Efficacy and safety of datopotamab deruxtecan in advanced/metastatic non-small cell lung cancer patients: a systematic review and single-arm meta-analysis

Introduction

Lung cancer remains the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of cases (1). Most patients with NSCLC are diagnosed at an advanced or metastatic stage. In recent years, improvements in diagnostic tools and therapies have shifted the treatment paradigm of NSCLC. Yet, patients still face limited survival (5-year survival rate of 10% at stage IVA and <1% at IVB) (1-3).

Over the past few years, a wide variety of treatment alternatives have emerged for advanced NSCLC. For patients harboring EGFR-mutations, the first-line treatment consists of osimertinib monotherapy or combined with other agents, based on findings of the phase III clinical trials FLAURA and FLAURA2 (4). In the randomized study KEYNOTE-189, a 40% improvement in overall survival (OS) was observed in favor of pembrolizumab plus chemotherapy compared to chemotherapy alone [hazard ratio (HR) 0.60, 95% confidence interval (CI): 0.50–0.72, P<0.001] in advanced NSCLC patients with programmed death-ligand 1 (PD-L1) expression lacking driver mutations (5). On the other hand, patients lacking targetable mutations (i.e., wild type) frequently receive chemotherapy-based regimens (4,5). Despite all advances in targeted therapies and precision oncology, a great percentage of patients still face disease progression. Therefore, there is an unmet need for new approaches in the scenario of advanced NSCLC.

Antibody-drug conjugates (ADCs), another innovative class of target therapies, have demonstrated remarkable results across several tumors. These agents are composed of a monoclonal antibody linked to a cytotoxic payload (6-9). Through their sophisticated design, ADCs have been shown to combine both high target selectivity and potent killing features. The ADC datopotamab deruxtecan (dato-DXd) is composed of the humanized antibody anti-trophoblast cell-surface antigen 2 (TROP2) linked through a tetrapeptide-based cleavable linker to the cytotoxic payload deruxtecan (7,10). The antibody component binds to the cell surface target, which results in internalization of the ADC. Within the cell environment, the linker is cleaved and releases the cytotoxic component. Deruxtecan is a potent topoisomerase I inhibitor and leads to DNA strand breaks and cell apoptosis. This agent has a half-life of approximately 5 days at the optimal dose of 6 mg/kg. Higher doses were associated with an unfavorable toxicity profile.

In the phase III TROPION-Lung01 study, 299 heavily pretreated NSCLC patients on dato-DXd at 6 mg/kg had a 25% lower risk of disease progression or death compared to 305 patients on chemotherapy (HR 0.75, 95% CI: 0.62–0.91, P=0.004) (7). However, in this same study, concerning rates of gastrointestinal and hematotoxicity were observed (11). Thus, despite encouraging results, the efficacy and safety profile of dato-DXd is yet to be explored. Therefore, we performed a systematic review and meta-analysis to compile all available evidence on the efficacy and safety of dato-DXd in patients with advanced or metastatic NSCLC. We present this article in accordance with the PRISMA reporting checklist (12,13) (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-583/rc).

Methods

This systematic review and meta-analysis were registered on PROSPERO under protocol number CRD42024582750.

Search strategy and data collection

A systematic search from inception until July 14, 2024, was performed on PubMed (https://pubmed.ncbi.nlm.nih.gov), Cochrane (https://www.cochranelibrary.com), Embase (https://www.embase.com), the European Society for Medical Oncology (ESMO, https://www.esmo.org), and the American Society of Clinical Oncology (ASCO, https://www.asco.org) databases. The search terms included “Datopotamab deruxtecan”, “dato-DXd”, and “DS-1062”. We did not apply any publication date or other filters in our search. The entire search is available in Appendix 1. Relevant reviews and unpublished clinical trials were evaluated for any additional studies.

Two authors (H.K. and P.V.Z.R.) independently screened reports by title and abstract, selected studies for a comprehensive review, collected data from individual studies, and performed the quality assessment. Disagreements were resolved by consensus or by consulting a third author (A.L.d.O.).

