bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of capmatinib in MET exon 14-mutated advanced non-small cell lung cancer (NSCLC): A systematic review.
Authors: Khan Israr , Ahmed Faiza , Hanif Nazma , Haider Mobeen Zaka , Khalid Farhan , Mishra Sakshi , Garimella Radhika , Andrews Kim , Pakala Ramya , Gara Sirisha , Guntipalli Prathima , Pacha Faris , Mohan Karthik , Thompson Andre , Mouchli Mohamad , Enebong Nya Godsgift 
Published: June 2021

e21150 Background: Capmatinib is a selective inhibitor of MET receptor that got accelerated FDA approval in May 2020 to treat NSCLC with MET ex 14 mutation (METex14). Here, we proclaim the first review of capmatinib efficacy and safety profile in METex14 positive NSCLC patients. Methods: A systematic literature search was conducted using PubMed, Cochrane Library, Clinicaltrials.gov, and Google Scholar. We compiled and analyzed the original studies evaluating the clinical response of capmatinib in MET ex14 mutated advanced NSCLC. Results: The most recent results (as of January 6, 2020) of the GEOMETRY Mono-1 phase 2 study showed an overall response rate (ORR) of 41% (69/97; 95% CI, 29-53) with 41% partial response (PR), and 36% stable disease (SD) in patients who previously received 1-2 prior therapy lines (cohort 4). While the ORR, PR, and SD were 68% ( n = 29/97; 95% CI, 48-84), 64%, and 25%, respectively in treatment naïve patients (cohort 5b). Median progression-free survival (mPFS) and duration of response (DOR) were 5.4 months (mon) and 9.7 mon (95%CI, 5.6-13.0) in cohort 4 vs. 12.4 mon and 12.6 mon (CI, 5.6- not estimated), respectively in cohort 5b. Moreover, disease control was shown in n = 54/69 patients in cohort 4 (95% CI 78 (97-87) and n = 27/28 patients (95% CI 96 (82-100). A post-hoc analysis of 19 patients out of 69 who were pre-treated with immunotherapy demonstrated an ORR of 57.9% (n = 11/19; 95%CI 33.5-79.7) with capmatinib. In contrast, treatment-naive had an ORR of 34% (n = 17/50; 95%CI 21.2-48.8) as per the investigator. Median PFS was 3.29 mon noted on prior therapy. In the phase 1 retrospective analysis reported by Choi et al., ORR was 50% with a median duration of 16.1 (5.3-36.4) mon. Among 45 Japanese pts with MET ex 14 mutated or MET amplified status, the ORR was 36.4% (95% CI 10.9%-69.2%) with a PFS of 4.70 mon in the MET ex 14 mutated groups who had received a second or third line of therapy. Most commonly reported adverse events were peripheral edema, nausea, vomiting, and elevated creatinine across all studies and were mostly grade 1-2. Conclusions: Our results showed that capmatinib has promising anti-tumor activity in patients with NSCLC harboring MET exon 14 skipping mutation. The efficacy and tolerability profile of capmatinib is remarkable, particularly in treatment-naïve patients. Although the GEOMETRY Mono-1 trial is still ongoing, further clinical studies with long-term follow-up are needed.
The role of PTEN and TP53 co-mutations in immunotherapy of lung cancer.
Authors: Ma Xiaolong , Zhang Ding , Chen Shiqing 
Published: June 2021

