Over the past two decades, non-small cell lung cancer (NSCLC) has witnessed encouraging advancements in basic and clinical research. However, substantial unmet needs remain for patients worldwide, as drug resistance persists as an inevitable reality. Meanwhile, the journey towards amplifying the breadth and depth of the therapeutic effect requires comprehending and integrating diverse and profound progress. In this review, therefore, we aim to comprehensively present such progress that spans the various aspects of molecular pathology, encompassing elucidations of metastatic mechanisms, identification of therapeutic targets, and dissection of spatial omics. Additionally, we also highlight the numerous small molecule and antibody drugs, encompassing their application alone or in combination, across later-line, frontline, neoadjuvant or adjuvant settings. Then, we elaborate on drug resistance mechanisms, mainly involving targeted therapies and immunotherapies, revealed by our proposed theoretical models to clarify interactions between cancer cells and a variety of non-malignant cells, as well as almost all the biological regulatory pathways. Finally, we outline mechanistic perspectives to pursue innovative treatments of NSCLC, through leveraging artificial intelligence to incorporate the latest insights into the design of finely-tuned, biomarker-driven combination strategies. This review not only provides an overview of the various strategies of how to reshape available armamentarium, but also illustrates an example of clinical translation of how to develop novel targeted drugs, to revolutionize therapeutic landscape for NSCLC.

Lung cancer is Asia's most prevalent cancer, accounting for the highest global patient share. A significant number of non-small cell lung cancer (NSCLC) patients in Asia exhibit mutations in the epidermal growth factor receptor (EGFR). Although clinical outcomes are improving with newer therapies, challenges persist in the effective management of EGFR mutant (EGFRm) NSCLC. Given the substantial disease burden, understanding the current diagnostic and treatment patterns for EGFRm NSCLC from an Asian perspective is essential. This expert opinion presents recommendations from Asian experts on molecular testing and treatment of first-line and second-line EGFRm NSCLC. The recommendations aim to optimize patient outcomes by providing a comprehensive approach to diagnosis and management, considering the high prevalence of EGFR mutations in the Asian population. The experts discussed and recommended approaches for optimal management of EGFRm NSCLC. Next-generation sequencing (NGS) testing is recommended to be included in the reimbursement scheme, and the turnaround time of testing should be shortened, considering the high burden of the disease in Asia. The panel recommended careful selection of patients for osimertinib+chemotherapy or lazertinib+amivantamab based on safety and efficacy profile, patient age, and disease status. While the panel agreed that osimertinib+chemotherapy is acceptable for these patients, dose adjustment and careful patient selection are recommended to optimize safety outcomes. For lazertinib+amivantamab, measures to mitigate adverse events such as the use of pre-medication with steroids, prophylactic anticoagulants, and dose modification are recommended. For patients progressing on one of the combination regimens, experts recommended repeat NGS testing and continued treatment with chemotherapy.

Bispecific antibodies have ushered in a transformative era in treating non-small cell lung cancer (NSCLC), enabling dual-pathway targeting with promising clinical outcomes in previously refractory disease subsets. Recent US Food and Drug Administration approvals-including amivantamab, an epidermal growth factor receptor (EGFR)/mesenchymal-epithelial transition factor-targeting monoclonal antibody for EGFR exon 20 insertions and frontline EGFR-mutant (Exon 19 and 21) NSCLC, and zenocutuzumab for tumors harboring neuregulin 1 fusions-highlight their expanding therapeutic footprint. However, a new spectrum of on-target toxicities and implementation challenges are essential considerations as part of this innovation. This review dissects the evolving clinical data for bispecific antibodies in NSCLC, focusing on amivantamab, and provides a practical framework for managing dermatologic, infusion-related, and class-specific adverse events. We explore quality-of-life outcomes, financial toxicity, and the role of subcutaneous formulations in improving patient adherence and treatment experience. Furthermore, we highlight an emerging PD-1/vascular endothelial growth factor-A bispecific antibody (ivonescimab) and its potential to reshape frontline therapy paradigms in NSCLC. By integrating clinical trial evidence with real-world considerations, this review aims to equip oncologists with the tools to optimize the use of bispecific antibodies in NSCLC and guide future therapeutic integration.

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.

Patients with advanced RET fusion-positive (RET+) non-small cell lung cancer (NSCLC) who experience disease progression following treatment with RET inhibitors (RETis) have limited treatment options. Identifying membrane protein targets may support the assessment of novel therapies, such as antibody-drug conjugates and bispecific antibodies.

To evaluate membrane target expression in RET+ NSCLC.

This multicenter cohort study used centralized immunohistochemistry (IHC) on archival tissue samples and whole transcriptome sequencing (WTS) in an independent cohort. Tissue samples were collected from 12 European centers, and WTS was performed on globally sourced patient samples submitted for molecular profiling. This study included samples from patients with RET+ NSCLC and RET-wild-type (RET-wt) adenocarcinoma controls that were analyzed by IHC and 203 RET+ and 19 579 RET-wt samples analyzed by WTS.

