bluuebunny/crossref_metadata_2025 huggingface dataset:
ANK2 mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Liu Hongbing , Zhao Lele , Liu Yaqin , Xiao Mingzhe , Zhang Qin , Qi Chuang
Published: June 2022

e21080

Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple cancers, in particular with non-small cell lung cancer (NSCLC). However, only a minority of patients could benefit from ICIs. Therefore, investigating predictive biomarkers of ICIs is important to identify the target population that derives the best therapeutic benefit. ANK2 encodes ankyrin-2, which plays a crucial role in cell development. Studies have shown a significant correlation between ANK2 expression levels and clinical outcomes in gastrointestinal cancers and pancreatic cancer. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to demonstrate the association between ANK2 and ICIs. Methods: 165 patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between ANK2 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: Patients with ANK2 mutation were significantly associated with better PFS (HR = 0.28; 95% CI, 0.15-0.53; P < 0.001), objective response rate (ORR, 69.0% vs 24.3%; P < 0.001) and durable clinical benefit (DCB, 72.4% vs 41.9%; P = 0.003) compared with those with wide-type in NSCLC. ANK2 mutation were associated with increased TMB (P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by the smoking status, PD-L1 expression and TMB, the association between ANK2 mutation and PFS remained significant (HR = 0.28; 95% CI, 0.20-0.82; P = 0.012).In TCGA, no association between ANK2 mutation and OS (LUAD: P =0.27 ; LUSC: P = 0.39) or PFS (LUAD: P = 0.21; LUSC: P = 0.63) was observed, suggesting that ANK2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, ANK2mutation was significantly associated with higher CD8+ T cells, higher M1 macrophage, and lower M2 macrophage. Moreover, ANK2 mutation was associated with increased TMB (P < 0.001) and neoantigen load (P < 0.001) in TCGA. In addition, GSEA analysis revealed that ANK2 mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway in LUAD. Conclusions: Our results demonstrated that ANK2 mutation is an independent classifier that could stratify patients with NSCLC for ICIs. The role of ANK2 in immunotherapy is needed to be further studied.
Safety monitoring practice during the initiation of tyrosine kinase inhibitors (TKIs) for NSCLC treatment.
Authors: Singh Avani , Rubiera Pepe Rafael , Shafique Michael Rahman , Hicks James Kevin , Tanvetyanon Tawee
Published: June 2022

e21090

Background: TKIs are standard treatment for non-small cell lung cancer (NSCLC) which harbors an actionable mutation. TKIs have a unique toxicity profile, distinct from conventional chemotherapy. Although the manufacturer of each TKI often issues a specific safety precaution on its label, no set schedule has been widely adopted. We surveyed the safety monitoring practice at a large academic institution. Methods: Electronic medical records of patients with ROS1, ALK or EGFR-mutated NSCLC who began a TKI during 2017-2021 were retrospectively reviewed. For each patient, the observation period started from the date of TKI prescription and lasted through day 60. Safety metrics were formulated based on drug label recommendations of each TKI. For each treatment course, the occurrence of 2 index safety monitoring activities (Table) were recorded. Results: Analysis included 130 treatment courses: 82 osimertinib, 20 alectinib, 15 crizotinib and 13 lorlatinib. Median age was 64.3 years, with 66% female, 81% white, 91% ECOG 0/1, 28% zero comorbidity, and 99% non-smoker. For osimertinib, EKG was obtained at baseline (within 30 days of treatment initiation) in 69.5% of observations, and LVEF, in 26.8%. By 60 days, these numbers barely increased (Table). Overall, absence of any index safety monitoring activity occurred in 41 of 130 (32%) treatment courses. Multivariable logistic regression analysis found a trend toward less monitoring among non-white patients: Odds ratio 0.35 (95% CI 0.11-1.09, p = 0.07). No association was found between the number of cardiac risk factors and LVEF monitoring or the use of QT prolonging medication and QTc monitoring. Conclusions: We observed a wide variation in the safety monitoring practice during TKI initiation. Deviation from the manufacturer recommendation was most pronounced for CPK monitoring in alectinib. Future study is needed to define the clinical significance of deviation and to identify barriers to safety monitoring.[Table: see text]
Prognostic significance of pleural effusion exhausted CD8+ T cell subsets in non-small cell lung cancer and mesothelioma.
Authors: Ye Linda , Dick Ian , Chiang Peter , Firth Tina , Creaney Jenette , Robinson Bruce WS , Redwood Alec
Published: June 2022