e21161 Background: Patients with non-small cell lung cancer (NSCLC) harboring PTEN mutations have a worse prognosis of immunotherapy in research with small sample size and case reports. However, the role of PTEN and TP53 co-mutations in immunotherapy of NSCLC has not been fully studied. Methods: Patients with NSCLC from our dataset were enrolled in this study. For the genomic profiling, only the pathogenic mutations and likely pathogenic mutations in clinical significance were rolled. The efficiency of immunotherapy was analyzed in a public cohort of 240 NSCLC patients by Rizvi. Patients with EGFR/ALK mutation were excluded in our analysis. Results: In our dataset, 1,428 patients were included in the analysis. 25 (1.75%) patients have PTEN mutations and 429 (30.04%) patients have TP53 mutations. In all patients with PTEN mutations, 84% with TP53 co-mutations. Median tumor mutational burden (TMB) was 12.29 mutations/MB (range, 3.35-36.87) and 6.98mutations/MB (range, 0.56-9.50) in patients harboring PTEN mutations with TP53 co-mutations and without TP53 co-mutations, respectively ( p= 0.02). In 240 NSCLC patients of Rizvi, the overall response rate (ORR) of the PTEN and TP53 co-mutations group, the PTEN mutations without TP53 mutations group and PTEN wild-type group was 33.33%, 0% and 20.26%, respectively. The disease control rate (DCR) was 83.33%, 0% and 54.74%, respectively. The median progression-free survival (PFS) in the PTEN and TP53 co-mutations group was the longest (7.5 months), while the median PFS in the PTEN mutations without TP53 mutations group was only 2.5 months. However, No significant differences of PFS were observed. Conclusions: Our findings suggested that patients with NSCLC harboring PTEN and TP53 co-mutations might benefit more from immunotherapy compare to those harboring PTEN mutation without TP53 mutations and PTEN wild-type. TMB may be an important factor that lead to the results. Further studies need to be explore in cohorts with larger sample sizes.
Association of TGFBR2 mutations with shorter survival in non-small cell lung cancer treated with immune checkpoint inhibitors.
Authors: Zheng Linxin , Yang Mengmei , Huang Mengli , Li Weifeng 
Published: June 2021

e21166 Background: Transforming growth factor beta receptor 2 (TGFBR2) is a transmembrane receptor that plays an important role in both cellular functions and immune reaction, including cell proliferation, cell differentiation and extracellular matrix production. It forms a heterodimeric complex with TGF-beta receptor type-1 and binds TGF-beta. The association between TGFBR2 gene mutations and efficiency of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC). Methods: Two published cohorts of NSCLC patients treat with ICIs were used to explore the immunotherapeutic predictive role of TGFBR2 gene mutations, including a discovery cohort (Gandara et al., Nature Genetics, 2018) and a validation cohort(Samstein et al. Nature Genetics, 2019). The Cancer Genome Altas (TCGA) Pan -Lung Cancer dataset was used for prognostic analysis. Results: TGFBR2 mutations were identified in 1.6% (7/429) and 2.3% (8/344) patients with NSCLC in the discovery and validation cohort, respectively. In the discovery cohort, patients with TGFBR2 mutations had shorter progression-free survival (PFS, median, 1.3 months vs 2.7 months; HR = 2.83; 95% CI, 1.33–6; p = 0.0046) and dramatically shorter overall survival (OS, median, 2.4 months vs 11.1 months; HR = 3.46; 95% CI, 1.63–7.35; p = 0.00058) than those with wild-type TGFBR2. Consistent with this, TGFBR2 mutations were significantly correlated with shorter OS (3 months vs 10 months; HR = 3.46; 95% CI, 1.63–7.35; p = 0.00058) in the validation cohort. In addition, no significant difference was found in OS between TGFBR2-mutant and TGFBR2-wild-type NSCLC patients with standard treatment in TCGA cohort (p = 0.821). Conclusions: TGFBR2 gene mutations are associated with shorter survival in NSCLC patients treated with ICIs, suggesting that TGFBR2 mutations be used as a potential biomarker of predicting the efficiency of immunotherapy and guiding NSCLC systemic treatment.
Immunotherapy in patients with lung cancer with driver mutations: A single center experience.
Authors: Vundemodalu Prathyush , Rauthan Amit , Patil Poonam , Aswath Rajashri 
Published: June 2021

e21170 Background: Immunotherapy has revolutionized treatment in metastatic non small cell lung cancer (NSCLC)without driver mutations. Trial data shows that programme death-1/ PDL1 blockade in epidermal growth factor receptor(EGFR) and other driver mutation positive lung cancers is not beneficial. Here we evaluated the efficacy of immune check point inhibitors in a series of patients with EGFR and other driver mutation positive advanced NSCLC. Methods: We retrospectively analysed 75 patients who received PD1/ PDL1 inhibitors for advanced NSCL between January 2017 to January 2020. 10 patients were detected to have driver mutations on either tumor tissue or blood by NGS. Results: Out of 10 patients, 7 were male and 3 were female. EGFR was detected in 6 patients (3 on tumor and 3 in blood NGS). We found MET exon 14 skip mutation in 2 and RAS in 2 patients. Immunotherapy combined with chemotherapy was given in 5(50%) patients, immunotherapy + bevacizumab+chemotherapy in 2(20%) and immunotherapy alone in 3 patients(30%). Immunotherapy was as started as first line in 4 patients as tumor tissue was negative for EGFR, ALK, ROS1 by single gene testing. On NGS testing at progression, EGFR mutation was detected in 1 patient, MET exon 14 skip mutation was detected in 2 and Ras mutation in 2 patients. Immunotherapy alone was used in 3 patients in view of advanced age and multiple comorbidities.The progression free survival(PFS) ranged between 2 to 11months. Conclusions: Single agent checkpoint inhibitors seem to have a limited impact in treatment in patients with driver mutations. Molecular testing by NGS is recommended either on tumor tissue or on blood by NGS if single gene testing for EGFR/ ALK/ ROS1 alterations is negative. We do see benefit in patients who received PD1/PDL1 inhibitors in combination with chemotherapy with/ without Bevacizumab. In conclusion, patients progressing on EGFR TKIs who are planned for immunotherapy should always be given in combination with chemotherapy+/- Bevacizumab.[Table: see text]
Algorithm to derive progression-based lines of therapy from a real-world non-small cell lung cancer (NSCLC) dataset.
Authors: Agrawal Smita , Priya Vandana , George Rohini , Manirevu Sai Vinod , Bhardwaj Tapasya , Prajapati Rambaksh , Chakkrapani Sangavai , Walker Mark S. , Vaidya Vivek Prabhakar , Narayanan Babu 
Published: June 2021

