Faculty Bibliography

Lung cancer, the leading cause of cancer-related deaths globally, includes non-small cell lung cancer (NSCLC) (85% of cases) and small cell lung cancer (SCLC) (13-15%). While accurate diagnosis and treatment selection are critical, the absence of reliable predictive or prognostic biomarkers remains a significant challenge. This study explored the combined use of radiomics from CT scans and pathomics from H&E slides in three contexts: (1) predicting disease recurrence in early-stage NSCLC, (2) predicting immunotherapy response in advanced-stage NSCLC, and (3) predicting chemotherapy response in SCLC. The integrated radio-pathomic model significantly outperformed individual models. In early-stage NSCLC (N = 194), it achieved an HR of 8.35 (C-index: 0.71, p = 0.0043). In advanced-stage NSCLC (N = 35), the combined model improved predictive performance (AUC: 0.75, p = 0.042). In SCLC (N = 50), the integrated model showed an AUC of 0.78, surpassing both radiomic and pathomic models. These findings highlight the potential of combining radiomics and pathomics for improved lung cancer risk stratification and treatment prediction.

IMPORTANCE/UNASSIGNED:Effective treatments for advanced or metastatic non-small cell lung cancer (NSCLC) are limited. Understanding clinical treatment patterns is critical for understanding unmet medical needs. OBJECTIVE/UNASSIGNED:To describe clinical treatment patterns and outcomes, including time to treatment discontinuation, progression-free survival, and overall survival, in patients who received platinum-based chemotherapy and anti-programmed cell death 1 protein or programmed cell death ligand 1 (PD-[L]1) regimens. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective cohort study used data from 2018 to 2023 from a US nationwide, electronic health record-derived, deidentified database with median duration of follow-up of 7.8 (range, 0-65.0) months. Patients 18 years or older with advanced or metastatic NSCLC in second- and third-line treatment settings were included. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, received platinum-based chemotherapy and anti-PD-(L)1 therapy in 1 (combination) or 2 (sequential) lines, and initiated at least 1 subsequent treatment between January 1, 2018, and June 30, 2023. Exclusion criteria included disease progression within 8 weeks after anti-PD-(L)1 treatment initiation. Follow-up was until death or last available data through June 30, 2023. EXPOSURES/UNASSIGNED:Antineoplastic drugs following platinum-based chemotherapy and anti-PD-(L)1 treatment. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Time to treatment discontinuation, progression-free survival, and overall survival were analyzed overall and by initial treatment. Exploratory subgroup analyses were stratified by patient characteristics and index treatment without adjustment for group differences. RESULTS/UNASSIGNED:In the 1793 patients (974 [54.3%] male) included in the analysis, mean (SD) age at index treatment was 67.4 (9.4) years and median time from advanced diagnosis to index treatment was 10.5 (range, 1.1-103.8) months. The most common index treatments were docetaxel plus ramucirumab (314 [17.5%]), docetaxel monotherapy (158 [8.8%]), and carboplatin plus paclitaxel (136 [7.6%]). Overall, median time from index treatment to treatment discontinuation was 3.71 (95% CI, 3.48-3.94) months; median progression-free survival, 5.29 (95% CI, 5.03-5.52) months; and median overall survival, 11.20 (95% CI, 10.48-11.93) months. In exploratory analyses, these outcomes were numerically shorter in patients who received chemotherapy monotherapy as index treatment vs the overall group; medians were numerically longer in patients who received index treatments of immuno-oncology monotherapy or chemotherapy plus immuno-oncology combination therapy. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this retrospective cohort study of patients with advanced or metastatic NSCLC, results underscored a significant need for novel treatments, including immuno-oncology combinations.

Molecular determinants of KRAS(G12C)inhibitor efficacy in KRAS^G12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRAS^G12C-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of TTF1 and KEAP1 co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest that early on-treatment clearance of KRAS^G12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRAS^G12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.