Eligibility criteria

We included clinical trials (phase I, II, or III) evaluating the efficacy and safety of dato-DXd in patients with confirmed diagnoses of advanced or metastatic NSCLC who received at least one dose of dato-DX and reporting the outcomes of interest. There were no restrictions regarding time or publication date, age, gender, histological subtype, line of therapy, and number of patients. Abstracts and presentations from conferences were also considered for inclusion. We excluded reviews, case reports, case series, case-control, and preclinical studies. Ongoing studies with results unavailable at the time of the search were excluded.

Intervention

The intervention of interest was the administration of dato-DXd as monotherapy or in combination with other agents. The dosing regimens varied between 4, 6, and 8 mg/kg, with most studies using 6 mg/kg every 3 weeks. Studies investigating combination therapies were included if they reported relevant efficacy or safety outcomes. A sensitivity leave-one-out analysis was performed to explore the influence of combined therapy studies on the overall effect of our primary outcome of interest.

Outcomes and subanalyses

The primary outcome of interest was the objective response rate (ORR). Secondary outcomes included the disease control rate (DCR), progression-free survival (PFS), and incidence of adverse events (AEs) of any grade, as well as serious AEs (grade ≥3).

Subgroup analyses were conducted stratified by dosing regimens (4, 6, or 8 mg/kg), treatment settings (monotherapy or combination therapy), and tumor histology (squamous cell carcinoma versus non-squamous cell carcinoma).

Quality assessment

The Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool was used to assess the quality of nonrandomized studies (12). For randomized controlled trials (RCTs), we used the Cochrane Risk of Bias 2 Tool (RoB 2) (14). Two independent reviewers (H.K. and P.V.Z.R.) carried out this assessment, and disagreements were resolved by consensus between the authors after reviewing the full article. Following this protocol, each study was classified as low, moderate, serious, critical risk of bias or no information based on seven domains: bias due to confounding, selection of participants into the study, classification of interventions, deviations from intended intervention, missing data, in the measurement of outcomes and the selection of the reported result. Egger’s test and funnel plots of individual study weights against point estimates were used to verify publication bias.

Statistical analysis

Statistical analysis was performed using R software (version 4.2.2). We used the R packages ‘meta’, ‘metafor’, and ‘weight’. Inverse variance and random-effect models were used for all proportional meta-analyses. We used the number of events per population to carry out proportional meta-analyses, and they were reported in percentages with 95% CIs. Logit transformation was used when the individual study proportion was higher than 0.8 or lower than 0.2. Double arcsine transformation was used in studies where the proportion was zero or one. Median OS and PFS were calculated using each study’s median values and 95% CI. Heterogeneity was assessed using the I² test.

Results

Our initial search yielded 242 results. After excluding duplicates and by titles and abstracts, 32 studies were fully assessed. Most were ongoing results without published data or exploring dato-DXd in other tumors. Finally, we included seven clinical trials (phase I, II, or III) studies (Figure 1) (2,7,15-19).

Figure 1 PRISMA flow diagram of study screening and selection. Blue vertical boxes indicate each stage of the screening, and the horizontal boxes present more detailed information about the process, including the steps performed in each stage. The search was last updated on September 20th, 2024. ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology.

Baseline characteristics

Overall, 914 patients with advanced or metastatic NSCLC were included in this systematic review and meta-analysis. The median age of patients ranged from 26 to 84 years, and a minority were Asian (18.5%; n=170/914). In most studies, patients were heavily pretreated with at least two prior lines of therapies in the metastatic setting. About 36% of patients were female (n=332/914). Among five studies reporting genetics, 24.6% (n=225/914) had actionable genetic alterations. The most common dosing regimen of dato-DXd was 6 mg/kg every 3 weeks. Three studies analyzed the 4 mg/kg dose, whereas 8 mg/kg was assessed in one study only. A detailed description of individual study characteristics is presented in Table 1.

Efficacy endpoints

The overall ORR was 35% (95% CI: 27–43%) among 890 patients (Figure 2A). Among seven studies with 890 patients, 78% achieved a DCR (n=700/890; 95% CI: 75–81%) (Figure 2B). The pooled analysis of 5 studies revealed a median PFS of 5.43 months (95% CI: 4.14–7.12) (Figure 2C). The pooled median OS across three studies was 11.93 months (95% CI: 10.43–13.65) (Figure 2D). In a subgroup analysis of three studies, patients with non-squamous histology had a numerically better ORR than squamous cell patients (28% versus 8%, respectively). Still, this difference was statistically non-significant (test for subgroup difference, P=0.23) (Figure 3A). Nonetheless, the pooled analysis of two studies revealed a significantly better PFS and OS for the non-squamous cohort P<0.001; Figure 3B,3C).

