bluuebunny/crossref_metadata_2025 huggingface dataset:
Afatinib in the treatment of advanced NSCLC with EGFR mutation: An observational real-world study.
Authors: Li Yun , Wang Xiaohua , Wang Li , Kou Yingying , Ma Xianglei , Feng Ji Feng , Xiao Mingzhe , Shi Meiqi , Tang Yiqun
Published: May 2019

e20518

Background: Compared with the first generation of EGFR-TKI, Afatinib has a broader spectrum of activity and can better inhibit tumor growth. At present, the therapeutic effects of Afatinib varies on patients with different EGFR mutations and studies on the mechanism of acquired Afatinib resistance are limited. The aim of this study was to evaluate the efficacy and safety of Afatinib in the treatment of EGFR-mutation NSCLC who hadn’t received EGFR-TKI in the past. Methods: 88 patients with advanced NSCLC who had EGFR mutations were enrolled and given oral 40 mg Afatinib daily until disease progression or adverse events that could not be handled by dosage reduction. Efficacy and safety in different subgroups were analyzed. Results: Among 88 patients, the common mutation rate of EGFR was 79.5%, and the rare mutation rate was 20.5%. The objective remission rate (ORR) was 54.5%, and the disease control rate (DCR) was 92.0%. The median progression-free survival (PFS) was 14.2 months (95% CI 11.4-18.5), 27 patients (30.7%) continued Afatinib treatment after tumor progression, and the median time to progression of clinical symptoms (TTSP) was 16.3 months (95% CI 12.7-19.3). A total of 13 patients (14.8%) reduced Afatinib dosage of due to adverse events. Subgroup analysis showed that Afatinib had better effect on patients harboring common EGFR mutation but not exon 20 mutation, and was not affected by brain metastasis, dosage and lines of therapy. Among patients who progressed on Afatinib, 65.4% harbored T790M mutation. Most T790M patients received the third generation EGFR-TKI including AZD9291 and oxetinib treatment. The most common adverse reactions were diarrhea, rash, paronychia and stomatitis. Conclusions: Afatinib showed good efficacy and tolerance in advanced NSCLC patients with EGFR mutations. Continuation of Afatinib treatment after cancer progression could delay the progression of disease symptoms. The third generation EGFR-TKI could become a treatment option after Afatinib resistance. These findings reflected the real-world clinical practice of Afatinib.
Impact of antibiotics and proton pump inhibitors on clinical outcomes of immune check point blockers in advanced non-small cell lung cancers and metastatic renal cell cancer.
Authors: Kulkarni Amit , Kumar Manoj , Pease Daniel Fellows , Wang Ying , DeFor Todd E. , Patel Manish
Published: May 2019

e20520

Background: Studies have suggested that antibiotics can negatively influence efficacy of immune check-point blockers (ICB) but the results are inconsistent. The impact of concomitant proton pump inhibitors (PPI) is not known. We evaluated whether antibiotic and PPI use in patients with advanced non-small-cell lung cancer (NSCLC) and metastatic renal cell cancer (RCC) affects ICB efficacy. Methods: We identified advanced NSCLC and RCC patients treated with anti-PD1/PD-L1 at our institution between 5/2015 to 1/2019. Data regarding systemic antibiotics and PPI use < 1 month or during ICB treatment were collected. The primary outcome was progression free survival (PFS) per response evaluation criteria in solid tumors (RECIST 1.1). Secondary outcomes were overall survival (OS) and objective response rate (ORR). Logistic regression and cox proportional hazards model were used for statistical analysis. Results: 87/148 (58%) and 40/55 (72%) patients received antibiotics and 57/148 (39%) and 17/55 (31%) received PPI < 1 month or during ICI therapy in NSCLC and RCC respectively. In RCC, antibiotic use was associated with inferior PFS (2.9 v 5.0 months, HR = 2.3 95%CI 1.0-5.0; p = 0.04) but OS and ORR were not affected. In NSCLC, antibiotic exposure was associated with superior PFS (5.0 v 2.5 months, HR = 0.5, 95% CI 0.3-0.7; p < 0.01), OS (13.0 v 8.0 months, HR = 0.5, 95% CI 0.3-0.8; p < 0.01) and ORR (33% v 11%, OR = 4.6, p < 0.01). On univariate analysis, there was trend towards inferior OS in NSCLC (9.0 v 13.0 months, p = 0.05) with PPI use. PPI use was not associated with other primary or secondary outcomes in both the cohorts. The antibiotic effect remained significant for PFS in NSCLC and RCC in multivariate analysis. Conclusions: Antibiotic use significantly affected PFS in both NSCLC and RCC. PPI use did not affect outcomes. In contrast to previous studies, this is the first study to show that antibiotic use was associated with favorable outcomes in NSCLC. More studies are needed to explain this association. Future clinical trials with ICB should consider stratification of patients based on antibiotic exposure.
Correlation between PD-L1 level and immunotherapy outcome in NSCLC in Lebanon, 2012-2018: A multicenter observational review.
Authors: Ghoche Ahmad , Nasr Lewis , Diab Saada , Nasr Fadi
Published: May 2019

