bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase II study of recombinant human endostatin in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer (NCT00912392).
Authors: Lu Shun , Li Lu , Luo Yi , Zhang Li , Chen Zhiwei , Gang Wu , Chen Ping , Huang Cheng , Guo Shuliang , Zhang Yiping , Song Xiangqun , Lv Meijun , Li Wei , Hu Chunhong , Hu Cheng-ping
Published: March 2020

7091

Background: Endostar (recombinant human endostatin) is a novel antiangiogenesis drug developed in China for non-small cell lung cancer (NSCLC). Because of promising efficacy signals, we performed a randomized phase II trial to assess the efficacy and safety of adding endostar to first-line standard chemotherapy for treatment of chemonaive extensive-stage small-cell lung cancer (SCLC). Methods: Extensive-stage SCLC patients with a performance status 0-2 were randomly assigned to endostar group (endostar 7.5mg/m2 D1-D14 with carboplatin AUC=5 plus etoposide 60mg/m2 D1-D5 of a 21-day cycle for six cycles) or the control group (the same dose of carboplatin plus etoposide). Patients in endostar treatment group with CR, PR and SD were treated with single-agent endostar until progression or unacceptable toxicity. The primary end point is progression-free survival (PFS). The secondary end points are overall survival (OS) and response rate (RR). Results: 140 patients were enrolled from June 2009 to June 2011, and 137 patients were included in full analysis set. 68 patients were randomly assigned to the endostar treatment and 69 patients to the control group. Median age was 57 years and 80.9% for male in the endostar group while median age was 58 years and 85.5% for male in the control group. Median PFS was similar for endostar and control group (6.2 v 5.9 months, P=0.163, HR 0.762; 95%CI 0.519-1.119). Median overall survival (OS) was also similar for both groups (12.4 v 12.3 months, P=0.475, HR 0.835; 95%CI 0.508-1.371). Overall RR were 76.5% for endostar group and 68.1% for the control group (p=0.275). 20 patients in the endostar group completed six cycles of therapy and subsequently treated with single-agent endostar as maintenance therapy and the median PFS and OS were 6.8 and 12.4 months respectively. The rate of ≥ 3 grade adverse events occurred in both groups was similar and no new or unexpected safety signals for endostar were observed. Conclusions: The addition of endostar to carboplatin plus etoposide for treatment of extensive stage SCLC didn’t improve the PFS significantly, with an acceptable toxicity profile. And no improvement in OS was observed.
ABEL trial: A phase II randomized trial adding bemiparin (B) to chemo-radiotherapy (CT-RT) in limited-stage small cell lung cancer (SCLC)—Final results.
Authors: Massuti Bartomeu , Lecumberri Ramon , Lopez Vivanco Guillermo M , Font Albert , Gonzalez-Billalabeitia Enrique , Marti-Ciriquian Juan Luis , Gómez-Codina Jose , Domine Manuel , Bover Isabel , Isla Dolores , Galan Antonio , Gurpide Alfonso , Vicente Vicente , Rosell Rafael , Monreal Mayte , Rocha Eduardo
Published: March 2020

7095

Background: Low molecular weight heparins (LMWH) could improve therapeutic outcomes in patients with advanced cancer. Heparin binding growth associated molecule is a member of growth factors involved in proliferation, angiogenesis and metastases in SCLC. LMWH associated with CT increase survival in cancer patients (Cochrane DB Systematic Reviews 2011). LMWH do not increase hemorrhagic events when used in neoplastic patients. Methods: Open randomized phase II multicentric trial to assess efficacy and safety of adding bemiparin to standard CT-RT in patients with SCLC with limited disease. CT: Cis/carboplatin + etoposide x 4-6 cycles. Concurrent early thoracic RT (45-50 Gy) and prophylactic cranial irradiation in case of response. Patients (p) were randomly allocated to addition of B at daily subcutaneous dose of 3.500 UI during 26 weeks. Primary end-point: progression free survival (PFS). Secondary end-points: response (RECIST), safety profile (CTC), venours thromboembolic (VTE) and hemorrhagic events incidence and overall survival (OS). Sample size 130 p. Preplanned interim analysis after inclusion 30 p. Results: From October-05 to January/10 39 p were included. Study was closed after interim analysis due to poor recruitment. 38 evaluable p. ITT analysis: 20 CR-RT + B vs 18 CT-RT. No significant disbalance in patient characteristics and prognostic factors. Median PFS 58.6 weeks (CT-RT+B) vs 38.8 w (CT-RT) (HR 2.576; Log-rank p=0,018). RR: 65% (CT-RT+B) vs 55% (CT-RT) (NS); Median OS 161.8 w (CT-RT+B) vs 49.3 w (CT-RT) (HR 2.96; Log-rank p=0,012). 2-year survival rate: 68.6% (CT-RT+B) vs 29.4% (CT-RT) (p=0,0042). Safety: G3-4 AE: 50% vs 67%; bleeding events: 10% vs 27% (NS); thrombocytopenia 15% vs 50% (p=0.024); VTE: 0 vs 22% (p=0.041). Conclusions: Addition of B (3.500 u/daily s.c. during 26 w) to CT-RT in SCLC with LD significantly increases PFS and OS. B does not increase hemorragic events and significantly reduces VTE. In spite of early closure of the trial due to poor accrual, these results warrants further research in this approach trying to improve current outcomes of SCLC. ClinicalTrials.gov Id: NCT00324558.
Investigation of PARP1 as a therapeutic target in small cell lung cancer.
Authors: Byers Lauren Averett , Nilsson Monique B. , Masrorpour Fatemeh , Wang Jing , Diao Lixia , Bhardwaj Vikas , Welsh James , Girard Luc , Coombes Kevin R. , Weinstein John N. , Lippman Scott Michael , Glisson Bonnie S. , Minna John D. , Heymach John
Published: March 2020

