bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplex testing for driver mutations in squamous cell carcinomas of the lung.
Authors: Paik Paul K. , Hasanovic Adnan , Wang Lu , Rekhtman Natasha , Ladanyi Marc , Kris Mark G. 
Published: March 2020

7505 Background: While the majority of lung adenocarcinomas (ADCL) harbor an identifiable driver mutation, targeted therapies for squamous cell lung carcinomas (SQCLC) have lagged in development due to a paucity of druggable oncogenic events. Three targets, which together occur in up to 50% of SQCLC, have been recently identified (FGFR1 amplification, DDR2 mutations, PIK3CA mutations/PTEN loss). Comprehensive molecular analysis of SQCLC tumors by The Cancer Genome Atlas is ongoing, with new therapeutic targets on the horizon. Methods: We have instituted prospective, multiplex testing of SQCLC tumors (Squamous Cell Lung Cancer Mutation Analysis Program, “SQ-MAP”). Tests include FISH for FGFR1 amplification (defined as FGFR1:CEP8 ≥ 2 in >10% of cells), IHC for loss of PTEN expression, and Sequenom MassARRAY for PIK3CA mutations (and others, below). We are also incorporating targeted exon sequencing (Agilent SureSelect/Ion Torrent) of a panel of over 80 lung cancer oncogenes and tumor suppressors in preparation for future studies. All tests were performed on formalin-fixed paraffin-embedded samples and with Institutional Review Board/Biospecimen Utilization Committee approval. Results: 40 SQCLC patient specimens have been processed through SQ-MAP over 3 months. 8 samples were excluded (insufficient tissue in 4, reclassification to ADCL in 4). Data are available for 28 patients. PTEN IHC was performed on 15 samples to date. Molecular results are summarized in the table. Events were non-overlapping. Results for the ≥80 gene sequencing component will be described. Based on SQ-MAP, accrual to 2 approved clinical trials (FGFR1 inhibition; PI3K inhibition) has begun, with a third planned (DDR2 mutations). Conclusions: Actionable defects were detected in 60% (95% CI: 37-75%) of SQCLC specimens. Mutation data for ≥80 other oncogenes and tumor suppressors will be available shortly (including DDR2). SQ-MAP serves as a platform supporting both personalized care and research. [Table: see text]
A randomized phase III trial of single-agent pemetrexed (P) versus carboplatin and pemetrexed (CP) in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2.
Authors: Lilenbaum Rogerio , Zukin Mauro , Pereira Jose Rodrigues , Barrios Carlos H. , De Albuquerque Ribeiro Ronaldo , Beato Carlos Augusto de Mendonça , Neron do Nascimento Yeni , Murad Andre , Franke Fabio A. , Precivale Maristela , de Lima Araujo Luiz Henrique , Baldotto Clarissa Serodio Da Rocha , Vieira Fernando Meton , Small Isabele Avila , Ferreira Carlos G. M. 
Published: March 2020

7506 Background: No standard of care exists for patients with advanced NSCLC and PS 2 and clinical practice ranges from supportive care to combination chemotherapy. Methods: In a Brazilian multicenter phase III randomized trial, advanced NSCLC patients, with any histology at first, amended to non-squamous only, PS 2, no prior chemotherapy, and adequate organ function, were randomized to P alone (500 mg/m2) or CP (AUC 5 + same P) administered every 3 weeks for 4 cycles. Stratification factors included stage (IIIB vs. IV); age (≥70 vs. <70); and weight loss (≥5 kg vs. <5kg). The primary endpoint was overall survival and the study was powered to demonstrate an improvement in median survival from 2.9 to 4.3 months based on a prior CALGB trial. Results: A total of 217 patients were enrolled from 8 centers in Brazil and 1 in the US from April 2008 to July 2011. Twelve patients were ineligible and excluded. The 2 arms (P=102; CP=103) were balanced for patient characteristics. 14 patients had squamous and another 12 had unknown histology. The response rates were P = 10% and CP = 24% (p=0.019). In the ITT population, the median PFS was P = 3.0 mo and CP = 5.9 mo (HR=0.46, 95% CI 0.34; 0.63, p<0.001) and median OS was P = 5.6 mo vs. CP = 9.1 mo (HR=0.57, 95% CI 0.41; 0.79, p=0.001). 1-year survival rates were 22% and 39% respectively. Similar results were seen when squamous patients were excluded from the analysis. Grade ¾ anemia (5.5%; 12%) and neutropenia (2.8%; 5.6%) were more frequent in CP. There were 4 treatment-related deaths in the CP arm. 30% of patients in each arm received 2nd line therapy Conclusions: Combination chemotherapy with CP significantly improves survival, with acceptable safety, in eligible patients with advanced NSCLC and PS 2, and represents a new standard.
Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement.
Authors: Shaw Alice Tsang , Camidge D Ross , Engelman Jeffrey A. , Solomon Benjamin J. , Kwak Eunice Lee , Clark Jeffrey W. , Salgia Ravi , Shapiro Geoffrey , Bang Yung-Jue , Tan Weiwei , Tye Lesley , Wilner Keith D. , Stephenson Patricia , Varella-Garcia Marileila , Bergethon Kristin , Iafrate A. John , Ou Sai-Hong Ignatius 
Published: March 2020

7508 Background: Chromosomal rearrangements of the ROS1 receptor tyrosine kinase gene define a new molecular subset of NSCLC. In cell lines, ROS1 rearrangements lead to expression of oncogenic ROS1 fusion kinases and sensitivity to ROS kinase inhibition. We examined the efficacy and safety of crizotinib, a small molecule tyrosine kinase inhibitor of MET, ALK and ROS, in patients with advanced, ROS1-rearranged NSCLC. Methods: Patients with advanced NSCLC harboring ROS1 rearrangement, as determined using a break-apart FISH assay, were recruited into an expansion cohort of a phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg BID. The objective response rate (ORR) was determined based on RECIST 1.0. The disease control rate (DCR; stable disease [SD] + partial response [PR] + complete response [CR]) was evaluated at 8 weeks. Results: Thirteen patients within the ROS expansion cohort received crizotinib and all were evaluable for response. The median age was 47 yrs (range 31–72), and all but one of the patients were never-smokers. All patients had adenocarcinoma histology. 12/13 patients were tested for ALK rearrangement and all were negative. The median number of prior treatments was 1 (range 0–3). To date, the ORR is 54% (7/13), with 6 PRs and 1 CR, with 6 responses achieved by the first restaging scan at 7–8 wks. There was 1 additional unconfirmed PR at the time of data cut-off. The DCR at 8 wks was 85% (11/13). Median duration of treatment was 20 wks (range 4+–59+). All responses are ongoing, and 12 patients continue on study. One patient had disease progression at first restaging and was discontinued from the study. The pharmacokinetics and safety profile of crizotinib in this group of patients were similar to that observed in patients with ALK-positive NSCLC. Conclusions: Crizotinib demonstrates marked antitumor activity in patients with advanced NSCLC harboring ROS1 rearrangements. Like ALK, ROS defines a distinct subpopulation of NSCLC patients for whom crizotinib therapy may be highly effective. This study represents the first clinical validation of ROS as a therapeutic target in cancer.
Response to EGFR tyrosine kinase inhibitor (TKI) retreatment after a drug-free interval in EGFR-mutant advanced non-small cell lung cancer (NSCLC) with acquired resistance.
Authors: Heon Stephanie , Nishino Mizuki , Goldberg Sarah B. , Porter Jennifer , Sequist Lecia V. , Jackman David Michael , Johnson Bruce E. 
