bluuebunny/crossref_metadata_2025 huggingface dataset:
First-in-human clinical trial with intratumoral BO-112 in solid malignancies: A novel immunotherapy based in double-stranded RNA (dsRNA).
Authors: Marquez Rodas Ivan , Rodriguez-Ruiz Maria E. , Lopez-Tarruella Sara , Perez-Gracia Jose Luis , de Miguel Enrique , Calvo Aitana , Blanco-Codesido Montserrat , Martin-Algarra Salvador , Martin Miguel , Melero Ignacio
Published: September 2018

3082

Background: BO-112 is a double stranded synthetic RNA, formulated with the cationic carrier polyethyleneimine that preclinically improves its intracellular delivery and resistance towards nuclease degradation. In melanoma mouse models, systemic administration activates MDA-5 and NOXA, leading to anti-tumoral activity connected to a sustained and extended expression of IFN-response genes. Intratumoral (IT) delivery, seeking a safer and more focused enhancement of local and systemic antitumor effects has been tested in transplanted mouse models. The potential of its IT use as an immune-modulatory treatment, as well as its toxicity profile, is being analyzed in this first in human, proof of concept, clinical trial (NCT02828098). Methods: Four patients with malignant solid tumors and palpable cutaneous/subcutaneous or lymph node metastases >1 cm were treated with a single BO-112 dose of 0.6 mg/ml IT. Pre and post treatment biopsies from the injected metastatic lesion were obtained. Pharmacokinetics, serum cytokines and circulating immune cells were sequentially studied in pre and post treatment samples. Results: Patients did not experience relevant toxicity with the exception of a single episode of completely reversible grade 4 thrombocytopenia in one patient, attributed to the drug. BO-112 was not detectable in bloodstream following IT delivery. No changes in circulating cytokines were detected. Main immunobiological effects are summarized in the table. Conclusions: BO-112 has shown changes in tumoral immune cells in 1/4 patients, while in 3/4 induced both necrosis and changes in circulating immune cells. This ongoing trial will compile more safety data with repeated sequential administrations, escalated to higher doses of BO-112, and will thoroughly characterize its biological effects in humans with solid malignancies amenable to IT injection. Clinical trial information: NCT02828098. [Table: see text]
PEGylated human IL-10 (AM0010) in combination with pembrolizumab in anti-PD1 and CTLA-4 refractory melanoma.
Authors: Naing Aung , Wong Deborah Jean Lee , Infante Jeffrey R. , Patel Manish R. , Pant Shubham , Chmielowski Bartosz , Janku Filip , Tapia Coya , Ratti Navneet , Van Vlasselaer Peter , Brown Gail Linda , Hung Annie , Oft Martin , Diab Adi
Published: September 2018

3084

Background: Melanoma has a high response rate to anti-PD-1 alone. More than 50% of melanoma on anti-PD-1 progress within one year. IL-10 inhibits inflammation and stimulates the cytotoxicity and proliferation of tumor infiltrating CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are induced on activated CD8 T cells, providing a mechanistic rationale for combining AM0010 and anti-PD1. AM0010 alone has established tolerability and anti-tumor activity in a phase 1 study. Objective responses were observed in 4 of 15 pts with RCC, one patient with uveal melanoma and cutaneous T cell lymphoma, each. Methods: 25 melanoma pts who had progressed on prior anti-CTLA4 and on prior anti-PD-1 containing regimen were treated with AM0010 (20mg/kg qd, SQ) and pembrolizumab (2mg/kg, q3wk IV). Patients had a median of 3.5 prior therapies (range 2-6) and a median of 2 prior immune therapies (range 1-6). Tumor responses were monitored following irRC. Immune responses were measured by analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Results: AM0010 plus pembrolizumab was well tolerated. All treatment related adverse events (TrAE) were reversible. DLTs and SAEs leading to study discontinuation were not observed. G3/4 TrAEs were observed in 11 of 25 pts and included fatigue (8) thrombocytopenia (6), anemia (4), rash (1) and hypertriglyceridemia (1). There were no objective tumor responses. 9 of 20 evaluable pts had stable disease (DCR = 45%). As of Jan. 31 2017, the mPFS was 2.0 mo. and the mOS was not reached, with a mFU of 15.5 mos (range 10.0-18.4). AM0010 plus pembrolizumab increased Th1 cytokines as well as the number and proliferation of PD1+ Lag3+ activated CD8 T cells in the blood while reducing inflammatory cytokines and TGFb. A de-novo oligoclonal expansion of T cell clones in the blood and an increase of tumor infiltrating Granzyme+ PD1+ CD8+ T cells in tumor biopsies of treated patients was observed. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated in refractory melanoma pts. The clinical activity and the observed CD8+ T cell activation may suggest to study AM0010 in combination with an anti-PD-1 in melanoma patients with less prior treatments. Clinical trial information: NCT02009449.
LTX-315, an oncolytic peptide, to convert immunogenically ‘cold' tumors to ‘hot' in patients with advanced or metastatic tumours: Results from an ongoing phase I study.
Authors: Spicer James F. , Baurain Jean-Francois , Awada Ahmad , Kristeleit Rebecca Sophie , Jossang Dag Erik , Marabelle Aurelien , Loirat Delphine , Wold Hedda , Nicolaisen Berit , Rekdal Oystein , Olsen Wenche Marie , Saunders Andrew , Brunsvig Paal
Published: September 2018

