 mg/kg IV every 3 weeks) or osimertinib (80 mg PO QD). Patients will be stratified by EGFR mutation type (Ex19del vs L858R), World Health Organization performance status (0 vs 1), and central nervous system metastasis (yes vs no). Treatment will continue until Resist Evaluation Criteria in Solid Tumors version 1.1-defined progression or unacceptable toxicity. The primary endpoint is progression-free survival by blinded independent central review. Overall survival is a key secondary endpoint.

Ethics:

The study is approved by independent ethics committees/institutional review boards at each center. Patients will provide informed consent.

Discussion:

TROPION-Lung14 will assess 1L osimertinib + Dato-DXd versus osimertinib alone in patients with EGFR-mutated LA/M NSCLC, potentially providing a new treatment option.

Trial registration:

ClinicalTrials.gov identifier: NCT06350097 (Registration Date: April 5, 2024).

Plain language summary

TROPION-Lung14: a clinical study comparing osimertinib in combination with datopotamab deruxtecan or osimertinib alone as the first line of treatment for patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with a mutation in the epidermal growth factor receptor (EGFR) gene

Epidermal growth factor receptor (EGFR) is a protein that controls cell growth and division. In some cancer cells the gene is mutated and allows cells to grow uncontrollably. Osimertinib is a medicine that blocks the activity of mutated EGFR on cancer cells, stopping their growth and is an option for treatment for people with EGFR-mutated NSCLC in various clinical situations. Most patients develop resistance to osimertinib and treatment options after the cancer gets worse are limited. Researchers are looking to see if osimertinib would be more effective when it is combined with other medicines. Datopotamab deruxtecan (Dato-DXd) is an antibody–drug conjugate that consists of an antibody (datopotamab) and an anticancer drug (DXd), joined via a plasma-stable cleavable linker. Dato-DXd has shown promising antitumor efficacy in previous studies in people with advanced or metastatic NSCLC. This study, called TROPION-Lung14, is designed to compare the combination of osimertinib and Dato-DXd with osimertinib alone as a first treatment for people with EGFR-mutated advanced NSCLC. Eligible patients will be randomly assigned to receive either osimertinib plus Dato-DXd or osimertinib alone. Patients will continue to receive treatment until their disease progresses, side effects become unacceptable, or they choose to leave the study. The main objective of the study is to see how long patients remain alive without their cancer growing or spreading (known as progression-free survival). The first results are expected to be available in early 2028, with the study expected to end in mid-2032.

Keywords

antibody–drug conjugate datopotamab deruxtecan epidermal growth factor receptor non-small cell lung cancer osimertinib topoisomerase I trophoblast cell-surface antigen 2 tyrosine kinase inhibitor

Introduction

Osimertinib is a third-generation, irreversible, central nervous system (CNS)-active, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).^1–5 Osimertinib is an option for first-line (1L) treatment for EGFR-mutated advanced non-small-cell lung cancer (NSCLC) as monotherapy or in combination with platinum-based chemotherapy, based on the phase III, randomized FLAURA and FLAURA2 trials^2,6,7; and in patients with early-stage, unresectable stage III, and locally advanced or metastatic EGFR-mutated NSCLC.^1,3,8,9

The 1L approval for osimertinib was based on the FLAURA study, a double-blind, phase III trial, which compared osimertinib versus standard of care (SoC; gefitinib or erlotinib) in patients with previously untreated EGFR-mutated NSCLC (exon 19 deletion (Ex19del) or L858R).² Median progression-free survival (PFS) and overall survival (OS) were significantly longer with osimertinib versus SoC.⁴ Safety was manageable with the most commonly reported adverse events (AEs) for osimertinib being rash or acne (58%), diarrhea (58%), and dry skin (36%).² Despite the clinical benefit seen with osimertinib, disease progression is common and due to multiple different resistance mechanisms.^10,11 One potential strategy to extend the efficacy of osimertinib and delay the onset of resistance is the use of a combination regimen with treatment(s) with broad antitumor activity. Data from the 1L phase III FLAURA2 trial demonstrated the feasibility of this approach with a statistically significant improvement in PFS and OS with osimertinib plus platinum-pemetrexed doublet chemotherapy versus osimertinib alone in patients with EGFR-mutated advanced NSCLC.^6,12

