bluuebunny/crossref_metadata_2025 huggingface dataset:
Third and successive–lines of chemotherapy in NSCLC patients without therapeutic targets: Experience of the Grupo Gallego de Cáncer de Pulmón.
Authors: Afonso Afonso Francisco Javier , Fernández Núñez Natalia , Vilchez Simo Rocio , Firvida Jose-luis , De Dios Alvarez Noemi , Campos Balea Begoña , Ruiz Bañobre Juan , Areses Manrique Maria Carmen , Agraso Busto Sara , Carmona Campos Marta , De Paz Árias Laura María , Cameselle Garcia Soledad , Pereiro Corbacho Diego , Vázquez Estévez Sergio , García Mata Jesús , Casal Rubio Joaquin , Constenla Manuel
Published: May 2019

e20579

Background: The current treatment of advanced non-small cell lung cancer (NSCLC) is conditioned by the presence of molecular and immunohistochemical biomarkers. In the absence of these, the therapeutic option is the use of chemotherapy with or without antiangiogenic agents. The efficacy of non-target systemic treatments is not proven, beyond a second-line and the experiences in their use are limited to retrospective analyzes. We present the experience of the Grupo Gallego de Cáncer de Pulmón in patients with advanced NSCLC treated exclusively with three or more lines of chemotherapy. Methods: Retrospective analysis of patients with advanced NSCLC, treated with three or more lines of chemotherapy in standard regimen, with or without antiangiogenic agents, in Galicia´s hospitals, Spain. Results: We included 168 patients (134 male and 34 female) treated with three or more chemotherapy lines, with a median age at the time of receiving the first-line, of 60.84 years (41-83). Of these, 51 (30,35%) received a fourth-line and 18 (10,74%) a fifth-line of treatment. None received antitarget therapy or immunotherapy. The median overall survival (OS) was 18.1 months. The median OS after the third line was 6.1 months, with 73% of patients alive at three months and 44% six months after the start of that therapeutic line. We did not appreciate differences in OS between those who received three lines and those who received the largest number of subsequent treatments. Our multivariate analysis (age, gender, histology, performance status at initiation of each teatment-line, response to previous treatments) identified that the individuals who benefited the most were those under the age of 60 years, PS-ECOG 0-1 at diagnosis and those with a more durable response to the first-line. Conclusions: The third-line of chemotherapy can benefit those patients with advanced NSCLC, under 60 years of age at the time of diagnosis, with good performance status and with long-lasting responses to the first line of treatment. We did not see benefit in adding fourth or fifth-line of chemotherapy. All data will be presented in the 2019 ASCO annual meeting.
The efficacy of ado-trastuzumab emtansine in patients with HER-2-aberrant non-small cell lung cancer.
Authors: Xia Yang , Huang Xiu , Jin Rui , Li Wen , Shen Huahao
Published: May 2019

e20584

Background: HER-2 aberrations, including gene mutation, gene amplification and protein overexpression, have been considered as oncogenic driver alteration in non-small cell lung cancer. However, the therapeutic effect of Ado-trastuzumab emtansine (T-DM1) is varied in HER-2 altered lung cancer. Thus, we aim to elucidate the efficacy of T-DM1 in treating different subtypes of HER-2 aberrations by integrating and reanalyzing the data from current available literatures. Methods: We sought published articles, case reports and ongoing studies that reported efficacy of T-DM1 in lung cancer with HER-2 aberration. Seven studies met the systematic review criteria. The main outcomes were the overall response rate (ORR). Results: 93 patients with various HER-2 aberrations were identified in 7 studies. HER-2 upregulation was prone to occurred in the patients with smoking history and adenocarcinoma, without gender difference, while HER-2 mutations were more common in female non-smoker with adenocarcinoma. The overall ORR of HER-2 aberration was 19.35%. Subgroup analysis showed the ORR was 35.00% for sole HER-2 mutation, 42.86% for HER-2 gene amplification, 2.78% for HER-2 protein overexpression, respectively. Of note, ORR was only 8.33% for HER-2 upregulation (protein overexpression and/or gene amplification), while ORR was significantly increased to 46.15% upon concomitant HER-2 upregulation and mutation. Furthermore, ORR was 25.00% for overexpression plus mutation, but ORR was up to 80.00% for gene amplification plus overexpression and mutation. Conclusions: T-DM1 is a promising agent targeting to HER-2 mutant or amplified lung cancers and the therapeutic efficiency might be more pronounced upon HER-2 mutation alone with amplification. Additional studies of this agent are warranted.
The molecular and immune characteristics, antitumor activity of crizotinib in non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping alterations.
Authors: Gan Jiadi , Fang Wenfeng , Feng Weineng , Zhang Jiexia , Deng Huojin , Zhang Lei , Li Yadan , Qian Juanjuan , Luo Hongli , Chen Yanhui , Yang Ying , Zhang Henghui , Zhang Li
Published: May 2019