3085

Background: Intratumoral LTX-315 disintegrates cytoplasmic organelles with release of tumor antigens in preclinical models accompanied by increase in tumor-infiltrating lymphocytes (TILs). LTX-315 induced complete regression in several rodent models, with systemic immune responses. LTX-315 is strongly synergistic preclinically with immune checkpoint inhibitors (ICI). We are conducting a phase 1 trial to evaluate LTX-315 in combination therapy. Methods: Patients with advanced metastatic solid tumours received injections of LTX-315 into a single accessible tumour over 6 weeks. Additional injections could be administered thereafter every 2 weeks. Biopsies of injected lesions were taken at baseline, and on treatment. Results: 28 have been enrolled to date, median age is 58 (range 32-80) and median prior treatments 2 (range 1-14). LTX-315 monotherapy was administered at doses of 2-7mg to a median of 1.8 tumour lesions (range 1-6) for a median of 9 weeks (range 1-33). In 24 patients all LTX-315-related adverse events were CTC grade 1 or 2, most commonly local erythema, flushing, pruritis and hypotension, most resolving within minutes of injection. Related grade 3 (3 patients) or 4 (1) allergic/anaphylaxis adverse event occurred and resolved without sequelae. Best response in 44 injected lesions in 20 evaluable patients included 2 complete responses, > 50% reduction in 5 tumours, and 20 stable (injected ). Significant increases in TILs occurred in 67% (14 of 21) patients with biopsies of injected tumours available. Regression of distant non-injected tumour has been observed clinically on biopsy (abscopal effect). No irRC response in non-injected tumours has been observed in 16 evaluable patients. Stable disease (median duration 14 weeks) occurred in 50% of patients as best response (melanoma (4), sarcoma (3), breast (1)). Conclusions: This phase 1 study demonstrates that intratumoural LTX-315 has a manageable safety profile and induces increases in TILs in pre-treated patients. Partial and complete regression was seen in some injected tumours. Evaluation of LTX-315 in combination with ICIs in breast and melanoma is ongoing. Clinical trial information: NCT01986426.
FOLFOX4/XELOX in stage II–III colon cancer: Efficacy results of the Italian three or six colon adjuvant (TOSCA) trial.
Authors: Sobrero Alberto F. , Lonardi Sara , Rosati Gerardo , Di Bartolomeo Maria , Ronzoni Monica , Pella Nicoletta , Scartozzi Mario , Banzi Maria , Zampino M. Giulia , Pasini Felice , Marchetti Paolo , Cantore Maurizio , Zaniboni Alberto , Rimassa Lorenza , Ciuffreda Libero , Ferrari Daris , Zagonel Vittorina , Maiello Evaristo , Rulli Eliana , Labianca Roberto
Published: September 2018

3501

Background: Six months of oxaliplatin-based treatment has been the standard of care as adjuvant therapy for stage III colon cancer and an accepted option for high-risk stage II. Given the cumulative neurotoxicity associated to oxaliplatin, a shorter duration of therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods: TOSCA was an open-label, phase III, multicenter, non-inferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months or 6 months of FOLFOX4/XELOX. Primary end-point was relapse-free survival. Results: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Two thirds were stage III. At the cut-off time for analysis the median time of follow-up was 62 months and 772 relapses or deaths have been observed. The RFS rate at 8 years is 75%. This analysis was done when 82% of the planned number of events was reached, with a power of 72% instead of 80%. The decision to anticipate the analysis was based on the participation to the IDEA joint collaborative analysis of studies sharing this clinical question. The Hazard Ratio of the 3months vs 6 months for relapse/death was 1.14 (95%CI 0.99-1.31, p for non inferiority = 0.253) and the confidence interval crossed the non inferiority limit of 1.20. Conclusions: TOSCA was not able to demonstrate that 3 months of oxaliplatin-based adjuvant treatment is as efficacious as 6 months. Nevertheless , because the absolute difference in RFS between the two treatment durations is small ( less than 3 % at 5 years ), the decision to complete the whole 6-month program should be individualized based on toxicity and patients’ attitude. This study is registered with ClinicalTrials.gov Registration Number: NCT00646607. It was supported by a grant from AIFA (Agenzia Italiana del Farmaco) Grant Code FARM5RWTWZ. Clinical trial information: NCT00646607.
MABp1 to improve clinical outcomes of patients with symptomatic refractory metastatic colorectal cancer patients: Per-protocol population analysis of phase III study (PT026).
Authors: Wyrwicz Lucjan , Saunders Mark P. , Andre Thierry , Sarosiek Tomasz , Nemecek Radim , Rogowski Wojciech , Leśniewski-Kmak Krzysztof , Fisher George A. , Stecher Michael , Mohanty Prasant , Simard John , Hickish Tamas
Published: September 2018

3530

Background: Refractory metastatic colorectal cancer (mCRC) patients derive minimal benefit from further exposure to toxic agents. MABp1 is an anti-interleukin 1 alpha antibody that is shown to prolong survival (NCT01767857) and improves outcomes when assessed with a primary endpoint based on a constellation of objective and patient self-reported measures (NCT02138422) (Hickish T. et al Lancet Oncology 2017). In the latter study, clinically advanced patients were enrolled (symptomatic, ECOG 1,2), and 18% of patients progressed prior to reaching the endpoint assessments. Here we present the outcomes in per-protocol population (PP), those patients completing week 8 assessments. Methods: 309 patients randomized 2:1 to receive MABp1 versus placebo. Patients were ECOG 1-2, with mCRC refractory to chemotherapy, any degree of weight loss, and cancer-associated symptoms. The composite primary endpoint assessed the rate of patients achieving stabilization or improvement in lean body mass (LBM) and two of three symptom measures (pain, fatigue, appetite loss) from screening to the week 8 assessment. The study was designed for placebo cross-over, thus OS analysis for MABp1 vs placebo was not possible. Results: 57 patients (38 MABp1 [18%] and 19 placebo [19%]) discontinued study prior to the week 8 assessment due to disease progression, including 17 (8%) and 11 (11%) deaths in MABp1 and placebo respectively. 62% of placebo patients received MABp1 after 8 weeks. 252 patients, 40% in MABp1 (68/169) vs 23% in placebo (19/83) met the primary endpoint (p = 0.003). 139 patients were available for PP survival analysis (90 MABp1 vs 49 Placebo). Median OS of those achieving the primary endpoint was 11.7 months vs 5.7 months for those that did not (HR 0.39; p < 0.0001). Radiographic stable disease was improved (42% vs 12%; p < 0.001) and incidence of SAEs (6% vs 15%; p = 0.11) reduced in those achieving the primary endpoint. Conclusions: Achieving the primary endpoint was associated with improvement in outcomes, RECIST stabilization, SAEs and survival. Further study should confirm the effect of MABp1 on survival in this population. Clinical trial information: NCT02138422.
Neoadjuvant radiotherapy vs. surgery alone for stage II/III mid-low rectal cancer with or without high risk factors: A multicenter randomized trial.
Authors: Wang Ziqiang , Deng Xiangbing , Liu Ping , Wang Xin , Jiang Dan , Wei Mingtian , Zhang Yuanchuan , Wu Qingbin , He Wanbin , Yang Xuyang , Yang Tinghan , Wang Meng , Wu Bing , Liu Yanjun , Meng Wenjian , Qiu Meng , Zhuang Hua , Li Yunfeng , Xu Feng , Zhou Zongguang
Published: September 2018

