bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of primary melanoma ulceration and clinical benefit of adjuvant vaccination with tumor-specific antigenic peptides
Authors: Baurain J. , Stas M. , Hammouch F. , Gillain A. , Feyens A. , Van Baren N. , Tromme I. , Van Wijck R. , Garmyn M. , Coulie P. G.
Published: August 2020

3022

Background: Therapeutic vaccination of metastatic melanoma patients with detectable disease is followed by tumor regression in ±10% of the patients, mostly with locoregional disease. Considering the absence of an effective treatment to prevent relapses of cutaneous melanoma, we have applied a multipeptide vaccine in the adjuvant setting. Methods and Results: We treated 45 HLA-A2-positive melanoma patients with no evidence of disease but at high risk of relapse. They received 5 vaccines every 3 weeks, then one every 3 months over 2 years. A first group (n=14) received 4 antigenic peptides derived from MAGE-A3, NA17, gp100 and Tyrosinase, emulsified independently in 4x1ml of Montanide ISA51. A second group (n=16) received the 4 peptides emulsified together in 1x1ml of Montanide. A third group (n= 15) received the 4 peptides alone. Forty-one patients were eligible for immune response analysis after 5 injections. A T-cell response to at least one peptide was detected in 21/27 patients vaccinated with Montanide, but in none of 14 vaccinated with peptides alone. Median follow-up time was 24 months ±10 months (SD). Relapse free survival (RFS) at 18 months was 37% for all the patients and no significant difference was observed between patients vaccinated with or without Montanide: 41% and 27%, respectively. Median distant metastasis-free survival time (DMFS) was doubled for patients vaccinated with vs without Montanide (p=0.132). Multivariate analysis for various prognostic factors including sex, age, PS, vaccine type, or immune response suggested that the ulceration of the primary tumor was associated with a better clinical course following vaccination (HR=0.295 with IC95%: 0.09–0.97). Conclusions: Vaccination with mutiple peptides in Montanide is well tolerated and elicits specific immune responses. Patients vaccinated with peptides in Montanide have a prolonged RFS and DMFS compared to whose vaccinated with peptides alone. Patients who had an ulcerated primary tumor seem to benefit more from this adjuvant vaccine. These results warrant further evaluation of such vaccines in a randomized trial with the ulceration of the primary tumor as a stratification factor.

No significant financial relationships to disclose.
Multicenter phase II study of sequential chemotherapy, radiotherapy, and immunotherapy in locally advanced pancreatic (Pa) and biliary tree (Bt) adenocarcinoma (ADK)
Authors: Recchia F. , Sica G. , Candeloro G. , Bisegna R. , Necozione S. , Bonfili P. , Tombolini V. , Rea S.
Published: August 2020

3047

Background: The aim of this study was to evaluate the activity and toxicity of a multistep, sequential treatment including induction chemotherapy (ICT), consolidation chemoradiotherapy (CXRT), and maintenance immunotherapy (MI) in untreated patients with locally advanced (LA), inoperable, or incompletely resected Pa and Bt ADK. MI with low-dose interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) was given in order to enhance the immune function, which could eradicate minimal residual disease, as previously shown (Clin Cancer Res 2001). Methods: From September 2003 to September 2007, 54 patients, 32 men, 22 women, 63% with Pa and 37% with Bt ADK, mean age of 63 years (range 36–75), were treated with an ICT consisting of 3 courses of cisplatin, 70 mg/m2 day 1, gemcitabine 1000 mg/m2 day 1 and 8 every 3 weeks. Patients who were progression-free (PF) after ICT received CXRT, 45 Gy in 25 fractions, using coplanar four-field technique, with concurrent capecitabine 850 mg/m2/day. Six weeks after completion of CXRT, patients were restaged: In the absence of disease progression, they received, as an MI, IL-2, 1.8 x 106 I.U. and RA, 5 mg/kg, 5 days/week, 3 weeks/month for 1 year and thereafter until progression. Results: After a median follow-up of 27.5 months, all patients were evaluable. A response rate of 26% (95% c.i. 15–40%), was observed, with 44.5% of patients achieving stable disease. Thirty-eight patients, 27 with Pa and 11 with Bt ADK, had a clinical benefit from ICT, and were treated with CXRT. Fourteen PF patients, 7 Pa and 7 Bt ADK, received an MI with IL-2 and RA. Median progression-free survival (PFS) and overall survival (OS) for all 54 patients were 6.8 and 12.1 months, respectively, while the 14 patients treated with MI had a 5-year PFS and OS rate of 36% and 58%, respectively. Grade 3–4 hematological and gastrointestinal toxicity were observed in 30% and 37% of patients, respectively, while 28% of patients had grade 1–2 autoimmune reactions. Conclusions: These results support the efficacy and safety of a multistep sequential treatment with ICT, followed by CXRT, and an MI with IL-2 and RA, in patients with LA, inoperable or incompletely resected Pa and Bt ADK. Further studies are necessary to validate this strategy.

No significant financial relationships to disclose.
A novel recombinant tandem repeat DNA vaccine targeting at MUC1
Authors: Wu W. , Jin D. , Lou W. , Fan J. , Wang D. , Qin X.
Published: August 2020

