bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I dose escalation trial (ARQ 197–111) evaluating combination of selective c-Met inhibitor ARQ 197 and erlotinib
Authors: Laux I. , Goldman J. , Just R. , Brady K. , Li J. , Schwartz B. , Savage R. , Garmey E. , Rosen L.
Published: August 2020

3549

Background: ARQ197 (A) is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Phase I data for ARQ 197 monotherapy is previously reported. Recent evidence suggests c-Met promotes resistance to EGFR-inhibition by driving ERBB3 (HER3)-dependent PI3K activation. Dual EGFR-Met inhibition is now proposed as a strategy for overcoming resistance to EGFR-inhibition. Methods: Patients (pts) were enrolled in a sequential-cohort dose-escalation trial seeking to define safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of A in combination with 150 mg daily oral erlotinib (E). Oral A was administered at escalating doses of 120, 240, and 360 mg bid. Intra-patient dose escalation was allowed in the absence of dose-limiting toxicity (DLT) through 1 cycle of therapy (21 days). Results: 25 pts (10 F/15 M; mean 60.5 yrs) received EA combination with starting A dose of 120 (8 pts), 240 (4 pts), and 360 (13 pts) mg bid. PK data reveal linear kinetics through 360 bid and no evidence of drug-drug interaction. Adverse events (AEs) considered related to combination therapy were reported in 13 (52%) of pts incl.sinus bradycardia (5 pts), fatigue (5 pts), rash (4 pts), itching (3 pts), and diarrhea (3 pts). 2 pts experienced related serious AEs incl. neutropenia (360 bid) and sinus bradycardia (240 bid). 1 death occurring on-study was considered unrelated to study drug. 9/10 evaluable pts demonstrated disease stabilization (SD) as their best RECIST response (5.9–27.1+ wks). Tumor regressions (2.3%-19.4%) were observed in 4/10 evaluable pts. Of note, 3/3 evaluable pts with NSCLC achieved SD for durations (14–32 wks) exceeding median PFS in BR.21 (9.7 wks). Conclusions: Continuous therapy with EA combination appears well tolerated and without drug-drug interaction. While no formal MTD was identified, a phase 2 combination dose (R2PD) of 360 mg bid A + 150 mg daily E is recommended. This RP2D is currently being investigated in an ongoing randomized trial comparing EA to E monotherapy in 2nd/3rd line NSCLC.

[Table: see text]
A single-center, open-label, dose escalation, safety, and pharmacokinetic study of ENMD-1198 administered orally to patients (pts) with advanced cancer
Authors: Nallapareddy S. , Gustafson D. , Leong S. , Messersmith W. , Arnott J. , Eckhardt S. G. , Sidor C. , Camidge D. R.
Published: August 2020

3562

Background: ENMD-1198 (2-methoxyestra-1, 3, 5, (10) 16-tetraene-3-carboxamide), an analog of 2-methoxyestradiol (2ME2), has both antiangiogenic and antiproliferative effects in various tumor types. ENMD-1198 inhibits MT polymerization by binding to β-tubulin at the colchicine-binding site and inhibits HIF-1alpha. This Phase 1 study is evaluating the safety of ENMD-1198 to determine the maximum tolerated dose. Methods: Eligible pts had advanced cancer for which no effective therapy exists that is either evaluable by RECIST criteria or tumor markers that could be monitored for clinical benefit. Phase 1 dose escalation in 3+3 design for first 5 cohorts; modified to 1 pt cohorts for subsequent cohorts until Grade 2 treatment related toxicity, and then standard 3+3 design. All pts treated with once daily oral ENMD-1198 in 28-day cycles (with post-treatment drug-free observation period of 7–14 days in Cycle 1 only). Pts are treated until the appearance of significant treatment-emergent toxicities or disease progression (PD) occurs. Results: To date, 27 pts have been enrolled in 12 dose cohorts (range 5 to 550 mg/m2/d). Median age/performance status is 61/1. Total # of treatment cycles to date is 68, with a median of 2 cycles (range <1 to 15 cycles). Most frequent toxicities (all grades, n=22) were pain (77%), fatigue (55%), constipation (36%), neuropathy and nausea (both 32%), and anemia (27%). 4 pts have experienced stable disease (SD) for more than 2 cycles. There have been no objective responses to date. 2 pts experienced dose limiting toxicity with Grade 4 neutropenia in the 550 mg/m2/d cohort. Following drug holiday, pts restarted at 425 mg/m2/d and continued for at least 1–2 more cycles before being removed from study for PD. One pt (neuroendocrine ca pancreas) is experiencing prolonged SD at 60 mg/m2/d >14 cycles and a 2nd pt (prostate ca) experienced SD at 30mg/m2/d for 10 cycles. ENMD-1198 was absorbed rapidly after oral administration. There was a linear relationship between dose and drug exposure as measured by AUC across all doses (5 - 550 mg/m2). The elimination half-life of ENMD- 1198 averaged more than 12 hours after a single dose. Conclusions: DLT was identified at 550 mg/m2/d. Cohort expansion at 425mg/m2/d is ongoing.

