bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic 18F-FDG Total body PET Imaging as a predictive marker of induction chemo-immunotherapy response in locally advanced non-small cell lung cancer.
Authors: Liu Hui , Qiu Bo , Wang DaQuan , Zhang Xu , Liu Hui , Zhou Yin , Li QiWen , Chu Chu , Liu FangJie , Chen NaiBin , Hu Nan , Ai XinLei , Guo JinYu , Fan Wei
Published: June 2021

e20551

Background: The purpose of this study was to evaluate the efficacy of dynamic 18F-FDG total body PET imaging as a predictive maker of induction chemo-immunotherapy response in locally advanced non-small cell lung cancer(NSCLC) by a prospective study. Methods: Stage IIIA-IIIC NSCLC patients were prospectively enrolled in a prospective total body PETCT study ( NCT04654234, GASTO-1067) and a randomized phase II clinical trial ( NCT04085250) between September 2020 and December 2020. All patients underwent a dynamic total-body 18F-FDG PET/CT scan before any treatment and after 2 cycles of induction chemo-immunotherapy (docetaxel+cisplatin+nivolumab). The primary lung tumor, metastatic regional lymph node and inflammatory lymph node before and after treatment were manually delineated by a nuclear medicine physician and a radiation oncologist. Total Body PET was acquired between 0 – 60 mins after the injection of FDG from the subject’s feet. Patients was separated into high dynamic FDG metabolic (H-DFM) group and low DFM(L-DFM) group by the scatter plot of SUV-mean and Ki-mean of primary lung tumor. We compared lesion heterogeneity and different image-derived PET metrics including the metabolic tumor volume(MTV), SUV total lesion glycolysis(SUV-TLG), Patlak-derived influx rate constant (Ki) TLG (Ki-TLG). Results: Fifteen patients were analyzed, 8 patients was in H-DFM group and 7 in L-DFM group. Patients in H-DFM group had significant decreased levels of MTV(p < 0.001), SUV-TLG(p < 0.001) and Ki-TLG(p < 0.001) both in primary lung tumor and metastatic lymph node by the induction chemo-immuotherapy. However, patients in L-DFM group only had a significant reduction of MTV in primary lung tumor(p < 0.05). There was no significant difference in the MTV of metastatic lymph node(p > 0.5), the SUV-TLG(p > 0.5) and Ki-TLG(p > 0.5) of primary lung tumor and metastatic lymph node, before and after induction chemo-radiotherapy. Conclusions: Patients in H-DFM group had the better treatment response of induction chemo-immunotherapy with significant decreased levels of MTV, SUV-TLG and Ki-TLG. Dynamic 18F-FDG Total body PET Imaging could be regard as a potential predictive marker of induction chemo-immunotherapy response in the setting of LA-NSCLC.
Cause of death among patients with non-small cell lung cancer treated with postoperative radiation therapy (PORT).
Authors: Singareddy Aashray , Waqar Saiama Naheed , Devarakonda Siddhartha , Ward Jeffrey P. , Govindan Ramaswamy , Robinson Clifford , Morgensztern Daniel , Samson Pamela Parker
Published: June 2021

e20555

Background: The indications for post-operative radiation therapy (PORT) in locally advanced non-small cell lung cancer (NSCLC) remain undefined and a major concern is the perceived risk of increased mortality from cardiopulmonary causes. The purpose of this study was to quantify the rate of cardiopulmonary death in patients with resected NSCLC receiving PORT using a large national database. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database for lung cancer, patients with Stage IIIA or Stage IIIB NSCLC according to the 6th AJCC edition treated with surgery followed by PORT, who also received chemotherapy were identified. Cause of death was categorized as due to lung cancer, other cancer, cardiac, pulmonary, or other and reported as a percentage of total deaths at one and 2 years. Kaplan-Meier survival analysis was done to compare overall survival between Stage IIIA and IIIB patients. Results: From 2004 to 2015, 4387 patients with stage IIIA and IIIB meeting the eligibility criteria were identified. The median age at diagnosis was 65 years old, most patients were male (53%), Caucasian (83%), had adenocarcinoma (54.8%), stage IIIA disease (69%), and N2 disease (78%). The median overall survival for Stage IIIA and IIIB patients was 39 months and 27 months respectively (p < 0.001). Among the 2586 patients that died during the study period, the most common COD was lung cancer (81.3%). Cardiac and pulmonary COD occurred in 86 patients (3.3% of deaths) and 84 patients (3.2% of deaths) respectively, whereas 158 patients (6.1%) died from other cancers and 154 (5.9%) from other causes. There were 77 deaths from cardiopulmonary cause at 2 years (1.7% of patients and 2.9% of deaths). Cardiopulmonary COD was more common in patients with stage IIIB compared to IIIA disease (4.9% vs 3.3% of deaths, p < 0.001). Lung cancer was the most common COD both at 1 and 2 years (85%) whereas cardiopulmonary was the COD in 5.2% of patients at 1 year and 5.1% at 2 years. Conclusions: This analysis showed a low cardiopulmonary mortality from PORT in the first 2 years. The role for adjuvant radiotherapy remains undefined and treatment decisions for patients with resected stage III NSCLC should be guided by co-morbidities and the competing risk for death from lung cancer.
Differential role of residual metabolic tumor volume in patients with inoperable stage III NSCLC after chemoradiotherapy ± immune checkpoint inhibition.
Authors: Unterrainer Marcus , Taugner Julian , Käsmann Lukas , Eze Chukwuka , Kunz Wolfgang G. , Tufman Amanda , Reinmuth Niels , Belka Claus , Manapov Farkhad
Published: June 2021