e20588

Background: MET exon 14 ( METex14) skipping caused by certain mutations in splice sites of METex14 has been regarded as a promising target for non-small cell lung cancer (NSCLC) treatment with crizotinib, and was observed with lower responsiveness to immunotherapy (Joshua K. et al ASCO 2017). The molecular and immune characteristics, antitumor activity of crizotinib for Chinese NSCLC patients harboring METex14 skipping alterations remain to be elucidated. Methods: Tumor genomic profiling was performed by next-generation sequencing (NGS) assay (GeneCast Biotechnology Co., Beijing) on 9722 samples (FFPE and/or peripheral blood derived from 9289 Chinese NSCLC patients). PD-L1 expression was determined by qualitative immunohistochemical assay. Multiplex immunohistochemistry (mIHC) analysis was adopted to evaluate the immune microenvironment of selected samples. Retrospective analysis was performed to explore antitumor activity of crizotinib monotherapy in 10 patients harboring METex14 skipping alterations. Results: A total of 62 (0.67%) patients with somatic mutations occurred in METex14 splice sites (± 3bp) were identified. Median age of these patients is 64.5 years and 39% patients are female. Main histologic types are adenocarcinoma (81%, 50/62) and squamous carcinoma (13%, 8/62). 30 patients harbored high frequency METex14 mutations ranged from 1.34% to 79.49% nearly without co-existed known driver variants. Other 32 patients had low frequency mutations (below 1%) with some crucial oncogenic mutations such as EGFR 19del/L858R. In addition, very few CD8+ T cells were observed in tumor region and significantly less infiltrated than in stroma region ( P< 0.01). The overall response rate of crizotinib monotherapy on the ten patients with METex14 skipping alterations was 70% (7/10 achieved partial response), with progression free survival range from 3 to 20 months. Conclusions: The occurrence rate of METex14 skipping mutations in Chinese NSCLC patients is low. Low frequency ( < 1%) METex14 mutations usually co-exist with other driver mutations while high frequency METex14 mutations do not. That little infiltration of CD8+ T cells in tumor region might be associated with poor responsiveness of NSCLC patients carrying METex14 skipping alterations to immunotherapy. Our clinical cases exhibited promising antitumor activity of crizotinib in Chinese NSCLC patients harboring METex14 skipping alterations.
Effect of concurrent TP53 mutation in EGFR/ALK/ROS1 positive non-small cell lung cancer treated with first-line TKI therapy: A Single Institution Retrospective Study.
Authors: Sharma Sandhya , Miao Emily , Fishbein Joanna Stein , Lee Chung-Shien , Sullivan Kevin M. , Seetharamu Nagashree
Published: May 2019

e20592

Background: Tyrosine Kinase Inhibitors (TKI) are the mainstay of therapy for patients (pts) with EGFR/ALK/ROS1 positive (pos) non-small cell lung cancer (NSCLC), however resistance to these drugs is inevitable and remains a clinical challenge. The cause for early resistance leading to progression has not been fully understood, but several mechanisms have been reported. We conducted a retrospective study to determine the impact of concurrent TP53 mutation (TP53m) in this population. Methods: NSCLC pts treated with first line TKI from 01/2014 to 06/2017 were studied. Descriptive statistics were computed. Progression was equated with TKI resistance (TKIr). We compared time to TKIr among pts with TP53m to those without. Standard survival analysis methods (i.e., Kaplan-Meier curves and multivariable Cox proportional hazards regression) were used. Results: Forty-two subjects on first line treatment TKI were included. The mean (SD) age was 67.2 (14.7) years. 37 (88%) were EGFR, 4 (10%) were ALK and 1 (2%) were ROS pos. 76% were female, 50% White, 74% non-smokers and 50% had a TP53m. The estimated median time to TKIr was 19.4 months. At 24 months from start of therapy, the predicted probability of not reaching TKIr was 46% (95% CI: 26-64%). The estimated median time to TKIr among those without TP53m is 19.4 months vs 14.4 months in those with TP53m (p = 0.13). The predicted probability of no TKIr at 12 months from start of therapy among those with and without TP53m were 59% and 80%, respectively. In multivariable analysis, TP53 status remained nonsignificant (p = 0.08) after adjusting for line of therapy. Conclusions: TP53m has been associated with worse prognosis in various cancers. The results from the studies looking at association between TP53m and NSCLC with targetable mutation have been mixed, with few studies demonstrating the association of TP53m with poor survival and earlier treatment resistance. In our study, although there was a tendency towards improved survival and delayed TKIr in the cohort without TP53m, it was not statistically significant, which may be due to small sample size. Further studies looking at concurrent TP53m and targetable mutation are required, which may help clinicians deciding how to direct therapy in this population.
The HGF-MET signaling pathway is enriched in LUAC brain metastases.
Authors: Velez Maria A , Yochum Zachary A. , Chandran Uma R. , Chakka Anish , Bhattacharya Saveri , Somasundaram Aswin , LaFramboise William , Wallweber Gerald , Ravanera Roy , Kurland Brenda F , Dacic Sanja , Stabile Laura P. , Burns Timothy F.
Published: May 2019

e20597

Background: Brain metastases occur in over 40% of non-small cell lung cancer (NSCLC) patients leading to a poor prognosis. c-Met (MET) is a receptor tyrosine kinase that upon binding hepatocyte growth factor (HGF), mediates proliferation, epithelial-mesenchymal transition (EMT), invasion, angiogenesis and metastasis. We have previously shown that the EMT transcription factor, TWIST1 is required for proliferation in MET driven NSCLC. Therefore, the HGF/MET/TWIST1 pathway may be a significant determinant of metastatic potential to the brain. Methods: We evaluated 125 lung adenocarcinoma (LUAC) brain metastases for MET amplification by FISH as well as other molecular alterations using targeted next generation sequencing in a subset of brain metastases (N = 74) and primary LUAC (N = 171) samples including 13 paired primary and brain sets. MET activation was examined in paired tumors using a HGF-MET proximity binding, dual-antibody assay (VeraTag; Monogram Biosciences). TWIST1 and EMT markers in the paired sets were measured by immunohistochemistry. Results: Compared to primary LUAC, we found that 17 pathogenic variants including TP53, SMAD4, RB1, RET, APC, ALK, FGFR3, EGFR, STK11 and MET alterations were significantly more common in LUAC brain metastases (adj. p values ≤ 0.02). Specifically, MET amplification was significantly enriched in LUAC brain metastases (23/125, 19%) compared to 2-4% in non-brain metastatic and primary sites. Among paired samples, 2/13 brain metastases had MET amplification that was not found in the primary tumor. MET mutations were also present in 16/74 brain cases (22%) compared to 9% (16/171) observed in the lung. VHL mutations were associated with MET altered cases compared to non- MET altered cases. MET expression was increased in the majority of brain metastases compared to the paired LUAC and there were 3 cases with brain specific MET activation. We found that TWIST1 was induced by HGF and determined response to MET TKIs in vitro. Among paired samples, TWIST1 was increased in brain metastases compared to primary LUAC in a subset of cases. Further analyses of TWIST1 and EMT markers is ongoing. Conclusions: Over a third of brain metastases have MET alterations compared to primary LUAC and may be responsive to MET inhibitors.
A phase I open prospective cohort trial of curcumin plus tyrosine kinase inhibitors for EGFR-mutant advanced non-small cell lung cancer.
Authors: Esfahani Khashayar , Boodaghians Levon , Kasymjanova Goulnar , Agulnik Jason Scott , Pepe Carmela , Sakr Lama , Small David I. , Jagoe Tomas R. , Cohen Victor
Published: May 2019

