First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2–Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non–Small-Cell Lung Cancer: TROPION-PanTumor01

Abstract

PURPOSE

This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate in solid tumors, including advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics.

RESULTS

Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. This population had a median of three prior lines of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving 6 mg/kg (n = 50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%), stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs occurred in 54% and 26% of patients, respectively. Interstitial lung disease adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of 50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of response was 10.5 months; median progression-free survival and overall survival were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6 months), respectively. Responses occurred regardless of TROP2 expression.

CONCLUSION

Promising antitumor activity and a manageable safety profile were seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further investigation as first-line combination therapy in advanced NSCLC and as monotherapy in the second-line setting and beyond is ongoing.

INTRODUCTION

Lung cancer is the leading cause of cancer-related mortality worldwide.¹ Most lung cancers are non–small-cell lung cancer (NSCLC), which is diagnosed predominantly at an advanced stage.^2-7 Although anti-PD-(L)1 agents and targeted therapies have improved outcomes in NSCLC, the disease inevitably progresses.^8-13 Current treatments for advanced (locally advanced or metastatic) NSCLC in the second-line setting and beyond offer limited clinical benefit and often have significant toxicity.^13-17 More effective, tolerable options that prolong survival and improve quality of life remain a significant unmet need.

CONTEXT

• Key Objective

• Despite recent advances to the treatment landscape for advanced non–small-cell lung cancer (NSCLC), the disease inevitably progresses. Current therapies in the second-line setting and beyond offer limited clinical benefit and often have substantial toxicity. More effective and tolerable options are needed. The TROPION-PanTumor01 first-in-human dose-escalation and dose-expansion study is determining safety and preliminary efficacy of the novel trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd), including in a cohort of patients with advanced NSCLC.

• Knowledge Generated

• Dato-DXd showed promising antitumor activity and a manageable safety profile in heavily pretreated patients with advanced NSCLC. At the recommended dose for further development, the objective response rate was 26%, median duration of response was 10.5 months, median progression-free survival was 6.9 months, and median overall survival was 11.4 months. Responses were seen regardless of TROP2 expression level. Most frequent any-grade treatment-emergent adverse events were nausea, stomatitis, and alopecia.

• Relevance (T.E. Stinchcombe)

• ADCs are a novel class of agents in NSCLC, and early-phase studies have revealed activity. Ongoing studies will determine the role of Dato-DXd in the treatment of patients with advanced NSCLC.*

  *Relevance section written by JCO Associate Editor Thomas E. Stinchcombe, MD.

Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein involved in the regulation of cellular proliferation, transformation, organogenesis, and regeneration.¹⁸ TROP2 is widely expressed in adult tissues, with expression primarily found in epithelial cells, including respiratory epithelium, breast glands, urothelium, excretory and intercalated ducts of the pancreas, and prostate.¹⁸ TROP2 is also broadly expressed in solid tumors; one analysis demonstrated expression in 100% of squamous cell carcinoma (n = 72) and 93.9% of adenocarcinoma (n = 181) tumor tissue samples, making it an attractive antigen for antibody-drug conjugate (ADC) binding.^18-23

Datopotamab deruxtecan (Dato-DXd) is a novel, investigational TROP2-directed ADC composed of a humanized anti-TROP2 immunoglobulinG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload (an exatecan derivative, DXd), via a stable, tumor-selective, tetrapeptide-based cleavable linker.²⁴ Dato-DXd was designed with an optimized drug-to-antibody ratio of approximately 4 to address the limitations of traditional chemotherapy by selectively delivering DXd directly to tumors while reducing systemic toxicity.^24,25 After internalization of Dato-DXd into TROP2-expressing cells, the plasma-stable linker is selectively cleaved by tumor cell–enriched lysosomal enzymes to release the payload, inducing tumor cell death and a bystander antitumor effect resulting in elimination of both target and neighboring tumor cells.^24,26,27

Findings are presented from the advanced NSCLC cohort of the phase I dose-escalation and dose-expansion TROPION-PanTumor01 study evaluating the safety and preliminary antitumor activity of Dato-DXd (ClinicalTrials.gov identifier: NCT03401385).

PATIENTS AND METHODS

Study Design and Patients

TROPION-PanTumor01 is an ongoing phase I, two-part, multicenter, open-label study of Dato-DXd conducted at 17 sites in the United States and Japan in patients with advanced NSCLC.