3066

Background: Tandem repeat (TR) is the key epitope of mucin 1 (MUC1) for inducing cytotoxic T lymphocytes (CTL) to kill the tumor cells specifically. A novel recombinant TR DNA vaccine was constructed to study its induced immune responses. Methods: A recombinant human TR (rhTR) gene encoding a single TR polypeptide of MUC1 was synthesized and cloned into the multiple cloning sites of plasmid pcDNA3.1/Myc-his (+) A to construct the recombinant plasmid pcDNA3.1-TR/Myc-his (+) A (pTR plasmid). Expression of pTR plasmid was confirmed by transfection assay and Western blot analysis. C57BL/6 (H-2b) mice were immunized with pTR plasmid (n=15) by tibial muscle injection. Mice inoculated with the empty vector (EV group, n=15) and 0.9% NaCl solution (NS group, n=15) were used as vector and blank control respectively. Four weeks later, all mice were immunized again. Specific antibody detection and cytotoxic assay were used to evaluate the vaccine-induced TR specific immune responses. Results: DNA sequencing confirmed that the pTR plasmid was exactly constructed. Transfection assay and Western blot analysis found that the transfected COS7 cells expressed TR polypeptide of MUC1 48 hours after transfection. Cytotoxic assay showed that immunization with pTR plasmid into C57BL/6 mice resulted in more efficient induction of CTL specific cytolysis against TR polypeptide than that of EV group and NS group (p<0.01). Vaccine immunized mice had a higher equivalent concentration of anti-TR specific antibodies (2324μg/ml±238μg/ml) than that of EV group (1896μg/ml±533μg/ml, p<0.01) and NS group (1736μg/ml±142μg/ml, p<0.01). Conclusions: The novel recombinant TR DNA vaccine targeting at MUC1 was exactly constructed, immunization with which could induce TR specific CTL response and antibodies response in mice.

No significant financial relationships to disclose.
A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (Pts) with advanced solid tumors
Authors: Schwartz G. K. , Robertson S. , Shen A. , Wang E. , Pace L. , Dials H. , Mendelson D. , Shannon P. , Gordon M.
Published: August 2020

3513

Background: XL281 is a potent and selective inhibitor of wild type and mutant RAF kinases showing anti-tumor activity in multiple xenograft models. Mutations in KRAS or BRAF can activate the RAF/MEK/ERK pathway in human tumors and may promote sensitivity to RAF kinase inhibitors. Methods: Pts were enrolled in successive cohorts of XL281 orally once daily on a 28-day cycle. Tumor response was assessed per RECIST every 8 wks. Plasma pharmacokinetic and pharmacodynamic samples were collected. The maximum tolerated dose (MTD) was expanded to 10 pts each with colorectal (CRC), melanoma, papillary thyroid (PTC) and NSCLC. Pre- and post-dose tumor and surrogate tissues were obtained. Biomarker and genotype analyses of pathway genes were performed. Results: The dose escalation phase is complete; 30 pts were treated with XL281. DLTs of fatigue, nausea, vomiting, and diarrhea were observed at the MAD (225 mg). The MTD is 150 mg. The most common related AEs included Grade 1/2, fatigue (48%), diarrhea (35%), nausea (35%), vomiting (35%) and anorexia (30%). Three pts had related AEs ≥G3: hypokalemia, nausea, and vomiting. One pt with an ocular melanoma demonstrated a cPR of 4 mos duration. Twelve pts had SD (3 -17+ mos), including 2 with I131-refractory PTC harboring BRAF V600E mutations (15+ and 17+ mos). Nine of these pts had decreases in target lesions (5–29%), including a pt with KRAS mutant CRC on study for 20 wks with marked symptomatic improvement. At the MTD, paired biopsies from 4 pts (3 melanoma, 1 NSCLC) show an average 72 % decrease in pMEK, 68 % decrease in pERK, 24 % decrease in Ki67 (proliferation) and 64 % increase in TUNEL (apoptosis). Three of 6 evaluable pts in the MTD cohort show SD at first assessment, including 1 melanoma pt with a NRAS Q61R mutation who showed a 20% decrease in target lesions. Conclusions: XL281 was generally well tolerated and the MTD was established at 150 mg. One cPR occurred in an ocular melanoma subject, and clinical benefit (PR or SD) occurred in 43% (13/30) of pts in the dose-escalation phase. XL281 demonstrates biological activity by modulation of the RAF pathway in tumor and surrogate tissue, with decreases in cell proliferation and increases in apoptosis.

[Table: see text]
Functional imaging using DCE-US: Which parameter for the early evaluation of antiangiogenetic therapies?
Authors: Lassau N. , Koscielny S. , Chebil M. , Chami L. , Bendjilali R. , Roche A. , Escudier B. , LeCesne A. , Soria J.
Published: August 2020

3524

Background: The early evaluation of anti-angiogenic treatments is a challenge in oncology. Functional imaging methods based on the measure of tumoral vascularization have been developed using different modalities (CT, MRI, US). We analyzed the response in four studies using different targeted treatments with dynamic contrast enhanced-ultrasonography (DCE-US). Seven parameters characterizing tumoral perfusion were estimated. The objective of the study was to determine which parameter is the most appropriate to confirm earlier the efficacy of treatments. Methods: A total of 823 DCE-US were performed in 117 patients included in 4 following studies (multikinase inhibitor targeting angiogenic-receptor with a cytotoxic or thyrosine-kinase inhibitor targeted angiogenic-receptor and C-kit or monoclonal antibody anti-VEGFR). Each DCE-US was performed using contrast agent (Sonovue, Bracco) with perfusion and quantification softwares (Toshiba) from raw linear data with a high temporal resolution: 4 frames per second during 3 minutes. Seven quantitative parameters of perfusion were estimated: peak intensity (PI) and area under the total curve (AUC), area under the wash-in (AUWI), area under the wash-out (AUWO), time to peak intensity, mean transit time (MTT), wash-in slope. DCE-US were performed before treatment and after D3, D 8, 15, 21 (according each study design) and every 2 months. Patients were classified in good responders and bad responders according the response (RECIST on CT-scan) after 2 cycles or 2 months. Results: Among the 7 parameters, 2 parameters related to the blood volume studies (AUC and AUWO) were always earlier significantly modified (p = 0.04 to p = 0.004). One was never modified: MTT. For the 4 others, it's depending of each study. Conclusions: DCE-US appears as a sensitive tool to evaluate tumoral response to anti-angiogenic drugs. Functional parameters related to the blood volume are more pertinent and represent a key add value to early evaluation of these therapies studies.

