bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular characteristics of EGFR exon20 mutations in NSCLC patients.
Authors: Ji Yinghua , Wang Jin , Meng Xiangli , Xie Jinling , Lu Ping , Li Mengmeng , Luo Ningning , Qi Yingxue , Zhu Xiaofeng
Published: June 2022

e21011

Background: EGFR exon 20 mutations are associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 20 mutations are usually not present alone, suggesting a more complex subtype of exon 20 mutations. Methods: In this study, we retrospectively analyzed the different subtypes and compound mutation profiles of EGFR 20 mutations. A total of 1,233 NSCLC patients’ tumors were collected and the mutations were detected by next-generation sequencing (NGS) from May 2020 to June 2021. Results: A total of 415 NSCLC patients' tumors harbored EGFR exon 20 mutations, accounting for 33.66% of the entire EGFR mutation cohort. Among these 415 patients, most of mutations were single-nucleotide variant (SNV) (379; 91.33%), and a few were indel or insertion mutations (39; 9.40%). The insertions were all in the back of exon 20, which were resistant to EGFR-TKIs. In addition, the subtypes of SNV were concentrated in T790M (270; 71.24%), S768I (48; 12.66%) and C797S (33; 8.71%), and all T790M mutations were accompanied by other mutations. Notably, the compound mutations of exon 20 have also been analyzed in this study. EGFR exon 20 combined with other EGFR mutations were detected in 345 patients. The compound mutations of exon 20-18, exon 20-19, exon 20-20 and exon 20-21 were detected in tumors from 52 (15.07%), 163 (47.25%), 43 (12.46%) and 140 (40.58%) patients respectively. Remarkably, the compound mutation subtype of exon 20-20 was T790M/C797X (29; 67.55%) and exon 20-21 was T790M/L858R (124; 88.57%). Conclusions: Diverse patterns of SNV mutations are seen in EGFR exon 20 mutations tumors. EGFR 20 mutations often accompany other mutations, which are associated with resistance to EGFR-TKIs. These data may help avoid the resistance of future adjuvant targeted therapy.
Clinical characteristic and outcomes of KRAS G13 mutant non-small cell lung cancers.
Authors: Muthiah Arun , Chudasama Rani , Mingrino Jennifer , Olszewski Adam J , Kurt Habibe , Garcia-Moliner Maria , Khan Hina
Published: June 2022

e21017

Background: KRAS is the most commonly mutated oncogene in lung adenocarcinoma. Different KRAS mutations (mts) have unique prognostic and therapeutic implications. New drugs to target KRAS G12C have raised interest in studying the unique clinical and molecular characteristics of the different KRAS subtypes. We sought to evaluate the clinical outcomes of KRAS G13C/D (*) mutant (mut) non-small cell lung cancers (NSCLC) patients (pts), compared to those with G12C and other non-G12C mutations. Methods: We identified 255 KRAS mt NSCLC pts at Brown University-Lifespan Cancer Institute that were diagnosed between 06/2016 to 12/2021. Demographics, therapies and outcomes were retrospectively recorded. Progression-free (PFS) and overall survival (OS) was compared using log-rank test. For clinical relevance, we divided pts into G12C, G13*, and other non-G12C groups. Treatments (tt) received were divided into chemotherapy alone and immune-checkpoint inhibitor (IO) containing regimens. Results: Across the KRAS cohort (n = 255), median age was 71 years and 62% were females. Most pts had advanced disease (85%) at diagnosis (dx) and > 90% were smokers. Most common KRAS mt was G12C (42%), and 7% of pts had G13*. Compared to other KRAS mut groups, G13 * had worse PFS counted from dx (median 4 vs 12 m, p = .037). When comparing outcomes of any tt among pts with G13*, G12C and other non-G12C KRAS mut, G13 group had the worst PFS (2.1 vs 10.3 vs 6.4 m, p = .004) and OS (4.1 vs 27.8 vs 18.1 m, p = .027). When treated with IO-based regimens, pts with G13 had also worse outcomes than those with other KRAS mts: PFS 1.8 vs 7.3 m, respectively, (p < 0.001) and OS 1.8 vs 16.5 m, respectively (p = .006). Within the G13 group, pts who received IO-based regimens had worse PFS (1.8 vs 7.9 m, p = .037) and OS (1.8 vs 16.1 m, p = .093), compared to chemotherapy alone. While response to all systemic therapies was poor in G13* group (disease control rate [DCR] 10%, p = .004), DCR was particularly low with IO-based tt in G13* (0%) compared to other groups (p = .023). Conclusions: Pts with KRAS G13C/D had poor survival and response to therapies in comparison with G12C and other non-G12C KRAS mts, particularly with IO-containing regimens. Recently (Judd et al, MCT-21-0201), STK11 and KEAP1 were reported to be frequently co-mutated with KRAS G13* (37.3 and 12.6%) compared to other KRAS mts, and this genotype may confer primary resistance to IO. We hypothesize that the poor outcomes and immune resistance in G13* mut may be secondary to higher prevalence of STK11 and KEAP1 co-mutations. Larger data sets should confirm our observations and correlate them with PD-L1 scores and co-mutations.[Table: see text]
Peripheral blood t cell responses to immunotherapy related adverse events in metastatic non-small cell lung cancer.
Authors: Amara Suneetha , Muzaffar Mahvish , Namireddy Praveen , Yang Li V.
Published: June 2022