How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

INTRODUCTION/UNASSIGNED:Osimertinib is now a standard first-line (1L) therapy for EGFR-mutated (EGFRm) advanced NSCLC. We aimed to characterize patterns of therapy and longitudinal risk of brain and liver metastasis in a cohort of EGFRm NSCLC. METHODS/UNASSIGNED:Patients with metastatic EGFRm NSCLC who received 1L systemic therapy at sites within the Academic Thoracic Medical Investigator's Consortium were included; demographic and clinical data including treatment patterns were described. Analyses of overall survival, time to next treatment, and incident brain and liver metastasis were performed using the Kaplan-Meier method, Cox regression, and cumulative incidence functions on patients who started 1L therapy in 2015 or later. RESULTS/UNASSIGNED:The full cohort included 1132 patients and the mean age of the participants was 63.4 years; among the participants, 53% were White individuals, 68% were female individuals, and 67% were nonsmokers. Among the participants, 830 patients received 1L systemic therapy in 2015 or later. The predominant first EGFR-tyrosine kinase inhibitor was erlotinib (65%) before 2018 and osimertinib (81%) after 2018. The median time to the next treatment after the start of 1L therapy was 13.9 months overall and the longest in patients receiving 1L osimertinib (28 months). In the post-2015 cohort, the baseline prevalence of brain metastasis (BM) was 54% and among patients without baseline brain metastasis, the probability of incident BM at 12, 24, and 48 months was 8%, 22%, and 44%, respectively. Development of an on-treatment brain metastasis among patients without baseline brain metastasis was associated with a 3.2 times higher risk of death. CONCLUSION/UNASSIGNED:Even in a contemporary era with prevalent osimertinib use, the baseline and longitudinal risk of BM development was high. The ongoing risk of developing BM, together with the associated survival detriment, argues for routine surveillance of the brain through magnetic resonance imaging for patients with EGFRm NSCLC, which is not currently included in the guidelines.

INTRODUCTION:Determining lines of therapy (LOT) using real-world data is crucial to inform clinical decisions and support clinical research. Existing rules for determining LOT in patients with metastatic non-small cell lung cancer (mNSCLC) do not incorporate the growing number of targeted therapies used in treatment today. Therefore, we propose rules for determining LOT from real-world data of patients with mNSCLC treated with targeted therapies. METHODS:LOT rules were developed through expert consensus using a real-world cohort of 550 patients with ALK+ or ROS1+ mNSCLC in the multi-institutional, electronic medical record-based Academic Thoracic Oncology Medical Investigators Consortium's (ATOMIC) Driver Mutation Registry. Rules were subsequently modified based on a review of appropriate LOT determination. These resulting rules were then applied to an independent cohort of patients with EGFR+ mNSCLC to illustrate their use. RESULTS:Six rules for determining LOTs were developed. Among 1133 patients with EGFR mutations and mNSCLC, a total of 3168 regimens were recorded with a median of 2 regimens per patient (IQR, 1-4; range, 1-13). After applying our rules, there were 2834 total LOTs with a median of 2 LOTs per patient (IQR, 1-3; range, 1-11). Rules 1-3 kept 11% of regimen changes from advancing the LOT. When compared to previously published rules, LOT assignments differed 5.7% of the time, mostly in LOTs with targeted therapy. CONCLUSION:These rules provide an updated framework to evaluate current treatment patterns, accounting for the increased use of targeted therapies in patients with mNSCLC, and promote standardization of methods for determining LOT from real-world data.

