Antibody–drug conjugates (ADCs) are complex molecules composed of a monoclonal antibody, a linker and a cytotoxic payload. Their design enables the selective delivery of cytotoxic agents to tumoral cells through antibody binding to a tumor-expressed antigen, followed by internalization, intracellular degradation and payload release, ultimately enabling the cytotoxic drug to exert its antitumor activity. ADCs have been evaluated in phase II and III trials in previously treated advanced non-small cell lung cancer (NSCLC), both in oncogene-addicted and in non-oncogene-addicted tumors, addressing resistance to standard therapies. Ongoing clinical trials are now expanding their use both in the first-line setting for advanced disease and in earlier disease stages. This narrative review summarizes the currently available data for ADC treatment in NSCLC, highlighting the need for improved patient selection to maximize benefit while limiting toxicity, incorporating clinical characteristics, pharmacogenomics and optimal treatment sequencing in the equation. Moreover, the understanding of resistance mechanisms and the development and validation of predictive biomarkers will be of utmost relevance to inform clinical practice.

Abstract Lung cancer is classically linked to tobacco, yet in East Asia, a striking proportion arises in never-smokers—accounting for up to 48% of cases in Singapore. Paradoxically, these lung cancers in never-smokers (LCINS), often driven by EGFR mutations, exhibit a lower tumour mutation burden than smoking-associated counterparts, yet remain highly aggressive. This is particularly relevant for Asian women, where EGFR mutations are found in over 70% of LCINS cases. To understand the oncogenic mechanisms in EGFR-mutant LCINS, we conducted the largest multi-region whole-exome and transcriptome sequencing study to date, spanning 578 tumour samples from 180 early-stage, treatment-naïve patients. Despite low point mutation rates, our findings revealed pervasive chromosomal instability and frequent clonal whole-genome doubling in EGFR-mutant LCINS. We observed recurrent arm-level amplifications of 1q, 5p, and 7p, suggesting a deterministic chromosomal evolution. Transcriptomic analysis further demonstrated that these amplified regions confer significant proliferative and survival advantages, identifying a key mechanism of EGFR-driven tumorigenesis in LCINS. Importantly, unsupervised clustering of EGFR-mutant LCINS cases identified four subtypes with distinct evolutionary trajectories: 1) “Mosaic”, characterized by genomic diploidy and high intra-tumour heterogeneity; 2) two chromosomally unstable subtypes, “Unstable” and “Doubler”, exhibiting increasing genomic chaos; and 3) a rare “Mutator” subtype, with high APOBEC activity and CD8+ T-cell infiltration. Together, our findings shed light on how EGFR mutations drive lung cancer in never-smokers and offer a framework for subtype-specific prognostication and therapeutic intervention in early-stage disease. Citation Format: Komal Gupta, Dawn Lau Pingxi, Kenneth Chow, Ngak Leng Sim, Mengyuan Pang, Stephanie P L Saw, Wanjin Hong, Anders Jacob Skanderup, Regina Hoo, Daniel Shao Weng Tan. How EGFR Mutations Shape Lung Cancer in Never-Smokers [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr LT05.

BACKGROUND:Despite surgery or EGFR-targeted therapy, EGFR-mutant lung adenocarcinoma frequently recurs. Conventional staging and binary EGFR mutation status lack sufficient precision for risk stratification. Although variant allele fraction (VAF) reflects tumor clonality and allelic imbalance, the prognostic significance of DNA- and RNA-derived VAF in early-stage disease remains unclear. METHODS:We analyzed multi-omics data from patients with EGFR-mutant LUAD in the Taiwan Cancer Moonshot Program (RFS, n=133; TKI, n=48) and an independent Singaporean validation cohort (RFS, n=54; TKI, n=17). Whole-exome and RNA sequencing were integrated to quantify DNA and RNA VAFs. Patients were stratified into risk groups based on combined VAF measures. Associations with relapse-free survival (RFS) in stage I-III disease and progression-free survival (PFS) during TKI therapy were evaluated using multivariable Cox model adjusted for clinical covariates. RESULTS:VAF-based stratification identified a Low-risk group with a 5-year relapse rate of 11%, independent of pathological stage (p<0.001). Within this group, elevated TP53 RNA VAF was associated with increased relapse risk and younger age at diagnosis. Exploratory analyses comparing timing of TKI therapy indicated context-dependent associations: High-risk patients had shorter PFS when TKI therapy was deferred until relapse (p=0.047). In the adjuvant setting, mid- and high-risk patients showed numerically improved PFS with TKI therapy compared with low-risk patients (p=0.13). CONCLUSIONS:Integration of DNA and RNA EGFR VAFs refines risk stratification beyond stage and mutation status alone and may inform the timing of TKI therapy. Prospective validation is warranted.