3537

Background: Neoadjuvant (chemo)radiotherapy (NRT) is the standard treatment for locally advanced rectal cancer (RC),which reducing local recurrence (LR) without survival benefit. There are also reports claiming similar local control achieved by surgery alone in selected patients, that raising the issue of omitting NRT in low risk patients. The aim of this study was to clarify the benefit of NRT in stage II/III RC with or without high risk factors. Methods: Eligible participants with mid-low cT3-4aN± RC were included and classified as high risk patients and low risk patients according to the clinical staging. High risk was defined as T3 tumor with extramural spread > 5mm, T4a or lymph node > 8mm. High and low risk patients were both randomized into two groups: high risk radiotherapy (HRR) or high risk surgery (HRS), low risk radiotherapy (LRR) or low risk surgery (LRS) separately. Patients in HRR and LRR received short term NRT (5*5Gy) + TME, while patients in HRS and LRS underwent surgery alone. The primary endpoint was 3-y LR. The secondary endpoints were OS, DFS, quality of surgery and safety. Results: From Jun. 2011 to Dec. 2015,401 consecutive patients were analyzed (LRS 99, LRR 97, HRS 102, HRR 103). As for primary endpoint, 3-y LR was obviously lower in low risk patients (3% vs. 9%, p = 0.026), but comparable in LRR vs. LRS (3% vs. 2%, p = 0.32) and HRR vs. HRS (11% vs. 7%, p = 0.42). Concerning secondary endpoints, low risk patients were favorable in 3-y OS (p < 0.001), DFS (p < 0.001), and distant metastasis (p = 0.001), compared to the high risk. And 3-y OS in HRR was higher than that in HRS (82% vs. 70%, p = 0.032). NRT caused 1.5% grade 3/4°radiation-related complications with a higher rate of late leakage (4.5% vs 0.0%, p = 0.004). Besides, positive CRM was higher in HRS (HRS 14.7% vs. HRR 4.9%, p = 0.017). Conclusions: Depth of extramural spread and lymph node status are favorable predictors for LR and survival. NRT may improve OS for high-risk RC. Low-risk RC has very low LR, suggesting against routine use of NRT. Relatively high LR and better OS in high risk patients justify use of NRT or NCR. Short-term radiation is safe for Asian patients, given caution be paid to more late leakage. Clinical trial information: NCT01437514.
Conditional survival analysis of stage IV colorectal cancer patients living >24 months.
Authors: Ali Nadia Dawn , Zandieh Shadi , Donohue Kristen , Chen Chunxia , Moore Dirk , Poplin Elizabeth , Carpizo Darren R.
Published: September 2018

3566

Background: The overall survival of patients with stage IV colorectal cancer (both in unresectable and resectable settings) has been increasing over recent decades due to improvements in chemotherapy, liver surgery and other liver-directed therapies. As a result of more patients living longer, there is a need to refine prognostic information to more accurately predict survival to assist multi-disciplinary cancer management teams in treatment decisions but also for patient quality of life. Methods: We performed a retrospective analysis of all patients with stage IV colorectal cancer seen at Rutgers Cancer Institute of New Jersey between Jan 1, 2005 to March 10, 2015 by ICD-9 code (N = 318 patients). This included patients who were deemed unresectable and patients who were resected with curative intent. Our study population was patients with documented survival for > 24 months (N = 158). Variables gathered included patient demographics, disease related (primary location, KRAS status, metastasis location, interval to metastases) and treatment related (chemotherapy regimens, radiation and surgery) data. Survival curve estimates are conditional on having survived 24 months. Results: Complete data was available for 125 patients (75 were resected for cure and 50 were not). Median overall survival of resected patients was not reached. The median overall survival of non-resected patients was 75.9 months. Univariate and multivariate analysis for surgery and non-surgery groups was performed. No statistically significant covariates were found beyond surgical resectability. The conditional survival probabilities of living 1, 2 or 3 years longer after 24 months of survival are 91.7%, 71.6% and 51.6% respectively in the patients with unresectable disease, and 98.1%, 92.2% and 88.8% in patients who were able to be resected with curative intent. Conclusions: These results indicate that patients who survive 24 months with stage IV colorectal cancer have an excellent prognosis. For patients who are unresectable and survive 24 months, this study suggests that they may benefit from resection of remaining metastatic sites if feasible. For resected patients this information may propose a possible benefit from repeat metastasectomy.
PEGylated human IL-10 (AM0010) monotherapy in refractory metastatic colorectal cancer.
Authors: Infante Jeffrey R. , Papadopoulos Kyriakos P. , Naing Aung , Autio Karen A. , Ott Patrick Alexander , Wong Deborah Jean Lee , Bendell Johanna C. , Bauer Todd Michael , Pant Shubham , Van Vlasselaer Peter , Brown Gail Linda , Oft Martin
Published: September 2018