e20524

Background: Immunotherapy targeting the PD1/PDL1 checkpoint pathway represents an important innovation in lung cancer treatment. In our research, we evaluate the correlation of PD-L1 expression with clinical outcomes (progression free survival, overall survival, objective response rate) in lung cancer patients in 4 centers in Lebanon. Methods: The 57 patients enrolled in this observational study were stage IIIB/IV NSCLC and SCLC who received immunotherapy with nivolumab, pembrolizumab or atezolizumab at any line of treatment, and were recruited between February 2012 and august 2018. Immunotherapy was continued until progression, death or unacceptable toxicity. PD-L1 expression was assessed on tumor samples either on diagnosis or at progression. Patients were divided into 3 categories according to PD-L1 level (< 1, 1-49, > 50%). Progression free survival defines the time from randomization to disease progression after each line of therapy. Overall survival defines time from randomization to death from any cause. Results: 70.18% had adenocarcinoma, 26.32% had squamous cell carcinoma, 1.75% had small cell lung cancer and one pathology was missing from the file. 66.66% were stage IV at diagnosis, 26.31% were stage 3. PD-L1 expression was > 50% in 40.35% of patients, 24.56% had a level between 1 and 50% and the remaining had a value of less than 1%. PD-L1 was missing or not done in 15.79%. Median PFS was 13.9 months. Median OS was 14.2 months. 22.81% received immunotherapy as first line and 75% of the remaining patients upon first progression. PFS1 was 4.2 months. Mean time to first progression on immunotherapy was 3.6 months in patients with PD-L1 > 50%, 10.5 months in PD-L1 between 1 and 50% and 14.3 months in those who had PD-L1 < 1%. At the date of data cutoff, 49.12 % of patients were still receiving immunotherapy. No grade 3 or 4 immune related adverse events were seen during follow-up. Conclusions: The efficacy and safety of anti-PD-1 medications for advanced NSCLC were comparable in real-world and clinical settings. Prediction of treatment response from tumor PD-L1 expression seemed less practical than that was expected
Comprehensive analysis of genomic alterations detected by next-generation sequencing-based tissue and circulating tumor DNA assays in Chinese patients with non-small cell lung cancer.
Authors: Yang Hua , Zhang Junjie , Zhang Lemeng , Wen Xiaoping , Luo Yongzhong , Yao Dingquan , Cheng Tianli , Cheng Huanqing , Wang Huina , Lou Feng , Guo Jing , Liang Xiayuan , Cao Shanbo , Chen Jianhua
Published: May 2019

e20534

Background: While tumor genotyping is the standard treatment for patients with non-small cell lung cancer (NSCLC), spatial and temporal tumor heterogeneity and insufficient specimens can lead to limitations in the use of tissue-based sequencing. Circulating tumor DNA (ctDNA) fully encompasses tumor-specific sequence alterations and offers an alternative to tissue sample biopsies. The aim of the study was to evaluate whether the frequency of multiple genomic alterations observed following ctDNA sequencing was similar to that observed following tissue sequencing in NSCLC. Methods: A total of 99 NSCLC patients were enrolled in this study, including 40 tissue and 59 plasma samples. All kinds of variants of oncogenic drivers in NSCLC were identified by next-generation sequencing (NGS) with Acornmed panel. Results: The frequencies of genetic alterations detected in ctDNA were significantly correlated to those detected via tissue profiling (Spearman’s r = 0.812, P = 0.022). Genomic data revealed significant mutual exclusivity between alterations in epidermal growth factor receptor ( EGFR) and tumor protein 53 ( TP53; P = 0.020) and between those in EGFR and Kirsten rat sarcoma viral oncogene homolog ( KRAS; P = 0.008), as well as potential mutual exclusivity between alterations in EGFR and Erb-B2 receptor tyrosine kinase 2 ( ERBB2; P = 0.059). Furthermore, the EGFR mutant allele frequency (MAF) was strongly correlated with the TP53 MAF in individual tumors (Spearman’s r = 0.773, P = 0.005), and there was a marked difference in the EGFR MAF between patients with and without the TP53 mutation (P = 0.001). Levels of the tumor serum marker CA242 in patients with ctDNA-detectable mutations were higher than those in patients without ctDNA-detectable mutations. Conclusions: This study provides a better understanding of the spectra of genomic alterations detected by tissue and plasma ctDNA assays in Chinese patients with NSCLC. The present data also highlights the importance of tissue and plasma ctDNA screening by NGS to guide personalized therapy and promote the clinical management of NSCLC patients.
Real-world immuno-oncology treatment patterns and outcomes in US patients with metastatic non-small-cell lung cancer.
Authors: Bruno Amanda , Bell Kelly , Stafkey-Mailey Dana , Murty Sharanya , Ballas Marc S.
Published: May 2019

e20537

Background: Three immune-oncology (IO) agents are approved by the FDA to treat metastatic NCSLC (mNSCLC). This retrospective observational study aimed to observe treatment patterns and real-world outcomes of mNSCLC patients treated in the community setting, predominantly in the southern region of the U.S. Methods: Electronic health records and charts were reviewed for patients with a diagnosis of mNSCLC initiating an IO between September 1, 2015 to September 30, 2017. Patient data were examined from the date of IO therapy initiation until death, loss to follow-up, or study end date (December 31, 2017), whichever was earliest. This study was hypothesis generating thus no statistical tests were performed. Results: Of the 2,864 patients who met initial study criteria, 750 were randomly chosen for full chart review and 577 met inclusion/exclusion criteria among whom 571 had metastatic NSCLC prior to initiating IO therapy. 464, 97, and 16 patients were initiated on nivolumab, pembrolizumab, and atezolizumab, respectively. Average age was 69.7 years and 65% of patients initiated treatment in 2015 or 2016. At diagnosis, 36% of patients had an Eastern Cooperative Oncology Group performance status of 0 versus 16% at time of therapy initiation. Duration of IO therapy was 5.15 months among all metastatic patients (5.37 months for 1L only) and 4.13. months among those who completed therapy during the study period. Median real world progression free survival (rwPFS) was 5.53 (4.31. 7.20) months for 1L patients and 3.32(2.76, 4.01) months for 2L+. Real world overall survival (rwOS) was 19.04 (13.03, NR) months for 1L patients and 12.01 (8.82, 15.92) months for 2L+. Conclusions: Median rwPFS and rwOS were slightly higher than published clinical trials, yet patients were older and with poorer performance status compared to clinical trial enrollees. Despite the differences in patient characteristics, results suggest that clinical real world outcomes for this population fall within the range of median OS and PFS values observed in immune checkpoint inhibitor trials. Future research should explore the use of EHR, chart and other data sources to confirm benefit and risk in the real world.
The clinical analysis of pulmonary lymphoepithelioma-like carcinoma with epithelioid granuloma: Fourteen cases and literature review.
Authors: Qin Yinyin
Published: May 2019