e20558

Background: PET-derived metabolic-tumor-volume (MTV) has shown to be an independent prognosticator in non-small cell lung cancer (NSCLC) patients treated with chemoradiotherapy (CRT). We analysed the prognostic value of residual MTV after completion of thoracic irradiation (TRT) in inoperable stage III NSCLC patients treated with CRT with and without immune check-point inhibition (ICI). Methods: Fifty-six inoperable stage III NSCLC patients (16 female, median age: 65 years) underwent 18F-FDG PET/CT at the same institution before and after completion of CRT. MTV was delineated on 18F-FDG PET/CT using a standard threshold (hepatic SUVmean + 2 x standard-deviation). Patients were divided in volumetric subgroups using median split dichotomization (residual MTV ≤4.0 ml & > 4.0 ml). Residual MTV, clinical features and ICI maintenance (RCT-IO; 21/56 (37.5%) patients) were correlated with clinical outcome (progression-free survival (PFS), local PFS (LPFS), metastasis-free survival (MFS), and overall survival (OS). Results: Median follow-up was 52.0 months. 52 (93%) patients were treated with CRT, 12 (21%) patients with CRT followed by durvalumab, and 9 (16%) patients treated with CRT plus nivolumab (concurrent and sequential). In the entire cohort, smaller residual MTV was associated with longer PFS (median 29.3 vs. 10.5 months, p = 0.015); PFS in patients treated with CRT and ICI was also significantly longer compared to the CRT-only subgroup (median 29.3 vs. 11.2 months, p = 0.010). However, residual MTV was predictive for longer PFS in CRT-only (median 33.5 vs. 8.6 months, p = 0.001), but not in the CRT-ICI patients (p = 0.909). Analogously, patients with smaller MTV had a longer LPFS (median 49.9 vs. 16.3 months, p = 0.002); CRT-ICI patients showed a significantly longer LPFS compared to CRT-only patients (median not reached vs. 16.9 months, p = 0.016). Residual MTV remained a significant prognosticator for LPFS in the CRT-only (median 49.9 vs. 10.1 months, p = 0.01), but not in CRT-ICI patients (p = 0.291). Again, smaller residual MTV remained a significant prognosticator for OS in the CRT-only subgroup (median 63.0 vs. 16.3 months, p = 0.004), but not in CRT-ICI patients (p = 0.720). Even in patients with larger residual MTV, the application of ICI significantly improved OS compared to CRT-only subgroup (median not reached vs. 22.9 months, p = 0.004). Conclusions: Smaller residual MTV is associated with superior clinical outcome in inoperable stage III NSCLC, especially in patients undergoing CRT-only. In contrast, in patients undergoing concurrent or sequential consolidation clinical outcome was independent of residual MTV. Hence, even patients with extensive residual MTV might significantly profit from ICI consolidation.
Efficacy and safety of PD-1/PD-L1 antibody combined with chemotherapy as second-line or third-line treatment for metastatic small cell lung cancer.
Authors: Wang Jun , Yin Beibei , Guan Yaping , Feng Dongfeng
Published: June 2021

e20574

Background: For a small subset of patients, immune checkpoint blockade heralds a promising strategy for achieving disease control in small cell lung cancer (SCLC). Nivolumab or pembrolizumab monotherapy has been granted accelerated approval for treatment of patients with extensive-stage SCLC with disease progression after platinum-based chemotherapy and at least one other line of therapy. Moreover, Based on IMpower133 and CASPIAN data, addition of PD-L1 antibody such as atezolizumab or durvalumab to first-line platinum-based chemotherapy prolongs overall survival over chemotherapy alone. However, it remains exclusive that whether PD-1/PD-L1 antibody combined with chemotherapy is effective against extensive-stage SCLC when progressed on previous chemotherapy. Methods: We reviewed patients with extensive-stage SCLC who have failed in first-line or beyond chemotherapy and received PD-1/PD-L1 antibodies with chemotherapy in a single institute. The efficacy and safety were evaluated. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results: A total of 11 patients were included in this retrospective cohort study. The median age was 46 years (range from 29 to 62). Seven patients were male. Four were current or former smokers. Six received two prior therapies. Nine had previously received radiation therapy. PD-1 and PD-L1 inhibitors were administrated in 5 and 6 patients, respectively. No patient had a complete response. 2 patients had a partial response, and the objective response rate was 18.2%. 5 patients were evaluated as stable disease with a disease control rate of 63.6%. The median overall survival and progression-free survival was 3.0 months and 2.3 months, respectively. A patient with partial response had a long duration of response of 5.2 months. The most common grade 3 or 4 treatment-related were neutropenia, anemia, and decreased neutrophil count. Most immune-related adverse events were grade 1 or 2, with rash, pruritus and hypothyroidism being the most common, and 1 patient had grade 3 pneumonia. Conclusions: Immunotherapy plus chemotherapy could be beneficial for a subgroup of extensive-stage SCLC patients who have progressed after previous chemotherapy. Further prospective, randomized studies are warranted.
Small cell lung cancer: Real-world data from two institutions in Lebanon for patients receiving carboplatin etoposide or atezolizumab in first line of treatment.
Authors: Nasr Fadi , El Khoury Reem , Yehia Intissar , Diab Saada , Al Ghoche Ahmad , Nasr Lewis
Published: June 2021

