A process to reanalyze clinical DNA sequencing data for biomarker matching in the Lung-MAP Master Protocol.

For cancer clinical trials that require central confirmation of tumor genomic profiling, exhaustion of tissue from standard-of-care testing may prevent enrollment. For Lung-MAP, a master protocol that requires results from a defined centralized clinical trial assay to assign patients to a therapeutic substudy, we developed a process to repurpose existing commercial vendor raw genomic data for eligibility: genomic data reanalysis (GDR). Molecular results for substudy assignment were successfully generated for 369 of the first 374 patients (98.7%) using GDR for Lung-MAP, with a median time from request to result of 9 days. During the same period, 691 of 791 (87.4%) tissue samples received successfully yielded results, in a median of 14 days beyond sample acquisition. GDR is a scalable bioinformatic pipeline that expedites reanalysis of existing data for clinical trials in which validated integral biomarker testing is required for participation.

CONTACT-01: A Randomized Phase III Trial of Atezolizumab + Cabozantinib Versus Docetaxel for Metastatic Non-Small Cell Lung Cancer After a Checkpoint Inhibitor and Chemotherapy.

PURPOSE: Although checkpoint inhibitors have improved first-line treatment for non-small cell lung cancer (NSCLC), a therapeutic need remains for patients whose disease does not respond or who experience disease progression after anti-PD-L1/PD-1 immunotherapy. CONTACT-01 (ClinicalTrials.gov identifier: NCT04471428) evaluated atezolizumab plus cabozantinib versus docetaxel in patients with metastatic NSCLC who developed disease progression after concurrent or sequential treatment with anti-PD-L1/PD-1 and platinum-containing chemotherapy. METHODS: This multicenter, open-label, phase III trial randomly assigned patients 1:1 to atezolizumab 1,200 mg intravenously once every 3 weeks (q3w) plus cabozantinib 40 mg orally once daily or docetaxel 75 mg/m2 intravenously once every 3 weeks. The primary end point was overall survival (OS). RESULTS: One hundred eighty-six patients were assigned atezolizumab plus cabozantinib, and 180 docetaxel. Minimum OS follow-up was 10.9 months. Median OS was 10.7 months (95% CI, 8.8 to 12.3) with atezolizumab plus cabozantinib and 10.5 months (95% CI, 8.6 to 13.0) with docetaxel (stratified hazard ratio [HR], 0.88 [95% CI, 0.68 to 1.16]; P = .3668). Median progression-free survival was 4.6 months (95% CI, 4.1 to 5.6) and 4.0 months (95% CI, 3.1 to 4.4), respectively (stratified HR, 0.74 [95% CI, 0.59 to 0.92]). Serious adverse events (AEs) occurred in 71 (38.4%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 3/4 treatment-related AEs occurred in 73 (39.5%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 5 AEs occurred in 14 (7.6%) and 10 (6.0%) patients in the atezolizumab plus cabozantinib and docetaxel arms, respectively (treatment-related in four [2.2%] and one [0.6%], respectively). CONCLUSION: Atezolizumab plus cabozantinib after disease progression following anti-PD-L1/PD-1 immunotherapy and platinum-containing chemotherapy for metastatic NSCLC did not improve OS compared with docetaxel. Safety was consistent with known profiles of these agents.

Systematic analysis of off-label and off-guideline cancer therapy usage in a real-world cohort of 165,912 US patients.

Patients with cancer may be given treatments that are not officially approved (off-label) or recommended by guidelines (off-guideline). Here we present a data science framework to systematically characterize off-label and off-guideline usages using real-world data from de-identified electronic health records (EHR). We analyze treatment patterns in 165,912 US patients with 14 common cancer types. We find that 18.6% and 4.4% of patients have received at least one line of off-label and off-guideline cancer drugs, respectively. Patients with worse performance status, in later lines, or treated at academic hospitals are significantly more likely to receive off-label and off-guideline drugs. To quantify how predictable off-guideline usage is, we developed machine learning models to predict which drug a patient is likely to receive based on their clinical characteristics and previous treatments. Finally, we demonstrate that our systematic analyses generate hypotheses about patients' response to treatments.