Published: March 2020

7525 Background: Patients (pts) with advanced NSCLC and sensitizing EGFR mutations who initially respond to gefitinib or erlotinib eventually develop acquired resistance to the TKIs. Anecdotal and retrospective reports suggest that EGFR-TKI resistant cancers can respond again to gefitinib or erlotinib after an interval off the TKI. This retrospective study was undertaken to investigate the impact of EGFR-TKI retreatment after a drug-free interval in EGFR mutant NSCLC with acquired resistance to gefitinib or erlotinib. Methods: Pts with stage IV or relapsed NSCLC with sensitizing EGFR mutations and acquired resistance to EGFR-TKI seen at the DFCI/MGH between 8/00 and 8/11 who were retreated with single agent gefitinib or erlotinib after an EGFR-TKI-free interval were identified from a prospective trial. The objective tumor response (CR, PR, SD, PD) was determined using RECIST 1.1. Results: 19 pts were eligible and had adequate scans for radiographic assessments after the reinstitution of an EGFR-TKI. The response rate and median PFS to the initial course of gefitinib (n=4) or erlotinib (n=15) were 16/19 (84%) and 9.8 months (95% CI, 7.8-11.3) respectively. All pts were retreated with erlotinib after 1 to 4 intervening systemic regimens. The median interval from EGFR-TKI discontinuation to erlotinib retreatment was 11 months (range, 2-46). 4 of the 19 pts (21%) had PD as the best response to erlotinib retreatment, 14 (74%) had SD for at least 1 month, and 1 (5%) had a PR. The median PFS was 4.4 months (95% CI, 3.0-6.7). 3 pts remained on erlotinib without progression for 6 months. 3 pts had their tumors rebiopsied before (n=2) or during (n=1) erlotinib retreatment; 1 of the 3 had EGFR T790M in association with the initial sensitizing EGFR mutation, and another had a secondary PIK3CA mutation. Conclusions: Our findings suggest that erlotinib retreatment is an option for EGFR mutated NSCLC with acquired resistance to EGFR-TKI after a drug-free interval and progression on intervening therapy. Additional advanced NSCLC pts without a documented EGFR mutation who fulfill the clinical definition of acquired resistance are undergoing review to expand our cohort.
First-line dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor, for patients with EGFR-mutant lung cancers.
Authors: Kris Mark G. , Mok Tony , Ou Sai-Hong Ignatius , Martins Renato , Kim Dong-Wan , Goldberg Zelanna , Zhang Hui , Taylor Ian , Letrent Stephen P. , Janne Pasi Antero 
Published: March 2020

7530 Background: Dacomitinib irreversibly inhibits EGFR, HER2 and HER4, and showed superior activity vs. reversible EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer models, including resistant forms. This open-label Phase II study evaluates dacomitinib as 1st-line treatment (tx) for patients (pts) with lung cancers. Pts with sensitizing EGFR deletions/mutations in exons 19 or 21 are reported here. Methods: Pts had stage IIIB/IV adenocarcinoma, no prior systemic tx, had smoked <10 pack years (none within 15 years of enrollment) or had known EGFR mutation. Pts received dacomitinib orally once daily continuously at 45 mg, or 30 mg with the option to escalate to 45 mg; evaluation was every 28 days. Endpoints included progression-free survival rate at 4 months (PFS at 4M, primary); PFS, and partial response (PR) rate. Results: 92 pts enrolled; 47 had EGFR mutation in exons 19 (n=25) or 21 (n=22), 33 were female and 27 Asian. 34/46 evaluable pts with EGFR exon 19 or 21 mutations had a PR (PR rate = 74%; 95% CI: 59–86; exon 19 = 72%; exon 21 = 76%). PR rates and preliminary PFS were not significantly different for exons 19 and 21. Preliminary PFS at 4M was 96% (95% CI: 84–99), preliminary PFS rate at 1 year was 77% (95% CI: 61–87) and preliminary median PFS was 17 months (95% CI: 13–24). Median tx duration was 13.1 months. For pts with EGFR wild-type lung cancers, PR and PFS at 4M rates were 7% (n=14; 95% CI: 0–34) and 33% (n=14; 95% CI: 11–58), respectively, and for pts with EGFR unknown lung cancers, 46% (n=22; 95% CI: 24–68) and 68% (n=24; 95% CI: 45– 83), respectively. 7 pts had lung cancers with non-sensitizing EGFR mutations; 2 had a PR and 3 SD. For all 92 pts, common side effects included dermatitis acneiform (grade 3/4 = 17%/0) and diarrhea (14%/0). 3/46 pts with EGFR exon 19 or 21 mutations discontinued tx due to drug-related toxicity. Conclusions: 74% of pts in this cohort with EGFR exon 19 or 21 mutant lung cancers experienced PRs with 1st-line dacomitinib; preliminary PFS rate was 77% at 1 year; preliminary median PFS was 17 months; further research is planned in this pt population. As dacomitinib is well tolerated, with preclinical activity against HER2, a cohort of pts with HER2 mutant lung cancers is recruiting.
