bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of osimertinib in patients with EGFR mutant lung cancer harboring the uncommon exon 19 deletion, L747_A750>P.
Authors: Grant Michael J , Aredo Jacqueline V , Starrett Jacqueline , Wurtz Anna , Piotrowska Zofia , Piper-Vallillo Andrew , Yu Helena Alexandra , Falcon Christina , Patil Tejas , Nguyen Christina , Aggarwal Charu , Scholes Dylan G. , Li Fangyong , Phadke Manali , Neal Joel W. , Walther Zenta , Politi Katerina A. , Goldberg Sarah B. 
Published: June 2022

e21112 Background: EGFR exon 19 deletions (del19) are largely considered to have uniform sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Approximately 70% of del19 tumors harbor the most common deletion, E756_A750del; however, many “uncommon” variants comprise the remainder of this group. In preclinical studies, the uncommon del19, L747_A750 > P, demonstrates diminished sensitivity to the third generation TKI, osimertinib [. Identifying differences in clinical outcomes with osimertinib treatment could have therapeutic implications for patients (pts) with EGFR del19 non-small cell lung cancer (NSCLC). Methods: We conducted a multi-center retrospective cohort study of pts with metastatic EGFR del19 NSCLC treated with osimertinib. We compared progression free survival (PFS, time from TKI initiation to clinically significant growth of existing lesions or new lesions on imaging or death) and overall survival (OS) of pts with tumors harboring E746_A750del and L747_A750 > P who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L). The Kaplan Meier method and Cox model were used to estimate PFS and OS, and multivariable logistic regression was used to estimate the odds of achieving PFS > 12 months. Multivariable analyses adjusted for baseline covariates- age, sex, race, and smoking. Results: From March 2013 to December 2021, 86 pts with EGFR E746_A750del and 36 with L747_A750 > P were treated with osimertinib. For 1L osimertinib, E746_A750del was associated with significantly prolonged PFS vs. L747_A750 > P (median 21.3 months (95% CI 17.0-31.7) vs. 11.7 months (10.8-29.4)) in the adjusted analysis (hazard ratio [HR] 0.52 [95% CI, 0.28-0.98, p = 0.043]). Pts with the common del19 mutation were more likely to achieve PFS > 12 months with 1L osimertinib than those with the L747_A750 > P mutation (Odds Ratio 4.14 (1.41-12.15), p 0.0097). OS exhibited a similar trend with a median OS that that was not reached (NR) at 40 months of follow-up among those with E746_A750del vs 26 months for L747_A750 > P (adjusted HR 0.52 [95% CI, 0.23-1.19], p = 0.120). For pts treated with ≥2L osimertinib, there was also a trend towards favorable PFS and OS for pts with tumors harboring E746_A750del. Conclusions: The del19 mutation L747_A750 > P is associated with inferior PFS compared to the common E746_A750del mutation in pts treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR del19 subtypes could alter management of these pts in the future.[Table: see text]
The efficacy of afatinib combined with bevacizumab in first-line treatment of EGFR-mutated advanced non-small cell lung cancer.
