bluuebunny/crossref_metadata_2025 huggingface dataset:
Lobectomy with mediastinal nodal dissection versus partial lobectomy in patients with bronchial carcinoid tumors: A NCDB analysis.
Authors: Westin Gustavo Figueiredo Marcondes , Alsidawi Samer , Leventakos Konstantinos , Halfdanarson Thorvardur Ragnar , Molina Julian R.
Published: September 2018

8549

Background: Bronchial carcinoid tumors are a rare group of neoplasms that usually have an indolent clinical behavior. Surgical resection is the main treatment modality for patients with early stage disease, however it is unclear if lobectomy with mediastinal lymph node dissection (L) is superior compared to partial lobectomy (PL). Methods: Utilizing the National Cancer Database from 2004-2012, 1551 patients diagnosed with T1N0 or T2N0 typical carcinoid tumors (CT), and 167 atypical carcinoid tumors (ACT), who underwent L or PL (segmental or wedge resection) as initial treatment strategy, and did not receive chemotherapy or radiation were identified. All patients had pathologically confirmed diagnosis, negative surgical margins, and complete follow up data. Overall survival (OS) was analyzed utilizing Kaplan-Meier curves, and log-rank tests were used for statistical comparisons. Cox proportional hazards were performed to control for age, sex, race, grade, year of diagnosis, Charlson/Deyo Score, insurance, income, and facility type. T-test was used to compare post-surgical hospital stay. Results: The entire cohort median age was 61 years (range 18-90), and male to female ratio was 0.43. 75% of patients with CT and 78% of ATC underwent L. The 90 day mortality following surgery was < 1 % in both surgical groups. Patients who underwent L had longer post-operative hospitalization stay (mean 5.3 vs. 4.3 days; p < 0.001). The 5 year survival for patients with CT was 95% in the L versus 93% in the PL group (p = 0.62), and for ACT 89% in the L versus 81% PL group (p = 0.28). In a multivariate analysis increasing age was the only prognostic factor, and was associated with inferior survival. The HR for death comparing PL to L was 1.09 (95% CI: 0.65-1.78; p = 0.71) for CT and 1.25 (95% CI: 0.45-3.23; p = 0.65) for ACT. Conclusions: Patients with localized node-negative CT and ACT have excellent 5 year survival. Performing a lobectomy with mediastinal node dissection may not provide additional benefit compared to partial lobectomy, but this may increase the length of hospital stay.
The correlation between mutation burden and disease free survival in patients with lung adenocarcinomas.
Authors: Wang Changzheng , Xin Shuang , Shi Xulian , Zhao Xin , Wu Kui , Zhang Li , Zhang Xiuqing
Published: September 2018

8550

Background: Lung cancer is one of the leading causes of cancerous deaths globally. High mutation burden is a special character in lung adenocarcinoma patients. Mutation burden is usually based on the number of non-synonymous mutations implying the instability of genome. We hypothesize genome-wide mutation burden indicates mutation degree and is correlated with prognostic in lung adenocarcinoma. Methods: Whole-exome sequencing was performed on 98 Chinese lung adenocarcinoma patients with tumor and normal tissue to a mean depth of 49.6ⅹ. The total number of non-synonymous somatic mutations was calculated from the sequencing data of each patient. Patients were divided into high mutation burden and low mutation burden groups in accordance with the mean mutation burden and Kaplan-Meier analysis was performed for survival analysis between these two groups. The association between mutation burden and age or smoking status was analyzed by Wilcoxon rank-sum test. Results: Among these 98 patients, the values of mutation burden varied from 5 to 1121 with mean value 161.8, 36 (36.7%) patients with smoking history and 34 (34.7%) patients were older than 65 years; the numbers of patients in I, II, III stage were 19 (19.4%), 16 (16.3%) and 63 (64.3%) respectively. 32 patients were classified into high mutation burden group, the other 66 patients classified into low mutation burden group. Survival analysis showed a significantly longer disease free survival (DFS) in low mutation burden group (p-value = 0.0133).Mutation burden was significantly associated with age ( < 65 vs ≥65, p-value = 0.0208) and smoking status (p-value = 8.67ⅹ10-4). Conclusions: The association between mutation burden and age or smoking status suggested the high risk for mutation burden accumulation. The significant difference of DFS between high mutation burden and low mutation burden groups reveals the potential of mutation burden as one of the prognostic factors in patients with lung adenocarcinomas.
Association of PD-L1 expression with tumor infiltrating immune cells and mutation burden in the high grade neuroendocrine carcinoma of the lung.
Authors: Kim Hye Sook , Han Ji-Youn
Published: September 2018

8564

Background: Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high grade neuroendocrine carcinoma of the lung and remain among the most fatal malignancies. Programmed death-ligand 1 (PD-L1) is expressed in a group of cancers that may be suitable for specific immunotherapy. We retrospectively investigated PD-L1 expression in tumor cells (TC) and tumor infiltrating immune cells (IC) and correlated this with mutation burden and clinical outcome. Methods: A total of 192 patients with LCNEC (n = 72) and SCLC (n = 120) were explored. PD-L1 expression was scored by immunohistochemistry in TC and IC. We used the Ion AmpliSeq Comprehensive Cancer Panel to identify mutation in all exons in 409 cancer-related genes. Results: The overall prevalence of PD-L1 expression on TC was 15.1 % (29/192). No significant difference was observed between LCNEC and SCLC (16.7% vs. 14.2%, p = 0.365). Tumor-infiltrating IC and PD-L1 positive immune cells (IC) were observed in 34.4% (66/192) and 31.3% (60/192), respectively. The prevalence of tumor-infiltrating IC and PD-L1 expression on IC were significantly higher in LCNEC compared to SCLC (57.6% vs. 23.3%, p < .001; 45.8% vs. 22.5%, p = .001, respectively). Tumor-infiltrating IC and PD-L1 expression on IC were correlated with higher nonsynonymous mutational load (p = 0.048 and 0.038, respectively). Tumor-infiltrating immune cells (median 11.3 vs. 6.8 months, p = 0.005), and its correlated PD-L1 expression on IC (median 11.3 vs. 7.0 months, p = 0.024) were related with better progression free survival. There was no relevance between biomarker status and overall survival. Conclusions: These findings suggest that the PD-1/PD-L1 pathway is activated in a fraction of HGNEC of lung with correlating higher mutational burden. Further studies are needed to determine the PD-L1 expression and correlated clinical features to refine role of anti-PD1 treatments in these patient population.
Evolution and clinical impact of genomic alterations detectable in circulating tumor DNA of 1150 advanced EGFR-mutant (mt) lung cancer patients.
Authors: Blakely Collin M. , Wu Wei , Gubens Matthew A. , Rotow Julia , Wang Victoria , Banks Kimberly , Lanman Richard B. , Mack Philip C. , Husain Hatim , McCoach Caroline Elizabeth , Doebele Robert Charles , Riess Jonathan , Bivona Trever Grant
Published: September 2018