7096

Background: Small cell lung cancer (SCLC) is an aggressive malignancy that differs from non-small cell lung cancer (NSCLC) in its metastatic potential and response to treatment. To date, no molecularly-targeted agent has prolonged survival of SCLC patients. Using a proteomic approach, we previously identified high expression of the DNA repair protein poly (ADP-ribose) polymerase 1 (PARP1) in SCLC cell lines and tumors. Here we test in vitro sensitivity of SCLC to PARP inhibition or knockdown. Methods: Cell lines were treated with PARP inhibitor olaparib or AG014699 for 14d +/- chemotherapy. Relative cell viability was assessed by cell count. siRNA against PARP1 was compared with scrambled siRNA and mock transfected cells. To assess DNA repair, RAD51 foci were counted after 1µM or 5µM olaparib and after 8Gy irradiation (RT). Results: SCLC cell lines were highly sensitive to PARP inhibition by olaparib (IC50s <0.5 µM for H69; ≤2µM in H524, H82, and H526) and AG014699 (IC50s <0.5 µM for H82, H69, and H524; 2.2 µM for H526 and H841). In contrast, A549 (NSCLC) was resistant to both drugs (IC50s >8µM). Because BRCA1/2 and PTEN mutations are associated with greater sensitivity to PARP inhibitors, we compared SCLC sensitivity with that of BRCA1-mutated (HCC1395) and PTEN-mutated (MDA-MB-468) breast lines. As expected, HCC1395 and MDA-MB-468 were sensitive to both PARP inhibitors. Remarkably, however, SCLC cell lines were as sensitive or more so. Combination of olaparib with topotecan or irinotecan (commonly used in SCLC) decreased tumor cell viability more than either agent alone (p <0.03). Consistent with the drug studies, knockdown of PARP1 by siRNA decreased growth of SCLC compared with that of controls. RAD51 foci increased in SCLC after olaparib treatment (>4-fold) and RT (>18-fold). Conclusions: SCLC lines were as sensitive to PARP inhibition as BRCA1- or PTEN-mutated breast cancer lines. Moreover, PARP inhibition enhanced the effect of chemotherapy on SCLC lines. Increased formation of RAD51 foci in SCLC cells after olaparib or RT suggests a deficiency in homologous recombination that may account for the sensitivity to PARP inhibitors. These results support the investigation of PARP inhibition as a novel therapeutic approach in SCLC lung cancer.
A prospective, phase II trial of induction chemotherapy with docetaxel/cisplatin for Masaoka stage III/IV thymic epithelial tumors.
Authors: Park Silvia , Park Keunchil , Ahn Myung-ju , Ahn Jin Seok , Sun Jong-Mu , Ahn Hee Kyung , Lee Su Jin , Maeng Chi Hoon , Hwang Deok Won
Published: March 2020

7104

Background: Thymic epithelial tumors (TETs), thymoma and thymic carcinoma, are the most common tumor of the anterior mediastinum. Initial complete resection is the most powerful prognostic indicator of survival. However, it is obviously related to stage. Here, we report the result of a prospective phase II study of neoadjuvant docetaxel/cisplatin in patients with locally advanced TETs. Methods: In this open-label, phase II, nonrandomized study, patients with histologically proven, Masaoka stage III/IV TETs at presentation were enrolled. Patients received docetaxel 75mg/m2 I.V for 1 hr, followed by I.V cisplatin 75mg/m2 over 1.5hr on day 1 of every 3 week. After 3 cycles of chemotherapy, subsequent surgical resection was performed, if resectable. Results: From March 2007 to July 2011, a total of 27 TETs patients were entered into the trial. The median age was 54 (range, 15-68), and Masaoka stage at presentation was III (n=8, 29.6%), IVA (n=17, 63.0%), and IVB (n=2, 7.4%). Histologic type by the WHO includes type B1 (n=2, 7.4%), B2 (n=3, 11.1%), B3 (n=5, 18.5%), and thymic carcinoma designated as type C (n=16, 59.3%). After completion of neoadjuvant chemotherapy, 17 (63.0%) achieved PR and 10 (37.0%) had SD. Nineteen patients (70.4%) underwent surgical resection, and 8 patients did not (surgeons’ decision, n=5; patients’ refusal, n=2; radiation therapy, n=1). Of the 19 patients undergoing surgical resection, 17 (89.5%) had complete resections and 2 (10.5%) did not. Major side effects of chemotherapy include grade 3 anorexia (n=1), nausea (n=2), diarrhea (n=3), alopecia (n=1). After completion of surgical resection, adjuvant therapy was performed as follows: radiotherapy (RT, n=8), chemotherapy (CTx, n=6), radiotherapy with chemotherapy (RT + CTx, n=2) and observation (n=3). Overall, 4yr OS and PFS was 79.4% and 40.6%. Patients with complete resection showed 93.8% of 4yr OS and 50.2% of 4yr PFS whereas patients without complete resection showed 47.6% of 4yr OS and 26.7% of 4yr PFS, respectively (OS, p=0.06; PFS, p=0.27). Conclusions: Neoadjuvant docetaxel/cisplatin was well tolerated and feasible, and improved the surgical respectability in patients with advanced TETs.
Factors affecting survival of patients with Masaoka stage IV thymic epithelial tumors (TET).
Authors: Suleiman Yaman , Radovich Milan , Rojas Luis , Porter Ryan Frederick , Conces Madison , Shirar Kristen Leigh , Nelson Robert P , Spittler Aaron John , Siddiqui Bilal Karim , Burns Matthew , Badve Sunil S. , Schneider Bryan P. , Loehrer Patrick J.
Published: March 2020