Authors: Liu Yangli , Chen Haihong , Liang Wei , Kuang Yukun , Guo Yubiao , Tang Ke-Jing 
Published: June 2022

e21124 Background: The addition of bevacizumab to first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) has shown promising efficacy in delaying TKI resistance and prolonging PFS in treating EGFR-mutated advanced lung cancer. However, data on the afatinib-bevacizumab combination therapy are limited. Methods: A total of 47 patients with EGFR-mutated advanced lung cancer were retrospectively analyzed, including 21 patients treated with afatinib combined with bevacizumab and 26 patients treated with afatinib monotherapy. Clinical data, survival outcomes and toxic effects were evaluated. Results: There was no significant difference in basic clinical features between the combination and monotherapy groups. The overall response rate (ORR), median progression-free survival (PFS) and overall survival (OS) in the combination group (afatinib 40 mg/day combined with bevacizumab 7.5 mg/kg every 3 weeks) were 42.9%, 16.5 months and 35.2 months, respectively, while the ORR, PFS and OS in the afatinib group was 53.8%, 13.8 months and 33.8 months, respectively. No significant difference was noted in ORR, PFS or OS between the two groups ( p＞0.05). However, among the subgroup with concurrent genetic mutations, combination therapy provided a significant PFS benefit (18.2 months, [95% CI 7.1-29.3] vs. 11.0 months [95%CI 7.5-14.5], p= 0.036). Although there was a longer trend in OS, no statistical difference was presented (35.2 months [95% CI 29.8-40.6] vs. 27.5 months [95% CI 13.1-41.9], p= 0.138). The safety of the combination therapy was acceptable and manageable. Conclusions: Afatinib-bevacizumab combination therapy could provide superior PFS benefit over afatinib alone in the subset of patients with concomitant genetic mutations in EGFR-mutated advanced NSCLC, and the safety of the combination therapy is acceptable.[Table: see text]
Blood gene expression changes in metastatic lung cancer under first-line immunotherapy according to clinical response.
Authors: Lusky Fabienne , Schindler Hannah , Elshiaty Mariam , Gaissmaier Lena , Daniello Lea , Bozorgmehr Farastuk , Kuon Jonas , Shah Rajiv , Schneider Marc A , Eichhorn Florian , Baum Philip , Trudzinski Franziska , Angeles Arlou , Janke Florian , Kirchner Martina , Kazdal Daniel , Stenzinger Albrecht , Sültmann Holger , Thomas Michael , Christopoulos Petros 
Published: June 2022

e21141 Background: First-line pembrolizumab monotherapy is a standard treatment for metastatic non-small-cell lung cancer (NSCLC) with high PD-L1 expression (TPS ≥50%). However, many patients do not respond, and reliable biomarkers are lacking. Methods: Blood samples of 33 patients with metastatic NSCLC were analyzed at baseline (BL) and after four cycles of pembrolizumab monotherapy (FU). The expression of 12 genes involved in tumor-specific immune responses ( FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, MKI67, TBX21) in whole blood RNA was quantified by RT-PCR in absolute terms using plasmids as standards. Results: Gene expression was significantly higher after immunotherapy for 11/12 genes analyzed ( FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, TBX21 with fold changes [FC] 1.99 – 5.45; all p < 0.001). Blood neutrophil and total leukocyte counts were significantly decreased (ANC BL:7.65/nl vs. FU:5.36/nl, p = 0.024; Leu BL:10.65/nl vs. FU:7.78/nl, p = 0.032), while lymphocyte counts did not change (ALC BL:1.41/nl vs. FU:1.47/nl, p = 0.267). Increases in the expression of RORgt, FASLv1, PRF1, PD1, CD247, GZMB and TBX21 remained significant (FC 1.9 – 3.7; all p < 0.001) even after correction for the blood lymphocyte/leukocyte ratio (Ly/Lc BL:0.151 vs. FU:0.197, p = 0.003). Patients with long-term response (LTR, i.e. lasting > 6 months) had significantly higher increases in the expression of 8 genes ( RORgt, FOXP3, IFNγ, FASLv1, GATA3, PD1, CD247, TBX21) compared with patients with rapid disease progression within 3 months (RP) (FC 2.34 – 4.62, all p < 0.05). There were no significant differences (FU-BL) between LTR and RP regarding ANC (RP:-1.00/nl vs. LTR:-2.63/nl, p = 0.50), ALC (RP:-0,14/nl vs. LTR:+0,12/nl, p = 0,33) or Ly/Lc (RP:0.015 vs. LR:0.0542, p = 0.259). Conclusions: Pembrolizumab monotherapy of metastatic NSCLC causes significant increases in the blood expression for several genes including FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, TBX21, as well as a decrease in circulating neutrophiles and total leucocytes. Long-term responders have more pronounced blood gene expression changes, which appear to correlate with long-term benefit, in contrast to blood count changes, which are not indicative. These results are currently being validated in a larger prospective study.
