bluuebunny/crossref_metadata_2025_split huggingface dataset:
Difference in incidence and pattern of salvage treatment after failure to first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and standard cytotoxic chemotherapy in pts with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations: Okayama Lung Cancer Study Group experience.
Authors: Kato Yuka , Ichihara Eiki , Hotta Katsuyuki , Hisamoto Akiko , Takigawa Nagio , Nogami Naoyuki , Kozuki Toshiyuki , Kudo Kenichiro , Tabata Masahiro , Shinkai Tetsu , Tanimoto Mitsune , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: March 2020

7576 Background: EGFR-TKI (E) therapy yielded a better PFS than standard cytotoxic chemotherapy (C) therapy and a comparable OS in untreated pts with EGFR-mt tumors, suggesting each of the treatments is now crucial for such subpopulation. But, it has not been fully evaluated yet which of each should be initiated first, and to what degree both of two are actually administered in early line setting in the treatment course. We here investigated a potential difference in incidence and pattern of delivery of subsequent crossover therapy after failure to each of the treatments in pts with EGFR-mt tumors. Methods: Consecutive 79 pts with advanced EGFR-mt NSCLC were retrospectively assessed who underwent E therapy (n = 39) or standard C therapy (n = 40) in the 1st-line setting between 2007 and 2011. Results: In E group 16 (41%) of 39 pts were still on 1st-line E therapy. Nine (39%) of the remaining 23 could not receive standard C therapy after failure to E therapy due to symptomatic CNS metastasis(mets) in 6, skeletal events in 2, and patient refusal in 1, whilst in C group only one (3%) of 40 failed to receive subsequent E therapy because of relapse (carcinomatous lymphangitis) (χ2-test; p < .001). Also, at the time of relapse to the 1-st line therapy, PS deteriorated more frequently in E group (8/23 vs. 7/40; p = .042) and, relapse with symptomatic CNS mets seemed frequently observed in E group (6/23 vs. 4/40; p = .093). Multivariate analysis revealed type of regimens undergone in the 1st-line setting (E vs. C) correlated with failure of administration of subsequent crossover therapy (odd ratio: 3.224, 95%CI: .1.032 – 5,417, p = .004). Conclusions: It seems that pts with EGFR-mt tumors who were treated with 1st-line C had better opportunity to receive post-progression E therapy than those treated with 1st-line E had chance to receive subsequent C therapy, possibly due to difference in PS deterioration rate and relapse pattern.
KIF5B-RET: Discovery of a novel fusion oncogene in lung adenocarcinomas by a systematic screen for tyrosine kinase fusions and identification of patients for a RET targeted therapy trial.
Authors: Suehara Yoshiyuki , Arcila Maria E. , Drilon Alexander Edward Dela Cruz , Ito Tatsuo , Wang Lu , Hasanovic Adnan , Khanin Raya , Rizvi Naiyer A. , Ladanyi Marc 
Published: March 2020

7578 Background: The mutually exclusive pattern of major targetable driver oncogenes in lung adenocarcinomas (ADC) suggests that other similar driver oncogenes may exist. We therefore performed a systematic screen for tyrosine kinase (TK) fusions in cases without known driver oncogenes by measuring aberrantly high RNA expression of kinase domain (KD) exons relative to more 5’ exons. Methods: We studied 74 patients whose lung ADC lacked mutations in KRAS, EGFR, BRAF, HER2, and ALK fusions. A NanoString-based assay was designed to query the transcripts of 90 TKs at two points: 5’ to the KD and within or 3’ to the KD. Tumor RNAs were hybridized to the NanoString probes and analyzed for outlier 3’ to 5’ expression ratios. The assay was validated on samples with known ALK and ROS fusions. Presumed novel fusion events were followed up by rapid amplification of cDNA ends (RACE) and confirmatory RT-PCR. Results: The NanoString assay identified aberrant 5’ to 3’ ratios in ROS and RET in 2 cases, respectively, out of 74. RACE analysis isolated a novel GOPC-ROS fusion in the former and a novel KIF5B-RET fusion in the latter, both confirmed by RT-PCR. Further screening by RT-PCR for KIF5B-RET identified one more positive sample in the study set that had not been detected by NanoString. At the RNA level, both fusions joined exon 15 of KIF5B to exon 12 of RET, thus retaining a portion of the dimerization domain of KIF5B and the entire KD of RET, analogous to RET fusions in papillary thyroid carcinoma (TC). One KIF5B-RET patient was a 60 y.o. female never smoker, the other, a 73 y.o. male former smoker. Conclusions: The novel KIF5B-RET fusion described here and also recently reported by Ju YS et al. (Genome Res, Dec 22, 2011) defines a new subset of lung ADC with a potentially targetable driver oncogene. Based on these genetic data and the preclinical activity of the RET inhibitor XL184 (Exelixis) in papillary TC and its known activity in medullary TC with RET mutations, we have initiated prospective testing for KIF5B-RET as part of our lung ADC screening panel in anticipation of a planned phase 2 trial with XL184 in patients with KIF5B-RET or related variant RET fusions.
Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI).
Authors: Gian Victor , Rubin Mark S. , Shipley Dianna , Burris Howard A. , Kaplan Joseph , Kosloff Rebecca A. , Shih Kent C. , Smith Frederick P. , Quinn Raven , Greco Frank A. , Hainsworth John D. , Spigel David R. 
Published: March 2020

