bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-omics analysis uncovers prognostic biomarkers and tumor ecosystem dynamics during sequential neoadjuvant treatment of dose-limiting chemotherapy combined with sintilimab for non-small cell lung cancer.
Authors: Yang Bo , Song Qi , Li Jie , Xiong Qi , Liang Chaoyang , Zhou Wenhao , Luo Haitao
Published: June 2022

e20564

Background: Patients with non-small cell lung cancer (NSCLC) can benefit from the treatment of preoperative neoadjuvant chemotherapy combined with immunotherapy. However, the selection in concurrent or sequential neoadjuvant treatment is still controversial. Therefore, the effective form of sequential neoadjuvant treatment as well as predictive biomarkers are still need to be further investigated. Methods: We carried out a multi-omics study on 12 enrolled NSCLC patients who received sequential neoadjuvant and adjuvant treatments. The responses to therapy were rigorously evaluated. Biopsies pre and post neoadjuvant therapy were performed with whole-exome sequencing, transcriptome sequencing. Plasma at the different timepoints during therapy were collected and sequenced with TCR sequencing and ctDNA sequencing. Results: After neoadjuvant therapy, 10 were major pathological responses (MPR) and 2 were non major pathological responses (non-MPR). The analysis of TCR sequencing showed that high diversity along with the increase of dominance of T-cell receptor repertoire were observed after chemotherapy. At baseline, tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were higher in MPR group when compared with non-MPR group. Furthermore, tumor infiltrating CD8+ naïve T cells, Tregs and monocytes were associated with clinical benefit and patients with high ratio of CD8+ naïve T cells and monocytes have better pathological response. Conclusions: In this study, sequential neoadjuvant treatment of dose-limiting chemotherapy combined with sintilimab showed a promising antitumor activity in patients with resectable NSCLC. The changes of genomic, transcriptome and TCR repertoire were comprehensively analyzed and correlated with clinical outcomes. TMB, TNB and TCR repertoire are associated with the clinical benefit. The sequential therapy would also impact the immune microenvironment. These result indicate that sequential neoadjuvant treatment of chemotherapy combined with immunotherapy could be a potential treatment for a defined group of patients with NSCLC.
Retrospective study to examine prognostic value of c-reactive protein (CRP) in patients with surgically resected non-small-cell lung cancer (NSCLC).
Authors: Azzoli Christopher G. , Huynh Lynn , Yi Denise , Cai Beilei , Duh Mei Sheng
Published: June 2022

e20569

Background: This study evaluated the association between baseline elevated CRP and lung cancer outcomes among adults with NSCLC who underwent surgery in the US. Methods: Optum Clinformatics Data Mart in the US (01/2007-09/2020) was used to identify adults with NSCLC who underwent lung cancer surgery and had at least 1 CRP measurement prior to or > 1 month following the index surgery. Baseline CRP levels were defined as the CRP closest to the index surgery in the pre-surgery cohort, and the CRP at least 1-month after in the post-surgery cohort. The association between elevated CRP (> 10 mg/L) and rate of NSCLC recurrence/risk of death was assessed separately for pre-surgery and post-surgery cohorts using multivariate regressions. The overall trend in CRP measurements over a 5-year period was examined using trend tests among those with persistently elevated CRP. Results: For adults in the pre-surgery cohort who had index lung cancer surgery between 2016-2020 (N = 104), after adjusting for age, sex, National Cancer Institute comorbidity, autoimmune disease, peripheral vascular disease, and smoking status, the adjusted-incidence rate ratio (IRR) for NSCLC recurrence was 2.17 (95% confidence interval [CI]: 1.03, 4.60; p < 0.05) among patients with elevated CRP compared with non-elevated CRP. A similar IRR (2.22 [95% CI: 1.05, 4.70]; p < 0.05) was observed among the 264 patients in the post-surgery cohort. Among the 234 patients in the pre-surgery cohort, there was a near two-fold increase in the risk of all-cause death associated with the elevated than the non-elevated CRP groups (odds ratio [OR]: 1.91 [95% CI: 1.06, 3.42]; p < 0.05), and there was a numerically increased risk associated with elevated baseline CRP for the post-surgery cohort (OR: 1.62 [95% CI: 0.88, 2.97]; p = 0.12). Among those with persistently elevated CRP prior to surgery, we observed a significant overall trend of increased CRP levels over the 5-year period. Conclusions: Using real world data in the US, results suggest that an elevated CRP at baseline is associated with a higher risk of NSCLC recurrence and mortality, for both pre- and post-surgery cohorts. An increasing trend of CRP level within 5 years prior to lung cancer surgery indicates the correlation of CRP (as a marker of inflammation) with tumor development. This study adds to a growing body of literature and may shed light into oncology treatments aimed at suppressing tumor-promoting inflammation.
Absence of CD4+ and CD8+ T cell expansion after primary multimodal treatment predicts early progression in inoperable stage III NSCLC.
Authors: Hofer Thomas Philipp , Nieto Alexander , Käsmann Lukas , Taugner Julian , Pelikan Carolyn , Katanov Dinar , Eze Chukwuka , Guggenberger Julian , Belka Claus , Noessner Elfriede , Manapov Farkhad
Published: June 2022

