Pembrolizumab monotherapy is a standard first-line treatment for PD-L1–high advanced non-small-cell lung cancer (NSCLC) without actionable genomic alterations (AGA). However, few patients experience long-term disease control, highlighting the need for more effective therapies. Datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2-directed antibody–drug conjugate, showed encouraging safety and antitumor activity with pembrolizumab in advanced NSCLC. We describe the rationale and design of TROPION-Lung08, a phase III study evaluating safety and efficacy of first-line Dato-DXd plus pembrolizumab versus pembrolizumab monotherapy in patients with advanced/metastatic NSCLC without AGAs and with PD-L1 tumor proportion score ≥50%. Primary end points are progression-free survival and overall survival; secondary end points include objective response rate, duration of response, safety and presence of antidrug antibodies.

Clinical trial registration: NCT05215340 (ClinicalTrials.gov)

Plain language summary

More than half of patients with non-small-cell lung cancer (NSCLC) are diagnosed when their tumor is advanced (unlikely to be cured with currently available treatments) or metastatic (spread to other parts of the body). These patients have poor survival outcomes. NSCLCs can grow by using a protein called PD-L1 to escape from the immune system. Pembrolizumab is an immunotherapy that targets PD-1, the protein on immune cells that detects PD-L1. Because of this, pembrolizumab prevents the tumor from escaping the immune system by blocking the interaction of PD-L1 with PD-1. Patients whose NSCLC tumors express PD-L1 often respond to pembrolizumab at first but, for most of these patients, their cancer eventually comes back. An investigational drug called datopotamab deruxtecan (Dato-DXd) is a type of therapy called an antibody–drug conjugate that delivers chemotherapy to tumors using an antibody. The antibody in Dato-DXd is directed against a protein called TROP2, which is commonly expressed by tumor cells. Results from early studies show that combining pembrolizumab with Dato-DXd may work well for patients with solid tumors, including NSCLC. This study will look at the benefits and side effects of Dato-DXd added to pembrolizumab compared with pembrolizumab alone as a first treatment option for patients with advanced NSCLC and high levels of PD-L1.

Tweetable abstract

TROPION-Lung08: a randomized phase III trial of datopotamab deruxtecan plus pembrolizumab versus pembrolizumab alone as first-line therapy for PD-L1–high advanced/metastatic NSCLC without actionable genomic alterations.

Keywords:

Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide, with an estimated 2.2 million new cases of lung cancer (11.4% of all new cases) and 1.8 million deaths (18.0% of all cancer deaths) globally in 2020 [1]. Non-small-cell lung cancer (NSCLC), which accounts for approximately 80–85% of lung cancers [2], is diagnosed at an advanced stage in >50% of patients and often confers a poor prognosis [3], with worsening outcomes observed after each line of subsequent therapy [4]. While first-line immunotherapy (with or without chemotherapy) has improved outcomes in patients without actionable genomic alterations, few patients experience long-term disease control [5–9].

Pembrolizumab is an anti-PD-1 antibody that blocks the interaction between the immune checkpoint PD-1 receptor and the PD-L1 ligand, thus suppressing a key mechanism that prevents the immune system from attacking many tumors [10,11]. Pembrolizumab is approved by the US FDA and the European Commission as monotherapy and in combination with other targeted agents and chemotherapies to treat a range of cancers [11–13]. Pembrolizumab monotherapy is a standard first-line treatment for patients with advanced NSCLC with a PD-L1 tumor proportion score (TPS) of ≥50% [14]. The estimated 5-year overall survival (OS) rates in patients with advanced NSCLC with a TPS of ≥50% treated with first-line pembrolizumab in the KEYNOTE-001, KEYNOTE-024, and KEYNOTE-042 studies were 29.6, 31.9, and 21.9%, respectively [5–7]. In a large, multicenter, real-world study (n = 974), median OS in patients with metastatic NSCLC with a TPS of ≥50% who were treated with pembrolizumab monotherapy was 15.8 months (95% CI: 13.5–17.5 months) [15]. More-effective first-line options, including combination approaches for advanced/metastatic NSCLC, will be needed to further improve outcomes.

TROP2 is a transmembrane glycoprotein that is widely expressed in NSCLC and is often associated with poor survival [16–19]. TROP2-directed therapies may have therapeutic potential in lung cancer; however, there are no TROP2-directed therapies currently approved for the treatment of NSCLC [20].