Membrane protein expression of MET, ERBB2 (formerly HER2), epidermal growth factor receptor (EGFR), human epidermal growth factor 3 (HER3), and trophoblastic cell surface antigen 2 (TROP2) was evaluated using IHC, with samples scored on a scale of 0 to 3. Scores of 2 or greater were considered positive. Target expression as analyzed by WTS was expressed as median transcript per million scores.

Biomarker positivity, coexpression of biomarkers, dynamic changes in paired biopsies, and clinical correlates with survival outcomes.

A total of 189 patients were included in the study (among 81 patients with RET+ NSCLC, the median [IQR] age was 62 [55-70] years, and there were 49 female individuals [60%]). In 93 samples from 81 patients with RET+ NSCLC, positive IHC scores were observed for MET in 51 of 86 (59%), ERBB2 in 3 of 84 (3.6%), EGFR in 24 of 84 (29%), HER3 in 31 of 82 (38%), and TROP2 in 59 of 65 (91%). Compared with RET-wt adenocarcinoma (n = 112), RET+ tumors showed higher MET (59% vs 43%; P = .03) and lower ERBB2 expression (3.6% vs 15%; P = .01). The WTS analysis from the independent cohort confirmed these results. Of 61 evaluable samples, 59 of 61 (97%) had at least 1 positive biomarker, 60 of 77 (78%) when excluding TROP2. MET/EGFR coexpression occurred in 17 of 79 evaluable samples (21.5%). Dynamic change in biomarker expression was observed in paired biopsy specimens. No significant survival differences based on target expression emerged in patients treated with RETi in the IHC and the WTS cohorts.

The results of this cohort study suggest that RET+ NSCLC tumors frequently express MET and TROP2, with MET positivity enriched vs RET-wt controls. Coexpression and biomarker dynamics highlight the need for membrane target screening and novel therapeutic strategies for this population.

Docetaxel is the standard of care for advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy and/or immunotherapy but is associated with modest clinical outcomes and considerable toxicity. Sacituzumab govitecan and datopotamab deruxtecan are trophoblast cell surface antigen (TROP)-2-directed antibody-drug conjugates (ADCs) that showed encouraging activity in pretreated patients with advanced NSCLC. This systematic review and pooled analysis aims to comprehensively assess the efficacy and safety of anti-TROP-2 ADCs compared to docetaxel in pretreated patients with advanced NSCLC.

A systematic search through PubMed and EMBASE before 31 January 2025 was performed to identify eligible studies. Randomized controlled phase III trials comparing an anti-TROP-2 regimen to docetaxel in patients with pretreated advanced NSCLC were included. Overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events (TRAEs) were extracted from the identified trials. A pooled analysis of reconstructed patient data and meta-analysis employing the random-effect model were used to summarize the efficacy and safety outcomes.

Across the two trials included, 1207 patients were enrolled, 598 in the TROP-2 ADC arm and 609 in the docetaxel arm. Anti-TROP-2 treatment did not produce significant improvements in OS (HR: 0.90; 95% CI, 0.78-1.03; P = 0.13) and PFS (HR: 0.84; 95% CI, 0.68-1.02; P = 0.08), compared to docetaxel, even in patients with a nonsquamous histology (OS HR: 0.86; 95% CI, 0.73-1.01; P = 0.06; PFS HR: 0.76; 95% CI, 0.52-1.12; P = 0.17). Across the subgroup analyses, a statistically significant improvement in OS was observed in patients with actionable genomic alterations (AGAs) (HR: 0.63; 95% CI, 0.41-0.95; P = 0.03). Compared to docetaxel, the anti-TROP-2 regimen demonstrated a lower risk of developing grade ≥ 3 TRAEs (RR: 0.76; 95% CI, 0.55-1.05; P = 0.09).

The anti-TROP-2 regimen showed a better safety profile but failed to demonstrate a relevant clinical improvement over docetaxel. Anti-TROP-2 ADCs could find a role in the management of patients with AGAs.

Epidermal growth factor receptor (EGFR) mutations represent targetable alterations in non-small cell lung cancer (NSCLC). The treatment landscape in the frontline setting for patients with advanced EGFR-mutated NSCLC is evolving with increasing treatment options. EGFR tyrosine kinase inhibitors (TKIs) have significantly improved outcomes, but resistance inevitably develops, necessitating alternative strategies.

