Faculty Bibliography

Lung cancer is the leading cause of cancer-related deaths globally, and early diagnosis and treatment are important for improving prognosis. Pulmonary nodules (PNs) are small pulmonary lesions frequently identified during clinical practice, with incidental detection increasing due to advances in imaging techniques and the expanded use of computed tomography scans for thoracic evaluation. The majority of incidental PNs (IPNs) are benign, however some represent early-stage lung cancer, therefore distinguishing benign from malignant IPNs is key to improving lung cancer outcomes. Current management guidelines differ by nodule type and involve biopsy to determine the malignancy status of the nodule. Here, we review current knowledge on the classification, prevalence, and detection of PNs, as well as the current management and risk stratification of PNs. We outline the role of oncogenic driver mutations in the pathobiology of PNs and assess current literature on targeted treatment of oncogene-driven PNs. Finally, we discuss evidence gaps and areas for future research.

BACKGROUND:) exon 20 insertion mutations. Data are needed on the efficacy and safety of sunvozertinib as a first-line treatment for NSCLC. METHODS:exon 20 insertions to receive sunvozertinib or chemotherapy (carboplatin-pemetrexed). The primary end point was progression-free survival as assessed by blinded independent central review. Crossover to the sunvozertinib group was allowed after disease progression was confirmed. Secondary end points included overall survival, investigator-assessed progression-free survival, objective response (complete or partial response), change in tumor size, and duration of response. RESULTS:A total of 324 patients were randomly assigned to receive sunvozertinib (163 patients) or chemotherapy (161 patients). Treatment with sunvozertinib led to significantly longer median progression-free survival than chemotherapy (10.3 vs. 7.5 months; hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.50 to 0.85; P<0.001). At 12 months, progression-free survival was reported in 46.1% of the patients in the sunvozertinib group and in 26.7% of those in the chemotherapy group; the data for overall survival were immature (38.9% maturity). The percentage of patients with an objective response was 58.9% in the sunvozertinib group and 31.1% in the chemotherapy group; the median best percentage change in tumor size was -42.1% and -24.7% respectively, and the median duration of response was 11.2 and 7.1 months. Grade 3 or higher adverse events were reported in 75.5% of the patients in the sunvozertinib group and in 56.7% of those in the chemotherapy group. In the sunvozertinib group, the most common adverse events of grade 3 or higher included increased serum creatine kinase levels, diarrhea, and anemia. No deaths were attributed to adverse events considered by the investigators to be related to sunvozertinib. CONCLUSIONS:exon 20 insertions. (Funded by Dizal Pharmaceuticals; WU-KONG28 ClinicalTrials.gov number, NCT05668988.).

BLU-451 is a potent and selective tyrosine kinase inhibitor designed to target uncommon epidermal growth factor receptor (EGFR) mutations, spare wild-type EGFR, and be active in the central nervous system (CNS). In vitro EGFR enzyme assays and engineered cell line models revealed selectivity and anti-proliferative potency of BLU-451 against a wide range of EGFR mutations in non-small cell lung cancer, including common mutations, atypical mutations, and exon 20 insertions. Particularly, BLU-451 demonstrated robust antitumor activity in EGFR exon 20 insertion cell-derived and patient-derived xenograft models and was well tolerated in animal studies. Pharmacokinetic and pharmacodynamics analyses showed that BLU-451 suppressed exon 20 insertion phosphorylated EGFR expression levels within tumor tissues but not in skin and intestinal tissues, potentially indicative of lower toxicity associated with wild-type EGFR. In intracranial tumor models with imaging-based analyses, BLU-451 showed CNS antitumor efficacy. Early clinical data from patients enrolled in the phase 1 portion of the phase 1/2 CONCERTO trial (NCT05241873) demonstrated the overall clinical potential of BLU-451, including its CNS antitumor activity in patients with EGFR exon 20 insertions and atypical mutations. Initial data suggest that BLU-451 is an active molecule. Further evaluation of the safety profile and pharmacokinetic properties of BLU-451 is needed.

