bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase 3 study of maintenance therapy with S-1 plus best supportive care (BSC) versus BSC alone after induction therapy with carboplatin plus S-1 for advanced or relapsed squamous cell lung carcinoma (WJOG7512L).
Authors: Tanaka Kaoru , Morita Satoshi , Ando Masahiko , Yokoyama Takuma , Nakamura Atsushi , Yoshioka Hiroshige , Ishiguro Takashi , Miura Satoru , Toyozawa Ryo , Oguri Tetsuya , Daga Haruko , Ko Ryo , Bessho Akihiro , Tachihara Motoko , Iwamoto Yasuo , Hirano Katsuya , Nakanishi Yoichi , Nakagawa Kazuhiko , Yamamoto Nobuyuki , Okamoto Isamu
Published: May 2019

e20531

Background: Our previous phase 3 study established carboplatin plus the oral fluorinated pyrimidine formulation S-1 as a standard option for first-line treatment of advanced non–small cell lung cancer (NSCLC) (J Clin Oncol 2010; 28:5240). The importance of maintenance therapy for patients with advanced squamous NSCLC has been unknown, however. Methods: WJOG7512L was designed as a randomized phase 3 study to evaluate whether maintenance therapy with S-1 improves clinical outcome after induction therapy with carboplatin plus S-1 in such patients. Before randomization, patients received carboplatin (AUC of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1 to 14 every 3 weeks) as induction therapy. Those who did not progress after four cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective was to confirm the superiority of S-1 plus BSC with regard to progression-free survival. Results: Of the 365 patients enrolled, 347 participated in the induction phase and 131 of these individuals were randomized to receive S-1 plus BSC ( n = 67) or BSC alone ( n = 64). Baseline demographics and clinical characteristics of the subjects, including the response to induction therapy, were well balanced. Patients receiving S-1 plus BSC showed a significantly reduced risk of disease progression compared with those receiving BSC alone (hazard ratio [HR], 0.548; 95% confidence interval [CI], 0.374–0.802; P = 0.0019). Median overall survival from randomization did not differ significantly between the two arms: 17.8 months for BSC alone and 16.7 months for S-1 plus BSC (HR, 0.890; 95% CI, 0.583–1.357). Time to deterioration in quality of life also showed no significant difference ( P = 0.8754 for FACT-TOI, P = 0.9016 for FACT-LCS). The incidence of adverse events during maintenance therapy was low, with neutropenia, anemia, and thrombocytopenia of grade 3 or 4 each occurring in ~1% to 4% of patients. Conclusions: Maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC. Clinical trial information: UMIN000010396.
Comprehensive genomic profiling identifies novel genetic predictors of response to anti-PD-(L)1 therapies in NSCLC.
Authors: Fang Wenfeng , Ma Yuxiang , Yin Jiani , Hong Shaodong , Zhou Huaqiang , Wang Ao , Wang Fufeng , Bao Hua , Wu Xue , Yang Yunpeng , Huang Yan , Zhao Hongyun , Shao Yang , Zhang Li
Published: May 2019

e20536

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many different cancer types, including non-small-cell lung cancer (NSCLC). However, our understandings of the molecular and immunologic determinants of response to ICIs remain incomplete. Methods: We performed whole-exon sequencing (WES) in 73 patients with advanced NSCLC who underwent anti-PD-(L)1 therapies to further explore predictive biomarkers for treatment efficacy. Novel somatic mutations and copy number alterations were identified to be predictive of response or resistance to anti-PD-(L)1 therapies. Results: We confirmed that high tumor mutation burden (TMB) was associated with improved clinical outcomes. Quantification of TMB by targeted next-generation sequencing using a customized panel including 422 cancer-relevant genes (Geneseeq) was strongly correlated with WES results (Spearman's Rho = 0.81, p < 0.001). Patients whose tumour harbored FAT1 mutant had higher durable clinical response (DCB) and objective response rate (ORR) compared with wild-type (62.5% vs 20%, p = 0.02, and 50% vs 12.3%, p = 0.02, respectively), whereas patients with activating mutations in EGFR or ERBB2 had significantly shorter mPFS compared with other patients (51 vs 70.5 days, p = 0.0037, HR = 2.47 [95% CI, 1.33-4.62]). Furthermore, We found copy number loss in specific 3p segments (mPFS, 61.5 vs 65 days; survival rates at 6 months, 0% vs 31%, p = 0.012, HR = 2.08 [95% CI, 1.09-4.00]), which contain the tumor suppressor ITGA9 (mPFS, 36.5 vs 64 days, p < 0.0001, HR = 9.09 [95% CI, 2.91-27.78]) and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome. These findings were further validated in two independently published datasets comprising multiple cancer types. Conclusions: Our findings suggest that comprehensive profiling of TMB and the aforementioned novel genetic alterations could result in greater predictive power of response in NSCLC patients treated with ICI therapies.
Phase Ib study of sintilimab in combination with chemotherapy for 1L advanced or metastatic non-small cell lung cancer (NSCLC).
Authors: Xu Nong , Ying Kejing , Wang Ziping , Liu Yunpeng , Jiang Haiping , Zhou Hui , Wang Shuyan
Published: May 2019

