This was a pooled analysis of data from weekly vinorelbine (VNR) treatment arms of four individual open-label, phase II studies to assess and refine the efficacy and tolerance of weekly oral VNR in a larger cohort of patients with advanced NSCLC.

All patients included in this pooled analysis received oral VNR at the dose of 60 mg/m2 weekly at cycle 1 (3-week cycle), followed by an increase to 80 mg/m2 weekly for subsequent cycles until disease progression or toxicity. Efficacy was based on objective response rate (ORR), progression-free survival (PFS), and disease control rate (DCR).

A total of 247 patients were included. The ORR and DCR were 8.9% and 57.5% respectively, median PFS and OS were 3.3 and 8.5 months, respectively. Less than half (40.7%) of patients reported ≥1 serious AE (regardless of causality), with 12.3% reporting ≥1 treatment-related serious AE (grade ≥3: 11.1%). The most reported grade ≥3 AEs were neutropenia (17.6%), fatigue (5.8%), and decreased appetite (4.9%).

This pooled analysis showed that weekly oral VRN is a valid option, with an acceptable safety profile, in this population of patients with advanced NSCLC, confirming results from previous individual studies.

KRAS G12C mutation occurs in ∼ 14 % of non-small cell lung cancer (NSCLC) patients and has been historically deemed undruggable, with immune-checkpoint inhibitors (ICIs) and platinum-based chemotherapy (PBC) representing the standard-of-care in the advanced setting. First-in-class, covalent KRAS G12C OFF-inhibitors sotorasib and adagrasib have revolutionized the therapeutic landscape and recently entered clinical practice. However, limited efficacy alongside toxicity profiles strengthen the need to design novel molecules and to optimize therapeutic strategies to address and overcome intrinsic and acquired resistance mechanisms. Moreover, KRAS G12C frequently co-occurs with STK11/KEAP1 mutations, that represent a negative prognostic factor, being associated with increased metastatic potential and reduced overall survival and poorer outcomes with ICIs. Furthermore, the high incidence of brain metastases is common in KRAS G12C-mutant NSCLC, and the efficacy of standard therapies and KRAS G12C inhibitors in treating or preventing central nervous system involvement is still suboptimal. In this context, novel inhibitors, such as broad-spectrum inhibitors targeting the active GTP-bound ON-state, pan-RAS ON inhibitors and allele-selective tricomplex inhibitors, have showed promising early clinical activity although their clinical utility needs to be further elucidated. In addition, targeting upstream, downstream and parallel signaling pathways through combination strategies might enhance the activity of KRAS G12C inhibitors and eventually improve clinical outcomes in this subset of NSCLC patients. Several combinations are currently under clinical investigation and promising approaches include combinations of KRAS G12C inhibitors with ICIs, SOS1, SHP2 inhibitors and PBC. Notwithstanding the potential improved efficacy of combination strategies, tolerability remains a critical challenge that must be carefully assessed and managed.

EGFR exon 20 insertion (EGFRex20ins) mutations are found in up to 4% of all patients with non-small cell lung cancer (NSCLC). These patients are often insensitive to EGFR-tyrosine kinase inhibitors (TKIs) and have worse prognosis than patients with more common EGFR mutations. In this multicenter, retrospective, real-world study, we sought to determine whether the administration of recently approved treatments that specifically target EGFRex20ins mutations could significantly improve outcomes in this patient population.

We evaluated the clinical features of 41 patients diagnosed with NSCLC and EGFRex20ins mutations, their evolution, and response to treatments received across 7 hospitals in the Valencian Community, Spain, between 31st December 2012 and 31st December 2022.

32 patients (72%) developed metastatic disease, and 29 (71%) of them received oncological treatment. We found that administering a targeted therapy against EGFRex20ins mutations (amivantamab, mobocertinib and/or sunvozertinib) at some point during the course of treatment, significantly increased the median OS of metastatic patients from 8 months (95% CI 0-21.7) to 30 months (95% CI 11.1-48.8; Hazard ratio = 0.297, p = 0.02).

Our findings contribute to the evolving standard of care for this specific population and highlight the clinical benefits of targeted cancer therapies.

Liquid biopsy (LB) has emerged as a transformative tool in oncology, providing a minimally invasive approach for tumor detection, molecular characterization, and real-time treatment monitoring. By analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), and microRNA (miRNA), LB enables comprehensive tumor profiling without the need for traditional tissue biopsies. Over the past decade, research in this field has expanded exponentially, leading to the integration of LB into clinical practice for specific cancer types, including lung and breast cancer. In 2024, the Journal of Liquid Biopsy (JLB) published innovative studies exploring the latest advancements in LB technologies, biomarkers, and their applications for cancer detection, minimal residual disease (MRD) monitoring, and therapy response assessment. This review synthesizes recent findings on the role of LB in cancer treatment and monitoring across different biomarkers, with a particular focus on newly published studies and their context within translational research. Additionally, it highlights emerging techniques such as fragmentomics, artificial intelligence, and multiomics, paving the way for more precise, personalized treatment decisions. Despite these advancements, challenges remain in standardizing methodologies, optimizing clinical validation, and integrating LB into routine oncological workflows. This mini-review highlights the evolving landscape of LB research and its potential to revolutionize cancer diagnosis, treatment monitoring, and therapeutic decision-making, ushering in a new era of precision oncology.

Bispecific antibodies (bsAbs) have emerged as a novel class of therapeutics, offering a dual-targeting strategy to enhance the therapeutic efficacy of monoclonal antibodies, which is often limited by tumor heterogeneity and the occurrence of resistance mechanisms. By simultaneously engaging two distinct antigens or pathways, bsAbs disrupt multiple signaling cascades simultaneously, preventing escape mechanisms and offering a more durable response. Furthermore, they can optimize immune activation, improving immune cell recruitment strategies. In particular, T-cell engager bsAbs facilitate immune cell-mediated tumor destruction by linking T cells to tumor antigens. Instead, dual immune checkpoint inhibitors (CPIs) enhance immune activation by blocking inhibitory signals. Additionally, bsAbs targeting tumor growth factors or receptor tyrosine kinases offer solutions for overcoming drug resistance in solid tumors. Although bsAbs have shown remarkable success in hematologic malignancies, their expansion into solid tumors faces key challenges, including tumor heterogeneity, limited tumor penetration, and the risk of on-target, off-tumor toxicities. Addressing these challenges requires innovative engineering strategies, optimized delivery mechanisms, and careful patient selection to maximize therapeutic benefit while mitigating adverse effects. The efficacy of bsAbs in clinical trials has led to their approval for both hematologic and solid malignancies, with numerous agents in development. Combination strategies with chemotherapy, targeted agents, and immune CPIs could represent a promising strategy to further expand their potential. As research progresses, bsAbs are expected to play a role in reshaping the future of precision oncology, offering more effective and tailored treatment options.

