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Introduction: Amplification of 3q is the most common genetic alteration identified in squamous cell carcinoma of the lung (LUSC), with the most frequent amplified region being 3q26 to 3q28., Methods: In this analysis, we aim to describe the prognostic relevance of 3q amplification by focusing on a minimal common region (MCR) of amplification constituted of 25 genes. We analyzed 511 cases of LUSC from The Cancer Genome Atlas and included 476 in the final analysis., Results: We identified a 25-gene MCR that was amplified in 221 (44.3%) cases and was associated with better disease-specific survival (not reported [NR] versus 9.25 y, 95% confidence interval [CI]: 5.24-NR, log-rank p  = 0.011) and a progression-free interval of 8 years (95% CI: 5.1-NR) versus 4.9 years (95% CI: 3.5-NR, log-rank p  = 0.020). Multivariable analysis revealed that MCR amplification was associated with improved disease-specific survival and progression-free interval., Conclusions: Amplification of the 25-gene MCR within 3q was present in 44% of this cohort, consisting mainly of Caucasian patients with early stage LUSC. This analysis strongly indicates the prognostic relevance of the 25-gene MCR within 3q. We are further evaluating its prognostic and predictive relevance in a racially diverse patient population with advanced LUSC., (© 2023 The Authors.)

Purpose: As screening chest computed tomography for patients at high risk for cancer has become more widely accepted, increasing numbers of patients with early-stage small cell lung cancer (SCLC) are being diagnosed. Although surgery is an accepted option for patients with early-stage SCLC, for patients who decline or cannot undergo surgery, stereotactic body radiation treatment (SBRT) is an alternative. Although prophylactic cranial irradiation (PCI) improves survival in patients with limited-stage SCLC, PCI for early-stage SCLC (stage T1-T2) has not been explored. This study defines survival and recurrence patterns in patients with early-stage SCLC who were treated with surgery or SBRT in the absence of PCI., Methods and Materials: In this single-institution retrospective study, 14 patients diagnosed with early-stage SCLC (stage T1-T2) between July 2015 and May 2021 at a single tertiary care hospital were treated with SBRT or surgery with no PCI. Primary outcomes were locoregional cancer recurrence, distant recurrence, recurrence-free survival, and overall survival. The secondary outcome was development of brain metastasis. Analyses included Cox regression, Kaplan-Meier survival, and log-rank tests., Results: A total of 14 patients (5 women and 9 men) were included in the study: 9 with stage T1 and 5 with stage T2 SCLC. Six patients (43%) received SBRT and 8 (57%) had surgical treatment. All patients except 1 received adjuvant chemotherapy. Median follow-up was 14.3 months (range, 2.4-64.4 months), and the median age at diagnosis was 71.5 years (range, 54-81 years). Cox regression and log-rank tests showed no significant differences in any outcomes between the surgery and SBRT groups, and no patients developed brain metastases during the study period., Conclusions: Data are lacking regarding the benefit of PCI in early-stage SCLC. Although the sample size in this study was too small to draw any conclusions, the findings add to the ongoing dialogue regarding the importance of PCI in this patient population. No difference was identified in survival and cancer recurrence in patients who received either surgery or SBRT in the absence of PCI., (© 2023 The Authors.)

Introduction: We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials., Methods: This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1 , and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11 , KEAP1 , and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome., Results: Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n  = 293; KEYNOTE-407, n  = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1 , STK11, or KRAS mutation status., Conclusions: These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen., (© 2022 The Authors.)

Introduction: The aim of this study was to evaluate the efficacy of pemetrexed and platinum plus pembrolizumab by baseline tumor burden., Methods: A total of 616 patients in the intention-to-treat population of the KEYNOTE-189 study were included in this analysis. Baseline tumor burden subgroups were identified on the basis of extent of distant metastasis (M1a versus M1b), median number (≤3 versus >3) of organ systems with lesions, or symptom severity score of patient-reported lung cancer-associated symptoms (≤median versus >median). Overall survival (OS), progression-free survival (PFS), and PFS-2 were evaluated by Kaplan-Meier and univariate Cox methods. Objective response rate was analyzed using logistic regression models, and duration of response was analyzed descriptively. Efficacy outcomes were also analyzed according to the programmed death-ligand 1 expression levels., Results: OS and PFS were significantly improved with pemetrexed and platinum plus pembrolizumab in all baseline tumor burden subgroups (M1a stage: OS hazard ratio [HR] = 0.54, p  = 0.0037; PFS HR = 0.48, p  = 0.0001; M1b stage: OS HR = 0.58, p ≤ 0.0001; PFS HR = 0.51, p ≤ 0.0001; number of organ systems with lesion ≤ 3: OS HR = 0.49, p ≤ 0.0001 PFS HR = 0.41, p ≤ 0.0001; >3: OS HR = 0.67, p  = 0.0068; PFS HR = 0.59, p  = 0.0001; symptom severity score ≤ median: HR = 0.51, p ≤ 0.0001; PFS HR 0.49, p ≤ 0.0001; > median: OS HR = 0.60, p  = 0.0003; PFS HR = 0.48, p ≤ 0.0001). PFS2 and objective response rate were also improved with pemetrexed and platinum plus pembrolizumab in all baseline tumor burden subgroups. Efficacy outcomes were generally consistent regardless of programmed death-ligand 1 expression levels., Conclusions: Pemetrexed and platinum plus pembrolizumab were found to have relevant efficacy regardless of the extent of baseline tumor burden and the variables used to define it. These results further support pemetrexed and platinum plus pembrolizumab as the standard of care in the first-line treatment of metastatic nonsquamous NSCLC., (© 2022 Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.)