3571

Background: Colorectal Cancer (CRC) has been refractory to immune therapies. The clinical benefit of immunotherapy is thought to depend on the expansion of activated, intratumoral, tumor specific cytotoxic CD8+ T cells which are low in most CRCs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Patients with CRC who have progressed on SOC first and second line of therapy have a reported 7.1 months OS with TAS-102 (Meyer et al. NEJM372;20, 2015). In this Phase 1 study the efficacy of AM0010 was studied in refractory metastatic CRC patients. Methods: CRC pts progressing on a median of 4 prior therapies (range 2-7) were treated daily with AM0010 in doses of 1 ug/kg SQ daily to 40 ug/kg in a dose escalation design. Tumor responses were assessed using irRC. Serum cytokines, activation of blood derived T cells and peripheral T cell clonality were analyzed. Pretreatment archival tissue samples were evaluated by IHC for tumor infiltration by CD8+T cells. Results: AM0010 was tolerated with reversible TrAEs. 10 pts (of 27) had a G3/4 TrAE. There were no objective responses. 11 patients were treated in dose escalation cohorts (1-10 ug/kg) and 16 pts were treated at or above RP2D (20 ug/kg or 40 ug/kg). Seven of 25 pts with at least one radiographic response evaluation had stable disease at 8 weeks. One patient had SD for 19.4 months. The mPFS (ITT n = 27 pts) was 1.6 months, mOS was 11.7 (range 2.4 – 32+) months. The median follow-up is 25.2 months (range 13-35). AM0010 increased Th1 cytokines IL-18 and IFNg in the serum of patients, while decreasing mediators of chronic, tumor promoting inflammation (Th17 cytokines) and TGFb. Tumor infiltrating granzyme B+ CD8+ T cells increased during the treatment. AM0010 induced de-novo oligoclonal expansion of T cell clones in patients. Conclusions: AM0010 is well tolerated in patients with refractory CRC. Although objective tumor responses were not seen in this very advanced CRC population, the observed immune activation including clonal T cell expansion, prolonged stable disease, and the mOS of 11.7 months is encouraging in this advanced CRC population. Future study of AM0010 in combination with FOLFOX in a second – line of therapy colorectal cancer patients is being planned. Clinical trial information: NCT02009449.
Impact of overall severity of adverse events (AEs) on long-term outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with first line systemic chemotherapy: Findings from 3,971 pts in the ARCAD database.
Authors: Zalcberg John Raymond , Shi Qian , Ferraro Danielle Angela , Meyers Jeffrey P. , Saltz Leonard , Goldberg Richard , Van Cutsem Eric , Hurwitz Herbert , Fuchs Charles , Bokemeyer Carsten , Sargent Daniel J. , De Gramont Aimery , Price Timothy Jay , Adams Richard
Published: September 2018

3582

Background: The prognostic importance of the incidence, severity, type and duration of AEs pts experience during chemotherapy varies between tumor types, and the available evidence across the board is often conflicting. Here we investigated the impact of the overall severity of AEs among pts with mCRC receiving first-line oxaliplatin (Oxa)- and/or irinotecan(Iri)-based regimens. Methods: The overall severity of AE data (i.e., max grade (G) of all AEs) were available on 3,971 pts (median age 61; 60% male, 47% ECOG PS 1+; 57% 2+ metastatic sites) enrolled onto 6 1st-line randomized trials. Around 46%, 45%, and 9% of pts had received Oxa-, Iri-, and Oxa+Iri-based regimens, respectively. Pts receiving biologic agents were excluded. Stratified multivariate Cox models were used to assess the associations with overall survival (OS) and progression-free survival (PFS); adjusted hazard ratios (HRadj) and 95% confidence intervals (CIs) are reported. Results: Pts who only received Oxa-based treatment reported the lowest rate of G3+ AEs (p < .0001) compared to pts treated with Iri- or Oxa+Iri-based regimens. Older age, female gender, and PS 1 or 2+ were associated with higher grade AEs (all p < .0001). Considering AEs experienced within 6w after randomization, 10% and 61% of pts experienced G4+ and G2-3 AEs, respectively. G3+ AEs were associated with a shorter OS for both pts receiving Oxa- (HRadj= 1.2, 95% CI, 1.1-1.3, padj < .0001) and Iri-based regimens (HRadj= 1.4, 95% CI, 1.2-1.5, padj < .0001). For the entire treatment course, 19% and 72% of pts experienced G4+ and G2-3 AEs, respectively. For Oxa-based regimens, pts with G3+ AEs had a longer OS (HRadj= 0.86, 95% CI, 0.78-0.94, padj = .0016), whereas G3+ AEs were associated with a shorter OS (HRadj= 1.2, 95% CI, 1.1-1.4, padj = .0004) for pts treated with Iri-based regimens. Similar patterns were seen for PFS. Conclusions: Pts who reported higher grade AEs during initial treatment (≤6w) have significantly worse outcome than those who do not. Further analyses with treatment exposure/detailed dose-AE profile and its impact on survival are warranted.
Prognostic signatures of oligometastasis in colorectal cancer liver metastasis.
Authors: Khan Sajid A. , Paty Philip , Zeng Zhaoshi , Lu Jun
Published: September 2018

