bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase III study of a cisplatin (CDDP) and docetaxel (DOC) with or without irinotecan (CPT) in pts with advanced NSCLC: Okayama Lung Cancer Study Group OLCSG 0403 trial.
Authors: Okada Toshiaki , Tabata Masahiro , Segawa Yoshihiko , Kamei Haruhito , Shibayama Takuo , Gemba Kenichi , Takigawa Nagio , Matsuo Keitaro , Tanimoto Mitsune , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: March 2020

7560 Background: CDDP-based doublet chemotherapy provides a significant but modest survival prolongation in untreated advanced NSCLC with MST of around 12 months. Based on the favorable efficacy profile in our previous phase II trial of triplet chemotherapy with CDDP, DOC, and CPT (response rate: 57.1%, MST: 17 months) (JTO 2007), we conducted a phase III study to compare this regimen with CDDP and DOC doublet therapy in the first-line setting. Methods: Pts were randomly allocated to the triplet therapy (A arm; CDDP 60 mg/m2, day 1; DOC 60 mg/m2, day 1; and CPT 60 mg/m2, day 2; q3 wks, determined based on our phase I study result) or a standard doublet chemotherapy (B arm; CDDP 80 mg/m2, and DOC 60 mg/m2, day 1; q3 wks). The primary endpoint was OS whilst secondary endpoints included response rates, PFS, and toxicity. Results: Between 2004 and 2009, 120 pts were enrolled (A/B: 60 pts each). Objective response was comparable between the arms (18 pts [30%] each, p = 0.571). As for toxicity, grade 3-4 neutropenia, principal toxicity, was observed in 93% vs. 58% (p < 0.001). Although grade 3 febrile neutropenia was observed in 53% and 18% of the pts (p < 0.001), none of whom further developed toxic deaths. At a median follow-up time of 64.2 months, median PFS time and 1-year PFS rate were 5.3 vs. 4.3 months and 13.3% vs. 11.7%, respectively (stratified logrank test; p = 0.872). There was also no difference in OS (MST, 16.8 vs. 12.2 months; 1-year OS rate, 68.0% vs. 53.0%; stratified logrank test; p = 0.846). Subgroup analysis for OS showed that never smokers (HR = 0.366; 95% CI = 0.072-1.866) tended to benefit from the triplet chemotherapy compared with ever-smokers (HR = 1.380; 95% CI = 0.771-2.473) despite no statistical significance (p for interaction = 0.150). Similar trend in interaction between treatment effect and smoking status was also observed in PFS. Conclusions: This triplet chemotherapy failed to produce a significant antitumor activity as compared with the standard doublet therapy.
A phase II study of erlotinib monotherpay in patients with previously treated advanced non-small cell lung cancer (NSCLC) without EGFR gene mutation who have never/light smoking history: NEJ006/TCOG0903.
Authors: Ishii Yoshiki , Maemondo Makoto , Okudera Koichi , Takamura Kei , Demura Yoshiki , Kobayashi Kunihiko , Morikawa Naoto , Gemma Akihiko , Ishimoto Osamu , Harada Masao , Miura Satoru , Fujita Yuka , Usui Kazuhiro , Saijo Yasuo ,   North East Japan
Published: March 2020

