bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of second-line erlotinib in combination with stereotactic body radiation therapy (SBRT) for patients with metastatic non-small cell lung cancer (NSCLC).
Authors: Iyengar Puneeth , Kavanagh Brian D. , Smith Irma , Ahn Chul , Gerber David E. , Dowell Johnathan , Hughes Randall S. , Abdulrahman Ramzi , Camidge D. Ross , Gaspar Laurie E. , Doebele Robert Charles , Bunn Paul A. , Choy Hak , Timmerman Robert D. 
Published: March 2020

8074 Background: Stage IV NSCLC patients who progress through first-line therapy have poor progression-free survival (PFS) and overall survival (OS), most commonly failing in existing sites of gross disease after systemic therapy. Cytoreduction with SBRT may aid systemic agents in prolonging survival. We decided to test this hypothesis in a multi-institutional phase II study with SBRT and erlotinib. Methods: Stage IV NSCLC patients with ≤ 6 sites of extracranial disease who failed first-line systemic therapy were eligible to receive SBRT to all sites of clinically apparent disease, utilizing equipotent fractionation schemes based on location of disease and risk of toxicity to critical normal structures, and erlotinib given daily (150 mg OD) until disease progression. Frequent SBRT fractionation schemes used included 33 Gy in 11 Gy fractions and 40 Gy in 8 Gy fractions. Safety and clinical endpoints were evaluated. Results: 23 patients (12 M: 11 F) with a median age of 67 (56-86) were enrolled in this trial with median follow-up of 14.7 months. All patients progressed through platinum-based chemotherapy, 14 with paclitaxel and 7 with pemetrexed as part of the doublet regimen. 20/23 patients received SBRT to 3 or fewer sites. Lung parenchyma and mediastinal lymph nodes represented most common sites of irradiation. Median PFS was 10.7 months and median OS was 20.8 months.A majority of patients progressed in new sites with only 4 patients failing locally. Most distant failures manifested in the liver. Only one grade 3 toxicity, pneumonitis, was radiation-related. The trial commenced before molecular profiling became standard; 5/10 patient tumors tested, however, had EGFR alterations by IHC/FISH, 0/10 were positive for an EGFR mutation. Conclusions: Use of SBRT with erlotinib for unselected stage IV NSCLC patients as a second-line therapy was well tolerated and resulted in significant PFS and OS, substantially greater than historical values for patients who only received second-line systemic agents. Debulking gross disease with local therapy results in a median PFS of nearly a year with patients relapsing most commonly in new rather than existing sites. Clinical trial information: NCT00547105.
The spectrum of genomic alterations in young adult non-small cell lung cancer (NSCLC).
Authors: Oxnard Geoffrey R. , Heng Jennifer C. , Mach Stacy L. , Lo Peter C. , Butaney Mohit , Jackman David Michael , Janne Pasi A. 
Published: March 2020

8077 Background: Identification of targetable genomic alterations in patients (pts) with NSCLC can have a profound impact on treatment and clinical outcomes. Given the complexity and cost of comprehensive genomic testing, clinical characteristics enriching for targetable genomic alterations are of interest. We hypothesized that young adults with NSCLC would have a higher prevalence of targetable genomics alterations compared to the general NSCLC population. Methods: An institutional database of pts with NSCLC was reviewed in an IRB-approved fashion to identify subjects with age < 40 at diagnosis. Clinical characteristics and risk factors were reviewed. Tumor genotyping for alterations in EGFR, KRAS, ALK, BRAF, HER2, and ROS1was pursued as part of an institution-wide genomics protocol. Targeted next-generation sequencing (NGS) of wild-type cases is underway. Results: From 2032 subjects with NSCLC, we identified 70 diagnosed at an age < 40 (3.4%). Pt characteristics: median age 35 (range 20-39); 63% never-smokers, 33% with ≥10 pack-years; 74% adeno, 9% squam, 14% undifferentiated, 3% neuroendocrine; 19% had a family history of lung cancer; 61% stage IV at diagnosis. Median survival from date of advanced disease was 15.8 months. Genotyping was performed on 51 pts with adeno or undifferentiated histology: 14 with EGFR mutations (27%), 5 with KRAS mutations (10%), 8 with ALK rearrangements (16%), 0 with BRAF mutations, 1 with a HER2 insertion (2%), 1 with a ROS1 rearrangement (2%). Compared to a reference prevalence from the Lung Cancer Mutation Consortium (Kris et al, ASCO, 2011), KRAS mutations were less common (p=0.01) and ALK rearrangements were more common (p<0.01). NGS of 2 cases to date has identified one pt with a novel 21 base-pair insertion mutation in FGFR2, not present in germline tissue. Conclusions: 47% (CI: 33%-60%) of pts diagnosed with NSCLC under age 40 harbor a targetable alteration in EGFR, ALK, HER2, or ROS1. These patients may be enriched for targetable genotypes and deserving of a unique treatment approach, and additionally represent an attractive population for genomic discovery.Supported in part by the Bonnie J. Addario Lung Cancer Foundation and the Conquer Cancer Foundation of ASCO.
Erlotinib after initial platinum-doublet chemotherapy in patients with epidermal growth factor receptor (EGFR) wild-type (WT) non-small cell lung cancer (NSCLC): Results of a combined patient-level analysis of the BR.21 and SATURN trials.
Authors: Osarogiagbon Raymond U , Cappuzzo Federico , Ciuleanu Tudor-Eliade , Leon Larry 
Published: March 2020