e20578

Background: Small-cell lung cancer (SCLC), accounts for approximately 15% to 17% of all diagnosed lung cancers. It is an aggressive high-grade neuroendocrine carcinoma, diagnosed during advanced stages in the majority of patients. Despite the fact that first line treatment provides response rates of up to 80%, the majority of patients relapse within 6 months after completion of initial treatment. Few advances have been made in the management of recurrent disease and treatments patterns are poor and limited in each line of the disease. The aim of this study is to present real world data regards survival outcomes such as progression free survival and overall survival in SCLC patients receiving carboplatine etoposide or tecentriq carboplatin etoposide regimens as first line of treatment. Methods: This is a retrospective (descriptive) study on 56 patients aged ≥ 18 years and with confirmed histological SCLC. Patients with extensive stage of SCLC were enrolled in this cohort study from 2 health institutions in Lebanon from July 2007 to December 2019 and followed up until progression or death. Primary end points were overall survival (time from randomization to death from any cause) and progression free survival at 6 and 12 months (time from randomization to disease progression). Secondary endpoints included objective response rate and the duration of response. Exploratory analyses included the assessment of survival outcomes of each type of treatment according to liver and brain metastasis. Results: Overall, 56 SCLC patients, diagnosed between 2003 and 2019, were observed (age <65: (27.0%, 10 patients); ≥65 (73.0%, 41 patients)). Most often prescribed treatment were etoposide-carboplatyl (80.8%, 42 patients) and atezolizumab (19.2%10 patients). Regarding metastasis at diagnosis, liver and brain metastasis were respectively (26.8%, 11 patients) and (17.1%, 7 patients). 27patients (71.1%) were alive at 6 months without progressive disease and 13 patients (34.21 %) alive at 12 months without PD. Median progression free survival incidence since diagnosis was 8.8 months. Overall survival was 10.86 months. Objective response rate after first line was 84.2%. In a cox regression analysis, liver metastasis, brain metastasis, survival at 6 or 12 months without progressive disease did not decrease significantly PFS or OS since diagnosis. Conclusions: To our knowledge, this is the first real world clinical data on SCLC in Lebanon. This study showed limited treatment options and short survival outcomes with PFS= 8.8months and OS= 10.86 months respectively for carboplatin etoposide regimen and tecentriq carboplatin etoposide regimen. There is an essential needs for clinical comparative studies in real world practicing between treatments at each line, specially for novel treatment like atezolizumab that may present new hope and directions for SCLC.
Clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC.
Authors: Gu Linping , Zhang Bei , Zhang Ding , Jian Hong
Published: June 2021

e20588

Background: Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the resistance mechanism of EGFR tyrosine kinase inhibitors. However, the clinical course of transformed SCLC and the difference of genomic profiling between de novo SCLC patients and transformed SCLC patients are still poorly characterized. Methods: Patients from our hospital diagnosed with SCLC were enrolled retrospectively in this study, including de novo SCLC patients and SCLC patients transformed from EGFR-mutant lung adenocarcinomas. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples by next generation sequencing (NGS). In statistical analysis, fisher ‘exact test was used. All tests were bilateral, with P<0.05 indicating significant statistical difference. Results: In total, 16 patients with SCLC transformed from EGFR-mutant lung adenocarcinomas and 230 de novo SCLC patients were included in our study. Transformed SCLC patients were more in younger (p=0.007), female (p<0.001) and non-smokers (p<0.001) than de novo SCLC patients. In transformed SCLC patients, 12 patients (75%) occurred SCLC transformation within 2 years after the lung adenocarcinomas diagnosis. Median transformation time was 20 months. During the treatment of adenocarcinomas, the overall response rate (ORR) was 75% and the median progression-free survival was 12 months. After the initiation of SCLC therapy, the ORR of 1st line chemotherapy was 40%. For the genomic profiling, EGFR mutations, including exon 19 deletion (56%), L858R (38%), and others (6%), were detected. 11 patients with acquired resistance were received EGFR T790M test, 82% of patients had acquired EGFR T790M mutation. 11 patients after transformation to SCLC had NGS test, 100% maintained their founder EGFR mutation, and other recurrent mutations included TP53, RB1 and EGFR amplification. Compared with the genetic alterations in de novo SCLC patients, TP53 mutations were significantly decreased (p=0.006) while EGFR mutations were significantly elevated (p<0.001) in transformed SCLC patients. However, no significant difference on RB1, ALK and ROS1 mutations were observed. Interestingly, a 60-year-old woman in our transformed SCLC cohort harbored EGFR 19 del mutant at allele frequency of 50.39%，she received osimertinib plus epirubicin/cyclophosphamide as 1st line treatment and reached partial response, with survival of 4 years to date. Conclusions: We demonstrated the clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC and found one patient still benefited from EGFR-TKI. Our study suggested that SCLC patients with EGFR mutation who transformed from lung adenocarcinoma may be potential benefit population using EGFR inhibitors.
Omics guided small molecule inhibitor screen for the identification of therapeutic vulnerabilities in metastatic lung adenocarcinoma.
Authors: Morris Benjamin B. , Gray Lisa G. , Gentzler Ryan D. , Jones David Randolph , Mayo Marty W.
Published: June 2021

