bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC).
Authors: Kim Dong-Wan , Ahn Myung-Ju , Shi Yuankai , De Pas Tommaso Martino , Yang Pan-Chyr , Riely Gregory J. , Crinò Lucio , Evans Tracey L. , Liu Xiaoqing , Han Ji-Youn , Salgia Ravi , Moro-Sibilot Denis , Ou Sai-Hong Ignatius , Gettinger Scott N. , Wu Yi Long , Lanzalone Silvana , Polli Anna , Iyer Shrividya , Shaw Alice Tsang 
Published: March 2020

7533 Background: Approximately 3–5% of NSCLC harbors ALK gene rearrangements. Crizotinib is a first-in-class, oral, small-molecule competitive ALK inhibitor with anti-MET activity. Methods: PROFILE 1005 is an ongoing global, multicenter, open-label, single-arm, phase II study evaluating the safety and efficacy of crizotinib (250 mg BID in 3-week cycles) in patients with advanced ALK-positive NSCLC who progressed after ≥1 chemotherapy for recurrent/advanced/metastatic disease. Tumor response was evaluated by RECIST 1.1 every 6 weeks. Patient-reported symptoms and global quality of life (QOL) were assessed using the EORTC QLQ-C30 and LC-13 at baseline, day 1 each cycle and at end of treatment. Results: As of June 2011, 439 patients were evaluable for safety and 255 patients for tumor response. Median age was 53 years. The majority of patients were female (53%), never smokers (65%), and had adenocarcinoma (92%), ECOG PS 0–1 (83%) and ≥2 prior chemotherapy regimens (85%). Among patients evaluable for efficacy, median treatment duration was 25 weeks (77% of patients still ongoing). ORR was 53% (95% CI: 47–60), disease control rate at 12 weeks was 85% (95% CI: 80–89), median duration of response was 43 weeks (96% CI 36–50) and median PFS was 8.5 months (95% CI: 6.2–9.9). The most frequent treatment-related AEs were visual effects (50%), nausea (46%), vomiting (39%), and diarrhea (35%), mostly grade 1–2. 29 patients (6.6%) had treatment-related SAEs, including dyspnea and pneumonitis (4 patients each; 0.9%), and febrile neutropenia and renal cyst (2 patients each; 0.5%). A statistically significant (p<0.05) and clinically meaningful (≥ 10 points) improvement from baseline was observed for patient-reported overall pain, pain in chest, cough, dyspnea, insomnia, fatigue and global QOL. Conclusions: Crizotinib demonstrated a high response rate and PFS, favorable tolerability profile and improvement in patient-reported symptoms. These results provide strong evidence for crizotinib as a standard of care for advanced ALK-positive NSCLC.
A novel targeted oral insulin-like growth factor-1 receptor (IGF-1R) inhibitor and its implications for patients with non-small cell lung cancer (NSCLC): A phase I clinical trial.
Authors: Ekman Simon , Harmenberg Johan , Frödin Jan-Erik , Bergström Stefan , Wassberg Cecilia , Eksborg Staffan , Larsson Olle , Axelson Magnus , Hedlund Åsa , Alvfors Carina , Ståhl Birgitta , Bergqvist Michael 
Published: March 2020