No significant financial relationships to disclose.
Correlation of plasma levels of free insulin-like growth factor 1 and clinical benefit of the IGF-IR inhibitor figitumumab (CP- 751, 871)
Authors: Hixon M. L. , Gualberto A. , Demers L. , Paz-Ares L. G. , Novello S. , Blakely L. J. , Langer C. L. , Lipton A. , Pollak M. , Karp D. D.
Published: August 2020

3539

Background: Free IGF-1 (fIGF-1) represents the biologically active fraction of IGF-1, the main circulating ligand of the Insulin-like Growth Factor type I Receptor (IGF-IR). Signaling through the IGF-IR induces tumor survival and resistance to cancer therapy. Figitumumab (F) (CP-751,871) inhibits IGF-1-induced IGF-IR autophosphorylation with an IC50 of 0.42 nmol/L. Methods: Plasma levels of fIGF-1 were measured in a phase 1b/2 multi-center study of Paclitaxel (T) and Carboplatin (C) and F in patients (pts) with treatment-naïve NSCLC. Other serum markers of the IGF-IR pathway, including circulating soluble IGF-IR (sIGF-IR), IGFBP3 and ALS (acid-labile subunit), were also investigated. The Kaplan-Meier method was used to estimate median survival times. Results: A total of 536 blood samples from 159 pts were analyzed. Baseline median and range fIGF-1 were 0.53 and 0.07–1.99 ng/mL. fIGF-1 directly correlated with IGFBP3 and ALS, and inversely with sIGF-IR (Rho=-0.430, p=0.03). Treatment with F resulted in dose-dependent accumulation of fIGF-1 with a sustained >10 fold increase in fIGF-1 plasma levels at the 20 mg/kg dose, suggesting complete systemic blockade of fIGF-1 binding to the IGF-IR. sIGF-IR decreased and IGFBP3 increased in response to F, but increases in IGBP3 were more modest than those of fIGF-1. Baseline plasma levels of fIGF-1 had a 96.6% negative predictive value for PFS status at 6 months (p=0.03). Median PFS were respectively 2.73 and 6.53 months for TC alone and TC with F (20 mg/kg) in the high fIGF-1 group (p=0.001) while no significant treatment effect of F was observed in the low (<0.54 ng/mL) fIGF-1 group. Sixty three percent of pts with high fIGF-1 had tumors of adenocarcinoma histology. Conclusions: IGF-1 is a key element in the biology of NSCLC of adenocarcinoma histology and its determination may contribute to the identification of pts who benefit from figitumumab therapy.

[Table: see text]
Analysis of biomarkers during early phase clinical development of AMG 479, an investigational fully human monoclonal antibody antagonist of type 1 insulin-like growth factor receptor (IGF-1R)
Authors: McCaffery I. , Tolcher A. , Puzanov I. , Sarantopoulos J. , Rosen L. , Deng H. , Paweletz K. , Friberg G.
Published: August 2020

3545

Background: AMG 479 showed anti-tumor activity in a phase 1 (P1) and phase 1b (P1b) trial (Tolcher, J Clin Oncol. 2007;25:3002; Sarantopoulos, J Clin Oncol. 2008;26:3583). We sought to identify predictive markers of response to AMG 479 in these trials by analyzing pharmacodynamic (PD) markers in serum, and expression and mutations of regulators of the IGF-1R pathway in tumors. Methods: Patients (pts) had advanced solid tumors and received AMG 479 (1–20 mg/kg Q2W) in the P1 trial or AMG 479 (6 or 12 mg/kg Q2W) + panitumumab (6 mg/kg Q2W) or gemcitabine (1,000 mg/m2 QW) in the P1b trial. Serum levels of IGF-1 and IGFBP-3 were measured pre dose on Day -1 and post dose at various time points. In the P1 trial, we examined relationships between tumor response (by RECIST) and: 1) levels of IGF-1 and IGFBP-3 (at baseline or PD change from baseline); 2) somatic mutations in key genes (including K-ras, and PTEN) of the IGF-1R pathway (in archival tumors); and 3) expression of PTEN (measured by immunohistochemistry in archival tumors). Results: Serum IGF-1 and IGFBP-3 increased in a concentration-dependent manner between 1 and 12 mg/kg AMG 479, with an apparent plateau between 12 and 20 mg/kg AMG 479. Baseline and PD changes in IGF-1 and IGFBP-3 were not substantially different in pts with a tumor response compared with those without a tumor response. A partial response to AMG 479 was observed in a pt with an activating K-ras mutation. No responses have been observed in tumors that lack expression of PTEN. Conclusions: The PD results suggest near complete biochemical coverage at 12-mg/kg AMG 479. Our hypothesis-generating analyses suggest that: 1) pre and postdose levels of IGF-1 and IGFBP-3 do not predict response to single-agent AMG 479; 2) activating K-ras mutations do not appear to preclude responsiveness to single-agent AMG 479 (in contrast to EGFR inhibitors); 3) expression and mutations of regulators of the PI3K/Akt pathway downstream of IGF-1R activation may be useful in predicting response to AMG 479.

[Table: see text]
Phase I study of temsirolimus (CCI-779), carboplatin, and paclitaxel in patients (pts) with advanced solid tumors: NCIC CTG IND 179
Authors: Oza A. M. , Kollmannsberger C. ,   NCIC Clinical Trials Group, Hirte H. , Welch S. , Siu L. , Mazurka J. , Sederias J. , Doyle L. A. , Eisenhauer E.
Published: August 2020