BACKGROUND:T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors. METHODS:This was a three-part, open-label, phase 1/2 study: part A, dose-escalation monotherapy, part B, dose-expansion monotherapy, and part C, combination therapy with pembrolizumab. The study was conducted at 32 sites in 7 countries. Adult patients with advanced solid tumors were enrolled and received intravenous nemvaleukin once daily on days 1-5 (21-day cycle) at 0.1-10 µg/kg/day (part A), or at the RP2D (part B), or with pembrolizumab (part C). Primary endpoints were RP2D selection and dose-limiting toxicities (part A), and overall response rate (ORR) and safety (parts B and C). RESULTS:T and natural killer cell expansion, and minimal regulatory T cell expansion were observed following nemvaleukin treatment. ORR with nemvaleukin plus pembrolizumab was 13% (19/144; 95% CI 8 to 20), with 5 complete and 14 partial responses; 6 responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types. Three responses were in patients with platinum-resistant ovarian cancer. The most common grade 3-4 treatment-related adverse events (TRAEs) in parts B and C, respectively, were neutropenia (49%, 21%) and anemia (10%, 11%); 4% of patients in each part discontinued due to TRAEs. CONCLUSIONS:Nemvaleukin was well tolerated and demonstrated promising antitumor activity across heavily pretreated advanced solid tumors. Phase 2/3 studies of nemvaleukin are ongoing. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT02799095.

BACKGROUND:Brain metastases (BM) are a common, severe complication in patients with non-small cell lung cancer (NSCLC) and are difficult to treat due to their complex tumor biology and the intricate microenvironment of the brain. OBJECTIVES/OBJECTIVE:This review examines the current role of immune checkpoint inhibitors (ICIs) in treating NSCLC with BM, focusing on the latest clinical trials, emerging strategies, current guidelines, and future directions. We highlight the efficacy of ICIs as monotherapy and in combination with other treatments such as radiotherapy, stereotactic radiosurgery, chemotherapy, and anti-VEGF agents. RESULTS:While no single treatment sequence is universally accepted, combining ICIs with traditional therapies forms the core of the current treatment protocols. ICIs targeting the PD-1/PD-L1 pathway have significantly advanced NSCLC treatment, demonstrated by improved overall and progression-free survival in various settings. However, optimizing these benefits requires careful consideration of potential side effects, including cognitive decline and radiation necrosis, and the impact of steroid use on ICI efficacy. CONCLUSION/CONCLUSIONS:The review underscores the necessity for a personalized, integrated multidisciplinary treatment approach. Future research should focus on refining combination therapies and understanding the optimal sequence and timing of treatment.

BACKGROUND:In clinical trials, frontline pembrolizumab for advanced NSCLC has demonstrated durable, clinically meaningful, long-term survival benefits over chemotherapy. Our objective was to evaluate 5-year survival rates outside the idealized setting of clinical trials for advanced/metastatic NSCLC treated with frontline pembrolizumab monotherapy. METHODS:Using a nationwide, electronic health record-derived, deidentified database in the United States, we studied adult patients with advanced/metastatic NSCLC (unresectable stage IIIB/IIIC, or stage IV), with PD-L1 expression ≥ 50%, no documented EGFR, ALK, or ROS1 genomic alteration, and ECOG performance status of 0-1 initiating frontline pembrolizumab monotherapy from November 1, 2016, through March 31, 2020, excluding those in clinical trials. Kaplan-Meier was used to determine overall survival (OS). Data cutoff was May 31, 2023. RESULTS:A total of 804 patients were eligible for the study, including 404 women (50%); median age was 72 years (range, 38-85 years), with 310 patients (39%) ≥ 75 years old. Median follow-up time from pembrolizumab initiation to data cutoff was 60.5 months (range, 38.0-78.7). At data cutoff, 549 patients (68%) had died. Median OS was 19.2 months (95% CI, 16.6-21.4), and survival rate at 5 years was 25.1% (95% CI, 21.7-28.7). Overall, 266 patients (33%) received 1 or more subsequent regimens, most commonly an anti-PD-(L)1 agent (as monotherapy or combination therapy) or platinum-based chemotherapy. CONCLUSIONS:With 5-year follow-up in a real-world population, frontline pembrolizumab monotherapy continues to demonstrate long-term effectiveness, with survival outcomes consistent with those of pivotal clinical trials, for treating patients with advanced NSCLC with PD-L1 expression of ≥ 50% and no EGFR, ALK, or ROS1 genomic alteration.