Patritumab deruxtecan is a novel antibody-drug conjugate targeted human epidermal growth factor receptor-3 (HER3), delivering a topoisomerase-I inhibitor payload to HER3-expressing cancer cells. Phase I and II studies have demonstrated efficacy in patients with EGFR-mutant NSCLC with disease progression after prior therapies, including third-generation EGFR TKIs and platinum-based chemotherapy. The phase-II trial reported an objective response rate of 39% and a median progression-free survival of 5.5 months. Patritumab deruxtecan is associated with notable toxicities, including grade 3 and higher hematologic adverse events, gastrointestinal toxicity, and interstitial lung disease (ILD). ILD occurred in 5.3% of patients in the Phase-II study. Early detection and management are crucial for minimizing the risk of complications.

Patients with advanced EGFR-mutant NSCLC who have received TKI therapy and chemotherapy have limited treatment options. Patritumab deruxtecan demonstrates clinical activity in this population with manageable side effects, addressing an unmet need for patients.

Targeted therapy with EGFR tyrosine-kinase inhibitors (TKIs) is the preferred first-line treatment for EGFR-mutated advanced non-small-cell lung cancer (NSCLC), but acquired resistance inevitably occurs in almost all responding individuals.

We aimed to comprehensively review the literature to investigate the efficacy and safety of distinct regimens in the subsequent-line setting, thereby identifying the optimal regimen for these TKI-resistant NSCLC patients.

A systematic review and network meta-analysis (NMA) using a Bayesian framework.

The PubMed, Embase, Cochrane Library databases, and abstracts of ASCO, ESMO, and WCLC were searched from database inception to November 3, 2024, to identify eligible randomized controlled trials (RCTs) that assessed distinct regimens for individuals with advanced EGFR-mutated NSCLC who progressed on TKIs. The outcomes of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade 3 or higher adverse events (⩾3AEs) were compared and ranked in overall patients and various subgroups among eight regimens by NMA and the surface under the cumulative ranking curve, respectively. The protocol is registered with PROSPERO, CRD42024601619.

In total, 14 RCTs, involving 3177 participants and 8 treatment regimens (chemotherapy plus ivonescimab (programmed cell death protein 1/vascular endothelial growth factor inhibitor; chemotherapy + ivonescimab (CT + IVO)); CT + amivantamab + lazertinib (CT + AMI + LAZ), CT + immunotherapy + bevacizumab (CT + IO + BEV), CT + AMI, CT + BEV, CT + IO, CT, and IO), were included. Overall, in patients, the most pronounced PFS benefit was observed with the "CT + IVO," followed by "CT + AMI + LAZ," "CT + IO + BEV," and "CT + AMI," ranked second, third, and fourth, respectively. In terms of OS, the regimen of "CT + AMI" ranked the best, followed by "CT + IVO." However, the comparisons of OS among different regimens did not reach statistical significance, possibly due to immature data. The results for ORR and DCR were similar to those for OS, with "CT + AMI" topping the rankings, followed by "CT + AMI + LAZ." In terms of safety, the incidence of ⩾3AEs was highest in "CT + AMI + LAZ," followed by "CT + AMI." In subgroup analysis, "CT + IVO" demonstrates stable PFS benefits across clinicopathological characteristics, ranking first in most subgroups. Due to the unavailability of OS subgroup data in most RCTs, many regimens were missing in the OS subgroup analysis.

Integrating the results of different clinical outcomes and subgroup analyses, we conclude that "CT + IVO" is the optimal treatment option with an acceptable safety profile for patients with advanced EGFR-mutated NSCLC who have progressed on TKIs. "CT + AMI + LAZ" and "CT + AMI" are alternative subsequent line options as well, with superior efficacy compared to immunotherapy-based or chemotherapy regimens, yet elevated toxicity profiles requiring vigilant management.

The blood-brain barrier (BBB) is crucial for brain homeostasis but is a major obstacle in delivering anticancer drugs to brain tumors. However, this perspective requires re-evaluation, particularly for malignant brain tumors, such as gliomas and brain metastases. In these aggressive tumors, the BBB undergoes significant alterations, leading to the formation of a more permeable blood-tumor barrier. While this increased permeability allows better drug penetration, heterogeneity in blood-tumor barrier (BTB) integrity across different tumor regions remains a challenge. Additionally, the main challenge in treating brain tumors lies not in BBB penetration but in the lack of effective drugs. Conventional chemotherapies, including temozolomide and nitrosourea agents, have shown limited efficacy, and resistance mechanisms often reduce their long-term benefits. The "BBB curse" has often been blamed for the slow progress in drug development. However, emerging evidence suggests that even larger-molecule therapies, such as antibody-drug conjugates, can successfully target brain tumors. This review aims to critically reassess the roles of the BBB and BTB in brain tumor therapy, highlighting their impact on drug delivery and evaluating the current landscape of chemotherapeutic strategies. Furthermore, it explores new approaches to overcome treatment limitations, emphasizing the need for personalized and targeted therapeutic strategies.