e20590

Background: There are no blood-based biomarkers for survival prediction in inoperable stage III NSCLC patients. We propose a method for calculation of novel area under curve (AUC) biomarkers of the dynamic change of multiple leukocyte subpopulations before, during, and after thoracic irradiation (TRT), chemoradiotherapy (CRT), and chemo-radio-immunotherapy (CRT-ICI) in this patient cohort. The extracted biomarkers identify patients with early progression after TRT. Methods: 20 patients (17 male, 3 female), at median age of 65.5 years (range 34 to 79) were enrolled in the study. The median follow-up time was 60 weeks. Eleven patients suffered from adenocarcinoma, 8 squamous cell carcinoma, and 1 undifferentiated NSCLC. They received TRT (2/20, 10%), CRT (11/20, 55%), or CRT-ICI (7/20, 35%). One patient (1/20, 5%) withdrew consent and was excluded from analysis. Primary endpoints were progression free survival (PFS) at 6 and 12 months. Patient blood was analyzed via flow cytometry for 7 circulating leukocyte populations at baseline, twice during radiotherapy, at the end of radiotherapy (RTend), and 10, 20, 35, 48, and 60 weeks after enrollment. We analyzed CD3+ total T cells, CD4+ T cells, CD8+ T cells, CD19+/CD20+ B cells, CD3-CD56+ NK cells, CD56 bright NK cells, and CD56 dim NK cells. Here, we report on CD4+ and CD8+ T cells. The AUC from RTend to zenith of absolute cell counts provided aggregate measures for the time-course data. We performed hierarchical clustering and cluster characterization. Relevant features were selected by stepwise drop-out. Results: Clustering of the AUC between RTend and zenith for CD4+ T cells and CD8+ T cells delineated two prognostic groups. The favorable group was characterized by higher AUC values for CD4+ and CD8+ T cells compared to the unfavorable group. All patients (9/9, 100%) in the favorable group versus 36.4% (4/11) patients in the unfavorable group were progression-free at 6 months (Fisher´s exact test, two-tailed: p-value = 0.00472). This effect was observed as a trend with PFS at 12 months. Here 66.6% (6/9) of patients had PFS at 12 months in the favorable group versus 27.3% (3/11) in the unfavorable group (Fisher´s exact test, two-tailed: p-value = 0.175). There is a directly proportional relationship of the reported AUC values to PFS at 6 months and 12 months. Conclusions: Patients who responded with T cell expansion after immunogenic cell death by TRT, CRT, or CRT-ICI had significantly longer PFS compared to those without increase. Longitudinal monitoring of CD4+ and CD8+ T cells and the AUC from RTend to zenith is a promising biomarker for detecting early progression in the present study which is the subject of validation in an ongoing prospective study (PRECISION, NCT05027165).
Characterizing platinum sensitivity among Medicare FFS patients with limited versus extensive-stage small cell lung cancer receiving NCCN category 1 preferred regimens.
Authors: Cockrum Paul , Dieguez Gabriela , Smith Rebecca A. , Ramirez Robert A.
Published: June 2022

e20601

Background: There is limited research evaluating real-world platinum sensitivity and treatment patterns among patients with limited vs. extensive stage small cell lung cancer (SCLC). Methods: We identified patients with SCLC in 2017 using ICD-10 diagnosis (Dx) and drug codes in the 2016-20 Medicare Parts A/B/D 100% Research Identifiable Files. Patients had 1+ lung cancer Dx and continuous enrollment in Parts A/B/D from the month prior to first Dx in 2017 (index) through 2020 or death. Patients with evidence of end-stage renal disease, prior lung or any metastatic cancer Dx within 12 months of index, lung resection/lobectomy, or use of a drug indicated only for non-SCLC or lung neuroendocrine cancer per NCCN guidelines were excluded. Use of systemic therapies cisplatin (ci), carboplatin (ca), etoposide intravenous (etIV), atezolizumab (at), durvalumab (du) and irinotecan (ir) were observed. Patients included in our study were treated with first-line NCCN Category 1 preferred regimens: ca/etIV, ca/etIV/at, ca/etIV/du, ca/ir, ci/etIV, ci/etIV/du, or ci/ir. First line of therapy (LoT1) was defined based on the first claim for a first-line regimen administered within 90 days following or up to 14 days before index. The end of LoT1 was defined as the earliest of death, 32 days after the last administration, or the start of a second line of therapy (LoT2). Patients initially treated with ca/etIV/at, ca/etIV/du, ca/ir, ci/etIV/du, or ci/ir regimens were flagged with extensive stage disease. Patients not receiving these regimens were classified as limited stage disease if they had 15+ days of radiation therapy over a 6-week period during or within 60 days of LoT1. Patients were deemed platinum sensitive (PS) if we did not observe a LoT2, hospice, or death within 6 months of LoT1. Uncategorizable patients were flagged Status Unknown (SU). All other patients were deemed platinum refractory (PR). Results: We identified 3,772 SCLC patients receiving NCCN Category 1 preferred regimens: 43% (1,607) had limited stage, and 57% (2,165) had extensive stage at index. Among patients with extensive stage, 71% (1,541) were PR compared with 34% (548) of patients with limited stage. On average, patients with extensive stage had fewer platinum cycles in LoT1 than those with limited stage. Conclusions: More platinum refractory patterns were observed among Medicare FFS patients with extensive stage SCLC than among patients with limited stage SCLC. Patients with extensive stage SCLC also underwent fewer platinum cycles in their first line of therapy.[Table: see text]
Peripheral blood mononuclear cells (PBMCs), an ideal liquid biopsy approach to evaluate systematic immunity and predict response of neoadjuvant chemo-immunotherapy in resectable NSCLC.
Authors: Zhang Lei , Hou Likun , Wu Junqi , Li Chongwu , Hu Tao , Zhu Changbin , Wu Chunyan , Chen Chang
Published: June 2022