8080 Background: Two double-blind, prospective, randomized, placebo-controlled trials demonstrated survival benefit in unselected populations with advanced NSCLC in the 2nd/3rd line (BR.21) and maintenance setting (SATURN). The efficacy of erlotinib in patients with EGFR WT NSCLC has been questioned. We examined the impact of erlotinib vs placebo in confirmed EGFR WT patients in both studies. Methods: Combined re-analysis of progression-free survival (PFS) (from date of randomization to investigator-assessed progression or death from any cause), and overall survival (OS) (from date of randomization to death from any cause) in patients with known WT EGFR. PFS and OS were estimated by Kaplan-Meier curves and compared by 2-sided log-rank test. Cox proportional hazards model was used to estimate hazard ratios (HR) adjusted for potential confounders. Sensitivity analyses assessed comparability of patients with known and unknown EGFR mutation status to determine generalizability of the two study populations. Results: 74% of the BR.21 population (n=150) and 89% of the SATURN population (n=388) with known EGFR mutation status had WT EGFR. PFS and OS for individual and combined analyses are shown (Table). Adjusting for non-randomized therapy after study therapy discontinuation, HR for OS was 0.74 (0.61–0.91); p<0.01. Baseline characteristics were similar for patients with known and unknown EGFR status, suggesting generalizability of the EGFR WT data. Erlotinib benefit was sustained in all clinical subsets. Conclusions: Erlotinib provided a consistent and significant improvement in survival for patients with EGFR WT NSCLC in both studies, individually and in combination. The benefit of erlotinib does not appear to be limited to patients with activating EGFR mutations. [Table: see text]
Prediction of survival outcomes in NSCLC using a new PRO index from the LCSS (Lung Cancer Symptom Scale): Results of a 622-patient prospective trial.
Authors: Gralla Richard J. , Hollen Patricia J , Thongprasert Sumitra , Kim Hoon-Kyo , Hsia Te-Chun , Yuankai Shi , Kohn Nina , Lesser Martin 
Published: March 2020

8087 Background: Accurate and easy prediction of survival at the onset of treatment for all patients is required for appropriate trial design and personalization of patient (pt) monitoring. No pt reported factor is routinely used for these purposes, as performance status (PS) is not pt rated. Methods: This prospective study, the AP-QL lung trial, enlisted 622 pts receiving initial docetaxel-based chemotherapy (80% with cisplatin or carboplatin) and correlated patient reported outcomes (PROs) from an electronic version of the LCSS (eLCSS-QL) every 3 weeks with survival outcomes. The eLCSS-QL requires < 3 minutes. Results: Baseline PROs and survival data were available for 96% of pts. Pts: 70% male; 65% adenoca; medians: KPS = 90; ECOG = 1 (27% ECOG 0); Stages: IV (72%), IIIB (28%). Survival: 12.8 months median; 52%, 1 year. Survival results were analyzed for differences for those living less than or greater than the median for each NSCLC symptom and LCSS global factor. For symptoms such as pain, dyspnea, or appetite, survival differences above and below the median varied from 2.5 to 4 months. Unlike individual symptoms which are found only in subsets of pts, LCSS pt-reported global items (symptom distress, activity level, and quality of life) each apply to all pts. Median survival differences above (positive factor) or below (negative factor) medians for each global item varied by 4 months (p < 0.003). An index was created using the number of negative factors, 0 to 3, based on survival less than the median for each of these 3 factors (Table). Conclusions: Several large and highly significant survival differences can be predicted by this simple LCSS HRQL-PRO Index, if assessed prior to chemotherapy. This index identifies more accurate survival differences than PS, can assist better trial design and analysis, and can aid in personalizing patient monitoring based on individual likelihood of risk and benefit. The results illustrate the strong correlations of PROs with survival. [Table: see text]
Phase I and pharmacodynamic study of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in previously treated advanced non-small cell lung cancer (NSCLC).
Authors: Gerber David E. , Skelton Rachael , Dong Ying , Loudat Laurin , Dowell Jonathan , Boothman David A. , Sarode Venetia , Zhang Wei , Xie Yang , Gazdar Adi , Frenkel Eugene P. , Schiller Joan H. 
Published: March 2020