Common EGFR mutations including exon-19 deletions and the L858R point mutation in exon 21 constitute predominant actionable genomic alterations in individuals with non-small cell lung cancer (NSCLC). The introduction of EGFR tyrosine kinase inhibitors (TKIs) has fundamentally changed the treatment landscape for such patients by improving both progression-free survival (PFS) and overall survival (OS). Among EGFR-TKIs, third-generation agents such as osimertinib have shown marked efficacy and favorable safety profiles and have become the standard of care in the first-line setting. The combination of osimertinib with platinum-based chemotherapy has recently been shown to improve PFS compared with osimertinib monotherapy in the FLAURA2 trial. Similarly, the MARIPOSA trial demonstrated clinical benefit of the combination of the EGFR-MET bispecific antibody, amivantamab, with the third-generation EGFR-TKI, lazertinib, further supporting the use of combination therapies as first-line treatment for EGFR-mutated NSCLC. Despite these advances, however, challenges such as brain metastases remain substantial barriers to successful treatment outcomes. Management of patients with such metastases often requires a multidisciplinary approach that integrates systemic treatment with local interventions such as radiation therapy. Finally, circulating tumor DNA has emerged as a promising biomarker for real-time monitoring of treatment response and evolution of drug resistance mechanisms. Analysis of such biomarkers can facilitate dynamic and personalized therapeutic adjustments, potentially improving outcomes. This review provides a comprehensive overview of the latest clinical evidence supporting therapeutic advances in the management of EGFR-mutated NSCLC, emphasizing the importance of tailoring treatment strategies based on tumor biology, patient-specific factors, and evolving therapeutic options.

Lung cancer remains the second leading cause of cancer-related morbidity and mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard first-line therapy for advanced NSCLC with EGFR mutations, offering significant improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to chemotherapy alone. Recent studies suggest that their effectiveness decreased with the emergence of acquired resistance, such as C797S and T790M. Immunotherapy alone also shows enhanced PFS and OS over chemotherapy; however, its applicability can be limited in cases with low programmed cell death ligand 1 (PD-L1) expression and result in immune-related adverse effects like those observed in retrospective, non-randomized studies. Emerging fourth-generation EGFR-TKIs, currently under clinical trials, show promising potential to address these resistance mechanisms. Advanced inhibitors, including BBT-176, BLU-945, and BLU-701, have effectively targeted resistant mutations and reduced disease progression. Studies have suggested that combining fourth-generation EGFR-TKIs with immunotherapies targeting novel pathways like LAG-3 and TIM-3 may enhance patient outcomes. Such combination regimens aim to optimize PFS, OS, and ORR while minimizing adverse effects and addressing the limitations of current therapies. This study explores the landscape of EGFR mutations, their clinical significance, and the integration of innovative fourth-generation EGFR-TKIs with immunotherapies, emphasizing the potential of precision medicine in advancing the management of EGFR-mutated NSCLC.

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.

While monoclonal antibody (mAb)-based therapies have revolutionized cancer treatment, challenges such as resistance mechanisms and tumor progression via alternative pathways underscore the need for novel therapeutic strategies. Bispecific antibodies (BsAbs), which target two distinct antigens simultaneously, represent a promising next-generation solution, improving therapeutic precision, efficacy, and safety. BsAbs also redirect cytotoxic effector cells to tumor sites, providing additional therapeutic mechanisms. Recent advancements in BsAb design, such as enhancements in pharmacokinetics and modular multi-specific formats, are expanding their use in hematological malignancies. Combining BsAbs with immune checkpoint inhibitors and other therapies may overcome resistance and improve clinical outcomes. Leading BsAbs, including mosunetuzumab, glofitamab, and blinatumomab, have demonstrated promising efficacy in clinical trials for leukemia and lymphoma subtypes. Despite remaining challenges, particularly in acute myeloid leukemia (AML), ongoing research into new targets and combination therapies is expected to enhance the efficacy of BsAbs in relapsed or refractory (R/R) disease. This review explores the structural and functional innovations of BsAbs, the challenges in current therapies, and their transformative potential in hematological malignancy immunotherapy.

Oligoprogressive disease (OPD) commonly occurs in patients with advanced EGFR mutation-positive non-small cell lung cancer (EGFR+ LC) on systemic therapy. While radiation therapy (XRT) to treat OPD can improve outcomes, the clinical and genomic predictors of benefit from local therapy for oligoprogression on osimertinib are unclear.

We conducted a single-center retrospective analysis of 81 patients with EGFR+ LC on osimertinib who received XRT for OPD (defined as progression in ≤5 lesions) between January 2014 and December 2022. Progression patterns were identified. Times from local therapy to progression, next therapy, and death were measured.

The median duration of osimertinib treatment before XRT was 16.9 months. After XRT, time on osimertinib was extended for a median of 9.7 months, with a median progression-free survival (PFS) and overall survival of 6.9 and 24.4 months, respectively. Post-XRT recurrence was most common in the lung (43%), viscera (35%), and bone (35%), with only 15% of patients experiencing in-field recurrence. Patients receiving XRT to lymph nodes or visceral metastases exhibited shorter PFS compared with other sites. EGFR mutation type, concurrent TP53/RB1 mutations, and mechanisms of resistance did not significantly predict outcomes.