e20611

Background: An increasing number of patients with lung cancer use natural products concurrently with conventional treatments, one of which is curcumin, or diferuloylmethane, the main ingredient in the popular spice known as curry. Curcumin has been shown to have anti-carcinogenic effects on human lung cancer cell lines and in vivo models, as well as the potential to modulate all three known pathways accounting for resistance to EGFR-TKIs. More specifically, curcumin dose-dependently suppresses EGFR expression, reduces transactivation of the MET oncogene, and reduces inflammation in the tumor microenvironment by selectively inhibiting TGF-β, IL-6, C-reactive protein (CRP) as well as TNF-α. Despite these promising findings, no studies have yet assessed the safety of introducing curcumin alongside EGFR-TKIs in a lung cancer population. Methods: We performed a phase 1 open prospective cohort study to assess the safety and feasibility of using an enhanced bioavailable formulation of curcumin (CURCUViva TM at 80 mg/ 1 capsule per day) approved and licensed by Health Canada (NPN 80027414) in conjunction with an EGFR-TKI in patients with advanced NSCLC (ClinicalTrials.gov: NCT02321293). The primary objective was to determine safety and feasibility. Exploratory objectives were monitoring changes in health-related quality of life using the standardized FACT-L questionnaire and evaluating anti-inflammatory properties of curcumin by measuring CRP. Results: 55 patients were approached, of whom 75% were interested in using curcumin. Completion rate (80%) and adherence (82%) levels were very high; most patients perceived the product as easy to take and were willing to take it again if it were available. Nine patients refused to participate solely due to frequent clinic visits. A total of 37 adverse events were reported, all of which were mild (Grade 1 or 2). The vast majority were pre-existing and related to TKI treatment. No biochemical or hematological evidence of toxicity was observed. Overall, there was improvement in quality of life, and improvement in the LCS of the FACT-L (p = 0.06). There was no significant change in CRP levels. Conclusions: This study provides preliminary evidence that short-term use of curcumin in EGFR-positive patients treated with TKIs is feasible and safe. We report high treatment adherence and improved quality of life with curcumin. These findings, as well as efficacy data and the effect of curcumin on other inflammation-associated biomarkers, warrant investigation in a larger phase 2 study. Clinical trial information: NCT02321293.
Clinical, pathological and molecular characterization of long-term survivors with advanced non-small cell lung cancer in a multicenter experience in Madrid: Final results.
Authors: Moreno Juan , Ponce Aix Santiago , Alvarez Alvarez Rosa Maria , Olmedo Garcia Maria Eugenia , Falagan Sandra , Mielgo Xabier , Navarro FÃ¡tima , Cruz Patricia , Cabezon-Gutierrez Luis , Muñoz Fernandez de Legaria Marta , Enguita Ana Belen , Cebollero Maria , Benito Amparo , Alemany Isabel , Castillo Torres Carolina , Ramirez de Molina Ana , Casado Enrique , Ramos Ricardo , Colmenarejo Gonzalo , Sereno Moyano Maria
Published: May 2019

e20621

Background: Long survivors (LS) in non-small-cell lung cancer (NSCLC), defined as an overall survival (OS) greater than 2 years, are less than 10% in most series. Classical prognosis factors include stage, weight loss and ECOG, but more information is missing in the literature. Recently, EGFR, ALK and ROS 1 population (less than 20%) reach OS longer than 2 years. Immunotherapy has demonstrated very promising results with more LS compared to chemotherapy in first and second line setting. In this study, we focused in the analysis of LS patients with advanced NSCLC EGFR wt (wild type) and ALK nt (non-translocated), defined as those with OS greater than 36 months, in 7 hospitals in Madrid. Methods: In this serie, first of all, we will try to make a clinical, histopathological characterization collecting data from clinical reports according to a previously defined information. In a second step, we will carry out a genetic analysis of these patient samples comparing to an opposite extreme short survivors (SS) samples (OS less than 9 months). Initially, we used a NGS method of RNA-seq technology to identify differentiating profiles of gene expression between the two opposite populations. And finally, we confirmed this preliminary profile by RT-PCR in the rest of samples. Results: Ninety-six patients were initially included. The majority were men, smokers or former with adenocarcinoma and ECOG 0- 1. We have obtained a differential transcriptome expression between samples from 6 LS and 6 SS, resulting 13 over-expressed and 42 down-expressed genes in LS comparing to SS transcriptome expression. Some of the genes involved in this initial profile belong to different cellular pathways: Secretin Receptor, Surfactant Protein, Trefoil Factor 1, Serpin Family, Ca-bindings Protein channel and Toll like Receptor family. Finally, we carried on by RT-PCR in 40 samples of SS and LS survivors and only four genes were significantly down-regulated in SS compared to LS in the multivariate analysis. These 4 genes were related to Surfactant Proteins: SFTPA1 (p = 0.023), SFTPA2 (p = 0.027), SFTPB (p = 0.02) and SFTPC (p = 0.047). Conclusions: We present a sequential genetic analysis of a LS population with NSCLC EGFR wt (wild type) and ALK nt (non-translocated), obtaining a differential RNA seq- and RT-PCR gene profile based on different surfactant proteins expression. A further confirmation in a larger sample is ongoing.
Clinical outcomes of NSCLC patients with acquired RET rearrangement after resistance to osimertinib.
Authors: Lu Chang , Cheng Jia-Tao , Kang Jin , Yao Yi-Hui , Li Xiang-Meng , Zhang Xuchao , Zhou Qing , Tu Hai-Yan , Wu Yi-Long , Yang Jin-Ji
Published: May 2019