e21111

Background: Following repeated tumor antigen stimulation, T cells lose functional capacity and become exhausted. T cell exhaustion is a progressive change in phenotype. Early in the pathway, stem-like exhausted T cells (Texstem) retain proliferative and cytotoxic potential. However, they differentiate into terminally exhausted T cells (Texterm) that become epigenetically fixed in a suppressed state and lose much of their effector function. Malignant pleural effusion is a peri-tumoral microenvironment that could offer insight into anti-tumor immune responses. In this study we characterized exhausted CD8+ T cells, examined the prognostic significance of Texstem and Texterm levels in the pleural effusions of patients with non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort. Methods: Pre-treatment malignant pleural effusions from 43 NSCLC (41 non-squamous and 2 squamous) and 50 mesothelioma patients were analyzed by flow cytometry. The percentages of Texstem (PD1midCD39- or PD1midCD39-CD28+) and Texterm (PD1hi CD39+) CD8+ T cells were correlated with overall survival (OS). Survival analysis was performed using Kaplan-Meier and multivariate Cox regression analysis adjusting for age, sex, histological and molecular subtypes, performance status, smoking history, comorbidities and the number of lines of systemic therapy. Results: The relative percentages of exhausted T cells within the CD8+ T cell compartment of pleural effusions from NSCLC and mesothelioma were similar (Table). In NSCLC patients, multivariate analysis demonstrated that the percentage of Texstem was an independent predictor of OS. The median OS for patients with high (above median) Texstem was significantly longer than those with low Texstem (9.9 vs 3.4 months, HR 0.398, p = 0.020). In addition, the ratio of Texstem to Texterm also showed a positive association with OS. Similarly, in mesothelioma patients, a greater percentage of Texstem was associated with longer OS in multivariate analysis (p = 0.049). The median OS for patients with high vs low Texstem was 33.5 vs 11.1 months (HR 0.302, 95% CI 0.129 – 0.705, p = 0.006). In addition, there was also a positive association between Texstem to Texterm ratio and OS. Conversely, Texterm CD8+ T cells did not impact OS in either cancer type. Conclusions: NSCLC and mesothelioma patients with greater abundance of pleural effusion stem-like exhausted CD8+ T cells exhibit better survival outcomes irrespective of patient and disease characteristics, supporting its role as a prognostic biomarker.[Table: see text]
Development and validation of longitudinal c-reactive protein as dynamic response predictor for PD-L1 blockade in advanced NSCLC: Findings from four atezolizumab clinical trials.
Authors: Zhou Jian-Guo , Chen Xiaofei , Wong Ada Hang-Heng , Wang Haitao , Tan Fangya , He Si-Si , Shen Gang , Wang YunJia , Wang Ruihong , Carr Shamus R. , Frey Benjamin , Fietkau Rainer , Hecht Markus , Ma Hu , Schrump David S. , Gaipl Udo S
Published: June 2022