e20546

Background: Anti-programmed death-1 antibodies (PD-1 Abs) have shown benefits in advanced NSCLC. The efficacy and safety of sintilimab, a PD-1 Ab, in combination with chemotherapy for 1L NSCLC is evaluated in this phase Ib study (NCT02937116). Methods: The study enrolled treatment-naïve unresectable locally advanced or metastatic non-squamous (nsq-) and squamous (sq-) NSCLC patients with neither EGFR mutations nor ALK rearrangements in cohort D and E respectively. Patients received sintilimab 200mg IV q3w in combination with pemetrexed 500mg/m2 and cisplatin 75mg/m2 IV q3w (4 cycles) in cohort D, or gemcitabine 1250mg/m2 D1,8 and cisplatin 75mg/m2 D1 IV q3W (6 cycles) in cohort E until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the efficacy and safety of the combination. Results: As data cutoff (15 Jan 2019), 21 and 20 patients were enrolled in cohort D and E respectively. ORR in nsq- and sq-NSCLC were 68.4% (95%CI, 43.4 to 87.4) and 64.7% (95%CI, 38.3 to 85.8) respectively based on data of 19 and 17 patients with at least one radiological assessment. Median PFS was 11.4 months (95%CI, 3.1 to NA) and 6.5 months (95%CI, 5.3 to 8.0) respectively (Table). Totally 38 (92.7%) patients experienced at least one treatment emergent adverse event (TEAE). Treatment-related AEs (TRAEs) occurred in 28 (68.3%) patients. TRAE ≥grade 3 occurred in 4 (9.8%) patients. Immune related AEs occurred in 10 patients (24.4%), the most common of which were skin rash (N = 5), pneumonitis (N = 3) and hypothyroidism (N = 2). There was no AEs leading to death. The biomarker analysis was ongoing. Conclusions: The combination of sintilimab and chemotherapy showed efficacy with an acceptable safety profile in 1L nsq- and sq-NSCLC. Two phase III trials are ongoing to evaluate the combination in 1L nsq- (NCT03607539) and sq-NSCLC (NCT03629925) respectively. Clinical trial information: NCT02937116. [Table: see text]
Matching insurance claims data with EMR molecular status data in non-small cell lung cancer (NSCLC) patients: Understanding real-world molecular testing and prevalence rates at the site and investigator level.
Authors: Cushion Michael Gregory , Krishnan Bhavani , Hodge Jeff Paul , Balusu Jaya Chandra , Wagner Joseph , Oliva Cristina , Edwards Dana
Published: May 2019

e20568

Background: Many targeted therapy clinical trials require a somatic gene mutation/alteration for eligibility. We assessed the feasibility of leveraging Real-World Data (RWD) to enrol NSCLC patients into clinical trials. Methods: US insurance claims data were extracted to identify lung cancer patients. These data were matched with EMR data also containing NSCLC patients’ details regarding the occurrence and results of molecular testing for EGFR, ALK, ROS1, JAK2, HER2 and RET somatic alterations, achieving a level of granular detail beyond that available in each individual dataset. A one-year extraction period was applied, with no gender or age restrictions. Results: Results for the matched dataset are summarised in the table below - the overall patient record match was 89.6%. Conclusions: The observed prevalence correlated reasonably well with literature reported prevalence for the molecular biomarkers associated commercially available targeted therapies in NSCLC (EGFR, ALK, ROS1). The sample size for the remaining biomarkers was too small to draw conclusions, though the presence of data correlating to these is of interest, considering that there are no currently approved targeted therapies in NSCLC tailored to these predictive biomarkers. This approach could be expanded upon to recruit patients into targeted therapy clinical trials as the dataset is fully linkable to sites and investigators. With the emergence of broad genomic profiling, the availability of molecular data to support clinical trial enrolment is also expected to grow.[Table: see text]
Alectinib exposure-response (ER) in ALK-inhibitor naïve ALK-positive NSCLC patients: Pooled analysis across phase III studies.
Authors: Smart Kevin , Hsu Joy C , Jaminion Felix , Guerini Elena , Shaw Alice Tsang , Zhou Caicun , Mok Tony S. K. , Bordogna Walter , Frey Nicolas , Morcos Peter N.
Published: May 2019

e20575

Background: Alectinib superiority to crizotinib has been demonstrated in ALK-inhibitor naïve ALK-positive NSCLC patients (pts) in Phase III studies conducted in Japanese (J-ALEX; JapicCTI-132316) pts receiving alectinib 300 mg BID and global (ALEX; NCT02075840) and Asian (ALESIA; NCT02838420) pts receiving alectinib 600mg BID. ER analyses are undertaken to confirm the appropriate alectinib dosing regimen for the global population. Methods: A previous population PK analysis (Hsu et al, ASCO 2016) assessed PK of alectinib and major metabolite, M4, to identify factors influencing PK variability. ER analyses across the 3 Phase III studies investigated the relationship between alectinib and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis. PK simulations for alectinib 300 mg and 600 mg BID doses were conducted to determine the proportion of pts falling above and below an identified optimal PK threshold for PFS. ER for key safety events were investigated for alectinib 600 mg BID using logistic regression. Results: Alectinib PK is influenced only by body weight and not by race/ethnicity. CPH analysis demonstrated a statistically significant relationship between alectinib exposure and PFS across the 3 Phase III studies, with an improved PFS above an identified optimal PK threshold (Table). PK simulations indicate 49% and 7% of global alectinib treated patients would fall below the optimal PK threshold for 300 and 600mg BID, respectively. Alectinib 600mg BID ensures a distribution of exposures that maximize the PFS benefit while lower alectinib doses/exposures could result in reduced efficacy. Baseline tumor size (BSIZ) was shown to negatively impact PFS with larger BSIZ seen in global pts. No significant exposure-safety relationships were identified for alectinib 600mg BID. Conclusions: Alectinib 600mg BID is the most appropriate dose in the global ALK-inhibitor naïve population. Clinical trial information: NCT02075840; JapicCTI-132316; NCT02838420. [Table: see text]
Sex is a strong prognostic factor for overall survival in advanced non small cell lung cancer patients and should be considered for survival rates estimations.
Authors: Barquin Miguel , Garcia-Garcia Francisco , Romero Atocha , Carcereny Enric , Rodriguez-Abreu Delvys , Lopez Castro Rafael , Guirado Maria , Camps Carlos , Bosch-Barrera Joaquim , Massuti Bartomeu , Ortega Ana Laura , Gonzalez-Larriba Jose-Luis , Garcia-Campelo Rosario , Domine Manuel , Agraso Busto Sara , Sala María Ángeles , Oramas Juana , Bernabé Reyes , Provencio-Pulla Mariano
Published: May 2019