Datopotamab deruxtecan (Dato-DXd) is an antibody–drug conjugate (ADC) comprising a humanized anti-trophoblast cell-surface antigen 2 (TROP 2) monoclonal antibody (Dato-DXd) conjugated to a potent, cytotoxic topoisomerase I (Topo-I) inhibitor via a plasma-stable, tetrapeptide-based, tumor-selective cleavable linker.¹³ In the phase III TROPION-Lung01 trial, Dato-DXd significantly improved PFS versus docetaxel in patients with pretreated advanced/metastatic NSCLC, which was driven by patients with non-squamous histology. A numerical improvement in OS was also observed in patients with non-squamous histology, although there was no statistically significant difference.¹⁴ In the TROPION-Lung05 and TROPION-PanTumor01 studies, Dato-DXd demonstrated activity in patients with actionable genomic alterations, including EGFR.^15,16 A pooled analysis of patients with EGFR-mutated NSCLC from TROPION-Lung01 and TROPION-Lung05 trials also demonstrated a confirmed objective response rate (ORR) for Dato-DXd by blinded independent central review (BICR) of 43%.¹⁷ Based on data from the TROPION-Lung05 trial and supported by data from TROPION-Lung01, Dato-DXd was recently approved for the treatment of patients with locally advanced or metastatic EGFR-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy.¹⁸ Dato-DXd is also approved for the treatment of patients with unresectable or metastatic hormone receptor-positive, human EGFR 2-negative breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease, based on data from the phase III TROPION-Breast01 study.¹⁸

Preclinical evidence has shown that osimertinib given in combination with Dato-DXd has enhanced efficacy compared with each agent given as monotherapy; osimertinib treatment was also shown to upregulate TROP2 expression both at the mRNA and protein level.¹⁹ Furthermore, results from the phase II ORCHARD study demonstrated promising efficacy for osimertinib plus Dato-DXd in patients with EGFR-mutated advanced or metastatic NSCLC who had progressed on 1L osimertinib. For those receiving osimertinib (80 mg) with Dato-DXd (6 mg/kg) median PFS (95% confidence interval (CI)) was 11.7 (8.3–not calculable) months and ORR (80% CI) was 36 (25%–49)%.²⁰ As monotherapy, Dato-DXd has demonstrated a manageable safety profile with the most common treatment-related AEs being nausea, stomatitis, and alopecia.^14–16 In combination studies, the safety profile of Dato-DXd was consistent with that reported for monotherapy and no new safety findings were observed.^20–22 Nevertheless, as the TROPION-Lung14 study will assess the combination of osimertinib and Dato-DXd as 1L therapy, and as there is a potential for overlapping toxicity between osimertinib and Dato-DXd, a safety run-in period is being included in the study. The safety and tolerability data from this limited number of patients during the run-in period will be reviewed by a Safety Review committee who will recommend whether the data support the initiation of the randomized period of the study. Furthermore, combined toxicity management guidelines have been developed for osimertinib and Dato-DXd, with interstitial lung disease (ILD)/pneumonitis identified as one of the overlapping toxicities for this combination; these guidelines will be regularly reviewed throughout the course of the study.

Here we describe the design of TROPION-Lung14, which is assessing the efficacy and safety of osimertinib in combination with Dato-DXd versus osimertinib alone in patients with previously untreated and unresectable EGFR-mutated NSCLC.

Methods

Study design

TROPION-Lung14 (NCT06350097) is an ongoing, phase III, two-arm, parallel, randomized multicenter study (Figure 1) investigating the efficacy and safety of osimertinib in combination with Dato-DXd compared with osimertinib alone in patients with locally advanced or metastatic EGFR-mutated NSCLC, who have not received any prior anticancer therapy for advanced disease. Patients will be enrolled from approximately 170 sites in 18 countries across the Americas, Europe, Middle East, and Asia-Pacific regions. Prior to randomization, a single-arm safety run-in period will evaluate safety and tolerability of osimertinib (80 mg orally once daily (QD)) in combination with Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) in approximately 20 patients. During the safety run-in period, safety and tolerability data will be reviewed by a Safety Review Committee (SRC), which will convene when safety data are available from at least 16 patients who have either received ⩾3 cycles of study treatment (osimertinib or Dato-DXd) or who have discontinued study treatment (either osimertinib or Dato-DXd) due to unacceptable toxicity. Following completion of their review, the SRC will make a recommendation based on the safety data and the trial will continue with the randomized study period. Patients included in the safety run-in period will not be eligible for inclusion in the randomized study period but may continue their allocated treatment, according to the study protocol.

Figure 1.