e21113

Background: Numerous studies suggested that pre-treatment C-reactive protein (CRP) is a survival predictive biomarker for cancer patients treated with anti-PD-(L)1 blockade. However, the application of longitudinal CRP levels as dynamic biomarker for advanced non-small cell lung cancer (NSCLC) patients treated with anti-PD-(L)1 remains unexplored. Methods: This study analyzed four international, multi-center clinical trials (OAK, BIRCH, POPLAR and FIR trials) to conduct post-hoc analyses of NSCLC patients undergoing atezolizumab (anti-PD-L1) single-agent treatment. CRP test was performed ≤ 96 hours before Day 1 of each cycle. 1438 patients with more than 2 times CRP results (a total of 11,253 records) in all 3 collection timepoints. The primary endpoint was overall survival (OS). First, multivariate survival analysis was conducted to include clinical factors such as gender, ECOG-PS, race and metastases as contributing risk factors. Then, multivariate joint modelling of longitudinal and time-to-event data was used to establish the relationship between longitudinal CRP and OS in the OAK study, whereas external validation was performed by time-dependent AUC analysis on the BIRCH, POPLAR and FIR studies. Results: Log-transformed longitudinal CRP levels (log(CRP)) in combination with clinical factors in absence of PD-L1 expression emerged as independent predictors of worse OS in the OAK study (HR of jointed model = 2.08, 95% CI: 1.84-2.35, p < 0.001) with a high accuracy (AUC = 0.74) for predicting OS. The predictive value of longitudinal CRP was validated in the external validation cohorts with good performance in OS (BIRCH: HR = 2.77 (95% CI: 2.31-3.44), AUC = 0.76; POPLAR: HR = 1.95 (95% CI: 1.50-2.64), AUC = 0.76; and FIR: HR = 1.83 (95% CI: 1.46 -2.39), AUC = 0.72). Conclusions: The Bayesian multivariate joint model demonstrated that longitudinal CRP is a strong survival dynamic predictor for atezolizumab-treated NSCLC patients.
Inflammatory signals hidden in the CBC are detectable prior to durvalumab-induced pneumonitis.
Authors: DeCarli Kathryn , Masel Rebecca , Olszewski Adam J , Belani Neel , Koffer Paul , Azzoli Christopher G.
Published: June 2022

e21116

Background: For patients with unresectable stage III non-small cell lung cancer (NSCLC), chemoradiation followed by 1 year of durvalumab is standard of care. Treatment-induced pneumonitis can be life-threatening. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune inflammation index (SII, defined as platelet x neutrophil / lymphocyte counts) are calculated from the CBC and have been studied as inflammatory biomarkers in a variety of settings. This study assessed trends in these indices among patients treated for stage III NSCLC. Methods: We reviewed medical records of adults with stage III NSCLC who completed chemoradiation and durvalumab from 1/2017 to 9/2021 as part of routine care. Patients who developed non-pneumonitis immune toxicity were excluded. NLR, PLR and SII were calculated at dates of first and last radiation dose and first durvalumab dose. For patients who developed pneumonitis, indices were also calculated at each of 8 weeks leading up to pneumonitis onset, defined as the first diagnostic CT scan and graded as 1-5 based on CTCAE criteria. Indices were compared between the pneumonitis and no pneumonitis group using rank-sum test. P values < 0.05 were considered statistically significant without adjustment for multiple testing. The slope of linear trend for each index was examined via log-gamma generalized linear regression model using a random intercept for each patient and robust standard error. Results: Of 65 patients who received chemoradiation followed by durvalumab, 2 were excluded because they were on clinical trial and 28 were excluded for non-pneumonitis immune toxicity. Among the 35 patients eligible for analysis, median age was 67 years; 20 (57%) were female; 6 (17%) were current smokers; 15 (43%) had COPD; and 17 (49%) developed pneumonitis (2 G1; 11 G2; 3 G3; 0 G4; 1 G5). In the pneumonitis group, NLR (p = 0.022), PLR (p = 0.007) and SII (p = 0.001) showed a statistically significant linear increase in the 5 weeks preceding pneumonitis onset. There were no differences in clinical characteristics, SII, NLR or PLR between the pneumonitis and no pneumonitis groups at the 3 time points examined. Conclusions: In this exploratory analysis, patients who developed pneumonitis showed a linear increase in inflammatory indices for 5 weeks before pneumonitis onset, suggesting information hidden in routine blood tests can anticipate development of a life-threatening complication. Our hypothesis-generating study will need validation in a larger prospective analysis with a control group. Future directions may also include examination of selected acute phase reactants or cytokines.
Therapeutic effects and clinical outcomes of immune checkpoint inhibitors on bone metastases in lung cancer.
Authors: Asano Yohei , Yamamoto Norio , Hayashi Katsuhiro , Takeuchi Akihiko , Miwa Shinji , Igarashi Kentaro , Yonezawa Hirotaka , Morinaga Sei , Saito Shiro , Tsuchiya Hiroyuki
Published: June 2022