7561 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated good response in NSCLC harboring EGFR gene mutation. However, survival benefit from erlotinib was observed also in NSCLC patients with wild type (wt) EGFR gene in subsets of several phase III trials. Additionally, smoking status could be a predictive factor of erlotinib efficacy, This study aimed to evaluate the efficacy of erlotinib in Japanese NSCLC patients with wt-EGFR and find a biomarker that predicts the efficacy of erlotinib other than EGFR gene mutation. Methods: The primary endpoint was an objective response rate. Secondary endpoints included disease control rate, overall survival, and safety. Advanced NSCLC patients without EGFR gene mutation who had received one to three prior chemotherapy regimens and who had never smoked or light smoked (Brinkman Index: less than200) were eligible in this study. EGFR gene status was evaluated by the PNA-LNA PCR clamp method. Erlotinib was administered daily (150mg/day) until disease progression or unacceptable toxicities. Results: Forty seven patients were enrolled between March 2010 and November 2011. One patient was excluded for evaluation because having mutation of EGFR. Efficacy and safety were evaluated among 46 patients. Best responses were PR 7 (15.2%), SD 12 (26.1%), PD 26 (46.4%), NE 1 (2.2%). Response rate and disease control rate were 15.2% (95%CI: 4.9-25.5%) and 41.3 % (95%CI 27.1-55.5%) respectively. Grade 3 or 4 adverse events were anorexia (4), skin rash (2), neutropenia (1), leukopenia (1), anemia (2), elevation of AST/ALT (1), rectal ulcer (1), and cerebral infarction (1).Two patients suffered grade 3 interstitial lung disease. Conclusions: This is the first report to evaluate Erlotinib efficacy in selected NSCLC who do not possess EGFR gene mutation. Erlotinib showed significant anti-tumor activity in pretreated never or light smoked Japanese NSCLC patients without EGFR gene mutation. The results of biomakr analysis will be presented at the meeting.
Phase II study of amrubicin (AMR) for patients (pts) with non-small cell lung cancer (NSCLC) as third-line or fourth-line chemotherapy: Hokkaido Lung Cancer Clinical Study Group trial (HOT) 0901.
Authors: Harada Toshiyuki , Ito Kenichiro , Takamura Kei , Kikuchi Eiki , Oizumi Satoshi , Kuda Tomoya , Sugawara Shunichi , Maemondo Makoto , Fujita Yuka , Kinoshita Ichiro , Inoue Akira , Hommura Fumihiro , Katsuura Yutaka , Akita Hirotoshi , Isobe Hiroshi , Nishimura Masaharu ,   Hokkaido Lung Cancer Clinical Study Group
Published: March 2020

7571 Background: Although an increasing number of NSCLC pts receive third-line chemotherapy with the established benefit of second-line chemotherapy, the role of cytotoxic agent in this setting has not yet been well defined prospectively. AMR, third-generation synthetic anthracycline agent, has found favorable clinical activity and acceptable toxicity for NSCLC as well as small cell lung cancer. This prospective trial was conducted to evaluate the efficacy and safety of AMR for NSCLC pts as third-line or fourth-line chemotherapy. Methods: Eligible pts had a performance status 0 to 2, failure of second-line or third-line chemotherapy, and adequate organ function. Pts received AMR 35 mg/m2 intravenously on days 1-3 every 3 weeks. The primary endpoint was disease control rate (DCR: CR + PR + SD). Secondary endpoints were overall survival (OS), progression-free survival (PFS), response rate (CR + PR), and toxicity profile. The estimated accrual was 37 pts to confirm a DCR of 50% as desirable target level and a DCR of 30 % as uninteresting with alpha = 0.05 and beta = 0.20. Results: From August 2009 to May 2011, 41 pts were enrolled from 10 institutions. Patient characteristics were: male/female 29/12; median age 66 (range 43–74); performance status 0/1/2 16/24/1; adenocarcinoma/squamous cell carcinoma/large cell carcinoma/not other specified 30/8/2/1; EGFR mutation positive/negative/unknown 7/26/8; treatment lines 3rd/4th 26/15. The median number of treatment cycles was 2 (range 1-9). The objective responses were CR 0, PR 4, SD 22, PD 14, and NE 1, giving a DCR of 61.0% (95% CI, 46.0-75.9%). Overall response rate was 9.8% (95% CI, 0.6-18.8%). Median PFS was 2.6 months, whereas median survival time was not reached. Grade 3/4 hematological toxicities were neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile neutropenia (17%). Grade 3/4 non-hematological toxicities were anorexia (12%), nausea (10%), and pneumonitis (2%). No treatment-related death was observed. Conclusions: AMR shows significant clinical activity with acceptable toxicities as third-line or fourth-line chemotherapyfor advanced NSCLC.
Cutaneous toxicity secondary to erlotinib therapy in patients with non-small cell lung cancer in the NCIC CTG BR.21 study: Time course and correlation with survival.
Authors: Perez-Soler Roman , Leon Larry , Wojtowicz-Praga Slawomir 
Published: March 2020