e20545

Background: Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare subtype of non-small cell lung cancer associated with Epstein-bar virus (EBV) infection. Even less reported were those with Epithelioid granuloma (EG) and were frequently misdiagnosed. Current study aimed at investigating the clinical presentation, pathological characteristics and treatments of PLELC complicated with EG to improve our understanding of this disease. Methods: Data was collected from January 2013 to December 2017. A total of 105 patients were diagnosed as PLELC, in which 14 patients were with EG. Their clinical features, pathological characteristics and treatment were analyzed. Results: The 14 patients with EG (13.3%) in our group were followed-up 15 months (10-31 months).The median age was 48.5 year-old (38-67 year-old) and 85.7% were under the age of 60, meanwhile females had a slightly higher proportion than males (1.8:1). Most patients were at early stage (71.4%) with nonspecific manifestations such as cough, expectoration and lack of rich-lewis phenomenon. EG were often located in tumor or beside the tumor (71.4%), others were located in lymph node. It was all negative in specific stain of pathology and all positive in situ hybridization of EBV-encoded RNA (EBER). In our study, two patients received palliative chemotherapy with the duration of progression-free survival in 8 and 10 months, respectively. Twelve patients underwent surgical resection including ten with adjuvant or neo-adjuvant chemotherapy. Three patients had disease relapsed in 8, 13 and 25 months after surgery, respectively. None of them had tuberculosis occurring, progression or relapse, even if anti-tuberculosis therapy were not taken. Conclusions: PLELC complicated with EG, a rare phenomenon, was lack of rich-lewis phenomenon and specific clinical characteristic compared with those without EG. The formation of EG may be caused by immunological hypersensitivity to tumor cell or EBV infection instead of tuberculosis. It was important for us to make an exact pathological diagnosis, and attention should be paid to obtain samples by biopsy and make differential diagnosis. PLELC complicated with EG could receive multimodality therapy such as chemotherapy and surgery. However, anti-tuberculosis therapy was not necessary.
BIOLUMA: A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in lung cancer and to evaluate biomarkers predictive for response—Preliminary results from the NSCLC cohort.
Authors: Fischer Rieke Nila , George Julie , Scheel Andreas H. , Schloesser Hans Anton , Vehreschild Maria , Brossart Peter , Engel-Riedel Walburga , Griesinger Frank , Grohé Christian , Kambartel Karl-Otto , Kern Jens , Hermes Barbara , Nachtkamp Kathrin , Panse Jens Peter , Sebastian Martin , Lehmann Markus , Wiewrodt Rainer Gerhard , Büttner Reinhard , Thomas Roman K. , Wolf Juergen
Published: May 2019

e20550

Background: Patient selection, dosing regimens and resistance mechanisms for immune checkpoint inhibitor combination therapy remain unmet medical needs in lung cancer. Combining blockade of PD-1 and CTLA-4 can be more effective than monotherapy but is accompanied by an increase in toxicity. Thus, to circumvent unnecessary toxicity it is of great interest to identify patients who will benefit from PD-1/PD-L1 blockade alone and to add ipilimumab only in case of primary or secondary progression. We present interim data from the non-small-cell lung cancer (NSCLC) cohort of the ongoing BIOLUMA trial which evaluates efficacy and safety of nivolumab and ipilimumab in lung cancer with a broad translational program to identify potential biomarkers predictive of response and/or resistance including whole exome sequencing (WES) of serial biopsies, functional analysis of peripheral T-cells and gut microbiome analyses. Methods: BIOLUMA is a multicentre non-randomised phase II trial in 2nd line patients with non-squamous NSCLC. Patients are treated with nivolumab 240 mg until disease progression and subsequently with a combination therapy of nivolumab 3 mg/kg q2w and ipilimumab 1mg/kg q6w. Primary endpoint is overall response rate (ORR) after addition of ipilimumab to nivolumab treatment. Analysis of sequential tumor biopsies, blood and gut microbiome is performed at different timepoints. Results: To date, 26 patients have been enrolled and 9 patients were transferred to the combination therapy after progression on nivolumab monotherapy. Drop out rate between the treatment arms is high, mainly due to rapid disease progression and adverse events which don’t allow addition of ipilimumab. ORR is available for 8 of these patients: 6 patients (75%) had PD as best response, and 1 (12.5%) each had a stable disease and partial response, respectively. The patient who achieved a PR had experienced primary tumor progression on nivolumab monotherapy before. Toxicity rate was similar to what has been reported from other trials. Conclusions: In NSCLC, addition of ipilimumab to nivolumab in nivolumab refractory patients seems to be safe, but the response rate is low and the drop out between the treatment parts high. Given these data, early termination of this cohort is currently discussed. Clinical trial information: NCT03083691.
Impact of baseline number of metastases on the efficacy of PD-1 inhibitor monotherapy for non-small cell lung cancer with high PD-L1 expression.
Authors: Miyawaki Taichi , Kenmotsu Hirotsugu , Miyawaki Eriko , Mamesaya Nobuaki , Kawamura Takahisa , Kobayashi Haruki , Nakashima Kazuhisa , Omori Shota , Wakuda Kazushige , Notsu Akifumi , Ono Akira , Naito Tateaki , Murakami Haruyasu , Mori Keita , Harada Hideyuki , Endo Masahiro , Takahashi Toshiaki
Published: May 2019