TROPION-Lung14 study design. Treatment will continue until RECIST v1.1-defined progression by investigator, unacceptable toxicity, or another discontinuation criterion is met. Following discontinuation, the choice of subsequent therapy will be at the discretion of the investigator. Patients will be followed for second progression on a subsequent treatment, defined according to local practice, and for OS.

In the randomized study, approximately 562 patients will be enrolled and randomized 1:1 to either osimertinib (80 mg orally QD) in combination with Dato-DXd (6 mg/kg IV Q3W) or osimertinib (80 mg orally QD) monotherapy. Recruitment of patients from Asian populations is expected to be approximately 70% of the total randomized patients. Randomization will be stratified by EGFR mutation type (Ex19del vs L858R), World Health Organization performance status (WHO PS) score (0 vs 1), and CNS metastasis status (Yes vs No). Treatment will continue until radiologic progression by Investigator assessment per Resist Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), unacceptable toxicity, or another discontinuation criterion is met. Dose modifications of study medications are permitted to manage treatment-related toxicities. Osimertinib monotherapy may continue for as long as a patient continues to derive clinical benefit after RECIST v1.1 progression, in the absence of any discontinuation criteria, and at the discretion of the study investigator.

The trial is being conducted in accordance with the Declaration of Helsinki, International Council for Harmonization Good Clinical Practice Guidelines, and all applicable legal and regulatory requirements. Written, informed consent will be provided by patients, and the study protocol will be approved by the independent ethics committees or institutional review boards at each site. The reporting of this study conforms to the SPIRIT 2025 statement (Supplemental Table 1).²³

Eligibility criteria

Key inclusion and exclusion criteria are presented in Tables 1 and 2, respectively. Eligible patients must be aged ⩾18 years (patients from Japan must be aged ⩾20 years), with histologically or cytologically confirmed non-squamous or mixed, locally advanced or metastatic NSCLC (based on the American Joint Committee on Cancer 8th Edition),²⁴ documented EGFR-TKI-sensitive mutations (at least one Ex19del or L858R, either alone or in combination with other EGFR mutations, which may include T790M), ⩾1 measurable lesion per RECIST v1.1, WHO PS of 0 or 1, and not amenable for surgical resection or definitive chemoradiation. Prior treatment with an EGFR-TKI other than osimertinib is not allowed, nor is receipt of any other systemic therapy for advanced or metastatic NSCLC. Prior adjuvant and/or neo-adjuvant therapies are permitted if treatment was received at least 12 months prior to the development of recurrent disease. For patients enrolled in the randomization period, it is mandatory to provide an unstained, archival tumor tissue sample to allow for central confirmation of the EGFR mutation status, and a baseline plasma sample for retrospective plasma EGFR testing. Patients with stable brain metastases after completion of definitive therapy, who are not on steroids, and have a stable neurological status for ⩾2 weeks after completion of definitive therapy and steroids can be enrolled. Patients with unstable spinal cord compression and/or brain metastases are ineligible. Patients with asymptomatic untreated brain metastases can be eligible for inclusion if, in the opinion of the investigator, immediate definitive treatment is not indicated.

Table 1.

TROPION-Lung14: key inclusion criteria.

Inclusion criteria
• Age ⩾18 years (⩾20 years in Japan) at the time of signing the informed consent form • Histologically or cytologically confirmed non-squamous NSCLC; mixed histology is also allowed • Locally advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC or recurrent NSCLC (based on the American Joint Committee on Cancer 8th Edition) not amenable to curative surgery or definitive chemoradiation at the time of randomization • ⩾1 documented EGFR-TKI sensitive mutation (Ex19del or L858R), either alone or in combination with other EGFR mutations, which may include T790M • Have not received prior EGFR TKIs or other systemic therapy for locally advanced or metastatic NSCLC. Prior adjuvant and/or neo-adjuvant therapies (target therapy, chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with or without regimens including target therapy, biologic therapy, investigational agents, are permitted as long as treatment was completed at least 12 months prior to the development of recurrent disease • For patients enrolled in the randomization period, mandatory provision of an unstained, archival tumor tissue sample for central confirmation of the EGFR mutation status, and a baseline plasma sample for retrospective plasma EGFR testing • WHO PS of 0 or 1 • Life expectancy >12 weeks at screening • ⩾1 measurable lesion per RECIST v1.1 not previously irradiated • Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention

Inclusion criteria

• Age ⩾18 years (⩾20 years in Japan) at the time of signing the informed consent form
• Histologically or cytologically confirmed non-squamous NSCLC; mixed histology is also allowed
• Locally advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC or recurrent NSCLC (based on the American Joint Committee on Cancer 8th Edition) not amenable to curative surgery or definitive chemoradiation at the time of randomization
• ⩾1 documented EGFR-TKI sensitive mutation (Ex19del or L858R), either alone or in combination with other EGFR mutations, which may include T790M
• Have not received prior EGFR TKIs or other systemic therapy for locally advanced or metastatic NSCLC. Prior adjuvant and/or neo-adjuvant therapies (target therapy, chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with or without regimens including target therapy, biologic therapy, investigational agents, are permitted as long as treatment was completed at least 12 months prior to the development of recurrent disease
• For patients enrolled in the randomization period, mandatory provision of an unstained, archival tumor tissue sample for central confirmation of the EGFR mutation status, and a baseline plasma sample for retrospective plasma EGFR testing
• WHO PS of 0 or 1
• Life expectancy >12 weeks at screening
• ⩾1 measurable lesion per RECIST v1.1 not previously irradiated
• Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention

EGFR, epidermal growth factor receptor; Ex19del, exon 19 deletion; NSCLC, non-small cell lung cancer; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; TKI, tyrosine kinase inhibitor; WHO PS, World Health Organization performance status.

Table 2.

TROPION-Lung14: key exclusion criteria.

Exclusion criteria
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study medication, and of low potential risk for recurrence • Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved to grade ⩽1 or baseline • Unstable spinal cord compression and/or brain metastases; patients with stable spinal cord compression and/or brain metastases after completion of local therapy and stable neurological status for at least 2 weeks after completion of the local therapy can be enrolled. Participants with asymptomatic untreated brain metastases are eligible for inclusion if, in the opinion of the investigator, immediate definitive treatment is not indicated • Significant third-space fluid retention (e.g., ascites or pleural effusion) not amenable for required repeated drainage • Clinically significant corneal disease • Any evidence of severe or uncontrolled diseases, including, but not limited to, active bleeding diseases, active infection, active ILD/pneumonitis, or cardiac disease • Active or uncontrolled HBV/HCV infection, uncontrolled HIV, uncontrolled infection requiring intravenous antimicrobials, suspected infection, an inability to rule out infection, active tuberculosis, or suspected ILD/pneumonitis that cannot be ruled out by imaging • History of ILD/pneumonitis, including drug-induced ILD or radiation pneumonitis requiring steroids, or current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging • Severe pulmonary function compromise resulting from intercurrent pulmonary illnesses • Resting ECG with clinically abnormal findings • Receipt of prior adjuvant and/or neo-adjuvant therapies within 12 months prior to the development of recurrent disease • Prior exposure to any agent including an ADC containing a chemotherapeutic agent targeting topoisomerase I, TROP2-targeted therapy • Previous treatment allocation (safety run-in period) or randomization (randomization period) in the present study

Exclusion criteria

• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study medication, and of low potential risk for recurrence
• Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved to grade ⩽1 or baseline
• Unstable spinal cord compression and/or brain metastases; patients with stable spinal cord compression and/or brain metastases after completion of local therapy and stable neurological status for at least 2 weeks after completion of the local therapy can be enrolled. Participants with asymptomatic untreated brain metastases are eligible for inclusion if, in the opinion of the investigator, immediate definitive treatment is not indicated
• Significant third-space fluid retention (e.g., ascites or pleural effusion) not amenable for required repeated drainage
• Clinically significant corneal disease
• Any evidence of severe or uncontrolled diseases, including, but not limited to, active bleeding diseases, active infection, active ILD/pneumonitis, or cardiac disease
• Active or uncontrolled HBV/HCV infection, uncontrolled HIV, uncontrolled infection requiring intravenous antimicrobials, suspected infection, an inability to rule out infection, active tuberculosis, or suspected ILD/pneumonitis that cannot be ruled out by imaging
• History of ILD/pneumonitis, including drug-induced ILD or radiation pneumonitis requiring steroids, or current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging
• Severe pulmonary function compromise resulting from intercurrent pulmonary illnesses
• Resting ECG with clinically abnormal findings
• Receipt of prior adjuvant and/or neo-adjuvant therapies within 12 months prior to the development of recurrent disease
• Prior exposure to any agent including an ADC containing a chemotherapeutic agent targeting topoisomerase I, TROP2-targeted therapy
• Previous treatment allocation (safety run-in period) or randomization (randomization period) in the present study

ADC, antibody–drug conjugate; ECG, electrocardiogram; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ILD, interstitial lung disease; TROP2, trophoblast cell surface antigen 2.