Datopotamab deruxtecan

Datopotamab deruxtecan (Dato-DXd) is a novel, investigational TROP2-directed antibody–drug conjugate (ADC) composed of a humanized anti-TROP2 immunoglobulin G1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload (an exatecan derivative) via a stable, tumor-selective, tetrapeptide-based cleavable linker (Figure 1A) [21–24]. Dato-DXd was designed to address the limitations of traditional chemotherapy by using a targeted approach to deliver a highly potent cytotoxic agent to the site of tumors while reducing systemic toxicity [21]. Dato-DXd is internalized by TROP2-expressing tumor cells, where lysosomal enzymes typically upregulated in tumor cells cleave the tetrapeptide-based linker [21–23,25] and release the topoisomerase I inhibitor payload (DXd) into the cytoplasm [22,25]. The released payload enters the cell nucleus, inhibits topoisomerase I, and damages the tumor cell's DNA. The DNA damage caused by the payload results in tumor cell death [21,22]. Furthermore, the payload has high cell membrane permeability, allowing for bystander killing once it is released from the tumor cell after death. This enables elimination of surrounding cells regardless of TROP2 expression [21,22,24]. The payload has a short systemic half-life, which may help reduce the risk of systemic toxicity [21,22].

Figure 1. **Mechanism of action of Dato-DXd alone and with pembrolizumab.**
**(A)** DXd-containing ADC induces direct (1) and bystander (2) killing of tumor cells. Adapted from [22]. Copyright © 2021, American Association for Cancer Research. **(B)** Dato-DXd-induced damage results in the release of antigens from the tumor cells that can be taken up by DCs (3) and the release of DAMPs to activate DCs, which subsequently activate T cells (4). Dato-DXd damage also results in increased expression of MHC class I molecules and PD-L1 on tumor cells (5). The increased MHC expression enhances CD8⁺ T-cell stimulation (6). The addition of pembrolizumab (7) blocks PD-L1/PD-1 interactions and thereby enhances T-cell proliferation and activation and promotes tumor infiltrating T cells (8). These processes come together to enhance T-cell killing of tumor cells (9).
ADC: Antibody–drug conjugate; DAMP: Damage-associated molecular pattern; Dato-DXd: Datopotamab deruxtecan; DC: Dendritic cell; DXd: Topoisomerase I inhibitor payload (an exatecan derivative); MHC: Major histocompatibility complex.

TROPION-Lung08 study

Here we describe the design of the TROPION-Lung08 trial (NCT05215340) [26], a phase III, randomized, open-label, two-arm study assessing the efficacy and safety of Dato-DXd plus pembrolizumab (combination therapy) or pembrolizumab alone (monotherapy) as first-line therapy in patients with advanced/metastatic NSCLC without actionable genomic alterations and with high PD-L1 expression (≥50%).

Background & rationale

Preclinical data suggest that DNA-damaging agents, including DXd ADCs, enhance antitumor immunity [27–30]. Mechanisms of enhanced antitumor immunity include induction of immunogenic cell death of tumor cells [27,31], which results in increased expression of immune-associated molecules on tumor cells, particularly major histocompatibility complex class I [28,29] and immunostimulatory damage-associated molecular pattern molecules [27,31], activation of dendritic cells [28,31], and increased tumor-infiltrating CD8⁺ T cells (Figure 1B) [28,29,31,32]. In addition, preclinical studies in mouse models have shown that the combination of a DXd ADC with an anti-PD-1 antibody results in extended animal survival compared with either agent alone [28].

Preliminary antitumor activity has been observed in patients who received Dato-DXd, including in combination with pembrolizumab. In the TROPION-PanTumor01 study (NCT03401385), an ongoing, phase I, two-part, open-label, first-in-human study of Dato-DXd in advanced solid tumors, Dato-DXd demonstrated encouraging antitumor activity and a manageable safety profile in heavily pretreated patients with NSCLC [33] and triple-negative breast cancer [34]. Interim results from the TROPION-Lung02 study (NCT04526691), an ongoing, phase Ib, two-part, randomized, open-label, multi-arm study, showed that Dato-DXd plus pembrolizumab with or without platinum chemotherapy had a tolerable safety profile and demonstrated promising efficacy signals in patients with metastatic NSCLC, regardless of PD-L1 expression, but including those with a TPS of ≥50% [35]. In this study, Dato-DXd plus pembrolizumab demonstrated an objective response rate (ORR) of 62% (8/13 patients) as first-line therapy, with a disease control rate of 100% (13/13). Dato-DXd also demonstrated a robust response rate and a manageable safety profile in combination with the immune checkpoint inhibitor durvalumab in patients with metastatic triple-negative breast cancer in the BEGONIA study (NCT03742102), an ongoing, phase Ib/II, two-part, randomized, open-label, multi-arm study of durvalumab in combination with novel oncology therapies [36]. These data support the potential benefit of combination therapy with Dato-DXd and a PD-L1 inhibitor in patients with solid tumors, including NSCLC, and provide the rationale for further evaluation of this combination in the TROPION-Lung08 study.