7107

Background: Thymoma and thymic carcinoma (TC) are rare tumors, but represent the most common neoplasms of the anterior mediastinum. The vast majority of TET present in early stages with little data existing on factors influencing survival in patients with advanced or stage IV disease. Methods: A retrospective analysis was performed on patients with confirmed TET (histology and with tissue blocks) seen at IUSCC diagnosed between 1976 and 2011. Patient demographics including Masaoka stage, histology, and sites of metastasis were linked with progression free survival (PFS) and overall survival (OS). Results: Our analysis included 102 patients with stage IV TET: 50 presented de novo and 52 developed stage IV disease following primary treatment. When stratified by tumor histology (thymoma or TC), patients with TC had considerably poorer PFS (p=1.87x10-7) and OS (p=7.72x10-8). The median PFS for TC was 13 months (range 4 to 39) and the MST was 36 months (range 4 to 115). PFS at 5-years was 21% and 0% but the five-year OS was 84% and 29% for thymoma and TC, respectively. Ten year OS was 55% for patients with thymoma and 0% for those with TC. Pleural (>3 vs. <3) metastases were significantly associated with a better PFS (p=0.036) and OS (p=0.0003). The PFS and OS of patients with lung nodules trended with those with pleural metastasis. Patients with pleural metastasis and lung nodules sites did considerably better than those with visceral disease (PFS, p=0.004, OS, p=2.09x10-5). Conclusions: Patients with TC have significantly poorer PFS and OS when compared to thymoma confirming that TC is a distinct clinical entity from thymoma. Patients with thymoma may have prolonged survival, despite having residual disease. Although current staging places patients with pleural metastasis (Masaoka stage IVA) and those with lung nodules (stage IVB) as separate categories, our data would suggest that those with lung nodules have similar survival with those who have pleural metastasis.
Phase II double-blind, randomized study of selumetinib (SEL) plus docetaxel (DOC) versus DOC plus placebo as second-line treatment for advanced KRAS mutant non-small cell lung cancer (NSCLC).
Authors: Janne Pasi A. , Shaw Alice Tsang , Pereira Jose Rodrigues , Jeannin Gaelle , Vansteenkiste Johan , Barrios Carlos H. , Franke Fabio A. , Grinsted Lynda , Smith Paul D. , Zazulina Victoria , Smith Ian C. , Crino Lucio
Published: March 2020

7503

Background: KRAS mutations are the most common (~20%) oncogenic alteration in NSCLC. There are no effective targeted therapies for this subset of NSCLC. Selumetinib (AZD6244, ARRY-142866) inhibits MEK1/2 signaling downstream of KRAS. We prospectively evaluated SEL + DOC vs DOC + placebo in advanced KRAS mutant NSCLC based on preclinical observations (NCT00890825). Methods: Patients (pts) with stage IIIB-IV, KRAS mutant NSCLC, who had received prior chemotherapy, received iv DOC 75 mg/m2, and po SEL 75 mg or placebo BD. The primary endpoint was overall survival (OS); secondary endpoints included: progression-free survival (PFS), objective response rate (RR), duration of response, change in tumor size, proportion of patients alive and progression-free at 6 mo, and safety and tolerability. Results: Between April 2009 and June 2010, 422 pts were screened across 67 centers in 12 countries; 113 had KRAS mutant NSCLC and 87 were randomized (DOC, 43; SEL/DOC, 44). Baseline characteristics were balanced (DOC vs SEL/DOC): WHO PS 0, 49%/48%; Female, 54%/52%; KRAS codon 12, 90%/93%. Median number of cycles: DOC, 4; SEL/DOC, 5. Most frequent grade 3/4 hematologic toxicity (DOC vs SEL/DOC): neutropenia (54.8%/67.4%), febrile neutropenia (0%/15.9%); most frequent grade 3/4 non-hematologic toxicity: dyspnea (11.9%/2.3%) asthenia (0%/9.1%), respiratory failure (4.8%/6.8%), acneiform dermatitis (0%/6.8%). Discontinuation due to AEs was similar: 18.2% SEL/DOC vs 11.9% DOC. OS was longer for SEL/DOC vs DOC (9.4 mo vs 5.2 mo; 56 events, median follow-up 219 days) but did not reach statistical significance; hazards were non proportional (HR 0.80; 80% CI 0.56, 1.14; 1-sided p=0.2069). All secondary endpoints, including RR (DOC 0%, SEL/DOC 37%; p<0.0001) and PFS (DOC 2.1 mo, SEL/DOC 5.3 mo; 71 events; HR = 0.58; 80% CI 0.42, 0.79; 1-sided p=0.0138), were significantly improved for SEL/DOC vs DOC. Conclusions: This is the first prospective study to demonstrate a clinical benefit of a targeted therapy (SEL + DOC) for patients with KRAS mutant cancer of any type. Our findings could have implications for the treatment of NSCLC and other KRAS mutant cancers.
Discovery of recurrent KIF5B-RET fusions and other targetable alterations from clinical NSCLC specimens.
Authors: Capelletti Marzia , Lipson Doron , Otto Geoff , Yelensky Roman , Ercan Dalia , Kim Jhingook , Sasaki Hidefumi , Kim Hyeong Ryul , Park Seung-Il , Ross Jeffrey S. , Stephens Philip , Cronin Maureen T. , Janne Pasi Antero
Published: March 2020