Although immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) have transformed the treatment of non-small cell lung cancer (NSCLC) across disease stages, real-world access remains highly unequal worldwide. Persistent cost barriers, fragmented reimbursement frameworks, and heterogeneous regulatory pathways limit equitable availability. The rapid proliferation of me-too agents has been proposed to counter monopolies; yet, this expansion has not consistently improved affordability. Heterogeneous evidentiary requirements-along with differences in clinical end points, comparator selection, crossover policies, and treatment duration-fragment therapeutic markets and complicate assessment of incremental clinical benefit. Divergent regulatory decisions, particularly between the US Food and Drug Administration and European Medicines Agency, underscore how trial design and geographic representation influence drug availability, especially when approvals rely on single-country data sets. These challenges are amplified in perioperative treatment strategies and rare oncogene-defined subgroups, where feasibility constraints and limited clinical equipoise hinder large randomized trials. As a result, an increasingly crowded therapeutic landscape makes cross-trial comparisons difficult and allows disparities in patient access to persist despite multiple approved therapies. Dose selection has historically followed maximum tolerated dose principles, even when preclinical and pharmacologic data suggest activity plateaus at lower exposure of ICI and TT. Dose and schedule optimization-through reduced dosing, extended intervals, or other deintensified strategies-therefore represents a rational and ethically grounded approach with a meaningful clinical impact. Such strategies may preserve efficacy while improving tolerability, reducing treatment burden, and mitigating financial toxicity, particularly in resource-limited settings. Aligning regulatory frameworks with dose optimization could promote more scalable, equitable, and sustainable NSCLC innovation.

The treatment of early-stage non-small-cell lung cancer (NSCLC) has evolved substantially in recent years. For decades, curative-intent surgery followed by platinum-based chemotherapy remained the standard of care (SOC), despite delivering only modest gains in long-term survival. Current evidence from randomised trials incorporating immunotherapy as a neoadjuvant or perioperative approach, along with targeted therapies, have defined a new SOC treatment approach for patients with resectable early-stage NSCLC. However, these advances have introduced uncertainties regarding optimal sequencing, treatment duration, patient selection, and the role of treatment escalation or de-intensification with immunotherapy and targeted therapies. The advances and uncertainties are discussed in this Series paper, along with the role of radiotherapy in this setting.

The role of radiotherapy (RT) in stage IV NSCLC has traditionally been palliative; however, with advancements in systemic therapies and insights into the evolutionary processes underpinning advanced disease, the rationale for aggressive primary-tumor control has received renewed interest. This International Association for the Study of Lung Cancer (IASLC) consensus statement evaluates the current evidence for the role, timing, dosing, target volumes, and safety of primary-tumor RT in both actionable genomic alterations (AGA) and non-AGA metastatic NSCLC populations.The IASLC Advanced Radiation Technology subcommittee convened a multidisciplinary, international expert panel including radiation oncologists and medical oncologists from the IASLC Multidisciplinary Clinical Sciences Committee. Randomized studies published from 2010 to 2025 evaluating RT to the primary lung tumor in metastatic NSCLC populations (AGA and non-AGA) were identified through PubMed, and relevant published and presented abstracts were included. Evidence was synthesized and discussed to achieve consensus recommendations.In EGFR-mutant oligometastatic NSCLC, randomized phase III evidence supports early delivery of RT, conveyed as consolidation after induction systemic therapy, as a promising life-prolonging approach. In non-AGA populations, direct randomized evidence isolating the impact of primary irradiation remains limited. Emerging randomized data suggest dose escalation of definitive thoracic RT regimens may improve locoregional control compared with lower-dose approaches. Fractionation should be individualized to the primary tumor location to mitigate cardiopulmonary adverse events. Optimal target volumes remain uncertain, and the benefit of excluding involved thoracic lymph nodes has not yet been formally investigated in large, randomized trials. Safety data indicate toxicity is generally additive when RT is integrated with systemic agents; however, careful monitoring and recording of adverse events are important to ensure the addition of RT does not affect systemic therapy discontinuation rates.Definitive-dose RT to the primary lung tumor in metastatic NSCLC is supported by a growing biologic rationale and emerging trial data, with the strongest evidence in EGFR mutant populations. For patients without AGAs, preliminary findings are encouraging but insufficient for definitive treatment recommendations. The paucity of data necessitates prospective trials that isolate the contribution of primary-tumor RT, confirm its safety, and define the optimal RT sequencing, dose, and target volumes.

