bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time-of-day infusion of immunotherapy may impact outcomes in advanced non-small cell lung cancer patients (NSCLC).
Authors: Barrios Carlos H. , Montella Tatiane Caldas , Ferreira Carlos G. M. , De Marchi Pedro , Coutinho Luiz Flavio , Lemos Duarte Igor , Costa e Silva Matheus , Duarte Paes Rafael , Correia e Silva Guilherme Munhoz , Dienstmann Rodrigo 
Published: June 2022

e21126 Background: Circadian rhythms have shown direct impact on toxicity and efficacy of anticancer treatments. Adaptive immune responses related to (or associated with) check point inhibitor (CPI) administration may have lower intensity later in the day. Notably, emerging evidence suggests that the time-of-day administration of different immunotherapies could have survival implications in different tumor types. Methods: We extracted de-identified data from curated the Real-World database of the Oncoclínicas Group, including 21 community-oncology practices in Brazil with EHR information on time-of-day administration of CPI in patients with advanced NSCLC. Only patients treated with single-agent CPIs with palliative intent (Nivolumab, Pembrolizumab or Atezolizumab) from Jan 2018 through Dec 2021 were analyzed. The primary endpoint was a comparative analysis of the median Time to Treatment Discontinuation (TTD) of CPI stratified according to time-of-day administration using a propensity-score (PS) matching model. On the basis of previous reports, we selected the cutoff of 20% of CPI doses administered after 4:00 pm as the late-day subgroup. Variables included in PS matching were: age (< 60, 60+); line of therapy (1st, 2ndor beyond); gender (male, female), and CPI agent (Pembrolizumab vs. others). Results: From a total of 1,603 patients with advanced NSCLC treated at Oncoclínicas during the study period, 508 received CPI as per inclusion criteria. Median age was 73 years (36-94), 66% were male, 63% received CPI in the 1stline setting, 50% with Pembrolizumab. Overall, 219 CPI infusions (15%) occurred after 4:00 pm and 9% of the patients (n = 43) qualified as late-day infusion subgroup (more than 20% of infusions after 4pm). Median TTD was 4.9 months (CI 95%, 2.83-13.5) in these patients. In the PS matched population with early-day infusions (2:1, n = 86), median TTD was 14 months (CI 95%, 8.87-23.4). Overall, with 73 events in 129 patients, we found a significantly increased risk of treatment discontinuation in the late-day subgroup (HR 1.61, CI95% 1.0-2.6, p = 0.05). With only 33 death events and median follow-up of 11 months, median overall survival was not reached in late-day or early-day subgroups (HR 1.25, CI95% 0.6-2.6, p = 0.5). Conclusions: This preliminary and exploratory real-world data analysis suggests that the time-of-day administration of CPI in patients with advanced NSCLC could have a meaningful impact on patient outcomes, in line with studies conducted in melanoma. This simple and inexpensive intervention merits further exploration in prospective controlled clinical trials.
Maximum somatic allele frequency-adjusted blood-based tumor mutational burden balances the effect of intratumor heterogeneity on response to immune checkpoint Inhibitors in non-small cell lung cancer patients.