e20580

Background: Biological differences between sexes have a major impact on disease and treatment outcome. In this paper, we evaluate the prognostic value of sex in advance NSCLC in the context of real world data. Methods: Clinical data from stage IV non-small cell lung cancer (NSCLC) patients from Hospital Puerta de Hierro (HPH) was retrieved from Electronical records using BigData Analytics (N = 387). In addition, data from Spanish Lung Cancer Group (GECP) Tumor Registry (N = 1382) and from a published study through cBioPortal (MSK) (N = 601) was analyzed. Survival curves were estimated using Kaplan-Meier analysis. Cox proportional hazards regression model was used to assess the prognostic factor of sex. Results: The median overall survival (OS) time was 12 months for men and 19 months for women (P < 0.001). Similarly, women with stage IV NSCLC harbouring an EGFR sensitizing mutation lived longer than men (median overall survival was 19 months for men and 32 months for women). Gender effect was still significant after adjustment by Cox regression for other potential confounding factors. The adjusted hazard ratios for sex were 0.65 (95% CI, 0.51-0.83), 0.84 (95% CI, 0.66-1.1) and 0.76 (95% CI, 0.65-0.88) for HPH, MSK and GECP data sets respectively. Similarly, in EGFR positive population adjusted hazard ratios for sex were 0.53 (95% CI, 0.25-1.1), 0.59 (95% CI, 0.35-0.98) and 0.60 (95% CI, 0.45-0.86) for HPH, MSK and GECP data sets respectively. Conclusions: Using real world data we confirm previous finding that among stage IV NSCLC patients, women live almost twice longer than men. This effect persisted after adjusting for several factors highlighting the fact that survival rates estimations which are usually performed grouping men and women together might not be accurate enough for prognosis assessments
Predictors of benefits to chemoimmunotherapy (CIT) in stage IV non-small-cell lung cancer (NSCLC): A meta-analysis.
Authors: El-Osta Hazem Edmond , Sabichi Anita Lyn
Published: May 2019

e20595

Background: Immune checkpoint inhibitors (ICIs) have changed the landscape of NSCLC therapy. In previous study, gender, smoking history, and PD-L1 status were found to influence the efficacy of ICI monotherapy in NSCLC. This meta-analysis evaluated the clinical and molecular factors predictive of benefit from the addition of ICIs to first-line (1L) chemotherapy in metastatic NSCLC. Methods: Using the random effect model, we computed and compared the pooled hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) among the selected subgroups. The correlation between PD-L1 expression level and outcome was analyzed by meta-regression. Results: 7 phase III randomized trials comparing CIT vs. chemo in the 1L treatment of stage 4 NSCLC were included. CIT evenly improved the PFS irrespective of age, gender, histology, smoking history and ECOG performance status (PS). While patients (pts) with liver metastasis or ALK/EGFR aberration had greater PFS with the addition of ICI to Bevacizumab (BEV) based chemo regimen, the derived benefit was no longer statistically significant among pts treated with non-BEV-based regimens. Whereas the PFS superiority conferred by CIT was noticed across all PD-L1 expression subgroups, the benefit correlated with PD-L1 level and was more pronounced in the “PD-L1 high” subset. Except for pts with EGFR/ALK abnormalities, squamous histology or liver metastasis, CIT yielded a consistent amelioration of OS across the other selected subgroups. Conclusions: Survival advantage associated with 1L CIT in metastatic NSCLC was observed in different pts population including those for which single-agent ICI has limited therapeutic benefit. Our findings support the role of chemo +/- VEGF blockade as enhancer of ICIs activity even in “less immunogenic” context. [Table: see text]
The continued osimertinib plus chemotherapy overcoming resistance after histologic transformation in EGFR-mutant lung adenocarcinoma treated with osimertinib.
Authors: Kang Jin , Li Xiang-Meng , Cheng Jia-Tao , Chen Huajun , Zhang Xuchao , Tu Hai-Yan , Zhou Qing , Wu Yi-Long , Yang Jin-Ji
Published: May 2019

e20615

Background: Although the third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is more potent, histologic transformation from lung adenocarcinoma to other histological types is still a mechanism of resistance in EGFR-mutant adenocarcinoma. Those with histologic transformation usually have poor prognosis. Hence, we focused on the unique molecular mechanism of histologic transformation after osimertinib and explore the strategy of treatment. Methods: Pathology was confirmed in 55 EGFR-mutant patients treated with osimertinib at baseline and disease progression. They were all lung adenocarcinoma at baseline. We established the patient-derived xenograft (PDX) mouse model from an EGFR-mutant adenocarcinoma transforming to neuroendocrine carcinoma. Preclinical efficacy of erlotinib versus osimertinib was evaluated in vivo. All the clinical data of these patients were analyzed. Results: The frequency of histologic transformation after resistance to osimertinib was 14.5% (8/55). Three of them were transformed to small-cell lung cancer totally, two transformed to complex small-cell lung cancer, two transformed to adenosquamous cell carcinoma and one transformed to neuroendocrine carcinoma without T790M mutation in which an PDX mouse model was successfully established. The genetic profiles of those transformed to small-cell lung cancer were characterized by Rb1, TP53 mutations, and PI3K/AKT/MTOR aberrances. Those transformed to adenosquamous carcinoma were characterized by KRAS amplification and EGFR amplification. The median progression-free survival (PFS) was not significantly different between the patients with histologic transformation and those without during the treatment of osimertinib (7.7 VS. 5.7 months, P = 0.763). One went on first-line osimertinib, added etoposide/ cisplatin (EP) chemotherapy meanwhile after progressive disease, and achieved minor response after 2 cycles. The other one received the treatment of EP + osimertinib + erlotinib, and acheived partial response with a PFS of 7 months without obvious toxicities. The PDX model showed more sensitivity to erlotinib than osimertinib. Conclusions: Continued osimertinib plus chemotherapy might be effective in overcoming the resistance. Particularly, the first-generation EGFR-TKI seems to be efficacious in histologically-transformed EGFR-mutant patients without T790M mutation. Further investigations of these patients and PDXs are warranted.
Prediction of EGFR-TKI efficacy in non-small cell lung cancer patients by metabolomics and genomics.
Authors: Zhang Lei , Luo Rongrong , Wang Lin , Yao Jiarui , Wu Di , Zhang Zhishang , Han Xiaohong , Shi Yuankai
Published: May 2019