e20551

Background: Pembrolizumab monotherapy and pembrolizumab combined with platinum-based chemotherapy are the standard therapies for advanced non-small cell lung cancer (NSCLC) patients with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) ≥ 50%. Apart from PD-L1 status, predictive factors for the efficacy of pembrolizumab treatment remain unclear. High tumour burden has been shown to be a negative predictor for the efficacy of PD-1 inhibitors in melanoma. Hence, the purpose of this study was to evaluate the association between tumour burden and efficacy of pembrolizumab in NSCLC patients with PD-L1 TPS ≥ 50%. Methods: This single-center retrospective observational study evaluated patients with advanced NSCLC with PD-L1 TPS ≥ 50% who received pembrolizumab monotherapy as first line therapy between March 2016 and November 2018. The primary endpoint was progression-free survival (PFS). Tumour burden was estimated by the baseline number of metastases (BNM) and the baseline sum of the target lesions’ longest diameters (BSLD; measured according to RECIST criteria). Results: Of 52 patients with target lesions, the median age was 69 years; ECOG-PS 0-1 94%; non-squamous histology 79%; and PD-L1 TPS ≥ 75% was 65%. The optimal cut-off values for predicting PFS were 4 for BNM and 115 mm for BSLD, based on the minimum P-value method for PFS. The low BNM group included 20 (38%) patients, and the low BSLD group 33 (63%). Low BNM was significantly associated with longer PFS (median PFS not reached vs 4.0 months, HR = 0.35, P = 0.021) and with higher response rate (60% vs 31%, P = 0.041) compared to high BNM. There was no significant difference in PFS between low BSLD and high BSLD groups (12.4 vs 4.0 months, HR = 0.52, P = 0.098). Multivariate analysis showed that both low BNM (≤ 4 vs. > 4, HR = 0.32, P = 0.02) and PD-L1 TPS (75-100% vs. 50-74%, HR = 0.41, P = 0.032) were significantly associated with longer PFS. There was no association between PD-L1 TPS and BNM (Spearman’s rho = -0.0985, P = 0.487) Conclusions: BNM may be an independent predictive factor of efficacy of pembrolizumab monotherapy. Patients with low BNM can be candidates for pembrolizumab monotherapy.
Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).
Authors: Thein Wai Lin , Tun Aung , Thein Kyaw Zin , Guevara Elizabeth
Published: May 2019

e20558

Background: Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers among which the metastatic disease represents ~ 57%, and long-term prognosis remains poor. Combined chemoimmunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through January 31, 2019. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (grade 3). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to significant heterogeneity among studies. Results: Nine phase 2 & 3 RCTs (Keynote – 021,189, 407, IMpower – 130, 131, 132, 150, checkmate-227, and Govindan et al) including 5042 patients with advanced NSCLC patients were included in the meta-analysis. The study arm used standard chemotherapy regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab while control arm used only standard chemotherapy regimens. The pooled HR for PFS was 0.65 (95% CI: 0.57-0.73; P = 0.00001), the pooled HR for OS was 0.72 (95% CI: 0.61-0.86; P = 0.0003), and the pooled RR for ORR was 1.45 (95 CI: 1.23-1.72; P = 0.0001). The pooled RRs for all-grade AEs and high-grade AEs were 1.03 (95% CI: 0.99-1.07; P = 0.13) and 1.21 (95% CI: 1.1-1.34; P = 0.0001), respectively. Conclusions: The combined chemoimmunotherapy can significantly improve PFS, OS, and ORR compared to standard chemotherapy for the first-line treatment of advanced NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.
Homeless outcomes in non-small cell lung cancer: A county hospital experience.
Authors: Concannon Kyle , Thayer John Henry , Wu Vicky , Jenkins Isaac , Baik Christina S , Linden Hannah M.
Published: May 2019

e20582

Background: Vulnerable populations such as homeless with non-small cell lung cancer (NSCLC) likely have higher mortality rates compared to the general population due to inadequate care, but their outcomes have not been described. We hypothesize that homeless patients with NSCLC experience greater mortality, shorter time from diagnosis to last known contact, delays in biopsy after imaging and treatment after biopsy, and greater rates of missed appointments following diagnosis. Methods: We conducted a retrospective review of all non-small cell lung cancer patients (N = 133) with appointments made between 9/2012 and 9/2018 at an academic county hospital with a dedication to the underserved in a major US city. Data were collected from electronic medical records manually and analyzed using ANOVA for continuous variables or Pearson's Chi-squared for categorical data. Results: Of the 133 patients diagnosed with non-small cell lung cancer, 21 (15.8%) were homeless at the time of their diagnosis. The mean time from diagnosis to last known contact was 1.4 vs 4.2 years (p = 0.0002) in localized disease and 1.41 vs 1.43 years (p = 0.95) in advanced disease for homeless vs housed patients. Kaplan Meier curve in advanced disease shows median survival time is 6.9 months (95% CI: 4.6 to N/A) for homeless (n = 13) vs 14.4 months (95% CI: 11.0 to 35.8) for housed (n = 67) patients (p = 0.51).The time from radiographic finding to biopsy, biopsy to intervention, and percentage of missed appointments in the year following diagnosis for homeless vs housed NSCLC with localized disease was 248 vs 116 days (p = 0.37), 20.1 vs 49.7 days (p = 0.19), and 21% vs 11% (p = 0.17) respectively; 35 vs 46 days (P = 0.64), 50 vs 58 days (p = 0.75), and 26% vs 16% (p = 0.034) among those with advanced disease. Conclusions: In this retrospective analysis, homeless with localized NSCLC experienced a significantly shorter time from diagnosis to last known contact. Homeless patients with advanced NSCLC had shorter median survival time compared to housed patients, although this was not statistically significant. Homeless patients with both localized and advanced disease had increased rates of missed appointments without significant delays in treatment. Further research is needed to improve outcomes.
Clinical predictors of efficacy for immune checkpoint inhibition in lung cancer patients.
Authors: Zhang Shijia , Pease Daniel Fellows , Joshi Shilvi , Wang Yucai , Patel Manish
Published: May 2019