THE IMPACT OF ROUTINE CARDIAC TROPONIN I-BASED CARDIOTOXICITY SCREENING ON CLINICAL OUTCOMES IN PATIENTS ON CANCER IMMUNOTHERAPY.

Purpose: Immune checkpoint inhibitors (ICI) used as cancer therapy have been associated with a range of cardiac immune-related adverse events (irAEs), including fulminant myocarditis with a high case fatality rate. Early detection through cardiotoxicity screening by biomarker monitoring can lead to prompt intervention and improved patient outcomes. In this study, we investigate the association between cardiotoxicity screening with routine serial troponin I monitoring in asymptomatic patients receiving ICI, cardiovascular adverse event (CV AE) detection, and overall survival (OS). Methods: We instituted a standardized troponin I screening protocol at baseline and with each ICI dose (every 2-4 weeks) in all patients receiving ICI at our center starting Jan 2019. We subsequently collected data in 825 patients receiving ICI at our institution from January 2018 to October 2021. Of these patients, 428 underwent cardiotoxicity screening with serial troponin I monitoring during ICI administration (Jan 2019-Oct 2021) and 397 patients were unmonitored (Jan 2018-Dec 2018). We followed patients for nine months following their first dose of ICI and compared outcomes of CV AEs and OS between monitored and unmonitored patients. Additionally, we investigated rates of CV AEs, all-cause mortality, and oncologic time-to-treatment failure (TTF) between patients with an elevated troponin I value during the monitoring period versus patients without elevated troponin I. Results: We found a lower rate of severe (grades 4-5) CV AEs, resulting in critical illness or death, in patients who underwent troponin monitoring (0.5%) compared to patients who did not undergo monitoring (1.8%), (HR 0.17, 95% CI 0.02-0.79, p = 0.04). There was no difference in overall CV AEs (grades 3-5) or OS between monitored and unmonitored patients. In the entire cohort, patients with at least one elevated troponin I during the follow up period, during routine monitoring or unmonitored, had a higher risk of overall CV AEs (HR 10.96, 95% CI 4.65-25.85, p<0.001) as well as overall mortality (HR 2.67, 95% CI 1.69 - 4.10, p<0.001) compared to those without elevated troponin. Oncologic time-to-treatment failure (TTF) was not significantly different in a sub-cohort of monitored vs. unmonitored patients. Conclusions: Patients undergoing cardiotoxicity screening with troponin I monitoring during ICI therapy had a lower rate of severe (grade 4-5) CV AEs compared patients who were not screened. Troponin I elevation in screened and unscreened patients was significantly associated with increased CV AEs as well as increased mortality. Troponin I monitoring did not impact oncologic time-to-treatment-failure in a sub-cohort analysis of patients treated with ICI. These results provide preliminary evidence for clinical utility of cardiotoxicity screening with troponin I monitoring in patients receiving ICI therapy.

HER2-Mutant Advanced and/or Metastatic Non-Small-Cell Lung Cancer: A US Electronic Health Records Database Analysis of Clinical Characteristics, Treatment Practice Patterns, and Outcomes.