Study design

TROPION-Lung08 is an ongoing, active-controlled, phase III study in patients with advanced NSCLC (Figure 2) [26]. Approximately 740 patients will be randomized to one of two arms: Dato-DXd 6 mg/kg plus pembrolizumab 200 mg every 3 weeks (arm 1) and pembrolizumab 200 mg every 3 weeks (arm 2).

Table 1. **Key inclusion and exclusion criteria in the TROPION-Lung08 trial.**
Inclusion criteria	Exclusion criteria
• Age ≥18 years (if the legal age of consent is >18 years old, follow local regulatory requirements) • Histologically documented NSCLC – Stage IIIB/C NSCLC (not candidates for surgical resection or definitive chemoradiation) or stage IV NSCLC – Documented negative test results for EGFR, ALK, and ROS1 AGAs • Patients with squamous NSCLC are required to undergo EGFR/ALK/ROS1 testing if they have no history of tobacco smoking or are <40 years of age – No known AGAs in NTRK, BRAF, RET, MET, or other actionable driver kinases with locally approved therapies – Patients whose tumors harbor KRAS mutations are eligible • Tumor tissue sample for the measurement of TROP2 protein expression and exploratory biomarkers • Tumor with high PD-L1 expression (TPS ≥50%) as determined by the PD-L1 IHC 22C3 pharmDx assay by central testing • Measurable disease using RECIST 1.1 • ECOG PS of 0 or 1 at screening • Adequate treatment washout period following major surgery • Adequate bone marrow function	• Prior systemic treatment for advanced/metastatic NSCLC • Prior treatment with any of the following, including in the adjuvant/neoadjuvant setting: – Any agent (including ADC) containing a chemotherapeutic agent targeting topoisomerase I; TROP2-directed therapy; any anti–PD-1/PD-L1/PD-L2 agent or any agent directed to another stimulatory or co-inhibitory T-cell receptor; or any other ICI • Prior radiotherapy ≤4 weeks before start of study intervention or >30 Gy to the lung within 6 months • Current or history of (noninfectious) ILD/pneumonitis that required steroids • Suspected ILD/pneumonitis that cannot be ruled out by imaging at screening • Clinically severe pulmonary compromise resulting from intercurrent lung illnesses • Uncontrolled or significant CV disease, including history of myocardial infarction within past 6 months • Clinically significant corneal disease • Active, known, or suspected autoimmune disease • Diagnosis of immunodeficiency or treatment with chronic systemic steroids or other immunosuppressive therapy within past 7 days • History of severe hypersensitivity reactions to either the drug substances or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd or pembrolizumab

ADC: Antibody–drug conjugate; AGA: Actionable genomic alteration; CV: Cardiovascular; Dato-DXd: Datopotamab deruxtecan; ECOG PS: Eastern Cooperative Oncology Group performance status; Gy: Gray; ICI: Immune checkpoint inhibitor; IHC: Immunohistochemistry; ILD: Interstitial lung disease; NSCLC: Non-small-cell lung cancer; RECIST: Response Evaluation Criteria in Solid Tumors; TPS: Tumor proportion score.

This global study will enroll patients at approximately 200 study sites in North America, South America, Europe and Asia Pacific.

