bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accumulation of active metabolite M-2 predicts overall survival (OS) of chemorefractory metastatic colorectal cancer patients treated with regorafenib (REGO).
Authors: Rousseau Benoit , Boukerma Arezki Khaled , Henriques Julie , Cohen Romain , Lucidarme Olivier , Borg Christophe , Tournigand Christophe , Kim Stefano Chong Hun , Bachet Jean-Baptiste , Mazard Thibault , Louvet Christophe , Chibaudel Benoist , Diaz Luis A. , Vernerey Dewi , Andre Thierry , Hulin Anne 
Published: May 2019

3121 Background: TEXCAN, a prospective phase II GERCOR study of treatment with REGO in chemorefractory metastatic colorectal cancer (mCRC) patients (NCT02699073) included a prospective pharmacokinetic (PK) ancillary study aiming to investigate correlations between OS and concentrations (C) of REGO and its active metabolites M-2 and M-5. Methods: 55 patients were included, with the same inclusion/exclusion criteria as CORRECT (NCT01103323), and treated orally with 160 mg REGO daily for 3 weeks on and 1 week off. 34 patients had PK samples at C1D15 and 26 at C2D15 for Cmin. REGO, M-2 and M-5 Cmin were measured by LC-MS/MS. PK analyses studied the link between OS and PK parameters: Cmin of REGO, M-2 and M-5 at C1 and accumulation of pharmacological active metabolites between C1 and C2, assessed by the C2/C1 ratio of M-2 or M-5 Cmin concentrations. Results: REGO, M-2 and M-5 Cmin [median (Q1-Q3)] were respectively 1.99 (1.03-2.73), 1.44 (0.89-2.49) and 1.61 (0.79-2.37) mg/L at C1D15 and 1.90 (1.10-2.76), 1.29 (0.77-2.24) and 1.17 (0.45-2.42) mg/L at C2D15. C2/C1 M-2 ratio and M-5 ratio medians were 0.82 (0.50-1.78) and 0.75 (0.41-1.93), respectively. Univariate analyses showed a major OS benefit in patients with C2/C1 M-2 ratio ≥median vs < median (12.6 vs 4.0 months respectively, hazard ratio = 0.35, 95% confidence interval 0.14-0.86, p-value = 0.023) but not for C2/C1 M-5 ratio ≥median. Multivariate analyses, including the CORRECT REGOSCORE groups, showedan independent 66% reduction in death risk in the group of patients with C2/C1 M-2 ratio ≥median. The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum) (0.53, p-value = 0.006). Restricted Cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio rises and when C1 Csum ranged between 2.5 and 5.5 mg/L. PK parameters were not associated with toxicities. Conclusions: M-2 accumulation between C1 and C2 is independently associated with improved OS in mCRC patients treated by REGO. M-2 accumulates and OS is favorable when C1 REGO+M-2+M-5 sum ranged between 2.5 and 5.5 mg/L. These results may lead to develop individual REGO dosage modification strategies based on PK monitoring. Clinical trial information: NCT02699073.
Larotrectinib efficacy and safety in adult TRK fusion cancer patients.
Authors: Hong David S. , Kummar Shivaani , Farago Anna F. , Lassen Ulrik Niels , Berlin Jordan , Schilder Russell J. , McDermott Raymond S. , Patel Jyoti D. , Dowlati Afshin , Doebele Robert Charles , Tan Daniel Shao-Weng , Lee James J. , Nanda Shivani , Childs Barrett H. , Ku Nora , Drilon Alexander E. , Hyman David Michael 
Published: May 2019