7510

Background: Many NSCLCs have driving oncogenic alterations including in EGFR, KRAS, ERBB2, BRAF, ALK and ROS1. Clinically effective drugs are approved for EGFR and ALK and clinical trials are underway for other genomic targets. Thus having a means of identifying genomic alterations in routine formalin fixed paraffin embedded (FFPE) clinical specimens is critical. Methods: We sequenced 24 FFPE NSCLC specimens with a next generation sequencing (NGS) assay that captures and sequences 2574 coding exons of 145 cancer relevant genes plus 37 introns from 14 genes often rearranged in cancer. Tumors from 643 additional patients were genotyped for KIF5B-RET. Results: We identified 50 alterations in 21 genes with at least one in 83% (20/24) of tumors (range 1-7). In 72% (36/50) of NSCLCs, at least one alteration was associated with a current clinical treatment or targeted therapy trial, including mutations in KRAS, BRAF, EGFR, MDM2, CDKN2A, CCNE1, CDK4, NF1 and PIK3CA. We also found an 11,294,741 bp pericentric inversion on chromosome 10 generating a novel gene fusion joining exons 1-15 of KIF5B to exons 12-20 of RET (K15:R12) in a Caucasian never smoker. This fusion gene contains the kinesin motor and coiled-coil domains of KIF5B and the entire RET tyrosine kinase domain. In 643 additional tumors we identified 11 fusion positive patients who were all wild type for known oncogenes (frequency of 6.3% (10/159)). Four unique KIF5B-RET variants were found: 8 K15:R12, 3 K16:R12, 1 K22:R12 and 1 K15:R11. We introduced K15:R12 into Ba/F3 cells and observed IL-3 independent growth consistent with oncogenic transformation. KIF5B-RET Ba/F3 cells were sensitive to sunitinib, sorafenib and vandetinib, multi-targeted kinase inhibitors that inhibit RET, but not gefitinib, an EGFR kinase inhibitor. Sunitinib, but not gefitinib, inhibited RET phosphorylation in these cells. Conclusions: We identified both known and novel genomic alterations from NSCLC FFPE specimens using a single test. Our findings suggest that RET inhibitors should be tested in prospective clinical trials in NSCLC patients bearing KIF5B-RET rearrangements and that NGS is a feasible approach to stratifying patients for treatment based on their genomic profiles.
A randomized double-blind trial of carboplatin plus paclitaxel (CP) with daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor receptors, or placebo (PLA) in patients (pts) with previously untreated advanced non-small cell lung cancer (NSCLC): NCIC Clinical Trials Group study BR29.
Authors: Laurie Scott Andrew , Solomon Benjamin J. , Seymour Lesley , Ellis Peter Michael , Goss Glenwood D. , Shepherd Frances A. , Boyer Michael J. , Arnold Andrew Michael , Clingan Philip , Laberge Francis , Fenton Dave , Hirsh Vera , Zukin Mauro , Stockler Martin R. , Lee Christopher W. , Chen Eric Xueyu , Montenegro Alexander , Ding Keyue , Bradbury Penelope Ann ,   NCIC Clinical Trials Group
Published: March 2020

7511

Background: In NCIC CTG study BR24, CED 30 mg/d + CP increased objective response rate (RR) and progression-free survival (PFS), but there were concerns regarding toxicity in some pts. BR29 tested a lower dose of CED 20 mg/d limiting accrual to pts without significant weight loss/hypoalbuminemia. Methods: Consenting, eligible adult pts with advanced incurable NSCLC of any histology were randomized to receive CED 20 mg/d or PLA with up to 6 cycles of C (AUC = 6) P (200 mg/m2); non-progressing pts continued CED/PLA after CP until progression, unacceptable toxicity or pt request. The primary endpoint was overall survival (OS). An interim analysis (IA) for PFS was planned after 170 events in the first 260 pts; the study would continue if the hazard ratio (HR) for PFS was < 0.7. Accrual continued until the required number of events was reached then held pending IA. Results: The trial was halted when the IA (n=260) revealed a HR for PFS of 0.89 (95% CI 0.66-1.20). A final analysis including all 306 randomized pts (median age 62, male 55%, PS 0 26%, PS 1 74%, adenocarcinoma 64%, squamous 13%, other histology 23%. RR was significantly higher with CED (52% vs 34 %, p = 0.001). For CED/PLA, respectively, median OS and PFS were 12.2/12.1 [HR: 0.95 (0.69-1.30, p=0.74)] and 5.5/5.5 months [HR: 0.91 (0.71-1.18, p=0.5)]. Grade >3 hypertension (15% vs 3%, p=0.0002), anorexia (7% vs 1%, p=0.02) and diarrhea (16% vs 1%, p<0.0001) were all significantly increased with CED; there were 2 deaths possibly-related to CED [1 each hemorrhage, leukoencephalopathy (prior radiation)]. Conclusions: Adding a lower dose of CED to CP increased RR and toxicity, but not PFS or OS.
Randomized phase II trial of erlotinib (E) plus high-dose celecoxib (HD-C) or placebo (P) in advanced non-small cell lung cancer.
Authors: Reckamp Karen L. , Koczywas Marianna , Cristea Mihaela C. , Dowell Jonathan , Gardner Brian , Milne Ginger L , Figlin Robert A. , Elashoff Robert M. , Dubinett Steven M.
Published: March 2020

7518

Background: Cyclooxygenase-2 (COX-2)-dependent signalling represents a potential mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in NSCLC. This is mediated in part through an EGFR-independent activation of MAPK/Erk by the COX-2 metabolite PGE2. In addition, PGE2 promotes downregulation of E-cadherin and epithelial to mesenchymal transition. We hypothesize that EGFR and COX-2 inhibition with E and HD-C will augment EGFR TKI efficacy by increasing tumor E-cadherin expression and blocking PGE2-mediated resistance to EGFR inhibition. Methods: Pts with stage IIIB/IV NSCLC who progressed following at least one line of therapy or refused standard chemotherapy were randomized to E (150mg/day)/HD-C (600mg/2x day) vs E/P in a 28-day cycle. Pts were stratified by smoking status and ECOG PS. The primary endpoint was PFS with 80% power to detect a 50% improvement; assessments were performed every 2 cycles. Secondary endpoints included response rate, OS and evaluation of molecular markers in tissue and serum to assess targeting COX-2-related pathways and evaluate EGFR TKI-resistance. All pts were required to have pre-treatment tissue available. Results: 107 pts were enrolled with comparable baseline characteristics in both arms. Disease control rate (DCR) was similar in both arms, and a trend toward improved PFS was seen in the E/HD-C arm with HR 0.81 (see Table). Analysis of those with EGFR wild type revealed a significantly increased PFS while those with EGFR mutation had similar PFS in both groups. Safety analysis showed similar toxicity in both arms. Additional biomarker correlations will be presented. Conclusions: The combination of E/C in metastatic NSCLC with HD-C is well tolerated and demonstrates significantly improved efficacy in EGFR wt population. This warrants further study into the COX-2-dependent mechanisms of primary resistance to EGFR TKI therapy. Supported by NIH 1P50 CA90388, K12 CA01727 and medical research funds from the Dept of Veterans’ Affairs. [Table: see text]
Rebiopsy of non-small cell lung cancer patients with acquired resistance to EGFR-TKI: Comparison between T790M mutation-positive and -negative populations.
Authors: Hata Akito , Katakami Nobuyuki , Yoshioka Hiroshige , Takeshita Jumpei , Tanaka Kosuke , Nanjo Shigeki , Kaji Reiko , Fujita Shiro , Imai Yukihiro , Monden Kazuya , Matsumoto Takeshi , Nagata Kazuma , Otsuka Kyoko , Tachikawa Ryo , Tomii Keisuke , Kunimasa Kei , Iwasaku Masahiro , Nishiyama Akihiro , Ishida Tadashi
Published: March 2020