Randomization will be stratified by Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs 1), histology (squamous vs nonsquamous), geographic region (East Asia vs rest of world) and smoking status (former/current vs never) and implemented using an Interactive Response Technology system. No crossover between the two study treatment arms is permitted. Patients will be treated until disease progression as assessed by the investigator and verified by blinded independent central review (BICR), unacceptable toxicity, withdrawal of consent by the patient, physician decision, protocol deviations deemed by the investigator to pose a safety risk, pregnancy, loss to follow-up, study termination by the sponsor, or patient death. If pseudoprogression is suspected, patients can continue receiving treatment until progression is confirmed by CT or MRI scans. Pembrolizumab, provided under agreement by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. (NJ, USA) will be administered for a maximum of 35 cycles. There is no prespecified limit for Dato-DXd. For patients enrolled in arm 1, if one study drug is interrupted or discontinued due to toxicity, the other study drug can be continued if the safety of that drug is acceptable. The end of the trial is defined as the time when all patients have discontinued the study or died, an alternative study becomes available for patients continuing to derive benefit from treatment with pembrolizumab and/or Dato-DXd, or the study is discontinued by the sponsor for other reasons.

Key eligibility criteria

Inclusion criteria

Eligible patients must be aged ≥18 years or of the minimum legal adult age (whichever is greater) at the time of informed consent and must have histologically confirmed NSCLC (stage IIIB or IIIC and not a candidate for surgical resection or definitive chemoradiation or stage IV) with high PD-L1 expression (TPS ≥50%) as determined by the PD-L1 IHC 22C3 pharmDx assay performed by a central laboratory. Documented negative test results for EGFR, ALK and ROS1 actionable genomic alterations are required; for squamous NSCLC, testing for EGFR, ALK, and ROS1 is required only if there was no history of tobacco smoking or if the patient was diagnosed with NSCLC at <40 years of age. In addition, although genetic testing for known genomic alterations in NTRK, BRAF, RET, MET, or other driver kinases observed with locally approved therapies was not required, patients whose tumors were confirmed to have these mutations were ineligible for this study. Patients whose tumors harbor KRAS mutations are eligible for the study.

Tumor tissue must be submitted for measurement of TROP2 protein expression and exploratory biomarker analysis. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, an ECOG PS of 0 or 1, and adequate bone marrow function. Additional criteria include an adequate treatment washout period before cycle 1 day 1, defined as ≥3 weeks following major surgery and ≥4 weeks following radiation therapy, including palliative radiation to the chest (Table 1).

Exclusion criteria

Patients who have undergone any of the following treatments may not participate in the study: prior systemic treatment for advanced/metastatic NSCLC or prior treatment with any of the following, including in the adjuvant/neoadjuvant setting: (i) any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I, (ii) any TROP2-targeted therapy, (iii) any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or agent directed against another stimulatory or co-inhibitory T-cell receptor, (iv) any other immune checkpoint inhibitors, or (v) prior radiotherapy ≤4 weeks before the start of study intervention or >30 Gy to the lung within 6 months. Patients who previously received adjuvant/neoadjuvant therapies other than those listed here may be considered for enrollment if therapy was completed ≥6 months prior to the diagnosis of advanced/metastatic disease.

Patients who have any of the following are also ineligible: (i) history of noninfectious interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening, (ii) clinically severe pulmonary compromise resulting from intercurrent pulmonary illness, (iii) uncontrolled or significant cardiovascular disease, including history of a myocardial infarction within the past 6 months, (iv) clinically significant corneal disease, (v) active, known, or suspected autoimmune disease, (vi) diagnosis of immunodeficiency or treatment with chronic systemic steroids or other immunosuppresive therapy, or (vii) history of severe hypersensitivity reactions to either the drug substances or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd or pembrolizumab (Table 1).

Dosing & schedule of therapy

Patients randomized to arm 1 will receive Dato-DXd 6 mg/kg intravenously (IV) and pembrolizumab 200 mg IV on day 1 of each 21-day cycle. Patients randomized to arm 2 will receive pembrolizumab 200 mg IV on day 1 of each 21-day cycle. The Dato-DXd 6-mg/kg dose was selected primarily based on better tolerability [37] than that of the maximum tolerated dose (8 mg/kg) identified in the TROPION-PanTumor01 study [38]. Interim results from TROPION-Lung02 suggest that Dato-DXd 6 mg/kg is a viable dose in combination with pembrolizumab [35]. The trial is open label and active controlled; no placebo is administered. Premedication is required prior to any dose of Dato-DXd and must include antihistamines and acetaminophen, with or without glucocorticoids. Patients should remain at the site for at least 1 h after infusion of every Dato-DXd dose to be closely observed for possible allergic reaction. An oral care plan for patients receiving Dato-DXd is recommended throughout the study and should include daily use of prophylaxis with a steroid-containing mouthwash.