3558

Background: Temsirolimus (T) has encouraging activity in many malignancies, including endometrial cancer and a combination with carboplatin and paclitaxel would logical regimen for further development. This trial was designed to assess the safety and tolerability of this combination and expand experience at the recommended dose in pts with endometrial and ovarian cancers. Methods: A 3+3 dose escalation Phase I study has been conducted in pts with advanced solid malignancies suitable for carboplatin and paclitaxel chemotherapy who had not received more than 2 prior lines of chemotherapy. To date, 31 eligible pts with a median age of 59 have been treated and 27 are evaluable for toxicity. Pts were entered in 6 dose levels, with the first two levels administering T on Days 8 and 15 and the next 4 levels switching to a D1, 8 administration. Eighteen had received prior chemotherapy and 15 prior radiation. Results: Day 8, 15 administration of T was not feasible due to myelosuppression on day 15. The combination of carboplatin and paclitaxel on day 1 with T on D1 and 8 has been well tolerated, and patients have received a median of 5 cycles of therapy. At dose level 6 (T 25 mg D1 and 8, paclitaxel 175 mg/m2 D1, carboplatin AUC 6 D1) dose limiting toxicity (DLT) was seen in one of 6 pts treated to date (Gr 4 thrombocytopenia) and a second pt had a possible DLT ( Gr 3 fatigue in presence of baseline fatigue). This dose level is being expanded in 4 endometrial and ovarian cancer pts. The regimen is active: of the 26 patients with follow-up data, there have been 10 with partial response (38.5%; med. duration 7.1 mo [1.0–12.7]) and 12 with stable disease (46%; med. duration 6.9 mo [1.3- 7.8]). One patient had progressive disease and three were inevaluable. Conclusions: The results indicate this combination is well tolerated and requires additional assessment in a Phase II setting. The recommended Phase II dose will be dose level 6 provided no further DLTs are observed in the additional 4 patients entered.

[Table: see text]

No significant financial relationships to disclose.
Evaluation of ALK-1 expression in circulating endothelial cells (CECs) as an exploratory biomarker for PF-03446962 undergoing phase I trial in cancer patients
Authors: Mancuso P. , Shalinsky D. R. , Calleri A. , Quarna J. , Antoniotti P. , Jilani I. , Hu-Lowe D. , Jiang X. , Gallo-Stampino C. , Bertolini F.
Published: August 2020

3573

Background: ALK-1 is a member of the TβRI family & a novel target for antiangiogenic therapy (Rx). PF- 03446962 (PF) is a fully human mAB (IgG2, κ) generated against ALK-1 with dose-dependent preclinical antiangiogenic activities (Hu-Lowe et al, Proc AACR, 2009). This study's objectives were to determine whether: 1) CECs in cancer patients express ALK-1; and 2) whether therapy with PF against ALK-1 will modulate ALK-1 expression or CEC function in an ongoing Ph I trial. Methods: The human mAb was conjugated with alexa fluor 647. ALK-1 expression was assayed by a standardized multicolor flow cytometry assay (Mancuso et al, CCR 2009). Results: ALK-1 expression was characterized on human vascular (HUVEC) & lymphatic (HDLC) endothelial cells; HUVEC & HDLC cells highly express ALK-1 (>99% of these cells are ALK- 1+). ALK-1 expression was assessed in healthy controls (n=17) & cancer patients after normalizing for CEC viability. Patients with advanced malignancies had increased numbers of ALK-1+ CECs: Patients with breast ca (n=12), melanoma (n=8), NSCLC (n=11), & CRC (n=4) had 16±12, 39±23, 50±30, & 62±25 ALK-1+ CECs/mL, respectively, vs 7±6 ALK-1+ CECs/mL in controls. In contrast, ALK-1 expression was minimally or not expressed in pts with hematologic malignancies; ALK-1 was absent in CD117+ or CD34+ bone marrow cells. In the Ph I trial, preliminary evidence suggests that PF may alter CEC function; ALK-1+ CECs were markedly reduced in the 1st two pts studied at EIO after 22 days on Rx. Conclusions: ALK-1 is expressed in CECs. Flow cytometry enables rapid assay of ALK-1 expression in cancer patient blood. ALK-1 is expressed in an increased number of CECs/mL in cancer pts with solid malignancies vs controls. ALK-1 expression in CECs in pts with NSCLC & CRC may correspond to high ALK-1 expression observed in corresponding nonmatched tumor microarrays in addition to other malignancies such as sarcoma, SCLC & neuroendrocine pancreatic ca (Fiedler, Proc ASCO, 2009). Additional preliminary Ph I results will be reported as part of assessing whether CECs may have any role as biomarkers to potentially detect patients with ALK-1+ solid malignancies or monitor anti-ALK-1 therapy.

[Table: see text]
Functional imaging of neoadjuvant chemotherapy response in women with locally advanced breast cancer using diffuse optical spectroscopy
Authors: Soliman H. , Gunasekara A. , Rycroft M. , Zubovits J. , Dent R. , Spayne J. , Jong R. , Yaffe M. , Czarnota G.
Published: August 2020

3591

Background: Functional imaging with tomographic near infrared diffuse optical spectroscopy (DOS) can quantitatively measure tissue parameters such as the concentration of deoxy-hemoglobin (Hb), oxy-hemoglobin (HbO2), percent water (%water), and scattering power (SP). The purpose of this study was to evaluate the correlation between DOS functional parameters with pathologic outcomes. Methods: Patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy or chemoradiotherapy were recruited to this study (n=10). Five scans were conducted per patient: a baseline scan taken up to 3 days prior to treatment and at 1 week, 4 weeks, 8 weeks, and after neoadjuvant treatment prior to surgery. Pulsed near-infrared laser light was used to scan the suspended breast at four different wavelengths and data was used for tomographic reconstruction. Volume-of-interest (VOI) weighted tissue Hb, HbO2, %water, and SP corresponding to the tumour was calculated and compared to pathological response as determined from full mount mastectomy specimens. Results: For all 10 patients the tumour-based VOI was significantly different than background tissue for all functional parameters (p<0.001). Five patients had a good pathologic response. Four patients were considered non-responders. One patient initially had a poor clinical response to chemotherapy but after a change in chemotherapy had a good clinical response. Responders and non-responders were significantly different for all of the functional parameters (p<0.05) at the 4 week scan. In the 5 patients with a good response the mean drop in Hb, HbO2, %water, and SP from baseline to the 4 week scan was 70.4% (SD=18.6), 66.5% (SD=24.5), 59.6% (SD=30.9), and 60.7% (SD=29.2), respectively. In contrast, the 4 non- responders had a mean drop of 17.7% (SD=9.8), 18.0% (SD=20.8), 15.4% (SD=11.7), and 12.6% (SD=10.2), for Hb, HbO2, %water and SP, respectively. Conclusions: Functional imaging using tomographic DOS parameters of Hb, HbO2, %water and SP could be used as an early detector of final pathologic tumour response. This could be evaluated in the future to assess response and potentially adjust chemotherapy regimens.