[Table: see text]
A phase I study of the combination of intravenous Reolysin (REO) and gemcitabine (GEM) in patients (pts) with advanced cancer
Authors: Arkenau H. , Evans J. , Lokelma M. , Roxburgh P. , Morisson R. , Coffey M. , Gill G. , Mettinger K. , Thompson B. , de Bono J.
Published: August 2020

3584

Background: REO (reovirus serotype 3) is a Dearing strain, naturally occurring, non-enveloped virus with limited pathogenecity in humans. REO replicates specifically in transformed Ras-activated cells due to inhibition of the dsRNA-activated protein kinase, resulting in cell-lysis. GEM has shown efficacy in a wide range of tumors commonly driven by activated Ras, and causes cell cycle arrest in S phase. Results from isobologram analysis suggest potential synergies of REO and GEM. Methods: This open-label, dose-escalating, two-centre phase-I trial studied the combination of iv REO, d1–5 and iv GEM, d1 and 8, qw3. The REO starting dose was 3x109 TCID50 over 1-hour, increasing in successive cohorts and GEM was given at a fixed dose of 1,000 mg/m2 over 30-min. Endpoints were the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and safety profile of REOGEM and to establish a RP2D. Secondary endpoints were to evaluate the immune response, to evaluate pharmacokinetics of REOGEM and to describe any antitumor activity. Results: Since July 2007, 15 heavily pre-treated pts with disease progression prior to trial entry (9M/6F, median age 56 years, ECOG 0/1: 3/12) were entered into this trial. After 2 pts had Grade >3 toxicities during the first cycle (1 pt: GGT and Trop-I increase and PD; 1 pt: Trop-I increase and unspecific ST-changes) considered probably related to both agents the protocol was amended and the dose of REO was adjusted to 1x109 TCID50, d1 of each cycle (C-1) and increased in subsequent cohorts to 3x109, 1x1010, and 3x1010 TCID50. In total 45 cycles were administered (median 3) resulting in mild and expected toxicities including fever, headaches, rhinorrhea, fatigue and myelosupression. The MTD was not reached. Of the 10 pts evaluable for response, 2 pts (breast and nasopharyngeal) had PR and/or clinical response and 5 pts had SD for 4–8 cycles, amounting for a total disease control rate (CR+PR+SD) of 70%. Conclusions: The combination of REOGEM was well tolerated and resulted in disease control for a majority of pts. A RP2D, of REO 3x1010, d1 and GEM 1000mg/m2, d1 and 8, qw3, was recommended and phase-2 trials are underway.

[Table: see text]
Further evaluation of 11C-PD153035 as a molecular imaging probe for the assessment of the epidermal growth factor receptor status in non-small cell lung cancer patients
Authors: Yu J. , Liu N. , Hu M. , Song X. , Xie L. , Meng X. , Wang X. , Kong L. , Yang G.
Published: August 2020

3590

Background: Epidermal growth factor receptor (EGFR) plays a key role in tumorgenosis and is therefore an important target for new therapeutic and prognostic strategies. Our pilot study has demonstrated that 11C-PD153035, a highly EGFR selective tracer for positron emission tomography (PET), accumulated in tumor mass of non-small cell lung cancer (NSCLC) and the tracer uptake correlated with EGFR expression. Here, we further evaluate correlation between the intensity of 11C-PD153035 uptake and EGFR protein expression level and gene mutation. Methods: Fourteen patients (45–71y, mean 59.2±9.2 y, Male: Female = 8:6, squamous carcinoma: adenocarcinoma = 9:5) with pathologically proved NSCLC were examined with PET using 11C-PD153035 one week before surgery. Radioactivity concentrations, derived from regions of interest (ROI), were analyzed mathematically to maximum standardized uptake value (SUVmax). The EGFR protein expression of surgical specimen was utilized by immunohistochemistry (IHC) with a three-tier system intensity scored and Western Blot assay. The EGFR genetic alterations in exon 19 and 21 were examined by direct sequencing of polymerase chain reaction (PCR) products. Results: 11C-PD153035 uptake was observed in 9 out of 14 NSCLC patients (mean SUV 3.94±1.06, range 0.8–5.9) and the biodistribution study further demonstrated accumulation of radioactivity in the tumor mass. The SUVmax of 11C-PD153035 molecular images did not correlate with tumor size and injection dose of the tracer. A closely correlation between SUVmax and EGFR protein expression as determined by IHC (r = 0.84, p = 0.005) was observed but not with the protein expression level of Western Blot analysis (r = 0.442, p = 0.114), as well as EGFR exon 19 (r = -0.078, p = 0.790) or exon 21 (r = 0.118, p = 0.689) gene mutation. With ROC analysis according to IHC intensity, the cut-off value of SUVmax was 2.45. Conclusions: PET with 11C-PD153035 might therefore be used to visualize EGFR pattern on tumor in NSCLC patients and for individualized planning of therapeutic strategies with EGFR targeted drugs, especially small-molecule TKIs (gefitinib and erlotinib) which targeting the intracellular EGFR tyrosine kinase domain as PD153035.

No significant financial relationships to disclose.
Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database
Authors: Jackson McCleary N. A. , Meyerhardt J. , Green E. , Yothers G. , de Gramont A. , Van Cutsem E. , O’Connell M. , Twelves C. , Saltz L. , Sargent D. ,   The ACCENT Collaborative Group
Published: August 2020

4010

Background: Prior studies suggested that older and younger pts with colon cancer receive similar benefit from IV fluoropyrimidine (FU) adjuvant (adj) therapy (rx). Combination and/or oral FU rx are increasingly given as adj rx. We sought to determine the impact of pts age <70 v ≥70 yrs on colon cancer recurrence and mortality from adj rx with these newer options. Methods: We used data from 10,499 pts <70 yrs and 2,170 pts ≥70 yrs in 6 phase III adj rx trials comparing IV FU to combinations with irinotecan, oxaliplatin or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer from the ACCENT database. Endpoints were overall survival (OS; time to death), disease-free survival (DFS; time to recurrence or death), and time to recurrence (TTR; censoring at last follow-up). Cox models were stratified by age and adjusted for gender and stage; interaction testing was used to explore the differential benefit by age. Results: Approximately 75% of pts had stage III disease (74% age<70, 77% age≥70). OS, DFS, and TTR were statistically significantly improved for those in the experimental v control arms among pts <70 but not those >70 ( table ); the interaction between age and rx was statistically significant for all endpoints (p=0.01 for OS, DFS, and TTR). These results were consistent whether experimental rx was oxaliplatin-based, irinotecan-based or oral FU. Deaths in first 6 month of adj rx were not statistically significantly different between experimental and control arm. Conclusions: Our results show conclusively that pts >70 do not receive the same benefit from combination and/or oral FU as those <70. Any benefit, if present, compared to IV FU/LV would not be clinically meaningful. Outcomes of experimental (combination or oral FU) vs control (IV 5-FU) by treatment and age