3122 Background: A broad range of pediatric and adult malignancies harbor TRK fusions involving the NTRK1, NTRK2, and NTRK3 genes. The highly-selective TRK inhibitor, larotrectinib, has previously shown a high overall response rate (ORR) and a favorable safety profile in patients (pts) with TRK fusion cancer. To better delineate efficacy in adults, as pediatric pts have a particularly high ORR, here we report updated efficacy and safety data from the adult subset of pts with TRK fusion cancer treated with larotrectinib. Methods: Adult pts (aged 18 or older) with TRK fusion cancer detected by local testing in 2 larotrectinib clinical trials (NCT02122913 and NCT02576431) were analyzed. Larotrectinib was administered 100 mg PO BID until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed by both investigator (INV) and independent assessment (IRC) using RECIST v1.1. Results: As of July 30, 2018, 83 adults (median age: 57 y, range 20–80 y) with TRK fusion cancer had been treated. Cancer types included salivary gland (23%) and thyroid cancer (19%), soft tissue sarcoma (14%), lung cancer (13%), colon cancer and melanoma (7% each), GIST (5%), and bone sarcoma, cholangiocarcinoma, and appendiceal, breast, and pancreas cancer (≤2% each). TRK fusions involved NTRK1 (40%), NTRK2 (2%), and NTRK3 (57%). 77% of pts had received prior systemic therapy (median lines: 2, range 0–10). In 74 pts evaluable per INV, the ORR was 76% with 9% CR, 57% confirmed PR, 9% PR pending confirmation, 12% SD, 11% PD, and 1% not determined; 9 pts were non-evaluable (NE) due to lack of post-baseline assessment. In 65 pts evaluable per IRC, the ORR was 68% with 17% CR, 51% PR, 15% SD, 12% PD, and 5% NE. With a median follow up of 17.2 and 17.5 mo per INV and IRC, respectively, the median duration of response had not been reached (ranges identical: 1.9+ to 38.7+ months). At data cutoff, 63% remained on treatment; 30% had discontinued due to disease progression. Adverse events were mostly grade 1–2. Conclusions: Larotrectinib demonstrated robust tumor-agnostic efficacy and a favorable safety profile in adult pts with TRK fusion cancer. These results support testing for TRK fusion cancer in pts with advanced solid tumors, regardless of site of primary diagnosis. Clinical trial information: NCT02122913 and NCT02576431.
Clinicopathologic characteristics of NRG1 fusion-positive cancers: A single-institution study.
Authors: Schram Alison M. , Benayed Ryma , Somwar Romel , Rekhtman Natasha , Arcila Maria E. , Ladanyi Marc , Hyman David Michael , Drilon Alexander E. 
Published: May 2019

3129 Background: NRG1 rearrangements are oncogenic drivers across several tumor types. Chimeric proteins encoded by NRG1 fusions activate HER3, resulting in heterodimerization with HER2 and activation of downstream signaling. Preclinical and preliminary clinical data suggest that targeting HER3 may be an effective treatment strategy for patients with NRG1 fusion-positive tumors. We aimed to describe the clinical and genomic characteristics of patients identified at our institution with NRG1 fusions. Methods: We analyzed results from prospective targeted exome and/or RNA sequencing performed at Memorial Sloan Kettering between 2014-2018 involving > 30,000 samples. NRG1 fusion-positive tumors were identified and these cases were manually reviewed. Results: NRG1 fusions were detected in 24 patients. Cancer types included lung (N = 9), pancreas (N = 7), breast (N = 5), prostate (N = 1), gallbladder (N = 1), diffuse large B-cell lymphoma (N = 1), and cancer of unknown primary (N = 1). 6/9 lung cancers had mucinous differentiation. The majority of patients were Caucasian (N = 17), half were female (N = 12) and ages ranged from 24-82 years-old. Targeted exome sequencing identified the fusion in 10/23 cases tested, including 2 not confirmed by RNA. The remaining 14 were detected using RNA. Fusion partners included CD74 (N = 6), SLC3A2 (N = 2), SDC4 (N = 2), ATP1B1 (N = 2), FOXA1 (N = 1), SLCA4 (N = 1), ROCK1 (N = 1), TNKS (N = 1), CCND1 (N = 1), PAK1 (N = 1), STAU3 (N = 1), RAD51 (N = 1), CD44 (N = 1), NCOR1 (N = 1), RBPMS (N = 1), and WHSC1L1 (N = 1). Pancreas cancers were KRAS wild-type and lung cancers had no co-occurring alterations in ALK, ROS1, EGFR, RET, MET, RAS, or RAF. All tumors were microsatellite stable. A durable response was achieved with anti-HER3 antibody therapy (GSK2849330) in a patient with a CD74- NRG1-rearranged invasive mucinous adenocarcinoma (previously reported). Four patients treated with an irreversible small molecule HER2 inhibitor (afatinib) did not respond to treatment, suggesting direct targeting of HER3 may be superior to HER2 inhibition in patients with NRG1 fusion-positive tumors. Conclusions: NRG1 fusions occur in several tumor types and may be amenable to targeting with HER3-directed therapy.
Actionable coalterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway.
Authors: Heeke Arielle Lutterman , Xiu Joanne , Lynce Filipa , Pohlmann Paula Raffin , Vidal Gregory A. , Isaacs Claudine , Swain Sandra M. , Schwartzberg Lee S. , Tan Antoinette R. 
Published: May 2019

