bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.