7587 Background: Erlotinib is an oral epidermal growth factor receptor kinase inhibitor used in the treatment of advanced non-small-cell lung cancer (NSCLC). Resistance develops in patients (pts) who initially respond to erlotinib leading to progressive disease (PD). Sorafenib is an oral inhibitor of vascular endothelial and platelet-derived growth factor receptors and Raf kinases which play important roles in PD. This randomized phase II study evaluated the role of sorafenib and continued erlotinib or sorafenib alone in pts with progressive NSCLC following initial benefit with erlotinib. Methods: Eligible pts had IIIB/IV NSCLC, an ECOG PS 0-2, and had received ≤2 lines of therapy with the last being single-agent erlotinib. Pts must have PD following clinical benefit (complete/partial response/stable disease) from erlotinib for >8 weeks. Pts were randomized 1:1 to continue erlotinib at the dose administered at the time of PD with the addition of sorafenib 400 mg orally twice daily (Arm A) or to sorafenib alone (Arm B). Cycles were 28 days with restaging every 2 cycles. The primary endpoint was progression-free survival (PFS). Results: 52 pts were enrolled from 2/2008 to 3/2011 (A 24; B 28). Baseline characteristics were balanced between arms and included: median age 65 years (41-87); 65% female; 69% adenocarcinoma/large cell; and 96% PS <2. 41% of pts were either never smokers or smoked <100 cigarettes/lifetime. Pts received a median of 8 weeks of treatment per arm (0.6–67 weeks). The median PFS was 3.1 (95% CI 1.7-3.7) and 2.3 (1.7-3.6) months for A and B, respectively (p=.84). There were no grade 3/4 hematologic toxicities in either arm except grade 3 anemia in 1 pt (A). Severe nonhematologic toxicities in >5% included: fatigue 17%(A)/7%(B); diarrhea 17%/0; dehydration 13%/7%; hand-foot skin reaction 8%/8%, and anorexia 4%/7%. Conclusions: Sorafenib has modest activity when used in combination with erlotinib or as a single agent in pts with PD following benefit with erlotinib alone. Additional study to identify potential subsets of refractory pts who might derive the greatest benefit from sorafenib are warranted.
Survival outcome segregated by KRAS mutation status in newly diagnosed stage IV non-small cell lung cancer (NSCLC) patients (pts) treated with first-line chemotherapy.
Authors: Brady Anna K. , McNeill Jonathan D , Judy Brendan , Evans Tracey L. , Cohen Roger B. , Langer Corey J. , Vachani Anil , Aggarwal Charu 
Published: March 2020