e21047

Background: There has been prospective and retrospective evidence for the onset of immunotherapy (IO) related adverse events (irAE) and efficacy of anti programmed death (PD1) and Programmed death Ligand 1(PD L1) antibodies. The incidence of irAE in these studies ranged anywhere from 30-44%. There have been attempts in the past to cluster irAEs into distinct subtypes by T cell profiling before and after immunotherapy. Identifying the trend of CD4/CD8 changes during irAE may aid in finding ways to mitigate the severe toxicities, so the benefits of immunotherapy can be extended to far more number of patients. Methods: We have collected blood samples from 20 patients of Non Small Cell Lung Cancer patients (NSCLC) before each cycle of immunotherapy with informed consent. We have measured the different inflammatory markers such as IL6, IL10 using ELISA and isolated cellular components such as CD4, CD8 T cells along with others using magnetic bead technique, from these samples in our research laboratory at East Carolina University. We have also collected clinical information including the adverse events with their (Common Terminology Criteria for Adverse events) CTCAE 5.0 grading, different cell counts and C- reactive Protein (CRP). Results: In the cohort of 20 patients, 9 experienced irAE, out of which 6 had grade 2, including thyroiditis, pneumonitis, dermatitis, cytokine release syndrome (CRS), 1 had grade 3 pneumonitis, 1 had grade 4 pneumonitis and 1 had grade 1 CRS. When we looked at the CD4/CD8 ratio before each cycle, the one prior to the incidence of the irAE had at least 30-40% drop in the ratio consistently although there were minor fluctuations in the ratio at other times in both directions. Conclusions: Although most irAEs can be treated and reversed with steroids and other immunosuppressive agents, prolonged immunosuppression can lead to reduced efficacy of IO and development of undue opportunistic infections. Experience with IO has shown that earlier initiation of immunosuppression shortens the required treatment. However, given the challenge in the subtility of the earlier presentation, therapies are frequently delayed. Hence, biomarker to identify the early manifestations is of critical importance for early intervention. Studies suggest there is clonal expansion of CD8 T cells preceding grade 2-3 irAEs. Studies also indicate that increased T cells in the tumor is indicative of response to immunotherapy. Our observation suggests that increased CD8 in proportion to CD4 in the peripheral blood precedes the onset of irAE. It is unclear as to how this leads to increased toxicity when the immunotherapy treatment works by affecting T cell function. One possible explanation is that the T cell response in the tumor tissue is beneficial, however, T cell response in the peripheral blood may indicate response against self antigens leading to toxicities in the form of irAE.
Short-term efficacy of furmonertinib in treatment of NSCLC patients with EGFR exon20 insertion.
Authors: Zhou Xiaoyue , Dong Huajie , Li Peng , Wu Changling , Lu Hongjun , Xiao Mingzhe , Zhou Tong
Published: June 2022

e21063

Background: EGFR is a key driver gene of lung cancer, in which exon 20 insertion (Ex20ins) mutation accounts for about 1-5%. However, the first- and second-generation EGFR-TKI had poor efficacy on patients with Ex20ins mutation (ORR = 6.9%, mPFS = 1.9 months, mOS = 12.9 months, DCR = 44.8%). Our study retrospectively observed the short-term efficacy and safety of furmonertinib in Chinese NSCLC patients with EGFR Ex20ins mutation. Methods: The study retrospectively collected 15 NSCLC patients with EGFR Ex20ins mutant who were treated in two medical institutions in Changzhou City, Jiangsu Province from April 2021 to December 2021. All patients received targeted therapy with furmonertinib. The last follow-up time was December 30, 2021. All patients received 160 mg furmonertinib orally until disease progression, drug intolerance, patient refusal or death. EGFR Ex20ins mutation was confirmed by ARMS or next generation sequencing (NGS). The patient's gender, age, score of Eastern Cooperative Oncology Group (ECOG), smoking history, pathological type, tumor stage, gene status and other basic clinical characteristics and adverse events (AES) were collected. The clinical efficacy was evaluated according to RECIST version 1.1, and the adverse events were evaluated according to the NCI-CTCAE version 5.0. SPSS 25.0 software was used to record and analyze the data. Results: All 15 patients had received ≥2 lines of therapy. The median age was 62 (25-80) years old, and there were 8 male patients (53.3%). Most patients had no smoking history (13 cases, 86.7%). ECOG score was mostly 1 (13 cases, 86.7%). In 15 patients, we found 10 different EGFR Ex20ins variants, among which p.A767_V769dup (n = 3) and p.A767_V769dup (n = 4) were more common. By the end of follow-up, 15 patients had completed at least one efficacy evaluation, and all had different degrees of tumor regression. No patient reached CR, 8 patients had PR and 7 patients had SD. This preliminary efficacy data showed that the overall ORR was 53.5% and DCR was 100%. No grade 3 or above adverse events were observed. The 3-months PFS rate was 100%. Conclusions: The results of this study in ≥2 lines patients treated with twice the conventional dose had a good curative effect (compared with 3 times of conventional dosage in FAVOUR study), which provided more treatment options for NSCLC patients in multiple lines of treatment and could alleviate part of their economic pressure, but the PFS and OS data still need further follow-up and verification of a larger sample size. The overall findings suggested that furmonertinib is a third generation EGFR-TKI with good efficacy and acceptable safety. Given the heterogeneity of EGFR Ex20ins mutation, the efficacy of targeted therapy may vary in different mutation types and requires further investigation.
Efficacy and prognosis of sequential 2G ALK-TKI in ALK-positive advanced NSCLC after crizotinib resistance: A real-world single-center research.
Authors: He Liyuan , Zuo Jing , Feng Li , Fan Zhisong , Wang Long , Zhou Xinliang , Han Jing , Zhang Xue , Liu Jiayin , Li Dan , Liu Feiran , Zhao Honghui , Wang Yudong
Published: June 2022