Endpoints

Endpoints for the study are presented in Table 3. The primary endpoint is PFS by BICR for osimertinib in combination with Dato-DXd versus osimertinib alone. PFS is defined as time from randomization until progression per RECIST v1.1 as assessed by BICR, or death due to any cause, regardless of whether the patient withdraws from study therapy, receives other anticancer therapy, or clinically progresses prior to BICR-confirmed RECIST v1.1 progression. Key secondary endpoints are OS, defined as the time from randomization until the date of death due to any cause, and CNS PFS per modified RECIST 1.1 assessed by CNS BICR, defined as the time from randomization to CNS BICR-confirmed progression in CNS or death due to any cause (in absence of CNS progression), regardless of whether the patient withdraws from study therapy or received other anticancer therapy. Other secondary endpoints include: PFS by investigator, defined as time from randomization until progression per RECIST v1.1 as assessed by investigator; ORR and duration of response per RECIST v1.1 by BICR; effectiveness of osimertinib in combination with Dato-DXd in the prevention of CNS metastases, by neuro-radiological assessment per CNS modified RECIST v1.1 to determine the presence/absence of CNS lesions at progression in patients without CNS metastases at baseline; and second PFS (PFS2), defined as the time from randomization to the earliest of a progression event (following initial investigator-assessed progression) after first subsequent therapy, or death. The pharmacokinetics of osimertinib in combination with Dato-DXd and the immunogenicity of Dato-DXd will be also investigated. Safety and tolerability parameters include AEs graded by Common Terminology Criteria for Adverse Events version 5.0, laboratory parameters, vital signs, physical examination, weight, left ventricular ejection fraction, electrocardiogram parameters, WHO PS, and ophthalmologic assessments.

Table 3.

Primary and secondary endpoints.

Endpoints	Osimertinib + Dato-DXd
Primary endpoint	PFS per RECIST v1.1 by BICR
Key secondary endpoints	OS CNS PFS per modified RECIST v1.1 by BICR PFS per RECIST v1.1 by investigator
Secondary efficacy endpoints	ORR and DoR per RECIST v1.1 by BICR and investigator Neuro-radiologist assessments according to CNS RECIST v1.1 PFS2 PFS by investigator by plasma EGFR mutation status Pharmacokinetics of Dato-DXd Immunogenicity of Dato-DXd
Safety endpoints	AEs graded by CTCAE version 5.0

PFS is defined as time from randomization until progression per RECIST v1.1 as assessed by BICR, or death due to any cause, regardless of whether the patient withdraws from study therapy, receives other anticancer therapy, or clinically progresses. OS is defined as the time from randomization until the date of death due to any cause. CNS PFS is defined as time from randomization to BICR-confirmed progression in the CNS or death due to any cause (in the absence of CNS progression), regardless of whether the patient withdraws from study therapy or receives other anticancer therapy. PFS is defined as time from randomization until progression per RECIST v1.1 as assessed by the investigator, or death due to any cause, regardless of whether the patient withdraws from study therapy, receives other anticancer therapy, or clinically progresses. ORR is defined as the proportion of patients with a confirmed CR or PR, as determined by BICR per RECIST v1.1. DoR is defined as the time from the date of first documented response until the date of documented progression per RECIST v1.1, as assessed by BICR (and investigator) or death due to any cause. PFS2 is defined as the time from randomization to the earliest instance of a progression event (following initial investigator-assessed progression) after the first subsequent therapy, or death.

AEs, adverse events; BICR, blinded independent central review; CNS, central nervous system; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; Dato-DXd, datopotamab deruxtecan; DoR, duration of response; EGFR, epidermal growth factor receptor; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PFS2, second PFS; PR, partial response; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.

Study procedures and assessments

Tumor assessments per RECIST v1.1 will be undertaken at Week 7, Week 13, and every 12 weeks thereafter until radiologic progression by investigator assessment using computed tomography (CT, preferred), or MRI scans. Screening/baseline imaging should be performed as close as possible to, and prior to, the first dose of study intervention and no more than 28 days before randomization. All patients will undergo a brain scan MRI (preferred) or brain CT with contrast at baseline and at the time of radiologic progression (using the same modality) for evaluation of CNS PFS per RECIST v1.1. If brain metastases are not detected at baseline, a brain MRI will be performed every 24 weeks from randomization until disease progression per RECIST v1.1.