e20626

Background: Resistance mechanisms to osimertinib have raised growing concerns, but those with acquired RET rearrangement is poorly characterized. Methods: We retrospectively identified advanced, EGFR-mutant NSCLC (non-small-cell lung cancer) patients treated with osimertinib between April 9th, 2015 and November 1st, 2018 at our institute. Clinicopathologic features and clinical outcomes were analyzed. Subsequent genetic profiling was performed at the time of progression by next-generation sequencing (NGS). Overall survival (OS) since 1st line treatment was calculated from first-line treatment start to death or last follow up, and OS post-progression was calculated from osimertinib progression. Median follow-up time was 43.4 months. Results: In the 192 patients treated with osimertinib, 57 had follow-up NGS information after progression, and six harboured acquired RET rearrangement (11%, 6/57). For patients with RET rearrangements when progressed on osimertinib, OS since 1st line treatment (22.9m vs 59.5m, P = 0.021) and OS post-progression (2.1m vs 10.0m, P = 0.031) were significantly shorter compared with non- RET-rearranged cases, whereas no significant difference was found in demographics at the initial lung cancer diagnosis or progression-free survival (PFS) of osimertinib (12.1m vs 5.8m, P = 0.34). Among these six patients, one received best supportive care, two continued to use drugs targeting EGFR but deteriorating soon, three patients tried osimertinib combined with cabozantinib with one benefit from this combination approach. Conclusions: RET rearrangements could exist in EGFR-mutant NSCLC with acquired resistance to osimertinib and linked to inferior survival. Study on the molecular evolution and heterogeneity during treatment course are warranted for further therapeutic strategies. [Table: see text]
CDKN2A/B gene loss and MDM2 alteration as a potential molecular signature for hyperprogressive disease in advanced NSCLC: A next-generation-sequencing approach.
Authors: Giusti Raffaele , Mazzotta Marco , Filetti Marco , Marinelli Daniele , Di Napoli Arianna , Scarpino Stefania , Scafetta Giorgia , Mei Monica , Vecchione Andrea , Ruco Luigi , Marchetti Paolo
Published: May 2019

e20628

Background: Hyperprogressive disease (HPD) incidence ranges from 8% to 21% in patients treated with anti-PD-1/PD-L1 mAbs in NSCLC and is associated with poor survival. Previously published data underlined a link between HPD across different cancers types and specific genetic alterations, such as MDM2 amplification and EGFR aberrations. We present a single-center cohort of patients with NSCLC and PD-L1 > 50% treated with 1st-line pembrolizumab. We performed NGS, IHC and FISH analysis to evaluate genetic correlations with the clinical phenotype. Methods: Clinical data from 20 patients with diagnosis of advanced NSCLC treated with 1stline immunotherapy pembrolizumab were retrospectively collected. HPD was defined by Time to Treatment Failure ≤2 months and raising in Tumor Burden ≥50% compared with basal CT-scan. MDM2 amplification was investigated by FISH on FFPE tissue sections using the MDM2/CON12 break apart FISH Probe. Positive cases were defined as those with > 10% positive tumor cells. We performed IHC for MDM2 protein on FFPE tissue sections. The staining was semiquantitatively graded for the intensity as: 0, negative; 1+, weak positive; 2+, moderately positive; 3+, strongly positive, and for the extent as 0– < 1% (negative), 1–50% (focal), and > 50% (diffuse). We also performed NGS analysis (FoundationOne CDX, Foundation Medicine Inc.) on 324 preidentified genes. Results: We identified 5 cases of HPD; all five cases showed MDM2amplification by FISH analysis and a focal protein expression by IHC with the strongest nuclear staining observed in the cases showing a higher degree of MDM2 amplification (8/9 dots) and a weaker expression in those with a lower MDM2amplification (4/5 dots). NGS analysis showed MDM2amplification in 1/5 HPD patient and a loss of CDKN2A/B in 4/5 patients. None of the non-HPD patients had IHC expression of MDM2 or amplification of the gene. Among the non-HPD patients no genetic alterations regarding MDM2 and/or CDKN2A/B were found on NGS analysis. Conclusions: Our data suggest a potential role of CDKN2A/B gene loss and alteration of MDM2 on the establishment of HPD in NSCLC patients treated with immunotherapy. Because the HPD logic is not yet clear, more data is needed to better understand the link between this genomic signature and the development of HPD.
Efficacy and safety of Crizotinib in patients with ALK positive non small cell lung cancer (NSCLC): Real-world findings.
Authors: Raposeiras Cristina Azpitarte , De Dios Alvarez Noemi , Garcia Jorge , Areses Manrique Maria Carmen , Fernández Núñez Natalia , Afonso Afonso Francisco J. , Amenedo Margarita , Veiga Nazaret Quiroga , Cebey Victor , Lazaro Quintela Martin , Firvida Jose-luis , Campos Balea Begoña , Ruiz Bañobre Juan , Varela Pose Vanesa , Agraso Busto Sara , Constenla Manuel
Published: May 2019