7573 Background: Cutaneous rash often develops in erlotinib-treated patients (pts) and is thought to be associated with improved response and survival. This analysis focuses on incidence, severity, and time course of skin rash secondary to erlotinib, as well as the correlation between rash development and overall survival (OS) in pts in the NCIC CTG BR.21 (NCT00036647) trial. Methods: Pts with stage IIIB or IV non–small cell lung cancer (NSCLC) who had failed first- or second-line chemotherapy were randomized 2:1 to erlotinib or placebo. Cutaneous toxicity was graded per NCI CTC v2.0 and managed at the discretion of the treating investigator. This retrospective analysis used a landmark approach, dividing pts into rash and no-rash groups, by the appearance of rash by week 10. Results: A total of 366 of 488 erlotinib-treated pts (75%) and 40 of 243 placebo-treated pts (16%) developed rash at any time point. Of the former, 75% of rash episodes occurred by week 2. The incidence of grades 1 and 2 rash peaked at week 3; grade 3 rash peaked at week 5. The erlotinib dose was reduced in 48 pts (10%) due to rash. In most erlotinib-treated pts with rash, severity decreased or plateaued over time (Table). Some 311 erlotinib-treated pts (rash group) developed rash by week 10. Median OS in the erlotinib-treated rash (n=311) and no-rash (n=65) groups were 37.4 and 11.1 weeks, respectively (hazard ratio=0.51 [95% confidence interval, 0.38–0.68]; P<.0001). Baseline factors significantly associated with prolonged OS in the rash population included race (Asian vs white), number of affected organs (<3 vs ≥3), and smoking status (never vs ever). Conclusions: For most pts, rash secondary to erlotinib presented within the first 2 weeks, peaked during weeks 3–5, decreased thereafter, and did not necessitate dose reduction, thus supporting SATURN results (Perez-Soler, ASCO 2011, abst. 7610). Development of rash by week 10 of erlotinib therapy was associated with significantly improved OS. [Table: see text]
Frequency of anaplastic lymphoma kinase (ALK) positive tumors among African American non-small cell lung cancer (NSCLC) patients.
Authors: Gadgeel Shirish M. , Cote Michele L , Bepler Gerold , Murphy Valerie , Malysa Agnes , Wozniak Antoinette J. , Sukari Ammar , Schwartz Ann G. 
Published: March 2020

7593 Background: ALK gene rearrangement is a recently identified molecular alteration in the tumors of a small proportion of NSCLC patients. Previous reports have shown that the rate of EGFR gene mutations may vary in NSCLC patients of different ethnic background. It is unclear if similar differences exist with regards to ALK positivity. We analyzed ALK expression in tumors of AA NSCLC patients and also assessed the epidemiologic features and outcomes of these patients, as well as the occurrence of known oncogene mutations. Methods: We identified 260 tumor tissues of AA NSCLC patients, enrolled on several epidemiologic studies conducted at our institution. Immunohistochemistry, using the anti-Alk D5F3 antibody (Cell Signaling Technology) was used to visualize ALK expression. Fifty-three of these tumors also underwent mutation analysis using the OncoCarta Panel V1 (Sequenom) to evaluate 238 mutations in 19 oncogenes. Results: Of the 260 tumors analyzed, 6 (2.3%, 95% CI- 0.5-4.1%) were ALK positive. All ALK positive patients had adenocarcinoma histology (6/157) while no patients with other NSCLC histologies were ALK positive, p=0.04. There was no difference in the rate of positivity based on sex, 1% (1/99) in males versus 3.1% (5/161) in females, p=0.27. Consistent with prior studies, patients with ALK positive tumors were slightly younger (median age 56 years vs 61 years, p = 0.27) and the positive rate was higher in never smokers 11% (2/18) than in ever smokers 1.6%, p=0.06. There was no correlation of ALK positivity with the stage of the disease at diagnosis. The survival of ALK positive and negative patients, adjusted for age, sex and stage, was similar (HR=0.77; 95% CI 0.19-3.13). Fifty-three tumors have been assessed for oncogene mutations in addition to ALK expression. Of these, 2 (3.8%) were ALK positive and neither of these tumors carried other tested mutations such as EGFR, Kras, PIK3 or AKT. Conclusions: The rate of ALK positive tumors among African-American NSCLC patients is similar to the general population and the demographic features of ALK positive AA patients is also similar to the general ALK positive NSCLC patient population.
Insulin-like growth factor 1 (IGF-1R) protein expression (PE) and gene copy number (GCN) for discrimination of response and outcome to figitumumab in NSCLC.
Authors: Wynes Murry W. , Ekman Simon , Reyna Asuncion Bernadette , Dziadziuszko Rafal , Glisson Bonnie S. , Wistuba Ignacio I. , Hirsch Fred R. 
Published: March 2020