BACKGROUND: Real-world data for advanced/metastatic non-small-cell lung cancer (NSCLC) with mutations in human epidermal growth factor 2 (HER2) are scarce. We aimed to assess treatment patterns and outcomes among patients with HER2-mutant advanced/metastatic NSCLC. PATIENTS AND METHODS: This retrospective nationwide electronic health record study evaluated patient characteristics, treatment patterns, treatment duration, and overall survival for adults with HER2-mutant advanced/metastatic NSCLC without epidermal growth factor receptor mutation. RESULTS: Of 55 included patients, median (quartile 1 [Q1]-quartile 3 [Q3]) age was 63.0 (58.0-72.0) years, 42 (76%) were women, and 39 (71%) were current/former smokers. In first-line therapy, 14 regimens were used for median (Q1-Q3) duration of 3.1 (2.4-6.2) months, with most patients (n = 39, 71%) receiving platinum-based chemotherapy alone or in combination with other agents. Median (95% CI) overall survival from first-line treatment initiation was 19.0 (12.2-not estimable) months, with no significant association with age, sex, or smoking status. Thirty-five (64%) patients received second-line therapy for median (Q1-Q3) duration of 3.3 (2.0-5.2) months. Fourteen second-line regimens were used; most commonly immunotherapy alone or in combination with other agents (n = 16, 46%). Sixteen (46%) patients received third-line therapy for median (Q1-Q3) duration of 1.9 (1.3-2.7) months. Nine third-line regimens were used, with 7 (44%) patients receiving HER2-directed agents. CONCLUSION: First- and second-line treatments for HER2-mutant NSCLC varied widely and treatment duration was short. The approval of trastuzumab deruxtecan for NSCLC supports wider HER2 testing to identify eligible patients for HER2-directed therapy.

Consolidation Osimertinib Versus Durvalumab Versus Observation After Concurrent Chemoradiation in Unresectable EGFR-Mutant NSCLC: A Multicenter Retrospective Cohort Study.

INTRODUCTION: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown. METHODS: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used. RESULTS: Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3). CONCLUSIONS: This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.

Risk model-based management for second primary lung cancer among lung cancer survivors through a validated risk prediction model.

BACKGROUND: Recent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). Recently, an SPLC risk-prediction model (called SPLC-RAT) was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. The predictive performance of SPLC-RAT was evaluated in a hospital-based cohort of lung cancer survivors. METHODS: The authors analyzed data from 8448 ever-smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997-2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC-RAT and further explored the potential of improving SPLC detection through risk model-based surveillance using SPLC-RAT versus existing clinical surveillance guidelines. RESULTS: Of 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person-years. The application of SPLC-RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10-year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC-RAT development cohort), the observed SPLC incidence was significantly elevated in the high-risk versus low-risk subgroup (13.1% vs. 1.1%, p < 1 × 10-6 ). The risk-based surveillance through SPLC-RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow-ups needed to detect one SPLC (162 vs. 202). CONCLUSION: In a large, hospital-based cohort, the authors validated the predictive performance of SPLC-RAT in identifying high-risk survivors of SPLC and showed its potential to improve SPLC detection through risk-based surveillance. PLAIN LANGUAGE SUMMARY: Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC). However, no evidence-based guidelines for SPLC surveillance are available for lung cancer survivors. Recently, an SPLC risk-prediction model was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. Using a large, real-world cohort of lung cancer survivors, we showed the high predictive accuracy and risk-stratification ability of the SPLC risk-prediction model. Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model-based surveillance strategies compared to the existing consensus-based clinical guidelines, including the National Comprehensive Cancer Network.

Personalized Accelerated ChEmoRadiation (PACER) for Lung Cancer: Protocol for a Bayesian Optimal Phase I/II Trial.

INTRODUCTION: Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs). METHODS: Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint. CONCLUSION: PACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer.

The effect of neighborhood socioeconomic disadvantage on smoking status, quit attempts, and receipt of cessation support among adults with cancer: Results from nine ECOG-ACRIN Cancer Research Group trials.

BACKGROUND: Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer. METHODS: A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression. RESULTS: A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods. CONCLUSIONS: Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Patient Selection and Outcomes for Hypofractionated Accelerated Radiation and Concurrent Chemotherapy for Non-Small-Cell Lung Cancer.

PURPOSE/OBJECTIVES: Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection. MATERIALS/METHODS: We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts. RESULTS: Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation CONCLUSION: In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients.

Phenotyping EMT and MET cellular states in lung cancer patient liquid biopsies at a personalized level using mass cytometry.