AEs will be recorded from screening until the end of the safety follow-up period following discontinuation of all study interventions, except for ILD/pneumonitis or any serious AEs, which will be recorded beyond the safety follow-up period, regardless of severity. Collected information will include WHO PS, vital signs, body weight, and physical examinations; laboratory assessments, ophthalmologic assessments, and cardiac testing will also be performed. If new or worsening pulmonary symptoms or radiological abnormality suggestive of ILD or pneumonitis is observed, an interruption to osimertinib is recommended, Dato-DXd will be delayed, and a full investigation will be required.

A daily oral care plan for stomatitis prophylaxis will be given to all patients; a steroid-containing mouthwash (dexamethasone, or an alternative per local guidelines) is highly recommended for patients randomized to treatment including Dato-DXd, and prophylactic cryotherapy (e.g., ice chips or ice water held in the mouth) should be considered during Dato-DXd infusion.

Statistical methods

The full analysis set population, comprising all patients randomized to study intervention, will be used for all efficacy analyses. The safety analysis set will comprise all randomized patients who received any amount of any study treatment, regardless of treatment group assignment.

PFS will be based on the BICR assessment of disease progression by RECIST v1.1 and will be analyzed using a log-rank test stratified by EGFR mutation type (Ex19del or L858R), WHO PS (0 vs 1), and CNS metastasis status as assessed by the investigator at baseline (Yes or No). A stratified Cox proportional hazard model will be used to estimate the HR, associated CIs, and p value. Kaplan–Meier estimates of PFS will be presented graphically by treatment group. Safety and other data will be summarized descriptively.

The study is powered to demonstrate the superiority of Dato-DXd in combination with osimertinib versus osimertinib in terms of PFS per RECIST v1.1 by BICR in the full analysis set. To preserve the overall type 1 error a multiple testing procedure will be implemented for the primary and key secondary endpoints.

Discussion

Osimertinib is a third-generation, irreversible, CNS-active, EGFR-TKI that is SoC in the EGFR-mutated advanced or metastatic NSCLC setting; however, treatment resistance is common. Dato-DXd has demonstrated efficacy in patients with EGFR-mutated NSCLC, as a monotherapy and in combination with osimertinib in patients who had previously progressed on 1L osimertinib.^14–16,20 The promising efficacy demonstrated by osimertinib in combination with Dato-DXd in the phase II ORCHARD study provides rationale for evaluating the combination of osimertinib with Dato-DXd in TROPION-Lung14 and TROPION-Lung15.²⁰ TROPION-Lung14 is a phase III trial assessing the efficacy and safety of 1L osimertinib in combination with Dato-DXd versus osimertinib alone in patients with EGFR-mutated advanced or metastatic NSCLC. Osimertinib in combination with Dato-DXd is also being investigated in the phase III TROPION-Lung15 study (NCT06417814), versus platinum doublet chemotherapy in patients with EGFR-mutated locally advanced or metastatic NSCLC who experienced disease progression on prior osimertinib.²⁵ In summary, TROPION-Lung14 aims to build upon previous studies assessing Dato-DXd as a monotherapy and those assessing Dato-DXd in combination with other agents and may provide a new treatment option for patients with EGFR-mutated NSCLC in the 1L setting.

Supplemental Material

sj-docx-1-tam-10.1177_17588359261430561 – Supplemental material for TROPION-Lung14 study protocol: a phase III study of osimertinib in combination with datopotamab deruxtecan versus osimertinib alone as first-line treatment for patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer

Supplemental material, sj-docx-1-tam-10.1177_17588359261430561 for TROPION-Lung14 study protocol: a phase III study of osimertinib in combination with datopotamab deruxtecan versus osimertinib alone as first-line treatment for patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer by Shun Lu, Mariano Provencio Pulla, Eldsamira Mascarenhas, Junko Tanizaki, Hye Ryun Kim, Yinglei Liu, Shengmei Feng, Biao Zhang, Laurence Toms, James Chih-Hsin Yang and Sarah B. Goldberg in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

The authors would like to thank Prof. Ying Cheng (who was unable to participate in publication activities when this article was prepared). Medical writing support, under the direction of the authors, was provided by Lydia Hallam, MPhil, of Ashfield MedComms (London, UK), an Inizio company, in accordance with Good Publication Practice (GPP) guidelines (), and funded by AstraZeneca. The details of this study protocol were previously presented at the American Society of Clinical Oncology Annual Meeting 2025 and the European Conference on Lung Cancer 2025.

Author’s note

Shengmei Feng: affiliation at the time of manuscript development.

Declarations

ORCID iDs

Shun Lu

Hye Ryun Kim

Supplemental material

Supplemental material for this article is available online.

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