e20618

Background: Immune checkpoint inhibitors (ICIs) dramatically improved clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC). However, ICIs are not the scenario of “One-size fits to all”. It is of great importance to explore biomarkers, especially via liquid biopsy-based approach, to predict or monitor treatment response. Besides comprehensive genomic profiling of primary tumor tissue, this study focused on gene expression profile of PBMCs at baseline as well as one week post 1st immunotherapy administration, and its association with major pathological response (MPR) of neoadjuvant chem-immunotherapy in resectable NSCLC patients. Methods: Pre-treatment tumor biopsies and PBMC at baseline (D0) and 7 days after neoadjuvant chem-immunotherapy (D7) were collected from 27 patients with stage IB-IIIB NSCLC from two prospective clinical trials (NCT04422392 and NCT04762030) between Aug 2019 and July 2021. Tumor biopsies were subjected for comprehensive genomic profiling by an NGS panel covering 571 cancer related genes, and RNA from PBMC was subjected to an RNA sequencing panel covering transcripts of 2660 genes. (Amoy Diagnostics, Xiamen, China). Single sample gene set enrichment analysis (ssGSEA) was used to assess enrichment of inflammatory-related gene sets. CIBERSORT and in-housed established DAISM-DNN algorithm were applied to estimate immune cell populations from PBMC-derived gene expression profile. Results: Patients received chemo-immunotherapy achieved 59.3% of MPR. Stronger signatures including effector T cell and IFN-γ/Effector T-cell were significantly enriched in baseline PBMC samples in MPR patients (p = 0.028, p = 0.042 respectively). In parallel, significant increasing Naïve CD8 positive T cells was observed in PBMC at D7 in MPR patients by both CIBERSORT (p = 0.047) and DAISM-DNN algorithm (p = 0.018). Interestingly, at D7, signature of M0 macrophage was enriched in PBMC from patients with non-MPR. In addition, comprehensive genomic profiling indicated a numerically higher level of tumor mutation burden (TMB) in pretreatment tumor samples in MPR patients (Median TMB, MPR 11.51 mut/Mb vs Non-MPR 7.19 mut/Mb, p = 0.074). Conclusions: Expression profile of baseline PBMC as well as dynamics of PBMC profile in a short period (7 days) may predict the clinical efficacy of neoadjuvant chemo-immunotherapy. More patients are being enrolled into this study. Moreover, to validate these findings, large-scale and prospective investigations are warranted. Clinical trial information: NCT04422392 and NCT04762030.
Efficacy of anlotinib for advanced SCLC patients: A real-world study.
Authors: Yao Yu , He Xiaopeng , Hou Xinli , Liao Hehe
Published: June 2022

e20621

Background: Anlotinib is a novel small molecule multi-target tyrosine kinase inhibitor, which has been approved as a third-line therapy for patients with advanced small cell lung cancer (SCLC) by NMPA in Aug 2019. ALTER 1202 trial has demonstrated that anlotinib significantly prolonged progress-free survival (PFS) and improved disease control rate (DCR) of advanced SCLC patients. Since the efficacy of patients in real clinical practice is affected by many factors, the objective of this study was to assess the efficacy of anlotinib for patients with advanced SCLC in real world. Methods: This is a multi-center, non-interventional, prospective real-world study and all registered data are collected from real clinical practice cases. Patients diagnosed as advanced SCLC and treated with anlotinib were included. The primary endpoint was PFS, and secondary endpoints included overall survival (OS), objective response rate (ORR), DCR and safety. Results: Until Dec 2021, a total of 44 eligible patients were included, with a median age of 62 years, including 34 males (77.3%) and 10 females (22.7%). Among them, 38 patients (86.4%) were diagnosed as a limited stage SCLC and 6 patients (13.6%) diagnosed extensive stage. All patients have not received other targeted therapies before. The median PFS was 6.0 months (95%CI 2.4-5.8), and the median OS was 15.9 months (95%CI 9.1-18.83). At the data cut-off date, 1 patient was assessed as CR, 22 patients were assessed as PR, 15 patients were assessed as SD and 4 patients were assessed as PD. The ORR was 52.3% and the DCR was 86.4%. Conclusions: Significant improvement in OS and PFS were found for advanced SCLC patients in this real-world study. This exhibited that anlotinib has a potential efficacy over previous treatment models. Of course, safety must be further observed subsequently.
MET kinase mutations in lung cancer patients.
Authors: Kalmuk Louise , Descarpentries Clotilde , Mascaux Celine , Munck Camille , Kherrouche Zoulika , Wasielewski Eric , Ulmer Lucie , Farchi Olivier , Escande Fabienne , Beau-Faller Michele , Cortot Alexis B
Published: June 2022

e21014

Background: Although mutations in the kinase domain of MET are well described in papillary renal cell carcinoma, they are rare and poorly studied in lung cancer, but could constitute a new therapeutic target given the availability of potent MET inhibitors. The characteristics of patients with MET kinase mutation in lung cancer are still unknown. Our objective was to describe the demographic, clinical and biological characteristics of these patients, and analyze their survival. Methods: We conducted a multicenter retrospective study including patients with lung cancer harboring a MET kinase mutation. Patients who had already received treatment with a MET TKI before the MET kinase mutation was found were excluded. Results: We identified 37 patients with a MET kinase mutation. Among them, 2 had already received a MET inhibitor and in 8 cases, the data were not accessible. A total of 27 patients were included in the final analysis, including 17 males (63%) and only 2 (8%) never smokers. The median age was 64 (range 43-86). Most patients had adenocarcinoma (n = 25, 93%). 19 patients were diagnosed at an advanced stage. The main metastatic sites were brain (n = 8, 42%), bones (n = 7, 37%) and lungs (n = 5, 19%). PDL1 expression level was available for 21 patients, and was < 1%, 1-49% and ≥50% in 4 (19%), 5 (24%) and 12 (57%) patients respectively. MET kinase mutations involved exon 15, 16, 17, 18 or 19 in 6 (22%), 7 (26%), 7 (26%), 3 (11%) and 4 (15%) patients respectively. The 2 most common mutations were H1112Y (4 patients) and H1097R (3 patients). 18 patients (67%) had a concurrent alteration by NGS including TP53 mutations (n = 11, 41%), KRAS mutations (n = 6, 22%) and NRAS mutations (n = 3, 11%). Overall, co-alterations involving known driver oncogenes were detected in 13 patients (48%). 19 patients received a first-line systemic treatment for advanced disease. Median progression-free survival with chemotherapy and immunotherapy was 10.5 and 6.4 months, respectively (p = 0.55). Median overall survival was 12.2 months. No patient received a MET inhibitor. Conclusions: MET kinase mutations are not associated with specific clinical characteristics and frequently occur together with other oncogene mutations. These results suggest that these mutations may not be sufficient to drive carcinogenesis by themselves.
Molecular characteristics and treatment strategy in advanced, EGFR-mutant non-small cell lung cancer with concomitant BRAF variations.
Authors: Wei Xue-Wu , Deng Jia-Yi , Xu Chongrui , Chen Zhihong , Zhu Dongqin , Wu Qian , Zhang Xuchao , Shao Yang , Wu Yi-Long , Zhou Qing
Published: June 2022