Efficacy and safety of recombinant human endostatin combined with whole-brain radiotherapy in patients with brain metastases from NSCLC.
Authors: Chen Lingjuan , Tong Fan , Peng Ling , Huang Yu , Yin Ping , Feng Yue , Cheng Shishi , Wang Jing , Dong Xiaorong 
Published: June 2022

e21158 Background: Brain metastasis (BM) is the first cause of poor prognosis in non-small cell lung cancer (NSCLC) patients. To date, localized whole-brain radiotherapy (WBRT) is still the therapeutic option for patients with extensive BM. However, effectiveness is currently unsatisfactory. This study aimed to investigate the effects of Rh-endostatin combined with WBRT on NSCLC patients with BMs. Methods: 43 NSCLC patients with BMs were divided into two groups randomly. Rh-endostatin combination group (n = 19) received WBRT combined with Rh-endostatin, and radiation group (n = 24) received WBRT alone. The primary endpoint of the study was progression free survival (PFS). The secondary endpoints were intracranial progression free survival (iPFS), overall survival (OS), objective response rate (ORR) and the change of cerebral blood volume (CBV), cerebral blood flow (CBF) of the contrast medium pre- and one month post-radiation. Results: Median progression-free survival (PFS) was 8.1 months in the Rh-endostatin combination group versus 4.9 months in the radiation group (95%CI: 0.2612-0.9583, p= 0·0428). Besides, median iPFS was 11.6 months in Rh-endostatin combination group versus 4.8 months in the radiation group (95%CI：0.2530-0.9504, p= 0·0437). Overall survival (OS) was 14.2 months in the Rh-endostatin combination group versus 6.4 months in the radiation group (95%CI：0.2508-1.026, p= 0·0688). Compared with radiotherapy alone, CBV and CBF in the Rh-endostatin combination group increased more significantly than before radiotherapy, indicating that Rh-endostatin may improve local blood supply and microcirculation. Conclusions: Rh-endostatin showed better survival and a safety profile, improved cerebral perfusion and increased the quality of life of NSCLC patients with BMs. Clinical trial information: NCT03614065.
Real-world assessment of clinical outcomes in NSCLC patients with MET exon 14 skipping mutation and brain metastases (BM) treated with capmatinib.
Authors: Paik Paul K. , Goyal Ravi K. , Cai Beilei , Price Mark , Davis Keith , Derrien Ansquer Valerie , Caro Nydia , Saliba Teddy Rassem 
Published: June 2022

e21171 Background: Capmatinib, a highly selective and potent MET inhibitor, was approved for patients (pts) with advanced MET exon 14 NSCLC in the US in 2020 based on the GEOMETRY mono-1 trial data. Subgroup analyses from that study showed intracranial (IC) efficacy in pts with BM. However, there were no data on the effectiveness of capmatinib in pts with BM in the real-world setting; IC effectiveness is particularly challenging to study as many pts are also treated with radiation therapy (RT) to the brain. The current study examined real-world clinical outcomes of pts with NSCLC with MET exon 14 skipping mutation and BM who were treated with capmatinib, including those who were RT-naïve. Methods: A retrospective medical record review was performed by panel-based oncologists recruited nationwide in the US. Eligible pts were aged ≥ 18 years, had confirmed BM diagnosis and MET exon 14 skipping mutated NSCLC, started capmatinib therapy in any line following BM diagnosis (with ≥ 1 IC lesion ≥ 10 mm), and had a follow up of ≥ 6 months after starting capmatinib (except death). Modified (pseudo) RECIST and RANO-BM criteria were used for response assessments. Key outcomes were IC and systemic real-world best overall response rate (rwORR), disease control rate (rwDCR), progression-free survival (rwPFS), and time-to-treatment discontinuation (TTD) assessed separately for first-line (1L) capmatinib and immunotherapy (IO)-containing regimens alone or in combination with chemotherapy (CT). The analyses are descriptive in