9009

Background: Advanced EGFR-mt lung adenocarcinomas (LUAD) frequently harbor additional genetic alterations. The clinical significance of these concurrent alterations and how they evolve with treatment are unclear. Methods: We performed next-generation sequencing (NGS) of ~70 cancer related genes from the circulating tumor DNA (ctDNA) of 1150 consecutive advanced LUAD patients (pts) with detectable EGFR mts. The analysis included 113 samples from 81 pts for whom clinical outcome data were known. Clinical response to EGFR TKI treatment was correlated to mutational status in 12 cancer-related pathways. Results: EGFR-mt cases contained an average of 3.6 genetic alterations (range 1-18). There was enrichment for co-alterations in TP53, CDK6, CTNNB1 and SMAD4 in EGFR-mt cases compared to a control cohort of 1008 EGFR WT cases. Enrichment for the EGFR T790M mutation was found upon progression to first-line EGFR TKI treatment, as expected. Analysis of 450 T790M-mt cases showed enrichment for co-alterations in genes controlling the cell cycle (28% vs. 21%, p = 0.01), DNA repair (12% vs. 8%, p = 0.03), and WNT (16% vs. 11%, p = 0.03) signaling. The number of genetic alterations increased during progression on each line of therapy in a manner unlinked to age, gender, or tobacco exposure (mean 3.2 pre-TKI vs. 6.4 after 2nd line, p = 0.001). Upon progression to second-line treatment, analysis revealed further selection for co-alterations in TP53, CCNE1, MYC and PIK3CA and the associated pathway-level classifications. We found an increased frequency of co-alteration in cell cycle genes in EGFR TKI non-responders versus responders (33% vs. 0%, p = 0.0005). Conclusions: Within the landscape of advanced EGFR-mt LUAD, we uncover features of evolutionary selection for multiple concurrent oncogenic pathway alterations including TP53, WNT, PI3K, MYC, and cell cycle genes. This large clinical and genetic dataset prompts a re-evaluation of the prevailing paradigm of monogenic-based molecular stratification to monotherapy, and highlights an alternative model of genetic collectives as a previously underappreciated determinant of lung cancer progression and therapy resistance.
STK11/LKB1 co-mutations to predict for de novo resistance to PD-1/PD-L1 axis blockade in KRAS-mutant lung adenocarcinoma.
Authors: Skoulidis Ferdinandos , Hellmann Matthew David , Awad Mark M. , Rizvi Hira , Carter Brett W. , Denning Warren , Elamin Yasir , Zhang Jianjun , Leonardi Giulia Costanza , Halpenny Darragh , Plodkowski Andrew , Long Niamh , Erasmus Jeremy J. , Papadimitrakopoulou Vassiliki , Wong Kwok-Kin , Wistuba Ignacio Ivan , Janne Pasi A. , Rudin Charles M. , Heymach John
Published: September 2018

9016

Background: Identification of molecular predictors of response to PD-1/PD-L1 inhibitors is critical in order to maximize their therapeutic potential. We previously reported that KRAS-mutant lung adenocarcinomas (LUAC) with co-occurring genetic events in STK11/LKB1(KL) or TP53 (KP) define subgroups with marked differences in immune contexture, including a paucity of CD8+ TILs in KL LUAC. Here, we assess clinical responses to PD-1/PD-L1 therapy in KL and KP subsets, with data assembled under the auspices of the SU2C/ACS Lung Cancer Dream Team. Methods: Patients (pts) with metastatic KRAS-mutant LUAC who received at least one cycle of PD-1/PD-L1 therapy, were alive for ≥14 days thereafter, and had available molecular profiling were identified retrospectively. Efficacy assessment was based on RECIST v1.1. PD-L1 expression was tested using 22C3 pharmDx or E1L3N IHC assays and quantified as percent of staining tumor cell membranes. Isogenic derivatives of the LKR10 KrasLA1/+ murine LUAC cell line with CRISPR/Cas9-mediated Lkb1knockout were used in preclinical experiments. Results: 165 pts with KRAS-mutant LUAC who received PD-1/PD-L1 therapy were included [KL: 27%, KP: 36%, K-only: 37%]. Best overall response differed significantly in the KL (PR: 9.1%, SD: 15.9%, PD: 75%) and KP (PR: 33.3%, SD: 20%, PD: 46.7%) sub-groups (P = 0.005, Fisher’s exact test). PFS was significantly longer in KP compared to KL LUAC (median 12.9 wks vs 8.4 wks, HR = 0.64, 95% CI 0.39-0.95, P = 0.032, log-rank test). ORR in K-only tumors was 21.3% and median PFS 11.4 wks. PD-L1 positivity (≥1%) was more frequent in KP tumors compared to KL (75% vs 22%, P = 0.03, Fisher’s exact test). In syngeneic murine models of KRAS-mutant LUAC, loss of LKB1 promoted resistance to PD-1 inhibitor monotherapy, suggesting a causative role. Conclusions: Mutational inactivation of STK11/LKB1 represents a novel genomic predictor of de novo resistance to immune checkpoint blockade in KRAS-mutant LUAC, whereas TP53 co-mutations are associated with high likelihood of response. Precision immunotherapy will require tailoring to the co-mutation status of individual tumors.
Rapid/warm autopsy to reveal APOBEC-mutagenesis as driver of heterogeneity of metastatic thoracic tumors.
Authors: Roper Nitin , Maity Tapan K , Gao Shaojian , Venugopalan Abhilash Karavattu , Zhang Xu , Biswas Romi , Perry Susan , Cultraro Constance , Kim Chul , Hassan Raffit , Thomas Anish , Rajan Arun , Kleiner David E , Hewitt Stephen M. , Khan Javed , Guha Udayan
Published: September 2018