e21075

Background: Advanced-stage anaplastic lymphoma kinase fusion-positive (ALK[+]) NSCLC has significantly benefited from ALK-TKI. It is still uncertain which second-generation(2G) ALK-TKI will benefit patients more after crizotinib resistance. Methods: We retrospectively analyzed the treatment history of 104 patients with ALK[+] NSCLC. Grouping was determined according to the type of 2G TKI patients selected after failure of crizotinib, including systemic and intracranial. Results: Overall, the median follow-up time was 24.2 (95%CI: 21.3-27.1) months, and 45(43.2%) eligible patients were alive at the end of follow-up. After Crizotinib treatment failure, 91(87.5%) patients received subsequent therapy (including targeted therapy and chemotherapy), and 90.1% (82/91) of patients received sequential 2G TKI treatment, with overall ORR of 68.3%, mPFS of 13.4 (95%CI:10.0-16.7) months, and mOS of 26.3 (95%CI:11.6-41.1) months. The mOS for Alectinib, Ceritinib, and Brigatinib were 34.5 (95%CI: 14.8-54.3), 19.4 (95%CI: 11.8-27.0) and 43.8 (95%CI: 10.0-77.6) months, respectively. The mPFS of Alectinib, Ceritinib, Brigatinib and Ensartinib were 17.3 (95%CI: 12.9-21.8) months, 13.4 (95%CI: 9.5-17.8) months, 10.7 (95%CI: 6.6-14.9) months and 8.4 (95%CI: 1.3-14.8) months, ORR were 68.6%, 70.8%, 69.2% and 60.0%, respectively (Table.1). For crizotinib resistant patient, 2G TKI showed no significant difference in prolonging PFS (P = 0.599) and OS (P = 0.681). Brain metastases were found in 67.1% (55/82) of crizotinib resistant patients, and mPFS of Alectinib, Ceritinib, Brigatinib and Ensartinib were 22.1 (95%CI:9.6-30.6) months, 12.6 (95%CI:8.3-16.9) months, 21.0 (95%CI:0.5-45.7) months and 14.7 (95%CI:3.8-25.5) months; ORR were 72.4%, 50.0%, 66.7% and 40.0%, respectively (Table.1). In particular, the ORR of Alectinib and Brigatinib was significantly higher than that of Ceritinib and Ensartinib (P < 0.000), while the mPFS of Alectinib was significantly better than Ensartinib (P = 0.029). Conclusions: After crizotinib resistance, nearly 90% of patients choose sequential 2G TKI. There was no significant difference in mPFS and mOS among patients treated with different 2G ALK-TKI. For patients with CNS metastases, treatment with Alectinib and Brigatinib results in higher ORR and PFS.[Table: see text]
Improved response prediction to immune checkpoint inhibition by combining TMB and WGS-based genomic features in NSCLC.
Authors: Pacewicz Klaudia , Kraszewski Andrzej , Medzin Michal , Nawrocka-Muszynska Paulina , Sypniewski Mateusz , Sielski Dawid , Sztromwasser Paweł , Majer-Burman Weronika , Piernik Maciej , Wozna Alicja , Zawadzki Paweł
Published: June 2022

e21077

Background: The appearance of immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in advanced NSCLC. The clinical efficacy and indications for ICIs are currently estimated using the immunohistochemistry (IHC) profile of programmed death-ligand 1 (PD-L1) protein. Recent findings indicate that tumor mutational burden (TMB) is a unique feature that may improve response prediction to ICIs across multiple cancer types [1]. Nevertheless, only a minority of NSCLC patients will benefit from ICIs. Therefore, unraveling the genomics of NSCLC and the subsequent discovery of novel predictive biomarkers remains a high unmet need. Whole-genome sequencing (WGS) bounded with AI may identify biomarkers and composed signatures which will better than TMB or PD-L1 predict response to ICIs. Methods: To develop the PD1Dx classifier with the highest predictive value for ICI response, we combined WGS data analyses with machine learning approaches. Consistently, we divided WGS data of 57 NSCLCs derived from the Hartwig Medical Foundation (HMF) database into training (n = 39) and hold-out (n = 18) sets. Patients treated with pembrolizumab or nivolumab alone were labeled based solely on clinical metadata provided by the repository, reaching a total of 22 responders and 35 non-responders. Results: Recursive Feature Elimination using SHAP importance (ShapRFECV) selected 15 top predictive genomic features, based on which the final random forest model was built. The random forest model achieved the best performance, with an accuracy of 0.72, a recall of 0.73, and a precision of 0.80. Using the same learning method and dataset, we built a model based on a single TMB feature whose performance determined by accuracy, recall and precision was 0.67, 0.64, and 0.78, respectively. Apart from TMB, we also identified other predictive features, among the 15 top of which were, e.g., features related to transcriptional strand bias and C > A/T single nucleotide variants correlating with mismatch repair. Conclusions: Our results confirm the predictive value of features other than TMB alone in predicting ICI responses in NSCLC. Further investigation is required to validate biomarkers of sensitivity and resistance to ICIs. Krieger T, Pearson I, Bell J, Doherty J, Robbins P. Targeted literature review on use of tumor mutational burden status and programmed cell death ligand 1 expression to predict outcomes of checkpoint inhibitor treatment. Diagn Pathol 2020;15:6.
The impact of pre-treatment plasma sex hormones on the immune checkpoint inhibitors response to metastatic non-small cell lung cancer.
Authors: Zhang Yumeng , Darville Lancia , Hogue Stephanie , Hallanger-Johnson Julie E. , Kim Youngchul , Gray Jhanelle Elaine , Robinson Lary A.
Published: June 2022