8088^ Background: Preclinical studies have demonstrated anti-tumor efficacy of the combination of the HDAC inhibitor romidepsin plus erlotinib in NSCLC models insensitive to erlotinib monotherapy (eg, KRAS mutation, EGFR resistance mutation, EGFR wild type). Methods: This phase I study evaluated safety, pharmacodynamics, and preliminary activity of romidepsin (8-10 mg/m2) given IV days 1, 8, and 15 every 28 days plus erlotinib 150 mg PO daily in previously treated advanced NSCLC. In Cycle 1, erlotinib was initiated on Day 3, permitting pharmacodynamic analysis of romidepsin alone and in combination. Results: As of January 31, 2013, 15 patients (pts) have been treated: median age 60 years; 7 F, 8 M; all former or current smokers; 6 had prior erlotinib exposure; 8 adenocarcinoma, 6 squamous, 1 large cell; 5 EGFR wild type 1 KRAS mutation, 9 unknown mutation status. Most common related AEs regardless of grade were nausea (87%), vomiting (73%), fatigue (60%), diarrhea and rash (both 53%), and decreased appetite (47%). Grade 3-4 AEs (all grade 3) included nausea and vomiting (both 20%); decreased appetite, diarrhea, fatigue (each 13%). Dose-limiting nausea and vomiting occurred at romidepsin 10 mg/m2 level despite aggressive antiemetic prophylaxis and treatment. At romidepsin 8 mg/m2, related grade 3 AEs included fatigue (n=1) and diarrhea (n=1), with no grade 3 nausea or vomiting. 9 pts were evaluable by RECIST; best response SD (n=6), PD (n=3). Median PFS was 3.3 months (range 1.4-16.5 months). At romidepsin 8 mg/m2, PFS range 2.0-16.5 months. At both dose levels, romidepsin inhibited HDAC activity and increased histone H3 and H4 acetylation status in peripheral blood mononuclear cells. Romidepsin also inhibited EGFR phosphorylation and, in 60% of pts, MAPK phosphorylation in skin biopsies. Conclusions: Romidepsin 8 mg/m2 plus erlotinib appears well tolerated, has encouraging evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population. Further studies are underway. Clinical trial information: NCT01302808.
First-in-human dose escalation study of LY2875358 (LY), a bivalent MET antibody, as monotherapy and in combination with erlotinib (E) in patients with advanced cancer.
Authors: Goldman Jonathan Wade , Rosen Lee S. , Algazi Alain Patrick , Turner Patricia Kellie , Wacheck Volker , Tuttle Jay , Wooldridge James E , Banck Michaela S. 
Published: March 2020

8093 Background: Activation of the hepatocyte growth factor (HGF)/MET receptor pathway promotes tumor growth, invasion and dissemination. LY is a humanized IgG4 monoclonal bivalent antibody against MET which inhibits ligand dependent- and ligand independent activation of MET. Based on preclinical results, we examined LY alone in patients with advanced solid tumors and LY+E in advanced NSCLC patients. Methods: LY monotherapy was administered 20-2,000 mg Q2W IV to 23 patients with advanced solid tumors. Combination therapy with 700-2,000 mg Q2W IV of LY and E (150 mg QD) was completed in 14 patients with advanced NSCLC. The primary objective was to determine a recommended phase II dose (RPTD) for LY and LY+E. Secondary objectives included assessment of toxicity, PK, PD (including MET extracelluar domain and HGF), and antitumor activity. Results: LY and LY+E were well tolerated. No dose-limiting toxicities, serious adverse events, or ≥ Grade 3 adverse events (AEs) possibly related to LY have been observed. The most frequent (≥5% of patients) AEs possibly related to LY2875358 monotherapy were nausea (8.7 %), vomiting (8.7%), and diarrhea (8.7%). The most frequent (≥10% of patient) grade 1 or 2 adverse event possibly related to LY2875358 in patients treated with LY+E were fatigue (21.4%) and anorexia (14.3%). Durable PR according to RECIST were observed for LY (n=1) and LY+E (n=2 out of 13 evaluable patients; both PR patients positive for MET protein expression). Conclusions: LY appears to be safe when administered as single agent and in combination with E up to 2,000 mg Q2W IV. The RPTD of LY is 750 mg Q2W IV for monotherapy and in combination with E based on PK/PD data. Clinical trial information: NTC 01287546.
Canadian ALK (CALK): A pan-Canadian multicenter study to optimize and standardize ALK immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for ALK gene rearrangements.
Authors: Tsao Ming Sound , Craddock Kenneth , Brandao Guilherme , Xu Zhaolin , Greer Wenda , Yatabe Yasushi , Ionescu Diana , Jung Sungmi , Carter Ronald F , Karsan Aly , Bojarski Anna , Sekhon Harmanjatinder S. , Bigras Gilbert , Deschenes Jean , Albadine Roula , Pintilie Melania , Cutz Jean-Claude , Tran-Thanh Danh , Torlakovic Emina , Couture Christian 
Published: March 2020