Authors: Dong Yiting , Xie Yinpeng , Wang Jie , Wang Zhijie 
Published: June 2022

e21137 Background: ctDNA abundance can influence the accuracy of blood-based tumor mutational burden (bTMB), driving a paradox of bTMB in predicting response and survival benefit of patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) therapy. However, the optimal algorithm of ctDNA adjusted bTMB remains largely unestablished. We aimed to develop a novel approach to optimize the calculation of bTMB by integrating maximum somatic allele frequency (MSAF) to better differentiate the ICI-beneficial NSCLC patients, as well as explore the correlated mechanism. Methods: A 1021-gene panel-based targeted capture sequencing was utilized to evaluate the correlation between MSAF and bTMB based on blood samples in 1679 Chinese NSCLC patients (GCGD database, N = 1679). The establishment of MSAF-adjusted bTMB (Ma-bTMB) was derived from three independent NSCLC cohorts treated with programmed death ligand 1 (PD-L1) or the programmed death 1 (PD-1) inhibitors, including POPLAR cohort (N = 231) as training set, and OAK (N = 642) and Wang (N = 81) cohorts as validation sets separately. PyClone was employed to estimate clonal and subclonal populations. Results: MSAF demonstrated a modest positive correlation between bTMB and MSAF (Spearman’s R = 0.41, P < 0.001, GCGD cohort) and was negatively correlated with survival benefit (Spearman’s rank sum test, overall survival (OS): R = −0.39, P < 0.001; progression-free survival (PFS): R = −0.41, P < 0.001, Wang cohort). Patients with high Ma-bTMB (Ma-bTMB-H) demonstrated improved survival outcomes of anti-PD(L)-1 therapy compared to chemotherapy in POPLAR (PFS, hazard ratio (HR) = 0.63, interaction P = 0.030; OS, HR = 0.44, interaction P = 0.020), which was validated in OAK cohorts (PFS, HR = 0.72, interaction P = 0.040; OS, HR = 0.50, interaction P = 0.010). In addition, Ma-bTMB-H was associated with a better clinical benefit compared to low Ma-bTMB (Ma-bTMB-L) in Wang cohort (PFS, HR = 0.55, P = 0.012; OS, HR = 0.46, P = 0.036). Furthermore, there was a positive correlation between intratumor heterogeneity (ITH) and MSAF (R = 0.37, P < 0.001) in GCGD database, and the effect of ITH on Ma-bTMB (subclones, P = 0.57; subclonal mutations, P = 0.8) was substantially reduced compared to traditional bTMB (subclones, P < 0.001; subclonal mutations, P < 0.001) in Wang cohort. Conclusions: We developed and validated Ma-bTMB, a convenient, readily available, non-invasive predictive biomarker, which reduced the confounding effect of ITH and could effectively differentiate beneficiaries of anti-PD(L)1 therapy, warranting investigation in future clinical trials. Clinical trial information: NCC2018-092.
The clinical and genomic characteristics of MSI-h/dMMR lung cancer.
Authors: Qin Jianwen , Shi Dongsheng , Yin Yan , Liu Bin , Wang Lei , Sun Tingting , Zhang Qin , Qi Chuang 
Published: June 2022

e21142 Background: Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) have been confirmed to be positively predictive biomarkers for immune checkpoint inhibitors (ICIs), especially in colorectal cancer and endometrial cancer. Numerous studies about molecular characteristic or clinical trails of MSI-H/dMMR have been achieved or ongoing. However, there are few researches of MSI-H/dMMR in lung cancer which has the highest morbidity in malignant tumors. Here, we explored clinical and genomic characteristics of MSI-H/dMMR lung cancer. Methods: We retrospectively analyzed 4996 lung cancer patients with available tissue NGS data. Microsatellite status was decided by MSI score which was tested by NGS combined with bioinformatics algorithms (MSI score < 0.05: MSS; MSI score > 0.15: MSI-H). In the absence of MMR IHC, dMMR was alternatively defined that DNA mismatch repair genes, including MLH2, PMS2, MSH2 and MSH6, had pathogenic or likely pathogenic mutations based on the American College of Medical Genetics and Genomics (ACMG) guidelines. RNA data of 552 lung cancer patients from The Cancer Genome Atlas (TCGA) was obtained to analyze immune microenvironment. Results: Of 4996 lung cancer patients, 58 (1.16%) patients were identified to be MSI-H/dMMR with a median age of 65.5 years old, of which 2.80% (9/322) patients were squamous carcinoma, significantly higher than adenocarcinoma 1.06% (30/2839) (p < 0.05). In MSI-H/dMMR, 8 (13.89%) patients were MSI-H, 41 (70.69%) patients were dMMR and 9 patients were both MSI-H and dMMR (15.52%). Compared with MSS patients, MSI-H/dMMR patients had more frame shift mutations. Moreover, it more often happened in dMMR than MSI-H that there were multiple mutations in one gene, which was indicated by Multi-Hit. Further exploration found that MSI-H/dMMR tumors had higher tumor mutation burden (TMB) than MSS (p < 0.05). RNA data revealed that enhanced anti-tumor immunity was observed in MSI-H/dMMR tumors. Activated CD4 memory T cell and CD8 T cell were more abundant in MSI-H/dMMR tumors. Conclusions: We analyzed clinical and genomic characteristics of MSI-H/dMMR lung cancer for the first time. Our data showed that MSI-H/dMMR was found in 1.16% lung cancer patients and more likely to occur in squamous cell lung carcinoma. MSI-H/dMMR in lung cancer was associated with higher TMB and may well enhance anti-tumor immunity.