e21021

Background: BRAF variants were reported resistant mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, concomitant somatic variations other than BRAF variants and efficacy of subsequent treatment remained unclear. Methods: From October 2016 to May 2020, advanced NSCLC patients who underwent next-generation sequencing and were detected with co-mutation of BRAF and EGFR activating mutations are retrospectively included. Since June 2020, EGFR-mutant patients with acquired BRAF V600E after progression from previous Osimertinib are prospectively arranged to explore efficacy of the EGFR-BRAF co-inhibition. Results: Fifty-eight patients were retrospectively identified and five patients were prospectively included. BRAF variants was acquired after a median time of 22.7 months from initial diagnosis. Variations of TP53, PIK3CA, RB1, MET, LRP1B, APC, CDKN2A, MYC, ERBB2 and SMAD4 were over 10%, which were enriched in cell cycle/p53 pathway, EGFR downstream and bypass pathway. Subsequently, median progression-free survival was 5.0 months for chemotherapy and 2.1 months for TKI treatment without targeting both EGFR and BRAF respectively (p = 0.019). Osimertinib plus vemurafenib (n = 4) or dabrafenib + trametinib (n = 1) was prospectively administrated in five patients. Median PFS was 7.8 months. Grade 3 rash was observed in one patient. Upon disease progression, activation of RAS signaling was observed. Conclusions: Variations of EGFR downstream or bypass pathway were also frequent in patient with co-mutation of EGFR and BRAF. Efficacy of subsequent TKI without targeting both EGFR and BRAF was inferior to chemotherapy. EGFR-BRAF co-inhibition showed improved efficacy. More treatment strategy should be explored in the future.
Clinicopathologic characteristics and outcomes for patients with KRAS G12D-mutant non-small cell lung cancer (NSCLC).
Authors: Cooper Alissa Jamie , Muzikansky Alona , Lennerz Jochen K , Mino-Kenudson Mari , Hung Yin P , Piotrowska Zofia , Dagogo-Jack Ibiayi , Sequist Lecia V. , Lin Jessica Jiyeong , Gainor Justin F. , Heist Rebecca Suk
Published: June 2022

e21024

Background: Co-occurring mutations in KRAS-mutant NSCLC are associated with discrete biological properties and modulate therapeutic susceptibilities. As G12D-specific inhibitors are expected to enter the clinic, we sought to define the clinicopathologic characteristics and outcomes of patients (pts) with KRAS G12D-mutant NSCLC. Methods: This was a retrospective single-institution study. Pts with NSCLC and KRAS G12D mutations detected by the Massachusetts General Hospital SNaPshot next-generation sequencing assay were identified. Clinical and pathologic characteristics, including co-mutation status and survival outcomes, were collected by chart review. Results: Among pts who underwent SNaPshot testing between May 2014 and August 2021, 665 had cancers that were positive for KRAS G12D, of whom 107 (16.1%) had NSCLC. Most common histology was adenocarcinoma (93, 86.9%). PD-L1 level was < 1% in 24 (22.4%), 1-49% in 19 (17.8%), > 50% in 13 (12.2%), and not assessed in 51 (47.7%). Co-occurring mutations were frequent: 17 NSCLCs had co-occurring STK11 mutations (15.9%), 36 (33.6%) TP53 mutations, and 11 (10.3%) SMARCA4 mutations, of which 2 were truncating. Genetic alterations were detected in a variety of other genes including in the RTK/RAS/MAPK (20, 18.7%), PI3K/AKT/mTOR (12, 11.2%), cell-cycle (17, 15.9%), and WNT (11, 10.3%) pathways. Among 58 tumors with KEAP1 mutation testing, 10 (17.2%) were positive. 75 (70.1%) pts had metastatic disease, including 51 pts who had metastatic disease at initial diagnosis. CNS metastases were present in 27 (36.0%) pts, including 14 pts with CNS metastases at initial diagnosis. Among the 57 pts with metastatic disease who received first-line therapy, 28 (49.1%) received platinum-based chemotherapy, 17 (29.8%) immunotherapy alone, and 12 (21.1%) platinum chemotherapy plus immunotherapy. Median PFS in pts treated with first-line therapy was 4.0 months (95% CI 2.1– 5.7) and median OS 14.3 months (95% CI 8.1 – 27.4). When stratified by co-mutation status, pts with STK11 mutations had significantly worse outcomes than STK11-wild-type (median PFS: 1.2 months vs 4.8 months, p = 0.0165; median OS: 4.3 months vs 21.6 months, p = 0.0015), whereas TP53 exerted no influence. Conclusions: Co-occurring mutations were common in pts with KRAS G12D-mutant NSCLC. Outcomes were poorer for KRAS G12D/ STK11 pts, whereas co-occurring TP53 did not impact survival. Clinical trials examining G12D inhibitors should stratify by STK11.
Treatment pattern and outcomes in patients with uncommon or compound EGFR mutations in India: CRSF 2020-03 study.
Authors: Avaronnan Manuprasad , Kothari Rushabh , Talele Avinash , Talreja Vikas , Goyal Gautam , Raut Nirmal Vivek , Karpe Ashay
Published: June 2022