e21118

Background: In recent years, advanced lung cancer patients who received immune checkpoint inhibitors (ICIs) reportedly had a more prolonged overall survival (OS) than those treated with conventional anticancer drugs. However, the therapeutic effect of ICIs on bone metastases remains unclear. The purpose of this study was to investigate the therapeutic effects of ICIs on advanced lung cancer with bone metastasis. Methods: This retrospective study included 58 lung cancer patients (42 men and 16 women; mean age, 66.2±7.8 years) who had been diagnosed with bone metastasis before the initiation of ICI treatment between 2016 and 2019, and the mean follow-up period was 23.2 months. The clinical data such as content of chemotherapy including the bone-modifying agent (BMA), skeletal-related events (SREs), and immune-related adverse events (irAEs) were investigated. The therapeutic effects of ICIs on the primary lung lesions and bone metastases were evaluated by the response evaluation criteria in solid tumors 1.1 (RECIST 1.1) and MD Anderson criteria, respectively. To assess the influence of ICI treatment on prognosis, OS from the diagnosis of bone metastases was compared to the prognostic prediction of Katagiri's score. Results: The most used ICI was pembrolizumab in 27 cases (46.6%). BMA was used in 38 cases (65.6%), and denosumab was used in 31 cases (81.6%). SREs and irAEs were observed in three cases (5.2%) and 13 cases (22.4%), respectively. In the primary lung lesions, the response rate (RR) and disease control rate (DCR) of ICIs were 14.3% and 38.1%, respectively, including one case in CR and 5 cases in PR. In the bone metastatic lesions, the RR and DCR were 38.6% and 75.0%, respectively, including 3 cases in CR and 14 cases in PR. In 17 cases that ICIs responded to bone metastases, nine cases were treated with pembrolizumab (52.9%), and all cases whose evaluations were CR had been treated with concomitant therapy of pembrolizumab and denosumab. The median survival time was 28.1 months and the 2-year OS rate was 51.7%. The 6-, 12-, and 24-month OS rates in this study were more favorable than the prognostic prediction of the Katagiri's score. Conclusions: ICI treatment showed favorable responses to bone metastases in NSCLC and better prognoses than conventional predictive prognosis. Particularly, pembrolizumab may be the most effective, and the therapeutic effect was enhanced by the concomitant use of denosumab.[Table: see text]
Medication use among lung cancer patients before and after initiating immune checkpoint inhibitors: A population study.
Authors: Mei Chuchu , Yang Amy , Shaver Amy L , Nikita Nikita , Banks Joshua , Keith Scott W. , Lu-Yao Grace L.
Published: June 2022