The prevalence of supraclavicular lymph nodes metastases (SNM) in advanced lung cancer has not been systematically evaluated, nor has then been a comparison of demographic, clinical, or molecular characteristics between patients with and without SNM.

In this prospective cohort study, the presence of SNM was evaluated using imaging studies (CT, PET, neck ultrasonography) in patients with suspected advanced lung cancer referred for biopsy aimed at diagnosis and molecular profiling. Ultrasound-guided biopsy confirmed or excluded metastatic involvement when suspicious supraclavicular nodes were identified. We assessed the prevalence of SNM and compared the demographic, clinicopathologic and molecular characteristics of patients with and without SNM.

Among the 348 patients with advanced lung cancer, 94 (27%) had SMN. SMN was more common in small cell lung cancer (24/48, 50%) and adenocarcinoma (61/248, 24.6%) than in squamous cell carcinoma (4/35, 11.4%). Compared to patients without SMN, those with SMN were more likely to have small-cell lung cancer, N2/3 disease (97.9 vs. 83.9%, P < .0001), liver metastases (29.8% vs. 16.1% P = .006), and metastases to less common sites (33.7% vs. 14.1%, P < .0001). The prevalence of genomic alterations and PD-L1 expression did not differ between biopsy samples obtained from SNM and those from the primary tumor or other metastatic sites.

SNM is common in patients with advanced small-cell lung cancer and adenocarcinoma. Ultrasound-guided biopsy of SNM is a simple and relatively inexpensive method for obtaining adequate tissue samples for diagnosis and comprehensive molecular profiling.

Non-small cell lung cancer (NSCLC) treatment has been revolutionized by the advent of targeted therapies for tumors harboring specific actionable alterations. Targeted agents are now approved for use in patients with advanced NSCLC with various drivers including ALK rearrangements, BRAF V600E mutations, EGFR mutations, ERBB2 mutations, KRAS G12C mutations, MET exon 14 skipping alterations, NTRK fusions, RET rearrangements, and ROS1 rearrangements. Importantly, the availability of these agents has raised the clinical question of how to optimally sequence their use alongside chemotherapy and/or immunotherapy strategies, which are indicated for broader populations. Key considerations include (i) evidence for better outcomes when first-line treatment is initiated following availability of molecular profiling data; (ii) the decreasing proportion of patients able to receive therapy in each successive treatment line; (iii) the efficacy of targeted agents demonstrated in either single-arm trials or head-to-head comparisons with chemotherapy and/or immunotherapy, as compared with evidence for poor or modest efficacy of immunotherapy in patients with tumors with actionable drivers; (iv) real-world data showing better outcomes of patients with tumors with actionable alterations who received targeted therapies compared with those who did not; (v) the generally favorable safety profile of targeted therapies, as well as the potential for increased toxicity when immunotherapy precedes certain targeted agents; and (vi) patient-centric factors including the greater ease of administration of oral targeted therapies over intravenous chemotherapy or immunotherapy strategies. In line with these considerations, guidelines typically recommend most targeted agents approved for first-line use as initial therapy over chemotherapy and/or immunotherapy. In this podcast, the authors discuss the current therapeutic landscape of NSCLC with actionable alterations and provide their perspectives on treatment algorithms, and how to optimally sequence therapies for patients with tumors harboring actionable alterations, using patient cases to illustrate key principles.

LIBRETTO-001 (ClinicalTrials.gov identifier: NCT03157128) is a registrational phase I/II, single-arm, open-label trial of selpercatinib in RET-dependent cancers. With 19 months of additional follow-up, we report the final efficacy and safety results of selpercatinib in patients with RET fusion-positive non-small cell lung cancer (NSCLC) who had previously received platinum-based chemotherapy (N = 247) or were treatment-naïve (N = 69). The objective response rate (ORR) was 62% for pretreated patients and 83% for treatment-naïve patients. Duration of response (DoR) was 31.6 months for pretreated and 20.3 months for treatment-naïve patients (median follow-up approximately 38 months). Median progression-free survival (PFS) was 26.2 months for pretreated and 22.0 months for treatment-naïve patients (median follow-up approximately 40 months). Median overall survival was 47.6 months in pretreated patients and was not reached in the treatment-naïve group (median follow-up approximately 43 months). At the 3-year landmark estimate, 57% of pretreated and 66% of treatment-naïve patients were alive. Among 26 patients with measurable CNS metastases at baseline, the CNS-ORR was 85% with a CNS-DoR of 9.4 months and CNS-PFS of 11.0 months. The safety profile of selpercatinib was consistent with previous reports. With substantial additional follow-up, selpercatinib continued to show durable responses and intracranial activity, with a manageable safety profile in patients with RET fusion-positive NSCLC.

Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC); however, innate and acquired resistance is clinically seen in many patients. Hence, a combinatorial approach with novel therapeutic agents to overcome chemoresistance is a promising option for improving patient outcomes. We investigated the combinational anticancer efficacy of cisplatin and narciclasine in three-dimensional NSCLC tumor spheroids.

To assess the efficacy of cisplatin and narciclasine, cell viability assays, live/dead cell staining, cell death enzyme-linked immunosorbent assay (ELISA), western blot analysis for proteins related to apoptosis, and in vivo xenograft experiments were performed. The synergistic effects of cisplatin and narciclasine were elucidated through transcriptomic analysis and subsequent validation of candidate molecules by regulating their expression. To clarify the underlying molecular mechanisms, the activation of unfolded protein responses and kinetics of a candidate protein were assessed.