Figure 2 Efficacy outcomes of NSCLC advanced/metastatic patients treated with dato-DXd. (A) Objective response rate; (B) disease control rate; (C) median progression-free survival; (D) median overall survival. Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% CI. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. Studies that appear more than once, represents subgroups according to the dose used. TROPION-Lung02 without (I) and (II) represents the whole number of patients, (I) represents a subgroup of combined 4 or 6 mg/kg Q3W, (II) represents patients on first line with 4 or 6 mg/kg Q3W; TROPION-Lung04 (I) represents cohorts that use dato-DXd on 4 mg/kg Q3W and (II) represents cohorts that use dato-DXd on 6 mg/kg; TROPION-PanTumor01 (I) represents a subgroup on 4 mg/kg Q3W, (II) 6 mg/kg Q3W, (III) 8 mg/kg Q3W. CI, confidence interval; dato-DXd, datopotamab-deruxtecan; DCR, disease control rate; mOS, median overall survival; mPFS, median progression-free survival; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; SE, standard error.

Figure 3 Efficacy of dato-DXd in NSCLC non-squamous cell vs. squamous cell carcinoma patients. (A) Objective response rate subgroup analysis; (B) median progression-free survival subgroup analysis; (C) median overall survival subgroup analysis. Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% CI. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. CI, confidence interval; dato-DXd, datopotamab-deruxtecan; mOS, median overall survival; mPFS, median progression-free survival; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; SE, standard error.

Safety endpoints

Dose reductions, dose interruptions, and treatment discontinuation due to AEs occurred in 20% (95% CI: 18–23%), 21% (95% CI: 12–35%), and 22% (95% CI: 10–40%) of cases, respectively (Figure S1A-S1C). Serious treatment-emergent AEs (TEAEs) were observed in 30% (95% CI: 19–45%) and 83 deaths were reported across 907 patients (Figure S1D,S1E).

Incidence of AEs

The incidence of all grade AEs (Figure S2) was as follows: stomatitis (n=440/907; 49%, 95% CI: 45–52%), nausea (n=400/907; 48%, 95% CI: 42–55%), alopecia (n=236/647; 39%, 95% CI: 32–46%), fatigue (n=86/317; 27%, 95% CI: 15–42%), constipation (n=86/336; 27%, 95% CI: 18–39%), anemia (n=126/668; 23%, 95% CI: 13–39%), decreased appetite (n=140/614; 23%, 95% CI: 19–26%), vomiting (n=68/317; 21%, 95% CI: 13–32%), rash (n=51/317; 16%; 95% CI: 10–26%) and diarrhea (n=59/477; 14%; 95% CI: 9–19%). Severe toxicity (grade ≥3) (Figure S3) was seen mainly with stomatitis (n=57/747; 9%; 95% CI: 1–22%), anemia (n=19/331; 7%; 95% CI: 3–17%), and nausea (n=57/733; 4%; 95% CI: 0–15%). Other severe AEs include fatigue (n=6/317; 1%; 95% CI: 0–3%), decreased appetite (n=6/614; 1%; 95% CI: 0–2%), vomiting (n=2/317; 0.6%; 95% CI: 0–2%), diarrhea (n=1/477; 0.2%; 95% CI: 0–1%) and constipation (n=1/336; 0.2%, 95% CI: 0–1%). Six studies reported interstitial lung disease (ILD). The pooled incidence of ILD was 7% (n=71/874; 95% CI: 3–13%) (Figure 4A), while grade ≥3 events occurred in 5% (n=36/774; 95% CI: 3–9%) (Figure 4B). Since not all studies contributed to all safety analyses, we included a supplementary table showing main AEs reported in each study (Table S1). For studies exploring different doses of dato-DXd, we included main AEs according to dose.

Figure 4 Incidence of ILD in advanced/metastatic NSCLC patients treated with dato-DXd. (A) All grade interstitial lung disease proportion; (B) grade ≥3 interstitial lung disease proportion. Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% CI. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. Studies that appear more than once, represents subgroups according to the dose used; TROPION-PanTumor01 (I) represents a subgroup on 4 mg/kg Q3W, (II) 6 mg/kg Q3W, (III) 8 mg Q3W. CI, confidence interval; dato-DXd, datopotamab-deruxtecan; ILD, interstitial lung disease; NSCLC, non-small cell lung cancer.