e21119

Background: Polypharmacy is an independent prognostic factor in older patients with lung cancer treated with immune checkpoint inhibitors (ICIs). Previous studies have shown that steroids, opioids, proton pump inhibitors, fluoroquinolone are associated with worsening overall survivals for lung cancer patients. The prevalence of drug use among lung cancer patients using ICIs is understudied. Methods: The study population consisted of older adults (aged 65 years or older) diagnosed with lung cancer from January 1, 2011, to December 31, 2016, in the Surveillance, Epidemiology, and End Results–Medicare linked database. Patients with a diagnosis of lung cancer and a claims record showing nivolumab plus ipilimumab combination therapy or anti–PD-1 therapy (ie, pembrolizumab or nivolumab) as their ICI prescribed were included in the analyses. Index date was defined as the date of first dose of ICIs. We examined medication usage within 90 days prior and after index date. Drug categories were classified, by mechanism of action from Lexicomp®, using Medicare Part D Drug event generic name. Descriptive analysis was used to show the percentage of concurrent drug usage for each drug category. McNemar test was used to compare the drug use prevalence before and after index day. Results: There are 669 patients in the study (male [48.56%], 65–74-year-old [67.10%]). Usage of steroids (89.09%), opioids (87.89%) was high before ICIs. Significant decreases were observed between before and after the index day for most prescribed drug categories, including anti-psychotics (-62.94%, p < .0001). But the use of thyroid products (35.83%, p < .0001) increased in usage after starting ICIs. Conclusions: To our knowledge, this is the first population-based study to quantify concurrent medication use amongst lung cancer patients undergoing immunotherapy. This study suggests the polypharmacy decreased significantly after initiation of ICIs. Future studies are required to investigate the reasons for the changes in medication use and increased utilization of thyroid products.[Table: see text]
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.
Prediction of immunotherapy response by integrating immune infiltration and neoantigen presentation score in late-stage melanoma.
Authors: Li Bailiang , Abbott Charles , McDaniel Lee , Pyke Rachel Marty , Navarro Fabio , Anbunathan Hima , Bartha Gabor , Harris Jason , Snyder Michael , Jang Sekwon , Boyle Sean Michael , Chen Richard
Published: June 2022

e21554

Background: Single modality biomarkers such as tumor mutational burden (TMB) fail to reliably predict response to immune checkpoint blockade (ICB) in part due to their incomplete characterization of complex tumor-immune interactions impacting response. We previously developed the composite biomarker, neoantigen presentation score (NEOPSTM), which integrates neoantigen processing and presentation information and showed it outperformed TMB and other single analyte biomarkers in predicting response in melanoma. Here we combined NEOPS with tumor immune infiltration analysis, and demonstrated further improved patient stratification for ICB response. Methods: We assessed the effect of 17 different immune and stromal cells on NEOPS using logistic regression with interactions in a retrospective cohort of 45 stage III/IV melanoma patients who underwent anti-PD-1 therapy. NEOPS and immune cell infiltration status were both generated using Personalis’ ImmunoID NeXT Platform®. The identified immune-selected phenotype that had a significant effect on NEOPS performance was validated in a cohort of 109 anti-PD1 treated late-stage melanoma patients. Results: The predictive strength of NEOPS was enhanced by considering the infiltration status of 4 distinct immune cell types derived from expression signatures: naïve CD4/CD8 T, exhausted CD8 T, and CD8 T cells. Highly correlated cells were aggregated into naïve (naïve CD4/8 T) and CD8 (exhausted and CD8 T) features. Both features independently boosted the accuracy of NEOPS in the validation cohort (naïve: Pint. = 0.048; CD8: Pint. = 0.11). In immune-selected patients in the validation cohort displaying both high naïve and CD8 features, NEOPS achieved an improved accuracy of 77.2% (vs 69.7% baseline performance, P = 0.013) and an AUC of 0.74 (vs 0.66, P = 0.055). In anti-CTLA4 treatment naïve patients, the immune-selected group attained even better NEOPS performance, with an accuracy of 81.8% (vs 70.6%, P = 0.015) and an AUC of 0.89 (vs 0.68, P = 0.005) in the validation cohort. A separate approach integrating NEOPS with naïve and CD8 features into a single composite biomarker resulted in an AUC of 0.82 (cross validation: 0.78 vs 0.71 baseline). Conclusions: Stratifying immune-selected patients based on cellular composition of the tumor microenvironment significantly increased the accuracy of our neoantigen-based biomarker of ICB response, NEOPS. These data highlight the potential for combining tumor microenvironment information with neoantigen analysis into a composite biomarker to provide more sensitive prediction of immunotherapy response.[Table: see text]
A tool to predict survival outcomes and guide adjuvant immunotherapy recommendations for patients with stage II melanoma.
Authors: Varey Alexander , Long Georgina V. , Scolyer Richard A. , Gershenwald Jeffrey E. , Simon Julie , Thompson John F. , Lo Serigne N.
Published: June 2022