e21088

Background: Immune checkpoint inhibitors (ICI) have changed the outcomes in metastatic non-small cell lung cancer (mNSCLC). The immune system partially determines the response to ICI. The impact of sex hormones on immune responses is well recognized in autoimmune disease and vaccine response. Little is known about the interplay between the sex hormones and the response to ICI in mNSCLC. Methods: This prospective, observational study included patients with mNSCLC at Moffitt Cancer Center who received ICI as monotherapy or combination with chemotherapy. Plasma was collected before the first ICI infusion. Extraction and detection of the hormones were optimized by modifying the previous method. Hormone levels were measured using ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS). Estrogens included propyl pyrazole triol (PPT), 17β-estradiol (E2), and S-equol. Androgens included 5-androstenediol, 3β-androstenediol (3β-diol), and dehydroepiandrosterone (DHEA).Patients were divided based on clinical benefits, defined as a complete or partial response or stable disease for at least 12 months. Categorical variables were compared using the Chi-square test or Fischer exact test; continuous variables were compared using the Mann-Whitney U test. Results: Sixty-one patients were included and 50.8% were female. The median age was 67 years. Twenty-eight patients had clinical benefits from ICI. Patients in the clinical benefit group had higher BMI. The clinical benefit group had significantly lower androgen levels but no difference in estrogen levels. The median DHEA level was 3.7 ng/ml in the clinical benefit group and 9.6 ng/ml in the group without (p < 0.001). The 5-Androstenediol was also lower in the clinical benefits group (table I). When normalized to the age/sex-adjusted reference range, the difference of DHEA and 5-androstenediol was retained (p < 0.001 and 0.014, respectively). 3β-diol was below the limit of detection. Conclusions: The serum DHEA and 5-androstenediol levels were lower in mNSCLC patients who benefited from ICI, regardless of sex. Larger studies are needed to confirm the role of pre-treatment androgens levels as negative biomarkers for ICI response. [Table: see text]
The use of medical cannabis concomitantly with immune-check point inhibitors (ICI) in non-small cell lung cancer (NSCLC): A sigh of relief?
Authors: Waissengrin Barliz , Leshem Yasmin , Merimsky Ofer , Wolf Ido
Published: June 2022

e21097

Background: In recent years, the use of medical cannabis rapidly increased among cancer patients in Israel. Yet, cannabinoid receptors are abundantly expressed on immune cells and modulate their activity. It is abundantly being use by metastatic NSCLC patients, shortly following diagnosis and is taken in parallel to first line treatment with ICI. Recent studies suggested that the use of cannabis may reduce the efficacy of ICI. However, these studies were biased by the heterogeneity of patients and the increased use of cannabis specifically in highly symptomatic patients with high disease burden. Methods: We first tested the interaction anti-PD-1 antibody and Δ−9-tetrahydrocannabinol (THC) in a preclinical model consisting of CT26 tumor-bearing mice, and examined the effects on tumor size, T-cell infiltrates, and mice survival. Mice were euthanized when tumor volume reached above 700 mm3. Next, we conducted a retrospective study of NSCLC patients, treated at a tertiary center, and included all consecutive patients treated with a single agent pembrolizumab as a first line treatment for advanced disease and evaluated clinical outcome and response to treatment. Results: Studies using the CT26 mice cancer model, indicated a potential beneficial effect for the combination an anti-PD-1 antibody and THC with a median overall survival (OS) of the mice receiving no treatment, THC, anti-PD-1 antibody or their combination being 21 days, 24, 31 days and 54 days, respectively (p < 0.05). Data of 201 NSCLC cancer patients who received first-line single agent pembrolizumab for metastatic disease, 102 (50.7%) patients received cannabis and 99 (49.3%) were cannabis naïve was analyzed. Their median age was 68 for the cannabis treated group and 74 for the cannabis naïve (p = 0.003), 34 (34.3%) in the cannabis treated group and 62 (60.8%) for the cannabis naïve were women (p = 0.002). Similar distribution of histology, smoking status and PDL1 expression was noted between the groups. The efficacy of pembrolizumab, as determined by time to progression (TTP) was similar for cannabis-naïve and cannabis-treated patients (6.1 vs. 4.8 months, respectively, p = 0.386), while OS was higher, though not statistically significant, in the cannabis-naïve group (54 vs. 23.3 months, respectively p = 0.08). Conclusions: Both preclinical and clinical data suggest no deleterious effect of cannabis on the activity of pembrolizumab as first line monotherapy for advanced NSCLC. The differences in OS can be most likely by attributed to higher disease burden and more symptomatic disease in the cannabis-treated group. While additional validation is required, these data provide somewhat reassuring data regarding the absence of a deleterious effect of cannabis in this clinical setting.
Transcriptional analysis of small cell lung cancer transformation in epidermal growth factor receptor mutated lung adenocarcinomas.
Authors: Xie Tongji , Li Yan , Hao Xuezhi , Wang Yan , Hu Xingsheng , Wang Lin , Wang Shouzheng , Teng Fei , Xu Ziyi , Ying Jianming , Junling Li , Xing Puyuan
Published: June 2022

e21100

Background: Epidermal growth factor receptor ( EGFR)-mutated lung adenocarcinoma (LUAD) could benefit from EGFR-TKIs (tyrosine kinase inhibitors) treatment, but drug resistance seems to be inevitable. Small cell lung cancer (SCLC) transformation counts for 3-15% of the resistance mechanism, and was amply studied at genomics level but rarely at transcriptional level. Methods: The expression of 730 mRNAs were investigated by Nanostring nCounter Pancancer Pathway Panel on 72 formalin-fixed and paraffin-embedded (FFPE) samples from 27 EGFR-mutated LUAD patients with SCLC transformation after EGFR-TKIs therapy (19 LUAD samples before transformation, LUAD-BT; 21 SCLC samples after transformation, SCLC-AT), 12 EGFR-mutated LUAD patients never SCLC transformed after EGFR-TKIs therapy (12 samples, LUAD-NT) and 20 stage IIĨIV primary SCLC patients (20 samples, SCLC-P). For patients enrolled in LUAD-NT group, tissue biopsies were performed at least twice, which were all diagnosed as pure LUAD, and the overall survival (OS) since first line therapy was longer than the median transformation time (mTt) of SCLC-transformed patients in our study. mRNA expression patterns and biological pathway scores were compared among four groups. The candidate predictive biomarkers from mRNA expression pattern analysis were validated by area under curve (AUC) of receiver operating characteristic curve (ROC) and the logarithm of fold change to the base 2 (log2FC). Results: On the last day of follow up (1st February 2022), the shortest OS of LUAD-NT patients was 28.4 months, whereas the mTt was 27.5 months. Among four groups, LUAD-NT and LUAD-BT showed the most similar mRNA expression patterns, and SCLC-P were significantly different from the others. 8.6% (63/730) mRNA showed significant downregulation after SCLC transformation, while 3.6% (26/730) showed significant upregulation ( p value adjusted by Benjamin & Hochberg’s method < 0.05, SCLC-AT vs LUAD-BT). In pathway enrichment analysis, the score of RAS and TGF-β pathways were significantly lower in SCLC-AT than LUAD-BT. Compared with SCLC-P, 6 upregulated mRNAs in SCLC-AT were observed (log2FC > 2, AUC > 0.85 and each raw p value < 0.05), including AR, COL5A1, GHR, HMGA2, IGFBP3 and IL6R, which could be further validated as diagnostic markers in a larger cohort. Moreover, compared with LUAD-NT, 4 mRNAs ( BRIP1, CCNE2, CDKN2A and MCM2) were found to be significantly upregulated (log2FC > 1, AUC > 0.75 and each raw p value < 0.05) in LUAD-BT, indicating the predictive value of SCLC transformation. Conclusions: The transformation of LUAD to SCLC may be promoted by transcriptional events. We also described some significantly different expressed mRNAs that could candidate as predictive or diagnostic markers for SCLC transformation, which should be further validated in a larger cohort.
High-sensitivity C-reactive protein as prognostic and predictive marker in metastatic non-small cell lung carcinoma : A prospective single center study.
Authors: Mondal Debapriya , Ganguly Sandip , Ghosh Joydeep , Roy Somnath , Pandey Prashant , Dabkara Deepak , Nair Reena , Biswas Bivas
Published: June 2022