The discovery of activating epidermal growth factor receptor (EGFR) mutations transformed the management of non-small cell lung cancer and has driven two decades of therapeutic advances in precision oncology across metastatic, resectable, and unresectable locally advanced disease, including central nervous system (CNS) control. Consequently, treatment outcomes for patients with tumors harboring classical EGFR mutations have markedly improved. Despite these advances, many questions remain unanswered, and the expanding number of treatment options has created new challenges in treatment selection and sequencing. This narrative review summarizes contemporary data on the management of classical EGFR-mutant NSCLC, encompassing novel therapeutic approaches across disease stages, biomarker-informed resistance strategies, multimodality treatment integrating radiotherapy, CNS-directed management, and challenging scenarios such as small-cell transformation. We also discuss emerging fourth-generation inhibitors, nucleic-acid delivery platforms, and data-enabled personalized treatment. We highlight evolving standards of care, unresolved knowledge gaps, and research priorities for the next decade.

MET alterations, mainly gene amplification and protein overexpression, represent a major mechanism of primary and acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated (EGFRm) NSCLC. Both de novo and acquired MET dysregulation can activate downstream oncogenic signaling, providing a strong rationale for dual inhibition of EGFR and MET. This review summarizes the data for targeting MET alterations in EGFRm NSCLC, with emphasis on the clinical relevance of distinguishing MET amplification from c-MET overexpression. We discuss contemporary diagnostic strategies, including tissue-based fluorescence in situ hybridization, next-generation sequencing, and immunohistochemistry, and the limitations of circulating tumor DNA (ctDNA) assays. We then review the clinical data supporting EGFR- and MET-directed approaches across the therapeutic classes, including tyrosine kinase inhibitors, antibody-drug conjugates, and bispecific antibodies. Finally, we highlight unresolved challenges including the lack of standardized biomarker thresholds, optimal timing of MET inhibition, and rational sequencing of available agents. As the therapeutic landscape continues to evolve, improved biomarker precision and optimization of treatment strategies will be essential to maximize the benefit of MET-targeted therapies in EGFRm NSCLC.

Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate currently under investigation in clinical trials of various solid tumors. In this manuscript, an international steering committee formed by medical oncologists, ophthalmologists, and pulmonologists reached consensus to provide multidisciplinary healthcare professionals (HCPs) with practical recommendations for Dato-DXd adverse event (AE) prevention, monitoring, and management in patients with advanced/metastatic non-small cell lung cancer. Experts’ recommendations focused on the following AEs: oral mucositis/stomatitis, interstitial lung disease/pneumonitis, ocular surface events, nausea, and vomiting. Based on available guidelines, clinical trials data, and real-world experience, 55 statements were developed and, as per Delphi methodology, all reached consensus with more than 75% of experts’ agreement. The key recommendations include preventive measures, such as proactive communication between patients and caretakers, regular clinical examinations, collaboration with multidisciplinary HCPs; and monitoring measures, such as treatment dosage and care planning decisions based on the level of severity of each AE. Experts pointed out real-world challenges and local differences on AEs management and gave insight into implementation of regional strategies with a multidisciplinary collaboration approach. Dato-DXd AEs awareness, understanding, and proper management via a well-established multidisciplinary collaboration is crucial to guarantee patients’ quality of life. This international consensus aims to provide comprehensive recommendations for Dato-DXd AEs management, considering the regional and institutional differences present in the healthcare system, such as access to examinations and treatment possibilities.

KRAS G12C-mutant non-small cell lung cancer (NSCLC) occurs in approximately 15% of NSCLC with historically limited targeted treatment options. Both KRAS "OFF"" G12C inhibitors, sotorasib and adagrasib, are considered standard second-line therapy, albeit with a modest progression-free survival benefit over standard chemotherapy. Emerging next-generation KRAS "OFF" G12C inhibitors, as well as KRAS "ON", dual "ON/OFF", and pan-(K)RAS "ON" inhibitors, show promising early efficacy and safety profiles in second-line, though confirmatory phase III trials are pending. In the first-line setting, KRAS inhibitor-immunotherapy combinations appear particularly promising in tumors with high programmed death-ligand 1 (PD-L1) expression. However, incorporating KRAS inhibitors into chemoimmunotherapy regimens may yield more consistent and clinically meaningful benefit across patient populations, irrespective of PD-L1 expression. Critical clinical questions remain open regarding the optimal patient population for combinations, the influence of co-occurring genomic alterations, intracranial activity of KRAS inhibitors and dose optimization. This review synthesizes current evidence on the biology, clinical efficacy, safety, and practical considerations for treating KRAS G12C-mutant NSCLC, providing clinicians with an up-to-date, evidence-based framework for therapeutic decision-making and highlighting areas requiring further investigation.