7539 Background: The small-molecule IGF-1R inhibitor picropodophyllin (PPP) is the active compound in the oral suspension AXL1717. PPP has shown extensive preclinical antitumor effects against a wide range of cancers supporting its use as a single agent treatment. Methods: The clinical phase Ia/b study on advanced progressive cancer patients with various solid tumors and without remaining treatment options aimed at establishing the recommended phase II dose (RPTD) and the maximum tolerated dose (MTD) of AXL1717. Phase Ia consisted of single day dosing and phase Ib multiday dosing (to an accumulated total of 28 days of treatment; 2*28 days following amendment) with 3 weeks intermission between treatments. Non-progressing patients could continue treatment in the extension study without time limitation (treated 119 weeks). PK samples were obtained at 10 different time-points after the morning dose when appropriate. Results: Phase Ia included 16 patients treated with 78 BID doses ranging from 5-2900 mg AXL1717 BID without any dose-limiting toxicity. Phase Ib included 39 patients treated with doses between 290-930 mg BID in periods between 7-28 days, totally for 147 weeks. Phase Ib showed that AXL1717 was well tolerated and neutropenia was the only detected dose-related, reversible, dose-limiting toxicity (DLT). RPTD dose was set at 390 mg BID to minimize neutropenia. Although the study was not designed for efficacy assessment, some patients, mainly with NSCLC, showed signs of clinical benefit, including 3 partial responses and 12 patients with stable disease. The 15 patients with NSCLC and treatment duration of more than 2 weeks with single agent AXL1717 in 3rd or 4th line showed a median time to progression of 31 weeks and a survival time of 60 weeks with 4 patients being alive at cut-off. Down-regulation of IGF-1R on granulocytes and increases of serum IGF-1 were seen. The systemic exposure of AXL1717 was dose-dependent and sufficient for antitumor effects. Conclusions: AXL1717 has a good safety profile and demonstrated promising clinical benefits in this severely ill and heavily pretreated patient cohort, especially in patients with NSCLC.
Skin toxicity associated with outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations in the EURTAC study.
Authors: Buges Cristina , Martinez Marti Alex , Rosell Rafael , Vergnenegre Alain , De Marinis Filippo , Massuti Bartomeu , De Castro Javier , Gervais Radj , Carcereny Costa Enric , Moran Teresa , Santarpia Mariacarmela , Felip Enriqueta , Majem Margarita , Porta Rut , Palmero Ramon , Drozdowskyj Ana , Heidecke Cordula , Gasco Amaya , Taron Miquel , Paz-Ares Luis G. 
Published: March 2020

7542 Background: Rash is reported in 75% of p treated with erlotinib and has been associated with improved overall and progression-free survival (PFS) in unselected p although not specifically in p with EGFR mutations. Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Overall PFS was 9.7 months (m) vs 5.2 m, respectively (P<0.0001). Rash was defined according to NCI CTC v3.0 and dichotomized by grades 0-1 vs 2+. Grade 2 is macular or popular eruption or erythema with pruritus or other associated symptoms, localized desquamation or other lesions covering <50% of body surface area. We examined outcome in the erlotinib arm according to rash grade. Results: 16 p in the erlotinib arm had no rash (grade 0), 30 had grade 1, and 40 had grade 2+. 80% of cases of rash grade 2+ occurred in p with exon 19 deletions, while only 20% were in p with L858R mutations (P=0.039). There were no differences in rash grade according to sex, age or smoking status. PFS was 11.2 m in p with rash grade 2+ and 8.4 m in p with grade 0-1 (HR, 0.52; P=0.018). There was no correlation between rash grade 0-1 vs 2+ and response or overall survival (OS). Interestingly, when p were divided into those with no rash (16 p) and those with grade 2+ (40 p), PFS was 11.2 m for p with grade 2+ vs 2.7 m for p with no rash (P=0.031), and OS was 24.9 m for p with grade 2+ vs 16.1 m for p with no rash (P=0.033). Conclusions: Although the biological reasons for the association of skin rash with better outcome to erlotinib have not been elucidated, this sub-analysis of the EURTAC trial has enabled us to confirm for the first time that skin rash – especially grade 2+ - can predict better outcome to erlotinib in p with EGFR mutations. In addition, the correlation between rash and type of EGFR mutation warrants further investigation.
A phase II, multicenter, placebo-controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens.
Authors: Zhang Li , SHI Meiqi , Huang Cheng , Liu Xiaoqing , Xiong Jian ping , Chen Gongyan , Liu Wei , Liu Wenchao , Zhang Yiping , LI Kai , Yu Hao , Jiang Haoyuan 
Published: March 2020