e20600

Background: Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of advanced NSCLC and SCLC. The populations in clinical trials generally were composed of patients (pts) with excellent performance status (PS), a minimal number of prior lines of therapy, and no history of (h/o) autoimmune disease (AD). The aim of this retrospective study was to investigate the predictors of survival in less fit and more heavily pretreated lung cancer pts at our institution. Methods: Medical records of lung cancer pts who started single-agent ICI from 2015 to 2018 were reviewed for data collection. Progression-free survival (PFS) and overall survival (OS) were compared by age, PS, smoking, PD-L1 expression, brain metastasis, prior lines of systemic therapy, h/o AD, and immune-related adverse events (irAE). Results: We included 150 pts who received at least 1 dose of nivolumab, pembrolizumab, or atezolizumab (median age 66, range 36-92, 56% female, 89% NSCLC, 97% stage 4, 13% never smoker, 34% ECOG ≥ 2, 37% ≥ 2 prior lines of therapy, 29% developed irAE). The overall response rate was 30% and clinical benefit rate 51% (3% CR, 27% PR, 21% SD). The median PFS was 3.7 months (m) overall and 12.3 m for those with ≥ 4 cycles of therapy. The median OS was 12.4 m overall and 26.0 m for those with ≥ 4 cycles. The median PFS and OS were not significantly different by age, PS, smoking, PD-L1, brain metastasis, prior lines of therapy, or h/o AD. The median OS was longer for pts with ECOG 0-1 than those ≥ 2 (14.6 vs 7.5 m, p < .001). The median PFS and OS for pts with irAE were longer compared to those without irAE (12.3 vs 2.6 m, p < .001 for PFS and 28.9 vs 9.1 m, p = .001 for OS). Multiple Cox regression analysis identified ECOG 0-1 (HR 0.54, p = .007) and irAE (HR 0.48, p = .003) to be independently associated with improved OS. 27 pts (18%) required steroids for irAE. There were no treatment-related deaths. Of 11 pts with h/o AD, only 1 experienced disease flare. Conclusions: The clinical benefit of ICIs persists in older or heavily pretreated pts. ECOG 0-1 and incident irAE predicted for improved survival. Survival for pts with ECOG ≥ 2 is very limited, suggesting ICIs should be used judiciously in this group. Therapy was well tolerated, with a low risk for flare of previous autoimmune disease.
Distinct resistant mechanism and genomic evolution during TKI treatment in non-small cell lung cancer patients with or without acquired T790M mutation.
Authors: Jin Ying , Bao Hua , Le Xiuning , Fan Xiaojun , Tang Ming , Fan Yun , Zhang Yiping , Xu Yang , Wu Xue , Shao Yang , Yan Junrong , He Jiachen , Chen Ming , Zhang Jianjun , Yu Xinmin
Published: May 2019

e20603

Background: EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Clonal and clinical analyses of genetic alterations at baseline and progressive disease (PD), as well as differences between acquired T790M and T790M-negative patients in drug-resistant mechanisms, have not been systematically studied. Methods: We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Correlation between genomic features and patients’ progression-free survival (PFS) was evaluated. Ten additional patients were sequenced using whole exome sequencing to infer the clonal evolution patterns. Results: We observed new pathways limiting EGFR-inhibitor response, including NOTCH1/ STK11 co-deletion, and TGF-beta alterations. Besides acquired T790M mutation, chromosomal instability (CIN) related genes including AURKA and TP53 alterations were the most frequently acquired events. CIN significantly increased with TKI treatment in T790M-negative patients. Transcriptional regulators including HNF1A, ATRX and NKX2-1 acquired alterations were enriched in T790M-positive patients, and diverse oncogenic pathway alterations were more common in T790M-negative patients. T790M-positive patients had improved PFS compared to T790M-negative patients. We identified subgroups within T790M-positive or T790M-negative patients with distinct PFS. Interestingly, we observed a death-and-birth process of RTK-RAS mutations during TKI treatment, and baseline and acquired RTK-RAS mutations had opposite effects on PFS. Clonal evolution analysis indicated progression of T790M-positive patients depends on competition between T790M and non-T790M resistant subclones. Conclusions: T790M-positive and T790M-negative patients display divergent landscape of acquired somatic events. Subgroups of patients were identified within T790M-positive and T790M-negative patients with distinct survival. Our results point the importance of clonal competition between T790M and non-T790M resistant subclones.
A modified recursive partitioning analysis for predicting overall survival in patients with non-small cell lung cancer and central nervous system metastases.
Authors: Muniz Thiago Pimentel , Jesus Victor Hugo Fonseca , Sousa Victor Aurelio Ramos , barbosa malu , Cordeiro De Lima Vladmir Claudio
Published: May 2019