INTRODUCTION:Even though PD-(L)1 inhibitors have dramatically changed the prognosis of patients with advanced non-small-cell lung cancer (NSCLC), resistance to treatment remains common. Rechallenge with PD-(L)1 based regimens has been explored in this context, but clinical benefit remains uncertain. METHODS:Two independent reviewer teams performed parallel searches of MEDLINE and EMBASE from 2019 to 2025 to identify clinical trials evaluating PD-(L)1 inhibitor based rechallenge strategies in patients with advanced NSCLC previously treated with PD-(L)1-based regimens. Randomised controlled trials (RCTs) were included in quantitative meta-analysis, while non-randomised single-arm studies were synthesised descriptively. The primary endpoint was overall survival (OS). Sensitivity analyses examined outcomes according to resistance pattern. All analyses used fixed-effects models. FINDINGS:A total of 10 RCTs (n = 3,081) and 106 non-randomised interventional trials were included. Across RCTs, PD-(L)1 based rechallenge strategies yielded modest improvements in both OS (HR 0.91, 95%CI: 0.82-0.99) and PFS (HR 0.89, 95%CI: 0.81-0.99) compared with the control arms, with no improvement in objective response rate (ORR). In sensitivity analyses, no benefit was observed in patients with primary resistance, whereas those with acquired resistance features (i.e., clinical benefit to prior immunotherapy) demonstrated a more favourable effect for OS (HR 0.86, 95%CI: 0.77-0.97). A more restrictive analysis excluding patients with < 3 months of prior PD-(L)1 exposure confirmed this pattern. Across the 106 single-arm trials, ORR varied widely, with only speculative signals of higher activity in regimens incorporating VEGF-targeting or chemotherapy. CONCLUSIONS:In the largest synthesis of rechallenge strategies to date, PD-(L)1 rechallenge produced statistically significant but clinically marginal improvements in OS and PFS compared with standard treatments, with no benefit in patients with primary resistance. A signal of benefit was observed in patients with acquired resistance to prior immunotherapy although this exploratory analysis was limited by heterogeneous resistance definitions across trials and a non-significant interaction test.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Unlike smoking-related NSCLC, the incidence of lung cancer among never-smokers in East Asia is rising, often driven by oncogenes such as EGFR. While Tyrosine Kinase Inhibitors (TKIs) have improved outcomes in EGFR-mutated NSCLC, resistance remains a significant challenge. Identifying the genomic and transcriptomic features that underpin tumour progression and relapse in early-stage EGFR-mutated NSCLC in non-smokers is crucial for developing novel therapeutic approaches to improve patient outcomes. Due to the diverse evolutionary trajectories of EGFR mutated NSCLC, our capacity to forecast disease trajectory is still limited. To address this, we performed 578 multi-region whole-exome and transcriptome sequencing from 180 treatment naïve early-stage EGFR-mutated resected NSCLC tumours. Among these, 56 (31%) patients eventually relapsed, while 124 (69%) did not, with a mean follow-up of 5.4 years. Our findings revealed that driver mutations in EGFR, TP53, and RBM10 were predominantly clonal, while a multitude of subclonal driver mutations contributed to increased tumour diversity. Interestingly, mutational signature SBS40a, of unknown origin, was prevalent as clonal alterations, suggesting early involvement in EGFR-mutated tumours. Notably, relapsed tumours exhibited distinct genomic features, including elevated subclonal APOBEC mutational signatures, higher rates of whole-genome doubling, and increased chromosomal aberrations, linking these features to greater mutational burden, intra-tumour heterogeneity and poorer outcomes. Overall, our results demonstrate the diversity of clonal and subclonal mutational processes that shape the clonal architecture of EGFR-mutated NSCLC in non-smokers and identify key features driving relapse. Ongoing efforts are focused on leveraging these features to identify potential prognostic markers for risk stratification and therapeutic targets for early-stage disease. Komal Gupta, Dawn Lau Pingxi, Ngak Leng Sim, Kenneth Chow, Lan Ying Wang, Mengyuan Pang, Stephanie Saw, Wanjin Hong, Anders Martin Jacobsen Skanderup, Regina Hoo, Daniel Shao Weng Tan. Decoding tumour evolution and relapse drivers in EGFR mutant NSCLC in never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1251.