e21172 Background: Analysis of Real World Data (RWD) from Electronic Health Records (EHR) for applications such as Health Economics and Outcomes Research (HEOR) or regulatory submissions requires identification of the lines of therapy (LoT) patients have received. LoTs are typically not captured in EHR and must be manually abstracted. As the use of RWD increases, there is a growing need to create algorithms that can work on RWD to extract LoT information in an automated manner with high accuracy. We present here the results of such an algorithm created on NSCLC RWD. Methods: 10950 advanced NSCLC patients from the ConcertAI Oncology RWD database who had received anti-neoplastic treatment after advanced diagnosis were used to build and validate this algorithm. These data were further enriched by expert nurse curators to fill in missing oral drug information and identify progression events. We developed a progression-based LoT (pLoT) model that identified LoT changes in sync with tumor progressions. If patients received multiple regimens before progression they were captured as nested regimens within the LoT. The algorithm uses complex rules to define combination of drugs as regimens (combination rule), identify resumption of regimens (gap rule) or dropping of drugs from regimens as new lines and to handle noisiness in RWD etc. Results: The LoT model accurately captures line changes triggered by progression events as well as any nested regimen changes due to adverse events etc. Patient level validation of LoT was carried out by clinical experts using an in-house tool and found to be consistent with literature & individual drug data. Cohort level analysis of top 3 combinations of therapies used in 1st & 2nd line treatment between 2015-2020 (8200 patients) are shown in Table. Sensitivity analysis on the combination rule showed that this parameter can be changed between 28-33 days without significantly impacting the LoT output (<1% impact). We use a 30 day combination rule as the default. Similarly, the gap rule parameter is quite robust and does not show significant variation between 45 – 90 days (<2% impact). We use 63 days. Conclusions: We have developed a robust algorithm to derive pLoT on RWD at scale assuming availability of curated progression data which can be used to support use cases such as HEOR, clinical development and regulatory submissions. pLoT is better suited for outcomes analysis compared to regimen based LoT since it distinguishes changes in treatment due to progression events from changes due to toxicity, drug availability, etc., and allows analysis on a more homogeneous patient population relating to their past clinical experience. [Table: see text]
A retrospective analysis examining the use of tissue-based and blood-based NGS in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Hines Adam , Hakim Nausheen , Wang Kevin , Shah Pratik , Lee Chung-Shien , Seetharamu Nagashree 
Published: June 2021