3588

Background: Knowledge of molecular differences between limited metastasis (oligometastasis) and widespread metastases may provide biomarkers for selection of patients who will benefit from curative metastasis resection and provide useful prognostic information. In this study, we detect messenger RNA expressional patterns in patients with colorectal cancer liver metastasis (CRCLM) and identify networks of coding and noncoding RNAs corresponding to oligometastatic phenotype. Methods: RNA was prepared from frozen tumor tissue of 55 patients with CRCLM patients treated with liver resection and/or biopsy of their metastatic tumors with greater than 15 years of follow-up. Survival was calculated and stratified according to risk of recurrence. Cases were subject to RNA-Sequencing experiments with paired end sequencing. Results: RNA analysis with TopHat and Cuffdiff found significant differences in transcript expression according to recurrence for 667 genes (P < 0.05). Of these transcripts, 166 had a greater than 2-fold gene expression between groups when comparing mean Fragments Per Kilobase of transcript per Million mapped reads (FPKM) (P < 0.05). Unsupervised hierarchical clustering revealed distinct genomic patterns based on clinical outcome. A supervised gene expression analysis revealed a differential expression of genes in the Homeobox ( HOX) family (P < 0.05). Overexpression of individual members of the HOX gene family are associated with prognosis. Upregulation of the HOXD11 gene was associated with cure in 60% of cases while downregulation was associated with 5-year overall survivals of 16% (P = 0.023). Furthermore, when clusters of HOX family members were compared, we found that expression correlated with survival, underlining the importance of this gene family in oligometastasis biology. A high ratio of the HOXD cluster to HOXA cluster was associated with a long recurrence free survival (P = 0.002). Conclusions: Common genomic signatures characterize patients with liver oligometastasis from primary colorectal cancer. The HOX gene family strongly correlates with prognosis and represents a unique molecular subtype of patients. Further mechanistic studies of the HOX gene family in metastases are underway.
Monitoring the effect of first-line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma.
Authors: Thomsen Caroline Brenner , Hansen Torben , Andersen Rikke Fredslund , Lindebjerg Jan , Jensen Lars Henrik , Jakobsen Anders Kristian Moeller
Published: September 2018

3593

Background: Personalized medicine calls for an early indicator of treatment failure. Circulating tumor DNA (ctDNA) is a promising marker in this setting and our prospective study explored the association between disease control and change of ctDNA during first line chemotherapy in patients with RAS/RAF mutated metastatic colorectal cancer (mCRC). Methods: The present study included 138 mCRC patients receiving standard first line combination chemotherapy. In patients with a RAS/RAF mutated tumor the same mutation was quantified in the plasma using droplet digital PCR (ddPCR). The fractional abundance of ctDNA (ctDNA level) was assessed in plasma before treatment start and at every treatment cycle until radiologically defined progressive disease (PD). Results: RAS/RAF mutations were detected in the plasma from 77 patients (94% of patients with a tumor mutation). Twenty patients progressed on treatment and 57 stopped treatment without progression. The presence of a RAS/RAF mutation in plasma correlated to overall survival (OS) with a median of 24.2 months for patients with a wild-type tumor compared to 12.7 months for patients with a mution in plasma. A substantial increase in ctDNA level was highly associated with progression on treatment (risk ratio = 4.58, 95%CI = 1.99-10.51, p < 0.0001). Furthermore, with a stable ctDNA level the chance of non-progression was 88.2% (range 76.1-95.6%). The first substantial increase in ctDNA level occurred at a median of 51 days (range 14-133 days) before radiologically confirmed PD. Conclusions: The results indicate that ctDNA level may be predictive of treatment effect in patients with mCRC. An increase was observed to correlate with high risk of progression with a relevant lead time, whereas an unchanging ctDNA level related to stable disease.
Emergence of KRAS mutations and acquisition of resistance to EGFR blockade.
Authors: Yamada Takeshi , Takahashi Goro , Iwai Takuma , Takeda Kohki , Ueda Kohji , Koizumi Michihiro , Shinji Seiichi , Yokoyama Yasuyuki , Hara Keisuke , Matsuda Akihisa , Matsumoto Satoshi , Ohta Keiichiro , Eiji Uchida
Published: September 2018

3598

Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in patients with metastatic colorectal cancer (CRC). However, most patients who benefit from EGFR blockade acquire resistance. Although RAS mutation is established as a main cause of primary resistance, the mechanisms of this acquired resistance remain unclear. Here, we aimed to identify the mechanisms underlying acquired resistance to EGFR blockade by using circulating cell-free (ccf)DNA to track emerging KRAS, BRAF and S492R mutations during chemotherapy. Methods: We enrolled 33 patients with metastatic CRC and no RAS mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy that included EGFR blockade. We obtained ccfDNA from each patient before they started chemotherapy, and every 2–3 months during chemotherapy until disease progression. We detected KRAS (codons 12, 13, 61, and 146), BRAF (V600E) and S492R mutations using digital polymerase chain reaction. Results: KRAS mutations were detected in the ccfDNA of 4 of the 33 patients (12%) before chemotherapy. The response rate was 88% (29/33); all four non-responders had KRAS mutations in their ccfDNA and one of the four had both KRAS and BRAF mutations before starting chemotherapy. A response was detected in all patients (29/29) with no KRAS or BRAF mutations in their ccfDNA before chemotherapy. Of the 29 initial responders, 14 (48%) acquired resistance. Emerging KRAS mutations were detected in the ccfDNA of 13 of these 14 patients (93%); eight of these patients had multiple mutations (e.g. G12D and G12V; G13D and Q61H). BRAF mutations were also detected in six patients (43%); none of the patients had solo BRAF mutations. Six patients (43%) had S492R mutations; none of the patients had solo S492R mutations. Only one patient had no KRAS, BRAF or S492R mutations. Conclusions: Emergence of KRAS, BRAF or S492R mutations that were undetectable before the start of chemotherapy may be a mechanism underlying acquisition of resistance to EGFR blockade. Notably, emerging KRAS mutations were detected in most of the patients (93%) who acquired resistance. This indicates that KRAS mutation emergence may play a major role in the acquisition of resistance to EGFR blockade.
The feasibility and efficiency of wait and see policy for patients with complete clinical response following neoadjuvant therapy in rectal cancer: A prospective cohort study from China.
Authors: Gu Jin , Du Changzheng , Li Ming , Peng Yifan , Yao Yunfeng , Zhao Jun , Zhan Tiancheng , Cai Yong , Li Yongheng , Jin Jing
Published: September 2018

