bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two-year follow-up of single PD-1 blockade in neoadjuvant resectable NSCLC.
Authors: Gao Shugeng , Li Ning , Gao Shunyu , Xue Qi , Wang Shuhang , Lv Fang , Zhao Liang , Zhang Fan , Zhao Ziran , Su Kai , Tan Fengwei , Ling Yun , Wang Zhijie , Tang Wei , Ying Jianming , Wu Ning , Wang Jie , He Jie 
Published: June 2021

8522 Background: Early stage non-small-cell lung cancer (NSCLC) could benefit from anti-programmed cell death-1 (PD-1) monotherapy; however, the survival profiles remain to be disclosed. Here, we presented the two-year follow-up outcomes from a phase 1b study of sintilimab, an anti-PD-1 inhibitor in the neoadjuvant setting of NSCLC. Methods: Treatment-naive pts with resectable NSCLC (stage IA–IIIB) received two cycles of sintilimab followed by surgical resection. Postoperative treatment of sintilimab was at the discretion of investigator. The primary endpoint was AE, and key secondary endpoints included major pathological response (MPR), disease free survival (DFS) rate of 1 year and 2 years, and overall survival (OS) rate of 2 years. Results: Among 40 enrolled pts, 36 (90%) underwent R0 resection and were included in the R0 resection population. By data cutoff (January 20, 2021), the median follow-up for DFS and OS for all the enrolled pts was 23.9 (IQR 20.5–24.4) months and 26.4 (IQR 24.2–29.0) months. A total of 12 (33.3%) pts experienced relapse, and 6 pts died. The 1-yr and 2-yr DFS rate was 91.7%/73.3%. The 2-yr OS rate for overall population and R0 population was 87.5%/91.7%, respectively. In the R0 resection population, the median DFS and OS were both not reached. Superior 2-year DFS rates were observed in pts who achieved MPR (MPR vs. Non-MPR: 86.7% vs. 63.8%). DFS of pts with non-squamous cell carcinoma tended to be shorter than that of pts with squamous cell carcinoma (HR 2.71 [95%CI 0.67–11.0], p=0.1479). Pts with tumor mutation burden (TMB) ≥10 mutations/Mb and PD-L1 tumor proportion score (TPS)≥50% tended to have a better 2-yr DFS rate compared to those with TMB<10 and TPS<50. [table] For the post-hoc event free survival (EFS) analysis, the same trend was observed with DFS among different subgroups, and patients with TMB ≥10 mutations/Mb had a significant improved EFS (HR 0.125[95% CI 0.02,1.03], P=0.0222). Conclusions: Anti-PD-1 monotherapy emerged to be a promising neoadjuvant therapeutic strategy for resectable NSCLC with improved clinical outcomes. MPR could serve as a surrogate efficacy biomarker in this setting. Clinical trial information: ChiCTR-OIC-17013726. [Table: see text]
Statewide rates of adjuvant checkpoint inhibitor use after definitive chemoradiation for stage III non-small cell lung cancer.
