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  Title	TROPION-Lung07: Phase III study of Dato-DXd + pembrolizumab ± platinum-based chemotherapy as 1L therapy for advanced non-small-cell lung cancer
  ID	4412411
  External ID	7257756945
  Author	Unknown
  Published Date	Oct. 29, 2024, 12:22 p.m.
  Summary	For patients with advanced/metastatic non-small-cell lung cancer (NSCLC) without actionable genomic alterations and low (<50%) PD-L1 expression, pembrolizumab plus pemetrexed and platinum chemotherapy
  Tags	None
  URL	https://www.tandfonline.com/doi/full/10.1080/14796694.2024.2409621
  Sentiment	Negative: 0.03036    Neutral: 0.85686    Positive: 0.11278
  Relevance	0.00426

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  Content ID	2629886
  Key	66148bd8-7cf2-42f7-9909-e22316865c00
  Content	For patients with advanced/metastatic non-small-cell lung cancer (NSCLC) without actionable genomic alterations and low (<50%) PD-L1 expression, pembrolizumab plus pemetrexed and platinum chemotherapy is a preferred first-line treatment. These patients have comparatively worse outcomes than those with higher PD-L1 expression, underscoring the need for new combination strategies. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, has demonstrated encouraging antitumor activity and safety in this patient population. We describe the rationale and design of TROPION-Lung07, a randomized, open-label Phase III study assessing Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and <50% PD-L1 expression. Primary study objectives are progression-free survival and overall survival. Clinical Trial Registration: NCT05555732 ClinicalTrials.gov Plain Language Summary Most patients discover they have non-small-cell lung cancer (NSCLC) after it has already spread beyond the lungs (metastasized) making it more challenging to treat. If patients with NSCLC also lack specific genetic changes, called “actionable genomic alterations”, or have low levels of a protein called PD-L1 (which cancer cells use to avoid attack from the immune system and continue to grow), current treatments may not fully help, or only help for a while. However, newer approaches are being investigated that may benefit these patients with fewer side effects than traditional chemotherapy. Datopotamab deruxtecan (Dato-DXd) is an investigational drug which combines an antibody with a chemotherapy agent to specifically target and kill cancer cells. The antibody in Dato-DXd attaches to a protein called TROP2, which is widely expressed in NSCLC tumors, and delivers chemotherapy directly into cancer cells to kill them. The TROPION-Lung07 study will assess the potential benefits and side effects of adding Dato-DXd to other drugs, including pembrolizumab (an immunotherapy which attaches to PD-1 on immune cells and triggers the death of cancer cells) and chemotherapy. Three treatment groups will be compared: pembrolizumab with chemotherapy; Dato-DXd with pembrolizumab; and Dato-DXd with pembrolizumab and chemotherapy. The study will help us to understand if adding Dato-DXd to other anticancer drugs allow patients to live longer without their disease getting worse. Article highlights Background NSCLC accounts for 80–85% of all new lung cancer diagnoses, with most patients diagnosed at an advanced or metastatic stage and thus having a poor prognosis. For patients with advanced/metastatic NSCLC without actionable genomic alterations and with low PD L1 expression (<50%), pembrolizumab combined with pemetrexed and cisplatin or carboplatin is a preferred first-line treatment option. Data suggest that outcomes with immunotherapy in patients with lower PD-L1 expression are comparatively worse than in those with higher PD-L1 expression, resulting in lower quality of life for these patients. Thus, new combination strategies, which have the potential to replace standard-of-care treatments without compromising safety or efficacy, are needed to improve outcomes. Datopotamab deruxtecan Dato-DXd is a novel TROP2-directed ADC that consists of a humanized anti-TROP2 immunoglobulin G1 monoclonal antibody covalently linked to a highly potent topo I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. In the ongoing TROPION-PanTumor01 study, Dato-DXd as monotherapy demonstrated promising antitumor activity and a manageable safety profile in heavily pretreated patients with NSCLC. In the Phase Ib TROPION-Lung02 combination study, Dato-DXd plus pembrolizumab with or without platinum-based chemotherapy also showed favorable tolerability and encouraging efficacy, regardless of PD-L1 expression, in patients with advanced/metastatic NSCLC. The TROPION-Lung04 Phase Ib study is evaluating the safety, tolerability and antitumor