A randomized discontinuation phase II trial of ridaforolimus in non-small cell lung cancer (NSCLC) patients with KRAS mutations.
Authors: Riely Gregory J. , Brahmer Julie R. , Planchard David , Crinò Lucio , Doebele Robert Charles , Mas Lopez Luis Alberto , Gettinger Scott N. , Schumann Christian , Li Xiaoyun , Atkins Barbara McCormick , Ebbinghaus Scot , Rosell Rafael 
Published: March 2020

7531 Background: Mutations in KRAS are present in ~25% of patients with advanced NSCLC. Preclinical data support the role of mammalian target of rapamycin (mTOR) in KRAS mediated oncogenesis. Ridaforolimus is an inhibitor of mTOR which has been shown to have efficacy in advanced endometrial cancer and soft tissue sarcoma. Everolimus, another mTOR inhibitor was previously evaluated in unselected patients with advanced NSCLC and found to have a response rate <5%. We hypothesized that by enrichment for patients with NSCLC and KRAS mutations, treatment with ridaforolimus would be associated with prolonged stable disease relative to available standard treatments for NSCLC. Methods: Patients with stage IIIB/IV non-small cell lung cancer with KRAS mutation who had received prior chemotherapy for NSCLC began treatment with oral ridaforolimus 40 mg once daily on a 5 day/week schedule. After 8 weeks, patients with >30% tumor shrinkage remained on ridaforolimus and patients with >20% tumor growth discontinued treatment. Patients with stable disease were randomized 1:1 to placebo or ridaforolimus. The primary endpoint of the study was progression-free survival (PFS) after randomization. Results: 79 patients were enrolled (40 women, median age 58 [range 28-85]). The overall response rate (CR+PR) at 8 weeks was 1/79 (1%, 95% CI 0-7%). 28 patients with stable disease at 8 weeks were randomized to ridaforolimus or placebo. Median PFS based on investigator assessment from randomization was significantly longer with ridaforolimus (4 months) than placebo (2 months, p=0.013, HR 0.36). Median OS from randomization was 18 months in the ridaforolimus treated arm and 5 months in the placebo treated group, (HR 0.46, p=0.09). The most common grade ≥3 adverse events were fatigue (10%), mucositis/stomatitis (10%), pneumonia (10%), dyspnea (9%), diarrhea (6%), and hyperglycemia (6%). Conclusions: In patients with KRAS mutant NSCLC who had stable disease after 8 weeks of ridaforolimus, ridaforolimus was associated with prolonged progression-free survival. Further evaluation of ridaforolimus in this patient population is warranted.
GAIN-(L): Efficacy and biomarker findings of RG7160 (GA201), a novel, dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with first-line cisplatin and pemetrexed in metastatic nonsquamous NSCLC.