e20636

Background: First or second line crizotinib has shown greater efficacy in clinical trials than chemotherapy in patients with NSCLC ALK positive and it was the first approved ALK inhibitor. However, there are limited data describing the use of crizotinib and its outcomes in real-world settings. Methods: This is a retrospective, observational study of patients crizotinib treated ALK positive metastatic NSCLC, who received treatment between 1 January 2013 and 30 november 2018. The primary objective was progression free survival (PFS); secondary objetives were overall survival (OS), response rates and toxicity. Results: Fifty-eight patients with NSCLC ALK+ were recollected, 33 women and 25 men. The median age was 61 years (25-88); 46.6% were never smokers, 31% were former smokers. The majority (96.6%) had confirmed adenocarcinoma histology and 25.9% had brain metastases at inicial treatment. Crizotinib was used as first line 55.2% and second line in 37.9%. Progression disease was the most frequent reason of discontinuation of crizotinib (74%) and in 5 patients was discontinued because of toxicity. The most frequent toxicities were edemas (37.9%), increased transaminases (27.5), diarrhea (24%) and nauseas (20%). Grade 3-4 toxicities were present in 4 cases with increase transaminases, 1 case of neumonitis and 2 patients with diarrhea. The response rate was 63.8%. The median PFS was 12.66 months (95% CI :7.95- 17.38) and median OS was 23.36 months (95%CI: 16.29-30.44).In patients with brain metastases (15) the response rate was 46.6% and median OS decrease to 15.36 months (95%CI: 0.1-30.8). Conclusions: Our findings indicate that the results of crizotinib in the real world are consistent or sightly improved with prior clinical trial in PFS and OS, despite our sample includes patients for first line and second/later line crizotinib and ¼ of patients had brain metastasic at crizotinib initiation.
Real-world treatment patterns, survival, and cost among elderly patients with small-cell lung cancer (SCLC).
Authors: Shao Changxia , He Jinghua , Kachroo Sumesh , Jin Fan
Published: May 2019

e20647

Background: Given a dearth of literature, this study aimed to investigate real-world use of systemic therapies, survival, and costs among elderly SCLC patients (pts) in U.S. Methods: Pts (65+ years old) with an initial diagnosis of SCLC during 2007-2013 were identified using the SEER-Medicare data. Overall survival (OS), duration of treatment (DOT) and time to next treatment (TTNT) were estimated based on the Kaplan-Meier method. Costs (2016 US dollars) were derived from Medicare claims. Results: A total of 11 812 pts were identified with 7 797 (66%) being stage IV at diagnosis. During an average of 10 months (m) follow-up post diagnosis, 6 509 (55%), 2 238 (19%) and 679 (6%) received first line (1L), 2L and 3L therapy, respectively. The median OS was 9 m from 1L start and 6 m from 2L or 3L start, suggesting existing treatment providing limited survival benefit. Majority pts (93%) received platinum-based therapy for 1L with Car + etoposide (Eto, 59%) being the most commonly used regimen, followed by Cis + Eto (18%) and Car monotherapy (8%). Car + Eto, Top and Pac were the top 3 regimens used in 2L and 3L. Median DOTs were 4-6 m, yet TTNT ranged from 7 to 18 m across lines of therapy. The average per person per month (PPPM) costs were $9.4k for 1L, $8.9k for 2L, and $8.8k for 3L. Conclusions: Advanced SCLC remains an aggressive malignancy with poor prognosis, lack of ideal therapy and high medical cost, which highlighted high unmet medical need of SCLC among elderly pts. [Table: see text]
Health care utilization associated with adverse events (AEs) among metastatic non-small cell lung cancer (mNSCLC) patients treated with immunotherapy or chemotherapy.
Authors: Engel-Nitz Nicole , Ryan Kellie , Johnson Michael P , Bunner Scott
Published: May 2019

e20655

Background: Chemotherapy and immunotherapy (IO) are associated with increased overall survival in patients with mNSCLC, yet real-world data on AE-associated healthcare utilization are sparse. This study assessed incidence and utilization associated with AEs among patients initiating first-line treatment for mNSCLC with IO, IO with chemotherapy (IC), or chemotherapy alone (CH). Methods: Data were claims from commercial and Medicare Advantage patients (Jan 2008-Feb 2018). Inclusion criteria were mNSCLC, health plan enrollment for ≥6 months pre- (baseline) and ≥1 month post-index date; initiation of recommended systemic therapy for mNSCLC. Excluded were targeted or small-cell lung cancer therapy, and baseline surgery or other systemic therapy. AE incidence and healthcare utilization were measured from start of 1st line therapy until earliest of start of 2nd line therapy or 180 days. AEs evaluated included hematologic, GI, endocrine, infections, infusion reactions, muscle, neurological, and respiratory. Results: Cohorts were 8,818 CH, 482 IO, and 412 IC. Mean age was older for IO (72 yrs, vs. 69 IC, 68 CH; P < 0.001). IOs used were atezolizumab (n = 12), nivolumab (n = 148), and pembrolizumab (n = 673). Common chemotherapies were carboplatin (74%), pemetrexed (30%), and paclitaxel or etoposide (22%). Overall, 74% had ≥1 AE; incidence rate ratios (IRR) vs. IO (95% CI) were IC 1.36 (1.15-1.60) and CH 1.43 (1.28-1.61). Frequent AEs were blood conditions (43%), GI (32%), and infections (29%). IRR vs. IO included infections (1.94 CH), GI (1.71 IC, 1.90 CH), anemia (4.05 IC, 5.68 CH), leukopenia (5.69 IC, 22.28 CH), and thrombocytopenia (3.70 CH). CH had lower rates vs. IO for hyperthyroidism (2% IO; IRR 0.16 CH) and hypothyroidism (12% IO; IRR 0.19 CH). AE overlaps with infection were common; 61% of patients with infection had a hospitalization that involved both infection and another AE. AE-associated visits varied by cohort; ambulatory: 46% (IO), 50% IC, 61% CH; ER: 25% IO, 27% IC, 30% CH; inpatient: 29% IO, 35% IC, 37% CH (P < 0.05 for all CH vs IO). Conclusions: AE-associated visits in mNSCLC were lower for IO-treated than for CH or IC-treated patients.
The role of low dose aspirin, vitamin D, or metformin in EGFR, ALK, and ROS positive non-small cell lung cancer: A single institution retrospective analysis.
Authors: Bernabe Ramirez Carolina , Sharma Sandhya , Sanchez-Escobar Jose G , Sullivan Kevin M. , Seetharamu Nagashree
Published: May 2019