7595 Background: KRAS mutations (MT) form a distinct subset of NSCLC, generally considered to have poor prognosis. Although KRAS MT is a well-establised prognostic and predictive marker in colorectal cancer, its role in NSCLC remains ambiguous. Pts with KRAS MT NSCLC do not respond well to epidermal growth factor receptor (EGFR) directed tyrosine kinase inhibitor therapy, but little is known about the ability of KRAS MT to predict outcome after first-line chemotherapy in newly diagnosed advanced or recurrent NSCLC. Methods: We analyzed outcomes of consecutive pts with newly identified Stage IV non- squamous NSCLC treated at University of Pennsylvania (Penn) between 05/2008 and 7/2010 and then compared survival based on KRAS status [MT vs wild type (WT)] using chi square, Kaplan-Meier methods, and Cox regression models. Results: Of 106 consecutive new pts with Stage IV non squamous NSCLC treated at Penn, 49 (46%) underwent molecular analysis for KRAS MT. Fifteen (34%) were KRAS MT. Of 34 KRAS WT pts, 6 were positive for EGFR MT. The median age of all 49 pts was 61 years; 83% were Caucasian, 45% male and 60% had a >10 pack year smoking history. Median duration of follow up is 16.4 mos. Majority of pts (92%) had adenocarcinoma histology. Most pts (88%) had ECOG PS 0-1 at presentation. Forty three pts received first line platinum-based combination chemotherapy (platinum and pemetrexed in 31 pts). KRAS MT was associated with smoking (p=0.04), but not with gender or age. Overall survival (OS) of pts with KRAS MT was similar to KRAS WT pts [median OS 15.6 vs. 19.0 mos; HR 1.24 (95% CI 0.57-2.67)]. Univariate analyses demonstrated superior OS among women compared to men (HR 0.40, 95% CI 0.20-0.85) in the entire pt cohort. Conclusions: In our population of stage IV non squamous NSCLC, pts with KRAS MT had similar OS to those with KRAS WT tumors. OS was slightly higher in KRAS WT pts, but this may have been confounded by the inclusion of 6 EGFR MT pts in this cohort. The potential prognostic or predictive role of KRAS MT in NSCLC pts undergoing chemotherapy requires further prospective study.
A large retrospective analysis of the activity of pemetrexed (PEM) in patients (pts) with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) prior to crizotinib (CRIZ).
Authors: Scagliotti Giorgio , Kim Dong-Wan , Shaw Alice Tsang , Ou Sai-Hong Ignatius , Riely Gregory J. , Gettinger Scott N. , Besse Benjamin , Thomas Michael , Salgia Ravi , Wilner Keith D. , Bartlett Cynthia Huang , Polli Anna , Gandara David R. 
Published: March 2020

7599 Background: Retrospective small cohort studies suggest ALK+ NSCLC may be particularly sensitive to PEM. Methods: PROFILE 1005 (NCT00932451; Pfizer) is a large phase 2 multi-center, single-arm study of CRIZ in previously treated ALK+ NSCLC. Eligibility criteria included pts with progressive disease from the PEM arm of companion trial PROFILE 1007. We retrospectively assessed objective response rate (ORR) and time to progression (TTP; 1st dose to objective progression) in pts who received PEM prior to CRIZ. ORR with CRIZ post-PEM was assessed. Results: Of the 439 ALK+ pts enrolled as of June 2011, 369 (84.1%) received prior PEM (single agent or combination; any line advanced/metastatic) with a cumulative ORR of 18.7%. In pts who received PEM combinations 1st-line (1L; n=120) or 2nd-line (2L; n=60), ORR was 24.2% and 16.7%; and median TTP was 6.9 months (mo; 95% CI: 6.0–7.4) and 6.9 mo (95% CI: 4.8–8.8), respectively. In pts who received 2L single-agent PEM (n=80), ORR was 12.5% and median TTP was 5.3 mo (95% CI: 3.0–6.6). In pts treated with PEM 3rd-line (3L) or later (n=138), ORR was 16.7%. By line of PEM treatment, ORR was lower and TTP shorter than that reported in small ALK+ cohorts evaluating multiple lines of treatment. In 2L, previously reported ORR and median PFS with single-agent PEM in adenocarcinoma NSCLC were 12.8% (n=158) and 3.5 mo (n=283), and comparable to our findings. Pts who received 2L single-agent PEM (n=80) subsequently achieved higher ORR with CRIZ (54%; 95% CI: 42–65). Similar analyses in the 1L and 3L groups are ongoing. Conclusions: This retrospective study in predominantly never-smokers with ALK+ NSCLC reports lower ORR and shorter TTP with PEM than that reported in smaller retrospective ALK+ NSCLC cohorts. This finding may be in part due to the inclusion of crossover pts from PROFILE 1007. This analysis and previous reports observed a tendency to a higher response rate and better PFS or TTP with PEM than in unselected populations in 2L, which may not be specifically related to ALK status but to a higher sensitivity to cytotoxic agents in never-smokers. Results from an ongoing phase 3 trial (PROFILE 1007) will provide additional information.
CALGB 50401: A randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma.
Authors: Leonard John , Jung Sin-Ho , Johnson Jeffrey L. , Bartlett Nancy , Blum Kristie A. , Cheson Bruce D. ,   Alliance for Clinical Trials in Oncology
Published: March 2020

