Lorlatinib is a third-generation tyrosine kinase inhibitor approved for first- and second-line treatment of ALK-positive advanced non-small cell lung cancer. The CROWN study demonstrated that first-line lorlatinib significantly improves progression-free survival and intracranial control compared to crizotinib, with sustained benefits observed over a follow-up period of up to 5 years. As lorlatinib is associated with a distinct adverse event (AE) profile, we aim to analyze lorlatinib's safety profile, focusing on AEs incidence, severity, timing and management. A comprehensive safety management framework is also outlined to address lorlatinib-associated toxicity, drawing on evidence from the literature and the clinical expertise of an Italian expert panel. The most frequent AEs associated with lorlatinib are hypercholesterolemia and hypertriglyceridemia, which emerge early after treatment initiation. The 5-year analysis of the CROWN study revealed minimal changes in most AE rates over time. Pharmacological and non-pharmacological approaches effectively resolved most AEs; lorlatinib dose reduction did not affect its efficacy. The proposed safety management framework emphasizes patient preparation and regular monitoring to predict AE occurrence, indicating AE-specific interventions, mitigation strategies and multidisciplinary collaboration to optimize outcomes. Lorlatinib's toxicity appears generally predictable and manageable; the safety framework offers pragmatic guidance to clinicians for appropriate management in clinical practice.

8504 Background: Pralsetinib, an oral tyrosine kinase inhibitor, selectively and potently targets oncogenic RET fusion and mutation proteins. Pralsetinib is FDA approved to treat adults with metastatic RET -altered NSCLC. We present efficacy and safety of pralsetinib vs standard of care (SOC) in first-line RET fusion-positive NSCLC from a randomized phase 3, open-label study, AcceleRET-Lung (NCT04222972). Methods: AcceleRET-Lung was conducted at 74 sites in 22 countries. Adults with RET fusion-positive advanced or metastatic NSCLC received pralsetinib 400 mg/d or platinum-based SOC therapy. Crossover to pralsetinib was optional upon progression. The primary end point was progression-free survival (PFS) per RECIST v1.1. Secondary end points included overall response rate (ORR), overall survival (OS), duration of response (DOR), and safety. Efficacy was evaluated in randomized patients (intent-to-treat population [ITT]). Safety was assessed in patients receiving ≥1 dose of study drug. Results: 223 ITT patients were randomized to pralsetinib (n=110) or SOC (n=113). Pralsetinib and SOC groups had similar baseline characteristics (median age: 62 and 63 y, respectively; female: 48% and 57%; median lesions: both 4; brain metastases: 15% and 16%). The study was terminated early per sponsor decision on January 27, 2025. ITT patients in the pralsetinib group had significantly greater median PFS vs SOC (18.7 vs 9.0 mo; P =0.003), ORR (65.5% vs 41.6%; P <0.001), and median DOR (20.6 vs 9.7 mo; P =0.004; Table). Safety was generally consistent with the known pralsetinib profile except for a higher rate of infection in the pralsetinib group vs SOC (71.3% vs 51.9%), including pneumonia (19.4% vs 5.8%), urinary tract infections (17.6% vs 7.7%), and opportunistic infections (9.3% vs 1.0%). There were 32 (30.0%) and 26 (25.0%) deaths in the pralsetinib and SOC groups, respectively, with 8 (7.4%) and 0 due to infection. Common grade ≥3 TRAEs in the pralsetinib vs SOC groups were hypertension (11.1% vs 0), neutropenia (10.2% vs 8.7%), anemia (8.3% vs 10.6%), and decreased neutrophil count (7.4% vs 4.8%). Conclusions: In a Phase 3 study, pralsetinib met the primary PFS end point and had a significantly greater and more durable ORR vs SOC, confirming the clinical utility of pralsetinib in RET fusion-positive NSCLC. Monitoring for infections with pralsetinib is warranted. Clinical trial information: (1) NCT04222972 ; (2) 2023-505035-12-00; (3) 2019-002463-10. Efficacy outcomes. Pralsetinib (n=110) SOC(n=113) Stratified hazard ratio/odds ratio (95% CI) P Value Duration of follow-up, mo, median (range) 20.5(0, 49.8) 16.0(0, 42.3) - - PFS, mo, median (95% CI) 18.7(11.1, 25.2) 9.0(7.1, 11.5) 0.59(0.42, 0.84) 0.003 ORR, % (95% CI) 65.5(55.8, 74.3) 41.6(32.4, 51.2) 2.81(1.61, 4.93) <0.001 OS, mo, median (95% CI) NR (29.6, NR) 39.8(39.8, NR) 1.09(0.65, 1.85) 0.742 DOR, mo, median (95% CI) 20.6(17.2, 31.8) 9.7(7.6, 15.9) 0.48(0.28, 0.80) 0.004