Malignant pleural effusions (MPEs) can be utilized as liquid biopsy for phenotyping malignant cells and for precision immunotherapy, yet MPEs are inadequately studied at the single-cell proteomic level. Here we leverage mass cytometry to interrogate immune and epithelial cellular profiles of primary tumors and pleural effusions (PEs) from early and late-stage non-small cell lung cancer (NSCLC) patients, with the goal of assessing epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in patient specimens. By using the EMT-MET reference map PHENOSTAMP, we observe a variety of EMT states in cytokeratin positive (CK+) cells, and report for the first time MET-enriched CK+ cells in MPEs. We show that these states may be relevant to disease stage and therapy response. Furthermore, we found that the fraction of CD33+ myeloid cells in PEs was positively correlated to the fraction of CK+ cells. Longitudinal analysis of MPEs drawn 2 months apart from a patient undergoing therapy, revealed that CK+ cells acquired heterogeneous EMT features during treatment. We present this work as a feasibility study that justifies deeper characterization of EMT and MET states in malignant cells found in PEs as a promising clinical platform to better evaluate disease progression and treatment response at a personalized level.

Efficacy of Mobocertinib and Amivantamab in Patients With Advanced Non-Small Cell Lung Cancer With EGFR Exon 20 Insertions Previously Treated With Platinum-Based Chemotherapy: An Indirect Treatment Comparison.

INTRODUCTION: Exon 20 insertions (ex20ins) mutations of the EGFR gene account for 1% to 2% of all non-small-cell lung cancers (NSCLCs). Targeted therapies have been developed to treat this cancer type but have not been studied in head-to-head trials. Our objective was to use a matching-adjusted indirect comparison (MAIC) to assess the efficacy of mobocertinib and amivantamab in patients with NSCLC EGFR ex20ins mutations who were previously treated with platinum-based chemotherapy. MATERIALS AND METHODS: An unanchored MAIC was conducted to estimate the treatment effects of mobocertinib and amivantamab using individual-level data from the mobocertinib phase I/II single-arm trial (NCT02716116) and published data from the amivantamab single-arm CHRYSALIS trial (NCT02609776). Confirmed overall response rate (cORR), progression-free survival (PFS), overall survival (OS), and duration of response (DoR) were assessed. RESULTS: Both trials were comparable in terms of study population, study design, and outcome definitions and included 114 patients who received mobocertinib and 114 patients who received amivantamab. After MAIC weighting, all reported baseline characteristics were balanced between mobocertinib and amivantamab. The weighted odds ratio (OR) [95% confidence interval (CI)] comparing mobocertinib to amivantamab was 0.56 (0.30-1.04) for independent review committee (IRC)-assessed cORR and 0.98 (0.53-1.82) for investigator (INV)-assessed cORR. The weighted hazard ratio (HR) comparing mobocertinib to amivantamab was 0.74 (0.51-1.07) for IRC-assessed PFS, 0.92 (0.57-1.48) for OS, and 0.59 (0.30-1.18) for INV-assessed DoR. CONCLUSION: MAIC analysis showed that mobocertinib and amivantamab had similar efficacy in patients with NSCLC harboring EGFR ex20ins mutations whose disease progressed during or after platinum-based chemotherapy. These findings may benefit patients by supporting future treatment options.

Second Primary Lung Cancer Among Lung Cancer Survivors Who Never Smoked.