Sensitivity analysis

The leave-one-out analyses for the ORR, DCR and safety outcomes (nausea, stomatitis, anemia) revealed consistent results with the overall effect (Figure S4). The sensitivity analyses leaving studies with different doses of dato-DXd (4 and 8 mg/kg) out also revealed similar results (Figure S5).

Quality assessment

Among the six non-randomized studies, two (TROPION-PanTumor02 and TROPION-Lung04) had a limited number of patients and did not meet the selection of participants criteria. All six non-randomized studies lacked adjustment for confounding factors and failed to meet the specified criteria for the first domain (Table S2). Therefore, they were judged at a moderate risk of bias. TROPION-Lung01 was the only RCT included in this study, and it met most of the criteria for all domains that were determined to be at low risk of bias (Table S3). The funnel plot analysis revealed a wide but symmetrical distribution of studies with similar weights around the central pooled estimate (Figure S6).

Egger’s test

The Egger test for publication bias was statistically positive (t=3.88, P=0.012). However, this result should be interpreted cautiously due to the limited number of included studies (n=7), which reduces the statistical power and reliability to detect publication bias.

Discussion

This single-arm meta-analysis of seven seven clinical trials (CT; one phase III and six phase I/II) encompassing 914 heavily pretreated patients with advanced/metastatic (a/m) NSCLC treated with dato-DXd revealed an ORR of 35% and a DCR of 78%. The pooled median PFS was 5.4 months, while the median OS was 11.9 months. Severe AEs (grade ≥3) included stomatitis (9%), anemia (7%), and ILD, with an incidence of 7% for all grade AEs and 4% for AEs grade ≥3.

In the past few years, the treatment landscape for advanced NSCLC has evolved significantly with the integration of immune checkpoint inhibitors (ICIs) into first-line therapy. Studies such as KEYNOTE-189 and IMpower150 (5,20), have shown that combining pembrolizumab or atezolizumab with platinum-based chemotherapy improves OS compared to chemotherapy alone. In KEYNOTE-189, combining pembrolizumab with chemotherapy resulted in a significantly improved survival benefit. At the same time, the IMpower150 trial demonstrated improvements in OS and PFS with atezolizumab and bevacizumab in metastatic NSCLC (5,20).

Nevertheless, combined therapy has failed to show such remarkable activity in patients progressing first-line therapy. Several treatment options are available as second-line treatment for metastatic NSCLC patients (21). Yet, in this scenario, few agents have proved superior efficacy to chemotherapy alone. Thus, docetaxel and pemetrexed remain among the most widely used chemotherapies in NSCLC patients following progression on first-line treatment, with no indication for immunotherapy (22). Yet, these agents exhibit modest benefits and are accompanied by significant toxicity. Therefore, an incessant effort has been made to develop novel therapies that balance a favorable safety profile with potent antitumor activity.

In recent years, ADCs have revolutionized the treatment landscape of various tumors in different settings and scenarios. As such, the phase III DESTINY-Lung02 trial showed significant efficacy of the anti-HER2 ADC, trastuzumab deruxtecan (T-DXd), in patients with HER2-mutant NSCLC (23), which granted T-DXd accelerated approval by the Food and Drug Administration (FDA). Dato-DXd is yet another ADC being explored in the NSCLC population. T-DXd and dato-DXd share the same payload, deruxtecan, a topoisomerase inhibitor that promotes DNA damage and cell death. The latter comprises an antibody targeting TROP2, a protein overexpressed in tumor cells linked with cellular proliferation and survival, attached to deruxtecan through a cleavable linker. Like others of their class, the antibody component of dato-DXD binds to the target proteins expressed in tumor cells and is internalized into the tumor cells. Then, the payload is enzymatically released, exerting its cytotoxic effects, and can diffuse to nearby cells.