8096 Background: ALK gene rearrangement (ALK+) has been found in 3-5% of advanced non-small cell lung cancer patients. FISH is considered the “gold standard” for identification of ALK+ tumors, but its cost-effectiveness and adoption as a screening assay has been debated. Recent reports suggested that ALK IHC may serve as an alternative screening or possibly a diagnostic method. In this context, CALK was initiated to assess the feasibility of implementing ALK IHC and/or FISH assays across Canadian hospitals. Methods: FISH-confirmed 22 ALK+ and 6 ALK- tumors were used as study samples. Unstained sections and scanned images of HE-stained slides from each tumor block were distributed to participating centres. IHC protocols with best signal to noise ratio using the 5A4 (Novocastra) or ALK-1 (Dako) antibodies were developed for various auto-stainers and implemented to suit the existing conditions of the participating centres. A common FISH protocol using the ALK break-apart probe (Abbott Molecular, Chicago, IL) was developed based on published reports. H-score was used to assess IHC. FISH signals were scored in 100 tumor cells/case by 2-3 pre-trained persons. A second round IHC study using newly distributed slides was completed by 8 centres. Results: Independent IHC scores from 12 centres and FISH scores from 11 centres were collected and analysed. The intraclass correlation coefficients (ICC) between centres for IHC and FISH were 0.84 and 0.68, respectively. Following the analysis of initial IHC results, a second round study resulted in improved ICC of 0.94. One of 23 tumors revealed IHC-/FISH+ discrepancy, with the FISH revealing unusual signal configurations that suggested an atypical rearrangement. However, the sensitivity and specificity of FISH results across centres using the 15 aberrant signals cut-off ranged from 86.7-100% and 100%, respectively. Conclusions: Standardization across multiple centres for ALK testing by IHC and FISH can be achieved. IHC detected all FISH+ ALK tumors, except for one discrepant case with atypical FISH finding of unknown clinical implication. The study was supported by a Pfizer Canada grant.
High-dose erlotinib for refractory leptomeningeal metastases (LM) after failure of standard dose EGFR-TKIs.
Authors: Kawamura Takahisa , Hata Akito , Otoshi Takehiro , Fujimoto Daichi , Tamai Koji , Takeshita Jumpei , Matsumoto Takeshi , Monden Kazuya , Nagata Kazuma , Otsuka Kyoko , Nakagawa Atsushi , Tachikawa Ryo , Otsuka Kojiro , Kaji Reiko , Fujita Shiro , Katakami Nobuyuki , Tomii Keisuke 
Published: March 2020