e20604

Background: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers. Most patients with NSCLC have metastases at diagnosis and 30-50% of them will present brain lesions during follow-up. Nonetheless, patients with central nervous system (CNS) spread are poorly represented in clinical trials and the management of this clinical scenario is not standardized. Prognostic tolls are needed to help to guide the best approach for these patients. Methods: Descriptive, analytical, retrospective, single center study. Patients > 18 years of age diagnosed with NSCLC who developed CNS metastases treated at AC Camargo Cancer Center from January 2007 to December 2017 were included. The primary endpoint was overall survival (OS). The secondary endpoint was intracranial progression-free survival (IC-PFS). An exploratory analysis of prognostic factors associated with OS was undertaken. The Kaplan-Meier method was used to calculate OS and IC-PFS. We used the Cox Proportional Hazard model to assess the prognostic role of clinical and pathological characteristics on IC-PFS and OS. Variables with p < 0.20 at univariate analysis were used to generate a multivariate model. A survival tree was generated based on the two most statistically significant variables in the multivariate model. A p < 0.05 was considered statistically significant. Results: 311 patients were included. Median age was 60 years-old (IQR 54-68), 72.6% had an ECOG performance status 0 or 1 and 18.3% had a driver mutation detected ( EGFR, ALK or ROS1). IC-PFS was 7.1 months (95%CI 6.1-8.6) and OS was 10.3 months (95%CI 8.7-13.1). At multivariate analysis, the two most statistically significant prognostic factors associated with poor OS were ECOG performance status 2-4 (HR 2.12; 95%CI 1.40-3.20; p < 0.01) and the absence of a known driver mutation (HR 3.30; 95%CI 1.50-3.87; p < 0.01). Based on the curves generated by the survival tree, a prognostic model was developed - the Modified Recursive Partitioning Analysis (mRPA). This model stratified our cohort in four subgroups with significantly different OS (3.1 to 43 months). mRPA was better than RPA and GPA to predict prognosis in our population. Conclusions: OS and IC-PFS in patients with NSCLC and CNS metastases were better than previously reported. However, prognosis is widely variable and is directed mainly by performance status and the presence of a driver mutation. We propose a new prognostic model that my help to guide the treatment of these patients in the future. This model needs external validation.
A 18F-FDG PET/CT-based radiomics model predicts prognosis of synchronous oligometastatic non-small cell lung cancer.
Authors: Zhu Xiaoxia , Zhang Yu , Zheng Zhihao , Luo Jiaxiu
Published: May 2019

e20610

Background: Oligometastatic non-small cell lung cancer (NSCLC) exists high heterogeneity with distinct outcome, and there is a lack of available biomarkers for patient stratification. In this study, we identified a positron emission tomography (PET)/computed tomography(CT)-based radiomics signature capable of predicting overall survival (OS) in patients with synchronous oligometastatic NSCLC. Methods: This study consisted of 46 patients with synchronous oligometastatic NSCLC (≤5 metastases) between 2012-2018. Clinicopathologic data was acquired from medical records and database. A total of 20648 radiomic features were extracted from pretreatment CT and PET images, which were generated from the same PET/CT scanner. A radiomics signature was built by using the least absolute shrinkage and selection operator (LASSO) regression model. Multivariate Cox regression analysis was performed to establish the predictive model. The performance was evaluated with Harrell' concordance index (C-index). Results: 7 radiomics features were selected to build the radiomics signature. Multivariate analysis indicated that the radiomics signature (P = 0.007) was an independent prognostic factor, with a C-index of 0.810. Smoking status (P = 0.01) was the only independent clinicopathologic risk factor for overall survival prediction. Incorporating the radiomics signature with clinicopathologic risk factors resulted in higher performance with a C-index of 0.899. Conclusions: This study developed a radiomics model for predicting OS in synchronous oligometastatic NSCLC, which may serve as a predictive tool to identify individualized treatment strategy. Further internal and external validation of the model are required. Support: 81572279, 2016J004, LC2016PY016, 2018CR033. [Table: see text]
Clinical features and progression pattern of T790M+ compared with T790M-EGFR mutant NSCLC.
Authors: Pasello Giulia , Dal Maso Alessandro , Lorenzi Martina , Roca Elisa , Pilotto Sara , Macerelli Marianna , Polo Valentina , Del Conte Alessandro , Nardo Giorgia , Buoro Vanessa , Scattolin Daniela , Monteverdi Sara , Urso Loredana , Zulato Elisabetta , Frega Stefano , Bonanno Laura , Indraccolo Stefano , Calabrese Fiorella , Conte Pierfranco
Published: May 2019