e21195 Background: Next generation sequencing (NGS) of tumor has become an integral part of cancer diagnostics and therapeutics today. While tissue-based (TB) NGS is still considered gold-standard, cell-free DNA NGS obtained from peripheral blood (blood-based or BB) offers many advantages because of its quicker turnaround time, minimally-invasive nature and ability to address tumor heterogeneity and track development of resistance mutations over time. It however does have its disadvantages, predominant of which is its lower sensitivity. Integration of BB and TB NGS can both optimize turnaround time and increase detection of targetable mutations. Methods: We conducted a single institution, IRB approved, retrospective study evaluating NGS testing patterns in patients with advanced NSCLC treated at our institution between 1/1/16 and 3/31/20. Our primary endpoint was to evaluate the number of patients who had BB NGS performed at any point during their clinical course in addition to TB NGS testing. Our secondary endpoint was to evaluate the number of patients for who BB NGS led to change in treatment plan. Exploratory points included the concordance rate between BB and TB NGS performed within 1 month of each other and the details of discordance if any. Results: There was a total of 437 eligible advanced NSCLC patients who were treated at our institution between January 2016 and March 2020. Out of these, 104 (23.8%) had BB NGS performed at some point in their disease course. The median number of BB NGS testing done for these patients was 2 and ranged from 1 to 4. 32/104 (30.8%) of patients had change in management because of BB NGS results. TB and BB NGS were performed within one month of each other in 52 patients. 11 of these (21.2%) had detection of identical actionable mutations (AM) on both BB and TB NGS assays. 5 of the patients (9.6%) had AM detected on TB NGS alone and 6 of the patients (11.5%) had AM detected on BB NGS alone. 30/52 patients (57.7%) had no AM identified on both BB and TB NGS. Conclusions: BB NGS has added tremendous value to diagnosis and treatment of NSCLC. It is increasingly used in practice, in tandem with TB NGS. Nearly a fourth of our patients had BB NGS performed at some point in their clinical course. Nearly 20% of simultaneously performed BB and TB NGS were discordant and an AM was identified in only one of the biopsies. Although further research is needed, our study supports simultaneous BB and TB testing at diagnosis and progression thereby maximizing therapeutic potential.
Overall survival comparison in patients with and without brain metastases treated with osimertinib for metastatic EGFR mutation positive non-small cell lung cancer (NSCLC).
Authors: Giffoni de Mello Morais Mata Danilo , Romero Maria Luisa , Carmona Gonzalez Carlos Amir , Thawer Alia , Doherty Mark , Menjak Ines B. 
Published: June 2021

e21216 Background: With the development of Epidermal Growth factor receptor (EGFR) tyrosine kinase inhibitors such as Osimertinib, the landscape of lung cancer treatment and outcomes has changed. We aimed to describe the outcomes of patients treated with Osimertinib who have brain metastasis compared to those without brain metastases. Methods: This study involved patients diagnosed with metastatic non-small cell lung cancer (NSCLC) with EGFR mutation, from January 2010 to December 2018, who had treatment with Osimertinib at a dose of 80 mg daily. Retrospective data was collected through the electronic medical records from Sunnybrook Health Sciences Centre. Descriptive statistics were used to summarize the population characteristics. The log rank test was used to compare the survival distributions. Results: A total of 56 patients were included, the mean age at initial diagnosis was 63 years (range 27 – 85 years). Overall, 82.2% of this patient population received Osimertinib in 2nd line setting. A total of 50% (n = 28) had brain metastasis, and14.3% (n = 8) had leptomeningeal metastasis. Of the patients with brain metastasis, 14.3% (n = 4) had brain surgery. All patients with brain metastasis received central nervous system (CNS) radiation. With respect to radiotherapy modalities, 67.9% (n = 19) of patients with brain metastasis received gamma knife radiation, 42.85% (n = 12) were treated with stereotactic radiosurgery (SRS), and whole brain radiation was given to 57.1% (n = 16). Of those with brain metastasis, equal numbers of patients, 46.4% (n = 13), had EGFR mutations with exon 19-deletion and exon 21-L858R, 7.1% (n = 2) had unknown gene location EGFR mutation. The median OS for patients without brain metastasis was 38.6 months (95% confidence interval [CI] 37.5 – 39.8 months], compared to 35.9 months (95% [CI] 28.3 – 43.5 months] for those with brain metastasis ; log Rank (Mantel-Cox) p = 0.874. The median OS for patients diagnosed with leptomeningeal metastasis was 21 months (95% [CI] 2.9 – 39.0 months); log rank (mantel-cox). When brain metastasis was examined by EGFR mutation sub-groups, the median OS for patients with EGFR-exon 19-deletion was 26.4 months (95% CI [14.3 – 38.4 months], compared to 36.8 months, 95% CI [34.3 – 39.2 months] for those with EGFR-Exon 21-L858R; log Rank (Mantel-Cox) p = 0.49. Conclusions: Although there is an equivalent prevalence of brain metastasis between the two NSCLC EGFR mutation populations, in unadjusted analyses, no difference in OS was seen between patients with brain metastases compared to those without brain metastases. However, in the small number of patients with leptomeningeal disease, survival was shorter and a larger population should be studied to further explore this finding.
Potential role of serum proteome in predicting immune-related adverse events from immune checkpoint inhibitors in non-small cell lung cancer.
Authors: Kim Leeseul , Chae Young Kwang , Jung Chan Mi , Yu Emma , Lee Alice Daeun , Choi Yoonhee , Jung Hojung , Park Inae 
Published: June 2021