8098 Background: EGFR-TKIs, gefitinib and erlotinib can demonstrate dramatic and durable response in patients with EGFR-mutant non-small cell lung cancer. Approximately one-third of patients develop central nervous system (CNS) metastases, including leptomeningeal metastases (LM) after initial response to EGFR-TKIs. Pharmacokinetic failure due to insufficient penetration of EGFR-TKIs is suggested as a cause of CNS failure. Therefore, high-dose EGFR-TKIs are considered reasonable therapeutic options for refractory CNS metastases after failure of standard dose EGFR-TKIs, but there is little present evidence of high-dose EGFR-TKI’s efficacy and tolerability. Methods: Between 2007 and 2012, we screened 279 patients harboring EGFR sensitive mutations, and identified 31 patients with LM. Ten of 31 patients received high-dose erlotinib, and the other 21 underwent only standard dose EGFR-TKIs (gefitinib and/or erlotinib). In these 10 patients, erlotinib was administered at 200 mg on alternating days (n=2), 300 mg on alternating days (n=6), 300 mg every 3 days (n=1), or 600 mg every 4 days (n=1). We retrospectively investigated the efficacy and tolerability of high-dose erlotinib. Additionally, survivals from the diagnosis of LM to death were compared in patients with or without high-dose erlotinib. Results: Regarding high-dose erlotinib, five of 10 patients were radiologically evaluable, and partial response was observed in 60% (3/5), stable disease in 20% (1/5), and progressive diasease 20% (1/5). Median time to CNS progression was 3.4 months (range, 0.3-6.6 months). Improvement of neurological symptoms was observed in 9 (90%) of 10 patients. No severe adverse events (≥ grade 3) associated with high-dose erlotinib were confirmed. Median survival from the diagnosis of LM in patients with high-dose erlotinib was 6.5 months (95% CI: 2.5-12.3 months), and that in those without was 5.8 months (95% CI: 1.1-7.8 months) (p =0.51). Conclusions: The efficacy and tolerability of high-dose erlotinib were suggested for refractory LM. It can be a therapeutic option in patients after failure of standard dose erlotinib. Optimal dose and schedule are unclear, and further investigations are warranted.
A phase Ib safety and tolerability study of a pan class I PI3K inhibitor buparlisib (BKM120) and gefitinib (gef) in EGFR TKI-resistant NSCLC.
Authors: Tan Daniel Shao-Weng , Lim Kiat Hon , Tai Wai Meng , Ahmad Aziah , Pan Summer , Ng Quan Sing , Ang Mei-Kim , Gogna Apoorva , Ng Yuen Li , Tan Bien Soo , Lee Haur Yueh , Krisna Sakktee Sai , Lau Dawn PX , Zhong Liz , Iyer Gopal , Chowbay Balram , Lim Alvin ST , Takano Angela , Lim Wan-Teck , Tan Eng-Huat 
Published: March 2020

8107 Background: Overcoming EGFR TKI resistance (R) is a major clinical challenge; reported mechanisms include EGFR T790M mutation (mt), MET amplification (amp) and PIK3CA mt. As the PI3K pathway is a central convergent signaling node, we hypothesized that addition of buparlisib (BKM) could overcome EGFR TKI-R. Methods: Patients (pt) resistant to EGFR TKI (Jackman JCO 2010) were enrolled to determine safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of BKM-gef. Using a “3+3” design, escalating doses of BKM were added to pt progressing on gef (Gp A). Pt not on gef preceding enrolment received a 2 wk run in (Gp B). Given the favorable CNS penetration of BKM, a CNS gp with brain metastases only was included. Pt had pretreatment biopsies and sequential PET-CT scans (baseline & d28). Results: 15 pt have been treated at 3 dose levels: BKM 80 mg/d (n=6), 100 mg/d (n=6), 80 mg 5d on 2d off (5/2, n=3), with gef 250 mg/d. Gp A (n=9, 1 CNS), B (n=6, 1 CNS), F:M (9:6), median age 63 (47-73) and majority >3 lines of therapy. DLT was G3 diarrhea observed in 2/6 pt at BKM100. Common adverse events (AE, all grades) include rash (80%), diarrhea (73%), fatigue (60%), anorexia (47%), mucositis (40%). Notably, 40% of pt had late (beyond DLT period) G3 toxicities such as rash and diarrhea. MTD is BKM 80/d and gef 250/d. To improve the overall safety profile, an intermittent schedule of BKM80 5/2 was also found to be feasible. In gp B, PET-CT done after 2 wk run-in of gef, 3/4 evaluable pt demonstrated reduction in SUVmax of which 1 had PR. With addition of BKM, reduction in SUVmax (>25%) was seen in 4/10 pt (gp A & B). Median PFS 2.8 m (95%CI 2.3 – 8.1), two pt in CNS gp had PFS of 2.8 and 10.7 m. Molecular analyses revealed 6/12 (50%) harbored T790M mt, 2/5 (40%) MET amp, 0/12 PI3KCA mt. In gp A, 4/9 pt (2 T790M; 1 MET amp) had clinical responses, including slight tumor shrinkage and reduced pleural effusion, but required dose reductions due to AE. PK profiles are being analyzed. Conclusions: MTD is gef 250-BKM 80/d. Antitumor activity has been observed with addition of BKM in EGFR TKI-R pt. In view of late toxicities and long t½ of BKM, exploring alternative schedules is warranted. A dose expansion cohort at MTD is currently ongoing. Clinical trial information: NCT01570296.