Narciclasine inhibited viability of NSCLC tumor spheroids and augmented the sensitivity of cisplatin-resistant tumor spheroids to cisplatin by inducing apoptosis. After conducting bioinformatic analysis using RNA sequencing data and functional validation experiments, we identified NOXA as a key gene responsible for the enhanced apoptosis observed with the combination of cisplatin and narciclasine. This treatment dramatically increased NOXA while downregulating anti-apoptotic MCL1 levels. Silencing NOXA reversed the enhanced apoptosis and restored MCL1 levels, while MCL1 overexpression protected tumor spheroids from combination treatment-induced apoptosis. Interestingly, narciclasine alone and in combination with cisplatin induced unfolded protein response and inhibited general protein synthesis. Furthermore, the combination treatment increased NOXA expression through the IRE1α-JNK/p38 axis and the activation of p53. Cisplatin alone and in combination with narciclasine destabilized MCL1 via NOXA-mediated proteasomal degradation.

We identified a natural product, narciclasine, that synergizes with cisplatin. The combination of cisplatin and narciclasine induced NOXA expression, downregulated MCL1, and ultimately induced apoptosis in NSCLC tumor spheroids. Our findings suggest that narciclasine is a potential natural product for combination with cisplatin for treatment of NSCLC.

SMARC4 is the catalytic subunit of the SWI/SNF chromatin remodeling complex and is one of the most common altered chromatin remodeling ATPases in cancer. Studies have indicated that SMARCA4 loss is associated with highly aggressive tumors, independently predicting shorter overall and disease-specific survival. SMARCA4-deficient non-small cell lung cancer (NSCLC) primarily affects male individuals, especially smokers, and is characterized by large, aggressive tumors. Cases of SMARCA4 deletion combined with actionable driver gene mutations (e.g., ALK) are rarely reported. In this report, we describe a male non-smoker diagnosed with SMARCA4-deficient, EML4-ALK non-small cell lung cancer who has been undergoing ensartinib targeted therapy for 3 months, resulting in a significant partial response. We also propose that, from a signaling perspective, the presence of SMARCA4 deficiency may influence the sensitivity of EML4-ALK NSCLC to targeted therapy, highlighting the need for further investigation into the underlying mechanisms and the exploration of novel therapeutic approaches.

Anaplastic lymphoma kinase (ALK) inhibitors (ALKi) are the standard treatment for metastatic, ALK-positive non-small cell lung cancer (NSCLC). Second- and third-generation ALKi, including alectinib, brigatinib, ensartinib, envonalkib, and lorlatinib, have shown better efficacy than crizotinib. However, due to the lack of direct head-to-head comparisons among these agents, the optimal treatment for metastatic ALK-positive NSCLC remains unclear.

This study used the IPDfromKM (Individual Patient Data from Kaplan-Meier) method to reconstruct patient-level data from Kaplan-Meier curves of seven randomized phase III trials, involving a total of 3,850 patients. Crizotinib arms were pooled as the common comparator. Progression-free survival (PFS) was the primary endpoint, assessed using Cox proportional hazards models and restricted mean survival time (RMST). Subgroup analyses focused on patients with baseline central nervous system (CNS) metastases.

All ALKi significantly improved PFS compared to crizotinib. Lorlatinib showed the most meaningful improvement, with the greatest benefit in both overall PFS (HR=0.28; 95% CI 0.21-0.38) and CNS PFS (HR=0.09; 95% CI 0.04-0.2). In direct comparisons, lorlatinib outperformed brigatinib (HR=0.59; 95% CI 0.39-0.87) and envonalkib (HR=0.52; 95% CI 0.35-0.77) in terms of PFS. While lorlatinib also showed improved PFS compared to alectinib (HR=0.72; 95% CI 0.50-1.04) and ensartinib (HR=0.73; 95% CI 0.48-1.10), these differences were not statistically significant. Lorlatinib demonstrated the greatest benefit in PFS among patients with baseline CNS metastases.

In this indirect comparison using reconstructed patient data, lorlatinib emerged as the most effective ALKi, showed the most favorable HR for PFS compared to the other ALKi, although it did not reach statistical significance versus alectinib and ensartinib. Additionally, lorlatinib showed the highest efficacy in the control of CNS progression.

Xevinapant, an inhibitor of apoptosis protein (IAP) inhibitor, has shown promising activity in combination with anticancer agents, including radiotherapy, and, in preclinical studies, anti-PD-(L)1 antibodies. This, in part, is due to its ability to restore apoptosis and increase antitumour immunity.

We report efficacy, safety and exploratory biomarker analyses of xevinapant plus avelumab (anti-PD-L1) in a two-part, open-label, nonrandomised, phase Ib study.

Part A assessed patients with advanced solid tumours who received xevinapant (100, 150, 200 or 250 mg/day, with no random allocation, on Days 1-10 and 15-24) in combination with avelumab (10 mg/kg) on Days 1 and 15 in 28-day cycle. Part B assessed patients with advanced non-small-cell lung cancer (NSCLC) who received xevinapant at the recommended phase II dose (RP2D) plus avelumab (maximum 26 cycles).

Part A assessed the safety and tolerability of the combination and established the maximum tolerated dose (MTD) and RP2D of xevinapant. Part B assessed the antitumour activity of xevinapant at the RP2D combined with avelumab compared with a historical control (avelumab alone). Exploratory biomarker analyses were also conducted.

In part A (n = 16), xevinapant 200 mg/day was established as the RP2D with avelumab and the MTD was not reached. The most common treatment-emergent adverse events (TEAEs) irrespective of xevinapant dose were nausea and fatigue (n = 11 (68.8%) each). In part B (n = 38; four patients received prior anti-PD-(L)1 antibody), the objective response rate (ORR) was 10.5% (95% confidence interval (CI), 2.9-24.8; partial response, n = 4) and the most common TEAE was decreased appetite (n = 13 (34.2%)). Levels of plasma IL-10, IL-1β, IL-13 and CD8+ T cells increased during the study, and circulating levels of CD4+ T cells and Tregs increased during cycle 1. Macrophage-related gene expression signatures increased in patients with a partial response or stable disease. Low baseline Ki-67 expression in tumour samples correlated with a partial response.

The RP2D of xevinapant with avelumab was established; however, the ORR was not superior to the historical control (avelumab alone). The combination had a manageable safety profile in both study parts. Biomarker analyses provide insights into drivers associated with efficacy in patients with NSCLC receiving xevinapant plus avelumab.

NCT03270176 (https://clinicaltrials.gov/study/NCT03270176). Registered on ClinicalTrials.gov on 29 August 2017.