3610

Background: It has been reported that non-operative treatment (wait and see) is feasible for the selected rectal cancer cases with a complete clinical response (cCR) following neoadjuvant therapy (NT). The aim of this study is to determine whether "wait and see" policy is efficient for the cCR patients in China. Methods: We designed a prospective cohort study in China (ChiCTR-TRC-12002488). From Jul 2012 to August 2016, totally 45 patients with locally advanced rectal cancer who were cCR following NT were enrolled in the study; within whom, 32 patients were assigned to wait and see group, and the remaining 13 patients were assigned to surgery group (intent-to-treat grouping). Results: The median follow-up time was 24 months (range: 3-51). Of the patients who were followed up more than 12 months (n=37), 8 patients developed tumor progression (7 in wait and see group and 1 in surgery group, respectively). In the wait and see group, the local regrowth took an account of 23.1% (6/26), while the distant metastasis rate was 3.8% (1/26). In the surgery group, there were 23.1% (3/13) of patients who has residual cancer confirmed by postoperative pathological assessment. All the patients with tumor regrowth underwent radical surgery and no body died of cancer. Conclusions: Wait and see policy has an acceptable safety and efficiency, it may become an alternative treatment for the patients who were cCR following NT. Clinical trial information: ChiCTR-TRC-12002488. [Table: see text]
ABSOLUTE: A phase 3 trial of nanoparticle albumin-bound paclitaxel (nab-PTX) versus solvent-based paclitaxel (sb-PTX) in patients with pre-treated advanced gastric cancer (AGC)—Efficacy and QOL results.
Authors: Koeda Keisuke , Shitara Kohei , Takashima Atsuo , Fujitani Kazumasa , Tsujimoto Hironori , Tsuji Akihito , Oki Eiji , Takagane Akinori , Takagi Masakazu , Hamamoto Yasuo , Baba Hideo , Omuro Yasushi , Okuda Hiroyuki , Nakano Yasuyuki , Sugimoto Naotoshi , Nakamura Michio , Imamura Kazuhiro , Ichikawa Daisuke , Kuwano Hiroyuki , Koizumi Wasaburo
Published: September 2018

4010

Background: Sb-PTX is a standard second-line treatment for patients (pts) with AGC. Nab-PTX was developed to avoid the toxicities with use of solvents in sb-PTX and potentially improve efficacy. Based on ABSOLUTE trial, we conducted the additional analysis to evaluate the efficacy and QOL of nab-PTX and sb-PTX. Methods: Pts who were refractory to a fluoropyrimidine-containing first-line treatment were randomly assigned (1:1:1) to receive intravenous q3w nab-PTX (260 mg/m2) on day 1 of a 21-day cycle, and q1w nab-PTX (100 mg/m2) or q1w sb-PTX (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle. The primary objective was to evaluate whether q3w nab-PTX and q1w nab-PTX were non-inferior to q1w sb-PTX in terms of overall survival (OS). Tumor shrinkage at 8 weeks and at the time of the best response were also investigated. For the QOL analysis, EQ-5D score were collected at baseline and every 8 weeks during the first 24 weeks, and thereafter at every 24 weeks. Time to deterioration of EQ-5D score was compared between each arm as a minimally important difference of 0.05. Results: 741 pts were randomly assigned to q3w nab-PTX, q1w nab-PTX, or q1w sb-PTX. Median OS (months) were 10.3, 11.1, and 10.9, respectively. Q1w nab-PTX was non-inferior to q1w sb-PTX (hazard ratio 0.97, 97.5% CI 0.76-1.23; non-inferiority one-sided p = 0.0085), whereas q3w nab-PTX was not non-inferior to q1w sb-PTX (1.06, 95% CI 0.87-1.31; non-inferiority one-sided p = 0.062).The response rate of target lesions at 8 weeks and at the time of the best response (%) were 22.1 and 27.7 for q3w nab-PTX, 28.2 and 34.9 for q1w nab-PTX, and 18.0 and 25.6 for q1w sb-PTX. Median time to deterioration of EQ-5D score (months) were 2.1 in q3w nab-PTX, 3.8 in q1w nab-PTX, and 3.7 in q1w sb-PTX. Conclusions: Q1w nab-PTX was non-inferior to q1w sb-PTX in terms of OS. In addition, q1w nab-PTX showed favorable effect in comparison with q1w sb-PTX in terms of response rate of target lesions and time at best response. QOL was similar between q1w nab-PTX and q1w sb-PTX. These results suggest that q1w nab-PTX is a useful second-line treatment for pts with AGC. Clinical trial information: 132059.
SWOG S1310: Randomized phase II trial of single agent MEK inhibitor trametinib vs. 5-fluorouracil or capecitabine in refractory advanced biliary cancer.
Authors: Kim Richard D. , McDonough Shannon L , El-Khoueiry Anthony B. , Bekaii-Saab Tanios S. , Stein Stacey , Sahai Vaibhav , Keogh George P. , Kim Edward Jae-hoon , Baron Ari David , Siegel Abby B. , Barzi Afsaneh , Guthrie Katherine , Javle Milind M. , Hochster Howard S.
Published: September 2018