activity of Dato-DXd plus immunotherapy with or without carboplatin in patients with advanced/metastatic NSCLC. TROPION-Lung07 study TROPION-Lung07 is a global, multicenter, randomized, open-label Phase III study assessing the safety and efficacy of Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pemetrexed in combination with platinum-based chemotherapy in patients with no prior therapy for advanced/metastatic non-squamous NSCLC, without actionable genomic alterations and with low PD-L1 expression (TPS <50%). Patients will be randomized in a 1:1:1 ratio into the following treatment arms: Dato-DXd 6.0 mg/kg plus pembrolizumab 200 mg IV plus platinum-based chemotherapy, Dato-DXd 6.0 mg/kg plus pembrolizumab 200 mg IV, and pembrolizumab 200 mg IV plus pemetrexed 500 mg/m plus platinum-based chemotherapy. Objectives The primary objectives of this study are to compare the efficacy of Dato-DXd in combination with pembrolizumab with or without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy, as measured by PFS and OS. The key secondary objective is to evaluate the efficacy of treatment in each arm as measured by ORR by BICR. Other secondary objectives include PFS, duration of response, time to response, disease control rate and PFS2. PROs, including time to deterioration in cough, dyspnea, or chest pain and treatment-emergent adverse events will be evaluated, and other safety parameters and Dato-DXd immunogenicity will be assessed. Exploratory objectives include evaluation of biomarkers and pharmacogenetics and pharmacokinetic exposures for potential association with efficacy and safety, and exploring how changes in biomarkers may relate to exposure, AEs and clinical outcomes. Biomarkers of interest include the proportion of tumor cells expressing TROP2. Conclusion The TROPION-Lung07 study will assess the safety and efficacy of Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pemetrexed in combination with platinum-based chemotherapy as a first-line treatment option in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and with low PD-L1 expression (TPS <50%). The outcomes of this study will help establish whether the Dato-DXd doublet and/or triplet regimens may replace the platinum doublet and/or the platinum partner in combination with pembrolizumab therapy as first-line treatment for patients with advanced/metastatic NSCLC. 1. Introduction Non-small-cell lung cancer (NSCLC) accounts for 80–85% of all new lung cancer diagnoses, with most patients diagnosed at an advanced stage and thus having a poor prognosis [ ]. For most patients with NSCLC who do not have actionable genomic alterations, immunotherapy has significantly improved outcomes compared with standard chemotherapy, although long-term disease control remains a challenge [ ]. Pembrolizumab is an immune checkpoint inhibitor (ICI) that targets the PD-1 receptor, preventing its interaction with PD-L1 and PD-L2 ( ) [ ]. For patients with advanced/metastatic NSCLC with high PD-L1 expression (tumor proportion score [TPS] ≥50%), pembrolizumab monotherapy is the standard first-line treatment option [ ]. However, for patients with advanced/metastatic NSCLC with low PD-L1 expression (TPS <50%), a preferred first-line treatment consists of pembrolizumab combined with a platinum-doublet (pemetrexed plus cisplatin or carboplatin) [ ]. For these patients, outcomes have consistently been shown to be comparatively worse than those with high PD-L1 expression [ ]. Figure 1. Mechanism of action of Dato-DXd, pembrolizumab, pemetrexed and cisplatin/carboplatin on a tumor cell. (A) Dato-DXd binds to TROP2 on the tumor cell surface. (B) This binding internalizes Dato-DXd into the tumor cell and releases the cytotoxic payload which damages intracellular DNA and can directly kill the tumor cell via apoptosis; the payload can also be released into the tumor microenvironment and penetrate neighboring tumor cells. (C) Dato-DXd-induced damage results in the release of antigens and DAMPs from the tumor cell; tumor antigens are captured and presented by dendritic cells while DAMPs activate dendritic cells, subsequently activating T cells. Dato-DXd-induced DNA damage also results in increased MHC class I expression and PD-L1/2 expression (potentially inhibitory of T-cell stimulation) on the tumor cell. Increased MHC class I expression enhances CD8 T-cell stimulation. (D) The addition of pembrolizumab blocks interaction of PD-1 with PD-L1/2 which leads to enhanced T-cell proliferation and activation. (E) Pemetrexed synergizes with cisplatin/carboplatin, which damages DNA and inhibits DNA synthesis. (F) T cells recognize, infiltrate and kill tumor cells. ADC: Antibody-drug conjugate; Dato-DXd: Datopotamab deruxtecan; DNA: Deoxyribonucleic acid. In the Phase III KEYNOTE-189 trial, previously untreated patients with metastatic non-squamous NSCLC were randomized to either a pembrolizumab plus platinum-doublet group or a placebo plus platinum-doublet group, with subgroup analyses based on PD-L1 expression [ ]. Patients with PD-L1 TPS ≥50% experienced greater relative benefit compared with patients with TPS 1–49% and TPS <1% for 12-month overall survival (OS), progression-free survival (PFS) and objective response rate (ORR), with the greatest differences between treatment arms observed for patients with TPS ≥50% [ ]. This trend continued in the longer term, with 5-year OS rates of 29.6% observed in patients with TPS ≥50% treated with pembrolizumab plus pemetrexed and platinum chemotherapy compared with 19.8% and 9.6% in patients with TPS 1–49% and TPS <1%, respectively [ ]. Additionally, there are notable toxicities associated with platinum-based chemotherapy and pemetrexed (e.g., pancytopenia, nausea, vomiting, neuropathy and diarrhea) that exert a negative impact on patient quality of life [ ]. Thus, new combination strategies, which have the potential to replace standard chemotherapeutic agents without compromising safety and efficacy, are needed to improve outcomes. TROP2 is a transmembrane protein broadly expressed in multiple tumor types, including NSCLC [ ]. Notably, this receptor also represents a clinically validated target for antibody-drug conjugate (ADC)-based therapeutic approaches in other malignancies [ ]. ADCs are designed to overcome limitations of systemic chemotherapy by directly targeting tumor cells, potentially reducing toxicity while improving response rates [ ]. Datopotamab deruxtecan (Dato-DXd) is a novel TROP2-directed ADC that consists of a humanized anti-TROP2 immunoglobulin G1 monoclonal antibody covalently linked to a highly potent topoisomerase I (topo I) inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker [ ]. Once internalized by TROP2-expressing tumor cells, cleavage of the tetrapeptide-based linker releases the topo I inhibitor payload (DXd) into the cytoplasm causing tumor cell death, as well as an additional bystander antitumor effect within the tumor microenvironment ( ) [ ]. Here, we describe the design of the TROPION-Lung07 trial (NCT05555732; registered 22 September, 2022), a global, multicenter, randomized, open-label Phase III study assessing the safety and efficacy of Dato-DXd in combination with pembrolizumab with or without platinum-based chemotherapy versus pembrolizumab in combination with pemetrexed and platinum-based chemotherapy in patients with no prior therapy for advanced/metastatic NSCLC, without actionable genomic alterations, and with low PD-L1 expression (TPS <50%). The trial design has been summarized in Figure 2. TROPION-Lung07 study design. Protocol deviations that are deemed to pose significant safety risk by the investigator and/or sponsor may lead to permanent study drug discontinuation. Participants who discontinue study treatment without radiographic disease progression will continue to undergo tumor assessments every 6 weeks (±7 days) for the first four cycles from randomization, followed by every 9 weeks (±7 days) up to 2 years and then every 12 weeks (±7 days) thereafter, during follow-up until radiographic disease progression as determined by BICR review, death, loss to follow-up or withdrawal of consent. AUC: Area under the curve; BICR: Blinded independent central review; Dato-DXd: Datopotamab deruxtecan; ECOG PS: Eastern Cooperative Oncology Group Performance Status; NSCLC: Non-small-cell lung cancer; OS: Overall survival; PFS: Progression-free survival; q3w: Every 3 weeks; R: Randomization; ROW: Rest of world; TPS: Tumor proportion score. 2. Background & rationale Considerable evidence exists to suggest that antitumor immunity may be enhanced by DNA-damaging agents, including topo I inhibitors ( ) [ ]. Proposed mechanisms include direct killing by induction of apoptosis, as well as increased tumor cell expression of MHC class I and/or immunostimulatory damage-associated molecules that in turn can activate dendritic cells and infiltrating CD8 T cells to promote tumor killing [ ]. Preclinically, it has been shown that inhibition of topo I combined with anti-PD-L1 antibodies results in synergistic antitumor effects [ ]. Moreover, the specific combination of an anti-PD-1 antibody with a DXd-containing ADC elicited superior survival over each individual agent alone in a murine model [ ]. As monotherapy, Dato-DXd has shown robust clinical activity in patients with advanced/metastatic NSCLC. The pivotal TROPION-Lung01 study (NCT04656652) met its dual primary endpoint of PFS with a statistically