nature. Outcomes were also analyzed in RT-naïve pts (no prior/concurrent BM RT). Results: A total of 68 eligible pt charts were abstracted (median age at BM diagnosis, 64.3 years; 60.3% male; 72.1% treated in academic setting; 83.8% de novo metastatic). For the 1L therapy after BM diagnosis, 80.9% (n = 55) received capmatinib, 16.2% (n = 11) received IO-containing regimens, and 2.9% received CT alone; 29 pts were RT-naive. The IC rwORR in RT-naïve pts was 85.0% for capmatinib 1L and 11.1% for IO 1L (Table). In the overall cohort, the IC rwORR was 87.3% (rwDCR 96.4%) for capmatinib 1L and 27.3% (rwDCR 45.5%) for IO 1L. Median systemic rwPFS was 14.1 months for capmatinib 1L and 5.1 months for IO 1L. The 1-year systemic rwPFS rate was 70.8% for capmatinib 1L and 18.2% for IO 1L. TTD was 13.2 months for capmatinib 1L and 5.1 months IO 1L. Conclusions: This study shows a substantial systemic and IC effectiveness associated with capmatinib 1L use in pts with NSCLC with MET exon 14 and BM in the real-world setting. These findings remain true in RT-naïve pts.[Table: see text]
Overall survival of patients with chronic obstructive pulmonary disease receiving immunotherapy for non-small cell lung cancer: A population-based analysis in Ontario, Canada.
Authors: Chan Sze Wah Samuel , Goffin John R. , Pond Gregory Russell 
Published: June 2022

e21172 Background: Outside of clinical trial eligibility criteria, there is limited data to guide the selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) therapy. Chronic obstructive pulmonary disease (COPD) and lung cancer are associated, independent of smoking history, with a common background of chronic inflammation. Previous studies have demonstrated that COPD is a negative prognostic marker for NSCLC, but the clinical benefit of ICI in patients with NSCLC and COPD is unknown. Methods: A population-level administrative data analysis of Ontario patients was performed through the Institute of Clinical Evaluative Sciences (ICES) Data Analytic Services. All patients with NSCLC diagnosed between Jan 2010 and Dec 2020 and treated with immune-checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab) were included. Demographics, comorbidity and marginalization scores, and COPD status were extracted along with outcome information. Overall survival (OS) was estimated using the Kaplan-Meier method, and compared between patients with or without COPD using Cox proportional hazards regression. The frequency of patients requiring hospitalization and duration of treatment was also estimated and compared using the chi-square and Wilcoxon rank-sum test. Results: 73331 NSCLC patients were identified, of which 4.5% (n = 3285) patients received ICI. COPD patients were less likely to receive immunotherapy (3.8% vs. 5.1%, p < 0.001). Among those receiving an ICI, 41% (n = 1362) of patients had a diagnosis of COPD prior to NSCLC diagnosis. Median (95% CI) OS was 17.3 (16.6 to 18.2) months for patients with COPD and 16.9 (16.2 to 17.8) for patients with no known COPD, which was not significantly different in univariate (hazard ratio = 0.96, 95% CI = 0.89 to 1.04, p = 0.35) or multivariate analysis (HR = 0.96, 95% CI = 0.89 to 1.05, p = 0.40). The 5-year survival was also similar between both groups (6.7% vs. 6.5%). The rate of hospitalization within 6 months (18.4% vs 18.0%, p = 0.82) and the duration of immunotherapy treatment (median = 80 vs 71 days p = 0.23) did not differ for the COPD vs. non-COPD groups. Conclusions: Despite an expectation of frailty, our data suggest that NSCLC patients with COPD receiving ICI maintained similar durations of treatment and similar rates of hospitalization, with no significant difference in survival time, compared with those without COPD. While a treatment selection bias cannot be excluded in this non-randomized dataset, our data suggest that a diagnosis of COPD itself should not be considered a contraindication to immune checkpoint inhibitor use in NSCLC.
