1544P Pre-treatment CT radiomics predicts survival in chemo-immunotherapy-treated small cell lung cancer

Background: The addition of checkpoint inhibitors to chemotherapy in SCLC patients provides modest benefit, with a median survival of 12 months. Development of non-invasive imaging predictors to identify patients most likely to benefit from chemo-immunotherapy would enable personalized management of SCLC. Methods: A cohort of 31 extensive-stage SCLC patients treated with atezolizumab, carboplatin, and etoposide from June 2020 to May 2021 were identified and pre-treatment CT scans were curated. The axial slice at the level of the carina (S1) was identified and center-cropped. 304 3D radiomic features from 5 slices surrounding S1 were extracted for analysis. After feature selection, the most discriminative radiomic feature was used to train and evaluate a random forest machine classifier for mortality prediction using leave-one-out cross-validation (LOOCV). A baseline classifier was trained using clinical variables. LOOCV mortality probabilities were recorded for each patient and used to stratify patient risk. Overall survival (OS) analysis was performed using Cox modeling. Results: Median follow-up was 343 days. Patient data included median age of 67 (46-85), race (24 white, 7 black), 58% female, and liver metastases at diagnosis in 29%. The Haralick difference variance feature had an AUC of 0.77 (c-index: 0.70) compared to the clinical baseline AUC of 0.56 (c-index: 0.64) for mortality and OS. The radiomic classifier identified low (N=12) and high (N=19) risk cohorts with median OS of 519.5 and 194 days, respectively (p=.01). There was no significant difference in OS for low and high risk cohorts identified by clinical features (p=0.47). Conclusions: Patient survival following chemo-immunotherapy in SCLC can be predicted using computational analysis of pre-treatment images. Our results encourage study of larger patient cohorts to further understand the relationship between imaging signatures and survival in SCLC, potentially leading to improved personalized disease management

Racial differences in lung cancer

Although race, in and of itself, is not a relevant biologic variable, racial differences in disease characteristics and outcomes have been reported in many malignancies, including lung cancer. The lung cancer incidence rate in blacks has been consistently higher than that in whites for many years. This racial disparity is seen primarily in men and is significantly greater in younger age groups. The reason for higher lung cancer incidence rates in blacks remains unclear, but racial differences in smoking habits, socioeconomic variables, and the metabolism of tobacco carcinogens may all play an important role. Blacks are also more likely than whites to present with squamous cell carcinoma and with advanced-stage disease. A significant racial difference in survival rates has developed over the past 30 years, with a poorer prognosis noted in black patients, particularly those with local- and regional-stage disease. This disparity appears to be due to a lack of improvement in the survival of black patients with lung cancer, but the biological and/or societal basis for racial variations in survival have not been determined. In summary, significant racial differences exist in lung cancer incidence and survival rates. Further research is required to determine the factors responsible for these differences and to develop effective preventative and therapeutic interventions that will impact favorably on the incidence and prognosis of this disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44537/1/10555_2004_Article_5111825.pd

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study

Pembrolizumab; Non-small-cell lung cancerPembrolizumab; Cáncer de pulmón de células no pequeñasPembrolizumab; Càncer de pulmó de cèl·lules no petitesClinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations

1317P Renal toxicity in black patients with non-squamous non-small cell lung cancer treated with combination platinum-pemetrexed-pembrolizumab therapy