7597 Background: Early clinical data suggested figitumumab (F), an anti-IGF-1R antibody, had clinical activity in several tumor types. However, two phase III studies, A4021016 carboplatin/paclitaxel (CP) +/- F in 1st line treatment or A4021018 erlotinib (E) +/- F in 2nd line therapy for patients with advanced NSCLC, were closed prematurely due to futility. Neither study used biomarker driven selection criteria. The aim of this study was to retrospectively examine the phase III specimens in order to determine if IGF-1R PE or GCN could discriminate response and/or outcome to F. Methods: IGF-1R PE was determined by immunohistochemistry (IHC) and the tumor specimens were scored using the H-score method (0-300) with separate enumeration of membranous and cytoplasmic components and then combination of these scores. GCN was evaluated by bright field silver in situ hybridization (SISH) with recording the average copy number for 50 tumor cells. Results: IHC was evaluable in 25 CP+F, 20 CP, 27 E+F and 26 E specimens whereas SISH was evaluable in 24, 17, 21 and 22 specimens, respectively. Median PE for membrane, cytoplasm and both in A4021016 were 130, 110 and 120 and in A4021018 they were 135, 140 and 140. Median GCN was 1.88 and 1.98 for A4021016 and A4021018, respectively. There were no significant differences in PE or GCN between treatment arms within each study. Neither PE nor GCN were able to discriminate between response/non-response or disease control/progression in either study. Likewise, neither study showed a significant difference in OS or PFS when using the median cut-points for either PE or GCN. Conclusions: Neither IGF1R PE or GCN were able to discriminate response or outcome in the limited quantity of specimens available from two studies that examined the IGF-1R targeted therapy figitumumab.
Clinical presentation of hepatotoxicity-associated crizotinib in ALK-positive (ALK+) advanced non-small cell lung cancer (NSCLC).
Authors: Schnell Patrick , Safferman Allan Zachary , Bartlett Cynthia Huang , Tang Yiyun , Wilner Keith D. 
Published: March 2020

7598 Background: Severe hepatotoxicity has been observed with most receptor tyrosine kinase inhibitors. Crizotinib, a first-in-class oral inhibitor of ALK, was recently FDA approved for the treatment (tx) of advanced (ALK+) NSCLC. We provide a review of hepatotoxicity in the crizotinib clinical development program. Methods: Relevant tx-emergent adverse event (AE) reports from 2 pooled single-arm trials in patients (pts) with ALK+ NSCLC who received crizotinib 250 mg BID (n=588) up to Jun 2011 were reviewed. Five reports of severe hepatotoxicity received through Dec 13, 2011 were also evaluated. Results: Incidence of elevation in ALT and AST lab values by CTCAE grade are shown in the table. Additionally, 16 all-grade (7 grade 3 or 4) cases of pertinent hepatic events have been reported. Transaminase elevations generally occurred in the first 2 months of tx and were usually reversible. Pts usually resumed tx at a lower dose without recurrence; however, 4 (<1%) required permanent discontinuation from tx. Five (<1%) cases of severe, potentially drug-related hepatotoxicity (2 fatal) were reported through Dec 13, 2011, with an estimated exposure of 1400 pts. Pts presented with fatigue, nausea, anorexia, weakness, and abdominal pain. Time from starting crizotinib to onset of hepatotoxicity was <6 weeks in 4 cases, while significant transaminase elevation was observed after 6 months in the fifth case. Significant hepatic metastases and abnormal enzymes at baseline were present in 1 (fatal) case, while baseline transaminases were normal in 3 cases, or just above the upper limit of normal in 1 case. Conclusions: Crizotinib is uncommonly associated with severe hepatotoxicity and was reported in <1% of pts. Nausea, malaise, decreased appetite, vomiting, and abdominal pain may indicate hepatic toxicity. ALT and total bilirubin should be monitored monthly and as clinically indicated. Discontinuation of crizotinib is recommended when severe drug-induced hepatic toxicity is suspected or diagnosed. [Table: see text]
Clinical characteristics of ALK+ NSCLC patients (pts) treated with crizotinib beyond disease progression (PD): Potential implications for management.
Authors: Otterson Gregory Alan , Riely Gregory J. , Shaw Alice Tsang , Crinò Lucio , Kim Dong-Wan , Martins Renato , Salgia Ravi , Zhou Caicun , Solomon Benjamin J. , Wilner Keith D. , Polli Anna , Tang Yiyun , Bartlett Cynthia Huang , Ou Sai-Hong Ignatius 
Published: March 2020