Immune-related molecular characteristics of Chinese lung cancer patients with different types of ALK rearrangement.
Authors: Li Xi , Liang Yueming , Huang Xiaochun , Liu Xinyi , Huang Mengli 
Published: June 2022

e21144 Background: Anaplastic lymphoma kinase ( ALK) gene rearrangements are found in approximately 5% of non-small-cell lung cancer (NSCLC). Since ALK-TKIs have been developed for patients with ALK-positive advanced NSCLC, it remained 20%-30% non-responders, thus other treatment strategies would be explored to prolong overall survival. Previous studies have shown that ALK rearrangement can upregulate PD-L1 expression via signaling pathways such as ERK/AKT, and the high expression of PD-L1 negatively affects the efficacy of crizotinib and would be more suitable for immunotherapy. However, only a few immunotherapy clinical studies recruited tiny amounts of ALK rearrangement NSCLC, making it difficult to investigate the relationship between this oncogenic gene alteration and therapeutic effects. Herein, we described the immune-related molecular characteristics of ALK-rearranged patients in a large group of Chinese lung cancer, hoping to provide more precise treatment strategies. Methods: A total of 1410 lung cancer patients harboring ALK rearrangement were included in this analysis. Using wide NGS panel testing, we elucidated ALK gene fusions, intergenic region fusions ( ALK-IR) as well as other genomic alterations and TMB levels in each patients’ tumor specimen. PD-L1 expression level was evaluated by the tumor positive score (TPS). Results: Over two hundreds of types of ALK rearrangement were identified. The whole population was divided into six subgroups according to types of ALK rearrangements: 3'- ALK-only (71.1%), 5'-non- EML4-ALK-only (1.0%), multi- ALK fusion (14.2%), single ALK-IR (3.2%), multi-3'- ALK-IR (10.1%), and multi-5'- ALK-IR (0.5%). The overall PD-L1 expression level was high in ALK rearrangement lung cancer, of which the proportion of patients with TPS ≥ 50% was 19.5%, and the TPS ≥ 50% proportion in the single ALK-IR subgroup was the highest (28.6%) among all subgroups. We then evaluated the distribution of TMB levels and found the median TMB level was higher than 30% lung cancer. Of note, the single ALK-IR subgroup also present a trend of higher TMB level among all subgroups. We also observed more DNA damage response (DDR) gene mutations (median number: 2, range: 1-22) in the single ALK-IR subgroup. Somatic copy number amplifications (SCNAs) were detected in 195 (13.8%) ALK -rearranged lung cancer patients, and the proportion of SCNAs in each subgroup was similar. The most frequently high-level amplified genes were MYC (23.9%) and EGFR (10.9%). Furthermore, the 3'- ALK-only subgroup mainly occurred low-level SCNAs (68.5%), whereas the multi- ALK fusion and multi-3'- ALK-IR subgroups were more likely to harbor high and moderate level SCNAs. Conclusions: Our findings demonstrated that lung cancer with ALK-IR might have active immune microenvironment, indicating it’s a subset of ALK-rearranged patients who would benefit from immunotherapy.