e20656

Background: Tyrosine kinase inhibitor (TKI) is the backbone therapy for EGFR, ALK and ROS positive (pos) non-small cell lung cancer (NSCLC). Metformin has shown to sensitize EGFR resistant lung cancer cells in vitro through IL-6/STAT pathways. COX-2 overexpression triggers activation of a transcription factor that binds to EGFR that activates MAPK signaling pathway. Vitamin D receptor (VDR) has shown to directly inhibit EGFR transcriptional activity. Some studies have shown that adding metformin, aspirin and vitamin D (MAD) to chemotherapy may improve progression free survival (PFS) and overall survival (OS) in lung cancer. However, data supporting use of MAD is unknown in EGFR, ALK and ROS pos NSCLC. Methods: Patients (pts) with EGFR, ALK, ROS pos NSCLC treated with first line TKI from January 2014 to June 2017 were included. Information on concurrent use of MAD was obtained. Patients were dichotomized based on use of these individual supportive medications. Two sample t-test was used to compare mean PFS and chi-square test to compare proportions of disease control rate (DCR) at 3 months between groups. Results: 74 patients were included. Vitamin D supplementation (n = 38, 51.3%) prolonged PFS by 16 m vs 11 m (p = 0.04; 95%CI 0.23 to 9.34). For those on aspirin (n = 23, 35%), mean PFS was 16m vs 12.5 m (p = 0.72; 95% CI -5.58to 3.88). Mean PFS for pts on metformin (n = 8, 10%) was 14 months (m) vs 13.5 m for those who were not (p = 0.93, 95% CI -7.27 to 7.87). DCR for metformin use was 26.5% vs 89% (p = 0.0001); for aspirin was 50% vs 65% (p = 0.17) and for vitamin D 48.6% vs 43.7% (p = 0.69). Conclusions: To our knowledge, no data has been published regarding use of MAD in NSCLC with driver mutations. In our study, concurrent use of vitamin D with TKI prolonged PFS in these pts. However, this effect was not seen with metformin or aspirin. Our study was limited by retrospective design, possible under-reporting of medication use by patients and small patient population. Further prospective studies using these medications is important to evaluate the synergistic benefit with the approved targeted therapy.
Correlating the effects of VeriStrat result, anti-PD1 therapy, and neutrophil-to-lymphocyte ratio (NLR) on progression-free survival (PFS) in patients with stage IV non-small cell lung cancer (NSCLC).
Authors: Randall Megan , Basu Sanjib , Batus Marta , Borgia Jeffrey Allen , Bonomi Philip D. , Fidler Mary J.
Published: May 2019

e20660

Background: Biodesix VeriStrat (VS) is a mass spectrometry assay found to be prognostic in previously treated and front-line NSCLC patients. A label assigns a “good” or “poor” result and is believed to in part represent host inflammatory reaction to tumor. This study looks to correlate VS good (VS-G) or poor (VS-P) label with the neutrophil to lymphocyte ratio (NLR) and outcomes in front-line NSCLC patients who were screened for actionable mutations as part of a companion diagnostic. Methods: Retrospective chart review was conducted of 76 patients with advanced NSCLC who had pretreatment VS testing. Included patients had at least 3-month follow up. Chi squared analysis was used to correlate VS label with patient characteristics and Cox proportional hazards was used to correlate PFS with VS label, NLR and other baseline characteristics in patients receiving anti-PD1 targeted therapy as part of their first treatment. Results: Median PFS was 6.31 months (follow up range 3-17 months). Of 76 tested patients, 23 never received treatment and 47 received anti-PD1 therapy. 51 had VS-G and 23 had VS-P (2 indeterminate). Using two standard NLR cutoffs of 3.5 and 5, 29 and 47, and 42 and 34 had values above and below the cutoff, respectively. VS-G vs VS-P correlated with performance status (PS) as well as NLR at both cut points and on a continuous scale. (P = 0.031, 0.043, 0.045, and 0.056 respectively, VS-G correlating with good PS and low NLR). There was no correlation with PDL1 or body mass index. On multivariate analysis VS label and NLR were also associated with PFS and OS (P = < 0.001 and P = 0.046). Among a subset of 47 patients treated with ICIs, VS-G and NLR < 5 were associated with longer PFS (P = 0.010 and 0.010) though PDL1 result was not. Conclusions: This is the first description of the performance of the VS mass spectrometry assay in front-line patients whose regimen included an anti-PD1 agent. The VS label was able to predict for PFS in this patient population despite relatively short follow up. VS-G label also correlated with low NLR by multiple methods analyzed. Further evaluation of the impact of cytotoxic chemotherapy to anti-PD1 is warranted.
A retrospective study of low-dose apatinib combined with S-1 in patients with advanced non-small cell lung cancer.
Authors: Zhou Tong , Zhou Xiaoyue , Li Peng , Wu Changling , Zhang Changsong , Dong Huajie , Lu Hongjun , Qi Martin , Ling Yang
Published: May 2019