No significant financial relationships to disclose.
Correlation of insulin-like growth factor 1 (IGF-1) expression and clinical outcome in K-RAS wild-type colorectal cancer patients treated with cetuximab-irinotecan
Authors: Scartozzi M. , Bearzi I. , Mandolesi A. , Loupakis F. , Zaniboni A. , Berardi R. , Pierantoni C. , Masi G. , Falcone A. , Cascinu S.
Published: August 2020

4017

Background: K-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies. Nevertheless 70% to 40% of these patients still does not seem to benefit from this therapeutic approach. Recent data suggested that in presence of IGF-1 system altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. The interaction between IGF-1 expression and K-RAS mutational analysis was tested in order to verify the ability of IGF-1 to identify a sub-group of patients more likely to benefit from EGFR-targeted antibodies treatment. Methods: IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. Results: Sixty-two patients were analyzed. IGF-1 was negative in 21 patients (34%). and overexpressed in the remaining 41 cases (66%). In IGF-1 negative and IGF-1 positive tumors we observed progressive disease in 6 (29%) and 26 (63%) patients respectively (p = 0.01). Median time to progression was 7.7 months in patients showing IGF-1 negative tumors and 2.3 months for IGF-1 expressing tumors (p = 0.005). Among K-RAS wild type patients, IGF-1 negative and positive tumors showed a partial response to cetuximab-irinotecan in 7 (50%) and 1 (5%) cases respectively (p = 0.004). Median time to progression in IGF-1 negative tumors was 11 months and 3.2 months in IGF-1 positive colorectal cancers (p = 0.03). Conclusions: IGF-1 proved to be a reliable predictive factor for resistance to anti-EGFR monoclonal antibodies in K-RAS wild type colorectal cancer. Combined IGF-1 and K-RAS analysis may represent an effective strategy for a better selection of responding colorectal tumors in this setting.

No significant financial relationships to disclose.
International randomized phase III study of capecitabine (Cap), bevacizumab (Bev), and mitomycin C (MMC) in first-line metastatic colorectal cancer (mCRC): Final results of the AGITG MAX trial
Authors: Tebbutt N. C. , Gebski V. , Wilson K. , Cummins M. , Chua Y. , Robinson B. , Broad A. , Cunningham D. , Simes J. , Price T.
Published: August 2020

4023

Background: The addition of Bev to oxaliplatin or irinotecan based doublet chemotherapy has shown benefit in mCRC. Cap± MMC are alternate chemotherapy regimens suitable for patients (pts) who are either unfit for or who do not require initial oxaliplatin/irinotecan. This phase III study compared Cap with Cap Bev and Cap Bev MMC. The aim was to develop a low toxicity regimen suitable for a broad population of pts with mCRC. Methods: Previously untreated pts with unresectable mCRC considered suitable for Cap monotherapy were randomised to arm A Cap (Cap 2000mg/m2/d or 2500mg/m2 d1–14 q21d), arm B Cap Bev (Bev 7.5mg/kg q3w) or arm C Cap Bev MMC (MMC 7mg/m2 q6w). Primary endpoint: PFS, secondary endpoints: RR, toxicity, OS, QoL . Randomisation was stratified by age, PS, centre and Cap dose. Response was assessed every 6w. The study was designed to detect an increase in the median PFS from 5.5m (arm A) to 8m (arm B or C) at p<0.025 with 80% power. Results: A total of 471 pts were randomised from July 2005-June 2007. Outcomes were evaluated on an intention to treat basis and included 15 ineligible pts. Baseline demographics were well balanced between arms with median age 67y (range 31–86y). Toxicity was reported: ASCO 2008 abstr 4029. The most common grade 3/4 toxicities were PPE (16%, 26%, 28%) and diarrhoea (11%, 17%, 16%) for arms (A,B,C). However, adjusted rates per cycle were similar as arms B & C received more cycles of Cap (A8.3, B10.8, C10.5). Other toxicity rates were generally <10%. The study achieved its primary endpoint with a highly significant improvement in PFS for arms B & C. RR and OS are summarized ( Table ). Conclusions: All treatment regimens were well tolerated in a relatively elderly patient cohort. The addition of Bev±MMC to Cap significantly improved PFS without significant additional toxicity. OS was similar for all arms. Cap Bev±MMC is an active, low toxicity regimen that may be considered as a treatment option for pts with mCRC.

[Table: see text]

[Table: see text]
Definition of oxaliplatin sensitivity in patients with advanced colorectal cancer previously treated with oxaliplatin-based therapy
Authors: de Gramont Lesparre A. H. , Chibaudel B. , Bourges O. , Perez-Staub N. , Tournigand C. , Maindrault-Goebel F. , André T. , Larsen A. K. , Afchain P. , Louvet C.
Published: August 2020

4024

Background: Oxaliplatin combined with fluoropyrimidines is standard adjuvant therapy in stage III colon cancer and first-line therapy in stage IV colorectal cancer. Oxaliplatin can be reintroduced either at relapse, or after maintenance or after chemotherapy holidays. In this study we defined the sensitivity to oxaliplatin reintroduction based on the oxaliplatin-free interval. Methods: Stage IV pts entered in the OPTIMOX1 and 2 studies (FOLFOX4, FOLFOX7 followed by maintenance without oxaliplatin or chemotherapy holidays) and pts having relapsed after metastases surgery and neoadjuvant or adjuvant FOLFOX for resectable stage IV were eligible if they were rechallenged with FOLFOX. Endpoints were: survival from reintroduction according to interval between the last cycle of oxaliplatin first-line and reintroduction, survival and response at reintroduction according to first FOLFOX response and PFS. Results: 330 pts were included: male 60%, colon/rectum/both 62%/35%/2%, resectable/unresectable: 14%/86%, PS 0–1 / >1: 90%/10%, sites 1/>1: 57%/43%. 23 pts had adjuvant and 22 pts had neoadjuvant chemotherapy. 58 pts (18%) had FOLFOX reintroduction before progression. PFS/OS from reintroduction according to induction FOLFOX response were 8.7/19.5 mths if CR, 4.6/15.2 mths if PR, and 3.2/9.7 mths if SD (P=.0019/.01). PFS/OS from reintroduction according to induction FOLFOX PFS were 2.9/9.3 mths if PFS<6 mths, 4.6/14.7 mths if PFS 6–12 mths and 8.5/23.7 if PFS=12 mths. Table shows results according to intervals. There was no difference between 0–3 and 3–6 mths or 6–9 and 9–12 mths intervals. Conclusions: A prolonged interval between two FOLFOX therapies or a prolonged PFS at first-line FOLFOX predict the efficacy of oxaliplatin reintroduction. The interval between two FOLFOX therapies does not identify a completely refractory population. Resistance (PD rate) is divided by two at each 6 month intervals.