e20627

Background: Metabolites and somatic mutations involved in EGFR-TKI efficacy remains unclear in non-small cell lung cancer (NSCLC) patients with EGFR sensitizing mutation (EGFRsm+). Here we performed a joint analysis of metabolomics and genomics data to identify metabolites and somatic mutations as biomarkers for EGFR-TKI efficacy. Methods: Metabolomic profiling of plasma samples (n = 43) from NSCLC patients with EGFRsm+, consisting of cohort A (n = 30) and B (n = 13), was conducted using UPLC or rapid separation LC-MS/MS. The 13 matched FFPE samples in cohort B were also used in the targeted sequencing below. FFPE samples (n = 18) from NSCLC patients with EGFRsm+ were subjected to targeted sequencing. According to progression free survival (PFS), all patients were assigned a status of poor (PFS≤42 weeks) and good responders (PFS > 42 weeks). A joint analysis of metabolomics and genomics data was adopted to identify biomarkers for EGFR-TKI efficacy. Results: The partial least squares discrimination analysis mothod was performed to establish a prediction model responsible for separation of good and poor responders in cohort A, comprising 27 metabolites with variable importance in projection score (VIP) > 1.5. Based on the prediction model, the ROC analysis demonstrated the sensitivity of 0.8, the specificity of 0.75, and the area under the ROC curve (AUC) of 0.7 in cohort B. The Welch’s t test method identified 15 significant metabolites ( P < 0.05) in cohort A. With the criteria of VIP > 1.5 and P < 0.05, four metabolites, 3-Methyl-L-Histidine, LysoPE(18:2(9Z,12Z)/0:0), Histamine, and SM(d18:1/16:0), were detected as potential biomarkers. To further validate them, associations of these metabolites and somatic mutations were explored in 13 patients with both metabolomics and genomics data available using the Welch’s t test. The results revealed patients with either CTCF R415X or PTK2B G491X had significantly lower Histamine level compared with those without either mutation (both P < 0.05), and significantly increased level of SM(d18:1/16:0) was observed in patients with either GATA2 P250A or MAGI1 S763X (both P < 0.05). Intriguingly, worse PFS was showed in patients with any mutation of GATA2 P250A ( P = 0.02), CTCF R415X ( P = 0.002), PTK2B G491X ( P = 0.002), and MAGI1 S763X ( P = 0.0007). Conclusions: Our joint analysis identified two plasma metabolites and four somatic mutations as biomarkers for EGFR-TKI efficacy. The present findings may provide insights into molecular mechanisms of EGFR-TKI efficacy. Further validation in prospective studies was warranted.
Adoption of immuno-oncology in NSCLC, a real-world study in EU5.
Authors: Martinez De Pinillos Alejandra , Ricote Lobera Isabel , Martinez Cristina , Anger Caroline , Guglielmetti Filippo , Bitton Roberto Jorge
Published: May 2019

e20631

Background: To date, there are no robust studies in real world practice describing the use of IO (immuno-oncology) treatments in advanced/metastatic (adv/m) NSCLC. The available evidence in Europe is limited to observational studies of small size. This study aims to understand the impact of IO in adv/mNSCLC and study the profile of patients currently receiving these treatments. Methods: 20,157 cases of 1st and 2nd line adv/mNSCLC patients between October 2016 and September 2018 in EU5 (France, Germany, Spain, Italy, UK) were identified within Oncology Dynamics, an IQVIA oncology syndicated cross sectional survey collecting anonymized patient-level data. Patient profile was described, and two groups were created to assess differences in the use of IO treatments (nivolumab, pembrolizumab, atezolizumab, ipilimumab, durvalumab) across 2 time periods: #1 October 2016 - September 2017 (n = 9,310); #2 October 2017 - September 2018 (n = 10,847). Results: IO treatments increased 15% in 1st line adv/mNSCLC (13% in non-squamous and 23% in squamous histology) and 11% in 2nd line across periods; reaching treatment shares of 20.3% and 67.9% in 1st line and 2nd line in Period 2. Within IO-treated patients, 9.5% in 1st line and 13.6% in 2nd line had ECOG ≥2, and 27% were > 71 years old. The use of IO in 1st line patients without mutations (EGFR/ALK/ROS1/BRAF) increased by 24%, while standard chemotherapy decreased by 21%. Conclusions: IO treatments had a rapid adoption in Europe last year, influenced by its approval in 1st line adv/mNSCLC and by clinical guidelines recommendations. Ongoing clinical trials may suggest a growing trend in the future that could potentially impact in healthcare systems. In addition, real world patients treated with IO are older and have a worse performance status than those widely included in clinical trials. An evaluation of these results sheds light into IO treatments in NSCLC and may contribute to the design of real-world studies to generate new evidence and optimize the use of these class of drugs in clinical practice.[Table: see text]
Pooled subgroup analysis of twelve randomized controlled trials of immunotherapy in non-small cell lung cancer.
Authors: Yang Fang , Wang Yucai , Mansfield Aaron Scott , Adjei Alex A. , Leventakos Konstantinos , Li Rutian , Wei Jia , Wang Lifeng , Liu Baorui , Molina Julian R.
Published: May 2019