4016

Background: No standard treatment options are available for patients with advanced BC who fail gemcitabine/platinum therapy. The rationale for evaluation of trametinib was based on the presence of MAPK alterations and on earlier promising results with other MEK inhibitors in BC. Methods: Pts with histologically proven BC who progressed on gemcitabine/platinum were randomized to trametinib (2mg qd) (Arm A) vs infusional 5FU at 2400 mg/m2 over 46 hours or capecitabine (1000 mg/m2PO days 1-14 BID) (Arm B). Patients were stratified by planned chemotherapy 5FU/LV vs capecitabine; and disease site: cholangiocarcinoma vs gallbladder. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS) and response rate (RR). 80 eligible patients (40 for each arm) were needed to detect an improvement in median OS from 5 months to 8.25 months (1.65 HR). A planned interim futility analysis of objective response was performed on the first 14 pts registered to the trametinib arm. Results: The study was stopped early based on the lack of measurable response in the trametinib arm. 53 pts were randomized (27 pts in Arm A vs 26 pts in Arm B). Median age was 62 years and the primary sites of tumor were cholangiocarcinoma (77%) and gallbladder (23%). Median OS was 4.3 months (95% CI 3.1-5.1) for Arm A, and 8.0 months (95% CI 3.2-14.6) for Arm B with a HR of 2.02 (95% CI 1.01-4.03, p=0.05). The median PFS was 1.3 months (95% CI 1.2-1.5) for arm A and 2.8 months (95% CI 1.4-6.9) for arm B with a HR of 2.95 (95% CI 1.38-6.30, p=0.01). Overall RR was 8% (95% CI 0%, 19%) in Arm A vs 10% (95% CI 0%, 23%) in Arm B (p>0.99), and 8% vs 45% had stable disease. Eight pts in Arm A experienced treatment-related ≥ grade 3 toxicities, including one death due to vomiting/dehydration. Seven pts in Arm B experienced treatment-related grade 3 toxicities; no higher grade toxicities were reported. Conclusions: To our knowledge, this is the first prospective randomized study of a targeted agent versus chemotherapy for the second line treatment of BC. In this unselected population, the lack of response to trametinib resulted in early closure. The PFS and OS for trametinib were inferior to 5FU. Clinical trial information: 02042443.
Association of a DNA damage response deficiency (DDRD) assay with prognosis in resected esophageal and gastric adenocarcinoma.
Authors: Turkington Richard C. , Knight Laura A , Douglas Rosalie V. , Blayney Jaine K. , Stevenson Leanne , McManus Damian , McCavigan Andrena , Walker Steven M. , Bornschein Jan , MacRae Shona , Noble Fergus , Underwood Timothy J , O'Neill Robert , McQuaid Stephen , Arthur Ken , James Jacqueline , Eatock Martin McKinlay , Harkin Paul D , Fitzgerald Rebecca C. , Kennedy Richard D.
Published: September 2018

4026

Background: Current strategies to guide the selection of neo-adjuvant or adjuvant therapy in esophageal and gastric adenocarcinomas (EAC/GAC) are inadequate. We assessed a clinically validated 44 gene DNA Damage Response Deficiency (DDRD) assay to predict prognosis following neo-adjuvant DNA damaging chemotherapy (CT) in EAC and adjuvant CT or chemo-radiotherapy (CRT) in GAC. Methods: Transcriptional profiling of 273 formalin fixed paraffin embedded pre-treatment endoscopic EAC biopsies was performed using the Almac Diagnostics Xcel array. All EAC patients were treated with cisplatin-based neo-adjuvant chemotherapy followed by surgical resection between 2003 and 2014 at four UK centers in the OCCAMS consortium. Further validation was performed using a publically available dataset of 270 resected gastric cancers treated with adjuvant platinum-based CT, CRT or surgery alone at the Samsung Medical Centre, Seoul, Korea. The association between the DDRD score and prognosis was assessed by Kaplan-Meier analysis and Cox Proportional Hazards regression. Results: A total of 66 EAC samples (24%) were characterized as DDRD positive with the remaining 207 samples (76%) being DDRD negative. DDRD assay positivity was associated with improved DFS (HR 0.58; 95% CI 0.36-0.93; p = 0.024) and OS (HR 0.56; 95% CI 0.34-0.92; p = 0.023) following multivariate analysis. DDRD positive patients had a higher pathological response rate (p = 0.033) and a higher rate of loco-regional versus distant relapse (30% vs 20%; p = 0.013). For GAC, 132 samples (49%) were characterized as DDRD positive with the remaining 138 (51%) being DDRD negative. DDRD positivity was associated with improved DFS (HR 0.48; 95% CI 0.25-0.96; p = 0.037) following D2 gastrectomy and adjuvant CT or CRT. DDRD status was not associated with DFS in the surgery alone cohort (HR 0.87; 95% CI 0.55-1.38; p = 0.562). Conclusions: The DDRD assay is strongly predictive of benefit from DNA damaging neo-adjuvant CT and esophagectomy in EAC and gastrectomy and CT/CRT in GAC and can be applied to routine diagnostic material.
A randomized, double-blind, multi-center phase III study evaluating paclitaxel with and without RAD001 in patients with gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC).
Authors: Lorenzen Sylvie , Riera Knorrenschild Jorge , Pauligk Claudia , Goetze Thorsten Oliver , Hegewisch-Becker Susanna , Seraphin Jörg , Thuss-Patience Peter C. , Kopp Hans-Georg , Dechow Tobias Nicolaas , Vogel Arndt , Luley Kim Barbara , Pink Daniel , Stahl Michael , Kullmann Frank , Hebart Holger Frithjof , Siveke Jens T. , Egger Matthias , Homann Nils , Probst Stephan , Al-Batran Salah-Eddin
Published: September 2018