Lung cancer in never smokers (LCINS) disproportionately affects younger women and East Asian populations and is characterized by distinct genetic susceptibility, environmental exposures, and molecular alterations. However, never smokers remain excluded from current screening guidelines despite rising incidence and identifiable high-risk subgroups. Family history confers substantial risk, with affected first-degree relatives showing 1.7-fold higher incidence, while genome-wide association studies and polygenic risk scores further refine genetic susceptibility. Female sex and Asian ethnicity are primary independent risk factors, exceeding family history in multivariable analysis. Asian never smokers have a 2.3-fold higher baseline incidence of lung cancer than non-Asian never smokers, and Asian female never smokers exhibit lung cancer detection rates comparable to Asian male ever smokers. Screening trials in never smokers demonstrated detection rates comparable to smoker-based trials, suggesting certain demographic subgroups may reach risk thresholds where screening could be beneficial. Environmental PM_2.5 exposure increases LCINS incidence and mortality in East Asian populations where both PM_2.5 exposure and EGFR mutation rates are elevated. Recent evidence implicates mitochondrial DNA mutations in LCINS susceptibility among Asian never smokers, suggesting integration of environmental exposures and molecular biomarkers may improve risk stratification for screening. The high prevalence of actionable oncogenic drivers in LCINS underscores the importance of early detection, as these tumors benefit from targeted therapies whereas immune checkpoint inhibitors responses are often lower. This review summarizes LCINS epidemiology, genetic susceptibility, molecular alterations, environmental risk factors, and tumor immunology, highlighting the need for greater focus on this underrecognized and growing patient population.

Lung cancer remains the leading cause of cancer-related deaths worldwide, partly because many patients are diagnosed at late stages, highlighting the urgent need for effective early detection and intervention strategies. Low-dose computed tomography (LDCT)-based screening reduces lung cancer mortality in high-risk populations defined by age and smoking history; however, the uptake of LDCT remains low among eligible individuals. Compounding this issue, modelling studies estimate that nearly half of lung cancers occur in individuals who do not meet eligibility criteria for LDCT-based lung cancer screening under current guidelines. Moreover, LDCT-based screening has inherent limitations, including a high rate of false-positive results that can lead to unnecessary invasive procedures, as well as substantial costs that limit scalability. Major efforts have been made to identify novel biomarkers such as radiomic features and liquid biopsy assays to enhance the accuracy of lung cancer risk prediction. Furthermore, the increasing detection of pulmonary nodules by LDCT or diagnostic CT scans has highlighted the importance of therapeutic interventions that can enable interception of high-risk precancerous nodules and halt their progression to invasive disease. In this Review, we summarize the current state of lung cancer screening, the disparities and infrastructural considerations for optimal implementation, and future directions in the development of biomarkers and design of precancer interception strategies that could transform both lung cancer prevention and early intervention.

PURPOSE/OBJECTIVE:AXL, a receptor tyrosine kinase related to oncogenic processes, is aberrantly expressed in various cancers and associated with treatment resistance. Enapotamab vedotin (EnaV), a novel anti-AXL human IgG1 and monomethyl auristatin E antibody-drug conjugate, demonstrated antitumor activity in preclinical models including non-small cell lung cancer (NSCLC). This phase 1/2 study assessed safety and preliminary efficacy of EnaV in solid tumors. PATIENTS AND METHODS/METHODS:This study comprised dose-escalation and dose-expansion phases; both phases investigated EnaV once every 3 weeks (Q3W), and EnaV on days 1, 8, and 15 of a 28-day cycle (3Q4W). Primary objectives determined maximum tolerated dose (MTD) (dose escalation) and safety (dose expansion). Pharmacokinetic profile, antitumor activity, and AXL expression were also assessed. RESULTS:During dose escalation, 32 patients received EnaV Q3W; 15 received EnaV 3Q4W. MTD and recommended phase 2 dose were 2.2 mg/kg in Q3W and 1.0 mg/kg in 3Q4W schedules. In dose expansion, 189 patients received EnaV Q3W; 70 received EnaV 3Q4W. Common adverse events in dose expansion included fatigue, constipation, nausea, decreased appetite, and diarrhea. Overall response rates ranged from 4.5-12.5% with Q3W schedule and from 9.1-11.5% with 3Q4W dose schedule. Disease control rates for NSCLC cohorts were 40.9-50.0%. NSCLC subset analysis demonstrated correlation between radiomics signature and disease control. The relationship between clinical activity and AXL expression was not apparent. CONCLUSIONS:EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued.