8000 Background: Lenalidomide (L) and rituximab (R) are active as single agents in follicular (FL) and other B-cell lymphomas, although combination strategies have not been previously assessed in a randomized fashion. Methods: CALGB 50401 is a randomized phase II study, initially designed to evaluate 3 regimens: R alone (375 mg/m2 weekly x 4), L alone (15 mg cycle 1, then escalated to 20 mg cycles 2-12, administered days 1-21 q 28 days x 12 cycles) or the combination of L+ R (other 2 arms combined). The R alone arm was discontinued due to slow accrual with 3 enrolled subjects. Eligibility included recurrent FL, prior therapy with rituximab alone or in combination, and TTP of ≥ 6 months from last rituximab dose. Prophylactic ASA or LMW heparin was recommended for patients at high risk for thrombosis. Results: Of 94 pts registered to L or LR, 89 (45 L and 44 LR) received at least one dose and had adequate data for analysis. Baseline characteristics include median age 63 (range 34-85) and 60% with intermediate- or high-risk FLIPI. Grade 3-4 adverse events (AE) were most commonly neutropenia (16% L,19% LR), fatigue (9% L, 14% LR) and thrombosis (16% - 7 pts L, 4% - 2 pts LR, p=0.158), and overall were seen in 49% (L) and 52% (LR) with 9% grade 4 in each arm. The full regimen was completed in 33% (L) and 59% (LR) of patients, with the difference due to more progressions or non-responders in the L group. In both arms about 19% of subjects discontinued therapy early due to AEs and dose intensity was over 80%. Objective response rates are L - 49% (13% CR) and LR - 75% (32% CR). With a median follow-up of 1.5 years (range 0.1- 3.6 years), median EFS is 1.2 years (L) and 2.0 years (LR), p=0.0063, log-rank test. Conclusions: Lenalidomide + rituximab is more active than lenalidomide alone in patients with recurrent FL with similar toxicity. A trend toward lower thrombosis risk with LR may relate to greater anti-tumor efficacy. The LR regimen warrants further study in FL including as a backbone for addition of novel agents in relapsed and frontline settings.
Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM).
Authors: Lonial Sagar , Baz Rachid C. , Wang Michael , Talpaz Moshe , Liu Guohui , Berg Deborah , Gupta Neeraj , Di Bacco Alessandra , Hui Ai-Min , Richardson Paul Gerard Guy 
Published: March 2020

8017 Background: MLN9708 is the first oral proteasome inhibitor to enter clinical investigation in MM. This study (NCT00932698) assessed safety, MTD, and response rate with twice-weekly oral MLN9708 in pts with relapsed and/or refractory MM, and characterized plasma pharmacokinetics (PK) and blood pharmacodynamics. Methods: Pts aged ≥18 yrs with measurable MM received MLN9708 on d 1, 4, 8, and 11 of 21-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD (2.0 mg/m2), pts were enrolled to relapsed and refractory [RR], bortezomib-relapsed [VR], proteasome-inhibitor [PI] naïve, and carfilzomib [CZ] expansion cohorts. Results: 57 pts (53% M) were enrolled, 37 to the expansion cohorts (16 RR, 14 VR, 6 PI naïve, 1 CZ). Median age was 65 yrs (range 50-86). Median number of prior lines of therapy was 4 (range 1-28); 88%, 84%, 61%, and 5% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 3 cycles (range 1-24) to date (data cut-off Dec 1, 2011); 7 (12%) have received ≥13 cycles. Drug-related AEs were seen in 89% of pts, including fatigue (46%), thrombocytopenia (40%), and nausea (30%); 63% had drug-related grade ≥3 AEs, including thrombocytopenia (33%), neutropenia (14%), fatigue (9%), and rash (7%). Only 6 (11%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 7 pts discontinued due to AEs. 2 pts died on study, due to PD and an unrelated cardiac disorder. Of 46 response-evaluable pts, 6 have achieved ≥PR, with 1 sCR (PI naïve cohort) and 5 PRs (2 in dose-escalation, 1 in RR, 2 in VR cohorts), and 1 VR pt has achieved MR, with duration of disease control of up to 18.6 mo. PK analyses showed MLN2238 (biologically active hydrolysis product) has linear plasma PK (0.8-2.23 mg/m2), Tmax of 0.5-1.25 hr, and terminal half-life of 4-6 d. A dose-dependent increase in whole blood 20S proteasome inhibition was observed. Conclusions: Current data suggest MLN9708 has clinical activity in heavily pretreated MM pts, with durable responses/disease control, and is generally well tolerated with infrequent low-grade PN.
Retreatment with brentuximab vedotin in CD30‑positive hematologic malignancies: A phase II study.
Authors: Bartlett Nancy , Brice Pauline , Chen Robert W. , Fanale Michelle A. , Gopal Ajay K. , Matous Jeffrey , Rosenblatt Joseph David , Grove Laurie E. , Forero-Torres Andres 
Published: March 2020