e21015

Background: Recent studies from our lab and others have demonstrated that double-strand DNA break accumulation, error-prone repair, and genomic instability are strongly linked to increased metastasis to distant organs. Our lab has shown that lung adenocarcinomas overexpressing the transcription factor MYBL2 display chronic replication stress, elevated error-prone repair, and widespread genomic instability. Importantly, this MYBL2-driven phenotype accounts for ̃21% of all lung adenocarcinomas and identifies aggressive disease enriched for metastases to brain, liver, and kidney. This study was performed to identify clinically actionable therapeutic vulnerabilities in MYBL2-driven metastatic lung adenocarcinoma. Methods: RNA-sequencing and proteomic data from the TCGA and ORIEN consortiums were mined to identify highly expressed druggable targets in MYBL2-driven lung adenocarcinomas. Identified targets were used to assemble a custom inhibitor library of 50 small molecules targeting DNA repair effectors, epigenetic factors, protein translation, kinase-signaling, autophagy, and post-translational modifications. Omics data from the Cancer Cell Line Encyclopedia was used to identify human cell line models (H1650 (pleura), H1568 (lymph node), H1299 (lymph node)) of MYBL2-driven metastatic disease. Inhibitors were tested at two doses, 5 uM and 500 nM, in triplicate, across replicate experiments. The PrestoBlue HS viability reagent was used to quantify cell viability in a 96 well plate format. The primary endpoint of this study was statistically significant cancer cell death, compared to vehicle controls. Results: Screen results demonstrated that, at nanomolar doses, inhibitors of protein translation have strong anti-tumor effects in MYBL2-driven disease. Interestingly, small molecules targeting EIF4G1 (SBI-0640756), ribosome biogenesis/RNA export (YM155), and rRNA synthesis (CX5461) were effective in inducing cell death while inhibitors blocking mTOR signaling, EIF2A phosphorylation, and EIF4F complex assembly were not. Bioinformatic analysis revealed that ̃60% of MYBL2-driven transcripts are dependent on EIF4G1 for translation. Importantly, effected transcripts include effectors controlling DNA repair, cell cycle coordination, and cell survival. Conclusions: Our data demonstrates that MYBL2-driven metastatic disease is uniquely sensitive to inhibitors of the protein translation machinery. Importantly, these inhibitors significantly outperform current standard-of-care agents cisplatin and pemetrexed. To our knowledge, our study is the first to demonstrate that blocking EIF4G1 effectively induces widespread cell death in metastatic lung adenocarcinoma models. Collectively, our work supports initiation of clinical trials testing the efficacy of SBI-0640756 in MYBL2-driven metastatic lung adenocarcinoma.
Costs of the immune check point inhibitors versus survival ratio in first-line non-small lung cancer, cost bundling proposal.
Authors: Guirgis Helmy M.
Published: June 2021

e21034

Background: Pembrolizumab (Pembro) demonstrated marked prolongation of 5-year overall survival (OS) in 1st-line advanced/metastatic (a/m)-non-small lung cancer (nsLC). Adjuvant Durvalumab (Durv), Atezolizumab/Bevacizumab (Atezo/Bev), Ipilimumab/Nivolumab (Ipi/Nivo) and Pembro-combination have since improved the outcome. Progress, however, came at high costs of the immune check point inhibitors (ICI). There is unmet need for cost-constraining policies. We purposed 1- Weigh costs of ICI vs outcome 2- Propose cost bundling at negotiable $450,000 - $550,000 thresholds, depending on the number of companies and drugs involved. Methods: OS, hazard ratio (HR) and survival ratio (SR), defined as (1.0-HR) were used. Chemo-drugs excluded, costs of ICI doses were calculated in US$. Results: Durv one-year costs in unresectable stage III were $130,956, OS gain 363 days and SR 0.47. Pembro one-year costs were $134,778, OS 474 and SR 0.37 in PD-L1 > 50%. At 5 years, costs were $673,890. Bundling negotiated at $450,000-$550,000 would save $123,112-$223,890. Costs of 35 cycles of Pembro-combination were $336,945, OS 339 and SR 0.51. Costs of Atezo/Biosimilar-Bev-comnination supplied by > one company, were $429,744, OS 135 and SR 0.22. Ipi/Nivo costs were $544,696, OS 141 and SR 0.34. Costs of Atezo/Bev and Nivo/Ipi used beyond 2 years exceeded $550,000 and multiplied by one more of use. Costs of Pembro-combination were 0.78 lower than Atezo/Bev and 0.62 than Ipi/Nivo. Pembro SR were 2.32 higher than Atezo/Bev and 1.65 than Ipi/Nivo. Lack of direct comparison undermined Pembro SR advantage. Conclusions: Costs of one-year adjuvant Durv, 3-year Pembro and 35-cycle Pembro-combination seemed equitable with their corresponding SR and below the $450,000 threshold. Pembro-combination costs were cheaper than Atezo/Bev and Nivo/Ipi. ICI costs of extended use tend to support the bundling proposal.
STAT6 polymorphism was correlated with gefitinib-induced diarrhea in patients with non-small cell lung cancer.
Authors: Guan Shaoxing , Chen Xi , Chen Youhao , Huang Min , Zhang Li , Wang Xueding
Published: June 2021

e21046

Background: Gefitinib-induced diarrhea can be severe, if not properly handled, and can result in severe dose reductions and treatment interruptions or discontinuation. However, the mechanism of gefitinib-induced diarrhea remains unclear. STAT6 promotes disruption of epithelial tight junction integrity, intestinal inflammation and allergic disorders in intestine. Therefore, we explored the correlation between variations in STAT6 and gefitinib-induced diarrhea in advanced non-small cell lung cancer (NSCLC) patients. Methods: A total of 160 advanced NSCLC patients carrying EGFR mutations were enrolled. 8 tag single nucleotide polymorphisms (SNP) in STAT6, including rs10876963, rs167769, rs3122929, rs3024975, rs841718, rs324013, rs324015 and rs703817, were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. The associations between tag SNPs of STAT6 and diarrhea were analyzed by Chi square test and multivariate logistic regression. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: 71 patients (44.4%) suffered at least grade 1 gefitinib-induced diarrhea. We found rs167769 was associated with gefitinib- induced diarrhea in NSCLC patients. STAT6 rs167769 TT carriers were all suffering from gefitinib-induced diarrhea (OR = 2.4*1010, p = 0.999). Patients with STAT6 rs167769 TT have higher risk of developing severe (grade ≥ 2) diarrhea than those with STAT6 rs167769 CC/CT. Conclusions: STAT6 rs167769 is a predictive biomarker for gefitinib-induced diarrhea and the analysis of polymorphisms of STAT6 rs167769 might be beneficial to optimize gefitinib treatment. Further studies are needed to clarify the underlying mechanisms. Clinical trial information: NCT01994057.
Monitoring C-reactive protein facilitates early discontinuation of immune oncology without compromising outcomes in stage IV non-small cell lung cancer.
Authors: Fugere Tyler , Spradley Ples , Safar Ahmad Mazen
Published: June 2021