e20639

Background: Multiple randomized controlled trials (RCTs) have shown a robust benefit of immunotherapy with immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). We did a meta-analysis to examine the benefit of ICI in various subgroups. Methods: PubMed was searched up to Jan 15, 2019 for RCTs comparing overall survival (OS) between ICI and control (without ICI) arms. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated for each subgroup. Interaction tests were done to compare relative benefit between opposed subgroups of interest (eg. men vs women; reported as Pheterogeneity). All analyses were performed with a random effects model in Comprehensive Meta Analysis (v2). Results: Twelve phase 2/3 RCTs involving 7244 patients were included. A significant OS benefit of ICI was found in both squamous and non-squamous histology. Current/former smokers, EGFR wild-type, and KRAS mutant patients had a significant OS benefit from ICI, but never smokers, EGFR mutant, and KRAS wild-type patients did not. An OS benefit of ICI was found in patients with or without baseline brain metastasis, PD-L1 < 1% or ≥1%, men or women, age < 65 or ≥65, and ECOG PS 0 or ≥1. No significant difference of relative benefit from ICI over control was found in patients with different PD-L1 expression, sex, age, or ECOG PS (Table). Conclusions: OS benefit of ICI in NSCLC was associated with a smoking history, wild-type EGFR or KRAS mutation. However, the OS benefit of ICI was seen regardless of histology, PD-L1 expression, sex, age, and ECOG PS. [Table: see text]
Radiotherapy with continued EGFR-TKIs for oligoprogressive disease in non-small cell lung cancer: A real-world study.
Authors: Wu Fang , Wu Sixuan , Hu Chunhong
Published: May 2019

e20640

Background: Almost all epidermal growth factor recept (EGFR)-mutated non-small-cell lung cancer (NSCLC) will develop tyrosine kinase inhibitors (TKIs) resistance. The treatment of oligoprogression is debatable after TKIs resistance. We conducted a real-world retrospective study to evaluate the efficacy of radiotherapy and continuation of TKIs in advanced NSCLC patients with oligoprogressive disease after EGFR-TKIs. Methods: From January 2011 to January 2019, we retrospectively analyzed EGFR-mutated NSCLC patients with oligoprogression in our institution. 33 patients were treated by radiotherapy and continuation of TKIs after oligoprogression. We used Kaplan-Meier and Cox regression model to analyse the prognostic factors of median progression-free survival (PFS) and median overall survival (OS) from the time of oligoprogression. Variables we selected for analyses included gender, age, smoking status, performance status (PS) score, stage at initial diagnosis, initial resectable, radiotherapy dose, EGFR mutation type, number of metastasis, sites of radiation, T790M status and the time of oligometastasis to radiotherapy. Results: 33 patients develop resistance to EGFR-TKIs at a median time of 11.0 months. The mPFS and mOS were 6.5 (95%CI, 1.4-11.6) and 21.8 (95%CI, 14.8-28.8) months, respectively. T790M mutation was tested in nine patients, four of which were mutation negative and five were positive. The mPFS was 15.5 (95%CI, 7.4-23.6) months in T790M mutation positive patients and 6.0 (95%CI, 0-14.0) months in negative patients. The mPFS in patients who started radiotherapy within or beyond 1 month after oligometastasis was 10.8 months (95% CI, 4.9-16.7 months) and 5.3 months (95% CI, 2.4-8.2 months). Cox regression model showed no variables significantly correlated with PFS difference. Univariate analysis identified female patients have longer OS (P = 0.038). The results of Multivariate analysis indicated that there was no OS-related prognostic factors. Conclusions: Radiotherapy with continued TKIs is an efficacious treatment option in advanced NSCLC patients with oligoprogressive disease after EGFR-TKIs. T790M mutation is a common mutation in NSCLC patients with oligoprogression. Gender was prognostic factors for OS. Moreover, there was a better prognosis in patients with T790M mutation positive or radiotherapy within 1 month after oligometastasis. However, this was not statistically significant. Larger sample size studies are needed to validate these clinical results.
Utility of the Lung Immune Prognostic Index (LIPI) in prognostication and disease control prediction in advanced NSCLC patients treated with nivolumab.
Authors: Ruiz Bañobre Juan , Areses Manrique María C. , García Campelo Rosario , Lopez Rafael , Afonso Afonso Francisco J. , Casal Rubio Joaquín , Vázquez Estévez Sergio , Raposeiras Cristina Azpitarte , Amenedo Margarita , Santomé Lucía , Fírvida Pérez José Luis , Mosquera Martínez Joaquín , Cortegoso Alexandra , Vilchez Simó Rocío , Huidobro Vence Gerardo , Fernández Núñez Natalia , Quiroga Veiga Nazaret , García Mata Jesús , Alonso-Jáudenes Curbera Guillermo , Anido Herranz Urbano
Published: May 2019