e21101

Background: Systemic inflammation has been linked to incidence, progression, and poor outcomes in various cancers including non-small cell lung carcinoma (NSCLC). High-sensitivity CRP (hs-CRP) assays, generally used to assess cardiovascular risk, have rarely been evaluated in lung cancer studies. This study aimed to evaluate if baseline and on-treatment measurements of serum hs-CRP could provide prognostic and predictive information for patients with metastatic NSCLC treated with chemotherapy. Methods: In this single institutional prospective study 85 patients with metastatic NSCLC without targetable alterations who were treated with chemotherapy were included between 1st January 2020 and 31st December 2020, with a minimum follow-up duration of 6 months. Patients with coronary artery disease, active infections, autoimmune conditions, and chronic liver disease were excluded. Measurements of hs-CRP for all patients were done at baseline and every 12 weeks while on treatment. Patients were grouped by changes in hs-CRP levels compared to baseline levels as reduction (≥ 20% decline), and non-reduction (< 20% decline) to assess association with radiologic response and progression- free survival (PFS). Results: Pre-treatment hs-CRP values were elevated for the majority (92.9% patients with ≥ 1 mg/L, 70.6% with ≥ 3 mg/L, and 42.3% with ≥ 10 mg/dL). No significant association was detected between the pre-treatment hs-CRP value and the number of metastatic sites (P = 0.4), histology (P = 0.3), or smoking status (P = 0.7). At a median follow-up of 13.7 months, the median PFS was 7.8 months (95% confidence interval [CI] 5.3 - 10.3). Patients with hs-CRP ≥10 mg/L had shorter PFS than those with hs-CRP < 10 mg/L (Median PFS 7.5 months [95% CI 4.9 - 10] vs. 8.4 months [95% CI 0.1 - 17.4]; hazard ratio [HR] 1.8, 95% CI 1-3.4, P = 0.04). hs-CRP reduction (≥20% decline) after 12 weeks of treatment initiation predicted radiological response (P < 0.001). Median PFS was 14.7 months (95% CI 7.4 – 22.1) in patients who demonstrated hs-CRP reduction (≥20% decline) at 12 weeks compared to 3.1 months (95% CI 2.3 – 3.9) in patients who did not (HR 0.17, 95% CI 0.08 - 0.33, P < 0.001). Conclusions: Elevated hs-CRP at baseline was found to be a poor prognostic factor, while hs-CRP reduction by 20% or more on treatment predicted radiologic response and longer PFS in metastatic NSCLC patients treated with chemotherapy. Our findings of potential predictive and prognostic value of hs-CRP in metastatic NSCLC warrant validation in larger prospective studies.
Selecting optimal timing of cranial radiotherapy-based on the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA) in patients with non-small cell lung cancer and brain metastases.
Authors: Zhai Xiaoyang , Li Ji , Jing Wang , Jia Wenxiao , Zhu Hui , Yu Jinming
Published: June 2022