The phase III TROPION-Lung01 trial is the first randomized study to explore the efficacy of dato-DXd in metastatic NSCLC (7). This study randomized 299 and 305 patients to dato-DXd and docetaxel, respectively. A 25% improvement in PFS was seen in favor of the ADC arm (HR 0.75, 95% CI: 0.62–0.910; P=0.004). The ORR and DCR were 26.4% and 77.3% for the dato-DXd arm, compared to 12.8% and 64.9%, respectively, for the chemotherapy group. However, in this study, dato-DXd failed to improve the OS of patients. The authors highlighted that the histological subtype played an essential role in its therapeutic efficacy. The subgroup of patients with nonsquamous cell tumors achieved superior survival rates on dato-DXd compared to the squamous cell group, with a median PFS of 5.5 versus 2.8 months, respectively. This may be attributed to heterogeneous TROP2, lysosomal proteases and drug efflux pump expression across different histologic subtypes. In our study, we found a trend toward higher but nonsignificant ORR in favor of the squamous cell cohort. Nevertheless, in the pooled analysis of two studies, significantly better PFS and OS were seen in favor of the non-squamous cell carcinoma cohort.

Our pooled analysis for ORR yielded a slightly higher rate (35%) compared to that reported in TROPION-Lung01. On the other hand, both the phase III trial and our meta-analysis yielded a DCR higher than 75%. The early-phase TROPION-Lung02 and -04 were phase Ib studies exploring dato-DXd at a dose of 4 or 6 mg/kg in combination with other agents (i.e., immunotherapy and chemotherapy). The responses reported across multiple cohorts varied from around 30 to up to 70%. This may be attributed to a somewhat heterogeneous population, in which some patients were heavily pretreated, and others received dato-DXd-combined regimens in the first-line setting. Yet, our leave-one-out sensitivity analyses for ORR, DCR and safety outcomes (nausea, stomatitis and anemia) yielded consistent results, which suggest that the use of different doses has not remarkably impacted the efficacy and safety of dato-DXd. While analyses according to histological subtypes (squamous vs. non-squamous) is clinically relevant, the available data were insufficient across the studies. The upcoming phase III TROPION-Lung07 and -08 trials will assess dato-DXd combined with pembrolizumab and platinum-based chemotherapy (NCT05555732) (24), and dato-DXd plus pembrolizumab (NCT05215340) (25), respectively, as first-line therapy for advanced NSCLC. These studies will provide robust evidence on dato-DXd-combined regimens in treatment-naive patients and will aid in establishing an ideal sequence of treatment for this population.

Moreover, mutational status may also affect the response to dato-DXd in NSCLC patients. In this meta-analysis, we could not perform pooled analyses according to the mutational profile due to the unavailability of data from individual studies. However, the TROPION-Lung01 trial demonstrated that the degree of benefit varied based on the presence of actionable genomic alterations (7). Dato-DXd showed numerically greater efficacy than docetaxel in patients harboring genomic alterations such as EGFR mutations or ALK rearrangements. Therefore, many factors play a role in determining ADC efficacy, highlighting the need to integrate molecular profiling into ADC treatment decision-making.

In this study, we found a substantial incidence of AEs. Specifically, all grade stomatitis, nausea, and alopecia were higher than 35%. Yet, severe toxicity rates were lower than 10%, with the most reported AEs being stomatitis, anemia, and nausea. One of the mechanisms related to ADC’s toxicity is the payload release and the mechanism of action. Both T-DXd and dato-DXd share the same payload. Interestingly, studies reported slightly different safety profiles. In the DESTINY-Lung01 study (26), the most common all-grade AEs were nausea (73%) and fatigue (53%). In this study, ILD was seen in 26% of patients, whereas in this meta-analysis, our analysis revealed an incidence of ILD of 7%, with grade ≥3 events occurring in 4% of patients. Several risk factors are common to both ILD and NSCLC. Therefore, early AE detection and management, and close vigilance are essential to mitigate ILD risks. In our meta-analysis, 22% of patients required treatment discontinuation. Although most patients were heavily pretreated, and we could not assess the impact of cumulative toxicity, the safety profile of dato-DXd requires further investigation.

Based on the findings of our meta-analysis, dato-DXd at the optimal dose of 6 mg/kg offers a promising option for advanced or metastatic NSCLC patients who have received prior lines of treatment. Patients and clinicians should be vigilant regarding potential AEs, mainly gastrointestinal events, alopecia, and ILD. As of the time being, dato-DXd for NSCLC patients is under priority review by the FDA, and a decision is expected in a few months (27). The promising results observed with dato-DXd in a/m NSCLC highlight its potential role beyond second-line settings. Future studies evaluating its use in earlier lines of therapy are awaited.

