Faculty Bibliography

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.

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.

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:Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions. MATERIALS AND METHODS/METHODS:Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action. RESULTS:Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority. CONCLUSIONS:Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials.

BACKGROUND/UNASSIGNED:We previously demonstrated in a meta-analysis there was no difference in risk ratio (RR) of lung cancer detected by low-dose computed tomography (LDCT) screening among female never-smokers (NS) and male ever-smokers (ES) in Asia. LDCT screening significantly decreased lung cancer death among Asian NS compared to Asian ES (RR =0.27, P<0.001). METHODS/UNASSIGNED:We investigated if race, age at diagnosis, and histology further differentiate lung cancer diagnosed by LDCT among in NS and ES using the 14 studies from our previous meta-analysis. RESULTS/UNASSIGNED:70.37%). CONCLUSIONS/UNASSIGNED:Among normal-risk individuals, LCINS had a significantly higher likelihood of being diagnosed among Asians than non-Asians, predominantly manifesting as ADC and diagnosed approximately 2 years younger than ES suggesting that the age limit to initiate lung cancer screening in NS may be set lower compared to LDCT lung cancer screening among ES.

The year 2024 is the 20^th anniversary of the discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Since then, tremendous advances have been made in the treatment of NSCLC based on this discovery. Some of these studies have led to seismic changes in the concept of oncology research and spurred treatment advances beyond NSCLC, leading to a current true era of precision oncology for all solid tumors. We now routinely molecularly profile all tumor types and even plasma samples of patients with NSCLC for multiple actionable driver mutations, independent of patient clinical characteristics nor is profiling limited to the advanced incurable stage. We are increasingly monitoring treatment responses and detecting resistance to targeted therapy by using plasma genotyping. Furthermore, we are now profiling early-stage NSCLC for appropriate adjuvant targeted treatment leading to an eventual potential "cure" in early-stage EGFR+ NSCLC which have societal implication on implementing lung cancer screening in never-smokers as most EGFR+ NSCLC patients are never-smokers. All these advances were unfathomable in 2004 when the five papers that described "discoveries" of activating EGFR mutations (del19, L858R, exon 20 insertions, and "uncommon" mutations) were published. To commemorate this 20^th anniversary, we assembled a global panel of thoracic medical oncology experts to select the top 20 papers (publications or congress presentation) from the 20 years since this seminal discovery with December 31, 2023 as the cutoff date for inclusion of papers to be voted on. Papers ranked 21 to 30 were considered "honorable mention" and also annotated. Our objective is that these 30 papers with their annotations about their impact and even all the ranked papers will serve as "syllabus" for the education of future thoracic oncology trainees. Finally, we mentioned potential practice-changing clinical trials to be reported. One of them, LAURA was published online on June 2, 2024 was not included in the list of papers to be voted on but will surely be highly ranked if this consensus survery is performed again on the 25^th anniversay of the discovery EGFR mutations (i.e. top 25 papers on the 25 years since the discovery of activating EGFR mutations).