[Table: see text]

No significant financial relationships to disclose.
Randomized phase II study of picoplatin in combination with 5-fluorouracil and leucovorin (FOLPI) as a neuropathy-sparing alternative to modified FOLFOX-6 as first-line therapy for colorectal cancer (CRC)
Authors: Earhart R. , Cheporov S. , Gladkov O. , Biakhov M. , Breitz H. , De Jager R.
Published: August 2020

4026

Background: Picoplatin (Pico) was designed to overcome platinum resistance and has the potential for improved safety compared to other platinum agents. FOLFOX (5-FU, LV, oxaliplatin [oxali]) treatment for advanced CRC has dose-limiting oxali- related neurotoxicity. The incidence of grade (G) 3–4 neurotoxicity with single-agent Pico across studies was <2%, suggesting that Pico may provide a neuropathy-sparing alternative to oxali. A Phase I trial identified the Pico MTD at 150 mg/m2 when infused Q4W with Q2W FU/LV. The present study evaluates Pico when administered Q4W with Q2W FU and LV (FOLPI) vs. modified (m) FOLFOX-6 (FOLFOX) as 1st line treatment for patients (pts) with advanced CRC. Methods: Each pt received LV and infusional FU per mFOLFOX-6 Q2W. Pts with no prior chemotherapy for advanced CRC received Pico Q4W (150 mg/m2) or oxali Q2W (85 mg/m2). Tumor response was assessed by RECIST using CT scans. Adverse events (AEs) were assessed with CTCAE. Neuropathy was assessed using the FACT-Neurotoxicity questionnaire and by a neurologist blinded to treatment. Results: 101 pts were randomized (50 to FOLPI, 51 to FOLFOX). Pts have received 213 (median 4, max 11) 4-week cycles of FOLPI and 414 (median 8, max 21) 2-week cycles of FOLFOX. Median dose intensity of Pico = 28 mg/m2/wk (range 19–44); mean relative dose intensity = 77%. Median dose intensity of oxali = 36 mg/m2/wk (range 28–43); mean relative dose intensity = 86%. Neurotoxicity was observed in 65% of pts on FOLFOX (10% G 3/4) and 28% of pts on FOLPI (no G 3/4). Most frequent G 3/4 AEs on FOLPI were neutropenia (60%), thrombocytopenia (40%) and anemia (14%). In the FOLFOX arm, other than neuropathy, the most frequent G 3/4 AEs were neutropenia (20%) and thrombocytopenia (12%). Disease control (CR+PR+SD) was 76% for FOLPI and 76% for FOLFOX. In the FOLPI arm there were 1 CR (2%) and 11 PR (22%). In the FOLFOX arm there were no CRs and 13 PR (26%). Conclusions: In this ongoing trial, FOLPI with Pico Q4W shows comparable disease control as measured by RECIST compared to FOLFOX. Neurotoxicity was less frequent and less severe in the FOLPI arm compared to the FOLFOX arm. Pico therefore may be a neuropathy-sparing alternative to oxaliplatin in CRC.

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KRAS mutation, cancer recurrence, and patient survival in stage III colon cancer: Findings from CALGB 89803
Authors: Fuchs C. , Ogino S. , Meyerhardt J. A. , Irahara N. , Niedzwiecki D. , Hollis D. , Saltz L. B. , Mayer R. J. , Bertagnolli M. M.
Published: August 2020

4037

Purpose: KRAS mutation in stage IV colorectal cancer predicts resistance to anti-EGFR targeted treatment (cetuximab or panitumumab). However, whether the presence of KRAS mutation independently predicts the survival of colon cancer patients remains uncertain. Methods: We conducted a prospective observational study of 508 cases identified among 1264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) between April 1999 and May 2001 (CALGB 89803; Saltz et al. J Clin Oncol 2007). KRAS mutations were detected in 178 tumors (35%) by Pyrosequencing. Kaplan-Meier and Cox proportional hazard models were used to assess the significance of KRAS mutational status and adjusted for potential confounders including age, sex, tumor location, T stage, N stage, performance status, adjuvant chemotherapy arm and microsatellite instability (MSI) status. Results: When compared to patients with wild-type KRAS, those with a mutation in KRAS did not experience any difference in disease-free (DFS), recurrence-free (RFS), or overall survival (OS) (log-rank P>0.56 for DFS, RFS, and OS). Five-year DFS was 62% for KRAS-mutated and 63% for KRAS-wild-type patients. Five-year RFS was 64% for KRAS-mutated and 66% for KRAS- wild-type patients. Five-year OS was 74% for KRAS-mutated and 73% for KRAS-wild-type patients. The effect of KRAS mutation on patient survival did not differ according to clinical features, chemotherapy arm or MSI status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status. Conclusions: In this large clinical trial of chemotherapy in patients with stage III colon cancer, KRAS mutational status was not associated with any significant influence on disease-free or overall survival.