e20645

Background: The lung immune prognostic index (LIPI) has been proposed as a new biomarker to select advanced non-small cell lung cancer (NSCLC) patients for anti-programmed cell death-1 or programmed death ligand 1 therapy. In this study, we investigate the prognostic and predictive utility of the LIPI in a multicentric nivolumab monotherapy-based cohort. Methods: 153 patients with available baseline LIPI were included. Survival estimates were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. The impact of the baseline LIPI on survival (PFS and OS), and DCR and ORR was assessed by Cox and logistic regression models respectively, adjusted for age, sex, ECOG-PS, smoking status, histology, TNM stage at diagnosis, presence of brain metastases and number of prior regimens. All p values were 2-sided, and those less than 0.05 were considered statistically significant. Results: 50.3% (n = 77) of the patients had a good (0 factors) LIPI, while 41.2% (n = 63) and 8.5% (n = 13) had intermediate (1 factor) and poor (2 factors) LIPI respectively. No significant differences were observed between the LIPI groups according to clinicopathologic characteristics. A high LIPI was significantly associated with poor OS in univariate (HR = 3.12, 95% CI 2.12 – 4.60; p < 0.0001) and multivariate (HR = 3.10, 95% CI 2.09 – 4.58; p < 0.0001) analyses. A high LIPI was associated with poor PFS (HR = 1.49, 95% CI 1.07 – 2.07; p = 0.02), but this correlation did not reach a statistical significance in multivariate analysis (HR = 1.37, 95% CI 0.98 – 1.92; p = 0.07). A higher LIPI was associated with a lower disease control rate in univariate (OR = 0.50, 95% CI 0.29 – 0.85; p = 0.01) and multivariate (OR = 0.55, 95% CI 0.31 – 0.98; p = 0.04) analyses. Conclusions: This study confirms the utility of the LIPI in prognostication and disease control prediction in advanced NSCLC patients treated with nivolumab in the second line of therapy or beyond.
Landscape of lung cancer molecular biology in a NON-selected population.
Authors: Marcos Rosa Ana , Ceballos Jaime , Filipovich Elena , Mazarico Jose Maria , Tur Raquel , Martin Maria Rocio , Ales-Martinez Jose
Published: May 2019

e20648

Background: The molecular study of non-small cell lung cancer (NSCLC) allows for targeted treatment. EGFR and ALK alterations have been observed in 14% and 5% of Caucasian patients (p) respectively. These alterations are mainly detected in women with adenocarcinoma (ADC) and non-smokers. In a non-selected (all comers) NSCLC population from Ávila (Spain) we found a different profile. Methods: We collected data from 185 consecutive p the Pathology Department database of Hospital Nuestra Señora de Sonsoles from 2012 to 2017. All p were tested for EGFR and ALK. Analyses were done with Cobas or Therascreen tests. Results: EGFR mutations were found in 11 p out of 185 (6.7%). Histology was ADC in 8 p (72.7%) and squamous cell carcinoma (SC) in 3 p (27.3%). Male (m) & smokers: 4/11 (36,4%). The type of mutation was: Exon 20: 3 p (27.3%). 2 m and 1 female (f). 2 smokers and 1 former smoker. 2 ADC and 1 SC; Del 19: 4 p (36.4%). 1 m and 3 f. 1 non-smoker, 2 former smokers and 1 smoker. 3 ADC and 1 SC; Exon 21: 4 p (36,4%). 2 m and 2 f. 3 non-smokers and 1 smoker. 3 ADC and 1 SC.

All p. received treatment with 1st generation anti-EGFR drugs for a median 6.4 months (m). Progression Free Survival was 6.39 m (exon 20: 5.1 m; Del 19: 6.5 m; exon 21: 7.2 m). Overall survival was 18.0 m (exon 20: 26.1 m; Del 19: 18.2 m; exon 21: 11.8 m). ALK translocation was found in 5 p out of 158 (3.2%). Histology was ADC in 3 p (60%) (all f, 2 non-smokers and 1 former smoker) and SC in 2 p (40%) (2 smoker m.) Conclusions: Although the small sample size prevents definitive conclusions, EGFR mutations in exon 20 are more frequent in smokers and mutations in exon 21 in non-smoking patients with ADC. ALK translocation was observed independent of sex, tobacco or histologic type. For EGFR and ALK alterations, screening based on sex or pathology would have missed findings with therapeutic implications. We conclude it is important to extend the analysis of molecular alterations to all patients with NSCLC since more of them could benefit from targeted drugs.[Table: see text]
Galician lung cancer group: Afatinib´s data as first-line treatment for elderly patients.
Authors: Agraso Busto Sara , Varela Vanesa , Fernández Núñez Natalia , Firvida Jose-luis , Santomé Lucía , Afonso Francisco Javier , Azpitarte Cristina , De Dios Alvarez Noemi , Garcia Jorge , Campos Balea Begoña , Areses Manrique Maria Carmen , Pereiro Corbacho Diego , Huidobro Gerardo , Lazaro Quintela Martin , Casal Rubio Joaquín
Published: May 2019

e20662

Background: There are scarcy data or studies on safety and efficacy of afatinib in elderly patients. Methods: Retrospective study on patients from differents hospitals in Galicia (Spain) diagnosed of metastasic lung adenocarcinoma with EGFR positive mutation who have received first line treatment with afatinib between July 2015 and September 2018 were included. Main objectives were to asses safety, dose reductions and as well as its effects on effectiveness of the treatment in patients 70 years old or older (elderly patients) comparing with data from patients under 70 years of age. Results: 45 patients were included in our analysis (33 women, 12 men). Median age was 71.2 years (39-91) with 24 patients (53.3%) being 70 years old or older. Common adverse events grade 3/4 were mucositis and skin toxicity (28.6% in patients under 70 years and 20.8% in elderly patients) and diarrhea (9.5% and 16.7% respectively). The dose was reduced in 47.6% patients under 70 vs 75% in elderly patients. Treatment was discontinued in 14.3% patients vs 20.8% patients respectively owing to adverse events. Overall response was 76% and 62.5% respectively. Disease control rates were 90.3% (95% CI: 96.7-83.8) and 83.3% (95% CI: 98.2-68.4) respectively. Median progression free survival (PFS) was 27 months (95% CI 14.8-39.1) and overall survival was not reached. By ages, median PFS was 20 months (95% CI: 7.4-32.5) vs not reached in elderly patients although being unable to demonstrate differences in progression-free survival between both groups. Conclusions: PFS was 20 months in people under 70 years vs not reached in elderly patients. Elderly patients need more treatment interruption or dose adjustments compared with younger patients, but this does not seem to impair safety and does not compromise effectiveness either.
Molecular profiling as predictor of outcomes in a Brazilian cohort of stage IV lung cancer.
Authors: Peruzzo Nicolas , Ce Coelho Juliano , Macedo Gabriel de Souza , Andreis Tiago Finger , Gössling Gustavo , Buiar Pedro Grachinski , Rocha Débora Leite , Ashton-Prolla Patricia
Published: May 2019