7528

Background: The secondary epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitors (TKI). A recent report has demonstrated the presence of T790M predicts a favorable prognosis and indolent progression, compared to the absence of T790M after TKI failure. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M. Methods: We investigated 73 patients harboring EGFR sensitive mutations who had undergone rebiopsy to confirm the emergence of T790M after TKI failure. The peptide nucleic acid-locked nucleic acid PCR clamp method was used in EGFR mutational analyses. Patient characteristics (age, gender, smoking history, performance status, EGFR mutation site, initial TKI, response to initial TKI, line of initial TKI, progression-free survival with initial TKI, and biopsy site) and postprogression survivals (PPS) after initial TKI failure, were retrospectively compared in patients with and without T790M. Results: We identified T790M in 2 (10%) of 21 central nervous system (CNS) (19 cerebrospinal fluid and 2 brain tissue) specimens, and in 20 (38%) of 52 other lesions (25 lung tissue, 24 pleural effusion, and 3 lymph node) (p = 0.0225). Other characteristics had no statistical association with the detection of T790M. Median PPS in patients with T790M was 34.0 months, and in those without T790M, 14.5 months (p = 0.0038). Although none of our patients received TKIs continuously after initial failure, 56 (77%) patients were re-administered TKIs. Regardless of T790M status, PPS in patients with TKI re-administration (23.4 months) was significantly longer than without re-administration (10.4 months) (p = 0.0085). Conclusions: The emergence of T790M in CNS is rare compared with other lesions. Patients with T790M after TKI failure have significantly better prognosis than those without T790M. The effectiveness of TKI re-administration or continuous administration beyond progression is suggested after initial TKI failure.
A randomized, double-blind, placebo-controlled phase II study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naive metastatic/unresectable non-small cell lung cancer (NSCLC).
Authors: Von Pawel Joachim , Hadler Dietrich , Fox Tara , Wang Qiang , Greenberg Jonathan , Beckman Robert A. , Krzakowski Maciej Jerzy , Reck Martin
Published: March 2020

7536

Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist induces apoptosis in human cancer cell lines and has shown activity in a phase 1 trial; phase 2 trials are ongoing in several tumor types. In NSCLC cells, single-agent T shows anti-cancer activity. Methods: Patients (pts) with histologically/cytologically confirmed (TNM ed6) NSCLC stage IIIB/IV, measurable disease by RECIST (v1.0), and ECOG-PS 0-1 were enrolled at 15 European sites. Pts received T or placebo (PL) IV + carboplatin/paclitaxel (C/P) every 3 weeks (wks) (1 cycle) for up to 6 cycles. In the case of complete response (CR)/partial response (PR) or stable disease, T or PL was given as maintenance therapy. The dosage regimen was T 10 mg/kg or PL at wk 1/cycle 1 and 8 mg/kg or PL every 3 wks thereafter; P: 175 mg/m2 every 3 wks; C: AUC 6 every 3 wks. Primary endpoint: progression-free survival (PFS); secondary endpoints: overall survival (OS) and objective response rate (ORR) (CR + PR), safety. Efficacy was assessed in both the full population and a prospectively-defined FCGR genotype subset. Results: 97/100 pts (9.3% stage IIIB wet; 90.7% stage IV; 70.1% non-squamous; 29.9% squamous) were eligible for efficacy analyses (49 to T; 48 to PL). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for T vs 4.3 months (4.1, 5.8) for PL; HR = 0.96; 95% CI: 0.6, 1.6. Median OS (95% CI) was 8.4 months (6.9, 16.3) for T vs 9.0 months (7.6, 14.5) for PL (HR = 0.95; 95% CI: 0.6, 1.6). 12 pts (24.5%) in the T arm and 11 pts (22.9%) in the PL arm had PR; no pt had CR. In a subset of pts (n = 25) with FCGR2A-H131R or FCGR3A-V158F genotypes, there was a non-significant trend towards increased PFS with T vs PL (HR = 0.47; 95% CI: 0.16, 1.35) but no difference in OS. T was well tolerated; the only increased grade 3/4 toxicity was grade 3 neutropenia (16% with T vs 4% with PL). The number of treatment cycles was similar in both treatment arms. Conclusions: T does not improve the efficacy of C/P as treatment for systemic therapy-naïve, unselected advanced NSCLC pts. T was well tolerated and is being investigated in other settings.
Intratumoral heterogeneity of EGFR mutation and clinical significance in Chinese patients with advanced non-small cell lung cancer.
Authors: Bai Hua , Wang Jie , Wang Zhijie , Duan Jianchun , Yang Lu , An Tongtong , Zhuo Minglei , Wu Meina , Wang Yuyan
Published: March 2020