9023

Background: Intratumor heterogeneity has been characterized among multiple cancer types. In lung adenocarcinoma, APOBEC-mutagenesis has been shown to be a source of heterogeneity. However, these data are largely limited to early stage primary tumors. There is limited information about the role of APOBEC-mutagenesis and somatic variants, copy number changes, transcript and protein expression in influencing tumor heterogeneity in metastatic lung adenocarcinoma and other thoracic tumors. Methods: We applied whole exome sequencing, RNA-seq, OncoScan CNV and mass spectrometry-based proteomic analyses on 46 tumor regions from metastatic sites including lung, liver and kidney, obtained by rapid/warm autopsy from 4 patients (pts) with stage IV lung adenocarcinoma, 1 pt each with pleural mesothelioma and thymic carcinoma. The autopsy procedure was initiated between 2-4 hours of death. Results: All tumors displayed organ-specific, branched evolution that was consistent across exome, transcriptome and proteomic analyses. The degree of heterogeneity at the genomic and proteomic level was patient-specific. There was extensive heterogeneity within the tumors of one of four patients with lung adenocarcinoma and in the thymic carcinoma patient (both non-smokers) with multiple driver mutations and copy number changes occurring in only some of the tumors suggesting ongoing late tumor evolution. Further examination of the heterogenous thymic and lung adenocarcinoma tumors showed strong enrichment with the APOBEC-mutagenesis pattern and high associated levels of APOBEC3B mRNA. Conclusions: Metastatic lung adenocarcinoma, thymic carcinoma and mesothelioma evolve through a branched, organ-specific process with marked differences in the acquisition of significant driver mutations and copy number changes. APOBEC3B is a potential driver of heterogeneity in pts with advanced, heterogeneous metastatic lung adenocarcinoma and thymic carcinoma and needs to be evaluated further.
Predictive impact of complete molecular response in plasma: A phase II, liquid biopsy study in EGFR mutated NSCLC patients treated with afatinib (WJOG 8114LTR).
Authors: Otsubo Kohei , Akamatsu Hiroaki , Koh Yasuhiro , Morita Satoshi , Fujimoto Daichi , Bessho Akihiro , Azuma Koichi , Nakagawa Kazuhiko , Yamamoto Nobuyuki
Published: September 2018

9027

Background: Liquid biopsy has been approved as an alternative method to detect clinically relevant EGFR mutations in NSCLC. However, it is unknown whether the early assessment of molecular response in plasma could be a surrogate of clinical response and/or longer efficacy. Here, we conducted a prospective, multi-institutional study of liquid biopsy in EGFRmutated NSCLC patients (WJOG 8114LTR). Methods: Chemotherapy naïve, advanced NSCLC patients with EGFR-sensitizing mutation received afatinib monotherapy (40 mg/body) until progressive disease (PD) or unacceptable toxicity. Plasma DNA was obtained from patients at baseline, weeks 2, 4, 8, 12, 24, 48, and at PD. Three types of clinically relevant EGFRmutations (exon 19 deletion, exon 20 T790M and exon 21 L858R) will be analyzed using plasma DNA with multiplexed, pico-droplet digital PCR assay (RainDrop system, RainDance Technologies, Billerica, MA). Complete molecular response (CMR) was defined as mutant allele event/frequency of exon 19 deletion or exon 21 L858R below the cutoff for the positivity by digital PCR in plasma. This study was registered at UMIN (ID: 000015847). Results: Fifty-seven patients were registered in the study. Efficacy of afatinib was comparable to previous reports (overall response rate: 78.6%, and median progression-free survival (mPFS): 14.2 months). At baseline, 62.5% of patients were positive for EGFR mutation in plasma. Plasma positive patients had slightly shorter PFS than plasma negative patients, but not significant (p = 0.24, log-rank). Among those who were positive at baseline, CMR was achieved in 60.6% of patients at two weeks, and 87.5% at four weeks, respectively. Patients with CMR at two weeks had significantly longer PFS than those without one (13.6 versus 7.5 months, p = 0.0001). Patients with CMR at four weeks also demonstrated longer PFS than those without one (13.6 versus 5.1 months, p < 0.0001). Among patients who achieved CMR by week four, time to achieve CMR did not affect PFS ( p= 0.59). Conclusions: This is the first report on the predictive impact of early CMR in plasma for longer therapeutic efficacy of afatinib in EGFR mutated NSCLC patients. Clinical trial information: 000015847.
Antitumor activity of osimertinib in NSCLC harboring EGFR exon 20 insertions.
Authors: Riess Jonathan , Floch Nicolas , Martin Matthew , Orme Jonathon , Staniszewska Anna , Menard Ludovic , Cuomo Maria Emanuela , O'Neill Daniel , Ward Richard , Finlay Raymond , McKerrecher Darren , Cheng Mingshan , Vang Daniel , Tsai Rebekah , Ye Chunting , Keck James G. , Gandara David R. , Mack Philip C. , Cross Darren
Published: September 2018