Patients were aged 20 years and older (Japan) or 18 years and older (United States) with pathologically documented unresectable advanced/metastatic NSCLC (with or without actionable genomic alterations [AGAs]) that relapsed or progressed after available standard treatments or without standard treatment available; Eastern Cooperative Oncology Group performance status of 0-1; and measurable disease on the basis of RECIST version 1.1. Patients consented to mandatory pretreatment and on-treatment (initially optional) tumor tissue biopsy; no minimum TROP2 expression level was required.

Exclusion criteria included history of malignancy other than NSCLC, clinically significant/suspected lung disease other than underlying NSCLC, clinically significant corneal disease, or clinically active brain metastases (untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control symptoms; patients with clinically inactive metastases were included if ≥2 weeks past whole-brain radiotherapy at the time of enrollment). See the Data Supplement (online only) for full inclusion/exclusion criteria.

Study Treatment

Dato-DXd was administered intravenously on day 1 of each 21-day cycle (once every 3 weeks). The dose-escalation part to determine maximum tolerated dose (MTD) evaluated Dato-DXd 0.27-10 mg/kg, once every 3 weeks, with ≥3 dose-limiting toxicity (DLT)–evaluable patients required per dose (Data Supplement, Fig A1 and Table A1) and was guided by the Bayesian logistic regression model following escalation with overdose control.^28,29 Premedication was not permitted before the first dose of Dato-DXd during the DLT evaluation period. Patients in dose expansion received Dato-DXd 4, 6, or 8 mg/kg. The initial dose was infused over approximately 90 minutes with following doses infused over approximately 30 minutes if no infusion-related reaction (IRR) occurred. Patients received Dato-DXd until unacceptable toxicity, progressive disease, or withdrawal of consent.

End Points and Assessments

The primary objective in dose escalation was safety and tolerability, including determination of MTD and recommended dose for expansion. Additional primary objectives in both parts of the study were further investigations of safety and tolerability, including treatment-emergent adverse events (TEAEs). Secondary objectives included assessment of antitumor activity and characterization of the pharmacokinetic (PK) properties of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a (DXd payload).

TEAEs and laboratory findings were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 (before April 2019) or 5.0. PK end points included plasma concentration and PK parameters of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a, which were estimated for each patient using standard noncompartmental methods. Tumor response was evaluated using RECIST 1.1 and included objective response rate (ORR), duration of response (DOR), disease control rate (DCR), time to response, progression-free survival (PFS), and overall survival (OS). Tumor assessments were performed at screening and every 6 weeks for 36 weeks after day 1 cycle 1 and thereafter every 12 weeks while patients received Dato-DXd. On-treatment tumor biopsies were collected at cycle 2 days 2-8. All efficacy data other than OS were analyzed by blinded independent central review.

Interstitial Lung Disease

An independent adjudication committee reviewed all potential cases of interstitial lung disease (ILD)/pneumonitis on the basis of a predefined list of preferred terms to confirm diagnosis and assess attribution to Dato-DXd. Additional data were collected for all cases brought for adjudication, including an in-depth review of medical history, diagnostic evaluation, treatment, and outcome.

Statistical Analysis

The data cutoff was July 30, 2021. Descriptive statistics were assessed for demographic, safety, efficacy, PK, and biomarker data by dose level and time, and were summarized as means, medians, standard deviations, and ranges. Categorical data were summarized using frequency counts and percentages. Time-to-event variables including DOR, PFS, and OS were analyzed by the Kaplan-Meier method. The median event time with two-sided 95% CI was calculated using the Brookmeyer and Crowley method. ORR and DCR with two-sided 95% exact CI were summarized using the Clopper-Pearson method.

Trial Oversight

This study was conducted in compliance with the Protocol (online only), ethical principles of the Declaration of Helsinki, International Council for Harmonisation consolidated Guideline E6 for Good Clinical Practice (CPMP/ICH/135/95), and applicable regulatory requirements. All patients signed informed consent forms approved by independent ethics committees or institutional review boards at each site.

RESULTS

Patients

Between February 2018 and October 2020, 210 patients with advanced NSCLC were treated (Data Supplement, Fig A2). A total of 180 patients received Dato-DXd 4-8 mg/kg (4 mg/kg, n = 50; 6 mg/kg, n = 50; 8 mg/kg, n = 80) once every 3 weeks across dose escalation and expansion.

Median ages were 61-64 years across 4-8 mg/kg dose groups (Table 1; see Data Supplement [Table A2] for nonexpansion doses). Of patients receiving Dato-DXd 4-8 mg/kg, 54%-64% had greater than or equal to three lines of therapy and 20%-24% had greater than or equal to five lines. Across dose cohorts, 76%-88% of patients received previous immunotherapy, and 96%-98% received previous platinum-based chemotherapy.