No significant financial relationships to disclose.
Analysis of prognostic (prog) Web-based models for stage II and III colon cancer (CC): A population-based validation of Numeracy (NUM) and ADJUVANT! Online (ADJ!)
Authors: Gill S. , Loprinzi C. , Kennecke H. , Grothey A. , Nelson G. , Woods R. , Speers C. , Alberts S. , Bardia A. , Sargent D.
Published: August 2020

4044

Background: To aid in decisions regarding adjuvant therapy (AT) for resected high-risk CC, two prog models are in common use: the Mayo Clinic NUM calculator developed from a pooled data analysis of 7 randomized 5FU-based AT trials, and ADJ! developed using SEER data. This study examines the accuracy of NUM and ADJ! utilizing a cohort of patients (pts) referred to the BC Cancer Agency (BCCA). Methods: Demographic, disease and treatment data for pts with stage II/III CC referred to the BCCA from 1995–1996 + 1999–2003 were collected. Observed (obs) 5-year relapse free survival (RFS) and overall survival (OS) were compared to predicted estimates (pred) using NUM and ADJ!, both overall and for all prog subgroups with ≥ 10pts, as stratified by T stage, N stage, tumor grade and age. Data are presented in a descriptive manner and using confidence intervals. Results: Median follow-up was 5.6 yrs for 2,033 pts - 53% male, median age 68y, 40% N0. The mean percentages of 5 year pred outcomes for each of the two models and the actual Kaplan Meier mean survivals are presented in the table . The percentage correct predictions of 5 y status is also presented, with correctness deemed accurate if the pt was alive and predicted to be alive by ≥ 50% as determined by each model or dead while the respective tool predicted < 50% possibility of being alive. For surgery alone pts, ADJ!pred were more often closer to what was observed, as compared to NUMpred, in the prog subgroups (for RFS 56%, OS 88%). For surgery + 5-FU pts, within these subgroups, NUMpred were more often closer to what was observed, as compared to ADJ!pred, for RFS (62%) and for OS (55%). Conclusions: In this independent population-based validation, NUM and ADJ! have acceptable and similar reliability with modest over-estimations of 5y RFS and OS. Both models thus appear to be useful adjuvant decision-aids.

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No significant financial relationships to disclose.
Wt Kras and gene expression levels of VEGFR2, EGFR, and ERCC-1 associated with progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line 5-FU or capecitabine with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)
Authors: El-Khoueiry A. B. , Pohl A. , Danenberg K. , Cooc J. , Zhang W. , Yang D. , Singh H. , Shriki J. , Iqbal S. , Lenz H. J.
Published: August 2020

4056

Background: While wild type (wt) Kras is associated with improved outcome to anti-EGFR therapy in pts with mCRC, there are no identified predictors of outcome for FOLFOX/BV. We evaluated Kras status and expression of genes involved in angiogenesis, DNA repair and 5-FU metabolism in 68 patients treated with FOLFOX/BV or XELOX/BV. These genes included VEGF, VEGF-receptor 2 (KDR), Cox-2, IL 6 and 8, chemokine-receptors 1 & 2, EGFR and ERCC-1. Methods: Tissue samples from 68 patients with mCRC were analyzed. mRNA was extracted from laser-capture-microdissected tumor tissue. cDNA was prepared by reverse transcription and quantitation of the candidate genes was performed using a fluorescence- based real-time detection method (TaqMan). Allele specific RT-PCR was performed to determine Kras mutation status in codons 12 and 13. Results: There were 68 pts (38 males, 30 females), median age: 56 years (range 29–81). All received first line 5FU, oxaliplatin and BV (28 FOLFOX/BV, 40 XELOX/BV). Radiologic response: 1 CR, 39/68 (57%) PR, 27/68 (40%) SD, and 1 PD. Median OS is not reached. At a median follow-up of 32.0 months (mo) (range: 2.3–47.8 mo), the median PFS was 12.4 mo (95% CI: 9.8–15.2). Kras mutation was identified in 39 pts (57%). RR was 64% in pts with wt Kras and 52% in pts with mutant Kras (p=0.33). PFS was significantly longer for pts with wt kras compared to pts with mutant kras (13.7 mo [95% CI: 6.9–13.2] versus 8.3 mo [95%CI: 6.9–13.2], P=0.039). High EGFR (median PFS: 15.2 mo; 95% CI 11.7–16.5 mo), high VEGFR2 (median PFS: 13.9 mo; 95% CI 11.0–16.5 mo), and low ERCC1 (median PFS: 12.4 mo; 95% CI 10.9–16.4 mo) were associated with longer PFS compared to low EGFR (median PFS: 7.9 mo; 95% CI 6.9–11.0 mo, P=0.040), low VEGFR2 (median PFS: 7.2 mo; 95% CI 6.5–8.1 mo, P=0.032), and high ERCC1 (median PFS: 9.6 mo; 95% CI 5.8–15.2 mo, P=0.045). Conclusions: To our knowledge, this is the first report of a potential association between Kras status as well as gene expression levels of VEGFR2, ERCC-1 and EGFR and clinical outcome to FOLFOX/BV therapy in pts with mCRC. Prospective clinical trials are needed to validate these results.

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Use of genetic variants to predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line 5-FU or capecitabine in combination with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)
Authors: Singh H. , Pohl A. , El-Khoueiry A. , Lurje G. , Zhang W. , Yang D. , Ning Y. , Shriki J. , Iqbal S. , Lenz H.
Published: August 2020