Objectives

The primary objective of this study is to compare the efficacy of Dato-DXd in combination with pembrolizumab versus that of pembrolizumab alone, as measured by progression-free survival (PFS) by BICR according to RECIST 1.1 and as measured by OS. Key primary and secondary end points are listed in Table 2.

Table 2. **TROPION-Lung08 study end points.**
Primary end points
• Progression-free survival by BICR^† • Overall survival
Key secondary end point
• Objective response rate by BICR^†
Other secondary end points
• Progression-free survival by investigator^† • Objective response rate by investigator^† • Duration of response by BICR and investigator^† • Time to response by BICR and investigator^† • Disease control rate by BICR and investigator^† • Time to death or progression after the next line of anticancer therapy (PFS2) • Patient-reported outcomes • Safety • Immunogenicity (antidrug antibody concentrations)
Exploratory end points
•Biomarkers, pharmacogenetics and pharmacokinetic exposures will be evaluated for potential associations with efficacy and safety

†Assessed per RECIST 1.1.

BICR: Blinded independent central review; RECIST: Response Evaluation Criteria in Solid Tumors.

The key secondary objective is to evaluate the efficacy of treatment in each arm as measured by ORR by BICR according to RECIST 1.1. Other secondary objectives are to further evaluate the efficacy of treatment in the arms as measured by PFS by the investigator, ORR by the investigator, duration of response by BICR and the investigator, time to response by BICR and the investigator, disease control rate by BICR and the investigator and time to progression after the next line of anticancer therapy or death (PFS2) as assessed by local standard clinical practice and analyzed in a similar manner as PFS by BICR; evaluate patient-reported outcomes (including time to deterioration in cough, dyspnea, or chest pain); and evaluate treatment-emergent adverse events (AE) and other safety parameters and Dato-DXd immunogenicity (antidrug antibody concentrations).

Exploratory objectives include evaluation of biomarkers and pharmacogenetics and pharmacokinetic exposures for potential association with efficacy and safety and clinical outcomes. Biomarkers of interest include the proportion of tumor cells expressing TROP2.

Evaluations

Tumor assessments will be performed at baseline (screening), every 9 weeks (±7 days) for the first 2 years (104 weeks), and then every 12 weeks (±7 days) thereafter until radiological disease progression (as assessed by the investigator and verified by BICR), death, loss to follow-up, or withdrawal of consent, regardless of discontinuation of study treatment or initiation of new anticancer therapy.

An ¹⁸F-fluorodeoxyglucose positron emission tomography/CT; (preferred) or MRI scan is required at baseline. Imaging must include CT or MRI scans of the chest, abdomen, pelvis and any other sites of disease and a brain CT or MRI scan (MRI preferred) at baseline screening for all patients. Follow-up bone imaging using the same type of scan from screening is required whenever progressive disease in the bone is suspected or to confirm a complete response in patients who have bone metastases.

Objective responses (complete or partial) must be confirmed at the next tumor assessment ≥4 weeks (28 days) from the previous assessment. All patients should be followed up for survival at least every 3 months (±14 days) after discontinuing the study drug until the end of the study. The serious AE reporting period starts during screening and continues until 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. The nonserious AE reporting period starts from administration of the first dose of study drug until 30 (+7) days after the last dose of study drug. A 30-day safety follow-up will occur at 30 (+7) days after the last dose of study treatment or before starting a new anticancer treatment, whichever occurs first. AEs of special interest with Dato-DXd include ILD/pneumonitis, infusion-related reactions, oral mucositis/stomatitis, mucosal inflammation other than oral mucositis/stomatitis, and ocular surface toxicity. AEs will be coded by the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) and graded by the National Cancer Institute Common Terminology for Adverse Events Version 5.0.

Patient-reported outcomes will be assessed using the following: (i) European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire along with a tumor-specific module (EORTC QLQ-LC13) to assess patient-reported tolerability and clinical benefit [39–41], (ii) a generic health status questionnaire, the EQ-5D-5L module, including EQ-VAS to assess patient-reported health utility for health economic evaluations [42] and (iii) three global anchors (Patient Global Impression [PGI] of Severity, PGI of Change and PGI of Treatment Tolerability) [43] included to estimate meaningful change thresholds for EORTC QLQ-C30/LC13 and treatment tolerability.