e20668

Background: Lung cancer is the leading cause of cancer deaths globally. In stage IV non-small cell lung cancer (NSCLC), identification of a tumor driver mutation is critical, since it tailors treatment. We aimed to analyze clinical outcomes according to molecular profiling in patients (pts) with stage IV NSCLC. Methods: In this retrospective cohort study, we enrolled 57 pts with stage IV NSCLC treated at a public hospital in Southern Brazil between 2016 and 2018. Results: Median follow-up was 20.3 months, 53% were men, mean age was 65 years, 86% had smoked, 84% had de novo metastatic NSCLC and 96% had non-squamous carcinoma. Regarding molecular profiling, somatic mutations in KRAS, EGFR and BRAF were identified in 33%, 16% and 4% of pts, respectively. None of the pts had ALK mutations, and in 47% no identifiable driver mutation was found. In the EGFR-mutated subgroup, 67% had a deletion of exon 19, 22% had the exon 21 L858R mutation and 11% had exon 20 mutations. Palliative systemic therapy (PST) was delivered to 60% of the pts. Two or more lines of PST were delivered to 23%. The main reason for upfront best supportive care was ECOG PS 3-4 (poor). In the subgroup of pts with sensitizing EGFR mutations (8 pts), 75% received Gefitinib, the only anti-EGFR drug available in our public health system; the other pts died before recognition of the mutation. Median Progression Free-Survival was 6.3 months overall, 10.3 months for EGFR-mutated pts, 7.6 months for KRAS-mutated, 7.5 months for BRAF-mutated, and 5.2 months for pts with no mutation identified. Median Overall Survival (OS) was 7.7 months overall, 13.2 months for EGFR-mutated pts, 7.4 months for KRAS-mutated, 12.9 months for BRAF-mutated, and 5.3 months for pts with no mutation identified. In the Cox regression multivariate analysis, poor PS (HR 3.80, P < 0.0001) and second-line PST (HR 0.23, P = 0.002) were independent predictors of OS. No driver mutations were predictors of OS, although we did find a tendency towards better OS in pts with EGFR mutations and worse OS in pts with KRAS mutations or no identifiable mutation. Conclusions: In this cohort, genotyping results did not predict survival outcomes. This is probably due to the small number of pts studied, and data should be reanalyzed in larger cohorts.
Therapeutic efficacy comparison of six major EGFR-TKIs in non-small-cell lung cancer patients with an activating EGFR mutation: A network meta-analysis.
Authors: Wu Fang , He Jingyi , Wu Sixuan , Huang Yan , Li Yizheng , Zhao Lishu , Hu Chunhong
Published: May 2019

e20671

Background: EGFR-TKIs are the standard in the first line treatment for patients with advanced NSCLC with EGFR activating mutations.This network meta-analysis was undertaken to compared all the EGFR-TKIs in terms of PFS, overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Methods: The PubMed and Embase databases were screened for relevant studies. We extracted data of ORR, DCR, PFS, and OS from enrolled studies and performed multiple treatment comparisons based on bayesian network meta-analysis. Due to the differences in design of each clinical study, two rounds of analysies were performed. We first compared the therapeutic efficacy of the first-generation TKIs (erlotinib and gefitinib), second-generation TKIs (afatinib or dacomitinib) and third-generation TKIs based on A7471028, ARCHER 1009, LUX-Lung 7, ARCHER 1050 and FLAURA studies. The following comparison between first-generation TKIs (gefitinib, erlotinib and icotinib) and second-generation TKIs was performed based on ICOGEN, A7471028, ARCHER 1009, WJOG 5108L, CTONG 0901, LUX-Lung 7 and ARCHER 1050 studies. Results: Eight trials with 2154 patients and 6 TKIs (gefitinib, erlotinib, icotinib, afatinib, dacomitinib and osimertinib) were included. The first round analysis indicated that Osimertinib ranked best among all the TKIs in terms of DCR, 1y-PFS and 1y-OS. Afatinib ranked first among these similar agents with ORR. The second round analysis showed that second-generation TKIs had potentially better efficacy compared with first-generation TKIs. Icotinib seemed to work best in first-generation TKIs and ranked first among first- and second-generation TKIs in terms of 1y-OS. Conclusions: The third-generation TKIs had better therapeutic efficacy compared with the first-generation TKIs and the second-generation TKIs. However, the second-generation TKIs had better efficacy compared with first-generation TKIs. [Table: see text]
Soluble biomarker signature to predict outcome of patients with non-small-cell lung cancer (NSCLC) treated with anti-PD1/PDL1 monoclonal antibodies.
Authors: Garde-Noguera Javier , Jantus-Lewintre Eloisa , Gallach Sandra , Vidal-Martinez Jose , Blasco Ana , Garcia Sanchez Jose , Zhang Feiyu , Aparisi Francisco , Honrubia Peris Beatriz , Condori Farfan Lauren , Torres Martinez Susana , Piera Molons Nuria , Murado-Pardo J. , Gisbert-Criado R. , Calabuig-Fariñas Silvia , Camps Carlos
Published: May 2019