The addition of XRT for OPD led to clinically meaningful time on continued osimertinib beyond progression, irrespective of molecular characteristics or resistance mechanisms.

The clinical application of lazertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has extended to the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC); however, the effects of its dose modification on its efficacy and safety have not yet been adequately established.

This prospective, multicenter, observational cohort study aims to evaluate the clinical implications of adjusting the lazertinib dose. Patients will be categorized into two groups based on the lazertinib dose administered during the initial 12 weeks of treatment in routine clinical practice: 160 and 240 mg groups. The primary endpoints are progression-free survival in the 160 mg group and identifying risk factors associated with dose modification during the 12-week period.

The findings from the present study will provide real-world insights into the clinical factors leading to lazertinib dose adjustments and deepen our understanding of the efficacy and safety of lazertinib in patients with NSCLC. Our research will contribute toward optimizing medical strategies for NSCLC treatment and aid clinicians in making accurate clinical decisions regarding dose modifications in routine practice.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

Osimertinib is the standard first-line treatment for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, treatment resistance is inevitable and increased c-Met protein expression correlates with resistance. Telisotuzumab vedotin (Teliso-V) is an antibody-drug conjugate that targets c-Met protein overexpression. In this article, we report the results of a phase I/Ib trial evaluating Teliso-V plus osimertinib in patients with NSCLC after progression on osimertinib.

This multicenter, open-label study (NCT02099058) enrolled patients with advanced EGFR-mutated, c-Met protein-overexpressing, non-squamous NSCLC that had progressed on prior osimertinib. Patients received Teliso-V (intravenously, every 2 weeks) plus osimertinib (orally, 80 mg once daily). Teliso-V was evaluated at 1.6 mg/kg in a safety lead-in phase and escalated to 1.9 mg/kg. Dose expansion included both doses. Endpoints included safety and tolerability, pharmacokinetics, objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS).

A total of 38 patients received Teliso-V (1.6 mg/kg, n = 20; 1.9 mg/kg, n = 18) plus osimertinib and were included in this analysis. No dose-limiting toxicities were observed. Most frequent any-grade treatment-emergent adverse events (TEAEs) were peripheral sensory neuropathy (50%), peripheral edema (32%), and nausea (24%). Most common grade 3/4 TEAEs were anemia (11%) and pulmonary embolism (8%). Five TEAEs led to death; none were reported as being related to Teliso-V or osimertinib. The pharmacokinetic profile of Teliso-V plus osimertinib was similar to Teliso-V monotherapy. After a median follow-up of 7.4 months, the ORR was 50.0% per independent central review (ICR) (DOR not reached), and median PFS per ICR was 7.4 months (95% confidence interval 5.4 months-not reached).

Teliso-V plus osimertinib had promising activity and a manageable safety profile in patients with c-Met protein-overexpressing, EGFR-mutated non-squamous NSCLC after progression on osimertinib. This combination has the potential to address an unmet medical need in this patient population.

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.

Treatment options for patients with EGFR-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy are limited.

CHRYSALIS-2 cohort A evaluated amivantamab plus lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy. Primary end point was investigator-assessed objective response rate (ORR). The patients received 1050 mg of intravenous amivantamab (1400 mg if ≥ 80 kg) plus 240 mg of oral lazertinib.

In cohort A (N = 162), the investigator-assessed ORR was 28% (95% confidence interval [CI]: 22-36). The blinded independent central review-assessed ORR was 35% (95% CI: 27-42), with a median duration of response of 8.3 months (95% CI: 6.7-10.9) and a clinical benefit rate of 58% (95% CI: 50-66). At a median follow-up of 12 months, 32 of 56 responders (57%) achieved a duration of response of more than or equal to 6 months. Median progression-free survival by blinded independent central review was 4.5 months (95% CI: 4.1-5.8); median overall survival was 14.8 months (95% CI: 12.2-18.0). Preliminary evidence of central nervous system antitumor activity was reported in seven patients with baseline brain lesions and no previous brain radiation or surgery. Exploratory biomarker analyses using next-generation sequencing of circulating tumor DNA revealed responses in patients with and without EGFR- or MET-dependent resistance. The most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). The most common grade greater than or equal to 3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%).

For patients with limited treatment options, amivantamab plus lazertinib demonstrated an antitumor activity with a safety profile characterized by EGFR- or MET-related adverse events, which were generally manageable.