e21034

Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resulted in significant improvement in the outcomes of patients with activating EGFR mutations. But the ideal treatment of patients harboring uncommon, or compound mutations is not well defined. This multicentric audit was conducted to study the distribution, treatment pattern, and outcomes of patients with uncommon or compound EGFR mutations. Methods: This was a multicentric retrospective study that included patients with uncommon (mutations other than Exon 19 deletions and Exon 21 L858R) or compound (double or complex) mutations treated during the period of 2017-2020. Statistical analysis was done using SPSS version 20.0. Descriptive statistics were used wherever appropriate. Kaplan Meier Aanlaysis was performed for estimation of PFS and OS. Results: Total 99 patients with uncommon or compound mutations were included in the study. The median age was 55 years (25-82 years). Majority were males (n=65,67%) and 47 (47%) were smokers. Sixty-seven patients (68 %) had a single uncommon mutation and the remaining 32 (32%) had compound mutations. Most common mutations were exon 20 insertion (n=34, 35%) and T790M (N=16,16%). Other frequent mutations observed were exon 18 G719X (n=7,7%) and exon 21 L861Q (n=3,3%). Twenty-three patients (n=23,23%) were eligible only for best supportive care. Thirty-two patients (32%) received first-generation TKI, 30 patients (30%) received palliative chemotherapy and 11 patients (11 %) received Osimertinib. Gefitinib with chemotherapy was used in 2 patients and combination of Gefitinib with Afatinib was used in one patient. Overall response rate and clinical benefit rate with first line treatment was 23% and 35% respectively. Response could not be assessed in 14 patients. Median PFS was 5 months (95% CI 3.4-6.9) and median OS was 8.3 months (95% CI 3.3- 13). In patients who received any form of systemic treatment, median PFS was 6.2 months (95% CI- 3.3-9.1) and OS was 11 months (95% CI -8.9-13.9). Conclusions: The most frequent uncommon mutations in India are exon 20 insertion followed by compound mutations and exon 20 T790M mutation. Outcomes of patients with these rare mutations are dismal in the real world setting with the available treatment options.
The impact of body mass index and serum albumin in patients with advanced-stage non-small cell lung cancer.
Authors: Bello Andreas , Makani Neeharika Srivastava
Published: June 2022

e21037

Background: Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Previous literature has evaluated associations between physical factors and outcomes in NSCLC. Throughout these studies, important physical factors that affect overall survival (OS) in NSCLC patients are body mass index (BMI) and serum albumin (SA) levels. In terms of BMI, previous research has come across the “obesity paradox.” That is, presenting an obese BMI serves as a protective role in patient survival. Hypoalbuminemia, defined as SA levels < 3.5 g/dL, has been shown to have a significantly adverse effect on both early and late stage patients’ outcomes. Our study aims to analyze the role of BMI and SA in patients with advanced-stage NSCLC. Methods: This retrospective study includes 112 patients with stage III and stage IV NSCLC identified between January 1st, 2014 through December 31st, 2018. Categorical and continuous analyses (Pearson’s chi-square and Kruskal-Wallis test) were performed to analyze the associations between median OS, BMI, and SA. BMI subgroups are classified according to the Center for Disease Control guidelines. BMI and SA are calculated at time of diagnosis. OS is defined as the date of diagnosis until the date of death. Other notable confounders investigated include treatment modality, histology, and comorbidities. Results: Of the 112 patients, 57% of patients identified as male. The study population mean age was 73 years. The majority (88%) of patients identified as white. The median BMI was 26.1, with 26% of patients presenting as obese. The median SA level of the population was 3.8 g/dL, with 34% of patients presenting as hypoalbuminemic. Study population median OS was 0.734 years. Median OS for the obese BMI subgroup was 1.42 years, compared to 0.70, 0.71, and 0.42 years for overweight, normal, and underweight BMI, respectively. Kruskal-Wallis analyses confirm that patient BMI plays a significant difference in terms of OS, with a significant subgroup difference between patients with obese and underweight BMIs (p = 0.05). Regarding SA, both chi-square and Kruskal-Wallis tests confirm that at the time of diagnosis, patients with normal SA have a longer median OS compared to their hypoalbuminemic counterparts (median OS 1.29 years vs 0.32 years, respectively; OR = 6.72, 95% CI [2.48, 18.22], p < 0.001). Conclusions: Our study reveals that an obese BMI plays a significant protective role regarding OS when evaluating prognostic outcomes between obese and underweight patients. Further, as SA levels are a known biomarker for nutritional status, our study highlights the importance of nutritional and educational optimization among healthcare professionals and patients alike prior to the diagnosis of malignancy. Future large prospective cohort studies are needed to analyze the efficacy of nutritional optimization, and further justify the “obesity paradox” and its underlying framework.
Evaluation of tumor gene expression profile (GEP) in minority patients with stage IV non-small cell lung cancer (NSCLC).
Authors: Villanueva Matthew , Uribe Carlos Carracedo , Brice Kayla , Dumais Katerine , Nano Olger , Rodriguez Mitchelle , Osmon Elizabeth , Raez Luis E.
Published: June 2022