[Table: see text]

[Table: see text]
Postoperative surveillance recommendations for early-stage colon cancer based on results from the clinical outcomes of surgical therapy trial
Authors: Tsikitis V. L. , Malireddy K. , Green E. A. , Christensen B. , Whelan R. , Hyder J. , Lauter D. , Marcello P. , Larach S. , Sargent D. , Nelson H.
Published: August 2020

4013

Background: Intensive postoperative surveillance is associated with improved survival and recommended for patients with late stage (stage IIB & III) colon cancer. We hypothesized that stage I & IIA colon cancer patients would experience similar benefits. Methods: Secondary analysis of data from the Clinical Outcomes of Surgical Therapy trial was performed by analyzing results according to TNM stage; early (stage I & IIA; 537 patients) and late (stage IIB & III; 254 patients) stage disease. Five-year recurrence rates were higher in patients with late (35.7%) versus early stage disease (9.5%). Early and late stage salvage rates, recurrence patterns and methods of first detection were compared by χ2 test. Results: Salvage rates for early and late stage disease patients with recurrence were the same (35.9% versus 37%, p=0.9 respectively). Median survival following second surgery after recurrence was 35.8 months late stage and 51.2 months for early stage patients respectively. Sites of first recurrence did not significantly differ between late and early stage disease: liver (37.4% vs. 27.2%); lung (29.7% vs.23.6%); intraabdominal (24.2% vs.10.9%); and locoregional (12.1% vs.10.9%). Methods of first detection of recurrence were also not significantly different: CEA (37.4% vs. 29.1%); CT scan (26.4% vs. 23.6%); chest X-ray (12.1% vs. 7.3%); and colonoscopy (8.8% vs. 12.7%), for late versus early stage disease, respectively. Conclusions: Patients with early stage colon cancer have similar sites of recurrence, and receive similar benefit from post-recurrence therapy as later stage patients; implementation of existing surveillance guidelines for early stage patients is appropriate.

No significant financial relationships to disclose.
Use of amphiregulin and epiregulin mRNA expression in primary tumors to predict outcome in metastatic colorectal cancer treated with cetuximab
Authors: Prenen H. , Jacobs B. , De Roock W. , Van Oirbeek R. , Biesmans B. , De Schutter J. , Fieuws S. , Laurent-Puig P. , Van Cutsem E. , Tejpar S.
Published: August 2020

4019

Background: To study the power of two epidermal growth factor receptor (EGFR) ligands, epiregulin (EREG) and amphiregulin (AREG) expression in primary tumors to predict the outcome in patients with chemorefractory metastatic colorectal cancer (cmCRC) treated with the combination of cetuximab plus irinotecan. Methods: Gene expression measurements and KRAS mutation analysis were performed on archival formalin-fixed paraffin-embedded primary tumors of 220 cmCRC patients. Response was measured using RECIST criteria. The relation between ligand expression levels and outcome was evaluated using logistic regression for response and Cox regression for survival data. ROC analysis was performed for response and survival data. Confidence intervals (CI) for the performance indices were obtained with a non-parametric bootstrap procedure. Findings were externally validated on a series of 67 samples treated in a similar setting. Results: In KRAS wild-type (WT) patients, there was a significant association between log-transformed ligand expression and response (EREG: Odds ratio for objective response 1.90 (p=0.0005, 95%CI:1.27–2.83), c-index=0.681; AREG: Odds ratio for objective response: 1.82 (p=0.0017, 95%CI:1.22–2.72), c-index=0.673). In a Cox- regression model log-transformed ligand expression was significantly associated to progression-free survival (PFS) and overall survival (OS) (EREG: hazard ratio (HR) for PFS: 0.61 (p<0.001, 95%CI:0.51–0.73), cτ-index=0.696; AREG: HR for PFS: 0.60 (95%CI:0.50–0.74), cτ-index=0.671; EREG: HR for OS: 0.61 (p<0.001, 95%CI:0.50–0.73), cτ-index=0.667; AREG: HR for OS: 0.65 (p<0.001, 95%CI:0.54–0.78), cτ-index=0.642). There was no predictive power of ligand expression in KRAS mutant patients. Conclusions: Expression of EGFR ligands in primary tumors significantly predicts favorable outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.

[Table: see text]
-93G>A polymorphism of hMLH1 associated with prognosis for patients with colorectal cancer
Authors: Kim J. , Chae Y. , Sohn S. , Kang B. , Lee S. , Lim K. , Choi G. , Baek J.
Published: August 2020

4039

Background: Polymorphisms in the DNA repair genes may contribute to variation in DNA repair capacity, thereby affecting the risk of carcinogenesis and prognosis of colorectal cancer. Accordingly, the present study analyzed polymorphisms of DNA repair genes and their impact on the prognosis for patients with colorectal cancer. Methods: Three hundred and ninety- seven consecutive patients with curatively resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue and 14 polymorphisms of DNA repair genes (XRCC1, hMLH1, ERCC2, ERCC4, VARS2[rs2074511, rs2249459], XPA, XPC, POLR2A, POLR2B, RFC1, RFC4, XAB2, DNMT3B) determined using a PCR-RFLP assay. Results: The median age of the patients was 63 years (range, 21–85), and 218 (54.9%) patients had colon cancer and 179 (45.1%) patients rectal cancer. Pathologic stages after surgery were as follows: stage 0/I (n=86, 21.7%), stage II (n=146, 36.8%), stage III (n=145, 36.5%), and stage IV (n=20, 5.0%). Multivariate survival analysis including stage, differentiation, age, and CEA level showed that the survival for the patients with the -93AA genotype of hMLH1 was worse than for the patients with the combined -93GG and GA genotype (overall survival: hazard ratio [HR]=2.953, 95% Confidential Interval [CI], 1.273–6.850, P=0.012; disease-free survival: HR=2.299, 95% CI, 1.417–3.730, P=0.001), whereas the other polymorphisms were not associated with survival. Conclusions: The -93G>A polymorphism of hMLH1 was found to be an independent prognostic marker for patients with colorectal cancer. Accordingly, in addition to the pathologic stage, the analysis of -93G>A polymorphism of hMLH1 can help identify patient subgroups at high risk of a poor disease outcome.