3132 Background: Homologous recombination (HR) deficient breast tumors may have genomic alterations that suggest responsiveness to targeted therapies other than PARP inhibitors. Methods: Comprehensive molecular profiles of 4,647 breast tumors performed at Caris Life Sciences using 592-gene NGS (average read depth 500X) were reviewed to identify somatic pathogenic mutations in HR genes ARID1A, ATM, ATRX, BAP1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, RAD50/51/51B & PALB2, as well 41 markers associated with treatment response. Results: Overall, 17.9% of breast tumors have HR mutations (HR-MT, 831/4647). HR-MT is seen most in HER2– disease [hormone receptor (hr)+/HER2– (18.3%, n=2183), TNBC (18.2%, n=1568), hr–/HER2+ (12.9%, n=217)]. Mean TMB is higher for HR-MT tumors across subtypes (9.2 mut/Mb vs 7.6 WT, p=<0.0001) & independent of MS status. HR-MT hr–/HER2+ tumors are more likely to have PD-L1 overexpression (25% vs 13.1% hr–/HER2+ WT, p=0.10), whereas MSI is more prevalent in HR-MT HER2– (hr+/HER2– 2.3%, TNBC 1.4%, HER2+ 0%). Mutations in chromatin remodeling genes (*) are more common in HR-MT. Additional co-alterations are outlined in the Table. Conclusions: In breast cancer, HR-MT is associated with HER2– disease & markers of response to immunotherapy. Clinical trials combining HRD targeted agents & immunotherapy are underway & could be enriched through comprehensive molecular profiling. Mutations were identified in both HR-MT & HR WT tumors that suggest other targets for treatment. [Table: see text]
MET exon 14 skipping analogs: Rare but potentially clinically actionable.
Authors: Feldman Rebecca , Ellis Michelle , Swensen Jeffrey , Korn Wolfgang Michael , Gatalica Zoran 
Published: May 2019

3141 Background: The DpY motif within the exon 14 juxtamembrane domain of the MET receptor gene is critical for Cbl-mediated negative regulation. Splicing alterations that delete this residue, known as exon 14 skipping mutations (ex14sk mt), lead to prolonged MET protein stability and oncogenic signaling. Specific mt at the Y1021 (aka 1003) residue are thought to lead to similar effects as ex14sk, but due to their rarity, their role in NSCLC is unknown. We sought to identify and characterize non-ex14sk mt that include/surround Y1021. Methods: Retrospective review of molecular profiles for non-ex14sk mt that include/surround the DpY motif (Y1021) in MET. Two NGS platforms were included: MiSeq (2014-2017; n=2865) and NextSeq (2017-2019; n=6084). Immunohistochemistry (IHC) of cMET (SP44) and co-occurring alterations (EGFR, KRAS, ALK, ROS) were also reviewed. Results: Of 8,949 NSCLC patients with successful NGS of MET gene by either platform, 13 cases or 0.2% were identified to have an alteration within the amino acids of interest. Eleven cases included substitutions at Y1021 (5 phenylalanine, 4 histidine and 3 arginine) and the remaining two cases included small insertion-deletions p.E1017_Y1021delinsH and p.D1020_Y1021delinsV, the latter was later excluded as it co-harbored an ex14sk mt. Conclusions: Similar to patients with ex14sk mt, substitutions and small indels at Y1021 exhibit Clinicopathological features such as previous smoking history and older age, mutual exclusivity with oncogene drivers and MET protein overexpression. The rarity of these analogous ex14sk mt suggests deletions of exon 14 provide cellular advantages beyond Cbl-mediated ubiquitinylation of MET. Although rare, the impact of these mt on efficacy of Met-directed therapy deserves further exploration.[Table: see text]
Association of colon cancer (CC) molecular signatures with prognosis and oxaliplatin prediction-benefit in the MOSAIC Trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer).
Authors: Pogue-Geile Katherine L. , Andre Thierry , Song Nan , Lipchik Corey , Wang Ying , Kim Rim S. , Feng Huichen , Gavin Patrick , Van Laethem Jean-Luc , Srinivasan Ashok , Hickish Tamas , Jacobs Samuel A. , Tabernero Josep , Lucas Peter C. , De Gramont Aimery , Wolmark Norman , Flejou Jean-François , Paik Soonmyung 
Published: May 2019