Clinical practice guidelines for nonsmall cell lung cancer (NSCLC) and small cell lung cancer include recommendations based on high-level clinical trial evidence, but complex clinical questions are frequently seen in real-world practice that are not clearly answered by prospective trial data. To address these questions, the Bridging the Gaps Lung Cancer Consensus Conference 2024 (BtG LCCC 2024) convened to develop US-focused expert guidance for clinical situations in which level 1 evidence is lacking. At BtG LCCC 2024, a multidisciplinary expert panel discussed ongoing clinical issues in small cell lung cancer management, targeted therapy in EGFR-mutated NSCLC, management of early stage NSCLC, identification and management of non-EGFR oncogene-driven NSCLC, and use of immunotherapy in advanced/metastatic NSCLC. By using a modified Delphi process, 12 consensus recommendations were developed with the goal of providing guidance on the use of novel diagnostic methods and treatments for clinicians who manage lung cancer. This report reviews these areas of consensus and discusses ongoing questions about ways to apply current clinical evidence.

Fourth-generation EGFR tyrosine kinase are in development to overcome common resistance mutations. We performed deep mutational scanning (DMS) of the EGFR kinase domain in the context of L858R by introducing a saturation library of ~17,000 variants into Ba/F3 cells. DMS library-expressing cells were exposed to osimertinib or BLU-945 to identify escape mutations. L718X mutations were enriched across all conditions. BLU-945 specific mutations included K714R, K716T, L718V, T725M, K728E, K754E/N, N771S/T, T783I, Q791L/K, G863S, S895N, K929I, and M971L. A secondary DMS screen combining osimertinib and BLU-945, exclusively enriched for L718X mutations. Clinically, L718X mutations emerged in two patients treated with BLU-945. One patient with baseline EGFR L858R and L718Q mutations experienced early progression. Another with baseline EGFR L858R, T790M, and C797S acquired an L718V mutation at progression. This study demonstrate how comprehensive resistance profiling of targeted therapies can predict clinically relevant mutations and guide rational combinations to delay or prevent resistance.

BACKGROUND:This exploratory analysis assessed datopotamab deruxtecan (Dato-DXd) in pretreated patients with advanced/metastatic NSCLC and EGFR mutations. METHODS:(TROPION-Lung01) once every three weeks. Endpoints included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS), all per blinded independent central review, overall survival (OS), and safety. RESULTS:In total, 117 patients with EGFR mutations who received Dato-DXd were included in the pool. The population was heavily pretreated (median three lines of prior therapies, range 1-5) and predominantly Asian (69%). The most common mutations were exon 19 deletion (51%), L858R (32%), and T790M (27%); more than one EGFR mutation could be present. The confirmed ORR was 43% (95% confidence interval [CI]: 34-52), including five complete responses (4%). Median DOR was 7.0 months (95% CI: 4.2-9.8). Median PFS and OS were 5.8 (95% CI: 5.4-8.2) and 15.6 months (95% CI: 13.1-19.0), respectively. The safety profile of Dato-DXd was consistent with the individual studies. No new safety signals were observed. Rates of grade ≥3 treatment-related adverse events and serious adverse events were 23% and 6%, respectively. CONCLUSION/CONCLUSIONS:Dato-DXd demonstrated meaningful clinical activity in patients with EGFR-mutated advanced/metastatic NSCLC who had progressed on EGFR-directed therapies and chemotherapy, with an acceptable safety profile.