e21043

Background: Differences in tumor gene expression profile (GEP) may contribute to disparities in lung cancer incidence and survival between racial and ethnic groups. For patients with stage IV NSCLC, tumor biomarker analysis is important for identification of potentially effective targeted therapies. However, despite advancements in biomarker testing and targeted therapy, minority patient enrollment in clinical trials remains low and it has been shown that minority patients are less likely to undergo next-generation sequencing (NGS) compared to Non-Hispanic Whites (NHW). As such, frequencies of tumor biomarkers in minority populations in the United States are not well-defined. This study aimed to determine the extent of tumor GEP diversity in minority patients vs NHW. Methods: This retrospective study included 196 adult patients with stage IV NSCLC that had a baseline NGS of tumor tissue or blood (liquid biopsy) performed between July 1, 2015 and June 30, 2021. Minority populations included Hispanic, African American, and Asian patients. Data collected utilizing the electronic medical record included patient demographics, detection of tumor biomarkers and treatment initiated. Descriptive statistics were calculated for all demographic and clinical variables. Comparisons of actionable epidermal growth factor receptor (EGFR) mutation frequency between NHW and minority patients were done using Chi-squared and Fisher’s exact tests. Results: Of the 196 patients evaluated, baseline characteristics included 46% male, 67% former smokers, 54% NHW, 31% Hispanic, 9% African American, 5% Asian, and 1% other. The median age at diagnosis was 66 ± 12 years. Actionable mutations (EGFR, KRAS, BRAF, ROS-1, ALK, MET, NTRK 1-3) were found in 50% of patients (see Table). The frequency of actionable EGFR mutations was higher in minority patients overall compared to NHW (39.3% vs 21.5%; p < 0.01). The frequency of actionable EGFR mutations was similar between NHW and Hispanic patients (21.5% vs 27.9%; p = 0.35), however differences were observed comparing NHW to African American (21.5% vs 50%; p = 0.02) and Asian (21.5% vs 90%; p < 0.01) patients, respectively. Conclusions: Among patients with stage IV NSCLC, the GEP of minority patients varied from that of NHW. Asian patients had the highest frequency of EGFR mutations, followed by African American and Hispanic patients, respectively. Larger studies are needed to validate these findings.[Table: see text]
Assessing effectiveness of first-line carboplatin, pemetrexed, and pembrolizumab in patients with recurrent/metastatic lung adenocarcinoma.
Authors: Ip Andrew , Gutierrez Martin , Warren Mary E. , Pfister David G. , Brady Owen , Shen Ronglai , Riely Gregory J.
Published: June 2022

e21045

Background: Randomized clinical trial data support the addition of immune checkpoint inhibitors to standard first-line platinum-doublet in patients with recurrent/metastatic non-small cell lung cancer. In the landmark KN189 Trial in which patients received carboplatin or cisplatin in combination with pemetrexed and pembrolizumab, the updated analysis (Gadgeel et al, JCO 2020) reported a median overall survival of 22 months. To explore the translation of this clinical trial-proven efficacy to clinical effectiveness in routine practice, we sought to explore patient outcomes with the combination of pemetrexed, carboplatin, and pembrolizumab as initial therapy for patients with recurrent or metastatic non-squamous non-small cell lung cancer. Methods: At two large, urban, academic medical centers (Hackensack University Medical Center and Memorial Sloan Kettering Cancer Center), we reviewed patient treatment data to identify all patient all patients with recurrent/metastatic non-squamous non-small cell lung cancer who received carboplatin, pemetrexed, and pembrolizumab as initial therapy for recurrent/metastatic NSCLC from June 2017 to December 2020. Patients with EGFR mutations or ALK gene fusions were excluded. From the medical record, we obtained baseline clinical characteristics, patient treatments and duration, as well as overall survival. Results: We identified 523 patients treated with carboplatin/pemetrexed/pembrolizumab, with 399 events occurring during the observation period. Baseline characteristics: 47% women and median age 66 (Interquartile range 59-72). The median overall survival from start of therapy was 11 months (95% confidence interval 9-12 months). Conclusions: In routine clinical practice, initiation of chemotherapy + immune checkpoint inhibitor as first-line therapy for patients with recurrent/metastatic NSCLC led to shorter median overall survival than reported in clinical trials. To further evaluate this finding, we will explore patient baseline characteristics including performance status, comorbidities, organ function as well as explore outcomes of a historical cohort of patients administered carboplatin and pemetrexed.
Prognostic effect of TP53 mutation combined with EGFR mutation or KRAS mutation on non-small cell lung cancer.
Authors: Li Ying , Jiang Da , Niu Xuhui , Zhou Xinliang , Hong Lei , Cui Yanzhi , Shi Ke , Jin Hui , Zhang Xue , Huang Fang , Song Wenya , Fan Shaoshuang , Deng Ruoying
Published: June 2022