e21218 Background: Early recognition of immune-related adverse events (irAEs) of immune checkpoint inhibitors(ICI) is important. Circulating proteome reflects host response to diseases and is being explored as a marker for response to immunotherapy. We previously have reported that a serum-based proteomics test, Primary Immune Response (PIR) demonstrated a trend that PIR-sensitive patients are more likely to tolerate ICI treatment longer without developing irAEs in non-small cell lung cancer (NSCLC) patients. The VeriStrat test is another serum-based proteomic assay, which was reported to be predictive of survival outcomes for all treatment regimens and lines of therapy including ICI in NSCLC. We explored the associations between the VeriStrat test and developing irAEs in NSCLC patients treated with ICI. Methods: Data of 70 consented NSCLC patients treated with any regimens and lines of therapy including ICI were collected. Samples were grouped into either VeriStrat ‘Good’(VS-G) or VeriStrat ‘Poor’(VS-P). We analyzed the durations from the immunotherapy initiation to each episode of irAE and each irAE above grade 2 using log-rank test. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Among the 70 patients, 18 patients (25%) experienced one or more irAEs. There was no significant difference in ‘Time to first irAE’ between VS-G and VS-P (p = 0.72, HR = 0.82, 95% CI = 0.29-2.32). Among 48 VS-G patients, 12(25%) had one or more irAE and 5(10%)had irAE graded over 2. Among 22 VS-P patients, 6(27%) had one or more irAE and 2(9%) had irAE graded over 2. There was no significant difference between VS-G and VS-P groups in the development of irAE and irAE graded over 2. Conclusions: There was no statistically significant association between the VeriStrat test and the development of irAEs. Further studies are warranted to investigate proper serum based proteomic assay to predict the development of irAE.
Immune status in merkel cell carcinoma: Relationships with clinical factors and independent prognostic value.
Authors: Yusuf Mehran , Gaskins Jeremy T. , Rattani Abbas , McKenzie Grant , Mandish Steven , Wall Weston , Farley Alyssa , Tennant Paul , Bumpous Jeffrey , Dunlap Neal E. 
Published: June 2021

e21509 Background: Immunosuppression (IS) is not currently considered in staging for Merkel cell carcinoma (MCC). We performed an analysis of the National Cancer Database (NCDB) to investigate immune status as an independent predictor of overall survival (OS) for patients with MCC and describe the relationship between immune status and other prognostic factors. Methods: The NCDB was queried for patients diagnosed with MCC from 2010 to 2016 with known immune status. Multivariable Cox proportional hazards models were used to define factors associated with OS. Adjuvant radiation and chemotherapy were treated as time-dependent predictors to limit immortal time bias. Secondary models were constructed to assess the association between IS etiology and OS. Multivariable logistic regression models were used to characterize relationships between immune status and other factors. Multiple imputation was used to minimize missing data bias. Results: The overall cohort included 3,882 patients (3,470 patients with known immunocompetence and 412 patients with known immunosuppression). Etiologies for profound IS included chronic lymphocytic leukemia (CLL, n = 118), Other including HIV/AIDS (n = 116), solid-organ transplant (n = 106), and Non-Hodgkin Lymphoma (NHL, n = 72). 2,864 patients (73.8%) underwent surgical nodal examination. The median follow-up time was 33 months (Interquartile Range: 18 to 55 months). The 3-year OS was lower for patients with IS (44.6%, CI 39.8-49.9%) compared to immunocompetent (IC) patients (68.7%, CI 67.1-70.4%, p < .0001). IS was associated with increased adjusted mortality hazard (HR 2.36, 95% CI 2.03-2.75). Etiology of IS was associated with OS ( p = .0015) with lowest 3-year OS (32.7%, CI 24.6%-43.5%) for patients with solid-organ transplantation. IS was associated with increased odds of greater nodal burden (OR 1.70, CI 1.37-2.11) and lymphovascular invasion (OR 1.58, CI 1.23-2.03). Conclusions: Immune status was independently prognostic for OS for patients with localized MCC. Etiology of IS may be associated with differential survival outcomes. Multiple adverse prognostic factors were associated with increased likelihood of IS. Immune status and potentially etiology of IS may be useful prognostic factors to consider for future MCC staging systems.