No significant financial relationships to disclose.
The impact of the number of lymph node metastases on the overall recurrence of colon cancer in the era of sentinel lymph node mapping
Authors: Arora M. L. , Saha S. , Sirop S. , Chakravarty B. , Korant A. , Soni M. , Wiese D. , Desai D. , Ganatra B. , Kaushal S. , Iddings D.
Published: August 2020

4049

Background: Sentinel Lymph Node Mapping (SLNM) in colon Cancerc (Cca) has been shown to be successful, sensitive and accurate. We aimed to evaluate the recurrence rates in patients(pts) with Cca after SLNM and correlate it to the number of positive(+ve) LNs. Methods: Between 1996 and 2006, pts diagnosed with Cca were enrolled in a prospective trial and underwent SLNM and oncologic resection including regional LNs. The primary outcome was development of recurrence with minimum follow-up (f/u) of 24 months. For recurrence analysis, exclusion criteria included: stage IV disease, benign pathology, lost to follow-up, refusal of indicated chemotherapy, non cancer related death or second cancer. A retrospective matched control (diagnosed with Cca undergoing standard colon resection without SLNM, gp B) from our own institution were analyzed and compared to the SLNM group for the same period. Results: A total of 486 pts with Cca were included. Of these, 272 consecutive pts underwent SLNM between 1996–2006. SLNM was successful in 99.8% of pts, with a sensitivity, negative (-ve) predictive value, and overall accuracy of 85.3%, 91.7% and 94.4% respectively. The nodal positivity was 46.0%; of these, 15.1% had micrometastasis. The average number of LNs resected / pt was 15.0 and the average number of SLNs / pt was 2.4. For recurrence analysis, 153/272 pts with minimum f/u 2 years were included. Of these, 49 had stage I, 46 had stage II and 58 had stage III disease. The recurrence rates were 4.1%, 8.6% and 15.5% in stage I, II, and III disease respectively. The recurrence rates were significantly lower when our 153 pts were compared to 214 matched controls ( table 1 ). The recurrence rates increased from 6.3% in pts with no +ve LNs to 11.5% when one LN was +ve, 16.7% when 2 LNs were +ve and 20% when 3 or more LNs were +ve. Conclusions: SLNM in Cca is associated with decreased rates of recurrence as compared to conventional therapy. The number of positive LNs is an independent risk factor for recurrence.

[Table: see text]

No significant financial relationships to disclose.
Colorectal cancer susceptibility variants and clinical outcome in adjuvant and metastatic colorectal cancer
Authors: Lenz H. , Lurje G. , Haiman C. A. , Yang D. , Pohl A. , Ning Y. , El-Khoueiry A. , Iqbal S. , Zhang W.
Published: August 2020

4051

Background: Recent genome-wide association studies had identified colorectal cancer susceptibility loci on chromosomes 8q24 (rs6983267), 15q13(rs4779584), 18q21(rs4939827, rs12953717 and rs4464148), 10p14(rs10795668) and 8q23.3(rs16892766). Although the function role of these germline variants are unclear, given the importance of these variants and colorectal cancer risk, we have carried out the first pilot study to explore the association of these variants and clinical outcome. We used pooled data from two CRC-cohorts (locally advanced and metastatic CRC), and investigated the hypothesis that these germline variants may be associated with clinical outcome in adjuvant and metastatic colorectal cancer patients. Methods: Whole blood was collected from 515 patients with locally advanced (n=197) and metastatic CRC (n=318). After extraction of genomic-DNA, germline variants were genotyped as previously described (Haiman et al, Nat Genet, 2007). The genotype success rate was 98%. Blinded repeat samples (5%) were included for quality control purposes; genotype concordance was ≥ 99%. Results: Our results suggest that rs10795668 at 10p14 and rs719725 are significantly associated with time to tumor recurrence in adjuvant colorectal cancer patients, patients with rs10795668 AA genotype had significantly increased risk of time to tumor recurrence compared with those harboring G allele (TG+GG) patients(p=0.05, log-rank test). In metastatic cancer patients, we found rs4939827 at 18q21.1 were significantly associated with overall survival in female patients and rs10795668 at 10p14 were significantly associated with OS in male patients, respectively (p<0.05). Conclusions: Our preliminary results suggest cancer risk alleles may also associated with clinical outcome in adjuvant and metastatic colorectal cancer. Moreover, this correlation is sex-specific in metastatic colorectal cancer. Further comprehensive trials warranted to confirm our pilot findings.

[Table: see text]
VEGF, EGF, HGF, and PDGF levels during chemotherapy in patients with metastatic colorectal cancer
Authors: Er O. , Inanc M. , Dikilitas M. , Ozkan M. , Karaca H. , Saraymen R. , Elmali F.
Published: August 2020