9030

Background: EGFR exon 20 insertions (Ex20Ins), the 3rd most common EGFR activating mutation, are generally unresponsive to 1st and 2nd generation EGFR-TKIs. Development of EGFR-TKIs that effectively target NSCLC with Ex20Ins mutations represents a major unmet need. Osimertinib is an EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M, but the potential of osimertinib remains to be fully assessed in patients (pts) with Ex20Ins NSCLC. Methods: CRISPR engineered Ex20Ins cell line xenografts representing the two most common Ex20Ins (D770_N771InsSVD and V769_D770InsASV) and pt derived xenograft (PDX) of 3 EGFR Ex20Ins (V769_D770InsASV, M766_A767insASV, H773_V774insNPH) were used for in vivo experiments. Xenografts were treated by oral gavage with vehicle, erlotinib (50 mg/kg/day) or afatinib (20 mg/kg/day), osimertinib metabolite AZ5104 (50 mg/kg/day) and osimertinib (25 mg/kg/day) and assessed for tumor growth inhibition (TGI). Immunoblotting was performed for EGFR and relevant signaling pathways. A pt from whom the V769_D770InsASV Ex20ins PDX was derived was treated on a UC Davis IRB approved protocol with osimertinib at 160 mg PO once-daily (QD). Results: At completion of treatment, QD administration of osimertinib or AZ5104 induced significant TGI in xenografts across the 4 EGFR Ex20ins tested (range 60-95% TGI, p < 0.001 compared to control for all models) that was superior to either afatinib or erlotinib. Robust decrease in p-EGFR, p-ERK, p-Akt, p-Stat3 was observed with osimertinib treatment. The patient corresponding to the V769_D770InsASV Ex20ins PDX treated with osimertinib exhibited clinical improvement and tumor shrinkage; unfortunately he was found to have interstitial pneumonitis that necessitated drug discontinuation. Conclusions: Osimertinib at clinically representative doses has in vivo activity across multiple EGFR Ex20ins that comprising the most common Ex20ins detected in patients (~50% prevalence); metabolite AZ5104 may contribute to efficacy. Tumor shrinkage was observed in a patient with lung cancer harboring an Ex20ins treated for a limited time with osimertinib. Based on this in vivo xenograft and pt data, osimertinib warrants further study in pts with EGFR Ex20ins NSCLC.
ASTRIS: A real world treatment study of osimertinib in patients (pts) with EGFR T790M positive non-small cell lung cancer (NSCLC).
Authors: De Marinis Filippo , Cho Byoung Chul , Kim Dong-Wan , Kim Sang-We , Hochmair Maximilian J. , Metro Giulio , Vansteenkiste Johan F. , Vicente David , Solomon Benjamin J. , Cheema Parneet K. , Freitas Helano C. , Provencio Mariano , Chen Yuh-Min , Wu Yi-Long , Milner Alvin , Rigas James R.
Published: September 2018

9036

Background: Osimertinib is an oral, irreversible, central nervous system (CNS) active EGFR tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing and T790M resistance mutations. We report results from the first predefined interim analysis of the ongoing ASTRIS study (NCT02474355). Methods: Pts received osimertinib 80 mg once daily. Eligible pts had Stage IIIB-IV NSCLC harbouring a T790M mutation determined by local validated molecular test (not restricted by sample type), received prior EGFR-TKI therapy, WHO performance status (PS) 0−2, acceptable organ and bone marrow function and no history of interstitial lung disease (ILD) or QTc prolongation. Asymptomatic, stable CNS metastases were permitted. The primary efficacy outcome was overall survival; other outcomes included investigator-assessed response rate (RR), progression-free survival and time to treatment discontinuation. Safety data are also reported. Results: From study start (18 Sept 2015) to data cut-off (DCO; 3 Nov 2016), 1217 pts received osimertinib from 120 sites with a median follow-up of 4.1 mths ( < 1−14 mths), median age 64 yrs (27–92 yrs), 67% female, 61% White, 37% Asian, 87% WHO PS 0/1, 44% prior chemotherapy, 45% prior radiotherapy. All pts tested positive for T790M, identified from tissue in 682 pts (56%), plasma ctDNA in 433 pts (36%) and from other specimens in 102 pts (8%). At DCO, 317 pts (26%) had discontinued treatment, 900 pts (74%) were ongoing, median duration of exposure 3.8 mths ( < 1–13.2 mths), 168 pts (14%) had disease progression and 156 pts (13%) had died. In pts evaluable for response, the investigator-assessed RR was 64% (569/886; 95% CI 61, 67). Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 122 (10%) and 54 pts (4%), respectively. Serious AEs were reported in 165 pts (14%) and AEs leading to death in 30 pts (2%). ILD/pneumonitis-like events were reported in 25 pts (2%), and QTc prolongation in 9 pts (1%). Conclusions: ASTRIS, the largest reported clinical study of osimertinib in T790M-positive NSCLC, demonstrates clinical activity similar to that observed in the osimertinib clinical trial program with no new safety signals. Clinical trial information: NCT02474355.
Describing the value of the most common first line NSCLC regimens in a real world setting.
Authors: Newcomer Lee N. , Byfield Stacey DaCosta , Chastek Benjamin , Korrer Stephanie , Horstman Thomas , Malin Jennifer
Published: September 2018