e21107

Background: C-Reactive Protein (CRP) is a non-specific inflammatory marker and reflects tissue destruction seen in metastatic cancer (ca). We have observed a tight correlation with CRP trends mirroring ca activity, hence it may prove to be a valuable marker to monitor response to Immuno-Oncology (IO) in non-small cell lung cancer (NSCLC) patients (pts). Once CRP levels stabilized, IO discontinuation was offered, and consenting pts were closely observed. This strategy resulted in shortened IO duration and impressive treatment-free progression-free survival (tf-PFS). We sought to examine the validity of this strategy using the rate of return to any form of ca therapy within 6 months after stopping IO. Methods: We analyzed all pts of a single provider since 2016 with stage IV NSCLC who had CRP checked while on IO, totaling 23 pts. We excluded pts who stopped IO for reasons besides stable CRP values (5 progressed on IO, 3 died while on IO, 1 had side effects, 1 stopped for a clinical trial, 1 opted to complete 2 years of IO, and 2 are still on IO). Of the remaining 10 patient cohort, all pts were males treated at the VA with ages between 56-75 years at diagnosis. 50% of the cohort had adenocarcinoma and 50% had squamous cell carcinoma. Results: Using the CRP trend to shorten the duration of IO resulted in durable drug-free holidays with none of the cohort returning to any form of ca therapy within 6 months and comparable rates of overall survival (OS) despite shorter IO duration. In KEYNOTE-042, the median OS for pts on the pembrolizumab arm was 16.7 months in the overall population and 20 months in the TPS ≥50% subgroup. Pts were treated for up to 35 months. In our cohort, median OS was 38 months, with all pts currently still alive, and median number of doses of IO was 9 cycles, or approximately 7 months. Our pts had ongoing progression free survival (PFS) after stopping treatment, which we report as tf-PFS. The median tf-PFS of our cohort was 23.5 months. Conclusions: In pts with stage IV NSCLC treated with IO, CRP appears promising as a marker to tailor IO therapy addressing tumor and clinical heterogeneity. Responding pts with stable CRP levels can be safely taken off IO. CRP should be monitored with stable values indicating continued PFS. tf-PFS rather than PFS may serve as a surrogate for cure and carries significant impact for pts financially, socially, and psychologically. [Table: see text]
Efficacy of camrelizumab (SHR-1210) plus apatinib with or without stereotactic body radiotherapy (SBRT) as higher-line therapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC).
Authors: Meng Rui , Wu Lu , Zhang Kai , Zhu KuiKui , Wu Gang , Liu Li
Published: June 2021

e21128

Background: Despite the dramatic response of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) as first-line treatment for EGFR-mutant NSCLC, the development of resistance is inevitable. The application of third-generation EGFR TKIs is increasing, of which the resistance mechanism is unknow. To date, the optimal strategy has not been defined after failure of EGFR TKIs. Several studies reported the tumor immunogenicity is higher in patients with poor response to EGFR TKIs, suggesting that they may benefit from immunotherapy. Moreover, other studies showed that apatinib (a VEGFR2 TKI) and radiotherapy might augment anti-tumor activity of immunotherapy. In the present study, we reported the efficacy of camrelizumab (an anti-PD-1 antibody) plus apatinib with or without SBRT as higher-line therapy for EGFR-mutant NSCLC. Methods: In this single-arm trial, immunotherapy-naive, NSCLC patients aged 18-75 years, with EGFR-sensitizing mutations, and progression after at least one kind of EGFR TKI were enrolled. All patients received intravenous camrelizumab (200 mg, D1) plus oral apatinib (250mg daily, 5 days on, 2 days off) for a 21-day cycle until disease progression or intolerable toxicity. SBRT (24-30 Gy in three fractions) to at least one metastatic site was completed in some patients. SBRT was decided by the investigator, and patients should have at least one unirradiated lesion to monitor out-of-field response. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall response rate (ORR), and safety. Results: Up to Feb 1, 2021, 24 eligible patients were enrolled. Seven patients were excluded because of treatment discontinuation. Thirteen evaluable patients were included in the efficacy analysis. One had received osimertinib and three had received osimertinib after gefitinib resistance. All patients were previously treated with at least one lines of chemotherapy after EGFR TKI resistance. Eight patients received radiotherapy before enrollment. The median follow-up was 3.5 months (range: 0.7-7.8 months). The median number of cycles was 5 (3-11) PFS and OS data were immature. ORR and disease control rate was 15% (2/13) and 62% (8/13), respectively. Three received SBRT, with ORR of and no disease progression. Conclusions: Camrelizumab plus apatinib with or without SBRT as higher-line therapy showed benefit to patients with EGFR-mutant NSCLC. For patients treated with SBRT, the regimen may have better efficacy. Further investigation is warranted. Clinical trial information: ChiCTR1900028363.
Stereotactic body radiotherapy to the lung primary lesion improves the survival of patients with non-oligometastatic NSCLC harboring EGFR activating mutation with first-line EGFR-TKIs: A real-world study.
Authors: Liu Yongmei , Wei Hao , Zhou Xiaojuan , Yang Hui , Gong Youling , Wang Jin , Xu Yong , Zhou Lin , Xue Jianxin , Wen Zou Bing , Zhang Yan , Zhu Jiang , Peng Feng , Huang Meijuan , Lu You
Published: June 2021