e20666

Background: Currently regimen for advanced non-small cell lung cancer (NSCLC) failing from standard treatment is deficient. This retrospective study aimed to assess the efficacy and safety of low-dose apatinib in combination with S-1 therapy in this NSCLC setting. Methods: In this retrospective study, advanced NSCLC patients who failed from standard treatment in Changzhou Cancer Hospital of Soochow University were screened for eligibility. Progression-free survival (PFS) was set as the primary endpoint. Overall response rate (ORR), disease control rate (DCR), Overall survival (OS) and safety profile were considered to be the secondary endpoints. Results: 31 eligible patients were included in this study. The median PFS (mPFS) was 102 days (95% CI: 57-147). 7 patients (23%; 95% CI: 11-38%) achieved an objective response and the DCR was maintained in 23 patients (75%; 95% CI: 58-86%). The median OS (mOS) was 422 days (95% CI: 148-696).Patients with smoking had a tendency for shorter overall survival without significant differences (HR = 4.105, 95% CI: 0.874-19.288, P = 0.074). Treatment-related grade 3 toxicity was observed in five patients (16%) and the common grade 1 or 2 adverse events were fatigue (42%), hypertension (32%), and hand-foot-skin reaction (23%). Conclusions: Combination of low-dose apatinib and S-1 could be effective and tolerable for advanced NSCLC patients failed from standard treatment, but further exploration in larger clinical trials is needed.
Phase II study of apatinib combined with vinorelbine in second-line treatment failure non-driver gene mutation advanced non-small cell lung cancer (NCT03652857).
Authors: Zhang Yongchang , Wu Fang , Xiong Yi , Zhang Xiangyu , Yang Nong
Published: May 2019

e20669

Background: There is currently no standard treatment strategy for non-driver gene mutation advanced non-small cell lung cancer (NSCLC) patients experiencing progression after two or more lines of chemotherapy. Our study assessed the efficacy and safety of apatinib combined with vinorelbine in non-driver gene advanced NSCLC patients for whom at least two lines of prior chemotherapy had failed. Methods: This is a Phase II, single arm clinical trial. 30 advanced NSCLC patients who had two or more prior lines of chemotherapy had failed enrolled in this study. All the patients received treatment of apatinib 500mg, po qd plus vinorelbine 60mg/m2 po qweek. The primary endpoint was overall response rate (ORR). Secondary endpoints were overall (OS), progression-free survival (PFS), disease control rate (DCR) and safety. Results: Between January 2016 and November 2018, 30 patients were enrolled. 25 patients finished all the treatment. 5 patients discontinued the treatment for adverse events. The ORR of all the patients was 36.3 %( 11/30). The DCR of all the patients was 76.3 %( 23/30). The median PFS of all the patients was 4.5months (95% CI 2.4-6.6m). The median OS of all the patients was 10months (3.8m-16.2m). The most common grade 3 to 4 adverse events were non-hematologic including hand-foot syndrome. Moreover, medicine reduction seem not be an important role in disease prognosis. Conclusions: These data show that apatinib combined with vinorelbine can be a good choose with an acceptable safety profile in non-driver gene mutation advanced NSCLC patients refractory to two or more lines of prior chemotherapy. Clinical trial information: NCT03652857.
Neoantigen-based personalized DC vaccine for lung cancer: An update of translational study.
Authors: Ding Zhenyu , Yang Li , Xu Heng , Li Qing , Li Qiu
Published: May 2019

e20674

Background: DC vaccine is a promising strategy for cancer therapy. We conducts a personalized, neoantigen-loaded DC therapy trial in advanced NSCLC (NCT02956551 & ChiCTR-ONC-16009100). Here we provide the updated data. Methods: Advanced lung cancer patients in their later lines of therapy were enrolled. Whole exon dequencing was performed from freshly obtained tumor tissues as well as the peripheral blood, while RNA-seq was performed in tumor-derived RNA. Somatic mutations were submitted ot systematical progream of neoantigen predication, considring personalized MHC affinity, gene expression, tumor herogeneity, and etc. 10-15 peptides with the highest score were synthesized and pulsed in PBMC-dericed DC, which was introduced to patients. All cells were prepared in a GMP workshop. The primary endpoint was safety and toleratility. Results: Totally 11 patients were enrolled up to now. Most (n = 5) were adenocarcinoma, and the rest were squamous cancer (n = 4) and NET (n = 2). They were heavily treated (lines of previous therapy: 2-5, median 2). 1 patient failed in re-biopsy, 1 lacked candidate neoantigen, and another died rapdily during the preparation of DC vaccine. 8 patient finally received vaccination (n = 6, male; n = 2, female). The number of neoantigens identified from each patient vairied greatly (35-441, median n = 68). Totally 37 times of vaccination was performed (5-17, median 5). The cell infusion was safe and highly tolerable and no significant side effects were observed, even for those with poor performance. The treatment achieved SD in 7 patients, and only 1 with PD. The median PFS was 5.7m (range: 3.8-10.0m). 5 patients are now maintained on therapy. Conclusions: The neoantigen based personalized DC vaccine is highly tolerable without obvious side effects. The vaccination strategy shows promise in efficacy. Clinical trial information: NCT02956551.
FDA analysis of outcomes in Asian patients (pts) with metastatic non-small cell lung cancer (mNSCLC) receiving immune checkpoint inhibitors (ICI).
Authors: Chang Elaine , Gong Yutao , Vallejo Jonathon Joseph , LIU QI , Mathieu Luckson Noe , Booth Brian , Sridhara Rajeshwari , Beaver Julia A. , Pazdur Richard , Blumenthal Gideon Michael
Published: May 2019