Efficacy and safety of dacomitinib in advanced non-small cell lung cancer patients harboring uncommon EGFR mutations: Real-world evidence from China.
Authors: Li Hong-Shuai , Yang Guangjian , Cai Yi , Li Junling , Xu Haiyan , Zhang Tao , Zhou Liqiang , Luo Jiancheng , Wang Yuying , Wang Jinliang , Hu Xingsheng , Liu Peng , Yan Xiang , Wang Yan 
Published: June 2022

e21163 Background: Dacomitinib has been approved for advanced non-small cell lung cancer (NSCLC) patients harboring common epidermal growth factor receptor ( EGFR) alterations; however, clinical evidence on its activity to uncommon EGFR mutations is currently limited. Methods: Patients were collected from the Chinese National Cancer Center and the Chinese PLA hospital between July 2017 and December 2021. The objective response rate and disease control rate were determined by RECIST 1.1. Adverse events were assessed by CTCAE 5.0. Kaplan-Meier method was utilized to assess progression-free survival (PFS). Results: In total, 38 advanced NSCLC patients harboring uncommon EGFR mutations treated with dacomitinib in multi-line settings were enrolled. Among these patients, 30 cases carried major uncommon mutations, of which 13 cases harbored G719A/C, 8 carried S768I + G719A/C/S, 7 had L861Q, 2 had L861Q + G719A, and the remaining 8 patients carried non-major uncommon mutations, of which 3 harbored E709X, 3 carried L747P, 1 had H183D, and 1 had G598V. The initial dose of dacomitinib (45 mg, 30 mg, or 15 mg once daily) was based on the performance status and comorbidities of the patient. In the whole cohort, 55.3 % of patients (21/38) had a confirmed partial response and 89.5 % (34/38) had disease control, and the median PFS was 10.3 months (95 % confidence interval [CI], 5.8–14.8). For non-major uncommon mutations, 62.5 % of patients (5/8) had a confirmed partial response and 87.5 % (7/8) had disease control, and the median PFS was 11.5 months (95 % CI, 6.2–16.8). Except for one case not available for brain evaluation, control of the intracranial metastases was observed in 16 patients (16/18, 88.9 %), and the median PFS was 6.6 months (95 % CI, 6.3–6.9). Subgroup analysis did not show a significant difference in PFS between patients with and without major uncommon mutations (HR = 0.786, 95 % CI 0.265-2.331, P = 0.639), but between those with and without brain metastases (HR = 3.350, 95 % CI 1.334-8.411, P = 0.005). No grade 4-5 adverse events (AEs) occurred, but all patients had grade 1–2 AEs, and 13.2 % (5/38) of patients required a dosage reduction due to intolerable AEs. Conclusions: This real-world study indicates that dacomitinib is potent and well-tolerated in NSCLC patients harboring uncommon EGFR mutations in multi-line settings, and has favourable activity for brain metastases.[Table: see text]
The safety and efficacy of immune checkpoint inhibitor rechallenge after immune-related adverse events in stage IV NSCLC patients.
Authors: Guo Mengni , Vanderwalde Ari M. , Yu Xinhua , Vidal Gregory A. , Tian, MD Gary G. 