Introduction: Lung cancer screening criteria should select candidates with minimal cardiopulmonary comorbidities who are fit for curative lung cancer resection., Methods: We retrospectively analyzed 728 patients with lung cancer for screening eligibility using the U.S. Preventive Services Task Force (USPSTF) 2013 criteria (n = 370). If ineligible for screening, they were further assessed for eligibility using the USPSTF 2021 (n = 121) and National Comprehensive Cancer Network group 2 (NCCN gp 2) (n = 155). Comparisons of cardiopulmonary comorbidities between patients selected by the different lung cancer screening criteria were performed. Excluding missing data, a similar comparison was done between USPSTF 2013 (n = 283) and PLCOm2012 (risk threshold ≥1.51%) (n = 118)., Results: Patients eligible for USPSTF 2021 and NCCN gp 2 had lower rates of airflow obstruction (forced expiratory volume in 1 s [FEV1]/forced vital capacity <0.7) compared with those in USPSTF 2013 (55.4% and 56.8% versus 70.5%). Both USPSTF 2021 and NCCN gp 2 groups had less severe airflow obstruction; only 11.6% and 12.9% of patients, respectively, had percent-predicted FEV1 less than 50% versus 20.3% in the USPSTF 2013 group. Comparing USPSTF 2013 and PLCOm2012 revealed no significant differences in age or the rate of airflow obstruction ( p = 0.06 and p = 0.09 respectively). Nevertheless, rates of percent-predicted FEV1 less than 50% and diffusing capacity of the lungs for carbon monoxide less than 50% were lower in the PLCOm2012 group compared with those in the USPSTF 2013 group (22.3% versus 10.2% and 32.6% versus 20.0%), respectively., Conclusions: The USPSTF 2021 qualifies an additional group of screening candidates who are healthier with better lung reserve, translating to better surgical candidacy but potentially more overdiagnosis. The PLCOm2012, with its better accuracy in selecting patients at risk of cancer, selects an older group with chronic obstructive pulmonary disease but with good lung reserve and potentially less overdiagnosis., (© 2022 The Authors.)

Introduction: Alectinib is a preferred first-line treatment option for advanced ALK -positive NSCLC. Combination regimens of alectinib with immune checkpoint inhibitors are being evaluated for synergistic effects., Methods: Adults with treatment-naive, stage IIIB/IV, or recurrent ALK -positive NSCLC were enrolled into a two-stage phase 1b study. Patients received alectinib 600 mg (twice daily during cycle 1 and throughout each 21-d cycle thereafter) plus atezolizumab 1200 mg (d8 of cycle 1 and then d1 of each 21-d cycle). Primary objectives were to evaluate safety and tolerability of alectinib plus atezolizumab. Secondary objectives included assessments of antitumor activity., Results: In total, 21 patients received more than or equal to 1 dose of alectinib or atezolizumab. As no dose-limiting toxicities were observed in stage 1 (n = 7), the starting dose and schedule were continued into stage 2 (n = 14). Median duration of follow-up was 29 months (range: 1-39). Grade 3 treatment-related adverse events occurred in 57% of the patients, most often rash (19%). No grade 4 or 5 treatment-related adverse events were reported. Confirmed objective response rate was 86% (18 of 21; 95% confidence interval [CI]: 64-97). Median progression-free survival was not estimable (NE) (95% CI: 13 mo-NE), neither was median overall survival (95% CI: 33 mo-NE)., Conclusions: The combination of alectinib and atezolizumab is feasible, but increased toxicity was found compared with the individual agents. With small sample sizes and relatively short follow-up, definitive conclusions regarding antitumor activity cannot be made., (© 2022 The Authors.)

Introduction: RET rearrangements define a distinct molecular subset of NSCLC. The multikinase inhibitor ponatinib reveals potent activity in preclinical models of RET -rearranged NSCLC., Methods: In this single-arm, multicenter, phase II trial, we evaluated the clinical activity of ponatinib in patients with advanced, previously treated, RET -rearranged NSCLC (NCT01813734). RET rearrangements were identified through fluorescence in situ hybridization or next-generation sequencing. Ponatinib was administered at a dose of 30 mg once daily. Patients without a documented objective response were eligible to dose-escalate ponatinib to 45 mg daily. The primary end point was objective response rate., Results: Between August 2014 and December 2017, nine patients were enrolled. The median age was 58 years (range 49-73 y). Eight patients (89%) had a history of brain metastases. The median number of previous lines of therapy was three (range 1-5). Of the nine evaluated patients, five (55%) experienced tumor shrinkage from baseline, but no confirmed responses were observed (objective response rate 0%). The disease control rate was 55%. With a median follow-up of 9.33 months, the median progression-free survival and overall survival were 3.80 months (95% CI: 1.83-5.30) and 17.47 months (95% CI: 6.57-19.20), respectively. The most common treatment-related adverse events were rash (n = 5; 56%), constipation (n = 4; 44%), and diarrhea (n = 4; 44%). No treatment-related thromboembolic or cardiac events were observed. The study was stopped prematurely owing to slow accrual and lack of clinical activity., Conclusions: Ponatinib has limited clinical activity in patients with RET -rearranged NSCLC. Continued development of more potent and selective RET inhibitors is needed., (© 2020 The Authors.)