Authors: Spicer James F. , Felip Enriqueta , Bosquée Lionel , Gregorc Vanesa , Lopez Calderero Iker , Martinez Pablo , Montes Ana , Sorlini Cristina , Ott Marion Gabriele , Golding Sophie , Mariconti Luisa , Longauer Banholzer Maria , Passioukov Alexandre , Carlile David , Manenti Luigi , Paz-Ares Luis 
Published: March 2020

7544 Background: GA201, a humanized, engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, has shown promising clinical activity in phase I and in the neoadjuvant treatment of head and neck cancer. This phase Ib study (NCT01185847) aimed to determine the safety, pharmacokinetics (PK), activity and recommended phase II dose (RP2D) of GA201 in combination with chemotherapy in non-squamous NSCLC. Methods: Successive cohorts received GA201 1000 mg or 1400 mg (IV d1, d8 then 2-weekly (q2W)) in combination with chemotherapy at standard doses. Data cut off was 7 months after enrolling the last patient. Results: 14 patients (4 female) with performance status 0-1 were enrolled. No maximum tolerated dose was reached. Most common adverse events (AEs – all grades) included rash (100%), hypomagnesaemia (71%), infusion-related reactions (64%), mucosal inflammation (57%) and anemia (50%). AEs of ≥ grade 3 included rash (71%), skin fissure (21%), dry skin (14%), paronychia (14%), and asthenia (14%). Median timeto improvement of rash grade 3 was 11 days. AEs led to dose reduction for 4 patients and discontinuation for 1 patient. There were 6 confirmed partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with stable disease >=9 weeks. Duration of response ranged between 5 and 42 weeks (3 patients still ongoing). Preliminary biomarker analysis shows a correlation between tumor-infiltrating CD16+ immune cells and target lesion shrinkage at first tumor assessment [R(spear)=-0.65 (p=0.02)]; no apparent correlation between EGFR H-score and response was found. PK data supports 1400 mg as the RP2D (d1, d8 then q2W). Conclusions: The RP2D of GA201 in combination with chemotherapy was established to be 1400 mg. The incidence of EGFR associated rash was high and guidelines to reduce its severity were implemented with a noted improvement in tolerability. Promising antitumor activity was observed. Biomarker data support the mode of action of GA201 via ADCC. A randomized phase II trial of this combination is ongoing and fully recruited.
FGFR1 amplification and EGFR mutation in Chinese squamous cell lung cancer.
Authors: Wei Zhigang , Wang Jie , Bai Hua , An Tongtong , Wang Zhijie , Zhuo Minglei , Wu Meina , Yang Lu 
Published: March 2020

7545 Background: Squamous cell lung cancer (SCC) lacks for effective targeted therapies. FGFR1 amplification has emerged as a potential biomarker. This study aimed to explore clinicopathologic characteristics of FGFR1 amplification in Chinese SCC patients and further explore the correlation between FGFR1 amplification and EGFR mutations. Methods: One hundred seventy-seven SCC patients were included in this retrospective study. Gene copy number of FGFR1 and EGFR mutations were detected by fluorescence in situ hybridization (FISH) and denaturing high-performance liquid chromatography (DHPLC), respectively. Results: FGFR1 amplifications were detected in 24.9% (44/177) Chinese SCC patients. FGFR1 amplification in SCC was more common in male (28.0%, 40/143) and smokers (28.7%, 39/136) than female (11.8%, 4/34, p=0.049) and nonsmokers (12.2%, 5/41, p=0.032). FGFR1 amplification and EGFR mutations were mutually exclusive (p=0.006), fourty-one of 139(29.4%) patients with wild-type EGFR had FGFR1 amplification, while 3 of 38 (7.9%) patients with EGFR mutation had FGFR1 amplification. Conclusions: FGFR1 amplification was common in Chinese squamous cell lung cancer, and mutually exclusive with EGFR mutations.
N0821: A phase II first-line study of a combination of pemetrexed (P), carboplatin (C), and bevacizumab (B) in elderly patients with good performance status (PS < 2).