9046

Background: We aim to describe clinical and economic outcomes of common chemotherapy regimens for first line therapy of metastatic non-small cell lung cancer (mNSCLC).The data are intended to help clinicians and patients understand the real world results for patients like themselves. Methods: This retrospective analysis used clinical data obtained from a prior authorization (PA) program for chemotherapy linked with administrative claims data from 6/1/2015 to 5/31/2016 from a large national managed care organization. Clinical data included cancer type, stage at diagnosis, biomarkers, treatment line and evidence of progression/relapse. Eligible patients were commercially insured members with a PA request for commonly used NCCN recommended regimens for first line therapy of mNSCLC. Outcomes, including duration of therapy, % of patients hospitalized and total cost of care were tracked from first claim for chemotherapy until end of treatment due to discontinuation, death or start of a second line, with remaining patients censored at 5/31/2016 or end of enrollment. Results: Of 830 mNSCLC patients, 498 (60%) completed first line therapy during the study period. 345 initiated one of the following: Carbo/cisplatin + pemetrexed (CA), Carbo/cisplatin + paclitaxel (CP), Carbo/cisplatin + bevacizumab + pemetrexed (CBA), nivolumab (N), and docetaxal (D). Outcomes are summarized in the Table. Conclusions: Patients treated with the five most commonly prescribed first line therapies for mNSCLC have much shorter duration of therapies (52-76 days) than reported in published clinical trials with a significant risk of hospitalization (18% -30%) and at substantial cost ($34,971 - $108,100). These data are an important consideration for the patient and clinician making treatment decisions in routine clinical practice and will become more valuable as the database grows over time. [Table: see text]
Third-line treatment: A randomized, double-blind, placebo-controlled phase III ALTER-0303 study—Efficacy and safety of anlotinib treatment in patients with refractory advanced NSCLC.
Authors: Han Baihui , Li Kai , Wang Qiming , Zhao Yizhuo , Zhang Li , Shi Jianhua , Wang Zhehai , Cheng Ying , He Jianxing , Shi Yuankai , Chen Weiqiang , Wang Xiuwen , Luo Yi , Nan Kejun , Jin Faguang , Li Baolan , Chen Yinglan , Zhou Jianying , Wang Donglin
Published: September 2018

9053

Background: Anlotinib hydrochloride, an oral TKI targeting VEGFR, FGFR, PDGFR and c-Kit, showed promising efficacy in PhaseⅡstudy. Here, we evaluated the efficacy and safety of anlotinib as third-line treatment for advanced NSCLC, a randomized, double-blind, placebo-controlled Phase Ⅲtrial (ALTER-0303). Methods: Eligible ⅢB/Ⅳ NSCLC pts who progressed after at least 2 lines of prior therapies were randomized 2:1 to receive anlotinib or placebo (12 mg QD from day 1 to 14 of a 21-day cycle) till progression or intolerable toxicity. Enrolled pts harboring EGFR or ALK mutations must had failed in previous match-targeted therapies. The primary endpoint is OS; secondary endpoint includes PFS, DCR and ORR. Results: As of Aug 2016, total of 437 pts from 31 sites were randomized. The baseline characteristics of Anlotinib arm (N=294) and placebo arm (N=143) were well balanced in the age, gender, ECOG PS and gene states. With 292 OS events (66.82%), significant superiorities in OS, PFS, DCR and ORR were observed in Anlotinib arm according to investigator-assessed results. Grade ≥ 3 treatment-related AEs were hypertension, dermal toxicity and hypertriglyceridemia. There was no treatment–related death in either arm. (Data presented in the Table.) Conclusions: ALTER-0303 trial met its primary endpoint. Anlotinib significantly improved OS and PFS in advanced NSCLC with a manageable safety profile. The results strongly suggest that anlotinib should be considered as a candidate for the third-line treatment or beyond in advanced NSCLC. Clinical trial information: NCT02388919. [Table: see text]
Clinical features of squamous cell lung cancer with targetable gene alterations in a nationwide genomic screening network in Japan (LC-SCRUM-Japan).
Authors: Sugiyama Eri , Matsumoto Shingo , Kobayashi Nobuaki , Aono Hiromi , Shingyoji Masato , Hotta Katsuyuki , Sekine Akimasa , Hara Satoshi , Furuya Naoki , Nakagawa Taku , Nakazaki Hirofumi , Harada Taishi , Sugawara Shunichi , Takata Saori , Okamoto Norio , Taima Kageaki , Tomii Keisuke , Yoh Kiyotaka , Goto Koichi
Published: September 2018

9057

Background: Molecular-targeted therapies for precision medicine in squamous cell lung cancer (SqLC) have not yet been established. To identify precise patients for targeted therapies and to reveal their clinical characteristics, we have operated clinical sequencing of advanced SqLCs in our nationwide genomic screening project in Japan (LC-SCRUM-Japan) since March 2015. Methods: As of December 2016, 190 institutions across Japan were participating and 263 advanced SqLC patients had been enrolled in this project. Submitted tumor samples were subjected to a next-generation sequencing system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: The median age of the 263 patients was 74 years (range, 27-87 years). Two hundred thirty (87%) were male and most patients (97%) were smokers. Among 211 available samples, potentially targetable gene alterations were detected in 58 (27%). Based on these gene alterations, the patients were subdivided into 4 groups, consisting of 25 (12%) with genetic alterations of FGFR family (FGFR type; 23 FGFR1 amplifications, 1 FGFR2 amplification and 1 FGFR3 fusion), 20 (9%) with genetic alterations of the PI3K pathway (PI3K type; 10 PIK3CA mutations, 8 PTEN mutations and 2 AKT mutations), 15 (7%) with other oncogene alterations (KRAS/EGFR/ALK type; 10 KRAS mutations, 3 EGFR mutations and 2 ALK fusions) and others. Comparative analyses of clinical characteristics between the 4 types showed that brain metastases were significantly more frequent in the FGFR type than the others (24% vs. 5%, p = 0.0007), and females (40% vs. 11%, p = 0.0009) and never-smokers (21% vs. 3%, p = 0.0004) were significantly frequent in the KRAS/EGFR/ALK type compared to the others. The prognostic significance of these genetic alterations has not yet been evaluated because of short follow-up time (median, 8.5 months). Conclusions: A series of potentially targetable gene alterations have been identified in SqLC patients. The SqLC patients had distinct clinical features according to the molecular subtypes, and genotype-directed therapeutic strategy should be developed for the individual subtypes.
Baseline frequency of brain metastases and outcomes with multikinase inhibitor therapy in patients with RET-rearranged lung cancers.
Authors: Drilon Alexander E. , Filleron Thomas , Bergagnini Isabella , Milia Julie , Hatzoglou Vaios , Velcheti Vamsidhar , Besse Benjamin , Mok Tony , Awad Mark M. , Wolf Juergen , Carbone David P. , Camidge D. Ross , Riely Gregory J. , Peled Nir , Mazieres Julien , Kris Mark G. , Gautschi Oliver ,   Global Multicenter RET Registry Investigators
Published: September 2018