e21131

Background: This study aimed to explore the clinical value of SBRT for lung primary lesions of EGFR-mutant NSCLC patients with non-oligometastatic disease during first-line EGFR-TKI treatment. Methods: Patients with stage IV EGFR-mutant NSCLC and more than five metastases at diagnosis were identified. All patients were treated with first-line EGFR-TKIs and SBRT for their primary lesions. The primary end points were the progression-free survival-1 (PFS1, time of first TKI dose relative to disease progression based on RECIST), and PFS2 (time of first TKI dose relative to disease progression after SBRT). The secondary endpoints were overall survival (OS) and safety. Results: 79 patients were enrolled, including 45 patients who received SBRT for their primary tumor at the maximal response of EGFR-TKI (the preemptive RT group) and 34 patients who received SBRT for their primary tumor after the occurrence of oligo-progression (the delayed RT group). The preemptive RT group had a significantly better median PFS1 than the delayed RT group (22.3 months vs. 12.9 months, P = 0.0031). The median PFS2 in the preemptive RT and delayed RT groups were 22.3 and 28.9 months, respectively (P = 0.17). The median OS did not differ significantly between the preemptive RT group and the delayed RT group (46.6 versus 51.3 months, P = 0.54). No severe toxicities (≥ grade 3) were recorded. Conclusions: This real-world study showed that preemptive RT to lung primary tumors is a feasible option for patients with EGFR-mutant non-oligometastatic NSCLC who had stable disease during first-line EGFR-TKI treatment, with significantly improved PFS and OS.
Efficacy of various types of chemotherapy for advanced non-small cell lung cancer with EGFR exon 20 in-frame insertions.
Authors: Tang Haibo , Li Xiaoning , Cai Jianhong , Wu Xiaomin , Zheng Yating , Huang Mengli
Published: June 2021

e21155

Background: Approximately 4% of epidermal growth factor receptor (EGFR)−mutated non-small cell lung cancer (NSCLC) present EGFR exon 20 in-frame insertions. These mutations confer intrinsic resistance to available EGFR tyrosine kinase inhibitors (TKIs), as they result in steric hindrance of the drug-binding pocket. Studies have shown that chemotherapy is superior to currently approved EGFR TKIs as a first-line or second-line treatment for EGFR exon 20 in-frame insertions. Nevertheless, the difference in the efficacy of different chemotherapy regimens in patients with EGFR exon 20 in-frame insertions remains unclear. Methods: Data from advanced NSCLC patients harboring EGFR exon 20 in-frame insertions from an independent cohort (Jenn-Yu Wu, 2019) was used to analyze the objective response rates (ORRs), disease control rates (DCRs), progression-free survival (PFS), and overall survival (OS) of different chemotherapy regimens. Results: Thirty-five advanced NSCLC patients harboring EGFR exon 20 in-frame insertions treated with chemotherapy were used to analyze, of which 7 received gemcitabine plus cisplatin (GC), 22 received pemetrexed plus cisplatin (PC), and 6 received taxol plus cisplatin (TC). ORRs were 31.82% for the patients received PC, 14.29% for GC, and 16.67% for TC. DCRs were 72.73% for the patients received PC, 42.86% for GC, and 16.67% for TC. Median PFS was numerically longer in patients who received PC chemotherapy (6.10 m; 95 % CI: 3.46–8.75) than GC (4.20 m; 95 %CI: 2.40–6.00; P = 0.14) or TC (3.40 m; 95 %CI: 1.96–4.84; P = 0.06). Median OS was significantly longer in patients who received PC chemotherapy (22.20 m; 95 % CI: 8.87–35.53) than GC (9.00 m; 95 %CI: 7.46–10.54; P = 0.04), and numerically longer than patients who received TC (8.10 m; 95 %CI: 0.00–22.62; P = 0.19). Conclusions: These results suggest that pemetrexed plus cisplatin may be the preferred chemotherapy for patients harboring EGFR exon 20 in-frame insertions, but further validation is needed in large clinical studies.
Does order matter? Real-world data on outcomes of successive regimens involving anti-PDx-1 in advanced and metastatic non-small cell lung cancer.
Authors: Hadley David , Gendy Shady
Published: June 2021