e21105

Background: The updated Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA) index will provide more accurate prediction of expected survival for patients with advanced non-small cell lung cancer (NSCLC) with brain metastases (BM). This retrospective study aims to evaluate optimal timing of cranial radiotherapy (RT) in NSCLC patients with BM stratified by Lung-molGPA index. Methods: This study retrospectively screened patients with NSCLC and initially diagnosed BM in our cancer center between February 2012 and July 2018. These enrolled patients were scored and stratified based on lung-molGPA index. The primary endpoint was overall survival time (OS), defined as the interval from the initiation of BM diagnosis to death caused by any reason or the last follow-up. And the secondary endpoint was progression free survival (PFS), referred to the interval from the initiation of BM diagnosis to disease progression or death caused by any reason. The effect of radiotherapy timing on survival time in groups stratified by lung-molGPA index was evaluated. The early RT was defined as receiving RT within three months after initial diagnosis of BM with no progression of BM prior to RT. And the delayed RT was defined as receiving RT after progression of BM or initial diagnosis of BM three months later. Results: Overall, 471 patients were enrolled in our study, including 260 patients receiving RT. The median follow-up time was 48 months. In entire cohort, median OS time and PFS were 15.0 and 9.0 months, respectively. In lung-molGPA0-2 group, OS of patients with or without RT was no statistical difference (HR, 0.78, 95%CI, 0.59-1.04, P= .071). While in lung-molGPA2.5-4 group, the addition of RT could prolong OS and PFS of patients (OS: HR, 0.51, 95%CI, 0.39-0.67, P< .001; and PFS: HR, 0.66, 95%CI, 0.51-0.85, P< .001). Moreover, in patients scored as 2.5-4.0, the median OS of early RT and delayed RT was 24.0 months and 15.0 months, respectively, and OS of patients receiving early RT was significantly superior to patients receiving delayed RT (HR, 0.50, 95%CI, 0.31-0.79, P< .001). While for patients scored as 0-2, no statistical difference was between OS of patients receiving early RT and delayed RT (HR, 0.75, 95%CI, 0.51-1.10, P= .115). Conclusions: With regards as patients scored 2.5-4.0 based on lung-molGPA index, early addition of cranial radiotherapy could benefit patients’ survival. While for patients scored 0-2, the survival benefit from cranial radiotherapy was limited.
A real-world study update: Efficacy and safety of anlotinib for advanced non-small cell lung cancer.
Authors: Wang Jinlin , Yi Tienan , Dong Youhong , Xu Xinhua , Cao Fengjun , Ran Ruizhi , Yin Yifa , Li Yinping , Fu Yang , Xu Yanhua , Kuang Li , Chen Guiming , Qu Guangqiao , Li Jun , Luo Zhiguo , Chen Yuan , Song Qibin , Chu Qian
Published: June 2022

e21106

Background: Anlotinib is an oral novel receptor tyrosine kinases (RTKs) inhibitor targeting multiple RTKs including VEGFR, PDGFR, FGFR, and c-kit. Due to its high efficacy and low side effects in ALTER 0303 trial, Anlotinib has been approved as a 3rd line therapy for pts with advanced non-small cell lung cancer (NSCLC) by NMPA in May 2018. The interim results of our real-world study suggested anlotinib substantially prolonged the progression-free survival (PFS) with manageable toxicity in later lines treatment of advanced NSCLC patients. Here, we update our latest results on the treatment experience in a broad NSCLC population. Methods: This is a multi-center, non-interventional, prospective real-world study. All registered data are collected from real-life clinical practice setting. Patients with advanced NSCLC treating with anlotinib were included. The primary endpoint was PFS, and the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: As of January 2022, a total of 371 pts were enrolled, of whom 347 were evaluable, with a median age of 63 years, 232 males (66.9%). There were 40 pts (11.5%) with brain metastasis, 52 pts (15.0%) with bone metastasis, and 29 pts (8.4%) with liver metastasis at baseline. 109 pts (31.4%) received anlotinib as first/second line treatment, whereas 238 pts (68.6%) as third/later line treatment. In the overall population, DCR and ORR were 84.7% and 18.7% respectively. The mPFS was 6.3 months (95%CI, 5.7, 6.9) and the mOS was 12.2 months (95%CI, 9.5,14.9). Subgroup analysis showed more details. A trend towards better ORR (33.3%) was observed in the first line setting while a significantly better DCR (89.5%) was observed in the second line setting. The mPFS of first-/second-line treatment (6.9 months) was longer than that of the third-line or above treatment (5.8 months). The mOS of the first-/second- and third-line or above treatment were 10.4 (7.8,13) and 13.5 (8.9,18.1) months respectively. 52 pts (15%) had any grade of adverse events, of which 10 pts (2.9%) had grade 3 or above AEs. The most common AEs were hypoalbuminemia (3.5%), alanine aminotransferase reduction (1.4%), proteinuria (1.2%) and hyponatremia (1.2%). Conclusions: The updated results showed that anlotinib prolonged not only PFS but also OS significantly with a favorable safety profile, especially for OS benefits in third-line or later treatment. These data also indirectly revealed that anlotinib is a promising treatment option for patients with advanced NSCLC despite of treatment line in the real world.
Inter-reader reliability of immune-specific response criteria (irRECIST & iRECIST).
Authors: Ruchalski Kathleen , Kim Hyun J. , Dewan Rohit , Douek Michael , Sai Victor , Villegas Bianca , Wong Koon-Pong , Lisberg Aaron E. , Goldman Jonathan W. , Goldin Jonathan , Garon Edward B. , Aberle Denise R.
Published: June 2022

e21108

Background: RECIST 1.1 can underestimate treatment benefits of immunotherapy, with irRECIST and iRECIST accounting for atypical responses. Inter-reader discordances are known to occur in a dual reader paradigm. Our objective is to compare inter-reader reliability between RECIST 1.1, irRECIST, and iRECIST. Methods: This is a retrospective analysis of advanced NSCLC patients treated with pembrolizumab at our institution as part of the KEYNOTE-001 study. All trial imaging was interpreted by two radiologists. RECIST 1.1, irRECIST, and iRECIST categorical responses and agreement for progressive disease (PD) was compared by kappa statistic. Time to progression (TTP) or time to censor was compared between readers by paired t test. Relationship to disease progression and overall survival (OS) was assessed by log rank. Results: Of 98 patients, 77 had baseline and subsequent imaging available for 5.8 mean timepoints with 42.9 weeks of follow up. From this group, 45 patients had imaging beyond iUPD for confirmation and were analyzed. PD occurred by reader 1, reader 2 in 34, 33 patients by RECIST 1.1 (k = 0.591, CI = 0.320-0.863), 31, 29 patients by irRECIST (k = 0.501, CI = 0.234-0.768), and 27, 22 patients by iRECIST iCPD (confirmed-PD) (k = 0.690, CI = 0.485-0.896). There was no significant difference in reader agreement by RECIST 1.1, irRECIST, iRECIST (p = 0.38, 0.60, 0.26). There was a significant difference in time to progression between RECIST 1.1, irRECIST and iRECIST, with median PFS 3.4 months (2.6-4.6), 4.7 (3.5-6.8) and 8.7 (6.9-14.5) (p < 0.0001). PD by any criteria was not significantly correlated with OS. Conclusions: PD confirmation by iRECIST resulted in substantial reader agreement compared to moderate reader agreement by RECIST 1.1 and irRECIST. There were significant differences in TTP between the criteria, with iRECIST having the longest TTP. PD by each criteria did not correlate with a significant difference in OS.[Table: see text]
Immune-suppressive microenvironment was revealed from NSCLC patients with hyperprogressive disease (HPD) from immunotherapy.
Authors: Wei Zhigong , Yu Min , Wang Weiya , Chen Lin , Yang Qidong , Xiao Mingzhe , Qi Chuang , Xi Wenjing , Luo Shifu , Peng Xingchen
Published: June 2022