e20685

Background: Immunotherapy with anti-PD1/PDL1 monoclonal antibodies has become the second line standard treatment for most patients diagnosed of advanced Non-Small-Cell lung cancer (NSCLC). The aim of this study is to assess the utility of circulating biomarkers such as sPDL1, sPDL2, sCD137, sIDO, sTIM3, sCD28, sCD27, sCTLA4, sHVEM, sLAG3, sCD80 and sGITR for predicting efficacy of immunotherapy with anti-PD1/PDL1 therapies. Methods: Blood samples were collected before treatment from 50 NSCLC patients who received anti PD1/PDL1 therapies (second line). Plasma biomarkers´ levels were measured by Multiplex bead-based assays. Continuous variables were categorized using the median as a cut-off. Non parametric test were used for correlations between analytical variables and clinical-pathological parameters and response rate analysis. For survival analysis (progression free survival-PFS and overall survival-OS) Kaplan Meier curves and long-rank test were performed. Results: 50 patients met inclusion criteria. Biomarkers associated with better outcome in terms of Response Rate or PFS were sPDL1, sIDO, sCD137 and sGITR. Median plasma levels of sPDL1, sCD137, sIDO and sGITR were 80.5, 168.7, 64.92s and 114.43 ng/ml respectively. ORR was higher in patients with high levels of CD137 (75 vs 25%, p = 0.28), GITR (83.3 vs 16.7%, p = 0.009) and sPDL1 (66.7 vs 33.3%, p = 0.07). Median PFS was significantly higher for patients with high sPDL1 levels (NR vs 3 months, p = 0.017), and there was a favourable trend for patients with higher serum levels of CD137 (NR vs 5.07, p = 0.11), sIDO (NR vs 5.57 months, p = 0.08); and sGITR (14.33 vs 5.57 months, p = 0.16). Combination of these biomarkers allowed the identification of three groups: group1 (0-1 positive biomarker), group2 (2 positive biomarkers) and group 3 (3 or 4 positive biomarkers), with significant differences in ORR (8.3 vs 25 vs 66.7%, p = 0.01), PFS (median 3.2, 1.1 and NR months, p = 0.01) and OS (median 2.3, 5.0 and NR months, p = 0.02). Conclusions: Circulating immune markers can be reliable detected in plasma of advanced NSCLC patients. In patients treated with anti-PD1 antibodies. sCD137, sIDO, sGITR and sPDL1 seem to be related to the degree of response or PFS. Combination of these biomarkers might be helpful to predict efficacy of immunotherapy treatment.
Initiation of targeted therapy based on ctDNA only in metastatic NSCLC.
Authors: Bustamante Alvarez Jean Gabriel , Dittmar Kristin , Janse Sarah A , Kiourtsis Stephanie , Owen Dwight Hall , Bertino Erin Marie , He Kai , Carbone David Paul , Otterson Gregory Alan
Published: May 2019

e20687

Background: Next generation sequencing (NGS) of circulating tumor DNA (ctDNA) can identify sensitizing and resistance mutations in Non-Small Cell Lung Cancer (NSCLC). ctDNA is helpful when tissue is insufficient for genomic testing, or repeat biopsy is undesirable. Here we report a single institution experience of ctDNA testing on diagnosis (DX) and progression (PD), and how this intervention can help avoid further invasive interventions and warrant change in management. Methods: This is a single institution retrospective study of advanced NSCLC patients (pts) who had ctDNA from plasma tested using Guardant360, which identifies somatic genomic alterations by massively parallel sequencing of target genes. An institutional CLIA tissue panel using FISH (for MET, RET, ROS1 and ALK) and NGS for selected genes was used for tissue analysis. Actionable mutations are those with FDA approved (EGFR, ALK, ROS, BRAF) or NCCN recommended targeted therapies (RET fusions and MET amplifications or MET Exon 14 skipping mutation). All the included patients had cancer confirmed by pathology analysis. IRB approval was obtained prior to data collection. Results: A total of 163 ctDNA samples from 143 pts were evaluated (82 at DX and 81 on PD) . 17 out of 82 (20.7%) ctDNA samples sent at DX had actionable mutations identified (4 EGFR exon 19 deletion, 2 EGFR Exon 21 L858R, 1 EGFR L861R, 4 EML4-ALK Fusion, 2 CD74-ROS1 Fusion, 2 MET exon 14 skipping mutation, 2 KIF5B-RET fusion). 7 out of 82 (8.5%) pts initiated targeted therapy based on ctDNA results only (5 with no or insufficient tissue available, 2 with negative tissue analysis). Among them, 1 CR, 5 PR, and 1 SD were achieved. For the 2 pts with negative tissue analysis , one had initial PR for 4 months with crizotinib and on progression tissue rebiopsy was positive for ALK rearrangement on FISH, for L1152R on NGS and on ctDNA for EML4-ALK Fusion, ALK G1202R and L1152P. On second line this patient achieved a near CR with Carboplatin/Pemetrexed/Pembrolizumab. The second patient with negative tissue had CD74-ROS1 fusion on ctDNA and achieved a CR with crizotinib for 8 months. The Response Rate for patients started on targeted therapies based on ctDNA only was 85%. Conclusions: A substantial number of NSCLC pts benefited from targeted ctDNA NGS by identifying actionable mutations that led to appropriate targeted treatments. Initiation of targeted therapy for advanced NSCLC was possible based on ctDNA testing only .