BACKGROUND:Integration of immune checkpoint inhibitors with perioperative chemotherapy has significantly improved pathological response rates and survival outcomes in patients with resectable NSCLC. In this context, an international expert panel convened to discuss optimal use of neoadjuvant and perioperative chemo-immunotherapy in individuals with early-stage/locally advanced resectable NSCLC, based on emerging trial data. METHODS:A virtual expert panel meeting was held on July 10, 2025 under the auspices of the Italian Association of Thoracic Oncology (AIOT). Seven thoracic oncology experts reviewed current evidence from pivotal trials. The panel addressed predefined clinical questions spanning pre-treatment evaluation, choice of neoadjuvant vs perioperative strategies, and patient selection. Shared-opinion statements were developed through moderated discussion. RESULTS:The panel endorsed pathological mediastinal staging and molecular testing in all candidates before therapy. Neoadjuvant and perioperative chemo-immunotherapy were considered a new standard for resectable stage II-III NSCLC after thorough and thoughtful multidisciplinary board discussion, having shown improved pathological complete response (pCR), event-free survival (EFS), and overall survival (OS), and was deemed overall safe without compromising surgery. PD-L1-negative tumors were not excluded from immunotherapy benefit, although magnitude of benefit was lower. The panel recommended neoadjuvant or perioperative approaches especially for resectable stage III and N-positive disease, whereas upfront surgery could be considered for selected stage II N0 cases. No evidence currently favors perioperative over neoadjuvant strategy in efficacy, or viceversa. The panel emphasized that regimen choice should consider trial eligibility criteria, local drug approvals, and patient factors. High-priority research areas identified included trials comparing neoadjuvant vs perioperative strategies, studies of biomarker-driven therapy personalization, and novel combination approaches to further improve outcomes. CONCLUSIONS:Chemo-immunotherapy is an essential component of therapy for subjects with operable and resectable NSCLC. Based on current evidence, the expert panel formulated guideline recommendations for clinical practice. These expert statements aim to guide clinicians in integrating emerging perioperative immunotherapy regimens while awaiting further data from clinical trials.

OBJECTIVES:This exploratory analysis investigated whether the disease-free survival (DFS) benefit seen with adjuvant alectinib versus chemotherapy in patients with resected, ALK-positive non-small cell lung cancer (NSCLC) from the phase III ALINA study (NCT03456076) was maintained across surgical characteristic subgroups and when re-classifying patients according to the 8th edition of the Cancer Staging Manual of the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC). METHODS:ALINA is a global, open-label, randomized trial. Eligible patients ≥ 18 years old with resected, ALK-positive NSCLC of stage IB (≥4 cm), II, or IIIA (per AJCC/UICC 7th edition) were randomized 1:1 to receive alectinib 600 mg twice daily for 24 months or four 21-day cycles of platinum-based chemotherapy. PRIMARY ENDPOINT:investigator-assessed DFS. Endpoints of this exploratory analysis included DFS by stage (8th edition AJCC/UICC), nodal status, tumor size, and other surgical characteristics, in the primary analysis population. RESULTS:Patient characteristics were generally well balanced across both treatment arms; most patients had a tumor measuring ≤ 3 cm (n = 147 [57.4%]), stage IIIA disease (n = 134 [52.1%]), and regional lymph node stage N2 (n = 130 [50.6%]). Consistent with the primary results, patients receiving alectinib had longer DFS versus those who received chemotherapy, irrespective of disease stage (AJCC/UICC 8th edition), nodal status, tumor size, or other surgical characteristics. CONCLUSIONS:Alectinib is the first ALK inhibitor to show a consistent DFS benefit over chemotherapy in patients with resected early-stage ALK-positive NSCLC, regardless of disease stage per AJCC/UICC 7th or 8th edition, nodal status, or tumor size. CLINICAL TRIAL REGISTRY NUMBER:NCT03456076.