Statistical analyses

For the primary analysis of PFS, 448 PFS events by BICR are required to have approximately 98% power to detect a hazard ratio of 0.65 at a two-sided α of 0.01, which corresponds to an improvement of 4.6 months in median PFS from 8.5 months in the pembrolizumab monotherapy arm to 13.1 months in the Dato-DXd plus pembrolizumab arm. For the primary analysis of OS, 458 deaths are required to have approximately 84% power to detect a hazard ratio of 0.75 at a two-sided α of 0.04, which corresponds to an improvement of 7.7 months in median OS from 23 months in the pembrolizumab monotherapy arm to 30.7 months in the Dato-DXd plus pembrolizumab arm. The key secondary end point, ORR by BICR, will be analyzed at the time of the PFS primary analysis. For this analysis, 740 patients will provide approximately 98% power to detect an ORR difference of 15% at a two-sided α of 0.05, which corresponds to an improvement from 45% in the pembrolizumab monotherapy arm to 60% in the Dato-DXd plus pembrolizumab arm.

The primary efficacy analyses of PFS and OS will compare the Dato-DXd plus pembrolizumab combination arm and pembrolizumab monotherapy arm using a log-rank test, stratified by the randomization stratification factors. Time-to-event end points, except for time to response, will be reported using Kaplan-Meier estimates. Descriptive statistics on continuous data will include the mean, median, standard deviation and range (as well as the geometric mean and geometric coefficient of variation for pharmacokinetic data). Categorical data will be summarized using frequency counts and percentages.

Subgroup analyses for PFS by BICR and OS will be performed if there are ≥20 events in each subgroup. Subgroups assessed for analysis will be histology type, region, ECOG PS prior to randomization, smoking status, tumor stage at baseline, gender, age, race and presence of CNS metastases at baseline.

Conclusion

The TROPION-Lung08 study will evaluate the addition of Dato-DXd to pembrolizumab as first-line treatment for patients with advanced/metastatic NSCLC without actionable genomic alterations and with PD-L1 expression of ≥50%. The TROPION-Lung07 study (NCT05555732) [44] is another study in the same clinical development program that is evaluating this combination with and without platinum chemotherapy as first-line treatment for patients with NSCLC but with PD-L1 expression of <50%. The planned AVANZAR study will evaluate first-line Dato-DXd with durvalumab and carboplatin for patients with advanced/metastatic NSCLC. Results from these studies will help define a role for Dato-DXd as part of first-line therapy for patients with advanced/metastatic NSCLC.

Executive summary

Background

Lung cancer is the second most common cancer, causing an estimated 1.8 million deaths worldwide annually.
Non-small-cell lung cancer (NSCLC) is diagnosed at an advanced stage in >50% of patients and often has a poor prognosis.
Pembrolizumab monotherapy is a standard first-line treatment for patients with advanced NSCLC without actionable genomic alterations (AGAs) and with high PD-L1 expression (≥50%); the estimated 5-year overall survival rate is <33% in three studies of first-line therapy in this patient population, indicating an unmet need for more effective therapies.

Datopotamab deruxtecan

Datopotamab deruxtecan (Dato-DXd) is a novel, investigational TROP2-directed antibody-drug conjugate composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker.
Dato-DXd is internalized by TROP2-expressing tumor cells, where lysosomal enzymes typically upregulated in tumor cells cleave its linker and release the topoisomerase I inhibitor payload (DXd) into the cytoplasm of the cell, leading to tumor cell death.
In the Phase I TROPION-PanTumor01 study, Dato-DXd demonstrated encouraging antitumor activity and a manageable safety profile in heavily pretreated patients with NSCLC.
Per interim results from the Phase Ib TROPION-Lung02 study, Dato-DXd + pembrolizumab ± platinum chemotherapy had a tolerable safety profile and demonstrated promising efficacy signals in patients with metastatic NSCLC, including those with a tumor proportion score of ≥50%.
Interim results from the TROPION-Lung02 study indicated that Dato-DXd 6 mg/kg is a viable dose in combination with pembrolizumab.

TROPION-Lung08 study

TROPION-Lung08 is a randomized, open-label, two-arm, phase III study assessing the efficacy and safety of Dato-DXd plus pembrolizumab compared with pembrolizumab alone as first-line therapy in patients with advanced/metastatic NSCLC without AGAs and with high PD-L1 expression (≥50%).
Patients are randomized to receive pembrolizumab 200 mg, with or without Dato-DXd 6 mg/kg, every 3 weeks.