e20612

Background: Acquired T790M EGFR mutation (mut) is not predictable by any clinical-pathological feature. The best time point for T790M mut detection by liquid or tissue biopsy is currently undefined. Methods: This is an observational study at 6 Italian Centers enrolling EGFR mutant NSCLC patients (pts) progressing after first/second generation EGFR TKI, between 2014 and 2018. The primary endpoint of the study was to compare clinical features in acquired T790M+ compared with T790M- cases. The secondary endpoint was to assess different progression (PD) patterns between the two groups. We also explored the PD pattern at the time of cfDNA negativity and subsequent positivity, in a subgroup of pts receiving serial liquid biopsies. Statistical analysis was performed by the Chi-square test to correlate clinical features with T790M status, and by the Kaplan-Meier estimator to evaluate median progression free (mPFS) and overall survival (mOS). Multiple logistic regression and log-rank tests were applied. Results: 219 pts were included. Median follow-up since diagnosis was 25 months. First line treatment was gefitinib (N = 119, 54%), erlotinib (N = 48, 22%) or afatinib (N = 52, 24%). In 108 (49%) cases a T790M acquired mut was detected in liquid (70), tissue (31) biopsy or both (7). Age younger than 65 years ( p= 0.05) and presence of sensitizing exon 19 deletion ( p= 0.04) were correlated with T790M mut; this association was confirmed at multivariate analysis ( p= 0.010 and p= 0.006, respectively). At the time of PD, new PD sites ( p= 0.005) and liver PD ( p< 0.001) were more commonly observed in T790M+ group; at multivariate analysis statistical significance was confirmed ( p= 0.01 and p= 0.008, respectively). Longer mOS was observed in T790M+ cases at univariate (53 versus 22 months, p < 0.0001) and multivariate analysis. In 13 pts undergoing serial liquid biopsies, an oligoprogressive disease was correlated with a negative test outcome, while PS/symptoms worsening, higher number of new lesions and PD sites were observed at the time of T790M positivity, although without statistical significance. Conclusions: This is the first caucasian series showing different clinical features and progression patterns of T790M+ versus T790M- EGFR mutant NSCLC.
Upfront EGFR TKI with or without brain radiotherapy (RT) in EGFR-driven non-small cell lung cancer (NSCLC) with brain metastases.
Authors: Villanueva Nicolas , Son Klarissa , Hattangadi Jona Ashok , Simpson Daniel Robert , Sanghvi Parag R. , Patel Sandip Pravin , Husain Hatim , Urbanic James John , Gold Kathryn A. , Mitchell William M. , Bazhenova Lyudmila
Published: May 2019

e20614

Background: The central nervous system (CNS) remains a common site of metastatic disease for NSCLC, especially in EGFR-driven disease. Surgery and RT are upfront treatment options but have potential early and late onset complications. Osimertinib (Osi) is now approved for use in the front-line setting for EGFR-mutated NSCLC and is highly CNS penetrant. A prior retrospective study showed that the use of early generation EGFR TKIs had an inferior overall survival (OS) compared to upfront RT in newly diagnosed brain metastases, but the applicability of this data in the Osi-era is unknown. Methods: This was a single institution retrospective analysis of patients with EGFR mutated NSCLC and brain metastases who were referred to Radiation Oncology from 1/1/2012 to 12/31/2018. We separated EGFR TKIs between Osi and non-Osi. The primary objectives were to evaluate OS, intracranial progression free survival (icPFS), and intracranial response (icORR) among upfront or delayed RT, and type of EGFR TKI. Results: 67 patients with a median age of 64 years old (33-89) were divided into one of four groups: non-Osi TKI with (N = 38) or without RT (N = 12), and Osi with (N = 14) or without RT (N = 3). Fourteen patients who did not get upfront Osi, received Osi with (N = 7) or without RT (N = 7) after intracranial progressive disease (icPD). Patients were predominantly female, never-smokers, and with an ECOG PS 0-1. Brain metastases were mostly asymptomatic and < 10 mm. The OS for the entire population was 26.7 months (95% CI, 23.9-29.5); there was no difference between groups, and use or type of RT versus TKI. The icPFS was 14.3 months (95% CI, 9.1-19.5), icORR was 64.2%, and icDCR was 82.7%, without any difference between groups. Among those patients who did not receive upfront Osi, use in the post-progression setting resulted in a significantly longer OS (54.8 vs. 23.0 months, p = 0.001). Conclusions: We found no statistical difference in OS, icPFS, or icORR in patients treated with upfront RT or EGFR TKI. Results should be confirmed with a prospective study.
Does the extent of brain metastasis affect outcome of non-small cell lung cancer patients treated with chemotherapy?
Authors: Choi Yong Won , Ahn Mi Sun , Lee Hyun Woo , Kang Seok Yun , Choi Jin-Hyuk
Published: May 2019

e20616

Background: More than one third of advanced non-small cell lung cancer (NSCLC) patients (pts) experience brain metastases in the course of their disease. Although the outcome of NSCLC pts with brain metastasis is generally poor, identifying subgroups of pts that could benefit from appropriate therapeutic approach is clinically important, particularly in EGFR tyrosine kinase inhibitor (TKI) era. Methods: A retrospective review was conducted on 85 NSCLC pts with synchronous brain metastasis who underwent at least first-line chemotherapy, after treatment (Tx) for brain metastasis (gamma knife surgery or fractionated stereotactic radiotherapy : 42, whole brain radiation therapy : 38, surgical resection : 1, and no Tx : 4) from Jan 2002 to Dec 2013. Overall survival (OS) of all pts was analyzed according to the clinicopathological characteristics, Tx modality for brain metastasis, and chemotherapy. Results: The median OS for all pts after the initiation of first-line chemotherapy was 9 months. In univariate analysis, pts who received TKI (13 months versus 6 months, p= 0.001) and third- or further-line chemotherapy (15 months versus 6 months, p< 0.001) had significantly longer median OS. The presence of extracranial extrathoracic metastasis, number of brain metastasis, and Tx modality for brain metastasis showed no significant association with OS. In multivariate analysis, third- or further-line chemotherapy (24 pts) was the only independent prognostic factor for favorable OS ( p< 0.001). Pts who underwent third- or further-line chemotherapy were characterized by high proportion of non-squamous histology ( p= 0.016), extracranial extrathoracic metastasis ( p= 0.015), and TKI Tx ( p< 0.001). Conclusions: The present study suggests that judicious but active use of chemotherapy after appropriate Tx for brain metastasis may result in favorable outcome in NSCLC pts with synchronous brain metastasis, regardless of the number of brain metastatic lesions or local Tx modalities.
Analysis of a profile of lipid metabolism genes in advanced non-small cell lung cancer.
Authors: Merino Maria , Fernández Lara , Ramirez de Molina Ana , Moreno Juan , Colmenarejo Gonzalo , Falagan Sandra , Gómez César , Lopez-Gomez Miriam , Zambrana Francisco , Jimenez Gordo Ana M. , Aguayo Cristina , Casado Enrique , Sereno Moyano Maria
Published: May 2019