TABLE 1.

Baseline Characteristics of the NSCLC Cohort

At data cutoff, 10% of patients receiving 4 or 6 mg/kg and 7.5% receiving 8 mg/kg remained on study treatment (Data Supplement, Table A3). Median duration on study was 15.9, 13.3, and 20.6 months and median exposure was 4.1, 3.5, and 3.3 months in patients receiving 4, 6, or 8 mg/kg, respectively.

PKs

The mean half-life of Dato-DXd at cycle 1 was 4.8 days for 6 mg/kg Dato-DXd, supporting once every 3 weeks dosing (Data Supplement, Fig A3). Exposure of Dato-DXd, total datopotamab antibody, and DXd payload increased proportionally with dose; systemic exposure of DXd was low. The PK profiles of datopotamab antibody and ADC were similar, suggesting high linker stability in plasma.

Efficacy

Antitumor response occurred across dose levels (Table 2; Fig 1; Data Supplement [Fig A4]). Forty-two patients achieved a confirmed partial response (PR), including 11 of 50 patients (22.0%) receiving 4 mg/kg, 13 of 50 (26.0%) receiving 6 mg/kg, and 18 of 80 (22.5%) receiving 8 mg/kg of Dato-DXd. One patient receiving 8 mg/kg achieved a confirmed complete response (CR). Overall, the confirmed ORR was 22.0% in patients receiving 4 mg/kg, 26.0% in patients receiving 6 mg/kg, and 23.8% in patients receiving 8 mg/kg of Dato-DXd. Including responses pending confirmation, the ORR was 30.0%, 32.0%, and 31.3% with Dato-DXd 4, 6, or 8 mg/kg, respectively. Many patients achieved stable disease, with a DCR of 76.0% at 4 mg/kg, 70.0% at 6 mg/kg, and 78.8% at 8 mg/kg. Representative tumor scans of patients who achieved a PR are shown in Figure 1C. ORR, including responses pending confirmation in patients with versus without AGAs, was 44.1% (15 of 34) and 28.1% (41 of 146), respectively. Median DOR was 12.7, 10.5, and 9.6 months with 4, 6, and 8 mg/kg of Dato-DXd, respectively, and 10.5 months across expansion cohorts (95% CI, 8.3 to 26.5 months). Nearly all tumors expressed detectable TROP2 by immunohistochemistry, with 64 of 87 (73.6%) having high TROP2 expression (H-score >100; Data Supplement [Fig A5]). No relationship was observed between TROP2 expression and antitumor response. In patients receiving Dato-DXd 6 mg/kg, median PFS was 6.9 months (95% CI, 2.7 to 8.8 months), and median OS was 11.4 months (95% CI, 7.1 to 20.6 months; Fig 2; Table 2; Data Supplement [Fig A6]).

TABLE 2.

Efficacy in the NSCLC Cohort

FIG 1.

Antitumor activity of Dato-DXd in the NSCLC cohort. (A) Maximum percentage change from baseline in the sum of target lesion diameters according to RECIST 1.1, with the 4, 6, or 8 mg/kg dose of Dato-DXd indicated by bar color. (B) Change in size of target lesions over time with Dato-DXd 6 mg/kg with responders and nonresponders indicated by line color. (C) Computed tomography scans depicting a right middle lobe lung mass target lesion (top) for a 51-year-old woman with a scan depicting PR after six cycles of treatment with Dato-DXd 4 mg/kg and right lower-lobe lung masses (bottom) for a 54-year-old woman with a scan depicting PR after eight cycles of treatment with Dato-DXd 4 mg/kg. Dato-DXd, datopotamab deruxtecan; NSCLC, non–small-cell lung cancer; PR, partial response.

FIG 2.

Kaplan-Meier estimates of survival outcomes in patients who received Dato-DXd 6 mg/kg in the NSCLC cohort. (A) PFS assessed by blinded independent central review. (B) OS. Dato-DXd, datopotamab deruxtecan; NSCLC, non–small-cell lung cancer; OS, overall survival; PFS, progression-free survival.

Safety

During escalation, three of 51 patients (5.9%) experienced DLTs: one patient receiving 10 mg/kg had grade 3 stomatitis, one receiving 10 mg/kg had grade 3 mucosal inflammation, and one receiving 6 mg/kg had grade 3 rash maculopapular. The MTD was established as 8 mg/kg once every 3 weeks.