Objectives

The primary objective of this study is efficacy, as measured by centrally assessed progression-free survival and by overall survival.
The key secondary end point is centrally assessed overall response rate.
Other secondary end points include progression-free survival and overall response rate by investigator, duration of response, patient-reported outcomes and safety.
Exploratory objectives include evaluation of biomarkers, pharmacogenetics and pharmacokinetic exposures.

Conclusion

TROPION-Lung08 will evaluate Dato-DXd added to pembrolizumab as first-line treatment for patients without AGAs with advanced/metastatic NSCLC with high PD-L1 expression (≥50%).
Results from this study will help define a role for Dato-DXd as part of first-line therapy for patients with advanced/metastatic NSCLC.

Author contributions

All authors made substantial contributions to the design and/or conduct of the TROPION-Lung08 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.

Acknowledgments

The authors wish to thank all patients and their families, the investigators, co-investigators, nurses, study coordinators, and operations staff at all participating clinical sites.

Financial & competing interests 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 (MSD). BP Levy received consulting fees from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Janssen, Mirati, Novartis, Pfizer, and Roche/Genentech. E Felip received consulting fees and/or honoraria from Amgen, AstraZeneca, Bayer, BerGenBio, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Roche, GSK, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Novartis, PeerVoice, Peptomyc, Pfizer, Sanofi, Takeda, and touchONCOLOGY and grant funding to her institution from Merck KGaA and Fundación Merck Salud. E Felip is an independent member of the Grífols Board of Directors. M Reck received consulting fees, honoraria, and support for attending meetings from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, GSK, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, Roche, and Regeneron and served on data safety monitoring boards for Daiichi Sankyo and Sanofi. JCH Yang received consulting or advisory fees from Ono Pharmaceuticals and Pfizer, grant funding to his institution from AstraZeneca and advisory or consulting fees to his institution from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Johnson & Johnson, Merck KGaA, MSD, Novartis, Puma Technology, Roche/Genentech, Takeda and Yuhan Pharmaceuticals. F Cappuzzo received consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, MSD, Novartis, Pfizer, PharmaMar, Roche, and Takeda. C Zhou received consulting fees and/or honoraria from Amoy Diagnostics, AnHeart Therapeutics, Boehringer Ingelheim, CStone Pharmaceuticals, Luye Pharma Group, Eli Lilly China, Jiangsu Hengrui Pharmaceuticals, Innovent Biologics, MSD, Qilu Pharmaceutical, Roche, Sanofi, and TopAlliance Biosciences. S Rawat is an employee of and owns stock and/or stock options in Daiichi Sankyo. P Basak and J Xie are employees of Daiichi Sankyo. L Xu was an employee at MSD at the time this study was designed and is a current employee of AstraZeneca. J Sands received consulting fees from AstraZeneca, Curadev, Daiichi Sankyo, Guardant Health, Jazz Pharmaceuticals, Medtronic, PharmaMar, Sanofi, and Takeda and is the treasurer of the Rescue Lung Society. Y Yoneshima declares no potential conflicts. 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. 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.

Medical writing support was provided by Jeffrey Dorfman, PhD, and Kristie Garza, PhD, of SciMentum, Inc, a Nucleus Holdings Ltd company, and was funded by Daiichi Sankyo, Inc. Editorial support was provided in accordance with Good Publication Practice guidelines (ismpp.org/gpp-2022).

Ethical conduct of research

This study was conducted in compliance with the protocol, the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) consolidated Guideline E6 for Good Clinical Practice (CPMP/ICH/135/95), and applicable regulatory requirements and was approved by the independent ethics committees or institutional review boards (IECs/IRBs) at each site. All patients signed IEC/IRB-approved informed consent forms, obtained by the investigator at each site.

Data sharing statement

This is a clinical trial protocol manuscript and no data are being reported.

Open access

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 19, No. 21

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History

Received 20 March 2023

Accepted 11 May 2023

Published online 30 May 2023

Published in print July 2023

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Keywords

Author contributions

Acknowledgments

The authors wish to thank all patients and their families, the investigators, co-investigators, nurses, study coordinators, and operations staff at all participating clinical sites.

Financial & competing interests disclosure

Ethical conduct of research

Data sharing statement

This is a clinical trial protocol manuscript and no data are being reported.

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This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

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