Importance: Lung cancer among never-smokers accounts for 25% of all lung cancers in the US; recent therapeutic advances have improved survival among patients with initial primary lung cancer (IPLC), who are now at high risk of developing second primary lung cancer (SPLC). As smoking rates continue to decline in the US, it is critical to examine more closely the epidemiology of lung cancer among patients who never smoked, including their risk for SPLC. Objective: To estimate and compare the cumulative SPLC incidence among lung cancer survivors who have never smoked vs those who have ever smoked. Design, Setting, and Participants: This population-based prospective cohort study used data from the Multiethnic Cohort Study (MEC), which enrolled participants between April 18, 1993, and December 31, 1996, with follow-up through July 1, 2017. Eligible individuals for this study were aged 45 to 75 years and had complete smoking data at baseline. These participants were followed up for IPLC and further SPLC development through the Surveillance, Epidemiology, and End Results registry. The data were analyzed from July 1, 2022, to January 31, 2023. Exposures: Never-smoking vs ever-smoking exposure at MEC enrollment. Main Outcomes and Measures: The study had 2 primary outcomes: (1) 10-year cumulative incidence of IPLC in the entire study cohort and 10-year cumulative incidence of SPLC among patients with IPLC and (2) standardized incidence ratio (SIR) (calculated as the SPLC incidence divided by the IPLC incidence) by smoking history. Results: Among 211 414 MEC participants, 7161 (3.96%) developed IPLC over 4 038 007 person-years, and 163 (2.28%) developed SPLC over 16 470 person-years. Of the participants with IPLC, the mean (SD) age at cohort enrollment was 63.6 (7.7) years, 4031 (56.3%) were male, and 3131 (43.7%) were female. The 10-year cumulative IPLC incidence was 2.40% (95% CI, 2.31%-2.49%) among ever-smokers, which was 7 times higher than never-smokers (0.34%; 95% CI, 0.30%-0.37%). However, the 10-year cumulative SPLC incidence following IPLC was as high among never-smokers (2.84%; 95% CI, 1.50%-4.18%) as ever-smokers (2.72%; 95% CI, 2.24%-3.20%), which led to a substantially higher SIR for never-smokers (14.50; 95% CI, 8.73-22.65) vs ever-smokers (3.50; 95% CI, 2.95-4.12). Conclusions and Relevance: The findings indicate that SPLC risk among lung cancer survivors who never smoked is as high as among those with IPLC who ever-smoked, highlighting the need to identify risk factors for SPLC among patients who never smoked and to develop a targeted surveillance strategy.

Risk Model-Based Lung Cancer Screening and Racial and Ethnic Disparities in the US.

Importance: The revised 2021 US Preventive Services Task Force (USPSTF) guidelines for lung cancer screening have been shown to reduce disparities in screening eligibility and performance between African American and White individuals vs the 2013 guidelines. However, potential disparities across other racial and ethnic groups in the US remain unknown. Risk model-based screening may reduce racial and ethnic disparities and improve screening performance, but neither validation of key risk prediction models nor their screening performance has been examined by race and ethnicity. Objective: To validate and recalibrate the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012) model-a well-established risk prediction model based on a predominantly White population-across races and ethnicities in the US and evaluate racial and ethnic disparities and screening performance through risk-based screening using PLCOm2012 vs the USPSTF 2021 criteria. Design, Setting, and Participants: In a population-based cohort design, the Multiethnic Cohort Study enrolled participants in 1993-1996, followed up through December 31, 2018. Data analysis was conducted from April 1, 2022, to May 19. 2023. A total of 105 261 adults with a smoking history were included. Exposures: The 6-year lung cancer risk was calculated through recalibrated PLCOm2012 (ie, PLCOm2012-Update) and screening eligibility based on a 6-year risk threshold greater than or equal to 1.3%, yielding similar eligibility as the USPSTF 2021 guidelines. Outcomes: Predictive accuracy, screening eligibility-incidence (E-I) ratio (ie, ratio of the number of eligible to incident cases), and screening performance (sensitivity, specificity, and number needed to screen to detect 1 lung cancer). Results: Of 105 261 participants (60 011 [57.0%] men; mean [SD] age, 59.8 [8.7] years), consisting of 19 258 (18.3%) African American, 27 227 (25.9%) Japanese American, 21 383 (20.3%) Latino, 8368 (7.9%) Native Hawaiian/Other Pacific Islander, and 29 025 (27.6%) White individuals, 1464 (1.4%) developed lung cancer within 6 years from enrollment. The PLCOm2012-Update showed good predictive accuracy across races and ethnicities (area under the curve, 0.72-0.82). The USPSTF 2021 criteria yielded a large disparity among African American individuals, whose E-I ratio was 53% lower vs White individuals (E-I ratio: 9.5 vs 20.3; P < .001). Under the risk-based screening (PLCOm2012-Update 6-year risk ≥1.3%), the disparity between African American and White individuals was substantially reduced (E-I ratio: 15.9 vs 18.4; P < .001), with minimal disparities observed in persons of other minoritized groups, including Japanese American, Latino, and Native Hawaiian/Other Pacific Islander. Risk-based screening yielded superior overall and race and ethnicity-specific performance to the USPSTF 2021 criteria, with higher overall sensitivity (67.2% vs 57.7%) and lower number needed to screen (26 vs 30) at similar specificity (76.6%). Conclusions: The findings of this cohort study suggest that risk-based lung cancer screening can reduce racial and ethnic disparities and improve screening performance across races and ethnicities vs the USPSTF 2021 criteria.

Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).

PURPOSE: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. METHODS: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons. RESULTS: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001). CONCLUSION: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial.

Importance: Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy. Objective: To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control. Design, Setting, and Participants: This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3). Intervention: Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3. Main outcome: Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up. Results: In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects). Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT01463423.

Real-World Response and Outcomes in Patients With NSCLC With EGFR Exon 20 Insertion Mutations.

Introduction: This study describes treatment patterns and outcomes in patients with NSCLC with EGFR exon 20 insertions (EGFRex20ins) in the United States. Methods: The Flatiron Health electronic health record database was used to select three cohorts among patients diagnosed with NSCLC with EGFRex20ins (January 1, 2011-February 29, 2020): (1) first-line (1L) or patients receiving 1L therapy after documented EGFRex20ins; (2) second or later-line (≥2L) or patients receiving ≥2L therapy after documented EGFRex20ins; and (3) ≥2L postplatinum trial-aligned, or ≥2L patients previously treated with platinum chemotherapy whose baseline characteristics aligned with key eligibility criteria (initiating new treatment after documented EGFRex20ins and ≥1 previous treatment excluding mobocertinib or amivantamab) of the mobocertinib trial NCT02716116. Real-world end points were confirmed overall response rate, overall survival, and progression-free survival. Results: Of 237 patients with EGFRex20ins-mutated NSCLC, 129 and 114 patients were included in the 1L and ≥2L cohorts, respectively. In 1L patients, platinum chemotherapy plus nonplatinum chemotherapy (31.0%) and EGFR tyrosine kinase inhibitors (28.7%) were the most common regimens. In ≥2L patients, immuno-oncology monotherapy (28.1%) and EGFR tyrosine kinase inhibitors (17.5%) were the most common index treatments. For any 1L, ≥2L, and ≥2L postplatinum trial-aligned patients, the confirmed overall response rate was 18.6%, 9.6%, and 14.0%, respectively; the median overall survival was 17.0, 13.6, and 11.5 months; the median progression-free survival was 5.2, 3.7, and 3.3 months, respectively. Conclusions: The outcomes for patients with NSCLC with EGFRex20ins were poor. This real-world study provides a benchmark on treatment outcomes in this patient population and highlights the unmet need for improved therapeutic options.

Overall Survival Among Patients With De Novo Stage IV Metastatic and Distant Metastatic Recurrent Non-Small Cell Lung Cancer.