4070

Background: Recent studies suggested polymorphisms involved in angiogenesis related genes associated with clinical outcome in pts treated with the VEGF-inhibitor bevacizumab. (Schneider et al. JCO 2008, Manegold et al ASCO 2008). We evaluated functional polymorphisms involved in angiogenesis- (VEGF, KDR, IL-6, CXCR1 and-2), apoptosis (p53) and cell-proliferation (MMP2,-7 and-9, ICAM)-related pathways in an expanded patient cohort for their potential prognostic or predictive role in clinical outcome. Methods: Genomic DNA was extracted from 79 mCRC pts (treated with first-line FOLFOX/BV or XELOX/BV at USC) from peripheral blood. Genotyping was performed using PCR-RFLP assays or direct sequencing. Results: 79 pts (47 men, 32 women) with a median age of 56 years (range 29–81), were treated with either FOLFOX/BV (33 pts) or XELOX/BV (46 pts). Radiologic response: 2/79 pts (3%) CR, 41/79 pts (52%) PR, 32/79 pts (41%) SD and 3/79 pts (4%) DP. At a median follow-up of 32.0 months (range: 1.4- 47.8 months), the median time to progression was 10.8 months (95% CI: 8.1–14.9). We found IL-6 G- 174C (p=0.025, Fisher's exact test) and p53 codon 72 (p=0.029, Fisher's exact test) polymorphisms associated with response to BV-therapy. Furthermore, there were statistically significant associations between genomic polymorphisms in MMP-9, CXCR-1 and PFS (p=0.023 and p=0.014, respectively, log-rank test). Pts with 2 G- alleles in CXCR-1 G+2607C (median PFS=13.7 months, 95% CI:8.4–16.4) and pts homozygous for the C-allele in MMP-9 C-1562T (median PFS= 13.9 months, 95% CI: 10.1–15.8) had longer PFS compared to pts with any C-allele in CXCR-1 G+2607C (median PFS = 7.9 months, 95% CI: 6.9–10.2) and pts with any T-allele in MMP-9 C-1562T (median PFS 7.2 months, 95% CI: 5.3–11.0), respectively. Conclusions: These are the first data to predict clinical outcome in mCRC pts treated with FOLFOX/BV or XELOX/BV. Our data demonstrate that functional polymorphisms in angiogenesis related genes predict response and PFS in pts treated with the angiogenesis- inhibitor BV. However, confirmation of these findings in larger, prospective genotype-guided clinical trials is warranted.

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Updated analysis of a phase II study (20060314) of panitumumab (pmab) with FOLFIRI as first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Greil R. , Letocha H. , Gamelin E. , Thaler J. , Hofheinz R. , Mineur L. , Fernebro E. , Karthaus M. , Wright L. , Köhne C. ,   20060314 Study Group
Published: August 2020

4085

Background: The fully human anti-epidermal growth factor receptor monoclonal antibody pmab, has proven monotherapy activity in chemotherapy refractory mCRC pts with wild-type KRAS-expressing tumors. This first-line, single-arm phase II study is prospectively evaluating whether KRAS status predicts response to treatment when pmab is combined with FOLFIRI. Methods: In this ongoing study, pts with histologically confirmed mCRC (no prior systemic treatment) and ECOG PS 0–2 were enrolled at 36 sites across Europe. Pmab (6mg/kg) and FOLFIRI are administered every 2 weeks. The primary endpoint is objective response rate; secondary endpoints include disease control rate, duration of response, time to response, progression-free survival, time to progression and safety. Results: Data cut-off for the initial interim analysis was 27 June 08 and pending approval of protocol amendment 2, the cut off date for 16 week response rate is 15 Oct 08. Of the 154 pts enrolled, 68% are male; median age is 64 yrs (range, 21–84) and the majority (95%) of pts had ECOG PS 0–1. All pts have received at least one cycle of study treatment; 18% of pts have received ≤2 cycles of full combination therapy and the median number of cycles received is 6. At time of data cut-off, 112 patients (73%) were still receiving at least one element of combination therapy and 29% had stopped treatment with pmab. The most common reason for discontinuing treatment was disease progression (10%). Median follow-up time was 14.3 weeks for all enrolled pts. A total of 97% of patients had experienced at least one adverse event (any grade) and 55% of patients had experienced a grade 3/4 adverse event. There were four reported grade 5 events (hematemesis, rectal hemorrhage, vena cava thrombosis, general physical health deterioration). At time of interim analysis, tissue samples for KRAS analysis are available for approximately 80% of patients. Conclusions: Combining pmab with FOLFIRI in the first-line setting appears to be a well-tolerated regimen. Response rate at 16 weeks in the overall population and by KRAS status and updated safety will be presented.

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Liver regenerative nodular hyperplasia consecutive to preoperative chemotherapy: Impact on outcome of liver surgery for colorectal metastases
Authors: Wicherts D. A. , de Haas R. J. , Sebagh M. , Ciacio O. , Lévi F. , Paule B. , Azoulay D. , Bismuth H. , Castaing D. , Adam R.
Published: August 2020

4097

Background: Regenerative nodular hyperplasia (RNH) represents the worst evolutive stage of vascular lesions induced by prolonged chemotherapy on the liver. Its incidence and impact on the outcome of resection for colorectal liver metastases (CLM) are however unknown. We evaluated the effect of RNH on postoperative morbidity and assessed its evolution in time at repeat hepatectomy. Methods: All patients that underwent hepatectomy for CLM between January 1990 and November 2006 after 1 line of chemotherapy of more than 6 cycles were included. Detailed histopathologic analysis of the nontumoral liver was performed at first and repeat hepatectomies according to a standard format. Results: Of 146 included patients, 24 (16%) received 5- fluorouracil (5-FU) and leucovorin (LV) alone, 92 (63%) had 5-FU, LV and oxaliplatin, 18 (12%) had 5-FU, LV and irinotecan, and 12 (8%) were treated by 5-FU, LV, oxaliplatin and irinotecan. Overall, RNH occurred in 22 of 146 patients (15%). Patients treated by oxaliplatin more often had RNH compared to oxaliplatin-naïve patients (22% vs 4%) (P=0.003). The presence of RNH was associated with increased postoperative hepatic morbidity (23% vs 11%) (P=0.05). None of the RNH patients died within 60 days postoperatively. A preoperative gamma-glutamyltransferase level >80 U/L and a total bilirubin level >15 μmol/L were independent predictive factors of RNH at first hepatectomy. Two of 22 patients with RNH underwent repeat hepatectomy. RNH disappeared at second hepatectomy in both patients following prolonged treatment with irinotecan. Conclusions: Patients with CLM that receive prolonged courses of preoperative oxaliplatin have an increased risk of RNH and associated postoperative hepatic morbidity. Upfront treatment with short courses of highly effective regimens may therefore be most appropriate. In addition, the continuation of oxaliplatin should be discouraged in case of RNH to avoid its negative effects on further surgery.

No significant financial relationships to disclose.