Across dose escalation and expansion, any-grade TEAEs were observed in 98% of patients receiving Dato-DXd 4 (30.0% grade ≥3) or 6 mg/kg (54.0% grade ≥3) and 100% of patients receiving 8 mg/kg (58.8% grade ≥3). Any-grade drug-related TEAEs occurred in 94.0% of patients receiving 4 mg/kg (14.0% grade ≥3), 82.0% receiving 6 mg/kg (26.0% grade ≥3), and 97.5% receiving 8 mg/kg (36.3% grade ≥3; Table 3; see Data Supplement [Table A4] for nonexpansion doses). Serious TEAEs occurred in 20.0%, 48.0%, and 48.8% of patients receiving Dato-DXd 4, 6, or 8 mg/kg, respectively. TEAEs associated with discontinuation occurred in 8 (16.0%), 7 (14.0%), and 19 (23.8%) patients receiving Dato-DXd 4, 6, or 8 mg/kg, respectively; TEAEs associated with dose reduction occurred in 2.0%, 10.0%, and 27.5% of patients, respectively.

TABLE 3.

Overall Safety Summary in the NSCLC Cohort

The most common any-grade TEAEs were nausea, stomatitis, and alopecia (Table 4). IRRs occurred in 24%, 20%, and 25% of patients receiving Dato-DXd 4, 6, or 8 mg/kg, respectively. The most common grade ≥3 TEAEs were pneumonia, anemia, and lymphocyte count decreased (Data Supplement, Table A5). Ocular surface toxicities (OSTs) occurred in 13 patients (any grade, 26.0%; grade ≥3, 0%) receiving 4 mg/kg, 12 (any grade, 24.0%; grade 3, 2%) receiving 6 mg/kg, and 33 (any grade, 41.3%; grade 3, 2.5%) receiving 8 mg/kg (Data Supplement, Table A6). Common OSTs were dry eye, lacrimation increased, and blepharitis. Grade 3 OSTs were keratitis (n = 1, Dato-DXd 8 mg/kg) and ulcerative keratitis (n = 1 each, 6 and 8 mg/kg; both considered serious TEAEs). Time to onset of select TEAEs is provided in the Data Supplement (Table A6).

TABLE 4.

TEAEs Observed in ≥15% of Patients and ILD

Stomatitis events were predominately grade 1 (51 of 180 patients [28.3%]) or 2 (39 of 180 patients [21.7%]). Grade 3 stomatitis occurred in one patient receiving Dato-DXd 6 mg/kg and three receiving 8 mg/kg; grade 4 stomatitis was observed in one patient receiving 8 mg/kg. Alopecia events were predominately grade 1 (44 of 180 patients [24.4%]); grade 2 (alopecia occurred in 28 of 180 patients [15.6%]).

Twenty-eight cases of potential ILD (defined in the Data Supplement) were reported across expansion doses. ILD adjudicated as drug-related occurred in five patients (10.0%) receiving Dato-DXd 4 mg/kg, three (6.0%) receiving 6 mg/kg, and 11 (13.8%) receiving 8 mg/kg (Table 4). These events were primarily grade 1 or 2 (n = 13 [7.2%]). Grade ≥3 events occurred in six patients (two grade 3, one grade 4, and three grade 5). All grade 5 events occurred in the 8-mg/kg cohort.

DISCUSSION

This first-in-human study of Dato-DXd demonstrated encouraging antitumor activity and a manageable safety profile in heavily pretreated patients with advanced NSCLC. On the basis of the safety, tolerability, PK, efficacy, and exposure-response modeling and simulation data, 6 mg/kg was selected for development.^30,31

The DXd payload of Dato-DXd is released after ADC internalization and proteolytic processing by tumor cell-enriched lysosomal enzymes.^24,26 High linker stability of Dato-DXd in plasma is demonstrated by the long half-life of intact ADC and low systemic exposure of free DXd payload.²⁶ The observed half-life, which may result in low levels of bone marrow suppression, supports once every 3 weeks dosing. Low systemic exposure to free DXd (previously established IC₅₀ of 0.31 μmol/L for inhibition of topoisomerase I)²⁶ may explain the modest hematologic and gastrointestinal toxicity, an uncharacteristic safety profile of an antitumor agent with a topoisomerase I inhibition mechanism of action.^25,27