3503 Background: MOSAIC and C-07 showed that oxaliplatin (OX) added to 5-fluorouracil plus leucovorin significantly improved disease free survival (DFS). However, OX is associated with neurotoxicity and the vast majority of patients do not receive OX-benefit; highlighting the importance of an OX-benefit predictor. In C-07, colon tumors with a CRCA (Colorectal Cancer Assigner) stem-like subtype were associated with a poor prognosis and no OX-benefit, but stage III patients with an enterocyte subtype did. We tested the association of CRCA and CMS molecular subtypes with prognosis and OX-benefit in stage III MOSAIC patients. Also, recombination proficiency scores (RPS) were tested for the same associations. RPS scores quantify the efficiency of DNA-damage repair. Low RPS have been associated with inferior overall survival (OS) in non-small cell lung carcinoma patients treated with surgery alone but better OS for patients who received surgery plus chemotherapy. Methods: Gene expression profiles from 590 stage III pts with follow up were successfully profiled by a custom designed nCounter code set. CRCA subtypes were determined by a locked down algorithm based on a re-estimated centroid using 72 genes (Song et al 2016). CMS subtypes were determined by modified single sample predictor (SSP) using 84 genes. RPS scores were determined as previously described by Pitroda et al (2014). Signature predictions were made while blinded to clinical outcome and signature performance was evaluated while blinded to gene expression. Results: The stem-like subtype was associated with a very poor prognosis (Stem-like vs others HR=1.56, p<0.01) and no OX-benefit. CRCA and CMS subtypes did not associate with OX-benefit. Using a median cut point, stage III patients with low RPS scores received significant OX-benefit (HR=0.67, p=0.033, N=290) and patients with high RPS scores did not (HR=1.2, p=0.32, N=300) with significant interaction p=0.025. Conclusions: The observation in C-07, that the stem-like subtype has the poorest prognosis and did not receive OX-benefit, was validated in MOSAIC, identifying patients who need new therapies. RPS scores may help to identify the subset of patients with OX-benefit in stage III CC, confirmation of this observation is currently being investigated in C-07. Support: PA DoH; NSABP; Sanofi.
A multicenter randomized phase III trial of capecitabine with or without irinotecan driven by UGT1A1 in neoadjuvant chemoradiation of locally advanced rectal cancer (CinClare).
Authors: Zhang Zhen , Sun Xinchen , Liu Anwen , Zhu Yuan , Zhu Yaqun , Zhang Tao , Jia Jianhui , Tan Shisheng , Wu Junxin , Zhou Juying , Wang Xin , Yang Jialin , Zhao Yuanyuan , Zhang Hongyan , Zhang Chen , Cai Gang , Zhu Ji 
Published: May 2019

3510 Background: Our phase I/II study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant CRT and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a prospective, randomized, open-label, multicenter, phase 3 trial in China from Nov.2015 to Dec.2017. Eligible patients with clinical stage T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to two arms. The approach in control arm (Arm A, n = 180) was pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT. The experimental arm (Arm B, n = 180) was pelvic radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Results: Surgery was performed in 86.5% and 88.2% of patients in two groups, with 38.9% and 30.5% of patients got abdominoperineal resection respectively. The pCR rate was 17.5% in Arm A and 33.8% in Arm B (P = 0.001). Four and 6 patients maintained a complete clinical response status at least 12 months and were marked as cCR. The CR rate, including pCR and cCR, was 17.4% in Arm A and 33.1% in Arm B (P = 0.001). The most common grade 3-4 adverse events during preoperative treatment were leucopenia (3.4% vs. 25.3%), neutropenia (1.7% vs. 19.7%) and diarrhea (1.7% vs. 13.5%) in two arms. The overall rate of surgical complications were not significantly different between arms (11.0% vs. 14.6%). Conclusions: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. This treatment can be as an option for ‘watch and wait’ approach. Clinical trial information: NCT02605265.
A phase II study of ipilimumab and nivolumab with radiation in microsatellite stable (MSS) metastatic colorectal adenocarcinoma (mCRC).
Authors: Parikh Aparna Raj , Clark Jeffrey William , Wo Jennifer Yon-Li , Yeap Beow Y , Allen Jill N. , Blaszkowsky Lawrence Scott , Ryan David P. , Giantonio Bruce J. , Weekes Colin D. , Zhu Andrew X. , Van Seventer Emily E. , Matlack Lauren , Foreman Bronwen , Ly Leilana , Drapek Lorraine C. , Ting David Tsai , Corcoran Ryan Bruce , Hong Theodore S. 
Published: May 2019