7537

Background: Whether exist intratumoral heterogeneity of epidermal growth factor receptor (EGFR) gene mutation remains controversial. This study aims to evaluate intratumoral heterogeneity of EGFR and its clinical significance in patients with non-small cell lung cancer (NSCLC). Methods: Samples were collected from 85 patients with stage IIIa-IV who had palliative surgery resection. All of the bulk tissues had been routinely detected EGFR mutation, in which contained 30 wild-type and 55 mutant-type EGFR. 28–34 tumor foci for each sample were microdissected. EGFR mutation was detected by ARMS. EGFR copy number was detected by FISH. 23 patients received EGFR-tyrosine kinase inhibitor (TKIs) therapy. Results: 1740 tumor foci from 55 EGFR mutant-type (Group-M) and 959 foci from 30 wild-type cases(Group-W) were fractionated. Mean mutation contents were 73.9%(1285/1740) in Group-M and 0 in Group-W. Accordingly, 28.2%(24/85)consisted of cells with both wild-type and mutated-type EGFR, with the proportion of EGFR mutant cells ranging from 1% to 90%, whereas 71.8%(61/85) samples contained pure mutant-type (n=31) or wild-type EGFR cells(n=30). 31 patients (36.5%) presented EGFR FISH positive. The patients with mutation heterogeneity, regardless of high or low mutation contents, presented lower EGFR copy number than those with pure mutation cases (16.7% vs 71.0%,p<0.05). Among 23 patients who received EGFR-TKIs therapy, the mean mutation content was higher in partial response (71.1%) and stable disease group (43.4%) than in progressive disease group (5.0%) (p=0.005). Conclusions: This study showed that the heterogeneity of EGFR mutation was found in introtumoral region with different degree. The response to EGFR-TKIs was correlated with EGFR mutant content.
A phase II multicenter study of aflibercept (AFL) in combination with cisplatin (C) and pemetrexed (P) in patients with previously untreated advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC).
Authors: Chen Hongbin , Modiano Manuel R. , Neal Joel W. , Brahmer Julie R. , Rigas James R. , Jotte Robert M. , Leighl Natasha B. , Liu Liming , Lisano Julie M. , Adjei Alex A. , Wakelee Heather A.
Published: March 2020

7541

Background: AFL is a recombinant human fusion protein that acts as a decoy receptor and prevents the interaction of vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor with their receptors. This study evaluated the efficacy and safety of AFL in combination with first-line chemotherapy of C and P in NSCLC. Methods: This phase II, single arm, open label, multicenter trial in patients with previously untreated, locally advanced, or metastatic NSCLC excluded patients with squamous histology, cavitating lesions, ECOG > 1, uncontrolled hypertension, or brain/CNS metastases. All patients received IV AFL 6 mg/kg, P 500 mg/m2, and C 75mg/m2, every 3 weeks for up to 6 cycles. For those who completed the combined chemotherapy, Q3W administration of AFL was to continue until disease progression, intolerable toxicity, or any other cause for withdrawal. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). Planned sample size was 72 patients. Results: The study was closed prematurely due to 3 confirmed cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 54.8% were male, 85.7% white and 50% ECOG 0. A median of 4 cycles of AFL was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. The 3 patients with RPLS were Caucasian women. Two had a history of hypertension and both experienced elevated BP and reduced CrCl. Of the 38 patients evaluable for response, ORR was 26.3% (95% CI, 12.3-40.3%) and median PFS was 5 months (95% CI, 4.3-7.1). Conclusions: The rate of RPLS observed in this study with AFL + C + P was higher than anticipated. A meta-analysis of safety from three large placebo-controlled studies reported no RPLS among 1333 patient treated with AFL + chemotherapy, and none was reported in prior combination studies of AFL + P or AFL + C + docetaxel. Though the study was stopped early, ORR and PFS were in accordance with most historical first-line NSCLC studies.
Delay of chemotherapy through use of post-progression erlotinib in patients with EGFR-mutant lung cancer.
Authors: Oxnard Geoffrey R. , Lo Peter , Jackman David Michael , Butaney Mohit , Heon Stephanie , Johnson Bruce E , Sequist Lecia V. , Janne Pasi A.
Published: March 2020

7547

Background: 1st-line tyrosine kinase inhibitor (TKI) therapy for patients (pts) with EGFR-mutant lung cancer prolongs progression free survival (PFS) and improves quality of life. When pts develop acquired resistance to TKI, chemotherapy is the only approved systemic treatment. Anecdotal evidence suggests that change of therapy can be delayed in some pts through continued TKI beyond progression (PD), but the effectiveness of this approach has not been quantified. Methods: Through an IRB-approved mechanism, pts with advanced lung cancer and EGFR sensitizing mutations treated on 3 prospective trials of 1st-line erlotinib were identified. Only pts with RECIST PD while on erlotinib were studied. Time from PD until use of an alternate systemic therapy (or death) and characteristics at PD (development of new extra-thoracic metastases or cancer-related symptoms) were assessed. Results: 42 eligible pts were identified with the following characteristics: median age 70, 86% female, 93% non-Asian, 50% never-smokers, 83% adenocarcinoma, 100% EGFR-mutant (55% exon 19, 36% exon 21, 9% exon 18). Median PFS on erlotinib was 13 months. After PD, alternate systemic therapy was delayed >3 months in 19 pts (45%; 95%CI: 31%-60%), through a combination of post-PD erlotinib (16 pts), radiation (6 pts), and/or surgery (3 pts), or on observation alone (2 pts). These 19 pts commonly had exon 19 deletions and were more likely to have no cancer-related symptoms at PD (Table), and had a median post-PD survival of 29 months. Alternate systemic therapy was delayed >12 months in 8 pts (19%). Conclusions: In a subset of pts with EGFR-mutant lung cancer and acquired resistance to TKI, chemotherapy can be delayed with the aid of post-PD TKI and local treatment modalities. This indolent PD is likely due to ongoing tumor EGFR dependence. In pts who are tolerating TKI and have asymptomatic progression, we recommend this palliative treatment strategy as an option for delaying chemotherapy and maximizing quality of life. [Table: see text]
Molecular marker analysis of SWOG S0636, a phase II trial of erlotinib and bevacizumab in never-smokers with advanced NSCLC.
Authors: Mack Philip C. , Moon James , West Howard Jack , Franklin Wilbur A. , Varella-Garcia Marileila , Wynes Murry W. , Wozniak Antoinette J. , Redman Mary Weber , Hirsch Fred R. , Gandara David R.
Published: March 2020