significant improvement in favor of Dato-DXd over standard-of-care docetaxel [ ]. A major finding of the trial was that patients with non-squamous histology achieved the most meaningful clinical benefit [ ]. With respect to combination studies, TROPION-Lung02 (NCT04526691) is a Phase Ib trial evaluating Dato-DXd plus pembrolizumab with or without platinum-based chemotherapy in patients with advanced/metastatic NSCLC [ ]. To date, that study has also revealed encouraging efficacy outcomes alongside a manageable safety profile [ ]. For example, the ORR with Dato-DXd plus pembrolizumab with platinum-based chemotherapy was 55% (95% confidence interval [CI], 39–70%) [ ]. Notably, antitumor activity was observed regardless of PD-L1 expression level [ ]. Another ongoing Phase Ib study, TROPION-Lung04 (NCT04612751), is evaluating the safety, tolerability and antitumor activity of Dato-DXd plus immunotherapy with or without carboplatin in patients with advanced/metastatic NSCLC [ ]. Taken together, these findings provide a rationale for assessing the safety and efficacy of combination therapy with Dato-DXd plus pembrolizumab with or without platinum-based chemotherapy in patients with advanced/metastatic NSCLC and low PD-L1 expression (TPS <50%). 2.1. Study design TROPION-Lung07 is a global, randomized, open-label Phase III study enrolling patients at approximately 250 study sites across North America, South America, Europe, East Asia and Oceania/Australia. Approximately 1170 eligible patients with advanced/metastatic non-squamous NSCLC, without actionable genomic alterations and with PD-L1 TPS <50% will be randomized in a 1:1:1 ratio (390 patients per arm) into the following treatment arms: Arm A – Dato-DXd 6 mg/kg intravenous (IV) plus pembrolizumab 200 mg IV plus platinum-based chemotherapy (four cycles of cisplatin 75 mg/m IV or carboplatin area under the curve [AUC] 5 mg/ml/min IV) every 3 weeks; Arm B – Dato-DXd 6 mg/kg IV plus pembrolizumab 200 mg IV every 3 weeks; and Arm C – pembrolizumab 200 mg IV plus pemetrexed 500 mg/m IV plus platinum-based chemotherapy (four cycles of cisplatin 75 mg/m IV or carboplatin AUC 5 mg/ml/min IV) every 3 weeks. Randomization will be managed through a central interactive response technology system which will assign a unique randomization number and treatment arm for each eligible participant. Randomization is stratified by PD-L1 expression (TPS <1% vs 1–49%), geographical region (East Asia vs rest of the world), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 vs 1) and intended platinum-based chemotherapy by investigator's choice (cisplatin vs carboplatin). No crossover between study treatment arms will be allowed. Patients experiencing clinical benefit will continue to receive study treatment until confirmed radiographic disease progression, clinical progression, death, unacceptable toxicity, withdrawal of consent, or physician decision. Discontinuation from study treatment may also result from protocol deviations that pose a patient-safety risk, pregnancy, loss to follow-up, or study termination. Patients who discontinue treatment for reasons other than blinded independent central review (BICR)-confirmed progressive disease (PD) will continue to undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans with contrast every 6 weeks (±7 days) for the first four cycles, followed by every 9 weeks (±7 days) for up to 2 years, then every 12 weeks (±7 days) thereafter. This monitoring will take place from randomization until radiographic disease progression as assessed by both the investigator and BICR, loss to follow-up, withdrawal of consent, or death. For patients enrolled in the Dato-DXd and pembrolizumab-combination arms (Arms A or B), if one study drug is interrupted or discontinued due to toxicity, the other combination drug(s) may be continued provided the safety profile remains acceptable. The overall end of study is defined as either: the time when all patients have discontinued or died; sponsor discontinuation of the trial; or an alternative study is available for patients continuing to derive treatment benefit from Dato-DXd and/or pembrolizumab with or without platinum-based chemotherapy. 2.2. Key eligibility criteria 2.2.1. Inclusion criteria Patients must be aged ≥18 years or minimum legal adult age at the time of providing informed consent for enrollment. Patients must have histologically confirmed non-squamous NSCLC with low PD-L1 expression (TPS <50%) that is either stage IV or stage IIIB or IIIC and not a candidate for surgical resection or definitive chemoradiation. PD-L1 expression will be determined by a central laboratory using the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay (Agilent Technologies, Inc.). Patients whose tumors harbor KRAS mutations are eligible for the study; however, negative test results are required for EGFR ALK and ROS1 . Patients with known actionable genomic alterations in NTRK BRAF RET MET , or other driver kinases with locally approved therapies will also be excluded. Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), an ECOG PS of 0 or 1, adequate bone marrow function and be willing to provide tumor tissue for assessment of TROP2 protein expression and exploratory biomarker analyses. An adequate treatment washout period before cycle 1 day 1 (defined as ≥3 weeks following major surgery and ≥4 weeks following any radiation therapy) is also required ( Table 1. Key inclusion and exclusion criteria 2.2.2. Exclusion criteria Patients with previous systemic treatment for advanced/metastatic NSCLC are ineligible for the study. In addition, those who received prior treatment (including in the adjuvant/neoadjuvant setting) with any of the following may not participate: any agent (including an ADC) containing a chemotherapeutic agent that targets topo I; any TROP2-directed therapy; any anti-PD-1, anti-PD-L1/L2 or agent directed against a stimulatory or co-inhibitory T-cell receptor; any other ICIs; or prior radiotherapy <4 weeks before the start of study intervention or a dose of >30 Gy to the lung within 6 months of cycle 1 day 1. Enrollment may be considered for patients who had previously received neoadjuvant/adjuvant therapy other than those listed above, if completed ≥6 months prior to the diagnosis of advanced/metastatic disease. Ineligibility also extends to any of the following conditions: current or suspected interstitial lung disease (ILD)/pneumonitis that cannot be ruled out by imaging at screening or a history of noninfectious ILD/pneumonitis that requires steroids; significant pulmonary compromise due to ongoing pulmonary illness; uncontrolled or significant cardiovascular disease (including a <6 month history of myocardial infarction); clinically significant corneal disease; active, known, or suspected autoimmune disease; diagnosis of immunodeficiency or ongoing use of chronic systemic steroids or other immunosuppressive treatments; or a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients of Dato-DXd, pembrolizumab, carboplatin, cisplatin or pemetrexed ( 2.3. Dosing & schedule of therapy Patients randomized to Arm A will receive Dato-DXd 6 mg/kg IV plus pembrolizumab 200 mg IV on day 1 of each 21-day cycle with either cisplatin 75 mg/m or carboplatin AUC 5 mg/ml/min (maximum of four cycles) until disease progression or unacceptable toxicity. Patients randomized to Arm B will receive Dato-DXd 6 mg/kg IV plus pembrolizumab 200 mg IV on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients randomized to Arm C will receive pembrolizumab 200 mg IV plus pemetrexed 500 mg/m IV on day 1 of each 21-day cycle with either cisplatin 75 mg/m or carboplatin AUC 5 mg/ml/min (maximum of four cycles) until disease progression or unacceptable toxicity ( ). Pembrolizumab is being provided by Merck Sharp & Dohme LLC (a subsidiary of Merck & Co., Inc., NJ, USA) and will be administered for a maximum of 35 cycles. There is no prespecified limit for treatment duration for Dato-DXd and pemetrexed. Premedication is required prior to any dose of pemetrexed in Arm C (folic acid 350–1000 μg, vitamin B12 1000 μg, and dexamethasone 4 mg) or Dato-DXd in Arms A and B (antihistamines and acetaminophen, with or without glucocorticoids). 2.4. Objectives The objective of TROPION-Lung07 is to compare the Dato-DXd–pembrolizumab combination with or without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy. The primary endpoints are PFS (per BICR according to RECIST v1.1) and OS. Study endpoints are listed in . The study is considered positive if either primary endpoint is statistically significant. Table 2. TROPION-Lung07 study endpoints Treatment efficacy in each arm measured by ORR (per BICR according to RECIST v1.1) is a key secondary objective. Other secondary objectives include investigator-assessed PFS and ORR as well as duration of response, time to response and disease control rate (both investigator- and BICR-assessed). PFS2 (defined as time to progression after the next line of anticancer therapy or death) will be assessed by local clinical practice. Patient-reported outcomes (PROs), safety parameters including treatment-emergent adverse events and Dato-DXd immunogenicity will also be assessed. Evaluation of biomarkers (including TROP2 expression), associations between efficacy and safety outcomes with pharmacokinetic exposure and pharmacogenetics are exploratory objectives. 