Background: In Keynote 189, an increased incidence of renal toxicity was observed with combination platinum-pemetrexed-pembrolizumab (PPP) therapy compared to chemotherapy alone. Studies have shown that compared to White Americans, Black Americans are at higher risk of morbidity and mortality associated with chronic kidney disease (CKD). We conducted a retrospective analysis of patients treated with PPP to assess the rate of renal toxicity in Black and White patients. Methods: Data of self-identified non-hispanic (NH) Black and NH White patients with advanced NS-NSCLC who were treated with PPP between January 1, 2017, and November 1, 2020, at the Henry Ford Health System was analyzed. Serum creatinine (Cr) and calculated glomerular filtration rate (GFR) before the first cycle of PPP and over the duration of PPP therapy were assessed. Acute kidney injury (AKI) was defined as an increase in Cr 1.5 times the baseline value. Reduction in GFR of ≥ 30% was considered significant. Multiple variables and outcomes were analyzed by two-group comparisons, univariate analysis, and Cox regression. Results: A total of 134 patients were included in the analysis. The mean age was 66.5 (SD 8.6) years, and 65 (48.5%) patients were men. A total of 33 (24%) patients were NH Black and 101 (75.4%) were NH White. There were 10 (8.1%) patients who developed AKI, and the median time to development of AKI was 4.5 months. No significant association of Black (3) or White (7) ethnicity with AKI was observed (p =.57). The odds of developing AKI was not increased in patients with a history of hypertension (p =.67), diabetes mellitus (p =.33), cardiovascular disease (p =.68), or CKD (p =.33). A total of 17 out of 127 (13.4%) patients had significantly reduced GFR, and patients with CKD were more likely to have reduced GFR (OR 4.8, p =.02). At the median follow-up of 24.5 months, the median survival was 15.2 months (95% CI, 12.7-22.2). Black ethnicity (HR 1.21, p =.46) and development of AKI (HR 1.13; 95% CI, 0.45–2.86) were not associated with increased mortality. Conclusions: Black patients with NS-NSCLC treated with PPP are not at higher risk of AKI or death than White patients. Development of AKI after PPP therapy was not associated with increased mortality

(P44) Is Prophylactic Cranial Irradiation Necessary in Stage I-IIA Small Cell Lung Cancer Patients? A Single Institution Experience

Background: The advent of screening chest computed tomography (CT) for high-risk patients has increased the patient population presenting with early-stage small cell lung cancer (SCLC). While surgical resection continues to be standard of care, stereotactic body radiation therapy (SBRT) is an option for non-surgical candidates. Although the effectiveness of PCI in patients with limited stage SCLC has been well established, decreasing the brain metastasis incidence from approximately 70% to 30%, the role of PCI in early-stage SCLC (T1-T2) has not been fully elucidated. This study reports our experience omitting PCI in early-stage SCLC. Objectives: This study reports our experience omitting PCI in early stage SCLC. Methods: Fourteen patients with early-stage SCLC, nine patients with clinical stage I (T1) and five patients with stage IA (T2) SCLC, ranging in age from 54-81 years old, treated with surgical resection or SBRT from July 2015 to May 2021 at our institution, were retrospectively reviewed. Positron emission tomography (PET) was used in the staging of 93% of patients. All patients had initial negative brain MRI and opted not to receive PCI. 71% of the patients had brain scan surveillance for follow-up. Risk factors including age, gender, and tumor size, were analyzed for overall survival (OS), loco-regional recurrence (LRR), and distant metastasis (DM) using the Log-rank test. Results: With a median follow-up of 13 months (range 2-63), none of our patients developed metastases to the brain. Adjuvant chemotherapy, with a mean of 4 cycles (2-6) was administered to 13 out of 14 patients (92%). The 2-year OS, LRR and DM estimates were 47% [95% CI (0.14, 0.75)], 57% [95% CI (0.19, 0.82)], and 51% [95% CI (0.17, 0.77)], respectively. The OS and the frequency of LRR were not found to be correlated with age, gender, or tumor size. DM was significantly higher in males vs females (P=0.016). Conclusions: Our experience in patients with Stage I-IIA SCLC treated with surgery or SBRT did not demonstrate any development of brain metastases. As PCI carries long term risks of neurotoxicity, close surveillance with regular brain imaging may be a reasonable alternative. Adjuvant systemic therapy remains an important component of treatment

Lung Cancer Screening Criteria and Cardiopulmonary Comorbidities

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 \u3c0.7) 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

Pemetrexed and Platinum Plus Pembrolizumab in Patients With Metastatic Nonsquamous NSCLC by Tumor Burden at Baseline: A Post Hoc Efficacy Analysis of KEYNOTE-189

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 \u3e3) of organ systems with lesions, or symptom severity score of patient-reported lung cancer-associated symptoms (≤median versus \u3emedian). 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; \u3e3: 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; \u3e 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

Concordance Between Tissue ALK Detection by Immunohistochemistry and Plasma ALK Detection by Next-Generation Sequencing in the Randomized Phase 3 ALEX Study in Patients With Treatment-Naive Advanced ALK-Positive NSCLC