e21159

Background: In 2020, 65% of newly diagnosed advanced (adv)or metastatic (met) NSCLC patients in US started first line (1L) systemic therapy on anti-PDx-1 regimen, 53% of second line (2L). Between broader approvals of anti-PDx-1, increasing use in different therapy lines, and in different regimen combinations, selecting initial and subsequent regimens can be challenging, especially with limited research on outcomes based on order. This analysis uses real-world data to summarize treatment decisions made in a network of oncology centers and relates them to time to second disease progression (PFS2) and overall survival (OS). PRA US medical & prescription claims – 2020 (Jan-Aug). Methods: Deidentified data on adv/met NSCLC patients were selected from Inteliquet’s Cancer Center Research Consortium partners, which comprises academic & community oncology practices as well as integrated delivery networks across the United States. Analysis was limited to patients who started 1L systemic treatment in 2017 & 2018 (index event), progressed and started 2L. Either 1L / 2L / both must have been anti-PDx-1 based regimen. Patients with known actionable driver mutations were excluded. Data from the following 24 months was used to identify regimens and time to progression. PFS2 and OS across the combined 1L and 2L treatment protocols were assessed by proportional hazards regression. The analysis was adjusted for age at diagnosis, gender, PS and treating organization. Results: 132 patients met the study criteria: 53% were female, the median age range at diagnosis was 60-69 years, and 73% were diagnosed with stage IV, and 76% had PS 0-2 at diagnosis. After 24 months, 86% were alive, all had one progression and 44% had a 2nd progression. The most frequently observed treatment patterns are summarized in the table. Conclusions: Same regimens in different order showed different outcomes. There is a significant benefit for both OS & PFS2 by starting with a platinum doublet followed by IO PT, versus the same start followed by IO MT. There is a significant disadvantage in OS by starting with IO MT followed by platinum doublet, versus the reversed order. 1L IO PT versus baseline showed non-significant improvement in PFS2, but not OS.[Table: see text]
Continuous infusion of Endostar combined with chemotherapy in patients with advanced or recurrent mucosal melanoma: A real-world cohort study.
Authors: Liu Xin , Jiang Shiyu , Zhang Xiaowei , Jin Feng , Cao Jun , Meng Yanchun , Xu Yu , Wang Chunmeng , Chen Yong , Yang Huijuan , Kong Yunyi , Luo Zhiguo , Hu Xichun
Published: June 2021

e21517

Background: Mucosal melanoma is rare and has distinct clinical and genetic features. Even with advances in targeted and immune therapy, the survival of patients with advanced or recurrent mucosal melanomas remains poor. The standard treatment remains controversial and we conducted this real-world study aimed to test continuous intravenous Endostar infusion plus chemotherapy in patients with advanced or recurrent mucosal melanoma in the first-line setting. Methods: In total, all 43 patients with advanced or recurrent mucosal melanoma treated at Fudan University Shanghai Cancer Center between April 2017 and August 2020 were retrospectively included. Patients received dacarbazine plus cisplatin or temozolomide plus cisplatin regimens per the investigators’ preference. Endostar (105 mg/m2) was administered with continuous infusion for 168 hours (Civ 168h). Results: Of the 43 patients, 72.1% had metastatic disease, and 27.9% had locally advanced disease. The most common primary site was the gastrointestinal tract (51.2%), followed by the sinonasal tract (32.6%) and genitourinary tract (14.0%). The most commonly observed mutation was NRAS (23.1%), followed by BRAF (7.7%) and CKIT (5.1%). An objective response was observed in 12 (30.0%) of the 40 evaluable patients, and disease control was achieved in 31 (77.5%) patients. With a median follow-up of 17.6 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively. Multivariate analysis indicated a high lymphocyte-to-monocyte ratio (LMR) was significantly correlated with favorable PFS (p = 0.012, hazard ratio [HR] 0.28, 95% CI: 0.10-0.76). Additionally, a high LMR (p = 0.023, HR 0.29, 95% CI: 0.10-0.84) and BRAF/KIT/RAS mutation (p = 0.028, HR 0.24, 95% CI: 0.07-0.86) were independently correlated with prolonged OS. Toxicity was manageable overall. Conclusions: Continuous Endostar infusion in combination with chemotherapy was effective and safe for the treatment of advanced or recurrent mucosal melanoma. Additionally, a high LMR was correlated with favorable PFS and OS in this patient population.
FAT4 mutation serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma.
Authors: Zhang Jifa , Chen Dongsheng , Zhang Qin , Duan Qianqian , Yang Qidong , Li Si , Xiao Mingzhe
Published: June 2021

e21553

Background: FAT4 functions as a tumor suppressor, and previous findings have demonstrated that FAT4 can inhibit the epithelial-to-mesenchymal transition (EMT) and the proliferation of gastric cancer cells. FAT4 is involved in the maintenance of PCP and inhibition of cell proliferation. FAT4 mRNA is repressed in breast cancer and lung cancer due to promoter hypermethylation. FAT4 gene is recurrently mutated in several types. Previous work suggested that FAT4 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of function in melanoma is needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the FAT4 mutation in 3547 tumor tissue or plasma ctDNA samples (including 122 melanoma) from different patients, and the public database of TACG was also compared. Data from Miao-249 study (n = 151, anti-PD-(L)1/CTLA-4 mono/ combined therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of FAT4 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 8.11 % (288 in 3547). Meanwhile, the frequency of FAT4 mutation in TCGA cohort was 10.08 % (1105 in 10953). In melanoma datebase, the frequency of FAT4 mutation in 122 melanoma tumor tissue or plasma ctDNA samples from different patients was 5.73 % (7 in 122). Meanwhile, the frequency of FAT4 mutation in melanoma in TCGA cohort was 38.2 % (169 in 422) We further analyzed Kaplan-Meier curves from Miao-249 study (n = 151, anti-PD-(L)1/CTLA-4 mono/ combined therapy). In Miao-249 melanoma cohort, mutation of FAT4 was associated with higher TMB (P = 0.032) and higher mutation count (P = 0.003) in melanoma. FAT4 mutation was associated with prolonged overall survival (OS) compared with FAT4 wt in melanoma (P = 0.0478). Conclusions: In our study, the frequency of FAT4 mutation in pan cancers and melanoma was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. FAT4 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma via upregulating TMB and mutation count.
Transcriptomic profiling of peripheral blood mononuclear cells in patients with multiple primary melanoma.
Authors: Karapetyan Lilit , Yang Xi , Mo Min , Wang Hong , Karunamurthy Arivarasan , Sander Cindy , Storkus Walter , Kirkwood John M.
Published: June 2021