Moreover, combined treatment with other agents, such as immunotherapy and ICIs, may potentiate antitumor activity, particularly in patients with elevated TROP2 expression. Comparative studies against other ADCs, such as T-DXd, could provide insights into optimizing patient selection and sequencing of these therapies. As ADC technology continues to advance, the development of next-generation linkers and payloads may further enhance efficacy while minimizing toxicity, particularly ILD. Furthermore, exploring the utility of dato-DXd in other TROP2-expressing malignancies may expand its therapeutic application. These advancements could redefine the standard of care in NSCLC, offering new horizons for patients with limited options and poor survival.

This study has limitations. Some studies included in this meta-analysis were conference presentations with preliminary results only, and others had small sample sizes, which may affect applicability. As most studies were non-randomized, single-arm trials, they were subject to confounders, limiting comparisons to standard-of-care regimens. Heterogeneity in study design, patient selection, and endpoint definitions varied across interpretations of results. Due to the lack of data from individual studies, we could not perform subgroup analyses based on essential factors such as brain metastasis status, number of prior treatments, targetable mutations or prior immunotherapy exposure. Similarly, the lack of uniform TROP2 expression reporting limited biomarker evaluation. We did, however, perform subgroup analyses according to histology and dosing. While ORR was a primary endpoint, PFS and OS are more clinically relevant for later-line treatment, as highlighted in our discussion. Lastly, the evaluation for publication bias is limited due to the small number of studies included (<10).

Conclusions

This meta-analysis of seven studies with 914 a/m NSCLC patients revealed remarkable antitumor responses of dato-DXd in this population. The ORR was 35%, and the DCR was 78%. Median PFS and OS were 5.4 and 11.9 months, respectively. We also observed quite elevated toxicity rates, mainly stomatitis and nausea. Nearly one-quarter of patients required treatment discontinuation due to AE. Additional data from ongoing studies will further clarify the efficacy and safety of dato-DXd in patients with a/m NSCLC.