Background:Radiomics and liquid biopsy represent minimally invasive approaches to assess disease characteristics in solid tumors. We integrated computed tomography (CT) radiomics and circulating tumor DNA (ctDNA) analysis to enhance prognostic stratification and longitudinal monitoring in patients with advanced non-small cell lung cancer (NSCLC). Methods:This study prospectively enrolled 91 patients with advanced NSCLC. Baseline molecular profiling was performed on both tumor tissue and plasma ctDNA using targeted next-generation sequencing. Radiomic features were extracted from baseline CT lung lesions using PyRadiomics, and radiomic scores (RS) were developed using LASSO-regularized Cox models. A subgroup of 21 patients with actionable molecular alterations underwent longitudinal CT scans and liquid biopsies during targeted therapy. Clinical, radiomic, and molecular associations with overall survival (OS) and disease-free survival (DFS) were evaluated using log-rank tests and included in multivariable models. Results:Overall concordance between tissue and ctDNA (n = 67 patients) was 85%. In the combined clinical-radiomic-genetic model (C-index: 0.73), the RS (p < 0.001) and the presence of actionable alterations (p = 0.041) were independent OS predictors. For DFS, the integrated model achieved a cross-validated C-index of 0.77, outperforming the clinical-only model (0.59). In patients with EGFR-mutant NSCLC, detectable baseline ctDNA was significantly associated with a higher risk of disease progression (p = 0.018). In this subgroup, the combined clinical-radiogenomic model achieved a cross-validated C-index of 0.80 for DFS. Longitudinal analysis showed that 17 of 21 patients achieved molecular clearance of ctDNA at the first follow-up, correlating with treatment response. Conclusions:Integrating radiomics with liquid biopsy provides a more robust prognostic assessment of advanced NSCLC than clinical or molecular data alone. This multi-modal approach may offer a minimally invasive strategy for personalized risk stratification and monitoring of treatment response in patients with NSCLC.Clinicaltrials.gov identifier: NCT06331975.

Early-stage (I–III) non-small cell lung cancer (NSCLC) can harbor oncogenic driver mutations that have critical implications for patient management and outcomes. Historically, molecular testing in resected NSCLC was limited, often focusing only on EGFR mutations or ALK rearrangements due to the lack of approved targeted therapies in the adjuvant setting until recently. However, with the advent of next-generation sequencing (NGS) and emerging evidence of actionable mutations in early-stage tumors, comprehensive genomic profiling is becoming increasingly relevant in this setting. Identifying these alterations is clinically significant: the presence of specific mutations can directly influence adjuvant treatment planning and refine the role of immunotherapy. Beyond guiding therapy selection, molecular profiles also provide prognostic insight: certain driver subtypes have been associated with higher recurrence risk in early-stage patients, suggesting a need for intensified surveillance. The expanding role of NGS enables personalized postoperative strategies, including tailored follow-up intervals and potential circulating tumor DNA monitoring to detect minimal residual disease. In summary, incorporating broad molecular testing in early-stage NSCLC empowers clinicians to optimize adjuvant treatment decisions and surveillance strategies, ultimately aiming to improve patient outcomes through precision oncology.