Authors: Bryant Alex K. , Yin Huiying , Schipper Matthew J. , Paximadis Peter Alexander , Boike Thomas Pence , Bergsma Derek P. , Movsas Benjamin , Ajlouni Munther Isa , Dess Robert Timothy , Mietzel Melissa A. , Kendrick Randi , Seferi Merita , Dominello Michael M. , Matuszak Martha , Jagsi Reshma , Hayman James , Pierce Lori J. , Jolly Shruti 
Published: June 2021

8523 Background: In the landmark PACIFIC trial, adjuvant durvalumab after definitive chemoradiation for unresectable stage III non-small-cell lung cancer (NSCLC) produced a 11% absolute overall survival benefit at two years compared to placebo, and the US Food and Drug Administration approved durvalumab for this indication in February 2018. We investigated the real-world use of adjuvant durvalumab and other immune checkpoint inhibitors (ICI) in a contemporary cohort of patients. Methods: We identified patients with unresectable stage III (AJCC 8th edition) NSCLC treated with definitive chemoradiation from February 2018 to March 2020 from a statewide radiation oncology quality consortium, representing a mix of community (n=22 centers, 336 patients) and academic practice settings (n=5 centers, 64 patients) across the state of Michigan. Use of adjuvant durvalumab or other ICI (atezolizumab, nivolumab, or pembrolizumab) was ascertained at the time of routine three- or six-month follow-up after completion of chemoradiation. Baseline characteristics of patients treated with or without adjuvant ICI were compared with the Chi-squared test for categorical variables and a two-sided t-test for continuous variables. Results: Of 400 patients with unresectable stage III NSCLC treated with definitive chemoradiation, 268 (67%) received adjuvant ICI. Of these, the majority received durvalumab (86%) followed by pembrolizumab (7.5%) and nivolumab (6.0%). The proportion of patients receiving ICI remained stable throughout the study period with no discernable time trends. Eight-five percent of white patients received ICI compared with 77% of black patients (p=0.04), but there were no differences in gender (54.5% male in ICI vs 52.3% no ICI), current smoking (42.2% ICI vs 37.9% no ICI, p=0.68), number of comorbidities (29.5% with 3 or more comorbidities in ICI vs. 26.5% in no ICI, p=0.86), baseline oxygen use (8.9% ICI vs 10.6% no ICI, p=0.59), age (median 66.4 years [IQR 60.3-73.4] for ICI vs. 66.9 years [IQR 61.1-72.2] no ICI, p=0.89), treatment at an academic center (16.0% ICI vs 15.9% no ICI, p=0.97), or ECOG performance status (59.3% ECOG 0 in ICI vs 62.8% no ICI). Conclusions: In a broad range of academic and community-based practices across a state including 27 sites, only two-thirds of potentially eligible stage III NSCLC patients received adjuvant durvalumab or other ICI agents despite a proven overall survival benefit. Receipt of ICI was not strongly associated with baseline demographic or comorbidity variables. Further work will seek to clarify the patient-level reasons behind non-initiation of adjuvant ICI.
Noninvasive identification of emergent mutations following cytotoxic therapy for lung cancer.
Authors: Moding Everett James , Hui Angela B. , Murciano-Goroff Yonina R. , Nabet Barzin , Schultz Andre , Qiao Yawei , Li Bob T. , Lin Steven H. , Alizadeh Ash A. , Diehn Maximilian 
Published: June 2021

8533 Background: Lung cancer is the leading cause of cancer death world-wide, and chemotherapy and radiation remain backbones of therapy for patients with locoregionally advanced and metastatic disease. However, the genetic mechanisms that mediate resistance to chemotherapy and radiation are largely unclear due to a lack of available tissue at the time of relapse. We hypothesized that circulating tumor DNA (ctDNA) analysis could identify emergent mutations after chemotherapy and radiation that may lead to treatment resistance. Methods: To identify emergent mutations at the time of progression following an initial response to chemotherapy and/or radiation therapy for lung cancer, we utilized CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) to analyze plasma samples and matched leukocytes collected pre-treatment and at the time of relapse. We analyzed a targeted panel enriched for lung cancer drivers and recurrently mutated genes for 27 patients treated with chemoradiation therapy for locoregionally advanced lung cancer. In addition, we performed ultra-deep whole exome sequencing ( > 2000X deduped depth) of pre-treatment and relapse cell-free DNA for 5 patients treated with combination chemotherapy for metastatic lung cancer. Functional enrichment analysis was performed on emergent mutation gene lists to identify significantly enriched pathways. Results: We identified emergent variants in 6 out of 27 patients using targeted sequencing after chemoradiation therapy. Emergent mutations after chemoradiation were enriched for plasma membrane adhesion molecules such as PCDH17, PCDH10, and FAT3 (adjusted P = 0.03). Using ultra-deep whole exome sequencing, we observed emergent mutations in 3 out of 5 patients treated with combination chemotherapy. After combination chemotherapy, there was a trend towards enrichment in mutations in ATP-binding cassette transporters, including ABCA13 and ABCB4 (adjusted P = 0.057). Notably, there were no recurrent emergent mutations within our cohort. Conclusions: Our results suggest that ultra-deep whole exome sequencing can non-invasively identify emergent mutations at the time of progression. Resistance to cytotoxic therapy is likely multi-factorial and analysis in expanded cohorts will be helpful to identify recurrently mutated pathways that may contribute to disease progression after an initial response to therapy.