e20619

Background: Non- small cell lung cancer (NSCLC) is one of the tumors with the highest mortality rate. The underlying metabolic alterations involved in its carcinogenesis are becoming more interesting. According to this, the analysis of the dysregulation of genes involved in lipid metabolism (LM) is subject to a growing research. To evaluate a profile of genes involved in lipid metabolism in NSCLC, we analyzed the correlation of this gene expression profile with different clinical-pathological variables. Methods: We performed a retrospective analysis of 22 genes related to LM in samples of NSCLC as well as clinical-pathological features. Advanced NSCLC patients enrolled from 2008 through 2015 were included. Clinical and pathological data were collected from medical reports. This study was approved in our ethical committee and all patients signed the consent inform. Samples were deparaffinated and RNA was extracted using RNeasy FFPE Kit (Qiagen Gmbh, Germany). A Taq-Man Low Density Array (Applied Biosystems) was specifically designed and gene-expression assays were performed in a HT-7900 Fast Real time PCR. RT-StatMiner software (Integromics Inc., Madison, USA) was used to detect and determine the quality control and differential expression analyses of data. Quantification of gene expression was calculated with the 2–ΔCt method. The Kaplan–Meier method was used for survival probabilities, and the log-rank test was to test differences between subgroups. Results: Ninety patients with advanced NSCLC were included. Median age was 64, 68/90 (75%) were male; 46/90 (51%) were ECOG 1; 68/90 (75%) adenocarcinoma vs 22/90 (24%) squamous; 47/90 (52%) smokers and 34% former smokers; metformine intake was presented in 9/90 (10%) and statins 24/90 (27%). In retrospective RT-PCR analysis including a lipid metabolism gene profile of 22 genes, we obtained an overexpression of 2 genes (an Acyl-CoA sintetase and a adipocine encoding gene). They were significantly correlated with overall poor survival in the multivariate analysis (table). These results were confirmed in an in silico validation using 994 NSCLC patients from TCGA study. Conclusions: This is the first study demonstrating a significant relation with a poor survival between a metabolic lipid gene profile expression and survival in advanced non- small cell lung cancer [Table: see text]
Clinical implication of inflammation-based serologic biomarkers and tissue biomarkers on hyperprogression in NSCLC patients receiving immune checkpoint blockers in real world.
Authors: KIM Seoree , Kang Jin-Hyoung , Chun Sang Hoon , Kim Joori
Published: May 2019

e20633

Background: Although immune checkpoint blockades (ICBs) therapy can lead to favorable and durable results by reinvigorating the anti-tumor immune response in some patients, many other patients experience poor prognosis and even tumor overgrowth can be seen in real practice. We aimed to assess these hyperprogressive disease (HPD) in patients who underwent ICB therapy. Methods: We retrospectively reviewed medical records of non-small cell lung cancer patients (n = 243) treated with anti-PD-1 or anti-PD-L1 monotherapy. HPD was defined as a tumor growth kinetics ratio > 2 during anti-PD-1/PD-L1 therapy and a time-to-failure of less than 2 months. We analyzed the association of Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and CRP-albumin ratio (CAR) with HPD and the difference of immune composition in TME by multiplex IHC. Results: Overall, 231 patients were included. The median age was 64.2 years; most patients were male (74.9%) and smokers (70.1%, n = 162). 25 patients (10.8%) met the criteria for HPD. Oncogenic drive mutant status was significantly associated with HPD (18.6% vs 9.04%; P = 0.001). Kaplan Meier overall survival estimates showed a clear trend toward worse outcomes for patients with HPD (median, 5.6 months; P < 0.001) than for those without (median, 7.4 months). We also analyzed the association of NLR, PLR and CAR with HPD. Serologic markers at the time of first response evaluation (post 6 weeks, i.e.,) showed a prognostic value for HPD after ICB use ( P < 0.001, 0.008, 0.017). In multiplex IHC, there was no difference in T cell related immune marker of CD 3/4/8/45RO and FOXP3, dendritic cell, NK cell and other co-inhibitory signal markers between two groups. However, the key point was the M2 polarized tendency in the HPD group when the macrophage M1 / 2 markers of CD68, CD163, CD206 and CCR7 were observed. This suggests that changes in the AXL pathway and EMT features associated with reinvigorating anti-tumor immunity in M2 polarized cells may lead to changes in poor prognosis to HPD. Conclusions: Despite improved recognition of HPD, its etiology and predisposing factors remain unclear, but it is clear that the prognosis becomes poor when it occurs. We observed that some serologic biomarkers (NLR, PLR and CAR. i.e.,) can be used to predict HPD. Multiplex IHC can be used not only to predict HPD, but also to validate its mechanism. Furthermore, we undergo whole exon sequencing and multiplex IHC to understand mechanism of Hyperprogression.