Acknowledgments

The abstract of this work was previously presented at the European Lung Cancer Congress (ELCC) 2025, Paris, by the author H.K.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-583/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-583/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-583/coif). V.C.C.d.L. received a consulting fee from Roche; received honoraria for lectures, presentations, manuscript writing, and educational events from Roche Brasil, MSD Brasil, BMS Brasil, Janssen, Daichii-Sankyo, Lilly, Pfizer, and Astra Zeneca; received financial support to attend scientific meetings and travels from Astra-Zeneca, Roche, and Daichii-Sankyo; participated in advisory boards for Roche Brasil, Amgen, Janssen, Daichii-Sankyo, Pfizer, Astra-Zeneca, and GSK; Additionally, he is on leadership or fiduciary role in other board, society, committee or advocacy group, is the actual president of The Brazilian Group of Thoracic Oncology, the vice-president of the Lung Cancer Steering Committee – Latin America Cooperative Oncology Group and the Coordinator of the Thoracic Cancer Committee of the Brazilian Society of Clinical Oncology. H.C.F. has received payment or honoraria for lectures, presentations, speaker bureaus, or educational from MSD, Roche, Lilly, Pfizer, Takeda, BMS, Amgen, Astra-Zeneca, and Merck; support for attending meetings or travel from BMS, MSD, Pfizer, Roche, Astra-Zeneca, Takeda, and Sanofi; participates in advisory boards for MSD, Pfizer, Takeda, Roche, BMS, Astra-Zeneca, and Sanofi. Additionally, his spouse works in the clinical research department of Astra-Zeneca. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74:12-49. [Crossref] [PubMed]
2. Sands J, Ahn MJ, Lisberg A, et al. Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study. J Clin Oncol 2025;43:1254-65. [Crossref] [PubMed]
3. Key Statistics for Lung Cancer [Internet]. Available online: https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html
4. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med 2023;389:1935-48. [Crossref] [PubMed]
5. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol 2023;41:1992-8. [Crossref] [PubMed]
6. Peters S, Loi S, André F, et al. Antibody-drug conjugates in lung and breast cancer: current evidence and future directions-a position statement from the ETOP IBCSG Partners Foundation. Ann Oncol 2024;35:607-29. [Crossref] [PubMed]
7. Ahn MJ, Tanaka K, Paz-Ares L, et al. Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study. J Clin Oncol 2025;43:260-72. [Crossref] [PubMed]
8. Lu Y, Liang S, Hong Y, et al. Application of the model-informed drug development paradigm to datopotamab deruxtecan dose selection for late-stage development. CPT Pharmacometrics Syst Pharmacol 2024;13:23-8. [Crossref] [PubMed]
9. Bardia A, Jhaveri K, Im SA, et al. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol 2025;43:285-96. [Crossref] [PubMed]
10. Okajima D, Yasuda S, Maejima T, et al. Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells. Mol Cancer Ther 2021;20:2329-40. [Crossref] [PubMed]
11. Heist RS, Sands J, Bardia A, et al. Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan. Cancer Treat Rev 2024;125:102720. [Crossref] [PubMed]
12. Higgins J. Cochrane Handbook for Systematic Reviews of Interventions [Internet]. 2024. Available online: https://training.cochrane.org/handbook/current
13. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372: [Crossref] [PubMed]
14. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. [Crossref] [PubMed]
15. Shimizu T, Sands J, Yoh K, et al. 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. J Clin Oncol 2023;41:4678-87. [Crossref] [PubMed]
16. Sun Y, Xiao Z, Cheng Y, et al. Datopotamab deruxtecan (Dato-DXd) in Chinese patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Results from the phase 1/2 TROPION-PanTumor02 study. J Clin Oncol 2024;42:suppl.8548.
17. Levy BP, Paz-Ares LG, Su WC, et al. Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC): Subgroup analysis from TROPION-Lung02. J Clin Oncol 2024;42:suppl 16; abstr 8617.
18. Papadopoulos KP, Bruno D, Kitazono S, et al. OA05.06 Datopotamab Deruxtecan (Dato-DXd) + Durvalumab ± Carboplatin in Advanced/mNSCLC: Initial Results from Phase 1b TROPION-Lung04. J Thorac Oncol 2023;18:S55.
19. Planchard D, Cozic N, Wislez M, et al. ICARUS-LUNG01: A phase 2 study of datopotomab deruxtecan (Dato-DXd) in patients with previously treated advanced non-small cell lung cancer (NSCLC), with sequential tissue biopsies and biomarkers analysis to predict treatment outcome. J Clin Oncol 2024;42:suppl.8501.
20. Zhou C, Dong X, Chen G, et al. Atezolizumab plus bevacizumab and chemotherapy in metastatic nonsquamous NSCLC: the randomized double-blind phase 3 IMpower151 trial. Nat Med 2025;31:2375-84. [Crossref] [PubMed]
21. Leighl NB, Ismaila N, Durm G, et al. Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3. J Clin Oncol 2025; [Crossref]
22. Leal TA, Dasgupta A, Latremouille-Viau D, et al. Real-World Treatment Patterns and Clinical Outcomes After Platinum-Doublet Chemotherapy and Immunotherapy in Metastatic Non-Small Cell Lung Cancer: A Multiregional Chart Review in the United States, Europe, and Japan. JCO Glob Oncol 2024;10:e2300483. [Crossref] [PubMed]
23. Janne PA, Goto Y, Kubo T, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant metastatic non–small cell lung cancer (mNSCLC): Final analysis results of DESTINY-Lung02. J Clin Oncol 2024;42:8543.
24. Okamoto I, Kuyama S, Girard N, et al. TROPION-Lung07: Phase III study of Dato-DXd + pembrolizumab ± platinum-based chemotherapy as 1L therapy for advanced non-small-cell lung cancer. Future Oncol 2024;20:2927-36. [Crossref] [PubMed]
25. Levy BP, Felip E, Reck M, et al. TROPION-Lung08: phase III study of datopotamab deruxtecan plus pembrolizumab as first-line therapy for advanced NSCLC. Future Oncol 2023;19:1461-72. [Crossref] [PubMed]
26. Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol 2024;25:439-54. [Crossref] [PubMed]
27. FDA Grants Priority Review to Dato-DXd in Advanced EGFR-Mutated NSCLC. 2025 Jan 14; Available online: https://www.targetedonc.com/view/fda-grants-priority-review-to-dato-dxd-in-advanced-egfr-mutated-nsclc#