2.5. Evaluations Baseline tumor assessment must be performed within 28 days prior to randomization. Tumor assessments will be performed at screening, every 6 weeks from randomization through the first four cycles (weeks 6 and 12) followed by every 9 weeks for up to 2 years. Assessments will continue, regardless of study treatment discontinuation or initiation of new anticancer therapy, every 12 weeks thereafter until investigator-assessed radiological disease progression (per BICR), loss to follow-up, consent withdrawal, or death. All patients should be followed up for survival at least every 3 months (±14 days) after follow-up completion until the end of the study. All patients will undergo a brain CT or MRI scan (MRI with contrast is preferred) at baseline screening. Patients with brain metastases at baseline should have brain MRI or CT scans performed every 6 weeks (±7 days) for the first four cycles followed by every 9 weeks (±7 days) for up to 2 years, and then every 12 weeks (±7 days) thereafter, commencing from randomization. Patients without brain metastases do not need additional brain scans for tumor assessment unless clinically indicated. Baseline whole body bone imaging using F-fluorodeoxyglucose-positron emission tomography/CT or MRI scan is required. If progressive disease in the bone is suspected (or confirmation of a complete response in patients with bone metastases) follow-up bone imaging is required. Adverse events (AEs) will be coded by the Medical Dictionary for Regulatory Activities (MedDRA) and both AEs and laboratory results will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0. All serious adverse events (SAEs) occurring after the patient signs the main informed consent form and up to 90 (±7) days after the last dose of study drug or 30 (±7) days following cessation of study treatment if the patient initiates new anticancer therapy, whichever is earlier, will be recorded. All non-serious AEs occurring after the patient has taken the first dose of study drug until 37 days after the last dose of study drug will be recorded. Oral mucositis/stomatitis, ocular surface events, ILD/pneumonitis and mucosal inflammation other than oral mucositis/stomatitis are all considered adverse events of special interest (AESIs) for Dato-DXd. AESIs with pembrolizumab include an overdose of pembrolizumab that is not associated with clinical symptoms or abnormal laboratory results, and elevated aspartate aminotransferase/alanine aminotransferase ≥3 × upper limit of normal (ULN) and elevated total bilirubin ≥2 × ULN and, alkaline phosphatase <2 × ULN. The following PROs were selected and will be evaluated for this study in the following order: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 Version 3; NSCLC-Symptom Assessment Questionnaire; EORTC Lung Cancer Module; Patient Global Impression of Change in Symptoms; Patient Global Impression of Change in Condition; Patient Global Impression of Treatment Tolerability; and EuroQoL Questionnaire-5 dimensions-5 levels [ ]. 2.6. Statistical analysis The full analysis set includes all intention-to-treat randomized patients. Planned trial enrollment is approximately 1170 participants. For the primary analysis of PFS, 468 PFS events by BICR are needed to achieve an approximately 97% power to detect a hazard ratio (HR) of 0.65 at a two-sided α = 0.005. For the primary analysis of OS, approximately 544 deaths are required to have approximately 93% power to detect a HR of 0.72 at a two-sided α = 0.019995. If PFS is positive and both PFS and OS from other arms are also positive, OS will be tested under two-sided α of 0.04999. Approximately 544 deaths will provide approximately 97% power to detect an HR of 0.72 at two-sided α = 0.04999. The primary efficacy analyses of PFS and OS will be analyzed using a log-rank test adjusted for stratification factors. A stratified Cox regression model will be used to estimate the HRs and the corresponding 95% CIs of PFS and OS between the treatment arms and the control arm. Kaplan-Meier plots will be used to graphically present PFS and OS across the treatment groups. The safety analysis set will include all patients who have received at least one dose of the study drug. Descriptive statistics will examine AEs by type, incidence, severity, seriousness and relationship to study treatments. Vital signs, clinical laboratory results and pharmacokinetic and biomarker analysis results will also be evaluated. 2.7. Ethics & dissemination This study will be conducted in compliance with the Declaration of Helsinki, the International Council for Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and all other applicable regulatory requirement(s). Informed consent is provided via a signed form. The study protocol, informed consent forms and other documents/procedures will be submitted to the independent institutional review board/ethics committee for ethical review and approval according to local regulations, prior to the study start. 