e21558

Background: Patients (PTs) with cutaneous melanoma (MEL) are at increased risk of developing subsequent MEL. The primary objective of the present study was to determine whether the peripheral blood gene expression profile (GEP) of PTs with multiple primary melanoma (MPM) differs from that of patients with single primary melanoma (SPM) and healthy controls (HCs). A secondary objective is to assess if the peripheral blood immune transcriptional profile varies in relation with clinical and immunopathological characteristics of MEL. Methods: Cases with MPM, SPM and HCs were retrieved from the University of Pittsburgh Human Biological Sample and Nevus Image Banking and Analysis Repository. NanoString PanCancer Immune Profiling of 770-immune related genes was used to define GEP in peripheral blood mononuclear cells (PBMCs). Quality control (QC), data normalization, and differential expression analyses were performed using the ROSALIND Analysis System. Genes with fold change ≥1.5 and p-value < 0.05 were considered as differentially-expressed between cohorts. Results: In total, 47 PTs including 10 with SPM, 40 with MPM, and 10 HCs, were included. GEP data from 3 cases did not meet QC requirements and were discarded. The majority of PTs had stage I/II disease (87.2%). The median Breslow thickness was 1 mm, ulceration was present in 6 (12.2%) MELs. Tumor-infiltrating lymphocytes (TILs) were absent, non-brisk, and brisk in 20%, 65%, 15% of cases, respectively. The expression of IFIT1, MX1, ISG15 was decreased in PTs with MPM in comparison to HCs. In comparison to SPMs, PTs with MPM demonstrated downregulation of B-cell receptor signaling pathway genes (CD19, CD22, CD79A, BLK). 14 genes involved in TNF-alpha effects on cytokine activity, cell motility, and apoptosis, and 12 genes in the IL18 signaling pathway were differentially expressed in PTs with Breslow thickness of >1mm vs ≤1mm. The top downregulated genes in >1mm thick MELs were CD83, VEGFA and CXCL3. Ulcerated MEL had decreased expression of CCL2, CCL3, CCL3L1, CCL4. Stage III MEL had decreased expression of GZMH, MHC Class II genes HLA-DMB, HLA-DRB3, lectin receptor family genes KLRC2 and KLRD1, as well as Type-1 immune-associated biomarkers IRF1, SYK, TBX21 in comparison to Stage I/II cases. Tumors deficient in TILs exhibited decreased expression of Granzyme A and B, T-box 21, and IL18RAP (enhances IL18R-mediated signaling) in peripheral blood. Tumors with brisk TILs had increased expression of the B-cell associated transcripts CD19, CD22, CD79A in peripheral blood. Conclusions: The GEP of PBMC's from PTs with MPM was similar overall to that of PTs with SPM/HC, with only a subset of genes exhibiting differentially expression in PTs with MPM vs. PTs with SPM and HCs. GEP varied in relation to Breslow thickness, stage, ulceration, and TIL content in MELs.
Effectiveness of surface mould brachytherapy in electron era.
Authors: Mehta Jyoti
Published: June 2021

e21562

Background: In India, skin cancers constitute about 1-2% of all diagnosed cancers.Surgery stays main modality of treatment with adequate surgical margin shown excellent local control rates - generally 95%.However, conditions where surgery is not feasible, brachytherapy is alternative approach.Advanced technology improved the ability to deliver safe and effective radiotherapy, resulting in renewed interest in this modality.Brachytherapy has many advantages: they can deposit a significantly higher dose within a tumor, with better sparing of adjacent normal structures over external beam radiotherapy or electron therapy, which sometimes require irradiating a large volume of tissue in order to provide adequately coverage, which in term increase toxicity. The purpose of our paper is to find out the clinical outcomes of skin tumors and superficial tumours of head and neck region treated with Surface mould brachytherapy (SMB), in terms of survival and toxicity.We report on our institution’s experience with using Co-60 based HDR SMB for the treatment of skin and head and neck superficial malignancies. Methods: A retrospective review of all patients treated with surface mould Co-60-based HDR brachytherapy at our center.A total of 23 patients, with 23 lesions, were treated during this period, and included in the analysis. A total of three of these lesions were treated with a palliative intent, and were included. The most common fractionation scheme was 35 Gy in 10 fractions given daily (52%, n = 12), though a range of doses were used, from 8/2 fractions to 36 Gy/12 fractions. Results: Median age at diagnosis was 52 (range = 28-91). The majority were Squamous cell (43%, n = 10) or Basal cell carcinomas (34%, n = 8). Most lesions were located in the head and neck region. The most commonly used RT dose was 3GyX10 fractions; all patients had individualized CT-based planning.The 5-year overall survival (OS) was 86 %( twenty patients). Three patients were died. Most deaths were from unrelated causes. Response was assessed in OPD 2-4 months post-treatment. Our complete response (CR) rate was 73.9% (seventeen patients), with partial response in three patients; two patients could not be assessed for response and one patient died due to other medical condition. We report a 2-year local control (LC) rate of 91.3%, and local recurrence was found in two patients. The procedure was well tolerated, with no grade 3 or more acute or late toxicities. There was one case of grade 3 ulcer (CTCAE). The 100% isodose line median depth was 0.5 cm, and median surface dose = 126.5%. The median V90 = 92.3%. Conclusions: Surface mould brachytherapy is a safe, effective modality for treatment of skin malignancies or tumors. Brachytherapy was overall well tolerated, with no grade 3-5 acute or late toxicities. This treatment is a good alternative option for those patients unwilling or unable to undergo surgery for their skin malignancies