e21046

Background: To explore the prognostic value of TP53 co-mutation with EGFR or KRAS in advanced non-small cell lung cancer. Methods: 314 patients with advanced non-small cell lung cancer (NSCLC) admitted to the Department of Oncology of the Fourth Hospital of Hebei Medical University from January 2016 to January 2021 were retrospectively analyzed, all with complete genetic information.According to the analysis results, EGFR and KRAS were identified as co-mutated genes.TP53 mutation was used as the experimental group and TP53 wild as the control group.Patients in TP53 mutation group were further classified and discussed according to different exon 4, 5, 6, 7, 8, other mutations and mutations could not be classified.Co-mutation group was studied according to TP53/KRAS mutation status, and according to KRASG12 mutation, Patients were divided into TP53/KRASG12C (wt/wt), TP53/KRASG12C (wt/mut), TP53/KRASG12C (mut/mut) and TP53/KRASG12C (mut/mut) for further grouping.In the study of TP53/EGFR co-mutation, TP53/EGFR mutation status was divided into groups, and subgroup analysis was conducted according to different TP53 exon mutations.SPSS 26.0 software was used to analyze the data, and P < 0.05 indicated statistical difference. Results: The frequency of single gene mutation in 314 patients was analyzed. The most common mutation was TP53 (64.3%), followed by EGFR (49.4%).TP53wt group compared with TP53mut group OS (34.3m vs 28.9m; HR = 1.263, 95% ci: 0.933 1.709;P = 0.131).The OS of Exon4 group was 23 months, Exon8 group was 44.5 months, and TP53wt group was 34.3 months, no statistical significance was observed (P = 0.159).In the TP53/KRAS co-mutation group, the median OS of KRAS/TP53 (mut/mut) group and KRAS/TP53 (wt/wt) group was 29.4m vs 34.3m; HR = 2.482, 95%Cl:1.378-4.471, P = 0.002).In subgroup analysis, the median OS of KRASG12Cmut/TP53mut group and KRASG12Cmut/TP53wt group were (8.9m vs 34.9m; HR = 38.268, 95%CL: 8.359-175.183, P = 0.199), (3.1m vs 34.3m; HR = 2.572, 95%Cl:1.344-4.922,P = 0.004).In the TP53/EGFR co-mutation group, the median OS of EGFRmut/TP53mut, EGFRwt/TP53mut, EGFRmut/TP53wt and EGFRwt/TP53wt were 32.9, 17.9, 42.7 and 31.2 months, respectively (P = 0.004).In subgroup analysis, the median OS of EGFRmut/ TP53Exon4-mut versus EGFRwt/TP53wt group was (25.8m vs 31.1m; HR = 2.909, 95%Cl: 1.438-5.886, P = 0.003). Conclusions: TP53 is a factor of poor prognosis in NSCLC patients, patients with TP53/KRAS co-mutation have poor survival, and kRASG12C-mut /TP53mut subgroup have worse prognosis.Patients with TP53/EGFR co-mutation had a better prognosis, and the EGFRmut/ TP53Exon4-mut subgroup had the worst prognosis.
The rate of venous thromboembolism in patients with non-small cell lung cancer treated with chemotherapy or check point inhibitors.
Authors: Singu Sriharsha , Bakalov Veli , Helfand Alexander M , Kancharla Pragnan , White Richard , Khattab Ahmed , Miller Katherine , Samhouri Yazan , Finley Gene Grant
Published: June 2022

e21053

Background: Treatment with immune checkpoint inhibitors (CPI) targeting PD-1 or PD-L1 significantly improves progression free survival and overall survival in patients with non-small cell lung cancer (NSCLC). Emerging literature suggests that the proinflammatory state of CPIs may increase the risk of thromboembolism, both venous (VTE) and arterial (ATE), which is of great concern as thromboembolism remains a major cause of mortality in patients with NSCLC. We performed a retrospective cohort study to evaluate thromboembolic outcomes in patients on immunotherapy for NSCLC. Methods: We reviewed the records of all patients diagnosed with stage IV NSCLC between December 2016 and December 2019 and treated with chemotherapy, CPIs, or both in one of the largest integrated academic health systems in Western Pennsylvania. Khorana scores (to predict the risk of future VTE) were calculated for each patient based on available data at the time of diagnosis. Logistic regression analyses were done to evaluate clinical predictors of VTE. Survival outcomes were analyzed using Kaplan-Meier estimates and a log rank test was used to compare survival estimates. Data was analyzed using SPSS v26 (IBM Corp). Results: A total of 110 patients with stage IV NSCLC were identified, 87.1% had ECOG ≤2, 67.0% had adenocarcinoma and 25.7% had squamous cell carcinoma, and 39.1% had PD-L1 staining ≥50%. Immunotherapy related adverse events (IrAE) of any grade were found in 28.2%. Overall, 25.5% received chemotherapy only, 27.7% received CPIs alone, and 45.5% received chemo + CPIs. A Khorana score of ≥2 was found in 43.6% of patients. Prophylactic anticoagulation was used in 0.9% of patients. VTE was detected in 18.3% and ATE in 10.0% of the cohort; therapeutic anticoagulation was given in 14.7% of patients. Median overall survival was 25.5 months (95% CI 18.7-32.3) in patients without VTE versus 13.7 months (95% CI 3.1-24.3) in patients with a VTE diagnosis (HR 1.96, 95% CI 1.11-3.45; p = 0.02). Khorana score of ≥2 was not a significant predictor of VTE in this cohort (univariate OR 1.34, p = 0.53, multivariate OR 1.13, p = 0.81), but was associated with worse survival (HR 2.38, 95% CI 1.48-3.83, p < 0.001). Conclusions: In this retrospective cohort, VTE was associated with decreased overall survival. While no significant association between elevated Khorana score and VTE was identified, elevated Khorana score at the time of diagnosis was an independent predictor of survival in patients with NSCLC. Of note, there was a low rate of prophylactic anticoagulation in this cohort.
Longitudinal sequencing of T cell receptor revealed radiotherapeutic efficacy and prognosis in non-small cell lung cancer patients with brain metastasis.
Authors: Dong Xiaorong , Tong Fan , Zeng Hao
Published: June 2022