7600 Background: Crizotinib is a first-in-class oral ALK inhibitor for the treatment (tx) of advanced ALK-positive (ALK+) NSCLC. Dramatic and prolonged responses to crizotinib are common, but pts do experience PD. Methods: Clinical characteristics of ALK+ NSCLC pts enrolled onto two multicenter, single arm trials of crizotinib (A8081001, PROFILE 1005) with investigator-defined PD who were allowed to continue crizotinib if, in the investigator’s opinion, there was reasonable evidence of ongoing clinical benefit were assessed. A period of ≥2 wks was chosen as a reasonable minimum duration of post-PD crizotinib tx. Results: As of 1 June 2011, 146 pts (A8081001, n=61, PROFILE 1005, n=85) had PD. PD was observed in new lesions only (1 organ site, n=62; >1 organ site, n=18), target ± new lesions (≥ 1 organ site, n=55), clinical PD (n=9), and no site assessment (n=2). Most common new lesions in single organ sites were brain (brain MRI not mandatory; n=25), liver (n=20), bone (n=4), and kidney (n=1). Of the 146 pts, 78 (53%) received crizotinib post-PD for at least 2 wks, 91% of whom had ECOG PS 0 or 1 at PD. In these 78 pts, PD was observed in new lesions only (1 organ site, n=39; >1 organ site, n=4), target ± new lesions (≥ 1 organ site, n=29), and clinical PD (n=6); the most common sites for single organ PD were brain (n=20), liver (n=9), and other (n=10). Best response before PD (% CR/PR, SD, PD) was 62/27/12 in the 78 pts who received ≥2 weeks’ tx post-PD and 31/37/32 in the 68 pts who received <2 weeks’ tx post-PD or discontinued. Median duration of crizotinib tx post-PD (n=78) was 10 weeks (range 2–84). 20 pts with PD in brain only (concurrent local tx or radiation permitted) continue to receive crizotinib (range 3–82 weeks post-PD). Conclusions: Following initial crizotinib tx, PD most commonly occurred at a single organ site in ALK+ NSCLC pts. The majority of pts receiving crizotinib post-PD had good PS, and tended to have single-site PD (most often the brain or liver), and a prior response on crizotinib. Given these observations, pts may be able to continue with crizotinib for a period of time following clinical or documented progression.
Impact of disease progression (DP) date determination method on post progression survival (PPS) and DP metrics in advanced lung cancer.
Authors: Mandrekar Sumithra J. , Foster Nathan R. , Qi Yingwei , Dy Grace K. , Jatoi Aminah , Molina Julian R. , Jett James R. , Stella Philip J. , Schild Steven E. , Adjei Alex A. ,   Alliance (North Central Cancer Treatment Group)
Published: March 2020

7605 Background: Overall survival (OS) can be partitioned into progression-free survival (PFS) and PPS. PPS helps to understand trial results, especially when PFS and OS data on trial treatment effects are discordant. At ASCO 2011, we reported that the magnitude of difference in the PFS estimates using different DP date methods was large enough to alter trial conclusions. Here, we investigate the impact of the DP date method on 1) PPS estimates, and 2) predictive utility of DP metrics on subsequent OS (SOS). Methods: Individual patient (pt) data from 14 trials were pooled. DP date was determined using: reported progression date (RPD) (method 1, M1), one day after last progression-free (PF) scan (M2), and midpoint between last PF scan and RPD (M3). PPS was estimated using the method of Kaplan-Meier for the 3 DP date methods. A flexible landmark analysis at 2, 4, and 6 months (mos) using Cox proportional hazards model was used to assess the impact of DP status (progression versus no-progression) on SOS (using M1, M2, or M3). Results: Among NSCLC (SCLC), 87% (91%) of pts reported DP. As expected, the PPS estimates were the lowest for RPD, highest for M2, and in-between for M3 (a direct consequence of the DP date method); with no difference by arm for the randomized trials. Regardless of the DP date method, patients who were progression-free had improved SOS (NSCLC: Hazard ratio, HR<=0.33; p < 0.0001; SCLC: HR<=0.48; p < 0.002) at each landmark time point, with comparable concordance index (SCLC: 0.57-0.65; NSCLC: 0.63-0.67), i.e., ability to discriminate patients with different SOS outcomes. Conclusions: While the DP date methods do not impact the predictive utility of the DP metrics, they significantly impact PPS estimates. The translation of a significant treatment effect on PFS to an effect on OS is influenced by PPS (longer PPS dilutes effect on OS). Standards for declaring DP date are thus critical to trial design and for trial go/no-go decisions. [Table: see text]