4057

Background: Colon cancer is the third most common type of cancer in USA. Angiogenesis is necessary for the growth and metastasis of tumors in colorectal cancer (CRC). Increased angiogenesis in the primary tumor has been associated with poor prognosis and relapse of the disease. The aim of the present study was to measure plasma levels of the angiogenic factors in metastatic CRC patients before and after chemotherapy and to correlate with prognosis, in order to estimate the possible predictive value of angiogenic factor levels. Methods: Thirty-eight patients with metastatic CRC were recruited to the study and blood samples were taken to measure VEGF, EGF, HGF and PDGF before chemotherapy. All patients received XELOX (Capecitabine+Oxaliplatin) and response was assessed according to their clinical and radiologic evaluation after three cycles of XELOX. Angiogenic factors were measured after third cycle of chemotherapy. Statistical analysis was performed by SPSS 15.0 package program. Kolmogorov-Smirnov, Wilcoxon and 2 sample T test were used. Results: Eighteen patients (47.3%) achieved partial response (PR), 10 (26.3%) stable disease (SD), and 10 (26.3%) progressive disease (PD). VEGF, EGF, HGF and PDGF levels at baseline and after three cycles of chemotherapy are summarized in table . After 3 cycles of XELOX therapy VEGF, EGF, HGF and PDGF levels significantly decreased respectively, (p<0.0001, p=0.011, p=0.049, p<0.0001), in PR group. PDGF levels significantly decreased in SD group (p<0.0001). However, other angiogenic factors were not influenced. Serum HGF levels significantly increased (p<0.046) after 3 cycles of chemotherapy, however, VEGF, EGF, and PDGF levels were not significantly different in patients with PD. Conclusions: Significant decrease in VEGF, EGF, HGF and PDGF levels correlate with PR and indicate good prognosis in patients with advanced CRC. However, increased HGF level is associated with PD.

[Table: see text]

No significant financial relationships to disclose.
EGFR polymorphism and KRAS mutational status as predictors of resistance to anti-EGFR therapy in advanced colorectal cancer (ACRC): A GEMCAD study
Authors: Maurel J. , Alonso-Espinaco V. , Alonso V. , Escudero P. , Jimeno M. , Garcia-Albeniz X. , Muñoz J. , Fernandez- Martos C. , Carcereny E. , Castellví-Bel S.
Published: August 2020

4060

Background: Single nucleotide polymorphism (SNP) in codon R497K of EGFR by reducing EGFR activity has been associated to resistance to anti-EGFR monoclonal antibodies in ACRC (Carcereny, ASCO2008). Methods: We retrospectively investigated the role of EGFR R497K and KRAS mutational status in primary CRC or metastases, in predicting response rate (RR), progression free survival (PFS) and overall survival (OS) of cetuximab or panitumumab in second or third line therapy in patients (pts) with ACRC. EGFR R497K was detected by real-time PCR using the TaqMan technology and KRAS mutation status in codons 12/13 was determined by sequencing. CT scans were done every 6–8 weeks (w) until progressive disease. Results: A total of 117 pts with available tissue out of 168 pts treated with anti-EGFR therapy in 6 Spanish Institutions, were analysed for EGFR R497K and KRAS mutational status. There were no differences in RR (18.8 vs.16.8%), PFS (13.2 vs. 12 w) and OS (31 vs. 28 w) between the whole and the selected cohort. We found no significant differences on RR (9/59;15.2 vs. 9/52; 17.3%), PFS (13.5 vs. 13.2 w) and OS (33 vs. 26.8 w) according to EGFR R497K (GG vs. GA/AA). Pts with wild-type (WT) KRAS had better response (20.7% vs. 8.1%;p=0.07) and PFS (14.4 vs. 11.7 w; p=0.006) compared with mutant KRAS. Interestingly, a significant increment on RR (30 vs. 0%, p=0.003), PFS (14.4 vs. 7.4 w, p=0.002) and OS (34.1 vs. 20 w, p=0.03) was observed only in those patients with WT KRAS and >1x upper limit of normal (ULN) lactate dehydrogenase (LDH) levels compared with mutant KRAS, but these differences were not found in pts with WT KRAS and <1xULN levels of LDH: [RR (14 vs. 14%, p=NS), PFS (14.4 vs. 13.1 w, p=NS) and OS (31 vs. 31 w; p=NS)]. Conclusions: EGFR R497K is not a predictive marker of efficacy to EGFR-inhibitors. Our study suggest that pts with WT KRAS and >1xULN levels of LDH, have major benefit to anti-EGFR therapy in second-third line therapy.

No significant financial relationships to disclose.
DUSPs as markers of MEK/Erk activation in primary colorectal cancer
Authors: De Roock W. , Janssens M. , Biesmans B. , Jacobs B. , De Schutter J. , Fieuws S. , Van Cutsem E. , Tejpar S.
Published: August 2020

4064

Background: DUSPs dephosphorylate P-MAPK and are activated as a negative feedback loop upon RTK signaling. Higher expression of DUSP 4 & 6 is also found in cells with constitutive Erk activation like KRAS mutant (MUT) cells (Bild et al. Nature 2005). We correlated DUSP1, 4, 6 (isoforms a & b) & 8 mRNA expression level in FFPE primary colorectal cancer (CRC) of 186 chemorefractory patients treated with cetuximab (CTX) with KRAS MUT state and progression-free survival (PFS) and overall survival (OS). Methods: KRAS codon 12,13, 61&146, BRAF V600E and NRAS codon 12&13 MUT were analyzed with the Sequenom MALDI TOF MassArray system. The DUSPs and 3 housekeeping genes were quantified by qRT-PCR. TwoStep cluster analysis was performed. PFS and OS were estimated by the Kaplan-Meier method. Results: KRAS MUT was associated with increased DUSP4 (MWU;p=.0006) & 6a (p=.0067). DUSP6a dephosphorylates P-Erk, DUSP4 also dephosphorylates P-JNK & P-p38. DUSP1 & 8 primarily dephosphorylate P-JNK & P-p38 and were not associated with KRAS MUT. KRAS MUT clustered into 3 groups according to DUSP4 expression: 32 high, 38 median & 13 low (t- test;p<.0001). The low MUT expression was comparable to wild-type (WT) expression. KRAS WT clustered into 2 groups: 69 low & 24 high DUSP4 (ANOVA;p<.0001). 7/24 of high expressors were found to have a BRAF or NRAS MUT. The 32 MUT high expressors had a longer median PFS (log-rank;p=.015) and OS (p=.065) after CTX. The 17 KRAS/BRAF/NRAS WT high expressors had a shorter median OS (p=.026), but not PFS (p=.745). Conclusions: There is a significantly higher DUSP4 & 6a mRNA expression in the KRAS MUT compared to WT primary CRC. However, this is not a black and white observation. In the KRAS MUT there are 3 distinct clusters of DUSP4 expression. The high expressors (= supposed attenuated Erk signaling) have a longer PFS and OS after CTX. Adaptation to constitutive KRAS signaling with differential levels of MEK/Erk activation needs to be further investigated and will be of help in selecting patients for therapy with MEK inhibitors. It suggests not all KRAS MUT will be good candidates for MEK inhibitors. In the cluster of high DUSP4 expressing KRAS WT 30% are BRAF or NRAS MUT. This suggests DUSP expression of FFPE samples could be a more sensitive marker of MEK/Erk activation and resistance to EGFR inhibitors than KRAS MUT analysis alone.