The advent of antibody-drug conjugates (ADCs) aims to transform the therapeutic landscape of advanced non-small cell lung cancer (NSCLC). The distinctive architecture of ADCs enables the targeted delivery of highly potent cytotoxic payloads directly to cancer cells that express the molecular target specified by their monoclonal antibody component. This precision targeting stems from the notion that ADCs may be highly effective therapeutic agents, particularly for treating NSCLC tumors harboring actionable genomic alterations (AGAs). In this context, ADCs can be categorized into two main types: Biomarker-selected ADCs, which require the tumor to present a specific pattern of the protein targeted by the ADC (e.g., MET overexpression, HER2 overexpression or mutation) and formally requiring biomarker testing, and biomarker-agnostic ADCs, which target proteins that are broadly expressed in lung cancer cells (e.g., anti-TROP2 or HER.3 ADCs), and hence no pre-testing is required. The cytotoxic payload is expected to be delivered in high concentration in the cancer cells carrying the corresponding target of interest, while minimizing off-target toxicity. In this review, we describe available evidence regarding the efficacy and safety of ADCs in NSCLC harboring AGAs. We also discuss the challenges with respect to appropriate biomarker selection, dose optimization, treatment duration, and optimization of the structural design of ADC components to maximize efficacy while minimizing off-target toxicity. Finally, addressing cost-effectiveness concerns remains critical for their successful adoption within healthcare systems.

INTRODUCTION:HER2-directed treatments for HER2-overexpressing (HER2-OE; immunohistochemistry [IHC] 3+/2+) NSCLC are needed. METHODS:DESTINY-Lung03 is an open-label, multi-arm, phase 1b study. Part 1 evaluated trastuzumab deruxtecan (T-DXd, 4.4 or 5.4 mg/kg) plus durvalumab (1120 mg) and cisplatin (60 or 75 mg/m2; Arm 1A)/carboplatin (area under the plasma concentration-time curve [AUC] 4 or 5; Arm 1B) or T-DXd 5.4 mg/kg monotherapy (Arm 1D) in pretreated metastatic HER2-OE NSCLC. Primary end points: dose-limiting toxicities (DLTs) and adverse events (AEs: Arms 1A and 1B). Secondary end points: safety (Arm 1D) and efficacy (all arms). RESULTS:At data cutoff (April 1, 2024), 11, 24, and 36 patients received treatment in Arms 1A, 1B, and 1D, respectively. DLTs reported in Arm 1A: febrile neutropenia (n = 1; grade [G] 5; 4.4 mg/kg/1120 mg/60 mg/m2 doses); decreased platelet count (n = 2; G4 and G5; 5.4 mg/kg/1120 mg/75 mg/m2 doses). DLTs reported in Arm 1B: febrile neutropenia (n = 1; G3; 4.4 mg/kg/1120 mg/AUC 5 doses; n = 1; G4; 4.4 mg/kg/1120 mg/AUC 4 doses); decreased platelet count (n = 1; G4; 5.4 mg/kg/1120 mg/AUC 5 doses). Drug-related serious AEs occurred in 63.6%, 37.5%, and 16.7% of Arms 1A, 1B, and 1D, respectively. Confirmed objective response rate (95% confidence interval) per investigator: 37.5% (18.8-59.4; Arm 1B) and 44.4% (27.9-61.9; Arm 1D). CONCLUSIONS:Data confirm the activity of T-DXd monotherapy in pretreated HER2-OE NSCLC but do not support T-DXd plus durvalumab and platinum chemotherapy use in this population. CLINICAL TRIALS: GOV IDENTIFIER:NCT04686305.