e21109

Background: Immune checkpoint inhibitors (ICIs) demonstrated clear survival benefit in advanced non-small cell lung cancer (NSCLC) and was considered as a standard treatment. However, 10%-20% of ICI treated patients presented hyper-progressive disease (HPD) and shortened OS (< 5 months). In this study, we analyzed the tumor immune microenvironment (TME) of HPD and non-HPD NSCLC patients, aiming to reveal their discrepancies. Methods: Advanced NSCLC patients treated with ICIs in West China Hospital from March 2015 to January 2020 were retrospectively analyzed. HPD was defined as: 1) RECIST progression at first response evaluation, or time-to-treatment failure (TTF) < 2 months; 2) increase in tumor volume > 50%; 3) tumor growth rate (TGR) > 2-fold. Total cellular RNA was extracted from FFPE samples and subjected to gene expression evaluation using NanoString nCounter. A customized code set consisting of a 289-gene panel related to the tumor, immune regulation, and tumor microenvironment was used. Results: A total of 296 patients were screened, including 26 (8.8%) HPD and 272 (91.2%) non-HPD patients. A total of 52 specimens were subjected to TME analysis. At last, data from 27 (8 HPD and 19 non-HPD) samples were suitable for final analysis. We revealed 22 differential expressed genes (DEGs) (fold change > = 2, FDR < 0.05) in the HPD group using DESeq2, including 14 up-regulated genes and 8 down-regulated genes. Gene ontology (GO) enrichment analysis revealed that the DEGs were significantly enriched in leukocyte migration, leukocyte chemotaxis, and neutrophil migration. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results revealed that the DEGs were significantly enriched in IL-17 signaling pathway. Levels and proportions of 16 immune cell types, tumor-infiltrating lymphocytes (TILs) score, cytolytic activity (CYT) score, cytotoxic T lymphocytes (CTL) level, IFN-γ signature, T cell markers, teff score and 18-gene T cell-inflamed GEP score were estimated using characteristic gene expression signatures. We found that immune cells had a lower tendency in the HPD group, and B-cells, CD45, cytotoxic cells, T-cells, and Th1-cells reached significantly lower levels. Further analysis revealed that the HPD group had significantly lower total TILs score, Teff score, and T cell-inflamed GEP score. Conclusions: HPD patients in NSCLC had immune-suppressive TME which were significantly different from non-HPD patients. Patients with low TILs score, Teff score, and T cell-inflamed GEP score may develop HPD and have a poor prognosis after receiving ICIs therapy. The TME signatures in the tissues before ICIs treatment might become a predictive biomarker of HPD risk.
The predictive values of POTEE mutations for response to immune checkpoint inhibitors in lung adenocarcinoma.
Authors: Yang Yi , Ren Fuqiang , Wang Yuan , Yang Qidong , Zhao Lele , Chen Lin , Liu Yaqin , Xiao Mingzhe
Published: June 2022

e21110

Background: Precise selection of patients who could benefit from immune checkpoint inhibitors (ICIs)is an important challenge for immunotherapy in lung cancer. POTEE is a member of one primate-specific gene family which have been identified as cancer-related antigens and potential target for immunotherapy of cancer. Here, we investigated the correlation between POTEE mutation and the clinical outcomes of ICIs treatment in lung adenocarcinoma (LUAD). Methods: We merged three independent cohorts from publicly accessible data, the Miao(n = 47), Rizvi (n = 29) and Hellmann (n = 59), to explore the associations between POTEE mutations ( POTEE-mut) and ICIs efficacy. Then we explored the relationship between POTEE mutation and tumor mutational burden (TMB) and PD-L1 expression in the merged cohort. Further, gene set enrichment analyses (GSEA) was used to explore the potential molecular mechanism in The Cancer Genome Atlas (TCGA)-LUAD cohort. Results: In merged cohort, the mutation frequency of POTEE was 7.41% (10 in 135). POTEE-mut group had a significantly higher objective response rate (ORR) (100% vs 27.2%; Fisher’s exact test; P < 0.001) compared to POTEE wildtype group. Kaplan-Meier analysis revealed that POTEE-mut was significantly associated with longer progression-free survival (PFS) (not reached vs 6.1 months, P = 0.001). And at multivariable analysis adjusted by cohort, age, smoking status, line of immunotherapy, PD-L1 expression and TMB, POTEE-mut group showed significant improved PFS with a HR of 0.09(95% CI 0.01-0.71, P = 0.022). Then we explored the association of POTEE alterations with TMB and PD-L1 expression. In merged cohort significantly higher TMB were found in LUAD patient with POTEE mutation (Mann-Whitney U test; p < 0.001). However, there was no association between POTEE mutation and PD-L1 expression. We further explored the potential mechanism of POTTE mutation affecting immunotherapy response using TCGA-LUAD data. GSEA analysis revealed prominent enrichment of signatures related to DNA repair in patients with POTEE mutation (P < 0.001). In detail, four DNA damage response (DDR) pathways, homologous recombination repair (HRR) (NES = 2.108, P < 0.001), translesion DNA synthesis (NES = 1.587, P = 0.01), checkpoint factors (NES = 1.865, P < 0.001) and base excision repair (NES = 1.737, P = 0.002), were all significantly enriched in POTEE-mut tumor. Conclusions: Our data indicated that POTEE mutations were associated with the better response for immunotherapy of LUAD, implying that it can be used as a biomarker for predicting the efficacy of LUAD immunotherapy. POTEE mutation was associated with higher TMB and changed the activity of DNA repair related pathways in LUAD. These may be the underlying mechanisms for POTEE mutations to affect the prognosis of immunotherapy.
Outcomes of sintilimab plus pemetrexed and platinum (SPP) according to stage of disease in patients (pts) with locally advanced or metastatic nonsquamous NSCLC (AMnsqNSCLC) in the phase 3 ORIENT-11 study.
Authors: Yang Yunpeng , Wang Zhehai , Fang Jian , Yu Qitao , Han Baohui , Cang Shundong , Chen Gongyan , Mei Xiaodong , Yang Zhixiong , Stefaniak Victoria Jennifer , Ferry David Raymond , Zhao Yumin , Wang Shuyan , Wang Yan , Sun Luyao , Zhang Li
Published: June 2022