Urothelial carcinoma is three to four times more common in men than in women, with a 73-year old mean age at diagnosis which is older than the average age at diagnosis of all cancers. Urothelial carcinoma is rare in people under 40 years of age. Smoking, exposure to industrial chemicals, and family history influence the development of bladder cancer, but age remains one of the most important risk factors. It is well established that women are more likely to be diagnosed with an advanced disease, impacting the prognosis and a higher stage-for-stage mortality compared to men. A gender difference is also observed when considering molecular features; for example, there a higher male/female ratio in Fibroblast Growth Factor Receptor 3 (FGFR3)-mutated bladder cancer. Epidermal Growth Factor Receptor (EGFR) amplifications, which are roughly depicted in 25-50% of urothelial carcinoma, have been correlated with a worse prognosis. Genomic alterations of clinical interest are mainly Human Epidermal Growth Factor Receptor 2 mutations and amplifications, as well as FGFR 3 alterations; however, no EGFR mutation has been routinely reported despite the frequency of its amplifications. Recurrently, no targeted inhibitors have demonstrated a benefit compared to platinum-based chemotherapy. We report a rare case of a 35-year-old woman presenting bone, hepatic, and lymph node metastatic urothelial carcinoma, harboring a deletion of 24 nucleotides in exon 19 of the EGFR gene with a 5-month response to osimertinib, a third-generation EGFR tyrosine kinase inhibitor.

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.

Bispecific antibodies (bsAbs) introduced a novel strategy in anticancer therapy when chemotherapy alone could not meet life expectancy. Nonetheless, the efficacy of monotherapy was limited, and the safety profile of bsAbs combined with chemotherapy remained uncertain.

Literature retrieval was carried out through PubMed, Embase, and Cochrane from inception to January, 2025. Progression-free survival (PFS), overall survival (OS), and overall response rate (ORR), along with adverse effects (AEs), were utilized to assess the efficacy and safety. Publication bias was calculated using Funnel plots and Egger's test. Heterogeneity was examined through subgroup and sensitivity analyses. The protocol was preregistered in the International Prospective Register of Systematic Reviews (CRD42025633628).

A total of 8 eligible clinical studies with 2,495 patients were included. Compared with chemotherapy alone, bsAb+chemotherapy exhibited positive outcomes in PFS (hazard ratio (HR): 0.52; 95% confidence interval (CI): 0.44-0.60; p<0.01), OS (HR: 0.67, 95% CI: 0.57-0.77; p<0.01), and ORR (HR: 0.31, 95% CI: 0.16-0.47; p<0.01). Subgroup analysis revealed that female patients, Asian patients, those under 65 years of age, and patients treated with IgG-like bsAb were more likely to benefit from the survival advantages of bsAb+chemotherapy. Despite the occurrence of leukopenia, metabolism-related, and skin-related AEs, RR of AEs in other systems showed no statistical significance.

BsAb+chemotherapy was superior to chemotherapy alone, especially in female patients, Asian patients, those under 65 years of age, and patients receiving IgG-like bsAb. Additionally, while the AEs associated with bsAb+chemotherapy are generally manageable, there is still room for improvement.

https://www.crd.york.ac.uk/prospero/, identifier CRD42025633628.

While EGFR tyrosine kinase inhibitors (TKIs) are effective in treating patients with non-small cell lung cancer (NSCLC) with EGFR mutations, acquired resistance is expected. We aimed to determine the prevalence and molecular correlates of EGFR resistance mutations in a large, real-world cohort of EGFR-mutated NSCLC.

NSCLC tumors (N = 46,505) were profiled by next-generation sequencing (NGS) and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Patient treatments and outcomes were obtained from insurance claims data.

EGFR sensitizing mutations (exon 19 deletions, L858R mutations) were present in 3,885 patients with NSCLC, and EGFR resistance mutations (C797, T790M, L718, G724, G721) in 71 patients; 58 patients had both sensitizing and resistance mutations. Among tumors with resistance mutations, the most prevalent co-alterations were TP53 (50%), PD-L1 positivity (40%), gLOH (20%), and CTNNB1 (23.2%). L718 mutations predominantly co-occurred with L858R without T790M, and 9/16 developed post-osimertinib treatment.

Acquired resistance mutations in EGFR-mutant NSCLC have a low observed frequency among molecularly-profiled tumors, possibly due to infrequent re-testing of resistant tumors. While T790M and C797S mutations are well-described, we also observed a significant number of L718 mutations in osimertinib-treated patients. These data support NGS evaluation of NSCLC that has become resistant to EGFR TKIs.