9069

Background: In phase 2 trials, multikinase inhibitors with activity against RET are active in a subset of patients (pts) with RET-rearranged lung cancers (response rate of 28%, phase 2 study of cabozantinib; Drilon et al Lancet Oncol 2016). Data on the incidence of brain metastases and outcomes with multikinase inhibitor therapy in pts with intracranial disease have not previously been reported. Methods: The frequency of brain metastases at diagnosis of metastatic disease was evaluated in pts accrued to a global registry of RET-rearranged lung cancer pts identified by a multicenter network of thoracic oncologists (Gautschi et al JCO 2017). A proportion of pts were treated with 9 multikinase inhibitors including cabozantinib, vandetanib, lenvatinib, alectinib, and ponatinib. On a prospective phase 2 trial (NCT01639508), patients with asymptomatic brain metastases were eligible. Intracranial response to cabozantinib (RECIST v1.1) was evaluated in an exploratory fashion. Results: 114 registry pts with RET-rearranged lung cancers had metastatic disease at diagnosis. Baseline brain metastases were identified in 27% (95%CI 18-34%, n = 20/75) of pts with available information. No differences (p > 0.05) in age, smoking history, or upstream fusion partner ( KIF5B100% vs 84%, with and without brain metastases, p = 0.53) were noted. In 37 pts treated with multikinase inhibitors with activity against RET, there were no significant differences in median PFS (2.1 vs 2.1 months, p = 0.41) or median OS (3.9 vs 7.0 months, p = 0.10) in pts with (n = 10) and without (n = 27) brain metastases. On a phase 2 trial of cabozantinib, baseline untreated brain metastases were present in 5 pts. Intracranial disease control (stable disease; -34% and -1% in 2 pts with measurable disease) was achieved in 4 of 4 pts with measurable or evaluable intracranial disease with time to treatment discontinuation ranging from 2.4 months to 2.9 years. Conclusions: Brain metastases are present in a substantial proportion of RET-rearranged lung cancer pts. Intracranial disease control can be achieved in select pts by a multikinase inhibitor. Novel RET-directed targeted therapy strategies should address intracranial disease. Clinical trial information: NCT01639508.
Efficacy of vemurafenib in patients (pts) with non-small cell lung cancer (NSCLC) with BRAFV600 mutation.
Authors: Subbiah Vivek , Gervais Radj , Riely Gregory J. , Hollebecque Antoine , Blay Jean-Yves , Felip Enriqueta , Schuler Martin H. , Goncalves Anthony , Italiano Antoine , Keedy Vicki Leigh , Chau Ian , Puzanov Igor , Raje Noopur , Makrutzki Martina , Riehl Todd , Pitcher Bethany , Hyman David Michael , Baselga Jose
Published: September 2018

9074

Background: BRAFV600 mutations occur in 1–2% of pts with NSCLC. We previously reported the efficacy of vemurafenib, a selective BRAFV600 inhibitor, in BRAF mutation-positive non-melanoma tumors (VE-BASKET study). We now present final data for the expanded NSCLC cohort. Methods: This open-label, histology-independent, phase 2 study included 6 prespecified cohorts (including NSCLC) plus one ‘all-others’ cohort. Pts received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (RECIST v1.1). Secondary endpoints included best overall response rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Because the pre-specified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded. ClinicalTrials.gov identifier NCT01524978. Results: Database lock was 12 Jan 2017. Of 208 pts enrolled at 25 centers worldwide, 62 pts had NSCLC: median age 65 years; 56% male; 13% had no prior systemic therapy; 50% had ≥2 prior therapies. Responses were seen in previously treated and untreated pts (Table). The most common all-grade adverse event (AE) was nausea (40%); grade 3–5 AEs included keratoacanthoma (15%) and squamous cell carcinoma of the skin (15%). Six pts discontinued vemurafenib due to AEs; two had non-treatment-related fatal AEs. Conclusions: Vemurafenib showed evidence of encouraging efficacy in pts with NSCLC with BRAFV600 mutation, with prolonged PFS in previously untreated pts; median OS was not estimable due to ongoing responses. The safety profile of vemurafenib was similar to that seen in melanoma studies. Our results suggest a role for BRAF inhibition in NSCLC with BRAF mutations. Clinical trial information: NCT01524978. [Table: see text]
Immune-related adverse events (IRAEs) in metastatic lung cancer patients receiving PD-1/PD-L1 inhibitors and thoracic radiotherapy.
Authors: Hwang William L. , Niemierko Andrzej , Willers Henning , Keane Florence K. , Gainor Justin F.
Published: September 2018