3. Conclusion TROPION-Lung07 (NCT05555732) is designed to assess the safety and efficacy of the Dato-DXd plus pembrolizumab combination with or without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy as first-line therapy for patients with advanced/metastatic non-squamous NSCLC with PD-L1 expression <50% and without actionable genomic alterations. Together with the findings from other ongoing studies in patients with advanced/metastatic NSCLC (TROPION-Lung08, NCT05215340; AVANZAR, NCT05687266), the outcomes of this study will provide insight into the role of Dato-DXd combination therapies for patients with advanced/metastatic NSCLC regardless of PD-L1 expression. Author contributions All authors made substantial contributions to the design and/or conduct of the TROPION-Lung07 clinical study. All authors provided intellectual input in the drafting of this publication, critically revised the publication and approved the final version for submission. All authors agreed to be accountable for all aspects of this publication. Financial disclosure This study is sponsored by Daiichi Sankyo, Inc. In July 2020, Daiichi Sankyo entered into a global development and commercialization collaboration agreement with AstraZeneca for datopotamab deruxtecan (Dato-DXd). Pembrolizumab is being provided under agreement by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Daiichi Sankyo, Inc., 211 Mt. Airy Road, Basking Ridge, New Jersey 07920, USA. +1 908 992 6400. CTRinfo@dsi.com. Writing disclosure Medical writing support, including assisting authors with development of the outline and initial draft and incorporation of comments, was provided by Nathan Andrade and editorial support was provided by Jess Fawcett, both of Core (a division of Prime, London, UK), supported by Daiichi Sankyo, Inc. according to Good Publication Practice guidelines ( Link Ethical conduct of research This study will be conducted in compliance with the Declaration of Helsinki, the International Council for Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95) and all other applicable regulatory requirement(s). Informed consent is provided via a signed form. The study protocol, informed consent forms and other documents/procedures will be submitted to the independent institutional review board/ethics committee for ethical review and approval according to local regulations, prior to the study start. Acknowledgments The authors would like to thank the patients, their families and all investigators involved in this study. The authors acknowledge Sun Jin (Laura) Kim of Merck & Co., Inc., Rahway, NJ, USA, for her contributions during protocol development. Competing interests disclosure I Okamoto reports receiving grants from Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Astellas, Novartis and AbbVie; and personal fees from AstraZeneca, AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol Myers Squibb, Pfizer, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Novartis and Chugai Pharmaceutical. S Kuyama reports honoraria from Chugai Pharmaceutical Co. Ltd., Bristol Myers Squibb K.K., Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K., Pfizer Japan Inc., Eli Lilly Japan K.K., Merck Sharp & Dohme K.K., Taiho Pharmaceutical Co., Ltd., Sanofi K.K., Kyowa Kirin Co., Ltd., Hisamitsu Pharmaceutical Co., Inc., Daiichi Sankyo Co., Ltd., Nippon Kayaku Co., Ltd. and Novartis Pharma K.K. N Girard reports research grants/support from AbbVie, Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Hoffmann-La Roche, Janssen, LeoPharma, Lilly, Merk Serono, Merck Sharp & Dohme, Novartis, Sanofi and Sivan; consultative services for AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Ipsen, Hoffmann-La Roche, Janssen, LeoPharma, Lilly, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Pierre Fabre, Sanofi and Takeda; participation on a data safety monitoring board for Hoffmann-La Roche; and employment of a family member with AstraZeneca. S Lu reports research support from AstraZeneca, Hutchison, Bristol Myers Squibb, Heng Rui, Beigene, Hansoh and Boehringer Ingelheim; speaker fees from AstraZeneca, Roche, Hansoh and Hengrui Therapeutics; advisory/consultancy for AstraZeneca, Pfizer, Bristol Myers Squibb, Hutchison MediPharma, ZaiLab, Yuhan Corporation, Menarini, InventisBio Co. Ltd., Shanghai Fosun Pharmaceutical (Group) Co., Ltd. and Simcere Zaiming Pharmaceutical Co., Ltd.; and independent directorship of the board of Innovent Biologics Inc. F Franke reports consulting