A clinically important subgroup of non-small cell lung cancer (NSCLC) is driven by common mutations in the epidermal growth factor receptor (EGFR). Over the past decade, first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs) have substantially improved clinical outcomes, although acquired resistance inevitably emerges. In particular, the third-generation TKI osimertinib has demonstrated superior progression-free survival (PFS) and overall survival (OS) compared to earlier-generation TKIs in the frontline setting, yet median OS remains approximately three years in pivotal trials. Efforts to extend disease control have led to various upfront intensification strategies, including combining EGFR TKIs with antiangiogenics or chemotherapy (e.g., the FLAURA-2 trial), and pairing novel bispecific antibodies such as amivantamab with third-generation TKIs. Upon progression on third-generation EGFR TKIs, platinum-based chemotherapy remains the standard second-line treatment, albeit with modest response rates. Emerging therapies targeting MET amplification (e.g., savolitinib plus osimertinib), leveraging antibody-drug conjugates (e.g., patritumab deruxtecan), or adding immunotherapy and antiangiogenics have shown preliminary promise in overcoming resistance. Ongoing trials are assessing optimal treatment sequencing and the use of circulating tumor DNA (ctDNA) to guide therapy escalation or de-escalation. Ultimately, the evolving landscape of EGFR-mutant NSCLC underscores the need for refined biomarker-driven approaches and personalized regimens to achieve further gains in survival. In this review, we discuss these strategies in detail, highlighting current evidence and future directions for EGFR-mutant NSCLC treatment.

Stage III non-small cell lung cancer (NSCLC) is a heterogeneous group and identification of subgroups with differential treatment responses is crucial. Addition of durvalumab to concurrent chemoradiotherapy (cCRT) has previously been shown to improve survival outcomes. Meanwhile, subgroups harboring KRAS mutations have been shown to have worse prognosis. We investigated whether KRAS mutational status may affect survival outcomes after adjuvant durvalumab following cCRT in stage III NSCLC.

In this multi-center retrospective study, we present a real-world dataset of all stage III NSCLC patients treated with curative-intent cCRT with molecular assessment, between 2016 and 2021 in the Västra Götaland Region of western Sweden. The study period includes the standard practice prior to the introduction of durvalumab, enabling evaluation of the potential impact of immune checkpoint blockade (ICB). Primary study outcomes were overall survival (OS) and progression free survival (PFS).

We identified 145 patients who received cCRT with curative intent, and 32 % harbored an activating mutation in the KRAS gene (KRASMUT; n = 46). Compared to patients with wild-type KRAS (KRASWT; n = 99), KRASMUT had worse OS (p = 0.047) and PFS (p = 0.038). This finding persisted on multivariate analysis with OS (HR 1.703, 95 % CI 1.074-2.702, p = 0.024) and PFS (HR 1.628, 95 % CI 1.081-2.453, p = 0.020). Within the subgroup that received cCRT alone, KRASMUT patients (n = 35) exhibited worse OS (p = 0.036) and PFS (p = 0.037) compared with KRASWT (n = 35). However, among those who received additional durvalumab after cCRT (KRASWT; n = 99. KRASMUT; n = 11) there were no significant differences in OS (0.788) or PFS (0.855) between the groups.

KRAS mutations are a negative prognostic factor after cCRT in stage III NSCLC, and the addition of durvalumab ameliorates the negative impact of harboring this mutation.

Lorlatinib, a third-generation ALK inhibitor, has demonstrated strong efficacy in treating advanced ALK-positive NSCLC, though real-world data, particularly from China, are limited. This study evaluates the real-world efficacy and safety of lorlatinib in Chinese patients with advanced ALK-positive NSCLC.

This retrospective study analyzed 65 patients with advanced ALK-positive NSCLC who received lorlatinib at Peking University Cancer Hospital between September 2017 and August 2024. The study assessed the overall response rate (ORR), progression-free survival (PFS), and safety outcomes, comparing first-line treatment to subsequent treatments after prior ALK inhibitor exposure.

The real-world ORR (rwORR) for all patients was 49.2%, with a real-world disease control rate (rwDCR) of 92.3%. In the first-line treatment group (n=8), lorlatinib showed an ORR of 100%, and no patients experienced progressive disease (PD) during a median follow-up of 9 months. The mPFS for the entire cohort was 37.83 months, with the median OS (mOS) not reached (NR, 95% CI: NR-NR). Patients who had received one prior ALK inhibitor had a mPFS of 49.73 months, while those who had received two or more prior ALK inhibitors had a mPFS of 12.17 months. A statistically significant difference in mOS was found between patients with one prior ALKi and those with two or more prior ALKis (p = 0.032). Lorlatinib demonstrated strong intracranial efficacy, with a 45.2% intracranial ORR in patients with brain metastases. The safety profile was consistent with previous reports, with the most common AEs being hyperlipidemia. However, the incidence of severe AEs was manageable with dose adjustments and supportive treatments.

Lorlatinib demonstrates strong efficacy and manageable safety, especially in first-line treatment of advanced ALK-positive NSCLC, supporting its role as an effective treatment option.

The advocacy Women Against Lung Cancer in Europe (WALCE) promoted the European Program for the Routine Testing of Patients With Advanced Lung Cancer (EPROPA) and provided a free-of-charge molecular profiling platform for NSCLC sample characterization with the aim of increasing the detection of targetable drivers and improving patients' access to clinical trials in Europe.

From January 2021 to December 2023, 20 centers located at five different European countries (Greece, Slovenia, Romania, Albania, and Italy) joined EPROPA, with 555 patients with advanced NSCLC registered to the program. Anonymized patients' clinical-pathological data were shared through the EPROPA web platform and tissue samples were collected at the Molecular Pathology Unit of the Reference Center (University of Turin) for molecular analyses. A comprehensive genomic profiling by a targeted next-generation sequencing approach has been performed and molecular reports have been discussed within the molecular tumor board to assess patients' eligibility for clinical trials.

The average turnaround time was eight days, with only 30 out of 555 tissue samples (6%) not suitable for molecular analysis. In the 525 analyzed samples, a total of 570 molecular alterations have been identified, including 264 pathogenic targetable oncogenic alterations and 113 cases with co-occurring mutations. A total of 18 molecular alterations with potential germline and hereditary cancer syndrome implications have been reported. The identification of a clinical trial was considered for 205 patients. After molecular tumor board discussion, 30 patients were enrolled and treated in clinical studies available in Europe. Survival outcomes were significantly improved in patients with targetable molecular alterations receiving a matched targeted therapy.