LAG3-PD1 or CTLA4-PD1 inhibition in advanced melanoma: Indirect cross comparisons of the CheckMate-067 and relativity-047 trials.
Authors: Nie Run-Cong , Wang Yun , Yuan Shu-Qiang , Chen Yingbo , Zhou Zhiwei 
Published: June 2022

e21511 Background: There remain unmet needs to identify novel immune checkpoint inhibitors to improve the benefit-risk profile of immunotherapy for advanced melanoma. The comparison between LAG3-PD1 inhibition and CTLA4-PD1 inhibition was lacked. To compare the inhibition of lymphocyte-activation gene 3 (LAG3) plus programmed cell death 1 (PD-1) versus the inhibition of cytotoxic T-lymphocyte antigen 4 (CTLA-4) plus PD-1 in patients with previously untreated advanced melanoma. Methods: The individual participant data (IPD) data were extracted from the KM plots using a graphical reconstructive algorithm through eligible. Log-rank, Cox proportional hazard model, Bayesian hierarchical model with time-varying hazard ratio (HR) effect, and restricted mean survival time (RMST) were performed to estimate survival benefits. The primary endpoint was progression-free survival. Results: The CheckMate-067 (N = 630) and RELATIVITY-047 (N = 714) trials were included for analysis. The graphical reconstructive algorithm showed that IPD had similar HRs and log-rank values as the original plots. The HR of nivolumab-relatlimab (LAG3 inhibitor) versus nivolumab-ipilimumab (CTLA4 inhibitor) was 1.19 (95% confidence interval [CI] 0.96 to1.48). The 24-months RMST of nivolumab-relatlimab versus nivolumab alone was 2.35 (95% CI 0.77 to 3.94) months, compared with 1.87 (95% CI 0.25-3.49) months for nivolumab-ipilimumab versus nivolumab. The Bayesian hierarchical model showed that patients treated with nivolumab-relatlimab had earlier PFS benefits than those with nivolumab-ipilimumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients using nivolumab-relatlimab and 55.0% of patients using nivolumab-ipilimumab. Conclusions: These findings suggest that the PFS of LAG3-PD1 and CTLA4-PD1 inhibition were similar and that LAG3-PD1 inhibition tended to exhibit earlier survival benefit and lesser TRAEs.
The role of surgery (metastasectomy) in advanced BRAF positive melanoma during modern therapy.
Authors: Orlova Kristina V. , Ledin Evgeny , Zhukova Natalia V. , Orlova Rashida , Protsenko Svetlana , Novik Alexey , Moiseenko Fedor Vladimirovich , Naskhletashvili David , Demidov Lev V. 