e21157

Background: In ORIENT-11, first-line (1L) SPP improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and duration of response (DoR) compared with placebo plus pemetrexed-platinum (PPP) in pts with AMnsqNSCLC. We report outcomes from ORIENT-11 (NCT03607539) for pts treated with SPP with stage III (b & c) compared with stage IV disease. Methods: Pts with treatment-naïve locally AMnsqNSCLC without sensitizing EGFR/ALK alterations were randomly assigned to SPP (n = 266) or PPP (n = 131), stratified by PD-L1 expression, platinum-chemotherapy and sex. Primary endpoint was PFS (RECIST v1.1). Secondary endpoints included OS, ORR, DoR and safety. Kaplan-Meier method was used to analyze median PFS, OS and DoR. Stratified Cox model was used to analyze the hazard ratio (HR) of SPP vs. PPP. Clopper-Pearson method was used to calculate the 95% confidence intervals (CI) of ORR for each group. Miettinen-Nurminen method was used to analyze 95% CI of ORR difference between SPP and PPP. Data cutoff for OS data was September 15, 2021, providing a median follow-up of 30.8 months. Cutoff for other data was November 15, 2019, providing a median follow-up of 8.9 months. Results: 21 pts (7.9%) receiving SPP had stage III disease and 245 pts (92.1%) had stage IV disease. Baseline sex, age and PD-L1 expression ≥1% were similar between subgroups (Table). There were differences between subgroups in number of pts receiving carboplatin and ECOG performance status at baseline. PFS, OS, ORR and DoR outcomes were comparable between pts with stage III and stage IV disease based on the ad-hoc analyses. Any-grade adverse events (AEs) (100.0% vs. 99.6%) and AEs of Grade ≥3 (57.1% vs. 62.0%) were similar in pts with stage III and stage IV disease. Conclusions: In ORIENT-11, outcomes for pts receiving SPP as 1L therapy in AMnsqNSCLC with stage III and stage IV disease were comparable. Clinical trial information: NCT03607539. [Table: see text]
Relevance of detection of RAF fusion in pan-negative melanoma in routine practice.
Authors: Jamme Philippe , Delzenne Guillaume , Mortier Laurent , Farchi Olivier , Boileau Marie
Published: June 2022

e21500

Background: Pan-negative melanomas (i.e. without MAPK kinase pathway alteration and C-kit wild type) account for 30% of melanomas (according to the AACR GENIE database). In case of immunotherapy failure, therapeutic options are limited. Oncogene fusions represent a target of interest in many solid cancers (NSCLC, Cholangiocarcinoma, Glioma, GIST, pancreatic acinar carcinoma, thyroid, and prostate cancers). In melanoma, the frequency of oncogene fusion is not well documented and not routinely investigated. Methods: We conducted a single-center retrospective study. The objective was to determine the frequency of oncogene fusion detected by RNA sequencing (Archer Fusion pLex) performed in routine practice, in patients with advanced or metastatic pan negative melanoma. Data on clinical, pathological, and molecular characteristics and patient outcomes were collected. Analysis was carried out on the genetic material available for the diagnosis of the disease except for 1 patient who benefited from a new anatomopathological sample during an unfavorable evolution. In parallel, an extended molecular alteration search was performed using extended targeted NGS (OncoMine Comprehensive Assay panel). Results: We identified 48 patients with an advanced pan negative melanoma between January 2021 and January 2022 with a median age at diagnosis of 63 years. It was a cutaneous melanoma in 72,9 % (35/48) of the cases, a mucous melanoma in 14,5% (7/48) of the cases and a melanoma of unknown primary site in 12,5% (6/48) of the cases. The detection of fusion transcript was made in 89,5 % (43/48) of the cases. We identified 6 patients with a RAF fusion, including 4 BRAF gene fusion (MKLN1-BRAF, AGK-BRAF, SNX29-BRAF, PTPRJ-BRAF) and 2 RAF1 fusion (MAP4-RAF1, EFCC1-RAF1). Of the other molecular alterations, NF1 mutation was the most frequent molecular alteration identified (25 % (12/48) of patients). At lower frequencies, 6,8 % (3/48) of patients had a PI3K mutation, and 8,3 % (4/48) of patients had NOTCH, PTCH1, GNAQ mutations. Among the 6 patients with RAF fusions, all the patients initially received treatment with anti-PD1+/- anti-CTLA4 immunotherapy. After immunotherapy failure, 4 patients benefited from second-line targeted therapy (2 with BRAF and MEK inhibitors combination, 2 MEK inhibitors alone). One patient presented an objective imaging response, the other three patients have not yet benefited from reassessment imaging. Conclusions: In a population of pan negative melanoma, we detected 12,5 % (6/48) of RAF fusion. Fusion detection allowed the introduction of a second line of targeted therapy, in the absence of a validated therapeutic option in 66,6 % (4/6) of cases This study suggests the relevance of detecting RAF fusion in a selected population.