[Table: see text]
Prospective pharmacogenetic analysis in advanced colorectal cancer (CRC) patients receiving first-line cetuximab-UFT-irinotecan therapy: Importance of gene polymorphisms related to antibody-dependent cellular cytotoxicity (ADCC)
Authors: Etienne-Grimaldi M. , Bennouna J. , Formento J. , Douillard J. , Francoual M. , François E. , Faroux R. , El Hannani C. , Jacob J. , Milano G.
Published: August 2020

4069

Background: Our purpose was to test the predictive value of germinal gene polymorphisms potentially linked to cetuximab, fluoropyrimidine and irinotecan pharmacodynamics on toxicity, clinical response, time to progression (TTP) and overall survival (OS). Methods: 52 patients with advanced CRC were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial (33 men, 19 women, mean age 63, range 36–84, PS 0–1). Treatment consisted in cetuximab (day 1-day 8-day 15, 250 mg/m2/week following a 400 mg/m2 loading dose) associated with irinotecan (day 1, 250 mg/m2) and UFT-folinic acid (day 1 to day 14, 250 mg/m2/day UFT, 90 mg/day folinic acid). Median number of administered cycles was 7 (range 1–8). The following gene polymorphisms were analyzed on blood genomic DNA: EGFR (CA repeats in intron 1, - 216G>T, -191C>A), EGF (61A>G), FCGR2A (131Arg>His), FCGR3A (158Phe>Val), UGT1A1 (TA repeats), TYMS (28 bp repeats including the G>C mutation on the 3R allele, 6 bp deletion in 3’ UTR), MTHFR (677C>T, 1298A>C). Results: Grade 3–4 toxicity was recorded in 59.6 % of patients. The toxicity score (sum of maximum grade for each toxicity pattern) was significantly linked to the FCGR2A genotype (median score 9, 9.5 and 13 in Arg/Arg, Arg/His and His/His patients, respectively, p = 0.035) and to the EGFR -191 genotype (median score 11 in CC patients versus 8.5 in CA patients, p = 0.040). Response rate was 49% (3 CR and 21 PR over 49 assessable patients) and was significantly higher in patients bearing the FCGR3A Val allele (62.1 % in Val/Val or Val/Phe versus 26.3 % in Phe/Phe, p = 0.020) or the TYMS 3RG allele (65.0 % versus 28.6 % in patients with no 3RG allele, p = 0.029). Gene polymorphisms did not influence TTP. A multivariate Cox analysis including gene polymorphisms and PS showed that overall survival was improved in patients bearing the FCGR3A Val allele (relative risk of death was 2.25 in Phe/Phe patients relative to Val-containing genotypes, 95% CI 1.03–4.91, p = 0.041). Conclusions: Present data suggest the importance of ADCC in cetuximab pharmacodynamics, as outlined by the role of FCGR gene polymorphisms on toxicity, responsiveness and survival.

No significant financial relationships to disclose.
Safety and efficacy of AMG 655 plus modified FOLFOX6 (mFOLFOX6) and bevacizumab (B) for the first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Saltz L. , Infante J. , Schwartzberg L. , Stephenson J. , Rocha-Lima C. , Galimi F. , Dillingham K. , Hsu M. , Wiezorek J. , Fuchs C.
Published: August 2020

4079

Background: AMG 655 is an investigational fully human monoclonal antibody (IgG1) agonist of human death receptor 5 (DR5). AMG 655 activates caspases and induces apoptosis in sensitive tumor cells. The primary objective of this phase 1b study was to determine the maximum tolerated dose (up to a target dose of 10 mg/kg IV every 2 weeks) of AMG 655 that can be safely administered in combination with mFOLFOX6-B to mCRC pts. Methods: Eligible pts were ≥ 18 years old with previously untreated mCRC, ECOG PS of 0 or 1, and adequate hematologic, hepatic, and renal function. Pts were enrolled into sequential cohorts of 3- or 10-mg/kg AMG 655 + mFOLFOX6-B administered on day 1 of each 14-day cycle. Study endpoints included incidence of dose-limiting toxicities (DLT), adverse events (AE), pharmacokinetic (PK) parameters of AMG 655, and objective response rate (by modified RECIST). Results: As of 09/08, 12 pts (6 per cohort) were enrolled and received ≥ 1 cycle of treatment; 8 were female. Median (range) age was 54 (37–75), median (range) time on AMG 655 treatment was 6.9 (1.6 to 11.4+) months; 8 pts continue on study treatment. There were no DLTs in the first 28 days of treatment. Eight pts had grade 3–4 AE; the most common were diarrhea, febrile neutropenia, peripheral neuropathy, neutropenia, DVT, and pulmonary embolism (2 pts each). Post baseline laboratory parameters grade ≥ 3: no ALT and AST; 1 grade 3 bilirubin (due to disease progression), and 3 grade 3 lipase (asymptomatic). No anti-AMG 655 antibodies were detected. AMG 655 PK values (Cmax, Cmin) were similar to those observed with single-agent AMG 655 (LoRusso JCO 2007; 25: abstract 3534). AMG 655 did not appear to affect PK of oxaliplatin or bevacizumab. Best overall tumor response: 5 partial responses (2 unconfirmed, both underwent resection); 6 stable disease; 1 pt had non-measurable disease at baseline. Time to disease progression (3 patients): 8, 42, and 44 weeks. Conclusions: The addition of AMG 655 does not appear to substantially alter the safety profile of mFOLFOX6-B. The randomized phase 2 part of the trial (mFOLFOX6-B ± AMG 655) is in progress.