Published: June 2022

e21512 Background: Improved overall survival in patients undergoing metаstasectomy for melanoma have been reported in several retrospective studies before era of modern therapy in melanoma. Rapid progress in BRAF and MEK targeted therapy (TT) and immunotherapy (IT) has led to significant improvements in objective response rates and survival rates in advanced melanoma patients. Unfortunately, part of patients have a resistance to modern therapy in one or more lesions. In 2019 Nelson DW et al published data when surgery followed by modern therapy in 47 matched pairs was associated with higher 5-year melanoma-specific survival (MSS) versus modern therapy alone (58.8% vs. 38.9%, p = 0.049). But data about modern therapy in BRAF + advanced melanoma with metastasectomy during therapy are limited. Methods: We conducted an observational retrospective chart review study and evaluated a subset of patients which underwent surgery (metastasectomy) with V600 BRAF-mutant advanced melanoma, who received therapy in a real-world setting in Russia. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Results: The observed population included 382 patients in Russia. The date of the first enrollment after all approvals was 8 October 2018, and the date of the last completed register was 27 April 2019. Among 382 patients, 107 (28%) patients received surgical treatment for advanced melanoma during modern therapy (removal of metastases from the brain, lungs, soft tissues and other organs). Surgery during first line therapy was performed in 60pts (56%), as second – in 25pts (23.4%) and third or higher line in 22pts (20.6%). Comparison of overall survival curves for all patients depending on the surgical treatment showed that the survival in the subgroup of patients with the presence of surgical treatment was higher than among patients who did not undergo metastasectomy: 24-months OS was 76.7 (95%CI, 65.6 – 84.6) and 53.7% (95%CI, 46.4-60.4), p = 0,0027). Conclusions: Our findings suggest that resection of distant metastases associated with improved overall survival despite all limitations in retrospective nature of the study. While modern systemic therapy have improved outcomes in advanced melanoma, metastasectomy remains associated with favorable survival. Surgery have to be a part of multidisciplinary care for patients with advanced melanoma.
A phase Ia/Ib study evaluating the safety and efficacy of intratumorally administrated OH2, an oncolytic herpes simplex virus 2, in unresected stage IIIC to IV melanoma patients.
Authors: Wang Xuan , Cui Chuanliang , Lian Bin , Si Lu , Chi Zhihong , Sheng Xinan , Kong Yan , Hu Han , Gu Xiangyong , Li Caili , Mao Lili , Bai Xue , Tang Bixia , Yan Xieqiao , Li Siming , Zhou Li , Liu Binlei , Guo Jun 
Published: June 2022

e21537 Background: OH2 is a herpes simplex virus type 2-derived oncolytic virus. It was engineered to selectively replicate within tumors and express granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance tumor-specific immune responses. We conducted a phase Ia/Ib clinical trial to evaluate the safety and preliminary efficacy in unresected stage IIIC to IV melanoma patients (pts). Methods: In this phase Ia/Ib trial, we enrolled pts aged between 18-75 with histologically confirmed unresectable stage III or distant metastatic melanoma failed with prior therapies. In phase Ia, nine pts were in the single-dose group, where 3 dose levels (106, 107, and 108 CCID50/mL) of OH2 were assessed. And six pts were in the multi-dose group testing multiple administration regimens. The recommended doses were then expanded in phase Ib. The primary objective was the safety and tolerability of OH2 injection as defined by the dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in phase Ia. Antitumor activity was assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase Ib. The clinical trial information: NCT04386967. Results: 35 pts were enrolled between November, 2018 and December, 2021. Among this, 37.1% were stageIVM1b-M1c; 88.6% had received of previous treatments: In the phase Ia study, OH2 was well-tolerated, neither serious AEs (SAEs) nor death were reported. No patient experienced TEAE leading to early withdrawal. Most TRAEs were Grade 1 in severity. There were no Grade 3 or above TRAEs. No DLTs were recorded, and the most frequent TRAEs were pyrexia (80%), Skin depigmentation (26.7), Oedema peripheral (26.7%), which were similar in three different doses of the single-dose group. The one-year survival rate was 93.3 % with median overall survival (mOS) being 20.8 months (still ongoing). In the phase Ib study, five pts achieved immune-partial response/partial response. The overall response rate (ORR) was 25.0 % and the five pts had ongoing responses. Six pts experienced stable disease (SD) with a disease control rate (DCR) being 55 %. The durable response rate (partial or complete response for ≥ 6 months) was 60 %. There were seven III-IV1a pts prior treated with anti-PD-1 antibodies. Three of the seven pts achieved iPR/PR (42.9 %), with DCR being 85.7 %. Conclusions: OH2 oncolytic virotherapy showed a favorable safety profile with no DLTs. And exhibited durable antitumor activity in pts. It warrants further investigation for the treatment of pts with unresectable melanoma. Clinical trial information: NCT04386967.