7548 Background: Apatinib is an oral, small molecular tyrosine-kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR). Phase II study has showed that apatinib significantly improved the outcome of patients with advanced or metastatic gastric cancer (Li J, et al. ASCO 2011). The primary object of this study is to determine whether apatinib can improve progression free survival (PFS) compared with placebo in patients with advanced non-squamous NSCLC who failed two lines of treatment. Methods: This study recruited histologically diagnosed advanced non-squamous NSCLC patients who failed more than two lines of treatment including EGFR TKIs. Other eligible criteria included ECOG ≤1, adequate organ function and no prior exposure to VEGFR-TKI. The patients were randomized to receive apatinib at a dose of 750 mg or placebo (at allocation ratio of 2:1) orally once daily until the disease progression or unacceptable toxicity. Results: 135 patients (90 in apatinib arm, 45 in placebo arm) were included at 20 centers in China until Aug 2011. Median PFS was 4.7 months for apatinib group versus 1.9 months for placebo group, hazard ratio (HR) was 0.278 (95% CI 0.170, 0.455) (p<0.0001). The response rate (RR) and disease control rate (DCR) were also significantly better in study arm (12.2% and 68.9%) than in placebo arm (0% and 24.4%)(P=0.0158 and P<0.0001). The most frequently observed AEs were hypertension, proteinuria, and hand-foot syndrome (HFS). These AEs were generally mild or moderate in severity and were manageable. Conclusions: This randomized phase II trial shows that apatinib has substantial clinical activity without significant additional toxicity in patients with advanced non-squamous and non-small cell lung cancer. Continued investigation of apatinib is warranted in future clinical studies.
Phase II study of pemetrexed (Pem) and cisplatin (Cis) plus cetuximab (Cet) followed by Pem and Cet maintenance therapy in patients (Pts) with advanced nonsquamous non-small cell lung cancer (NSCLC).
Authors: Schmid-Bindert Gerald , Gebbia Vittorio , Mayer Frank , Arriola Edurne , Marquez-Medina Diego , Syrigos Konstantinos N. , Biesma Bonne , Leschinger Monika Iris , Visseren Grul Carla M. , Frimodt-Moller Bente , Ripoche Veronique , Myrand Scott , Nguyen Tuan , Zimmermann Annamaria , Schuette Wolfgang 
Published: March 2020

7554 Background: A prospective, nonrandomized, multicenter study was conducted to assess the effect of adding cet to pem and cis in pts with advanced nonsquamous NSCLC. Methods: 113 Caucasian performance status 0-1 pts received 1st line pem (500 mg/m2) and cis (75 mg/m2) on day 1 (21d cycle) for 4-6 cycles and cet (400 mg/m2 loading dose followed by 250 mg/m2) weekly. Non-progressive pts received pem 500 mg/m2 on day 1 (21d cycle) plus cet (250mg/m2 weekly) until progression. Pts received vitamin B12/folic acid and dexamethasone. Primary endpoint was objective response rate (ORR) (RECIST 1.0). Secondary endpoints were progression free survival (PFS), 1 year survival rate, translational research (TR) and safety. Results: Pts’ characteristics: median age 59.7 years, 64% male, 50% PS 0, 92% stage IV, and 78% adenocarcinoma. All pts completed ≥ 1 cycle of induction therapy and 45% and 43% completed ≥ 1 cycle of maintenance with pem and cet, respectively. ORR (n=109) was 38.5% (80% CI 32.2-45.1), all partial responses. Disease control rate (response/stable disease) was 59.6% (80% CI: 53.1-65.9). Median PFS was 5.82 months (80% CI: 4.40-6.70). One year survival rate was 0.45 (80% CI: 0.39-0.51). Significant associations were seen between high EGFR by IHC and increased PFS (cytoplasm: HR=0.46, p=0.035; membrane: HR=0.41, p=0.008), and between high nuclear TTF-1 and increased ORR (OR=7.73, p=0.021) / PFS (HR=0.21, p<0.001) / OS (HR=0.25, p=0.035). Of 113 pts evaluated for safety, 73 (64.6%) pts had drug related CTC Grade 3/4 adverse events (AE): most frequent were neutropenia (14.2%), rash (15%), and vomiting (8.8%). Drug related serious AEs were reported in 27.4% pts: most frequent were anemia (5.3%), neutropenia (5.3%), vomiting (3.5%), and rash, renal failure, diarrhea and fatigue (1.8% each). There were 2 potential on-study drug related deaths (sudden death and large intestinal perforation). Conclusions: Pem, cis and cet appeared efficacious and tolerable. These results support further evaluation in a randomized trial. The TR outcomes are hypothesis generating given the study’s size and nonrandomized nature.
Interim analysis of afatinib monotherapy in patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy following progression on afatinib monotherapy.
Authors: Schuler Martin H. , Planchard David , Yang James Chih-Hsin , Kim Joo-Hang , De Marinis Filippo , Chen Yuh-Min , Zhou Caicun , Bennouna Jaafar , Liu Xiaoqing , Feng Ji Feng , Bidoli Paolo , Strausz Janos , Ou Sai-Hong Ignatius , Chand Vikram K. , Wang Bushi , Munzert Gerd Michael , Park Keunchil 
Published: March 2020