7552

Background: S0636 investigated the combination of erlotinib and bevacizumab in never-smoking NSCLC patients with confirmed adenocarcinoma histology (H. West ASCO 2011). Patient eligibility was not restricted by molecular selection. Median PFS and OS were encouraging at 8 and 26 months. An analysis of molecular markers was undertaken, focusing initially on the EGFR pathway. Methods: EGFR analysis included gene copy number, mutation and protein expression. Copy number was conducted by FISH using the Colorado scoring system. An immunohistochemistry H score was developed for EGFR protein expression analysis, ranging from 0 to 400. Specimens were evaluable from 42 of the 85 eligible patients. Results: FISH positivity was identified in 17/35 pts (49%), 11 with high polysomy and 6 with true gene amplification. EGFR activating mutations were seen in 10/33 pts (30%). IHC H-score >200 was observed in 17/40 pts (43%). All EGFR markers were significantly correlated with one another. In the EGFR WT subgroup, FISH-positive patients outperformed FISH-negative pts (mPFS 20 vs, 6 months, p=0.06). Conclusions: Careful analysis of EGFR markers (mutation, FISH and IHC) identified S0636 patients with favorable PFS and encouraging trends for OS. EGFR FISH and IHC provided additional predictive information beyond that of EGFR mutation status. Supported in part by DHHS: CA32102 and CA38926, and in part by Genentech. [Table: see text]
Radiographic assessment and therapeutic decisions at RECIST progression in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors.
Authors: Nishino Mizuki , Heon Stephanie , Dahlberg Suzanne Eleanor , Jackman David Michael , Ramaiya Nikhil H. , Hatabu Hiroto , Rabin Michael S. , Janne Pasi Antero , Johnson Bruce E
Published: March 2020

7553

Background: EGFR mutated advanced NSCLC treated with EGFR TKIs typically progresses after initial response due to acquired resistance. TKI therapy is often continued beyond RECIST progression (PD). We investigated the frequency of this practice and patterns of RECIST PD via imaging findings, as well as the association between patient characteristics and discontinuation of TKI among patients (pts) who progressed while on TKI. Methods: Among a cohort of 101 advanced NSCLC pts with sensitizing EGFR mutations treated with first-line erlotinib or gefitinib at DFCI, 70 pts treated between 2002 and 2010 had at least two CT scans for retrospective radiographic assessments using RECIST1.1; 56 pts had experienced PD by the data closure date of June 2011. Results: Among 56 pts experiencing PD, 46 (82%) were female, median age was 63 (range 35-79), 28 (50%) were never-smokers, 32 (57%) had distant mets, 32(57%) had exon 19 deletion, and 50 (89%) received erlotinib. 49 pts (88%) continued TKI therapy for at least 2 mos beyond retrospectively assessed PD. 31/32 (97%) pts who progressed by increase of target lesions continued TKI. 13/16 (81%) pts who progressed by new lesion remained on TKI. Two pts with PD in non-target lesions discontinued therapy at PD. 5/6 (83%) pts with both increase of target lesions and new lesion at PD continued TKI. In 49 continuing pts, the median time from RECIST PD to termination of TKI was 10.1 mos (range: 2.2-64.2 mos). 15/49 (31%) pts who continued TKI received additional chemo compared to 0/7 pts who discontinued (Fisher’s p=0.17). Pts who discontinued therapy (n=7) were significantly younger (median 48 yrs) than those who continued TKI at PD (median 64 yrs, Wilcoxon p=0.003). Median OS beyond RECIST PD among those who continued TKI was 31.8 mos (95% CI 15.9- not reached) and though underpowered, this did not appear to be impacted by TTP when adjusted in a Cox model (p=0.84). Conclusions: 88% of EFGR-mutant NSCLC pts who progressed on first-line TKI continued therapy beyond RECIST PD, which is not the single determining factor for terminating TKI in EGFR-mutant NSCLC pts. Additional progression criteria specific to this population are needed to better guide therapeutic decision making.
Elderly and younger patients with non-small cell lung cancer (NSCLC) derive similar benefit from second-line chemotherapy: A retrospective subset analysis of second-line chemotherapy trials conducted from the Hellenic Cooperative Research Group (HORG).
Authors: Agelaki Sofia , Hatzidaki Dora , Vamvakas Lampros , Pallis Athanasios G. , Karampeazis Athanasios , Agelidou Athina , Agelidou Maria , Chandrinos Vassilis , Polyzos Aristidis , Georgoulias Vassilis
Published: March 2020