e21556

Background: Patients diagnosed with AJCC stage II melanoma have a 10-year melanoma specific survival (MSS) of 84%, ranging from 88% for stage IIA to 75% for stage IIC. The 12%-25% rate of melanoma mortality correlates with the rate of recurrence for these patients. Current prognostic tools are based on the AJCC 8th Edition (AJCC-8), which gives MSS based on tumor thickness and ulceration status but does not consider any other patient or tumor characteristics. The rate of recurrence-free survival (RFS) may be more important than MSS in deciding whether a patient should be offered adjuvant immunotherapy. We have therefore developed a risk prediction tool to assist in this process. Methods: Data were extracted from a large Australian melanoma treatment center research database for patients diagnosed with stage II melanoma (n = 3243). Parameters included: age, sex, tumor thickness, mitotic rate, ulceration status, lymphovascular invasion, presence of tumor infiltrating lymphocytes, regression, sentinel node status, presence of satellites, body site, recurrence (including time to event) and date of last follow-up. Multivariable Cox regression analyses were performed to develop models for survival prediction. These were then externally validated using a dataset from a large US melanoma treatment center (n = 703). Discrimination and calibration of each model were assessed using the C-statistics and calibration plots respectively. Results: The table shows the C-statistics for the Australian RFS model and the AJCC-8 staging, along with validations. These demonstrated statistically significant discrimination gains by using the Australian model over the AJCC model, which ranged from 8.3% to 12.2%. The Australian model was well calibrated. Conclusions: There was good discrimination of the RFS model for individual patients over both 5 and 10 years, which held true on external validation. This model offers considerable improvement in discriminative accuracy for predicting RFS compared to using the AJCC-8 staging and therefore may be clinically useful to guide adjuvant immunotherapy recommendations. An online tool will be made available at www.melanomarisk.org.au.[Table: see text]
The drug targets genomic alterations detected in female tumor tissue with melanoma.
Authors: Li Zhongwu , Wang Xintong
Published: June 2022

e21558

Background: Due to the rapid development of next-generation sequencing (NGS) and precision medicine, molecularly driven targeted therapy, for different tumor types, plays an important role in cancer patients with drug targets. mucosal melanoma (MM) is aggressive disease with a poor prognosis. there are few studies focusing on its target drug. Methods: We enrolled female patients with melanoma (n = 24) from 2019.** to 2021.** cancer database with a gynecological tumor site. Subsequently, we chose to use WES sequencing to predict possible targets in patients. Results: In all mutations of the 24 melanoma patients, we screen the mutations about the drug targets. And the result shown that BRAF somatic mutations were identified in 6 of the 24 samples (25%), which are the highest frequency drug targets. V600E substitutions accounted for 3 (50%) of these mutations as target drug. Other activating mutations at NRAS codons 61 and 12/13 were lower frequent (Q61*, n = 3; G13D, n = 1; G12A, n = 1). TP53 and TOP2B were mutated in 4(16%) tumors were found as drug targets. Conclusions: This study aimed to analyze the target drug interaction of MM in China and lay a support for targeted therapy. NGS in MM is feasible with potential impact in half of our cohort. Earlier testing and improved trial drug from drug bank database access is necessary to increase the like hood that MM patients may benefit from drug target guided therapy.