fees and/or honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Ipsen, Janssen, Merck Sharp & Dohme, Novartis, Pfizer and Roche. Z Li declares no competing interests. P Danchaivijitr reports participation in speaker's bureau for Merck Sharp & Dohme, Roche, AstraZeneca and Bristol Myers Squibb; and participation in advisory boards for Merck Sharp & Dohme, Roche, AstraZeneca and Bristol Myers Squibb. J-Y Han reports honoraria from AstraZeneca, Takeda, Novartis, Merck Sharp & Dohme, Janssen, Pfizer, Yuhan and Roche; and consulting/advisory roles with AbbVie, Takeda, Janssen, Lantern Pharma, Daiichi Sankyo Inc., AstraZeneca and Amgen. J-M Sun declares no competing interests. S Sugawara reports personal honoraria from Pfizer, Chugai, Merck Sharp & Dohme, AstraZeneca, Ono, Bristol Myers Squibb, Nippon Boehringer Ingelheim, Taiho, Eli Lilly, Novartis, Kyowa Kirin, Takeda, Nippon Kayaku, Merck Sharp & Dohme, Amgen, AbbVie, Otsuka, Thermo Fisher Scientific, Towa Pharmaceutical, Sysmex and Eisai; and institutional contracts with AstraZeneca, Chugai, Merck Sharp & Dohme, Daiichi Sankyo Inc., Bristol-Myers Squibb, AnHeart, Nippon Boehringer Ingelheim, Ono, AbbVie, Amgen, Taiho, Accerise, Parexel, EPS, PPD, A2 Healthcare and Syneos Health. E Pan, N Ren, A Chen and R Rajagopalan are employees of Daiichi Sankyo, Inc. AE Lisberg reports consulting, lectures, or advisory roles at Bayer, Daiichi Sankyo, Inc., AstraZeneca, Novocure, Eli Lilly, Oncocyte, Novartis, Regeneron, Janssen Oncology, MorphoSys, Sanofi group of companies, Molecular Axiom, Amgen, IQVIA, G1 Therapeutics, Bristol Myers Squibb, Leica Biosystems, Jazz Pharmaceuticals and Pfizer; and grant/research support from Daiichi Sankyo, Inc., Calithera, AstraZeneca, Dracen, WindMIL, Duality Biologics and Effector Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Data availability statement De-identified individual participant data and applicable supporting clinical trial documents may be available on request at Vivli-Center for Global Clinical Research Data. In cases where trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial patients. Details on data sharing criteria and the procedure for requesting access can be found online. Additional information Funding This study is sponsored by Daiichi Sankyo, Inc. References American Cancer Society [Internet]. Key statistics for lung cancer. [ cited 2023 September 4]. Available from: https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html (open in a new window) Shields MD, Marin-Acevedo JA, Pellini B. Immunotherapy for advanced non-small-cell lung cancer: a decade of progress. Am Soc Clin Oncol Educ Book. (open in a new window) :e105–e127. doi:10.1200/edbk_321483 Walsh RJ, Soo RA. Resistance to immune checkpoint inhibitors in non-small-cell lung cancer: biomarkers and therapeutic strategies. Ther Adv Med Oncol. (open in a new window) :1758835920937902. doi:10.1177/1758835920937902 Kian W, Roisman LC, Levitas D, et al. non-small-cell lung cancer PDL1 >50%-should we go single or combo? Precis Cancer Med. (open in a new window) :7. doi:10.21037/pcm.2019.11.08 European Medicines Agency [Internet]. Keytruda: EPAR – Product information. [ cited 2023 September 4]. Available from: https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-information_en.pdf (open in a new window) National Comprehensive Cancer Network [Internet]. NCCN Guidelines Version 3: non-small-cell Lung Cancer. [ cited 2023 September 1]. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450 (open in a new window) Vidula N, Yau C, Rugo H. Trophoblast Cell Surface Antigen 2 gene (TACSTD2) expression in primary breast cancer. Breast Cancer Res Treat. (open in a new window) (open in a new window) ):569–575. doi:10.1007/s10549-022-06660-x Ogitani Y, Hagihara K, Oitate M, et al. 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(open in a new window) Suppl. 2 (open in a new window) ):S1305–S1306. doi:10.1016/j.annonc.2023.10.061 Girard N, Okamoto I, Lisberg AE, et al. 59P – Datopotamab deruxtecan (Dato-DXd) in patients with previously treated advanced non-small-cell lung cancer (NSCLC): nonsquamous (NSQ) histology in the Phase III TROPION-Lung01 trial. Ann Oncol. (open in a new window) :1–53. doi:10.1016/esmoop/esmoop102569 Levy B, Paz-Ares L, Rixe O, et al. MA13.07 TROPION-Lung02: initial results for datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy in advanced NSCLC. J Thorac Oncol. (open in a new window) Suppl. 9 (open in a new window) ):S91. doi:10.1016/j.jtho.2022.07.152 Goto Y, Su W-C, Levy BP, et al. TROPION-Lung02: datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small-cell lung cancer (aNSCLC). J Clin Oncol. 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