Dato-DXd demonstrated a manageable safety profile. The most common any-grade TEAE was nausea, observed in 48%-64% of patients across expansion doses (grade ≥3, 0%-4%). Patients also experienced IRRs (any grade, 20%-25%). Cases of stomatitis were predominately grade 1 or 2. It should be noted that the frequency of some TEAEs may have been exacerbated because of exclusion of premedication during the DLT evaluation period. Hematologic toxicity was notably mild; neutrophil count decrease (including neutropenia) was observed in 10 patients (any grade, 5.6%). Most cases of neutropenia were grade 1 or 2, with no grade ≥4 cases of neutropenia or any-grade cases of febrile neutropenia. Rates of diarrhea were low: 10.0% (n = 5) in the Dato-DXd 4-mg/kg cohort, 18.0% (n = 9) in the Dato-DXd 6-mg/kg cohort, and 18.8% (n = 15) in the Dato-DXd 8-mg/kg cohort; no grade ≥3 diarrhea occurred. OSTs occurred most frequently with 8 mg/kg and were mainly of low grade. Prophylaxis with antiemetic medication for nausea; steroid mouthwash for stomatitis; antihistamines, acetaminophen, and/or glucocorticoids for IRRs; and artificial tears and avoidance of contact lenses for OSTs was implemented in Dato-DXd clinical studies. An ongoing TROPION-PanTumor01 substudy is aimed at providing further insight into potential mechanisms of stomatitis and appropriate prevention strategies and clinical management.

ILD is an important risk with DXd ADCs and is being closely monitored in ongoing studies.^32,33 Out of an abundance of caution, a broad group of preferred terms was used to elicit adjudication of potential ILD in this study. Mitigation efforts include careful assessment of patients for signs/symptoms of ILD, including use of patient education materials and implementation of management guidelines. If ILD was suspected, Dato-DXd was immediately interrupted and steroids were initiated promptly with sufficient duration, on the basis of pulmonary toxicity guidelines. Three patients who received prior immunotherapy had grade 5 ILD/pneumonitis after two to four treatment cycles of Dato-DXd 8 mg/kg. It is difficult to conclusively attribute these deaths exclusively to ILD/pneumonitis since two patients had coincident grade 5 adverse events related to progressive disease (respiratory failure and dyspnea). Overall, the ILD incidence was low at the 6-mg/kg dose selected for development (three of 50 patients [6.0%]).

The current standard of care (SOC) for advanced NSCLC in the second-line or later settting, docetaxel with/without a vascular endothelial growth factor (VEGF) inhibitor, is associated with higher rates of neutropenia (range, 14%-67%), febrile neutropenia (range, 2%-16%), diarrhea (range, 2%-42%), and TRAEs leading to death (range, 0%-16%).^14-17 Additionally, the safety profile of Dato-DXd differs from that of the TROP2-directed ADC sacituzumab govitecan, which is under investigation in NSCLC. Neutropenia occurred in 61% of patients (grade 3/4 neutropenia, 47%; febrile neutropenia, 7%) and diarrhea occurred in 65% of patients treated with sacituzumab govitecan (grade 3/4, 12%).³⁴

Dato-DXd antitumor activity was demonstrated across expansion doses. Dato-DXd 8 mg/kg was associated with higher rates of treatment discontinuation, dose reduction, and ILD; stomatitis and other TEAEs were also more frequent and severe.³⁵ In comparison, 6 mg/kg demonstrated a more tolerable safety profile with better or comparable efficacy, including ORR of 26%, DCR of 70%, median DOR of 10.5 months, and median PFS of 6.9 months. Although promising efficacy and a favorable safety profile were observed with the 4-mg/kg dose, 6 mg/kg was determined to have the optimal benefit-risk ratio because of the promising efficacy and acceptable safety profile observed with this dose. Robust population PK and exposure-response modeling supported 6 mg/kg once every 3 weeks as the optimal dose.^30,36 The 4-mg/kg dose provides an effective dose reduction option.

Responses to Dato-DXd were observed regardless of TROP2 expression level. The lack of association of TROP2 levels with clinical response suggests that additional factors beyond TROP2 binding affect response to Dato-DXd. These factors may include variability in differing internalization rates of membrane TROP2:Dato-DXd complexes, variable levels of lysosomal protease release of DXd, and varying sensitivity to topoisomerase I inhibition and cell death. However, the potency of the DXd payload suggests that in general, low expression of TROP2 may be sufficient to achieve an antitumor response. This postulate is supported by the efficacy of the related DXd ADC, trastuzumab deruxtecan, in breast cancer with low human epidermal growth factor 2 expression.³⁷ Additionally, the high membrane permeability of the Dato-DXd payload after cleavage may allow for a bystander antitumor effect and elimination of nearby tumor cells regardless of TROP2 expression.²⁷ Given the wide expression of TROP2, Dato-DXd may provide clinical benefit in a broad population of patients.