9079

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with unique IRAEs, including pneumonitis (PNS). Thoracic radiotherapy (TRT) is also associated with PNS but it is unknown whether TRT+ICI increases the risk of PNS or other IRAEs. Furthermore, low serum LDH levels are associated with better response/survival to ICI but its potential role as a biomarker for IRAEs is unexplored. Methods: We retrospectively reviewed 164 pts with metastatic lung cancer (95% NSCLC, 5% SCLC) consecutively treated at our institution from 2013-2016 with PD-1/PD-L1 inhibitors and a minimum of one month follow-up, except in cases of rapid death from an IRAE ( n =4). Pts were grouped according to TRT received (+ vs -). IRAE grades were assigned using NCI CTCAE v4.0. Outcomes were compared using Fisher’s exact test and two-sided Student’s t-test. Results: Baseline characteristics such as age, gender, smoking status, supplemental oxygen requirement, median number of chemotherapy lines prior to ICI (1 vs 1), median ICI cycles (5 vs 3), and median follow-up after ICI initiation (8 vs 7 months) were similar in the +TRT ( n = 73) and -TRT ( n =91) groups. Rates of grade ≥ 2 IRAEs (18.1 vs 14.4%, p = 0.67), all-grade PNS (8.2 vs 5.5%, p= 0.54), and grade ≥ 2 PNS (4.1 vs 3.3%, p = 1) were not significantly different between the +TRT and -TRT cohorts. Mean TRT dose was similar between those pts who developed PNS and those who did not (55.8 vs 55.9 Gy). In the +TRT group, 85% received TRT a median of 8.6 months before ICI. Among 7 pts (10%) who had concurrent TRT+ICI, none developed symptomatic PNS. Patients who developed grade ≥ 2 IRAEs ( n= 26) had significantly higher mean serum LDH before initiation of ICI than patients who did not (283 vs 214, ref 98-192 IU/L, p= 0.03). Conclusions: TRT in lung cancer pts receiving ICI was not associated with increased risk of PNS in this series. LDH may be a negative predictive biomarker as pts who suffered grade ≥ 2 IRAEs had significantly higher baseline LDH than those who did not. Larger cohorts and prospective studies would be helpful to validate these findings.
Use of PD-1 pathway inhibitors among patients with non-small cell lung cancer (NSCLC) and preexisting autoimmune disorders.
Authors: Leonardi Giulia Costanza , Gainor Justin F. , Azimi Roxana S. , Riess Jonathan , Rizvi Hira , Hellmann Matthew David , Awad Mark M.
Published: September 2018

9081

Background: Since patients (pts) with NSCLC and autoimmune (AI) disease were largely excluded from immune checkpoint inhibitor clinical trials, we aimed to determine the safety of PD-1 inhibitors in NSCLC pts with a history of AI diseases. Methods: As part of a multi-center, retrospective study, we collected clinicopathologic data from pts with advanced stage IIIB or stage IV NSCLC with a history of AI disease and who received treatment with a PD-1 inhibitor as monotherapy. Qualifying AI disorders included but were not limited to: thyroiditis (excluding hypothyroidism without clear autoimmune etiology), inflammatory bowel disease, as well as rheumatologic, neurologic and dermatologic conditions. Results: We identified 46 pts with NSCLC treated with a PD-1 inhibitor who also had a history of AI disease. At the time of PD-1 inhibitor treatment initiation, 13% of pts had active AI symptoms and 19% were receiving immunomodulatory agents for their AI condition. The median period of follow up after initiation of anti-PD-1 therapy was 17.4 weeks (range 0.6-72.1 weeks). Exacerbation of the underlying AI condition occurred in 8 pts (17%). Two of these pts required steroid treatment (both for rheumatoid arthritis), and three of these pts required temporary interruption of treatment due AI disease flare. Overall, twelve (26%) pts developed at least one immune-related adverse event (irAE) unrelated to the underlying AI condition (8 grade 1-2, 4 grade 3); there were no cases of grade 4-5 irAEs. PD-1 therapy was permanently discontinued in 3 cases due to the development of an irAE (1 for grade 1 pneumonitis, 1 for grade 3 transaminitis, 1 for grade 3 diabetes insipidus). Conclusions: In pts with NSCLC and a history of AI conditions treated with PD-1 blockade, symptomatic flare of underlying AI disease was uncommon. The rate of immune-related toxicities in this population appears similar to published studies in pts without baseline AI conditions. Further analysis of pts with active AI conditions is needed to clarify the safety profile in this population.
Response to salvage chemotherapy following exposure to immune checkpoint inhibitors in patients with non-small cell lung cancer.
Authors: Leger Paul Denis , Rothschild Sasha , Castellanos Emily , Pillai Rathi Narayana , York Sally Jane , Horn Leora
Published: September 2018

9084

Background: Immune checkpoint inhibitors are active for patients with stage IV NSCLC who have progressed following platinum-based chemotherapy. We evaluated responses to chemotherapy in patients who had progressed on a checkpoint inhibitor. Methods: Eligible patients were adults with NSCLC who received salvage chemotherapy following PD-1/PD-L1 inhibitors (cases) versus no PD-1/PD-L1 inhibitors (controls). CT-imaging was done within 4 weeks of initiation of salvage chemotherapy and every 6 weeks thereafter. Revised RECIST guidelines were used to define response. Clinical and imaging data were abstracted from review of electronic medical records. Multivariate logistic regression analysis was used to calculate probability of response. Results: Three-hundred and fifty patients’ charts were reviewed and 82 patients met eligibility criteria. Among evaluable patients, 46 were males. Sixty-seven patients were cases versus 15 controls. Fifty-six patients received nivolumab, 7 pembrolizumab and 4 atezolizumab. Sixty-three (77%) had adenocarcinoma, 18 (22%) squamous cell carcinoma and 1 (1%) large cell carcinoma. The mean number of chemotherapy regimens prior to salvage chemotherapy was 2.37 (95% C.I. 2.10-2.64)) in cases versus 1.93 (95% C.I: 1.32-2.54) in controls. Salvage drugs included docetaxel (62%), pemetrexed (20%), gemcitabine (12%), paclitaxel (6%). Eighteen (27%) cases had partial response to chemotherapy versus 1(7%) controls. Fifteen (22%) cases had progressive disease versus 6 (40%) controls. Thirty-four (51%) cases had stable disease versus 8 (53%) controls. The odd ratio for achieving a partial response was 0.30 (95% CI: 0.18 to 0.50, P = 0.000). In multiple logistic regression model, age, gender, number of prior chemotherapy regimens, tumor histology, smoking status, different salvage chemotherapy regimens were not associated with the likelihood of achieving a partial response. Conclusions: The odds of achieving a partial response to salvage chemotherapy were more than 3 times higher inpatients with prior exposure to PD-1/PD-L1 inhibitors. Ongoing investigations include the duration of response as well as evaluation of toxicity.
Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC.
Authors: Wong Deborah Jean Lee , Schneider Jeffrey Gary , Aljumaily Raid , Korn Wolfgang Michael , Infante Jeffrey R. , Patel Manish R. , Autio Karen A. , Papadopoulos Kyriakos P. , Naing Aung , Gabrail Nashat Y. , Munster Pamela N. , Goldman Jonathan Wade , Van Vlasselaer Peter , Brown Gail Linda , Hung Annie , Oft Martin , Garon Edward B.
Published: September 2018