Atypical Epidermal Growth Factor Receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) account for approximately 12% of all EGFR alterations. In contrast to classical mutations (exon 19 deletions and exon 21 L858R) and exon 20 insertions, for which therapeutic strategies have significantly evolved, relatively little progress has been achieved in the management of patients with atypical EGFR-mutated NSCLC. To date, afatinib remains the only approved agent specifically indicated for tumors harboring selected atypical variants-namely S768I, L861Q, and G719X-based on regulatory approvals by the FDA and EMA in 2018. For the wide spectrum of these and other atypical mutations, treatment recommendations remain undefined, and clinical decision-making is often extrapolated from strategies validated in classical EGFR-mutant disease or relies on conventional chemotherapy. In this context, we conducted a comprehensive review of all available clinical studies addressing patients with atypical EGFR mutations, encompassing therapeutic outcomes from first-generation TKIs through to newer therapeutical approaches. The objective of this review is to delineate the clinical characteristics of this heterogeneous population and to clarify the therapeutic activity and limitations of current treatment approaches. Specifically, we will examine the efficacy of first-, second-, and third-generation EGFR TKIs in this subgroup, discuss the mechanisms underlying resistance, and highlight the clinical implications of the recently proposed structure-function-based classification of EGFR mutations. Finally, we will review emerging evidence from ongoing clinical trials of novel therapeutic agents, including bispecific antibodies and next-generation inhibitors, which may offer new opportunities for patients with atypical EGFR-mutant NSCLC.

8502 Background: Median progression-free survival (PFS) was not reached (NR) with lorlatinib in the phase 3 CROWN study after 5 yrs of f/u, representing the longest PFS reported in advanced non-small cell lung cancer (NSCLC). Due to the unprecedented PFS benefit with lorlatinib after 5 yrs of f/u and the decreased event rate after the first 24 mos in the study, we aimed to quantify long-term outcomes at 7 yrs. Methods: 296 treatment-naive patients (pts) with advanced ALK + NSCLC were randomized 1:1 to receive lorlatinib 100 mg once daily (n=149) or crizotinib 250 mg twice daily (n=147). This post hoc analysis presents investigator-assessed efficacy outcomes, safety, and biomarker analyses. Formal statistical testing between arms was not performed. Results: As of October 31, 2025, 66 of 149 pts (44%) vs 4 of 142 (3%) were receiving lorlatinib vs crizotinib. With a median f/u for PFS (95% CI) of 83.0 (81.2-86.3) and 77.2 mos (36.8-not evaluable), respectively, median PFS (95% CI) was NR (68.5-NR) with lorlatinib and 9.1 mos (7.4-10.9) with crizotinib (HR, 0.19; 95% CI, 0.13-0.26); the 7-yr PFS (95% CI) was 55% (46-63) and 3% (1-8). In the lorlatinib arm, pts without a PFS event at the end of 24 mos had a 79% probability of survival without progression at yr 7. PFS benefit was consistent across all prespecified subgroups. No new intracranial (IC) progression events occurred after the first 30 mos on lorlatinib. Median time to IC progression (95% CI) was NR (NR-NR) with lorlatinib and 16.4 mos (12.7-21.9) with crizotinib (HR, 0.06; 95% CI, 0.03-0.12). The number of overall survival (OS) events for a protocol-specified analysis has not been met; OS f/u is still ongoing. The safety profile was consistent with the 5-yr results, with all-cause grade 3/4 adverse events (AEs) in 77% of pts with lorlatinib and 57% with crizotinib. Treatment-related AEs (TRAEs) led to permanent treatment discontinuation in 5% of pts with lorlatinib and 6% with crizotinib. No new permanent discontinuations due to TRAEs occurred after the first 26 mos with lorlatinib. Dose reductions were reported in 34% of pts in the lorlatinib arm (17% had 1 dose reduction and 17% had 2 reductions). Long-term efficacy was similar between pts with and without dose reduction. Exploratory translational analyses of outcomes in pts with different molecular subtypes and resistance mechanisms at the end of treatment are ongoing. Conclusions: With median PFS yet to be reached after 7 yrs of f/u in CROWN, lorlatinib continues to show unprecedented and highly durable benefit in treatment-naïve pts with advanced ALK + NSCLC. In pts without a PFS event at 24 mos, the probability of survival without progressive disease at 7 yrs was 79%. Longer f/u showed very few additional PFS events, no new IC progression, and no new treatment-related discontinuation, suggesting long-term substantial benefit with lorlatinib for the majority of pts with advanced ALK + NSCLC. Clinical trial information: NCT03052608 .