7557 Background: The benefit of sustained ErbB family blockade in NSCLC patients with acquired resistance (AR) to EGFR TKIs is unknown. We investigated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC, who had failed chemotherapy and E/G. Methods: This was a Phase III, randomized, open-label, multi-center trial. Patients with pathologically confirmed Stage IIIB/IV metastatic NSCLC after ≥1 line of chemotherapy who failed E/G received oral afatinib 50 mg until disease progression (Part A). After progression, patients with clinical benefit (≥12 wks) were eligible to continue afatinib 40 mg plus paclitaxel or receive investigator’s choice chemotherapy (Part B). Primary endpoint for Part A was PFS (RECIST 1.1; CT scan every 6 wks). Available tumor samples were collected for central EGFR mutation testing; local mutation data were also collected. An interim analysis of Part A, assessing afatinib monotherapy, is reported. Results: Part A enrolled April 2010 through to May 2011; 1154 patients received afatinib monotherapy. The majority had adenocarcinoma (85%), 57% were female, 43% were Asian, 54% were never smokers. Best response to prior E/G was CR (2%), PR (31%), SD (42%) and PD (20%). Median PFS for afatinib was 3.3 mths; 88 patients (8%) achieved an objective tumor response, 648 (56%) had SD. For EGFR mutation positive patients (n=49, centrally confirmed), PFS was 4.2 vs. 2.6 mths for EGFR mutation negative patients (n=35). When applying clinical enrichment criteria for AR, PFS was 4.2 mths for those with enrichment (n=597) vs. 2.8 mths for those without (n= 557; logrank test p<0.0001). The most common grade 3/4 adverse events were diarrhea (17%) and rash/acne (11%). In Part A, 99 patients remain on treatment. Conclusions: Afatinib monotherapy provided a clinically meaningful benefit in this large, treatment-refractory NSCLC trial, similar to LUX-Lung 1. Those clinically enriched for AR to EGFR TKIs achieved prolonged disease control upon continued ErbB blockade.
First-line gefitinib for elderly patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations: A combined analysis of NEJ studies.
Authors: Narumi Sodai , Inoue Akira , Morikawa Naoto , Minegishi Yuji , Maemondo Makoto , Okinaga Shoji , Kobayashi Kunihiko , Harada Toshiyuki , Hagiwara Koichi , Nukiwa Toshihiro , Gemma Akihiko 
Published: March 2020

7563 Background: The first-line treatment with gefitinib has been established as a standard of care for advanced NSCLC patients with EGFR mutation by previous studies including NEJ002. Since the percentage of elderly population in those studies was lower than that of real situation, further validation of its usefulness for elderly patients with EGFR-mutated NSCLC is warranted. Methods: The efficacy and safety data of fit elderly patients (70 years or older with PS 0-2) with EGFR-mutated NSCLC who received the first-line gefitinib in NEJ001 (phase 2), NEJ002 (phase 3), and NEJ003 (phase 2) were combined. Same population treated with the first-line carboplatin plus paclitaxel in NEJ002 (n=34) were also examined their efficacy and safety for reference. Regarding the toxicity and quality of life (QOL), the comparison between elderly patients and younger patients (< 70 years old) both treated with first-line gefitinib in NEJ002 was also performed. Results: Data from 71 patients (7 from NEJ001, 33 from NEJ002, 31 from NEJ003) treated with first-line gefitinib were combined. Patients’ characteristics were as follows; mean age: 76.8 years (range 70-89), female: 73%, never smoker: 75%, PS 0-1: 92%. Overall response rate (73.2%) and median progression-free survival (14.3 months) in this group were significantly better than those in the reference group (26.5% and 5.7 months, respectively). Despite fewer patients received second-line chemotherapy in the first-line gefitinib group, its median overall survival (30.8 months) was not inferior to that of reference group (26.4 months). Regarding toxicities such as liver dysfunction, rash, diarrhea, and pneumonitis, and QOL examined by self questionnaires, there were no difference between the elderly patients and younger patients in NEJ002. Conclusions: First-line gefitinib still achieved high efficacy with acceptable toxicity in fit elderly patients with advanced NSCLC harboring EGFR mutation. Considering that elderly patients tend to receive fewer treatment lines compared with younger patients, first-line gefitinib would be strongly recommended for this population to avoid the risk of missing its administration.
Efficacy of pemetrexed as second-line therapy in advanced NSCLC after either treatment-free interval or maintenance therapy with gemcitabine or erlotinib in IFCT-GFPC 05-02 phase III study.
Authors: Bylicki Olivier , Ferlay Celine , Chouaid Christos , Lavolle Armelle , Barlesi Fabrice , Gervais Radj , Westeel Virginie , Crequit Jacky , Corre Romain , Vergnenegre Alain , Zalcman Gerard , Monnet Isabelle , Le Caer Herve , Fournel Pierre , Linard Pauline , Perol David , Perol Maurice 
Published: March 2020