Early detection of lung cancer with an incidental lung nodule program (ILNP).
Authors: Smeltzer Matthew , Liao Wei , Meadows-Taylor Meghan , Faris Nicholas , Fehnel Carrie , Goss Jordan , Williams Sara C. , Akinbobola Olawale , Pacheco Alicia , Epperson Amanda , Luttrell Joy , McCoy Denise , Tokin Keith , Optican Rob , Wright Jeffrey , Robbins Edward Todd , Satpute Shailesh R. , Harris Parker , Ray Meredith , Osarogiagbon Raymond U. 
Published: June 2021

8553 Background: Lung cancer early detection improves survival, but risk-based low-dose CT screening (LDCT) only identifies a minority of patients. We implemented an ILNP in a community healthcare system, and evaluated its risks and benefits. Methods: Patients with lung lesions on routinely-performed radiologic studies were flagged by radiologists and triaged using evidence-based guidelines. We tracked demographics, clinical characteristics, procedures, complications, and health outcomes. We analyzed ILNP subjects’ eligibility for LDCT by National Lung Screening Trial (NLST), Center for Medicaid Services (CMS), NEderlands Leuvens Screening ONderzoek (NELSON), National Comprehensive Cancer Network (NCCN) Risk Groups 1 and 2 (screening recommended), NCCN Risk Group 3 (screening not currently recommended), and US Preventive Services Task Force (USPSTF) criteria from 2013 and 2020. Statistical analysis used the chi-square test and Kaplan Meier method. Results: From 2015-2020, 13,710 patients were evaluated in the ILNP program: median age, 64 years; 42% male; 65% White, 29% Black; 667 (4.9%) were diagnosed with lung cancer. Lung cancers diagnosed from ILNP were 39% adenocarcinoma / 20% Squamous Cell with clinical stage distribution 49% I, 8% II, 17% III, and 16% IV. 832 (6.1%) had invasive diagnostic testing- CT-guided biopsy (50%), bronchoscopy (30%), and/or EBUS (26%); 11% of the 832 had >1 invasive diagnostic test. The most common complications from invasive testing were pneumothorax and chest tube placement. Only 11%-20% of all ILNP patients would have been eligible for LDCT. In ILNP patients diagnosed with lung cancer, only 33% were eligible for screening by NLST criteria; the proportion increased substantially when USPSTF 2020 or NCCN Group 2 criteria were applied (Table). Compared to NLST, NCCN Group 2 criteria increased screening eligibility among cancer patients by 22% (from 33% to 55%), while only increasing screening eligibility by 6% (from 8% to 14%) in non-cancer patients. Aggregate 1-year and 3-year survival rates for lung cancer patient diagnosed through ILNP were 76% (95% CI: 73, 80) and 64% (95% CI: 59, 69). Conclusions: The ILNP identified early-stage lung cancer more frequently than most LDCT programs, with promising survival rates. The majority of subjects with lung cancer were not eligible for LDCT, we still need to optimize risk-based screening criteria. Even with new, expanded criteria for LDCT, structured ILNP is necessary to expand early detection of lung cancer.[Table: see text]
Comprehensive molecular profiling of pleural mesothelioma according to histologic subtype.
Authors: Dagogo-Jack Ibiayi , Madison Russell , Mata Douglas A. , Schrock Alexa Betzig , Janovitz Tyler , Decker Brennan , Huang Richard S.P. , Lin Douglas I. , Killian Jonathan Keith , Ramkissoon Shakti H. , Gjoerup Ole , Danziger Natalie , Venstrom Jeffrey Michael , Alexander Brian M. , Ross Jeffrey S. 