8027 Background: Brentuximab vedotin comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, MMAE. In pivotal phase 2 studies in patients (pts) with relapsed/refractory Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL), objective response rates were 75% and 86% and median durations of response were 6.7 and 12.6 mo, respectively. A phase 2 study was initiated to investigate if pts who have previously responded to brentuximab vedotin could achieve another remission with retreatment (ClinicalTrials.gov #NCT00947856). Methods: Pts had a CD30-positive hematologic malignancy, achieved an objective response (per Cheson 2007) with prior brentuximab vedotin treatment, and experienced relapse after discontinuing treatment. Brentuximab vedotin was administered IV 1.8 mg/kg every 21 days; antitumor activity was assessed by the investigator. Results: 14 HL pts and 8 sALCL (5 ALK-negative) pts were enrolled (median age 34 yr, range 16–72). Pts had received a median of 4 prior chemotherapy regimens (range 2–12). Median time since the previous brentuximab vedotin treatment was 6.9 mo (range 1–44). Median number of retreatment cycles was 7 (range 1+ to 32+). Adverse events (AEs) in >25% of pts were nausea (41%), fatigue (36%), peripheral sensory neuropathy (36%), and diarrhea (27%). The most common Grade 3/4 AEs were anemia, fatigue, and hyperglycemia (3 pts each). Of the 11 pts who had pre-existing peripheral neuropathy, 3 (27%) had worsening with retreatment. Best clinical responses in pts with HL were 3 CR, 5 PR, 3 SD, 3 PD. Among pts with sALCL, 5 achieved a CR, 1 had PD, and 2 were not yet evaluated. Of the 8 pts with CR in retreatment, previous best responses to brentuximab vedotin treatment were 4 PR and 4 CR. Median duration of retreatment response was 10.8 mo (range 0+ to 10.8), and in pts who achieved CR, the median duration of response was not reached (range 0+ to 10.5 mo); 11 pts remain on retreatment. Conclusions: Retreatment with brentuximab vedotin was generally well tolerated. Objective responses were observed (13 of 20; 65%) in this heavily pretreated population. Enrollment to the phase 2 retreatment study is ongoing.
Clarithromycin, pomalidomide, and dexamethasone (ClaPD) in relapsed or refractory multiple myeloma.
Authors: Rossi Adriana C. , Mark Tomer Martin , Rodriguez Melissa , Shah Manan , Quinn Ryann , Pearse Roger N , Zafar Faiza , Pekle Karen , Speaker Stephanie , Jayabalan David , Ely Scott , Coleman Morton , Chen-Kiang Selina , Niesvizky Ruben 
Published: March 2020

8036 Background: Clarithromycin has been shown to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is an immunomodulatory agent effective in relapsed/refractory MM (RRMM). We hypothesized that clarithromycin may similarly enhance pomalidomide + dexamethasone in RRMM. We now report updated results from a phase 2 trial of ClaPD in RRMM. Methods: 73 patients with RRMM were enrolled in a single-institution phase 2 study of ClaPD. All subjects had ≥ 3 prior lines of therapy, one of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; dexamethasone 40mg weekly; and pomalidomide 4mg for days 1-21 of a 28-day cycle. All patients had VTE prophylaxis with aspirin. Monthly disease response evaluation included immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM responses. Treatment continued as tolerated until disease progression. Results: The 66 patients who completed ≥ 1 cycle of ClaPD are reported. Median number of cycles was 6 (range 1-17). Responses were progressive disease: 10%, stable disease: 21%, minimal response: 12%, partial response: 33%, very good partial response: 18%, stringent complete remission: 5%, for an overall response rate (ORR) of 56% and ≥VGPR rate of 23%. Median time to PR was 1.25 cycles (range 1-8). Median PFS was 5 months. Response and PFS were not different in patients refractory to lenalidomide (85%), bortezomib (82%), or double-refractory patients (76%). After a median follow up of 12 months,28 pts (42%) remain on study without progression and 56pts (85%) are alive. Two pts withdrew due to toxicity (1 Grade 3 fatigue, 1 Grade 4 muscular weakness). One patient withdrew consent. Conclusions: ClaPD is highly effective for heavily pre-treated RRMM, particularly in lenalidomide-refractory disesase and compares favorably to previously published Phase 2 data of Pom/Dex (ORR 56% vs 40% - Lacy et. al JCO 2009) without excess toxicity. Response to ClaPD is rapid, well tolerated, and sustained over 7 months in most subjects. These data support the clinical efficacy of pomalidomide based regimens in RRMM.