7574 Background: Continuous exposure of tumor cells to maintenance therapy in advanced NSCLC might lead to resistance to subsequent treatments. IFCT–GFPC 0502 study showed a progression-free survival (PFS) benefit with gemcitabine (G) or erlotinib (E) maintenance compared to observation (O) after cisplatin-G induction chemotherapy. The trial included a pre-defined second-line therapy with pemetrexed (P), allowing post-hoc assessment of its efficacy according to previous maintenance treatment or treatment-free interval. Methods: Stage IIIB/IV NSCLC patients (pts) with a PS of 0-1 were randomized after 4 cycles of cisplatin-G chemotherapy to O or to receive maintenance therapy with G or E until disease progression. P was given as second-line treatment on disease progression in all arms. PFS and OS were assessed from the beginning of P therapy according to randomization arm. Tumor response to P and tolerance were also analyzed. Results: Of the 464 pts randomized to either O (155), G (154) or E (155), 360 pts (78 %) received P as second-line therapy, i.e. 130 (84%), 114 (74%) and 116 (75%) in O, G and E arm, respectively. Baseline characteristics remained well balanced between arms (overall median age of 58 years, 28% female, 91% stage IV, 41% PS 0, 65/19/16%, adenocarcinoma/squamous/other, 10% non-smokers and 56% responders to induction CT). Median number of delivered P cycles was 3 (1-40) in all arms. Response rate was 19%, 7% and 15% for non-squamous pts in O, G and E, respectively. Median PFS did not significantly differ between G and O (4.2 vs 3.9 months, HR [95% CI] 0.81 [0.62-1.06]) or E and O (4.2 vs 3.9 months, HR 0.83 [0.64-1.09]). OS data showed a non-significant improvement with G vs O (HR 0.81 [0.61-1.07]) or E vs O (HR 0.80 [0.61-1.05]), with a median of 7.5, 8.3 and 9.1 months for O, G and E, respectively. Results were similar when analysis was restricted to non-squamous pts. Grade 3-4 treatment-related AEs were similar in O (33.1%), G (31.6%) and E (25%). Conclusions: Maintenance therapy with continuation of G or switch to E does not impair the efficacy of second-line P by comparison with administration after a treatment-free interval.
Family history of lung cancer in never smokers with non-small cell lung cancer (NSCLC) and its association with tumors harboring epidermal growth factor receptor (EGFR) mutations.
Authors: Gaughan Elizabeth Mary , Cryer Sarah K , Yeap Beow Yong , Jackman David Michael , Costa Daniel Botelho 
Published: March 2020

7579 Background: Inherited susceptibility to lung cancer is an understudied subject, however it has been described among never smokers (<100 cigarettes/lifetime). Never smokers with NSCLC comprise an important subgroup of patients enriched for tumors harboring oncogene aberrations in the EGFR and ALK genes. We aimed to better characterize the incidence of family history of lung cancer in the setting of routine tumor genotyping among never smokers with NSCLC. Methods: Clinicopathologic data plus tumor genotype (EGFR, KRAS, ALK) from 230 consecutive never smokers seen at Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute was compiled. We retrospectively analyzed the incidence of a family history of any cancer and lung cancer in these patients. Results: In our cohort, the average age was 56 years, 67% of the patients were women, 75% were white, 41% had advanced NSCLC and 87% had adenocarcinoma histology. In these tumors, 98/230 (43%) had an EGFR mutation, 16/155 (10%) had KRAS mutations and 27/127 (17%) had an ALK translocation. Family history of any cancer was common (57%) and specific family history of lung cancer was present in 42/230 cases (18%). Out of thecases with a family history of any cancer, 22/53 (41.5%) EGFR-mutated, 1/6 (17%) KRAS-mutated and 3/20 (15%) ALK-translocated cohorts had a family history of lung cancer. The rate of family history of lung cancer to family history of cancer was significantly higher in the EGFR-mutated cohort when compared to the ALK translocated plus KRAS-mutated cohorts (p=0.023). Conclusions: Family history of lung cancer is common in never smokers with NSCLC, and there seems to be a particular link in families in which the proband has an EGFR-mutated tumor. Further study of families with EGFR-mutated NSCLC may yield insights into the pathogenesis of this tumor type.