4027

Background: There is a need for effective treatments in the second- or further line setting in advanced gastric cancer, especially for new agents. In the current trial we evaluated paclitaxel with RAD001 (everolimus) in patients with gastric carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen. Methods: This is a randomized, double-blind, multi-center phase III study. Patients with gastric carcinoma or adenocarcinoma of the esophagogastric junction (EGJ) who have progressed after treatment with a fluoropyrimidine/platinum-containing regimen were randomly assigned to receive Paclitaxel (80 mg/m2) on day 1, 8 and 15 plus placebo (arm A) or RAD001 (10mg daily, arm B) d1-d28, repeated every 28 days as 2nd, 3rd or 4th line therapy. Primary end point was overall survival (OS), secondary endpoints were best overall response, disease control rate, progression free survival (PFS) and toxicity. Results: 300 patients (median age: 62 years; median lines prior therapy: 2; 47.7% of patients had prior taxane therapy) were randomly assigned (Arm A, 150, Arm B, 150). In the intention to treat population, there was no significant difference in median PFS (placebo, 2.07 vs. RAD001, 2.2 months, HR 0.88, p = 0.3) or median OS (placebo, 5.0 vs. RAD001, 6.1 months, HR 0.93, p = 0.54). For patients with prior taxane use, RAD001 improved PFS (placebo 1.8 vs. RAD001, 2.7 months, HR 0.69, p = 0.03) and OS (placebo 3.9 vs. RAD001, 5.8 months, HR 0.73, p = 0.07). Combination of paclitaxel and RAD001 was tolerable, but the RAD001 arm was associated with significantly more grade 3-5 mucositis (13.3% vs. 0.7%; p < 0.001). Conclusions: The addition of RAD001 to paclitaxel/RAD001 did not improve outcomes in pretreated metastatic gastric/EGJ cancer. Of note, activity was seen in the taxane pretreated group. Additional biomarker studies are planned to look for subgroups that may have a benefit. Clinical trial information: 2009-018092-14.
Current trends and survival in patients with esophageal squamous cell carcinoma: An analysis of the National Cancer Database from 2007 to 2013.
Authors: Chapman Brandon C. , Weyant Michael J. , Hosokawa Patrick W , Overbey Douglas M , Hilton Sarah , McCarter Martin , Gleisner Ana , Edil Barish H. , Gajdos Csaba
Published: September 2018

4032

Background: Although surgical resection is the treatment of choice for patients with esophageal squamous cell carcinoma (ESCC), some evidence suggests that definitive chemoradiation (CR) may have equivalent survival compared to surgery alone. The objective of this study was to evaluate current trends in the treatment of ESCC and its impact on overall survival (OS). Methods: Using the NCDB (2004-2013), patients with non-metastatic/loco-regional ESCC were categorized into definitive CR, neoadjuvant CR/surgery, surgery alone, and surgery/adjuvant therapy. Multivariate Cox proportional hazard models by stepwise selection were applied to estimate hazard ratios (HR) of predictors of OS. Results: We identified 11,229 patients with ESCC undergoing definitive CR (n = 8855, 78.9%), neoadjuvant therapy/surgery (n = 953, 8.5%), surgery alone (n = 1130, 10.1%), and surgery/adjuvant therapy (n = 291, 2.6%). The distance of primary tumor from incisors was comparable for all four groups. On multivariable analysis, treatment modality had the largest impact on OS followed by AJCC stage, age and annual surgical volume. Compared to neoadjuvant therapy/surgery, both surgery only (HR 1.17, 95% CI 1.04-1.32) and definitive CR (HR 1.51, 95% CI 1.37-1.66) were associated with increased long-term mortality. However, there was no difference in mortality in the surgery/adjuvant therapy group (HR 1.10, 95% CI 0.94-1.30) compared to the neoadjuvant therapy/surgery group. Patients treated at facilities performing more than 20 esophagectomies per year, regardless of whether they underwent surgical resection, had improved OS compared to facilities performing 10-19 per year (HR 1.47, 95% CI 1.29-1.68), 5-9 per year (HR 1.44, 95% CI 1.29-1.62), and < 5 per year (HR 1.53, 95% CI 1.38-1.70). Conclusions: Patients receiving either neoadjuvant therapy or adjuvant therapy and esophagectomy for ESCC have improved OS compared to patients undergoing esophagectomy alone and definitive CR. These findings suggest that patients with ESCC should be considered for multimodality treatment at high-volume centers and surgery should be included in the treatment plan whenever possible.
How many lymph nodes is enough? Defining the optimal lymph node dissection in stage I-III gastric cancer using the National Cancer Database.
Authors: Sura Karna Tushar , Ye Hong , Vu Charles C , Robertson John M. , Kabolizadeh Peyman
Published: September 2018

4034

Background: Gastric cancer is one of the most causes of cancer-related death worldwide. Surgical resection with lymph node dissection is the primary therapeutic modality. However, the appropriate extent of lymph node dissection remains controversial. Herein, the National Cancer Database (NCDB) was used to determine the optimal number of lymph nodes (LNs) to be dissected for resectable gastric cancer. Methods: The NCDB was queried from 2004-2013 for patients with invasive gastric cancer who underwent surgical resection with negative margins. The optimal number of LNs dissected was determined using a univariate χ2 cut-point analysis. Actuarial survival was determined using the Kaplan Meier method, and comparisons of survival estimates were completed with log-rank tests. Multiple sensitivity analyses were utilized to decrease bias. Results: 17,851 patients were included. The mean (±SD) number of LNs examined was 16 ± 11. For all patients, the optimal number of LNs needed to be examined was 20+ nodes. When correcting for stage migration ( < 7 LNs removed), the optimal cut-off value was 20+ LNs. When stratifying by pathologic nodal stage, the cutpoint was 10+ LNs for pN1 and pN2. The 5-year survival was 30.6 ± 1.6% for 0-9 removed LNs compared to 48.2 ± 1.2% for 10+ removed LNs (p < 0.001) in pN1 disease and 18.3 ± 1.7% for 0-9 removed LNs compared to 32.6 ± 1.2% for 10+ removed LNs (p < 0.001) in pN2 disease. For pN3 disease, the optimal cut-off point was 20+ LNs; the 5-year survival was 17.2 ± 1.3% for 0-19 removed LNs compared to 28.5 ± 1.7% for 20+ removed LNs (p < 0.001). Moreover, the outcome was inferior among patients who had > 10% positive dissected LNs (p < 0.05). Conclusions: The optimal number of dissected LNs of 20+ LNs was associated with superior survival. Extended LN dissection is to be considered especially in patients with > 10% positive dissected LNs.