Published: June 2021

8555 Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited therapeutic options. Immunotherapy has emerged as an effective therapeutic strategy, particularly in the non-epithelioid MPM subgroup. An improved understanding of the molecular profile of MPM may inform targeted therapeutic approaches and provide insights into factors underlying differential sensitivity to therapies. Methods: We performed comprehensive genomic profiling of MPMs from 980 patients, with histologic subtyping on a subset (n = 340; n = 235 epithelioid, n = 48 sarcomatoid, n = 57 biphasic). Analyses included quantifying tumor mutational burden (TMB), assessing microsatellite instability (MSI), and evaluating PD-L1 expression (Dako 22C3). Results: Median TMB of MPM was 1.74 (0.87-2.61) mutations per megabase (mut/mb). Median TMB was comparable for non-epithelioid (biphasic, sarcomatoid) vs epithelioid MPM (1.25 mut/mb vs 1.25 mut/mb, p = 0.43). In the overall cohort, inactivating alterations in the following genes were most prevalent: CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (35%), and NF2 (33%). MTAP loss co-occurred with CDKN2A and CDKN2B loss in > 99% and 94% of cases, respectively. MTAP loss was observed in 28% of epithelioid vs 46% of non-epithelioid MPMs (p = 0.03). BAP1 alterations were detected in 51% of epithelioid vs 36% of non-epithelioid MPMs (p = 0.81). PD-L1 expression was assessed in 308 MPMs, among which 153 (49%) had PD-L1 ≥1%, including 35 (11%) with PD-L1 ≥50%. Among 164 specimens that underwent histologic subtyping and PD-L1 evaluation, PD-L1 was expressed in 46 (71%) non-epithelioid MPMs compared to 49 (51%) epithelioid MPMs (p = 0.03). Given the high prevalence of alterations involving the two genes, we evaluated impact of BAP1 and MTAP status on PD-L1 and TMB. TMB (1.74 mut/mb vs 1.74 mut/mb) and PD-L1 expression (50% vs 54%) were comparable in BAP1-altered vs wildtype specimens. Although TMB was comparable in MTAP-deficient and MTAP-intact tumors (1.25 mut/mb vs 1.74 mut/mb), more tumors with MTAP loss expressed PD-L1 (68% vs 44%, p = 0.0004). Conclusions: Compared to epithelioid MPM, non-epithelioid tumors demonstrate comparable TMB, higher PD-L1 expression, and enrichment for MTAP loss. As MTAP is frequently altered in MPM, further study is indicated to explore the relationship between MTAP status and MPM biology, including sensitivity to therapeutics such as immunotherapy and synthetic lethal approaches.
Safety and efficacy of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer: Update from the ARROW trial.
Authors: Curigliano Giuseppe , Gainor Justin F. , Griesinger Frank , Thomas Michael , Subbiah Vivek , Baik Christina S , Tan Daniel Shao-Weng , Lee Dae Ho , Misch Daniel , Garralda Elena , Kim Dong-Wan , Paz-Ares Luis G. , Mazieres Julien , Liu Stephen V. , Kalemkerian Gregory Peter , Houvras Yariv , Bowles Daniel W. , Mansfield Aaron Scott , Zalutskaya Alena , van der Wekken Anthonie J. 
Published: June 2021

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]
Clinicopathologic and genomic correlates of tumor-infiltrating immune cells and immunotherapy efficacy in NSCLC.
Authors: Alessi Joao Victor Machado , Ricciuti Biagio , Nishino Mizuki , Weirather Jason L. , Le Ann-Elisabeth , Lindsay James , Sharma Bijaya , Felt Kristen , Sholl Lynette M. , Rodig Scott J. , Awad Mark M. 