Authors: Dy Grace K. , Molina Julian R. , Qi Yingwei , Ansari Rafat H. , Thomas Sachdev P. , Ross Helen J. , Meyers Jeffrey P , Adjei Araba , Mandrekar Sumithra J. , Adjei Alex A. ,   North Central Cancer Treatment Group
Published: March 2020

7555 Background: In a retrospective exploratory analysis of E4599, patients (pts) > 70 yo had a higher frequency of and more severe toxicities without apparent survival benefit from the addition of B to C+paclitaxel. We hypothesized that in this pt population, B will have better safety and efficacy profile when used in combination with C+P. Methods: Pts >/= 70 yo with previously untreated stage IIIB/IV (TNM 6th ed) nonsquamous NSCLC, ECOG PS 0-1, measurable disease and adequate organ function were eligible. C at AUC 6, P at 500 mg/m2 and B at 15 mg/kg were administered on day 1 of each 21-day cycle for up to 6 cycles followed by maintenance P+B in patients with CR, PR or SD. The primary endpoint was 6-month progression-free survival (PFS) rate. The treatment would be considered promising based on a single arm one-stage binomial design if 34 or more successes out of 55 patients were observed. This design had an exact significance level of 0.05 at 93% power to detect a true success rate of at least 70%. Polymorphisms in VEGFA, FPGS, GGH, SLC19A1 and TYMS in germline DNA were correlated with treatment outcome. Results: 58 eligible pts were enrolled; 29 males/29 females. Median age was 75. Median treatment cycles received was 6. Grade 3 or higher adverse events (AE) were reported in 49 (85%) pts. There were no treatment-related deaths. The most common grade 3/4 AEs(regardless of attribution) were hypertension (10%), fatigue (28%), dehydration (9%), neutropenia (43%) and thrombocytopenia (21%). There were 3 (5%) grade 3/4 hemorrhagic events. 8 (14%) had grade 4 neutropenia and 3 (5%) had grade 4 thrombocytopenia. Grade 3/4 ischemic/thromboembolic events occurred in 6 pts (10%). Thirty-four out of the first 54 (63%, 95% CI: 48.7-75.7%) evaluable pts met the primary endpoint (4 pts were lost to follow-up prior to 6 months). The confirmed ORR was 37.9% (95% CI: 25.5-51.6%). Median time to treatment failure was 4.8 months (95% CI: 3.9-6.4). Median PFS was 7.1 months (95% CI: 5.9-11.7), median OS was 13.7 months (95% CI: 9.4-15.7). Results of SNP analysis will be presented. Conclusions: C+P+B followed by maintenance P+B is an active and tolerable first-line regimen for elderly patients with good PS.
Final overall survival and updated biomarker analysis results from the randomized phase III ICOGEN trial.
Authors: Sun Yan , Shi Yuankai , Zhang Li , Liu Xiaoqing , Zhou Caicun , Zhang LI , Wang Dong , Li Qiang , Zhang Shucai , Qin Shukui , Hu Chunhong , Zhang Yiping , Chen Jianhua , Song Yong , Feng Ji Feng , Cheng Ying , Zhang Helong , Wu Yi Long , Xu Nong , Zhou Jianying 
Published: March 2020

7559 Background: A total of 399 pretreated patients with advanced NSCLC were randomly assigned to receive gefitinib or icotinib in the phase III ICOGEN trial, the first head-to-head phase III trial of EGFR-TKIs. The results of the primary endpoint, PFS, have been reported previously. This report represents the final OS and biomarker analysis results. Methods: EGFR mutation was evaluated by using Scorpion ARMS (QIAGEN, n=152). Overall survival was analyzed by Cox proportional-hazards model analysis at 82% maturity. Results: Median OS was 13.3 months for icotinib and 13.9 months for gefitinib (hazard ratio [HR] = 0.90; 95% CI, 0.79 to 1.02; P = .109). The EGFR mutation rate was 43% in the icotinib group and 59% in the gefitinib group. Compared to wild type patients, patients with EGFR mutation had longer PFS (median, 6.2m vs. 2.3m; P=.00001) as well as OS (median, 20.5m vs. 7.7m; P=.00001). There were no significant differences in PFS or OS between the two treatment groups in EGFR mutation-positive subgroup (median PFS, 7.8m vs. 5.3m for icotinib and gefitinib, respectively, P =.3162; median OS, 20.9m vs. 20.2m for icotinib and gefitinib, respectively, P =.7611.) or in EGFR mutation-negative subgroup (median PFS, 2.3m vs. 2.2m for icotinib and gefitinib, respectively, P =.1531; median OS, 7.8m vs. 6.9m for icotinib and gefitinib, respectively, P =.7885.). Conclusions: There is no statistically significant difference between icotinib and gefitinib in PFS or OS when given to NSCLC patients. This suggests that icotinib can provide similar OS benefits to gefitinib in advanced NSCLC patients. Moreover, EGFR mutation status is the strongest predictor in identifying which patients are most likely to benefit from icotinib.