This data confirmed the feasibility and usefulness of the program in the real-world practice scenario, supporting the implementation of next-generation sequencing-based molecular characterization of NSCLC samples, to reduce the unequal access to tests, drugs, and clinical trials in Europe.

The combination of amivantamab and lazertinib (AL) has demonstrated clinically significant efficacy in patients with previously untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC). However, its economic value relative to the standard therapy, osimertinib, remains unclear. This study evaluates the cost-effectiveness of AL regimen compared with osimertinib in US and Chinese healthcare settings.

A partitioned survival model, comprising progression-free survival (PFS), post-progression, and death states, was developed using a Markov model. Clinical data were obtained from the recent Phase III MARIPOSA trial. Direct medical costs (including drug acquisition, administration, and adverse event management) were obtained from US and Chinese healthcare system data, public databases, and the literature. Health-state utilities were sourced from the literature. Incremental cost-effectiveness ratios (ICERs) were calculated based on quality-adjusted life years (QALYs). Threshold analysis was performed to identify pricing strategies at specified willingness-to-pay (WTP) thresholds. Model robustness was assessed through sensitivity and scenario analyses, and additional subgroup analyses performed.

In the base case analysis, the average costs of AL and osimertinib regimen were $1,030,524.3 (China: $234,270.87) and $466,922.0 (China: $20,075.35), respectively, and the QALYs achieved were 4.08 (China: 3.66) and 2.60 (China: 2.66), respectively. The ICERs for AL compared with osimertinib in the US and China were $563,602.3 and $214,195.51, respectively. Based on the respective WTP thresholds in the US and China, the AL regimen did not represent a cost-effective option. Sensitivity, scenario, and subgroup analyses confirmed the robustness of these findings.

Although AL regimen prolongs QALYs compared with osimertinib, it may not meet cost-effectiveness thresholds given current US pricing and simulated Chinese prices. These findings emphasize the need to consider policy implications and future pricing strategies.

The seminal identification of epidermal growth factor receptor (EGFR) mutations as pivotal oncogenic drivers in non-small cell lung cancer (NSCLC) has catalyzed the evolution of biomarker-guided therapeutic paradigms for advanced disease. Currently, third-generation EGFR tyrosine kinase inhibitors (EGFR-TKI) have revolutionized first-line treatment for advanced EGFR-mutated NSCLC, yet acquired resistance remains an inevitable and formidable clinical challenge. This review systematically summarizes molecular mechanisms underlying treatment resistance, with a focus on clinical challenges associated with central nervous system (CNS) metastases. Therapeutic resistance mechanisms are categorized into EGFR-dependent (on-target) pathways, typified by acquired kinase domain mutations (e.g., C797S), and EGFR-independent (off-target) pathways, involving compensatory activation of parallel signaling effectors (e.g., MET amplification, HER2 activation) or phenotypic transformation. We further evaluated contemporary diagnostic modalities for identifying resistance drivers and appraised emerging therapeutic strategies, including fourth-generation EGFR-TKI, various combination therapies, and antibody-drug conjugates (ADCs), and so forth, with emphasis on ongoing clinical trials that may transform the existing treatment paradigm. By synthesizing preclinical and clinical insights, this review aims to advance mechanistic understanding and propose therapeutic strategies to overcome acquired resistance to third-generation EGFR-TKI in first-line treatment.

Central nervous system (CNS) metastases are common among patients with epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC). Osimertinib in combination with chemotherapy beyond osimertinib progression may minimize CNS progression.

In this retrospective analysis, patients with advanced EGFR mutation positive NSCLC and brain metastases who received platinum-based chemotherapy (PbChT) after disease progression on osimertinib were enrolled. The primary endpoint was real-world CNS progression-free survival (rwCNS-PFS) between patients who received PbChT with and without osimertinib continuation. Secondary endpoints included competing risk analysis of CNS progression and incidence of salvage radiotherapy to brain.

A total of 101 patients were analyzed, out of which, 39 (39%) continued osimertinib with chemotherapy (OSI+ cohort) and 62 (61%) received chemotherapy alone (OSI- cohort). Median rwCNS-PFS was significantly longer in the OSI+ cohort (9.0 months, 95% CI 6.6-11.4) than the OSI- cohort (5.7 months, 95% CI 4.6-6.9) (HR 0.37, 95% CI 0.18-0.76, P = .007). This remained significant after adjustment for EGFR mutation, line of osimertinib treatment, prior radiotherapy to brain, and CNS progression on osimertinib monotherapy. Estimated probability of CNS progression at 6 months was 5.6% in OSI+ cohort versus 20.9% in OSI- cohort. Incidence of salvage radiotherapy to brain was lower in the OSI+ cohort (15%) compared to OSI- cohort (24%).

In patients with EGFR mutation positive NSCLC and brain metastases, continuing osimertinib with chemotherapy after progression on osimertinib significantly reduced risk of CNS progression. Prospective studies are warranted to define the optimal treatment strategy for this patient population.

Next-generation sequencing (NGS) allows the detection of multiple genetic targets in different tumor types. This study aimed to confirm the benefits of implementing in-house NGS testing for non-small-cell lung cancer (NSCLC) samples in molecular pathology laboratories. A multi-institutional study was conducted to evaluate the analytical performance, turnaround time, and feasibility of in-house NGS testing of 50 genes from 283 NSCLC samples. The first phase was a retrospective study with interlaboratory testing (21 samples), and the second phase was a prospective study with intralaboratory testing (262 samples). The retrospective study showed a 100% sequencing success rate for DNA and RNA, high interlaboratory concordance (95.2%), and a strong correlation (R2 = 0.94) between observed and expected single-nucleotide variant/insertion and/or deletion variant allele fraction. The prospective study showed a sequencing success rate of 99.2% for DNA and 98% for RNA. NGS identified 285 relevant variants (81.1% single-nucleotide variants/insertion and/or deletion variants, 9.8% copy number variants, and 9.1% gene fusions). Co-mutations with potential clinical relevance were detected in 20.5% of samples positive for the main oncogenic drivers in NSCLC. Additionally, 11% of samples wild type for the main oncogenic drivers carried alterations in other relevant genes. The in-house NGS testing had a median turnaround time from sample processing to molecular report of 4 days. This study demonstrates the advantages of implementing in-house NGS testing in molecular pathology laboratories.