Abstract Immune checkpoint inhibitors combined with chemotherapy have become the first-line standard of care for extensive-stage small cell lung cancer (ES-SCLC), yet durable responses remain limited. In the LUMINANCE Phase IIIb study —a single-arm, multi-center international trial evaluating first-line durvalumab plus platinum-etoposide in ES-SCLC— we assessed circulating tumor DNA (ctDNA) clearance as a dynamic biomarker to predict survival outcomes and recurrence risk. We utilized a tumor-agnostic, methylation-based ctDNA assay (GRAIL) to assess ctDNA detection and clearance longitudinally in 148 patients. All patients had detectable ctDNA at baseline (C1D1), with gradual decrease in ctDNA detection suggesting treatment benefit (88.9% detection rate at C2 and 46% detection rate at start of maintenance period (Mtx start)). The highest clearance rates were observed at the start of Mtx (53.6%). ctDNA clearance from baseline was associated with significant overall survival (OS) benefit (C2 p = 0.0017; Mtx start p < 0.0001; Tumor Assesment 1 (TA1) p = 0.001), as well as progression-free survival (PFS) benefit (C2 p < 0.0001; Mtx start p < 0.0001; and TA1 p = 0.00026). Patients who achieved sustained ctDNA clearance from baseline through C2 and start of Mtx experienced the most favorable survival outcomes (median OS (mOS) not reached; mPFS 19.4 months). Those with late clearance (ctDNA-positive at C2 but cleared by Mtx start) had intermediate benefit (mOS 20.8 months; mPFS 7.9 months), while patients who never cleared ctDNA showed the poorest outcomes (mOS 11.0 months; mPFS 6.0 months). Overall, differences in ctDNA clearance timing were strongly associated with both OS (p = 0.00014) and PFS (p < 0.0001). When incorporating an additional timepoint coinciding with tumor assessment during Mtx (TA1), early and sustained ctDNA clearance during induction and Mtx phases continued to predict the most favorable survival (mOS and mPFS not reached). Patients who initially cleared ctDNA but became positive at TA1 (relapsed) demonstrated intermediate benefit (mOS 24.2 months; mPFS 8.5 months) compared to the never-cleared group (mOS 11.0 months; mPFS 6.0 months). Additionally, ctDNA dynamics aligned closely with longitudinal tumor assessments and clinical response. This study shows that ctDNA clearance, assessed using a tumor-agnostic methylation assay, may predict prognosis in patients with ES-SCLC receiving first-line durvalumab with platinum-etoposide. Patterns of clearance over time are strongly linked to OS and PFS, highlighting ctDNA clearance as a meaningful biomarker. Changes in ctDNA status during treatment may serve as a surrogate for response and survival outcomes. ctDNA may complement other biomarker strategies to guide precision therapy, disease monitoring, and understanding of resistance mechanisms in ES-SCLC. Citation Format: Gozde Kar, Mingchao Xie, Niels Reinmuth, Filippo de Marinis, Mustafa Özgüroğlu, Natasha B. Leighl, Ugochinyere Emeribe, Natalia Donner, Yashaswi Shrestha. ctDNA clearance as a prognostic biomarker in ES-SCLC: Insights from the LUMINANCE phase IIIb study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT175.