Published: June 2022

e21173 Background: Despite their anti-tumor efficacy, immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs). Grade ≥2 irAEs require ICI discontinuation. The decision to resume ICI treatment often remains challenging. Methods: We retrospectively studied 1051 adult patients with stage IV NSCLC treated with ICIs at West Cancer Center between January 2015 and December 2020. 99 (9.4%) patients with grade≥2 irAEs necessitating treatment interruption were identified. 40 patients underwent retreatment (rechallenged group), while 59 discontinued treatment (discontinued group). All patients were rechallenged with the initial ICI. Results: The baseline characteristics of patients in the two groups were similar in terms of age, gender, ethnicity, ECOG, smoking status, cancer histology, type of ICI, and PD-L1 status. No differences in types of irAEs or timing of the initial irAEs were seen. Initial irAEs were less severe in the rechallenged group, with fewer grade 3 irAEs (20% vs. 62.7%, p < 0.001), no grade 4 irAEs (0% vs. 6.8%, p < 0.001), less IV corticosteroid use (2.5% vs. 23.7%, p = 0.01), and less frequent hospitalizations for irAEs (7.5% vs. 42.4%, p < 0.001). After rechallenging, 24 of 40 (60%) patients had recurrence of the same or de-novo irAEs. 20 (50%) developed second grade≥2 irAEs with 13 (32.5%) grade 2, and 7 (17.5%) grade 3. No grade 4 irAE or irAE-related death occurred after rechallenging. Among the 24 patients with second irAEs, 6 (25%) still had residual grade 1 irAEs upon rechallenging, while none of the 16 patients without second irAEs had residual irAEs (p = 0.03). With a median follow-up of 572 days, no statistically significant differences in overall survival (p = 0.67, HR 1.15 with 95% CI 0.60-2.22) or PFS (p = 0.57, HR 0.83 with 95% CI 0.43-1.59) were noted between the two groups, which were adjusted for age, gender, ethnicity, ECOG, PD-L1 status, grade of initial irAEs, and best objective response (OR) prior to initial irAEs. Conclusions: In real-world practice, clinicians tend to rechallenge patients with less severe irAEs. Our study showed that rechallenge was associated with a relative high risk of second grade≥2 irAEs. The risk was less if the initial irAEs were resolved. The second irAEs were not more severe than the first. Rechallenge can be performed under close monitoring, ideally, after the initial irAEs have completed resolved. The survival outcomes of ICI rechallenge and discontinuation were similar. ICI discontinuation is one feasible strategy after grade≥2 irAEs, especially severe irAEs.[Table: see text]
Association of immune-related adverse events with immune-checkpoint inhibitors and treatment response in melanoma patients.
Authors: Rodriguez Benigno , Martínez-Herrera José Fabián , López Zepeda Lorena , Olivares Guillermo , Villalobos Alberto , Perez Fernando , Camacho Limas Christian Patricio , Serrano Juan Alberto , Serrano Villamayor Omar , Enciso López Ervin Saúl , Shveid Gerson Daniela , Camarin Sanchez Efrain Isaias , Bonilla Molina Diana , Tovar Cabrera Juan Manuel , Nehmad Cecilia , Juarez - Vignon Whaley Juan Jose , Gerson Raquel 
Published: June 2022

e21522 Background: Immune-related adverse effects (irAE´s) of immune-checkpoint inhibitors (ICIs) have been linked with a better treatment response in melanoma patients, especially cutaneous toxicities. However, little is known regarding other irAE´s which is important as they can be used as clinical markers of an adequate therapeutical response. Methods: We conducted a retrospective study on patients who were diagnosed with melanoma and received treatment with ICI´s between January 2015 until December 2021, immune related adverse events and their relationship with overall survival in melanoma patients treated with ICIs was the main objective of this study. Results: 53 records of patients with advance melanoma treated with ICIs between january 2016 to december 2021, demographic characteristics were as follow: 64.2% were male, mean age at diagnoses was 60.3 years, 41.5% had smoking history and 15.1% were Jewish. At diagnosis 73.6% of patients had a good functional status (ECOG 0-1). The most