The peri-operative management of non-small cell lung cancer (NSCLC) in earlier stage disease has seen significant advances in recent years with the incorporation of immune checkpoint inhibitors and targeted therapy. However, many unanswered questions and challenges remain, including the application of clinical trial data to routine clinical practice. Recognising the unique demographic profile of Asian patients with NSCLC and heterogeneous healthcare systems, the Asian Thoracic Oncology Research Group (ATORG) convened a consensus meeting in Singapore on 26 April 2024 to discuss relevant issues spanning diagnostic testing to post-neoadjuvant treatment considerations and future directions. An interdisciplinary group of 19 experts comprising medical oncologists, thoracic surgeons, radiation oncologists, pulmonologists and pathologists from Singapore, Hong Kong, Mainland China, Korea, Japan, Taiwan, India, Malaysia, Thailand, Vietnam and Australia met to discuss emerging data, identify existing gaps in clinical care and develop a multidisciplinary, multinational expert consensus statement on the peri-operative management of NSCLC tailored to the Asia-Pacific region.

Background: The predictive value of PD-L1 to select patients for immunotherapy in resectable NSCLC remains imprecise, confounded by different assays used across trials and intra-tumoural heterogeneity (ITH). We sought to compare the concordance between 3 PD-L1 antibodies stratified by EGFR mutation status, evaluate ITH and implications on survival outcomes. Methods: Tissue microarrays were constructed from stage IA-IIIA NSCLC with 3 tumour cores per patient. Tumour proportion score (TPS) was evaluated by 3 pathologists for SP263, SP142, 22C3 and analysed in tertiles of < 1 %, 1-49 % and >= 50 %. ITH was defined as discordant TPS in >= 2/3 tumour cores. Cohen's kappa test was used to assess agreement. Survival outcomes were estimated using Kaplan-Meier. Results: A total of 561 patients were included, 59.5% (334/561) were EGFR-mutant. Stage IA comprised 45.5%(255/561), IB 24.1%(135/561), IIA 12.7%(71/561), IIB 4.5%(25/561) and IIIA 13.4%(75/561). Across 1683 tumour cores, SP263 and 22C3 had the highest concordance (Kappa = 0.689), followed by 22C3 and SP142 (Kappa = 0.354), then SP263 and SP142 (Kappa = 0.284), similar between EGFR-mutant and EGFR-wildtype. Agreement between pathologists was almost perfect. ITH by SP263 was observed in 14.1 % of EGFR-mutant versus 24.2 % in EGFR-wildtype(p = 0.002). Discordance was highest among TPS 1-49 % at 92.6 % (88/95) followed by >= 50 % at 37.8 % (14/37) and least among < 1 % at 0 % (0/429) (p < 0.001). For tumour cores scored 1-49 %, 63 %/70 % of adjacent cores were scored < 1 % for EGFR-wildtype/mutant respectively. Histological grade was the only independent predictor of PD-L1 ITH on multivariable analysis. PD-L1 ITH was not associated with survival on multivariable analysis. Conclusion: PD-L1 scoring by SP263 and 22C3 are interchangeable but not SP142 regardless of EGFR status. PD-L1 ITH was more common in EGFR-wildtype versus EGFR-mutant tumours. Extra care should be taken to select the most representative tumour core for tumours with high histological grade or TPS 1-49% as this may influence peri-operative treatment decisions.

Antibody-drug conjugates (ADCs) represent a rapidly evolving class of therapeutics in non-small cell lung cancer (NSCLC), offering targeted delivery of cytotoxic payloads to tumor cells while minimizing off-target toxicity. Although ADCs have demonstrated promising results in NSCLC, their efficacy in treating central nervous system (CNS) metastases has been uncertain due to concerns over blood-brain barrier (BBB) penetration and the lack of dedicated CNS-specific evaluations in clinical trials. However, emerging evidence challenges this paradigm. While earlier-generation ADCs such as T-DM1 exhibited limited CNS efficacy, newer ADCs employing optimized linkers and cytotoxins demonstrate more favorable efficacy and toxicity profiles. Selected agents, including trastuzumab deruxtecan, datopotamab deruxtecan and patritumab deruxtecan, have all shown intracranial responses in patients with advanced NSCLC with brain metastases (BM). Proposed mechanisms facilitating CNS activity include BBB disruption by BM, membrane-permeable and highly potent cytotoxic payloads, and bystander effects that enable tumor cell killing beyond the target antigen. Nevertheless, several limitations remain, including variability in trial designs, limited number of patients with untreated CNS disease, and a lack of CNS-specific endpoints. Given the high incidence of BM in NSCLC and their significant impact on patient outcomes, there is an urgent need to better understand the intracranial activity of ADCs and whether they can prevent the development of CNS metastases, especially as some of these ADCS are being tested in the curative-intent setting. This review synthesizes current evidence and highlights ongoing trials, with a focused examination of the evolving role of ADCs in the management of BM.