In PAPILLON, frontline amivantamab + carboplatin + pemetrexed (ACP) demonstrated superior efficacy over carboplatin + pemetrexed in patients with advanced or metastatic non-small-cell lung cancer (aNSCLC) harboring mutations in epidermal growth factor receptor (EGFR) exon 20 insertions (exon20ins). Real-world (RW) treatment patterns and comparative effectiveness of ACP versus RW treatments are unknown.

The present study (NECTAR) retrospectively analyzed frontline treatments prescribed 2012-2023 for patients with aNSCLC and confirmed EGFR exon20ins from English (ENG-NCRD), French (FR-ESME), and US (US-COTA and US-ConcertAI) datasets. Overall survival (OS), time to next treatment (TTNT), and progression-free survival (PFS) were assessed in RW pooled and individual treatment classes and in indirect treatment comparisons (ITC) between ACP from PAPILLON and RW treatments using Cox proportional hazards model adjusted for prognostic factors.

NECTAR assessed 208 RW patients: ENG-NCRD, n = 23; FR-ESME, n = 91; US-COTA, n = 39, and US-ConcertAI, n = 55. Common frontline treatment classes were platinum-based chemotherapy (33.7 %), platinum + immunotherapy (23.1 %), EGFR tyrosine kinase inhibitors (TKIs) alone (15.4 %), platinum + VEGF inhibitors (VEGFi) (11.1 %), and immunotherapy alone (7.7 %). Compared with platinum-based chemotherapy, none of the evaluated treatment classes demonstrated improved OS, TTNT, and PFS. Exceptions were platinum + VEGFi in TTNT and PFS and platinum + immunotherapy in TTNT. In ITCs, ACP significantly improved OS over pooled RW treatments (HR = 0.48 [95 % CI, 0.32-0.71]; P < 0.001), platinum-based chemotherapy (HR = 0.48 [0.30-0.77]; P = 0.003), platinum + immunotherapy (HR = 0.41 [0.23-0.73]; P = 0.003), and EGFR TKI alone (HR = 0.48 [0.23-1.02]; P = 0.055). TTNT and PFS results were similar to OS.

In patients with EGFR exon20ins aNSCLC, frontline ACP was superior to common RW treatments, highlighting the need for practice change.

Epidermal growth factor receptor (EGFR) mutations are described in 10-15% of Caucasian patients and in 50% of Asian patients with non-squamous non-small cell lung cancer (NSCLC). The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapeutic scenario and has changed the natural history of the disease. Despite the results obtained with osimertinib, a third-generation TKI, most patients experience disease progression. The search for new therapeutic strategies both to enhance first-line treatment and to ensure adequate second-line therapies represents an unmet medical need, towards which all efforts are being concentrated. In this review, we describe the main strategies identified to improve the prognosis of patients with EGFR-mutated NSCLC.

In Spain, next-generation sequencing (NGS) is currently available in a limited number of specialized centers and remains inaccessible to a significant proportion of patients. The ATLAS study aims to explore the tumor molecular profile beyond known EGFR mutations and ALK translocations using NGS on tumor biopsy samples.

Patients with EGFR-sensitizing mutations or ALK translocations were excluded. A total of 455 patients with advanced non-small cell lung cancer (NSCLC) were enrolled from 22 Spanish hospitals. DNA and RNA were extracted from formalin-fixed paraffin-embedded samples, and libraries were prepared using the Oncomine Focus Assay. The Trialing app was used to identify active clinical trials in Spain.

Mutations were detected in 65.7 % of the cases. Local pathology assessments detected druggable mutations in only 7.9 % of cases, while centralized NGS testing increased this detection rate to 25.9 %. The most prevalent druggable alteration was KRAS G12C (53.6 %), followed by MET amplification (8.1 %) and MET exon 14 skipping (7.3 %). Additionally, 34.5 % of patients had molecular alterations matching clinical trials, offering potential treatment opportunities. Women had a significantly higher probability of harbouring druggable mutations (36 % vs. 20.3 %, p < 0.001), including the KRAS G12C which was significantly more frequent in females (22.6 % vs. 10 %). KRAS mutations were more common in adenocarcinomas and increased with tumor differentiation grade (p < 0.001 and p = 0.049, respectively). Likewise, ALK translocations, EGFR mutations, BRAF V600E, MET exon 14 skipping, and RET/ROS1 fusions were mainly found in adenocarcinomas whereas copy number variations were more frequent in squamous carcinomas (28.6 % vs. 15.1 %; p = 0.003) and in men (22 % vs. 11.6 %; p = 0.008).

The ATLAS study demonstrates the utility of comprehensive NGS testing, which detects clinically relevant mutations in more than one-third of patients and may extend therapy options.

1-2 % of metastatic colorectal cancers (mCRC) harbor an activating KRAS-G12C mutation. This study aims to pool the results of available clinical trials of KRAS-G12C inhibitors, comparing monotherapy and combinations.

A systematic literature search was conducted in the MEDLINE database and ESMO/ASCO meeting abstracts. Phase I-II-III trials that investigated a KRAS-G12C inhibitor in patients with mCRC were included. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Pooled proportions and comparative subgroup analyses for monotherapy and combinations were presented with the random effects model.

596 patients with previously treated mCRC in 14 study cohorts treated with one of sotorasib, adagrasib, divarasib, or olomorasib as monotherapy or in combination with cetuximab/panitumumab were included. Combination treatment revealed an ORR of 33.9 % (95 %CI: 20.7-48.4) (I2: 87.1), which is significantly higher than monotherapy [16.7 %, (95 %CI: 8.3-27.3) (I2: 73.2)] (p = 0.045). Median PFS was significantly longer with the combination [5.7 months (95 %CI: 4.4-7.1) (I2: 80.8) vs. 4.2 months (95 %CI: 3.6-4.7) (I2:0.0), p = 0.027]. Grade 3-4 treatment-related adverse events (TRAEs) were significantly more frequent with the combination [32.8 % (95 %CI: 26.4-39.6) (I2:42.5) vs.16.5 % (95 %CI: 4.9-33.1) (I2: 84.2), p = 0.047]. Common adverse events specific to the combinations were skin toxicities, paronychia, and hypomagnesemia.