common histological subtypes were epithelioid (34%), and nodular (22.6%). Lung metastases was the most common affected site (49.1%), followed by brain 43.4% and non-regional nodes 42.5%. BRAF mutations was determined in 81.1% of the biopsies and 36% of them being V600E mutation. ICI´s was the preferred first line treatment in 83% of cases, median number of administered cycles were 6 (range 1-54 cycles), 60.4% of patients received pembrolizumab, 37.7% nivolumab plus ipilimumab, 20.8% nivolumab monotherapy and 5.7% ipilimumab. Throughout the studied period IrAE´s were reported in 34% of patients with 66.7% of them being grade 1-2 and 33.3% grade 3-4. The most common IrAE’s: vitiligo 38.8%, hypothyroidism22% and 3.8% pneumonitis. Median PFS at 12 months and OS was significantly better in the group of patients with irAE´s: Patients who develop an irAE´s are 7 times more likely to be disease free at 12 months and 4.1 times more likely to have a longer OS regardless of severity and type of toxicity. The impact of developing irAEs is significantly important for PFS (HR: 11.9, CI 95%: 3.28-4.71) as median PFS was not yet reached in this group. Conclusions: Development of irAEs is associated with favorable outcomes to ICIs with patients being 7 times more likely to be 12-month disease free and 4.1 times more likely to have a longer OS. irAEs can be used as clinical markers of an adequate treatment response.[Table: see text]
Phase Ib study of anlotinib in combination with anti-PD-L1 ab (TQB2450) in patients with advanced acral melanoma.
Authors: Mao Lili , Chen Yu , Du Yu , Bai Xue , Dai Jie , Lin Jing , Chen Ling , Chi Zhihong , Cui Chuanliang , Sheng Xinan , Lian Bin , Tang Bixia , Wang Xuan , Wei Xiaoting , Yan Xieqiao , Li Siming , Zhou Li , Li Juan , Guo Jun , Si Lu 
Published: June 2022

e21543 Background: Acral melanoma, the most common subtype of cutaneous malignant melanoma in Asians, is often diagnosed at an advanced stage but responds poorly to current PD-1/PD-L1 inhibitors. Here, we report an open-label, multicenter, single-arm, phase Ib study, aiming to evaluate the safety and efficacy of the combination therapy of TQB2450, a humanized monoclonal antibody against PD-L1 and anlotinib, an anti-angiogenic oral multi-target tyrosine kinase inhibitor in patients with advanced acral melanoma. Methods: Eligible patients were adults (ECOG PS of 0 or 1) with pathologically confirmed metastatic acral melanoma. In this dose-escalation and cohort-expansion study, patients received TQB2450 1200mg every 3 weeks in combination with anlotinib 10mg or 12mg once daily, 2-week on/1-week off until conformed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary end points were dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and objective response rate (ORR). The secondary end points included adverse events, disease control rate (DCR), progression-free survival (PFS), overall survival (OS). Results: By December 8, 2021, 19 patients has been enrolled. The majority of patients (16 of 19 patients) were naive to systemic therapy. No DLT was observed. Eighteen (95%) of 19 patients experienced treatment-related adverse events (TRAEs), but most were grade 1 or 2. The most common TRAEs were hypothyroidism, hypertension, blood triglyceride elevation, hyperglycemia, blood cholesterol elevation, neutropenia, blood uric acid elevation, bilirubin elevation. Grade 3 or greater TRAEs occurred in 6 patients (31.6%). Among all patients with advanced acral melanoma assessed by investigator according to RECIST version 1.1, two patients achieved confirmed complete response and two patients achieved confirmed partial response. The ORR were 21.1% (95% CI, 6.1% to 45.6%). The DCR was 73.7% (95% CI, 48.8% to 90.9%). The median PFS time was 5.5 months (95% CI, 2.8 months to not reached) per RECIST version 1.1. The median OS was 20.3 months (95% CI, 10.2 months to not reached). Conclusions: The combination of TQB2450 plus anlotinib showed promising benefit and was tolerable in patients with advanced acral melanoma, which needed further investigation of the combination therapy in advanced acral melanoma. Clinical trial information: NCT03991975.