Importance: Despite recent breakthroughs in therapy, advanced lung cancer still poses a therapeutic challenge. The survival profile of patients with metastatic lung cancer remains poorly understood by metastatic disease type (ie, de novo stage IV vs distant recurrence). Objective: To evaluate the association of metastatic disease type on overall survival (OS) among patients with non-small cell lung cancer (NSCLC) and to identify potential mechanisms underlying any survival difference. Design, Setting, and Participants: Cohort study of a national US population based at a tertiary referral center in the San Francisco Bay Area using participant data from the National Lung Screening Trial (NLST) who were enrolled between 2002 and 2004 and followed up for up to 7 years as the primary cohort and patient data from Stanford Healthcare (SHC) for diagnoses between 2009 and 2019 and followed up for up to 13 years as the validation cohort. Participants from NLST with de novo metastatic or distant recurrent NSCLC diagnoses were included. Data were analyzed from January 2021 to March 2023. Exposures: De novo stage IV vs distant recurrent metastatic disease. Main Outcomes and Measures: OS after diagnosis of metastatic disease. Results: The NLST and SHC cohort consisted of 660 and 180 participants, respectively (411 men [62.3%] vs 109 men [60.6%], 602 White participants [91.2%] vs 111 White participants [61.7%], and mean [SD] age of 66.8 [5.5] vs 71.4 [7.9] years at metastasis, respectively). Patients with distant recurrence showed significantly better OS than patients with de novo metastasis (adjusted hazard ratio [aHR], 0.72; 95% CI, 0.60-0.87; P < .001) in NLST, which was replicated in SHC (aHR, 0.64; 95% CI, 0.43-0.96; P = .03). In SHC, patients with de novo metastasis more frequently progressed to the bone (63 patients with de novo metastasis [52.5%] vs 19 patients with distant recurrence [31.7%]) or pleura (40 patients with de novo metastasis [33.3%] vs 8 patients with distant recurrence [13.3%]) than patients with distant recurrence and were primarily detected through symptoms (102 patients [85.0%]) as compared with posttreatment surveillance (47 patients [78.3%]) in the latter. The main finding remained consistent after further adjusting for metastasis sites and detection methods. Conclusions and Relevance: In this cohort study, patients with distant recurrent NSCLC had significantly better OS than those with de novo disease, and the latter group was associated with characteristics that may affect overall survival. This finding can help inform future clinical trial designs to ensure a balance for baseline patient characteristics.

Improved Survival Outcomes in Patients With MET-Dysregulated Advanced NSCLC Treated With MET Inhibitors: Results of a Multinational Retrospective Chart Review.

BACKGROUND: We evaluated the disease and patient characteristics, treatment, and MET testing patterns, predictive biomarkers and survival outcomes in patients with MET-dysregulated metastatic non-small-cell lung cancer (NSCLC) in a real-world setting. PATIENTS AND METHODS: This was a multinational, retrospective, noninterventional chart review study. Data from medical records of patients with advanced/metastatic EGFR wild-type, MET-dysregulated NSCLC (December 2017-September 2018) were abstracted into electronic data collection forms. RESULTS: Overall, 211 patient charts were included in this analysis; 157 patients had MET exon 14 skipping mutations (METex14; with or without concomitant MET amplification) and 54 had MET amplification only. All patients were tested for METex14, whereas MET amplification was evaluated in 168 patients. No overlap was reported between MET dysregulation and ALK, ROS1 or RET rearrangements, or HER2 exon 20 insertions. Overall, 56 of 211 patients (26.5%) received MET inhibitor (METi) therapy in any treatment-line setting (31.2% in the METex14 cohort; 13% in the MET-amplified only cohort). In the METex14 cohort, median OS in patients receiving METi was 25.4 months versus 10.7 months in patients who did not (HR [95% CI]: 0.532 [0.340-0.832]; P = .0055). In the MET-amplified only cohort, median OS was 20.6 months in patients treated with METi compared with 7.6 months in those without METi (HR [95% CI]: 0.388 [0.152-0.991]; P = .0479). CONCLUSIONS: MET alterations in NSCLC typically occur in the absence of other oncogenic driver mutations and are associated with poor survival outcomes. Notably, METi therapies are associated with improved survival outcomes in patients with MET-dysregulated NSCLC.