This analysis suggests that KRAS-G12C inhibitors in combination with anti-EGFR agents may provide a doubled ORR and 1.5-month PFS benefit compared to monotherapy in previously treated mCRC patients, but with a doubled grade 3-4 TRAEs, including skin toxicities, paronychia, and hypomagnesemia. Treatment preferences should be individualized in these highly pretreated patients.

Continuous monitoring of the oncological process is essential for identifying inefficiencies and areas of improvement, enabling better resource allocation in the care of lung cancer patients.

The objective is to define key indicators and identify critical variables for monitoring lung cancer care, aiming to improve early detection, reduce delays in diagnosis and treatment, and enhance biomarker research, ensuring timely and effective treatments for all patients.

A multidisciplinary expert group conducted a consensus process based on a review of national guidelines and initiatives related to lung cancer care. The experts defined relevant indicators and identified variables for monitoring overall care, addressing delays, and improving biomarker research. The feasibility of incorporating these indicators into existing information systems was also assessed.

The proposed indicators provide a structured approach for assessing lung cancer care and outcomes. Their inclusion in healthcare information systems would improve the monitoring and evaluation of care quality and patient outcomes. Additionally, these indicators would also promote interoperability and continuous patient care across different centers and regions, allowing informed decision-making in the improvement of healthcare processes by those responsible for healthcare management.

The adoption of standardized indicators for lung cancer care monitoring can drive continuous improvement in healthcare processes. Implementing these indicators in information systems will enable better resource allocation, timely and effective treatment, and enhanced coordination among healthcare providers, ultimately improving patient outcomes.

Background/Objectives: Recent advances in the treatment of non-small cell lung cancer (NSCLC) have shifted from conventional chemotherapy to targeted therapies aimed at specific genetic mutations, particularly in the adenocarcinoma subtype. These therapies have improved overall survival and quality of life. However, some patients still face barriers to accessing these treatments due to challenges in diagnosing advanced-stage NSCLC. Limited tumor cellularity in small biopsies and cytological samples hinders the ability to perform further molecular analyses. Additionally, the increasing number of genetic alterations requiring testing complicates the diagnostic process. To overcome this challenge, we propose combining endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) with next-generation sequencing (NGS) and immunohistochemistry for PD-L1. Methods: A total of 120 EBUS-TBNA samples were consecutively collected during the first year of integrating NGS at a reference hospital in Castilla y León, Spain. Depending on the histology and patient characteristics, a total of 67 NGS analyses and 116 PD-L1 determinations were performed. Results: The cytological sample obtained in these cases successfully achieved the triple objective proposed by the NCCN for lung cancer (diagnosis, staging, and molecular analysis in a single procedure) in 97% of instances. Conclusions: Our study highlights the effectiveness of EBUS-TBNA as a comprehensive, cost-effective, and safe diagnostic tool for NSCLC, successfully achieving the triple objective of diagnosis, staging, and molecular analysis in 97% of cases. The procedure consistently provided high-quality samples for NGS and PD-L1 testing, with minimal complications, reinforcing its value as a reliable approach for optimizing personalized treatment strategies.

EGFR-tyrosine kinase inhibitors, including osimertinib, have revolutionized EGFR-mutated non-small cell lung cancer (NSCLC) treatment; therefore, early identification of EGFR mutations is essential. We report post-hoc analyses of pooled EGFR mutation tissue testing across osimertinib clinical trials, highlighting testing challenges and supporting best practice.

Pooled central Cobas® EGFR Mutation Test data from nine global osimertinib NSCLC clinical trials were analyzed by specimen type, disease stage, and geographical region for specimen adequacy for testing and valid test results.

Across 4,864 biopsies and 2,402 resections, 91% were adequate for testing, of which 95% of biopsies and 99% of resections had valid test results. Of biopsies, 12% were inadequate for testing (mainly due to insufficient tumor content [42%] and insufficient tissue volume [35%]) and 3% of resections were inadequate (insufficient tumor content [55%] and incorrect specimen preparation [12%]). Inadequacy varied by disease stage, from 3% in resectable stage IA2-IIIA to 10%-15% in first and second/later-line advanced/metastatic settings, and 16% in unresectable stage III. Test success rates among adequate specimens ranged from 93% (unresectable stage III) to 99% (resectable stage IA2-IIIA). Data were similar by geography.

Most tissue specimens were adequate for EGFR testing. Inadequacy was commonly due to insufficient tissue volume or tumor content and higher in biopsies versus resections, and unresectable stage III and first-line advanced/metastatic versus other disease stages. Based on these controlled trial data, pre-analytic variables of tissue specimens are a major driver of testing success; hence maintaining optimal conditions from sample collection to biomarker analysis, as well as improving tissue-sampling techniques is critical to increase testing success rates.

NCT01802632, NCT02094261, NCT02151981, NCT02296125, NCT04035486, NCT02511106, NCT05120349, NCT03521154, NCT04351555.

BRAF mutations are critical drivers in cancers such as melanoma, colorectal cancer, and non-small-cell lung cancer. The most common mutation, BRAF V600E, is a key therapeutic target. Targeted treatments with BRAF and MEK inhibitors have significantly improved progression-free and overall survival in melanoma patients. However, in cancers like metastatic colorectal cancer, BRAF mutations are associated with poor outcomes due to aggressive disease behavior and resistance to conventional chemotherapy. Despite progress, resistance to BRAF/MEK inhibitors remains a major challenge, often driven by secondary mutations in the mitogen-activated protein kinase (MAPK) pathway, activation of alternative pathways such as phosphoinositide 3-kinases (PI3Ks)/protein kinase B (AKT), or changes in the tumor microenvironment. These challenges have motivated ongoing research into combining BRAF inhibitors with immunotherapies to enhance and prolong treatment effectiveness. Future research must also account for the role of the cancer's tissue of origin, as the biological context significantly influences response to targeted therapies, highlighting the need for a deeper understanding of tumor biology, micro-environment, and genetics.

Subsolid nodules emerged as frequent radiological variants of lung adenocarcinoma. Radiological features including solid-component prevalence and larger tumour dimensions prompt tumoral invasiveness guiding prognosis and management. Thus, we aimed to clarify the molecular grounds that dictate these radiological appearances and clinical behaviour in a real-life European-cohort. Additionally, following the growing interest toward targeted-therapies in early-stage diseases, we aimed to present real-life epidemiological data of actionable mutations in these patients.