Published: June 2021

9121 Background: Tumor-infiltrating immune cells and PD-L1 expression are associated with improved clinical outcomes in patients (pts) with NSCLC treated with immune checkpoint inhibitors (ICIs). However, as tumor-infiltrating immune cells are not a well-established biomarker for NSCLC, further data are needed to integrate and identify clinicopathological and genomic factors that influence the tumor microenvironment. Methods: We collected clinicopathologic and genomic data from pts with NSCLC who underwent multiplexed immunofluorescence. Uniform Manifold Approximation and Projection (UMAP) was used to identify distinct immunophenotypic clusters according to the number of intratumoral PD-1+ immune cells (ICs), CD8+, and Foxp3+ T cells, as well as PD-L1 on tumor and immune cells. An unbiased recursive partitioning (URP) algorithm was used to investigate an optimal cluster with respect to objective response rate (ORR) in the subset of pts treated with ICIs. Results: Among 304 pts, UMAP identified 5 clusters: PD-L1-high with high vs low CD8+ and PD-1+ ICs (clusters A & B, respectively); PD-L1-low with high vs low CD8+ and PD-1+ ICs (clusters C & D respectively); PD-L1-low and moderate levels of CD8+ and PD-1+ ICs (cluster E). Clinicopathological characteristics of the clusters shown in Table. URP analysis identified immune rich clusters A and C as optimal responders to ICIs. From the start of ICIs, we observed a significantly higher ORR (53.3% vs 4.3%; P<0.001), a significantly longer median progression-free survival (mPFS 25.6 vs 3.7 months; HR: 0.12 [95% CI: 0.05-0.32]; P<0.001), and longer median overall survival (mOS 45.1 vs 22.3 months; HR: 0.25 [95% CI: 0.1-0.68]; P=0.006) in clusters A + C (N=15) vs other clusters (N=23). After adjusting for other variables such as performance status, histology, presence of oncogenic driver mutation, and line of treatment, clusters A + C were significantly associated with improved mPFS (HR: 0.08 [95% CI: 0.03-0.24], P<0.001) and mOS (HR: 0.11 [95% CI: 0.03-0.40], P<0.001). Conclusions: Incorporation of multiplex immunofluorescence may improve prediction of response and resistance to immunotherapy in NSCLC.[Table: see text]
Toxicity, response, and survival in older adults with metastatic melanoma treated with checkpoint inhibitors.
Authors: De Glas Nienke A , Bastiaannet Esther , van den Bos Frederiek , Mooijaart Simon , Van Der Veldt Astrid Aplonia Maria , Suijkerbuijk Karijn , Aarts Maureen J.B. , van den Berkmortel Franchette , Blank Christian U. , Boers-Sonderen Marye , van den Eertwegh Alfonsus Johannes Maria , de Groot Jan Willem , Hospers Geke , Haanen John B. A. G. , Piersma Djura , Van Rijn Rozemarijn , Ten Tije A. J. , Wouters Michel W.J.M. , Portielje Johanna Elisabeth A. , Kapiteijn Ellen 
Published: June 2021

9544 Background: Checkpoint inhibitors have strongly improved survival of patients with metastatic melanoma. Trials suggest no differences in outcomes between older and younger patients, but only relatively young patients with a good performance status were included in these trials. The aim of this study was to describe treatment patterns and outcomes of older adults with metastatic melanoma, and to identify predictors of outcome. Methods: We included all patients aged ≥65 years with metastatic melanoma between 2013 and 2020 from the Dutch Melanoma Treatment registry (DMTR), in which detailed information on patients, treatments and outcomes is available. We assessed predictors of grade ≥3 toxicity and 6-months response using logistic regression models, and melanoma-specific and overall survival using Cox regression models. Additionally, we described reasons for hospital admissions and treatment discontinuation. Results: A total of 2216 patients were included. Grade ≥3 toxicity did not increase with age, comorbidity or WHO performance status, in patients treated with monotherapy (anti-PD1 or ipilimumab) or combination treatment. However, patients aged ≥75 were admitted more frequently and discontinued treatment due to toxicity more often. Six months-response rates were similar to previous randomized trials (40.3% and 43.6% in patients aged 65-75 and ≥75 respectively for anti-PD1 treatment) and were not affected by age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity, but age, comorbidity and WHO performance status were associated with overall survival in multivariate analyses. Conclusions: Toxicity, response and melanoma-specific survival were not associated with age or comorbidity status. Treatment with immunotherapy should therefore not be omitted solely based on age or comorbidity. However, the impact of grade I-II toxicity in older patients deserves further study as older patients discontinue treatment more frequently and receive less treatment cycles.[Table: see text]