Lung cancer with the highest number of new cases diagnosed in Europe and in Poland, remains an example of malignancy with a very poor prognosis despite the recent progress in medicine. Different treatment strategies are now available for cancer therapy based on its type, molecular subtype and other factors including overall health, the stage of disease and cancer molecular profile. Immunotherapy is emerging as a potential addition to surgery, chemotherapy, radiotherapy or other targeted therapies, but also considered a mainstay therapy mode. This combination is an area of active investigation in order to enhance efficacy and overcome resistance. Due to the complexity and dynamic of cancer's ecosystem, novel therapeutic targets and strategies need continued research into the cellular and molecular mechanisms within the tumour microenvironment. From the genetic point of view, several signatures ranging from a few mutated genes to hundreds of them have been identified and associated with therapy resistance and metastatic potential. ML techniques and AI can enhance the predictive potential of genetic signatures and model the prognosis. Here, we present the overview of already existing treatment approaches, the current findings of key aspects of immunotherapy, such as immune checkpoint inhibitors (ICIs), existing molecular biomarkers like PD-L1 expression, tumour mutation burden, immunoscore, and neoantigens, as well as their roles as predictive markers for treatment response and resistance.

Drug resistance remains a major clinical challenge in EGFR-mutant NSCLC tumors owing to pathway reactivation, pathway bypass, and pathway indifference resistance mechanisms to evade tyrosine kinase inhibitor (TKI) suppression. Fusion of receptor tyrosine kinases (RTKs), such as RET, ALK, and FGFR3, has been reported to mediate EGFR TKI resistance. Given the rarity of these fusions and the heterogeneous nature of the condition, no prospective clinical trials evaluated the incidence, safety, and therapeutic benefit of dual EGFR-RTK inhibition.

We queried clinical databases from multiple institutions to identify patients who had RTK fusions detected on next-generation sequencing testing results from tissue or blood at five institutions: the Second Affiliated Hospital Zhejiang University School of Medicine, Hunan Cancer Hospital, Prince of Wales Hospital Chinese University of Hong Kong, Chao Family Cancer Center, and the University of Texas MD Anderson Cancer Center from March 1, 2016, to September 30, 2023. The data analyzed included objective response rate (ORR) to treatment post RTK fusion detection, duration of treatment, and safety. A comprehensive literature search was conducted to identify patients with RTK fusion as the primary resistance mechanism in EGFR-mutated NSCLC patients.

Twenty-seven patients were identified to be eligible in the analysis. ALK fusions were most reported (42.9%), followed by RET fusions (35.7%). Fifteen patients received dual TKI after fusion detection and nine received fusion targeting single TKIs. The median time on treatment was 169 days or 5.8 months (35-1050 d). ORR by the Response Evaluation Criteria in Solid Tumors in the evaluable 25 patients was 24% and the disease control rate was 80%. In 14 evaluable patients who received dual TKI therapy, ORR by the Response Evaluation Criteria in Solid Tumors was 21.4%, and the disease control rate was 78.6%. No new toxicities were observed with dual EGFR-RTK inhibition. In the literature review, after pooling 291 patients from 59 studies, RET fusions were the most common (50.0%), followed by BRAF (13.3%), ALK (13.3%), FGFR (10%), NTRK (5.3%), EGFR (1.7%), ROS1 (1.3%), MET (1%), and ERBB (0.7%).

The emergence of RTK fusions is one of the mechanisms of bypass resistance of EGFR TKI. Dual inhibition of EGFR-RTK was safe and efficacious in patients with targetable RTK fusion after progression to EGFR TKIs.

Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2-directed antibody-drug conjugate with a highly potent topoisomerase I inhibitor payload. The TROPION-Lung05 phase II trial (ClinicalTrials.gov identifier: NCT04484142) evaluated the safety and clinical activity of Dato-DXd in patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations progressing on or after targeted therapy and platinum-based chemotherapy.

Patients received Dato-DXd 6 mg/kg once every 3 weeks. The primary end point was objective response rate (ORR) by blinded independent central review. Secondary end points included duration of response (DOR), safety, tolerability, and survival.

Among 137 patients who received at least 1 dose of Dato-DXd, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6). The confirmed ORR was 35.8% (95% CI, 27.8 to 44.4) overall, and 43.6% (95% CI, 32.4 to 55.3) and 23.5% (95% CI, 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements, respectively. The median DOR was 7.0 months (95% CI, 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI, 71.0 to 85.3). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (preferred term; any grade: 56.2%; grade ≥3: 9.5%). Five (3.6%) patients experienced adjudicated treatment-related interstitial lung disease/pneumonitis, with 1 (0.7%) grade 5 event.

Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ≥3 toxicities was comparable with previous observations, and no new safety signals were observed.

Approximately half of lung adenocarcinomas in East Asia harbor epidermal growth factor receptor (EGFR) mutations. EGFR testing followed by tissue-based next-generation sequencing (NGS), upfront tissue-based NGS, and complementary NGS approaches have emerged on the front line to guide personalized therapy. We study the cost effectiveness of exclusionary EGFR testing for Taiwanese patients newly diagnosed with advanced lung adenocarcinoma.