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Phase II efficacy results using an oncolytic herpes simplex virus (NV1020) in patients with colorectal cancer metastatic to liver (mCRC)
Authors: Geevarghese S. K. , Chen A. , Geller D. A. , de Haan H. A. , Iagaru A. , Knoll A. , Nemunaitis J. , Reid T. R. , Sze D. Y. , Tanabe K.
Published: August 2020

4089

Background: NV1020 is a genetically engineered oncolytic Herpes virus. Published Phase 1 dose-ranging results reported no significant related toxicity except for a mild (<24 hr) viral syndrome. Initial Phase 2 tumor response data using the optimal biological dose (OBD) are now presented. Methods: Patients with heavily pretreated, progressing liver mCRC received 4 doses of NV1020 (1 X108 pfu) by weekly hepatic artery infusion followed by two cycles of conventional chemotherapy. Follow-up (≥1 year) evaluation included 4 X 3-monthly scans, then telephone contact to determine survival. Blinded, independent radiologists interpreted CT (modified RECIST) and FDG PET (EORTC) scans. Results: All 22 patients had prior 5FU-based treatment: 77% and 58% also had oxaliplatin or irinotecan, respectively (50% both agents); 86% had one targeted therapy (24% ≥2 such agents); 29% had radiofrequency ablation. Mean time from primary resection was 95 weeks, mean CEA was 182 ng/mL, and 55% had pulmonary lesions. Two patients received only 2 NV1020 infusions due to rapidly progressing disease. Virus tolerability was unchanged from Phase 1 and no related, serious or Grade 4 toxicity was found. NV1020 neutralizing antibodies rose in all patients but no NV1020 was shed (saliva, skin). After NV1020 alone, 10/22 (45%) and 8/20 (40%) on CT and PET, respectively, showed stable disease. 21 patients subsequently received chemotherapy, 45% with drugs to which they were previously refractory and 36% with only one new drug. 14% refused both planned cycles. Best response observed with CT was 55% (1 CR, 1 PR, 10 SD) and 59% (5 PR, 8 SD) with PET. Despite intrahepatic delivery, some remote responses were observed. Response did not correlate with initial tumor size, SUV, or CEA, with time since primary resection, pre- or post NV1020 chemotherapy type. Nine (41%) remain alive > 1 year. Kaplan-Meier median time to progression is 28 weeks (95% CI [9–37]); median survival probability is 52 weeks (95% CI [36–90]). Conclusions: NV1020 stabilizes liver metastases in highly advanced mCRC and may sensitize tumors to salvage chemotherapy resulting in extended overall survival. A controlled Phase 2/3 trial is justified.

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Preoperative hepatic and regional arterial chemotherapy in the prevention of liver metastasis after colorectal cancer surgery
Authors: Xu J. , Zhong Y. , Niu W. , Qin X. , Wei Y. , Ren L. , Wang J. , Chen J. , Qian S.
Published: August 2020

4090

Background: To investigate whether preoperative hepatic and regional arterial chemotherapy are able to prevent liver metastasis and improve overall survival in patients receiving curative colorectal cancer resection. Methods: Patients with Stage II or Stage III colorectal cancer (CRC) were randomly assigned to receive preoperative hepatic and regional arterial chemotherapy (PHRAC group, n=256) or surgery alone (control group, n=253). The primary endpoint was disease-free survival, whereas the secondary endpoints included liver metastasis-free survival and overall survival. Results: There were no significant differences in overall morbidity between PHRAC and Control groups. During the follow-up period (median, 42 months), the median liver metastasis time for patients with stage III CRC was significantly longer in the PHRAC group (16±3 months v.s. 8±1 months, P=0.01). In stage III patients, there was also significant difference between the two groups with regard to the incidence of liver metastasis (18.9% vs 27.3%, P=0.01), 5-year disease-free survival (70.2% vs 52.0%, P=0.0076), 5-year overall survival (80.3% vs 69.5%, P=0.020) and the median survival time (40.1± 4.6 months vs 36.3 ± 3.2 months, P=0.03). In the PHRAC arm, the risk ratio of recurrence was 0.63 (95% CI, 0.51–0.79, P=0.0001), of death was 0.50(95% CI, 0.32–0.67; P=0.005), and of liver metastasis was 0.70 (95% CI, 0.52–0.86; p=0.01). In contrast, PHRAC seemed to be no benefit for stage II patients. Toxicities, such as hepatic toxicity and leucocyte decreasing, were mild and could be cured with medicine. Conclusions: Preoperative hepatic and regional arterial chemotherapy, in combination with surgical resection, could be able to reduce and delay the occurrence of liver metastasis and therefore improve survival rate in patients with stage III colorectal cancer.