Introduction:Crizotinib, the first approved targeted therapy for ALK-positive advanced NSCLC, is also indicated for ROS1-rearranged NSCLC. This post hoc analysis of the phase II METROS trial explores long-term survival outcomes with crizotinib, focusing on the impact of baseline brain metastases (BM). Methods:This post hoc analysis of the METROS study assessed survival outcomes in patients with ROS1-rearranged NSCLC, evaluating progression-free survival (PFS), overall survival (OS), and the incidence and severity of adverse events, both in the overall cohort and by baseline BM status. Results:Among 64 patients with ROS1-positive NSCLC with a median follow-up of 54.4 months, median PFS and OS were 13.8 months (95% CI: 7.4-20.2) and 40.5 months (95% CI: 27.9-53.1), respectively. Patients with BM (N = 17) had significantly shorter PFS (6.8 versus 17.4 mo) and OS (16.4 versus 42.8 mo) than those without BM. The safety profile of crizotinib remained consistent with previous reports, with most adverse events being grade 1 or 2 and no new safety concerns identified. Conclusion:This analysis supports the efficacy of crizotinib in patients with advanced NSCLC and ROS1 rearrangements, although its activity in patients with BM remains limited, highlighting the need for brain-penetrant tyrosine kinase inhibitors to improve outcomes in this patient group.

Amivantamab, a bispecific EGFR-MET antibody, has demonstrated efficacy in EGFR-mutant non-small cell lung cancer (NSCLC) across multiple trials and is poised to enter first-line therapy. However, as with EGFR-targeted therapies, amivantamab is associated with distinctive cutaneous toxicities. This perspective summarizes clinical evidence on the frequency, nature, and severity of skin-related adverse events from key studies, outlining how, despite concerns initially raised among clinicians about its tolerability in routine practice, clinical experience indicates that amivantamab's cutaneous toxicities are manageable with proactive strategies and education. Acneiform rash, paronychia, and xerosis are among the most common toxicities observed, generally low-grade but impacting patient quality of life. Emerging evidence and expert consensus indicate that these cutaneous events are manageable with patient education, multidisciplinary dermatologic care, and proactive interventions. Proactive management roughly halved the incidence of moderate-to-severe rash and significantly reduced high-grade events, enabling most patients to continue therapy. In practice, close collaboration with experienced dermatologists, early management of symptoms, and thorough patient education on skincare can dramatically improve tolerability. As a result, initial fears about severe skin toxicity can be overcome, ensuring that patients are not denied the benefits of this efficacious therapy due to manageable side effects. In light of the significant survival benefit shown by amivantamab-based therapy in the MARIPOSA trial, preventing, recognizing and optimally managing its skin toxicities will be crucial to maximizing patient outcomes.

INTRODUCTION:In resected non-small cell lung cancer (NSCLC), molecular testing is currently limited to EGFR mutations and ALK rearrangements, as these guide approved adjuvant therapies. The role of next-generation sequencing (NGS), routinely used in metastatic NSCLC, remains unclear in earlier stages. The prevalence of other driver mutations and their impact on outcomes is not well established. METHODS:We retrospectively analyzed clinical, molecular, and survival data from patients (pts) with stage IA-IIIB NSCLC (AJCC 8th) who underwent surgery and NGS at our Institute from January 2020 to December 2023. The primary endpoint was the prevalence of driver alterations. Exploratory analyses assessed recurrence, disease-free survival (DFS), overall survival (OS), and correlation with mutation status. RESULTS:Of 221 pts, 216 were eligible. Oncogenic alterations were found in 71% (73% in stage I), most commonly KRAS (30%) and EGFR (26%), followed by MET exon 14 skipping (6%), BRAF (4%), HER2 exon 20 mutations (3%), and ALK and RET rearrangements (1%). Alteration distribution differed by sex and smoking status. With a median follow-up of 20 months, 36% of pts experienced recurrence, including 10 stage I cases. Median time to recurrence was 14 months. Recurrence rates were higher in pts with driver mutant NSCLC (39.6%) versus wild-type (29.6%). Highest recurrence was seen in pts with oncogenic fusion positive NSCLC and EGFR exon 20 insertions. CONCLUSIONS:Driver mutations were detected in 70% of resected NSCLC, including stage I. The recurrence patterns observed support integrating NGS into early-stage management and exploring tailored adjuvant therapies, even for stage I tumors.