3514 Background: mCRC remains a lethal cancer and immunotherapy in MSS mCRC has yet to show significant activity. In preclinical models, radiation induced cellular damage may increase responsiveness to immunotherapy via the abscopal effect, with evidence for synergy between radiation therapy (RT) and dual checkpoint blockade. In this study, we assessed dual blockade of CTLA-4 and PD-1 combined with RT as a strategy to stimulate an immune response for patients with MSS mCRC. Methods: In this open-label, single arm phase-2 study, we enrolled 40 MSS mCRC patients (pts). Eligible pts had histologically-confirmed MSS mCRC, ECOG PS 0-1, and progression on at least two lines of therapy. Treatment (Tx) consisted of ipilimumab (1mg/kg q6 weeks), nivolumab (240 mg q2 weeks) and 3 fractions of 8 Gy of RT at cycle 2 every other day. Tx continued until progression, discontinuation or withdrawal. The primary endpoint was Disease Control Rate (DCR), with radiological evaluations every 3 months. Exploratory endpoints included ORR, PFS, OS and safety. Response was defined as disease control outside the radiation field. We obtained serial tumor biopsies pre-tx, during checkpoint blockade alone (cycle 1) and 2 weeks after initiation of radiation. Intention-to-treat analysis (ITT) includes all pts receiving at least one dose of study agent. Results: 40 pts (median age 59 years (26-83), 58% male) enrolled and started treatment from 7/2017 to 12/2018. DCR was 17.5% (7/40) with a 7.5% (3/40) ORR by ITT. Median duration of disease control was 77 days in the ITT; 252 days for those with disease control (n=7) based on the first re-staging scans at 3 months or censored (n=3) and 70.5 days for pts with PD (n=17) or who did not receive RT due to clinical progression (n=13). In the modified ITT (all pts receiving RT and restaged), N=24 pts, excluding 1 pt pending 1st scans post-RT, DCR was 29.2% (7/24) and ORR 12.5% (3/24). Median duration of disease control in mITT was 77.5 days: 252 days for those with disease control and 77 days for those with PD. TRAEs were reported in 22/40 (55%). 20/40 (50%) with grade ≥3 toxicities, with fatigue, nausea, vomiting, diarrhea, infusion-related reaction and dyspnea being the most common. 1(2%) pt died of respiratory failure possibly related to tx. Conclusions: Dual blockade of CTLA-4 and PD-1 with RT is feasible and demonstrates durable activity in pts with MSS mCRC. There are 3 pts who have not completed RT or had their post-RT re-staging. We will report updated efficacy data and outcomes from correlative serial tumor biopsies upon trial completion. Clinical trial information: NCT03104439.
Tumor dynamics with fluorouracil/folinic acid, irinotecan, and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (mCRC): Central radiologic review of VOLFI—A randomized, open label, phase-2 study (AIO KRK0109).
Authors: Modest Dominik Paul , Noerenberg Dominik , Seidensticker Max , Ricke Jens , Martens Uwe Marc , Riera-Knorrenschild Jorge , Greeve Jobst , Florschütz Axel , Wessendorf Swen , Ettrich Thomas Jens , Kanzler Stephan , Held Swantje , Buechner-Steudel Petra , Atzpodien Jens , Heinemann Volker , Tannapfel Andrea , Reinacher-Schick Anke C. , Geissler Michael 
Published: May 2019

3530 Background: The VOLFI trial demonstrated improved objective response rate (ORR) with the addition of pmab to modified triplet chemotherapy with FOLFOXIRI in a 2:1 (63 patients FOLFOXIRI plus pmab; 33 patients FOLFOXIRI) randomized, controlled, phase II trial in patients with untreated RAS wildtype mCRC. Methods: Radiologic images from the study were centrally examined according to RECIST 1.1. We further assessed early tumor shrinkage (=ETS: 20% shrinkage of tumor diameter at first re-assessment) and depth of response (=DpR= maximum shrinkage of lesions defined as relation of smallest tumor diameter to baseline). Moreover, time to depth of response was calculated (randomisation to depth of response image). Results: Images were available for 88 of 96 patients (91.7%), 86 patients (89.6%) had at least one follow-up image and were included in the central review. According to central review, objective response rates were 89.2% vs 66.7% with FOLFOXIRI plus pmab vs FOLFOXIRI alone (P=0.02). ETS was also significantly more frequent (Fisher’s exact test; P=0.01)) and DPR (Wilcoxon test; P= 0.004) significantly greater with pmab as compared to chemotherapy alone. See table for details. Time to DpR was similar in the panitumumab- vs chemotherapy alone arm (3.9 (95% confidence interval 2.8-4.7) vs. 4.2 (95% CI 3.6-5.7) months, respectively. P=0.63). Conclusions: In this central review, pmab significantly improves ORR, the rate of ETS and also DpR when added to a mFOLFOXIRI regimen. Our findings underline the potential of this highly active regimen in patients with RAS wildtype mCRC that need to achieve early and profound shrinkage of the tumor. Additional analysis including molecular subgroups and tumor sidedness will be shown at the meeting. Clinical trial information: NCT01328171. [Table: see text]