e20690

Background: Asian pts tend to be well-represented in mNSCLC clinical trials, and drug development in Asia is growing. We sought to investigate outcomes of Asian pts enrolled in clinical trials testing ICI in mNSCLC. Methods: We identified 11 ICI mNSCLC randomized trials submitted to FDA 2014-2018. We divided the trials into 3 groups: 1st-line monotherapy (1L-M), 1st-line combination with chemotherapy [chemo] (1L-C), and 2nd-line monotherapy (2L-M). Overall survival (OS) and progression-free survival (PFS) were evaluated with Kaplan-Meier methodology. We performed meta-analyses to assess if treatment effect is consistent across Asian and non-Asian populations. Results: There were 3399 patients enrolled in five 2L-M trials, 1579 in two 1L-M trials, and 2500 in four 1L-C trials. Most Asian pts were located geographically in Asia (90%). Asians comprised 15% of patients enrolled in 2L-M trials, 27% in 1L-M, and 11% in 1L-C. Compared to non-Asians, a higher proportion of Asians were never-smokers (32% vs. 13%) and EGFR-mutated (13% vs. 4%). Asian pts had better unadjusted and adjusted OS than non-Asian pts for each treatment in each line of therapy. The 3 covariates with greatest prognostic impact on OS in 2L-M were race, performance status, and histology. The magnitude of ICI treatment effect relative to chemo was similar for Asian and non-Asian pts. Conclusions: Asians appear to have better prognosis than non-Asians; no uniquely better or worse benefit was observed from ICI when compared to chemotherapy. [Table: see text]
Impact of cholesterolemia and body mass index on outcome of metastatic non small cell lung cancer treated with immunotherapy.
Authors: Galli Giulia , Corsetto Paola , Ferrara Roberto , Prelaj Arsela , Proto Claudia , Signorelli Diego , Zilembo Nicoletta , De Toma Alessandro , Pagani Filippo , Randon Giovanni , Ganzinelli Monica , Sica Antonio , De Braud Filippo G. , Garassino Marina Chiara , Lo Russo Giuseppe
Published: May 2019

e20691

Background: Immunotherapy (IO) is effective against metastatic Non Small Cell Lung Cancer (mNSCLC). Nonetheless, a minority of patients (pts) gains a benefit from IO and predictive variables of response are scarcely understood. Previous retrospective studies have showed a superior outcome for obese pts and preclinical data suggest a role of lipid profile. We aimed at investigating these topics in a cohort of pts with mNSCLC. Methods: We retrospectively collected data about all consecutive pts with mNSCLC treated with IO at our Institution between 12/2017 and 12/2018. Body Mass Index (BMI) was calculated as weight/height2; pts were classified as overweight if having a BMI≥25 kg/m2. Basal Cholesterolemia (BC) was dosed between one month (mo) before and one mo after the beginning of IO, with a cut-off for normality of 200 mg/dL. Survival was estimated with Kaplan-Meier method. Cox model was used for multivariate analyses. Results: We identified 55 pts. Thirty-three had a normal baseline BMI, the remaining were overweighted. Median BC was 171.5 mg/dL (range 15-313); 14 pts had hypercholesterolemia. No correlation was evident between BMI and BC ( p .1772). Neither BMI nor BC were associated to first and best response to IO. Median Progression Free Survival (PFS) was 3.75 mos; median Overall Survival (OS) was 6.78 mos. Hypercholesterolemia was related to longer PFS (9.44 vs 3.71 mos, p .0484), confirmed at multivariate analysis ( p.0392). Both hypercholesterolemia and BMI≥25 kg/m2 were associated to longer OS (15.56 vs 5.13 mos, p.0411, and 16.67 vs 4.97 mos, p.0222, respectively), but only BMI retained significance at multivariate analysis ( p .0279). Conclusions: Hypercholesterolemia shows a positive impact on outcome of mNSCLC treated with IO. The independence of this correlation from BMI suggests the existence of a true different metabolic pathways. Moreover, overweight patients have a longer OS than those with normal BMI. This result confirms previous data on obese patients, extending the range of BMI values that are linked to a better prognosis. In conclusion, the role of metabolism and body composition in defining the benefit from IO in mNSCLC is likely multifaceted, warranting further investigation.
A survey of healthcare professionals and oncology patients at the McGill University Health Centre reveals enthusiasm towards establishing a post-mortem rapid tissue donation program.
Authors: Dankner Matthew , Senecal Julien , Neubarth Noah , Bertos Nicholas , Park Morag , Issa-Chergui Badia , Asselah Jamil , Siegel Peter , Bouganim Nathaniel
Published: May 2019

e23005

Background: In the early developmental phase of a post-mortem Rapid Tissue Donation (RTD) program for metastatic cancer patients, we surveyed health care professionals (HCPs) and oncology patients at the McGill University Health Centre (MUHC) to assess their knowledge and attitudes pertaining to RTD from metastatic cancer patients for research purposes. Methods: A 23-item survey was developed and distributed to HCPs at tumour board meetings, and a related 26-item survey was developed and distributed to oncology patients at the MUHC Cedars Cancer Centre. Results: 73 HCPs, including 37 attending physicians, and 102 oncology patients participated in the study. Despite the fact that 88% of HCPs rated their knowledge of RTD as none or limited, 42% indicated that they would feel comfortable discussing RTD with their cancer patients. 67% of HCPs indicated that their current knowledge of RTD would impact their decision to discuss such a program with patients, implying the importance of educating HCPs to facilitate enrolment of patients into an RTD program. 78% of patients indicated that they would not be uncomfortable if their doctor discussed RTD with them, and 61% indicated that they would like for their doctor to discuss RTD with them. HCPs and patients felt that the best time for patients to be approached about consenting to an RTD program is in the transition to palliative care when there are no treatment options remaining. Conclusions: HCPs and patients at the MUHC are generally enthusiastic about adopting an RTD program for metastatic cancer patients. Education of HCPs and patients will be an important determinant of the program’s success.