Although patients were more heavily pretreated (>50% of patients with greater than or equal to three lines of therapy and 21.7% with greater than or equal to five lines of therapy) than those in trials that established the second-line SOC, Dato-DXd demonstrated greater efficacy with an acceptable safety profile. Historical results from pivotal trials included ORRs ranging from 3.3% to 14%, DCRs of 41.3%-53%, median DORs of ≤9.1 months, and median PFS of 2.7-3.0 months in patients who received docetaxel^14-17 (with PFS of 3.5-4.3 months in recent trials^38,39). Addition of a VEGF inhibitor resulted in modest improvement (ORR, ≤23%; median PFS, 4.5 months; DCR, 64%).^16,17 However, cross-trial comparisons are confounded by differences in patient populations.

The unique ADC platform characteristics and emerging clinical profile in advanced NSCLC support further development of Dato-DXd in NSCLC and other tumors.^40-44 A comprehensive phase III development program in advanced NSCLC includes evaluation of Dato-DXd as monotherapy in previously treated patients with advanced NSCLC with or without AGAs (TROPION-Lung01, ClinicalTrials.gov identifier: NCT04656652) and as first-line therapy combined with pembrolizumab for patients with a PD-L1 tumor proportion score (TPS) of ≥50% (TROPION-Lung08, ClinicalTrials.gov identifier: NCT05215340), combined with pembrolizumab with or without a platinum agent in nonsquamous NSCLC with a PD-L1 TPS of <50% (TROPION-Lung07, ClinicalTrials.gov identifier: NCT05555732), and combined with durvalumab and carboplatin (AVANZAR, ClinicalTrials.gov identifier: NCT05687266). Additionally, promising antitumor activity and a similar safety profile were seen in the breast cancer cohorts of TROPION-PanTumor01 and in combination with durvalumab in BEGONIA (ClinicalTrials.gov identifier: NCT03742102).^45-47 Investigations in other tumors are ongoing.

In summary, Dato-DXd demonstrated a manageable safety profile and promising antitumor activity with durable responses in heavily pretreated patients with advanced NSCLC. On the basis of the dose-response relationship and optimal benefit-risk profile, the 6-mg/kg once every 3 weeks dose was selected for further development. Multiple randomized confirmatory studies are further evaluating Dato-DXd as a treatment for NSCLC in first-line and later settings.

DATA SHARING STATEMENT

Anonymized individual participant data on completed studies and applicable supporting clinical study documents may be available upon request at https://vivli.org/. In cases where clinical study data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo Companies will continue to protect the privacy of the company and our clinical study subjects. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/.

AUTHOR CONTRIBUTIONS

Conception and design: Jacob Sands, Melissa L. Johnson, Anthony W. Tolcher, Jon Greenberg, Yui Kawasaki, Hong Zebger-Gong, Fumiaki Kobayashi, Penny Phillips, Aaron E. Lisberg

Financial support: Fumiaki Kobayashi

Administrative support: Funda Meric-Bernstam, Fumiaki Kobayashi

Provision of study materials or patients: Jacob Sands, Alexander Spira, Edward B. Garon, Funda Meric-Bernstam, Anthony W. Tolcher, Noboru Yamamoto, Jon Greenberg, Hong Zebger-Gong, Fumiaki Kobayashi, Aaron E. Lisberg, Rebecca S. Heist

Collection and assembly of data: Toshio Shimizu, Jacob Sands, Alexander Spira, Satoru Kitazono, Melissa L. Johnson, Funda Meric-Bernstam, Anthony W. Tolcher, Noboru Yamamoto, Jon Greenberg, Yui Kawasaki, Hong Zebger-Gong, Fumiaki Kobayashi, Penny Phillips, Aaron E. Lisberg, Rebecca S. Heist

Data analysis and interpretation: Toshio Shimizu, Jacob Sands, Kiyotaka Yoh, Alexander Spira, Edward B. Garon, Melissa L. Johnson, Funda Meric-Bernstam, Anthony W. Tolcher, Noboru Yamamoto, Jon Greenberg, Yui Kawasaki, Hong Zebger-Gong, Fumiaki Kobayashi, Penny Phillips, Aaron E. Lisberg, Rebecca S. Heist

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2–Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non–Small-Cell Lung Cancer: TROPION-PanTumor01

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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