INTRODUCTION:Treatment selection in patients with advanced NSCLC is based on programmed death-ligand 1 (PD-L1) expression, which is usually scored manually and is subject to intra- and inter-pathologist variability. A PD-L1 clone-agnostic artificial intelligence (AI) model for AI-based measurement of PD-L1 (AIM-PD-L1) was developed and assessed in advanced NSCLC using clinical samples from two phase 3 trials. METHODS:IMpower110 evaluated atezolizumab versus chemotherapy in PD-L1-positive metastatic, stage IV, squamous or nonsquamous NSCLC. IMpower150 evaluated atezolizumab, carboplatin, and paclitaxel, with or without bevacizumab, versus carboplatin, paclitaxel, and bevacizumab in patients with metastatic nonsquamous NSCLC. AIM-PD-L1 was developed and deployed on SP263-stained whole slide images (IMpower110, n = 509; IMpower150, n = 766) for digital scoring of tumor cell (TC) PD-L1 expression and identification of human-interpretable features (HIFs) associated with survival outcomes. RESULTS:Overall percentage agreements between scoring methods for TC more than or equal to 50% and more than or equal to 1% cutoffs were high. Survival analyses were similar for PD-L1 subgroups between scoring methods at both TC cutoffs. A nonsignificant improvement in survival outcomes was observed in patients treated with atezolizumab-containing regimens and classified as positive by digital scoring but missed by manual scoring. Two HIFs in the cancer epithelium-density of all PD-L1-positive TC and immune cells-were nominally associated with overall survival. Many HIFs were identified to be predictive of significantly improved progression-free survival with atezolizumab-containing regimens versus control. CONCLUSIONS:AIM-PD-L1 digital SP263 PD-L1 scoring is concordant with manual scoring, revealing similar predictivity for benefit, and could potentially be used as a predictive marker for patient stratification and selection for anti-PD-(L)1 therapy.

Epidermal growth factor receptor (EGFR) mutations occur in approximately 10–20% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In the last decade, the third-generation EGFR-TKI osimertinib has represented the first-line standard of care for EGFR-mutant NSCLC. However, the development of acquired mechanisms of resistance significantly impacts long-term outcomes and represents a major therapeutic challenge. The mesenchymal–epithelial transition (MET) gene amplification and MET protein overexpression have emerged as prominent EGFR-independent (off-target) resistance mechanisms, detected in approximately 25% of osimertinib-resistant NSCLC. Noteworthy, variability in diagnostic thresholds, which differ between fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) platforms, complicates its interpretation and clinical applicability. To address MET-driven resistance, several therapeutic strategies have been explored, including MET-TKIs, antibody–drug conjugates (ADCs), and bispecific monoclonal antibodies, and dual EGFR/MET inhibition has emerged as the most promising strategy. In this context, the bispecific EGFR/MET antibody amivantamab has demonstrated encouraging efficacy, regardless of MET alterations. Furthermore, the combination of the ADC telisotuzumab vedotin and osimertinib has been associated with activity in EGFR-mutant, c-MET protein-overexpressing, osimertinib-resistant NSCLC. Of note, several novel agents and combinations are currently under clinical development. The success of these targeted approaches relies on tissue re-biopsy at progression and accurate molecular profiling. Yet, tumor heterogeneity and procedural limitations may challenge the feasibility of re-biopsy, making biomarker-agnostic strategies viable alternatives.