INTRODUCTION: The Blood First Assay Screening Trial revealed the clinical applicability of blood-based next-generation sequencing to identify patients with ALK-positive NSCLC for alectinib treatment. To understand the relationship between tissue-based versus blood-based testing, we retrospectively investigated concordance between VENTANA ALK (D5F3) CDx immunohistochemistry and the FoundationACT (FACT; Foundation Medicine, Inc.) plasma assay, and compared clinical efficacy between phase 3 ALEX study subpopulations. METHODS: Patients with advanced ALK-positive (by immunohistochemistry) NSCLC were randomized 1:1 to alectinib 600 mg or crizotinib 250 mg, twice daily. Assessable baseline plasma samples were analyzed for ALK positivity by FACT; positive percent agreement with immunohistochemistry was evaluated. Progression-free survival (PFS), duration of response, and objective response rate were compared between intention-to-treat (ITT) and biomarker-evaluable populations, and plasma ALK-positive and plasma ALK-negative subpopulations. RESULTS: In the ITT population (303 patients; alectinib, 152; crizotinib, 151), all patients had ALK-positive tumors by immunohistochemistry. In the biomarker-evaluable population (149 patients; alectinib, 76; crizotinib, 73), 105 had plasma ALK-positive and 44 had plasma ALK-negative tumors. Positive percent agreement between immunohistochemistry and FACT was 70.5% (105 of 149; 95% confidence interval: 62.5-77.7). Baseline characteristics were generally balanced, with some exceptions, notably tumor burden. Median PFS in plasma ALK-positive and ALK-negative patients was 22.4 months and not estimable with alectinib and 7.3 months and 12.9 months with crizotinib, respectively; median duration of response was 25.9 months and not estimable with alectinib and 5.6 months and 11.5 months with crizotinib, respectively. CONCLUSIONS: Reasonable concordance between FACT and immunohistochemistry was observed; both methods are valuable in identifying ALK-positive patients, separately or concurrently. Alectinib was found to have superior PFS in the plasma ALK-positive population, as in the ITT population

Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs

Abstract Background Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKIs) benefit Non-small cell lung cancer (NSCLC) patients, and an EGFR-TKIi erlotinib, is approved for patients with recurrent NSCLC. However, resistance to erlotinib is a major clinical problem. Earlier we have demonstrated the role of Hedgehog (Hh) signaling in Epithelial-to-Mesenchymal transition (EMT) of NSCLC cells, leading to increased proliferation and invasion. Here, we investigated the role of Hh signaling in erlotinib resistance of TGF-β1-induced NSCLC cells that are reminiscent of EMT cells. Methods Hh signaling was inhibited by specific siRNA and by GDC-0449, a small molecule antagonist of G protein coupled receptor smoothened in the Hh pathway. Not all NSCLC patients are likely to benefit from EGFR-TKIs and, therefore, cisplatin was used to further demonstrate a role of inhibition of Hh signaling in sensitization of resistant EMT cells. Specific pre- and anti-miRNA preparations were used to study the mechanistic involvement of miRNAs in drug resistance mechanism. Results siRNA-mediated inhibition as well as pharmacological inhibition of Hh signaling abrogated resistance of NSCLC cells to erlotinib and cisplatin. It also resulted in re-sensitization of TGF-β1-induced A549 (A549M) cells as well the mesenchymal phenotypic H1299 cells to erlotinib and cisplatin treatment with concomitant up-regulation of cancer stem cell (CSC) markers (Sox2, Nanog and EpCAM) and down-regulation of miR-200 and let-7 family miRNAs. Ectopic up-regulation of miRNAs, especially miR-200b and let-7c, significantly diminished the erlotinib resistance of A549M cells. Inhibition of Hh signaling by GDC-0449 in EMT cells resulted in the attenuation of CSC markers and up-regulation of miR-200b and let-7c, leading to sensitization of EMT cells to drug treatment, thus, confirming a connection between Hh signaling, miRNAs and drug resistance. Conclusions We demonstrate that Hh pathway, through EMT-induction, leads to reduced sensitivity to EGFR-TKIs in NSCLCs. Therefore, targeting Hh pathway may lead to the reversal of EMT phenotype and improve the therapeutic efficacy of EGFR-TKIs in NSCLC patients

Brief Report: Prognostic Relevance of 3q Amplification in Squamous Cell Carcinoma of the Lung

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