In this retrospective single-centre study, targeted next-generation sequencing was performed continuatively in all the resected subsolid lung adenocarcinomas in the period between May 2016 and December 2023. Clinico-radiological data were collected. The genetic landscape of our real-life European subsolid adenocarcinoma population is defined. Common and actionable mutations (frequency > 5%) relation to key clinico-radiological features are evaluated.

Overall, 156 subsolid adenocarcinomas were analysed. KRAS-mutations, mostly KRAS p.G12C, were the most prevalent followed by EGFR, including 25% uncommon EGFR-mutations, TP53 and MET mutations. Amongst the clinico-radiological variables, KRAS-mutations and KRAS p.G12C-mutation were associated to smoking history (≥ 20 pack/years), aggressive histologic subtype and higher consolidation-to-tumor ratio (CTR). Moreover, KRAS-mutated nodules had faster tumour-doubling-time. Conversely, EGFR-mutations were associated to female sex and lower CTR. The latter not being confirmed in common EGFR-mutations. Additionally, in common EGFR-mutated nodules, aggressive histological components were rarer.

Our study presents the molecular profile of subsolid lung adenocarcinoma in a real-life European-cohort. KRAS-mutations were the most prevalent, and were related to smoking history, higher CTR and faster growth. Conversely, common EGFR-mutations were rarer than expected and unrelated to smoking history and radiological features.

Treatment of lung adenocarcinoma has changed and now includes checkpoint inhibitors (CPIs) or, in the case of an EGFR mutation, third-generation EGFR TKI osimertinib. Few data compare the long-term overall survival (OS) of current and historic subgroups.

This real-world analysis (KOMPASS study) included stage IV lung-adenocarcinoma patients with either EGFR, KRAS, or no mutation. Patients were assigned to the "current" EGFR, KRAS, or no-mutation cohort if they had mutation testing using NGS (n = 199; median date of diagnosis 2021). If they had an EGFR PCR test only, they were assigned to the "historic" EGFR or no-mutation cohort (n = 127; median date of diagnosis 2014).

Both the current and the historic EGFR cohorts had significantly longer OS than the respective no-mutation cohorts (HR 0.58 and 0.60, respectively). The current no-mutation and EGFR cohorts had a strong trend to longer OS than the respective historic cohorts. In the no-mutation cohorts, the improvement was due to an increase in long-term survivors (HR 0.71), whereas in the EGFR mutation cohorts, the median OS was improved without long-term survivors (HR 0.70). The KRAS cohort showed OS like the no-mutation cohort, with a plateau of long-term survivors around 20%.

A comparison of our data with that of the phase III trials KEYNOTE-189 and FLAURA suggests that the improved outcomes are due to the use of CPIs or osimertinib. The clinical trial results are well translated into real-world clinical practice with comparable OS. KRAS patients benefit from CPI treatment like no-mutation patients.

Metastatic organotropism in lung cancer significantly influences prognosis, yet current treatment and clinical management guidelines are largely generalized for metastatic disease, regardless of organ site involvement. Notably, up to 30% of non-small cell lung cancer (NSCLC) patients present with brain metastases (BM) at diagnosis, underscoring the need for a more nuanced understanding of metastatic patterns. However, real-world clinical data on metastatic organotropism in well-characterized patient cohorts remain surprisingly scarce. Here, we evaluate patterns of metastasis, clinical characteristics and survival outcomes in patients with lung adenocarcinoma (LUAD), the major histological NSCLC subtype.

We performed a multi-center retrospective study including 913 stage IV LUAD patients, diagnosed and molecularly assessed in western Sweden between 2016-2021. Our primary study outcome was the distribution of specific metastatic sites and its impact on Overall Survival (OS).

Out of 913 stage IV LUAD patients, 23.4% had BM. These patients exhibited markedly different metastatic patterns compared to those without BM, and median survival was significantly shorter (6 months) than those without BM (7.8 months) (p = 0.021). In addition, more than one metastatic tumor in the brain coincided with worse OS, compared to those with no, or with only one metastatic tumor in the brain. Importantly, OS was also influenced by metastasis in specific extracranial organs, like the pleura and lungs.

Our study highlights the distinct metastatic patterns and survival outcomes associated with BM in stage IV LUAD. These findings emphasize the need for site-specific approaches in managing metastatic disease due to BM's impact on survival.

In EGFR-mutated lung adenocarcinoma (EGFRm LUAD), EGFR mutations do not necessarily result in increased EGFR expression (EGFR-exp), which differs among patients. However, the factors influencing EGFR-exp and the impact of EGFR-exp on tumor characteristics in patients with EGFRm LUAD remain unclear.

Whole-exome and RNA sequencing were performed for patients with early- and advanced-stage EGFRm LUAD. The patients were classified into low or high EGFR-exp groups based on the median transcripts per million. We retrospectively examined the association between EGFR-exp, genomic characteristics, downstream EGFR signaling activity, tumor microenvironment (TME) status, and clinical outcomes.

This study included 450 and 45 patients in the early- and advanced-stage cohorts, respectively. In both cohorts, the EGFR-exp low group exhibited a lower incidence of TP53 co-mutations and EGFR amplification and a higher incidence of EGFR subclonal mutations than the EGFR-exp high group. Furthermore, downstream EGFR signaling pathways, such as the MAPK signaling, were less activated in the EGFR-exp low group. However, this group showed significantly enriched adaptive immune response pathways (Q < 0.0001) and an immune-inflamed TME. Additionally, a low EGFR-exp was a significantly favorable factor for postoperative relapse (odds ratio [OR], 0.6; P = 0.04). However, in the advanced-stage cohort, a low EGFR-exp was a significant risk factor for non-responders to osimertinib (OR, 17.5; P = 0.03).

In EGFRm LUAD, significant associations were observed between EGFR-exp levels and both EGFR signaling pathways and adaptive immune status, which in turn influence clinical outcomes. This large-scale multi-omics analysis highlights the heterogeneity among patients with EGFRm LUAD and emphasizes the need to assess EGFR-exp levels alongside mutation status for optimal treatment strategies in EGFRm LUAD.