This economic evaluation was conducted from the perspective of the healthcare sector with a lifetime horizon. Simulated patients were entered into a joint model combining decision trees and partitioned survival models upon diagnosis of advanced lung adenocarcinoma. We compared exclusionary EGFR testing with upfront tissue-based NGS and complementary NGS approaches. The model inputs were derived from regional estimates (prevalence of targetable gene alterations), trials (testing accuracy, survival outcomes, and adverse events), ACT Genomics (testing costs), National Health Insurance payments, retail prices (drug costs), and hospital cohorts (utility values). All costs were made equivalent to 2023 US dollars. An annual discount rate of 3% was applied. We adopted a willingness-to-pay threshold of US$70,000 per quality-adjusted life-year. One-way deterministic and probabilistic analyses were performed.

The incremental cost-effectiveness ratio of exclusionary EGFR testing versus upfront tissue-based NGS was US$15,521 per quality-adjusted life-year, whereas the incremental net monetary benefit was US$2530. The costs of osimertinib and pembrolizumab were the major determinants. The incremental net monetary benefit of exclusionary EGFR testing versus complementary NGS approach was US$2174, and its major determinants included the true-negative rate of EGFR testing and the prevalence rate of an EGFR mutation. Given the willingness-to-pay thresholds of US$35,000, US$70,000, and US$105,000 (1, 2, and 3 per capita gross domestic product) per quality-adjusted life-year, the probabilities that exclusionary EGFR testing would be cost effective were 79.1%, 95.6%, and 91.2%, respectively.

Our analysis suggests that exclusionary EGFR testing is a cost-effective strategy for Taiwanese patients newly diagnosed with advanced lung adenocarcinoma.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide, with resistance to targeted therapies and the need for novel therapeutic agents driving ongoing research. In this study, we investigated the anti-lung cancer activity of lotusine, a natural alkaloid, in the A549 (non-EGFR mutant), and EGFR-mutant HCC827 NSCLC cell line (deletion in exon 19). Our results demonstrated that lotusine significantly inhibited cell proliferation in a concentration- and time-dependent manner of HCC827 cells in comparison to A549 cells. Mechanistic analysis revealed that lotusine induced apoptosis in HCC827 cells, as evidenced by increased expression of pro-apoptotic markers (Bax and cleaved caspase-3) and decreased levels of anti-apoptotic proteins (Bcl-2). Cell cycle analysis indicated that lotusine caused G0/G1 phase arrest. Importantly, lotusine exerted its effects through the inhibition of the epidermal growth factor receptor (EGFR) EGFR-Akt-ERK signaling pathway, as evidenced by reduction of p-EGFR, p-Akt, and p-ERK in a western blot analysis in HCC827 cells. These findings suggest that lotusine exerts potent anti-cancer effects via a multifaceted mechanism, including inhibition of proliferation, apoptosis induction, and cell cycle arrest, predominantly mediated by EGFR suppression. This study highlights lotusine as a promising therapeutic candidate for the treatment of EGFR-mutant NSCLC and provides insights into its molecular mechanisms of action, paving the way for further preclinical and clinical evaluations.

ABC-lung explores the potential effect of combining atezolizumab and bevacizumab with either carboplatin/paclitaxel (ABCPac) or pemetrexed (ABPem) in patients with EGFR-mutant NSCLC, resistant to tyrosine kinase inhibitors (TKIs).

ABC-lung is a 1:1 randomised, non-comparative, phase II trial, stratified by prior treatment with a third-generation EGFR TKI, evaluating atezolizumab (1200 mg, Q3W) and bevacizumab (15mg/kg, Q3W) with either 4-6 cycles of carboplatin (AUC5, Q3W) and paclitaxel (175-200mg/m2, Q3W) or pemetrexed (500 mg/m2, Q3W) until progression (PD). The study aimed to improve the 1-year progression-free survival (PFS) rate from 18% to 37%, assessed per RECISTv1.1, separately in each arm. To reject the null hypothesis, at least 14 of 45 evaluable patients in each arm needed to be progression-free at 1-year (power 83%, 1-sided a=0.023). Secondary endpoints included overall survival (OS), objective response rate (ORR), PFS, quality of life (QoL) and adverse events (AEs).

Between 09/2020 and 09/2022, 95 patients were randomized (ABCPac:45; ABPem:50) with median follow-up time of 19 months. From the evaluable patients, 9 in ABCPac and 11 in ABPem arms reached 1-year without progression, lower than the success criterion of 14patients. Median PFS was 6.4 months in ABCPac and 7.6 months in the ABPem arms, while median OS was 15.4 months and 15.6 months, respectively. Grade ≥3 treatment-related AEs were experienced by 50% and 42% of patients in ABCPac and ABPem arms, respectively, while no grade 5 AEs were recorded.

The observed 1-year PFS rate with atezolizumab, bevacizumab in combination with either carboplatin-paclitaxel or pemetrexed was below the aspired rate of 37% in both arms. The safety is consistent with the known toxicity profiles. Clinical trial identification: NCT04245085.