7564

Background: Elderly patients (pts) achieve a similar survival benefit, with acceptable toxicity, from first-line chemotherapy for the treatment of advanced NSCLC compared with their younger counterparts. There have been no second-line trials specifically designed for elderly pts and few data exist on the efficacy and tolerability of second-line therapy in this population. Moreover, little if any information exists on the frequency of administration of second-line chemotherapy in these pts. Methods: The files of 2004 pts with advanced NSCLC enrolled into first-line chemotherapy trials performed by HORG from 1995 to 2007 were reviewed. A total of 600 pts who received second-line chemotherapy within the context of clinical trials were identified. Patients’ data were analysed for efficacy and toxicity according to age. Results: Second-line chemotherapy was administered in 24% and 34% of pts ≥65 and <65 years old after failure of prior therapy (p=0.0001). A total of 219 (24.8%) of 600 pts who received second-line treatment were ≥65 years old (median age 70 yrs, range 65-82). Response rates to second-line therapy were 11.9% for older pts compared to 12.3% for younger pts (p=ns). TTP was 2.8 and 3.1 months for older and younger pts, respectively (p=ns). Elderly pts receiving second-line chemotherapy had a median survival of 7.7 months compared with 8.2 months for younger pts (p=ns). Similar rates of haematological and non-haematological toxicities were encountered between the two groups. Conclusions: The participation of elderly pts to second-line chemotherapy trials was lower compared to younger patients. There was no significant difference in outcome or toxicity between elderly and younger pts. For elderly pts with advanced NSCLC and good performance status, second-line chemotherapy is appropriate. However, specific second-line trials in older pts are required since those included in the current analysis were probably highly selected to fit the inclusion criteria.
Rare and complex mutations of epidermal growth factor receptor (EGFR) and efficacy of tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC).
Authors: Keam Bhumsuk , Kim Dong-Wan , Park Jin Hyun , Lee Jeong-Ok , Kim Tae Min , Lee Se-Hoon , Jeon Yoon-Kyung , Chung Doo Hyun , Heo Dae Seog
Published: March 2020

7566

Background: Other than in-frame deletional mutation (MT) in exon 19 and Leu858Arg point MT in EGFR gene, there are many rare and complex MT. The purpose of this study was to investigate was to clarify the clinical significance of rare and complex MT, and the efficacy of EGFR TKI in these patients. Methods: Rare MTs were defined any MT other than deletional MT in exon 19, Leu858Arg in exon 21, and Thr790Met in exon 20. Complex MT was defined two different EGFR MTs co-occurring within the single tumor sample. We have analyzed consecutive database of NSCLC patients who were treated with either gefitinib or erlotinib at Seoul National University Hospital between Jan. 2002 and Dec. 2011. For analysis of EGFR MT, coding sequences from exon 18 to 21 were amplified by nested PCR and subjected to direct sequencing methods. Results: Among the 1,159 TKI treated patients, 301 patients had EGFR MT (177 patients (58.8%) with del-19, 104 patients (34.6%) with Leu858Arg, and 20 patients (6.6%) with rare MT). Twenty-three (7.6%) patients have complex MT, and 55 (18.3%) patients have Gln787Gln polymorphism particularly associated with Leu858Arg MT. Identified rare MT were follows; exon 18: Leu692Phe, Glu707Lys, Glu709Gly, Lys714Asn, Gly7Ala, Thr725Thr, exon 19: Ala755Asp Lys737Thr, exon 20: Val786Met, exon21: Ala871Gly, Gly873Gln, Leu833Val, Val834Leu, Arg836Cys, Pro848Leu, Ala859Thr, Leu861Gln. When categorizing 3 groups (group A: classic MT alone, group B: complex MT with classic + rare MT, group C: rare MT alone or complex MT with rare MTs), response rate (RR) to TKI was different between each groups (RR= 78.7% in group A vs. 69.2% in group B vs. 38.5% in group C, respectively, P < 0.001). Progression-free survival (PFS) was also poorer in rare MT (median PFS: 12.1 mo vs. 7.6 mo vs. 2.1 mo, respectively, P= 0.020,). Gln787Gln polymorphism of exon 21 was not associated with RR or PFS (P= 0.101, P= 146, respectively) Conclusions: In this large case series, NSCLC patients who harboring rare MT other than del-19 and Leu858Arg, does not seems response to EGFR TKI. However, complex MT with the classical MT showed similar treatment efficacy toward EGFR TKI with that of classical MT alone.
A phase II study of erlotinib followed by chemotherapy on progression in an unselected population of advanced non-small cell lung cancer (NSCLC) patients.
Authors: Horn Leora , Li Chung-I , Pao William , Keedy Vicki Leigh , Johnson David H. , Carbone David P
Published: March 2020

7568

Background: Erlotinib is now accepted as first line therapy for advanced NSCLC patients with EGFR mutated tumors. However, some patients with EGFR wild-type tumors may benefit as well, and there are no accepted biomarkers to define this subset of patients or to define which patients benefit from chemotherapy. We conducted a single arm phase II trial of erlotinib followed by chemotherapy on progression (carboplatin + paclitaxel +/- bevacizumab) in treatment naïve patients with stage IV NSCLC. Methods: In this multicenter prospective phase II trial, patients with stage IV NSCLC were eligible for enrollment. Blood, frozen tissue and FFPE biopsies for molecular analysis were mandatory at the time of study entry and optional at the time of progression on erlotinib. Additional eligibility included ECOG performance status (PS) 0-2, measurable disease, and adequate marrow, renal and hepatic function. Patients with stable treated brain metastases were allowed. Patients were treated with erlotinib 150 mg daily until disease progression at which time they underwent a biopsy and were switched to carboplatin/paclitaxel +/- bevacizumab. Disease status was assessed after 4 weeks of erlotinib to detect early progression. Results: From 10/07 to 06/11, 127 patients were enrolled: 59% male, 90% Caucasian, 6% African American, 4% Asian, 30% never smokers. 7 patients failed screening. Among evaluable patients on erlotinib, 13% had PR, 48% SD, and 27% PD. Median PFS on erlotinib was 4.7 months (95% CI 3.5 to 8.3 months). In patients who went on to receive chemotherapy on protocol, 24% had PR, 27% SD, and 20% PD. In patients who went on to receive chemotherapy on protocol median progression-free survival (PFS) on chemotherapy was 8.1 months (95% CI 5.5 to 10.9 months). Among the 55 patients who did not receive chemotherapy, 23 had a decline in PS, 14 patients refused, 2 patients enrolled on another protocol, and 6 patients had other therapy. Conclusions: This is the first study to report on PFS in unselected NSCLC patients following first line therapy with erlotinib. Translational studies on this large prospectively collected cohort of tissue samples prior to initiation of erlotinib are ongoing.