No significant financial relationships to disclose.
A phase I/II study of bevacizumab (beva), erlotinib (erl), and 5-fluorouracil (5-FU) with concurrent external beam radiation therapy (RT) in locally advanced rectal cancer (LARC)
Authors: Blaszkowsky L. S. , Hong T. S. , Zhu A. X. , Kwak E. L. , Mamon H. J. , Shellito P. C. , Cusack J. C. , Berger D. , Horgan K. , Ryan D. P.
Published: August 2020

4106

Background: The German Rectal Cancer Study Group established neoadjuvant therapy as a standard of care in patients with T3/T4 rectal cancer. Beva, a vascular endothelial growth factor (VEGF) inhibitor with demonstrated activity in colorectal cancer, and erl, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor may both serve as radiation sensitizers. Methods: Twenty one pts with LARC, defined as T3 or T4 disease by MRI or endorectal ultrasound, were enrolled from May 2006-December 2008. Pts had adequate hepatic, renal and hematopoietic function, and an ECOG performance status of ≤2. Treatment consisted of 5-FU 225 mg/M2/day by continuous infusion for the duration of radiation (50.4 Gy). Beva 5 mg/kg was administered on days 1, 15 and 29. The first cohort received erl 50 mg, the second cohort 100 mg, and third cohort 150 mg daily until completion of radiation. Pts underwent surgery 6–9 weeks following the radiation. The primary endpoints were determination of the maximally tolerated dose (MTD) and pathologic complete response (pCR). Secondary endpoints included toxicity (TOX), local control (LC), progression free survival and median survival. A total of 25 pts will be treated at the MTD. Results: Twenty-one pts began study therapy: 2 withdrew consent prior to completing study therapy, and 2 pts were removed prior to completion for clostridium difficile colitis and cardiac ischemia. No dose limiting toxicities were achieved. Erl 100 mg was chosen as the MTD. Two pts have not yet completed study treatment. Fifteen pts have completed study therapy and have undergone surgery, of whom 7 (47%) have demonstrated a pCR. At a median follow-up of 7 months, there have been no local recurrences in patients who completed study therapy. Grade 3–4 treatment related TOX included: lymphopenia 6 (59%), diarrhea 4 (24%), rash 2(12%), cardiac ischemia 1(6%), transaminitis 1(6%), mucositis 1(6%). One pt developed an anastomotic leak. Conclusions: Beva and erl in combination with infusional 5-FU and RT appears to be a highly active preoperative regimen for locally advanced rectal cancer.

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Neutropenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOX
Authors: Shitara K. , Matsuo K. , Takahari D. , Yokota T. , Ura T. , Muro K.
Published: August 2020

4115

Background: FOLFOX combined with bevacizumab is established as standard first-line chemotherapy for metastatic colorectal cancer (MCRC), and neutropenia is one of the most common of its side effects. Neutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several type of cancers, although there are no reports in MCRC. We aimed to assess whether neutropenia during chemotherapy could be a marker of improved survival of patients with MCRC. Methods: Patients with MCRC who received FOLFOX with or without bevacizumab as first-line chemotherapy were retrospectively analyzed to assess whether neutropenia during chemotherapy is associated with improved survival. Several background characteristics and chemotherapy features (grade of neutropenia, use of bevacizumab, use of irinotecan, reintroduction of oxaliplatin, and tumor progression) as time-varying covariates (TVCs) were analyzed as potential prognostic factors. Results: Of 153 patients, mild neutropenia (grade 1–2) occurred in 60 patients (39%) and severe neutropenia (grade 3–4) occurred in 46 patients (30%). The other 47 patients (31%) did not experience neutropenia. In 106 patients experiencing neutropenia, 66% of patients experienced their highest grade within 4 cycles. According to a multivariate Cox model with TVCs, hazard ratios of death were 0.55 (95% CI, 0.31–0.98; P = 0.044) for patients with mild neutropenia and 0.35 (95% CI, 0.18–0.66; P = 0.002) for those with severe neutropenia. If the analysis of neutropenia was limited to 4 cycles of FOLFOX, mild or severe neutropenia remained a significant prognostic factor according to survival analysis with TVCs. Conclusions: Both mild and severe neutropenia during chemotherapy are associated with improved survival in patients with MCRC. Prospective trials are required to assess whether dosing adjustments based on neutropenia may improve chemotherapy efficacy.

No significant financial relationships to disclose.
Metastatic colorectal cancer (mCRC): Recent patterns of chemotherapy and monoclonal antibody (MoAb) therapy in clinical practice
Authors: Hess G. P. , Wang P. F. , Quach D. , Barber B.
Published: August 2020

4120

Background: New systemic chemotherapies, particularly the MoAbs, bevacizumab (BMab), cetuximab (CMab), and panitumumab (PMab) have advanced therapy for mCRC. However, the optimal combination and sequencing of these and other chemotherapies are not established, and little is known about their patterns of use in clinical practice. We examined the frequency, patterns of use, and dosing changes of MoAbs across lines of therapy. Methods: The dataset consists of Varian and Impac electronic medical records for 304,654 cancer patients from 91 practice sites across 19 states. Inclusion/exclusion criteria were applied: ≥18 years old, newly diagnosed with mCRC or developed metastases during 1/1/2004 - 1/31/2008, and could be observed ≥3 months beyond their dates of metastases. Patients on a clinical trial at any time during the analysis were excluded. Results: The study sample included 1,655 patients (52% male, mean age 61.9 years). 11% received all five therapeutic classes: fluoropyrimidines, irinotecan, oxaliplatin, EGFR MoAbs (PMab and CMab), and VEGF MoAb (BMab). 19% received at least 3 treatment classes. BMab, fluorouracil, leucovorin, oxaliplatin (BMab+FOLFOX) was the most frequently observed 1st line regimen in 26% of patients. Across the study period more patients received BMab than PMab or CMab (69%, 7%, and 22%, respectively, for any exposure); 55% received BMab for 1st-line therapy. A BMab dose increase within a line of therapy was recorded in 22% of patients for 1st-line, 21% for 2nd-line, and 15% for 3rd-line. Among patients who continued BMab from 1st to 2nd line (N=239) and 2nd to 3rd line (N=88), 44% and 39%, respectively had a dose increase (mean/month 890mg to 1078mg, and 844mg to 1053mg). Conclusions: The most frequent 1st-line chemo regimen was FOLFOX. BMab was the most commonly administrated MoAb. Trends toward dose-escalation of BMab were observed both within lines of therapy and across lines of therapy.

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