9091

Background: Although IL-10 has anti-inflammatory properties, it stimulates cytotoxicity and proliferation of intratumoral antigen activated CD8+ T cell at higher concentrations. AM0010 is anticipated to activate antigen stimulated, intratumoral CD8 T cells while PD-1 inhibits them, providing the rationale for combining AM0010 and anti-PD-1 antibody. Methods: We treated a cohort of 34 NSCLC pts with AM0010 (10-20mg/kg QD, SC) and a PD-1 inhibitor [pembrolizumab (2mg/kg, q3wk IV; n=5) or nivolumab (3mg/kg, q2wk IV; n=29)]. Tumor responses were assessed by irRC every 8 weeks. Immune responses were measured by analysis of serum cytokines (Luminex), activation of blood derived T cells (FACS) and peripheral T cell clonality (TCR sequencing). Tumor PD-L1 expression was confirmed by IHC (22C3). Results: Pts had a median of 2 prior therapies. Median follow-up is 9.6 mo (range 0.5-77.3) in this fully enrolled cohort. AM0010 plus anti-PD-1 was well-tolerated. TrAEs were reversible and transient, with most being low grade, most commonly fatigue and pyrexia. G3/4 TrAEs were thrombocytopenia (7), anemia (6), fatigue (4), rash (3), pyrexia (2), hypertriglyceridemia (1) and pneumonitis (1). As of Jan. 31 2017, 22 pts had at least 1 tumor assessment. Partial responses (PRs) were observed in 8 pts (36.4%). 17 of these 22 pts had tissue for analysis of percent of tumor cells with PD-L1 expression (22C3): 58.8% had <1%, 17.7% had 1-49% and 23.5% had >50%. Best response data stratified for PD-L1 are shown in the table. Median PFS and OS for the entire cohort have not been reached. Updated outcome data that includes all enrolled pts will be available at the meeting. AM0010 plus anti-PD1 increased serum Th1 cytokines (IL-18, IFNγ), the number and proliferation of PD1+ Lag3+ activated CD8+ T cells and a de-novo oligoclonal expansion of T cell clones in the blood while decreasing TGFβ. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated in advanced NSCLC pts. The efficacy and the observed CD8+ T cell activation is promising. Clinical trial information: NCT02009449. [Table: see text]
Nivolumab (N) plus ipilimumab (I) as first-line (1L) treatment for advanced (adv) NSCLC: 2-yr OS and long-term outcomes from CheckMate 012.
Authors: Goldman Jonathan Wade , Antonia Scott Joseph , Gettinger Scott N. , Borghaei Hossein , Brahmer Julie R. , Ready Neal E. , Gerber David E. , Chow Laura Q. , Juergens Rosalyn A. , Shepherd Frances A. , Laurie Scott Andrew , Geese William J. , Li Ang , Li Xuemei , Hellmann Matthew David
Published: September 2018

9093

Background: The fully human anti–PD-1 antibody N offers long-term OS benefit in patients (pts) with previously treated adv NSCLC. Adding I (anti–CTLA-4 antibody) to N has been shown to improve clinical activity vs either agent alone in multiple tumor types. We present long-term data for 1L N+I treatment of pts with adv NSCLC from CheckMate 012. Methods: In two cohorts in this phase 1 study, pts with recurrent stage IIIb/IV, chemotherapy-naive NSCLC and ECOG PS 0–1 received N 3 mg/kg Q2W combined with I 1 mg/kg Q12W (n=38) or Q6W (n=39) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed ORR (RECIST v1.1) and PFS. Exploratory endpoints included OS and efficacy by tumor PD-L1 expression. Results: In the N+I Q12W and N+I Q6W cohorts, respectively, 42% and 31% of pts experienced grade 3–4 treatment-related (TR) AEs; 18% in each cohort discontinued due to any-grade TRAEs. The most frequently reported any-grade TRAEs were pruritus (26%) and diarrhea (21%) with N+I Q12W, and fatigue (26%) and diarrhea (23%) with N+I Q6W. There were no TR deaths. N+I showed promising efficacy (table). While efficacy was enhanced with increasing PD-L1 expression, activity was noted in pts with <1% PD-L1 (table). Of 6 complete responses (CRs), 3 were in pts with <1% PD-L1. Conclusions: 1L therapy with N+I demonstrates a manageable safety profile and promising, durable efficacy (including pathological CRs) in adv NSCLC; efficacy was enhanced in pts with ≥1% PD-L1 tumor expression. Longer follow-up data, including 2-yr OS and characteristics of long-term survivors, will be presented. Clinical trial information: NCT01454102. [Table: see text]