e21056

Background: Liquid biopsy has played a unique role in long-term surveillance of brain metastasis in non-small cell lung cancer (NSCLC), due to the inaccessibility of solid metastatic biopsies. T cell-mediated immunity is critical in the oncogenesis and metastasis of NSCLC, and sequencing in T cell receptor (TCR) provides a robust method to quantify T cell diversity. Therefore, we aimed to explore the alteration of TCR through liquid biopsy before and after radiotherapy of NSCLC brain metastases. Methods: Thirty NSCLC patients with brain metastases receiving brain radiotherapy were enrolled in this study. Cerebrospinal fluid (CSF) and peripheral blood were collected at baseline, 24 hours (T0) and 28 days (T28) after treatment. TCR sequences were identified by high-throughput sequencing in both compartments. Results: At baseline, dimension reduction analysis identified distinct signatures of V and J gene recombination in blood and CSF TCR sequences. Throughout treatment, both compartments experienced a TCR diversity decrease, however, the degradation of low-abundance clones and the expansion of emerging clones might be two separate processes underwent in blood and CSF, respectively. Diversity changes in blood were possibly related to pulmonary responses, while the increase of maximal clone abundance in CSF might indicate a favorable intracranial response. Superior blood TCR diversity at T28 against baseline was associated with longer OS (HR = 5.700, p = 0.039). Patients with increase of maximal clone abundance ≥ 50 in CSF also had a better intracranial PFS (HR = 8.320, p = 0.011). The predictive effects of these markers were independent of other clinical factors in multivariate Cox analysis. Conclusions: CSF and peripheral blood were independent compartments showing disparate TCR signatures. Longitudinal surveillance of both compartments could be a promising method to predict clinical outcomes for NSCLC patients with brain metastases.
Anti-neoplastic drugs for malignant pleural effusion in non-small cell lung cancer: A meta-analysis.
Authors: Ababneh Obada Ehab , Syaj Sebawe , Ahmed Yaman Belal , Hatamleh Zaid , Saleh Sara , Zaitoun Alaa , Akhdar Marah , Alsaid Ahmad Mohammad , Al-shdaifat Raghad , Hamouri Shadi
Published: June 2022

e21060

Background: Malignant pleural effusion (MPE) occurs in 7-23% of advanced non-small cell lung cancer (NSCLC) patients with overall survival (OS) of 8.5 months only. The optimum anti-neoplastic regimen in MPE is yet to be determined. Thus, we conducted a meta-analysis to determine the optimum anti-neoplastic agent in managing MPE in NSCLC. Methods: We searched PubMed, Scopus, CENTRAL, ASCO, ESMO, and IASLC meetings libraries to retrieve relevant trials. We included single-arm and controlled trials in which patients with MPE were treated by anti-neoplastic drugs such as chemotherapy and/or targeted therapy. Patients treated with radiotherapy were excluded. Primary and secondary endpoints were efficacy and safety, respectively. Meta-analysis was conducted for the primary endpoint estimated by OS and objective response rate (ORR). In addition, subgroup analysis was conducted to investigate the effect of route of administration (ROA) and randomization on ORR. Results: We included 11 trials with a total of 542 patients. There were 5 randomized clinical trials, 5 phase II trials, and 1 phase I trial with a total of 16 relevant arms. Five arms used single-agent chemotherapy (SC), 11 combined therapy (CT) and 6 arms bevacizumab-based (BEVA) therapy. The ROA was intrapleural (IP) in 10 arms and intravenous (IV) in 6 arms. We pooled 124 patients from 5 trials that reported ORR results for SC patients. The pooled ORR was 41.7% (95% CI: 32.8 to 50.8%) with no heterogeneity ( I2 = 0%, p = 0.47). Pooling of 396 patients who underwent CT in 10 studies results in an ORR of 64.1% (95% CI: 52.7 to 74.8%) with a high heterogeneity rate ( I2 = 84%, p< 0.01). Analysis of BEVA studies yielded an ORR of 62.2% (95% CI: 43.5 to 79.2%), representing 133 patients from 5 trials. The table shows the effect of randomization and ROA on ORR. One-year OS was reported in 4 studies that used CT; pooled 1-year OS estimate for 216 patients was 81.2% (95% CI: 75.5 to 86.4%). As for grade 3/4 AEs, the occurrence of nausea/vomiting (N/V) was higher in CT than SC (14% vs 2%). Chest pain rate was similar (9.8% vs 7.0%), leukopenia was higher in BEVA than SC (19.1% vs 9.8%), and neutropenia was more prevalent in BEVA than CT (22.1% vs 8.1%). Incidence of any-grade N/V was more common in BEVA than SC (42.9% vs 19.3%). Conclusions: Both CT and BEVA-based regimens were effective and safe in treating MPE. IP was superior to IV in CC and BEVA based regimens. ORR was higher in randomized trials, suggesting a better response of MPE under optimum clinical conditions. Further trials of these agents are needed to confirm these results.[Table: see text]
Overall survival benefits of first-line treatments for Asian patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer harboring L858R mutation: A systematic review and network meta-analysis.
Authors: Chan Sik-Kwan , Choi Cheuk-Wai , Lee Victor Ho-Fun
Published: June 2022

e21064

Background: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and their biologically synergistic combinations with other treatments for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) as first-line treatment for EGFR-mutant NSCLC have recently gained considerable attention, in particular for those with L858R mutation, a known worse subgroup compared to exon 19 deletions. However, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with the L858R mutation remains unclear. Methods: We performed a systematic review and fixed-effects frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE Ovid, Embase, Cochrane Library, CINAHL Databases, trial registries and other sources. P-score was used to rank the treatments. We included published and gray sources of randomized clinical trials comparing two or more treatments in the first line setting for Asian patients with advanced EGFR mutated NSCLC harboring L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD42022295897). Results: Eighteen trials involved 1852 Asian patients and 12 treatments: including EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucizumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with the L858R mutation had no significant OS benefits from all EGFR TKIs or combination treatments over chemotherapies. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib and erlotinib plus bevacizumab were shown to be consistent in yielding the best progression-free survival benefit, with their corresponding P-scores of 93%, 79%, 77% and 70%. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, which caused the most adverse events of grade 3 or higher. Conclusions: In Asian patients with advanced NSCLC harboring L858R mutation, EGFR TKIs and combination treatments demonstrated no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with the L858R mutation.